National Institute of Neurological
^ and Communicative Disorders
and Stroke
Annual
Report
Fiscal Year 1982
US. DEPARTMENT
OF HEALTH
AND HUMAN SERVICES
Public Health Service
National Institutes of Health
ANNUAL REPORT
October 1, 1981 through September 30, 1982
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents*
TAB
OFFICE OF THE DIRECTOR, NINCDS (OD) 1
DIRECTOR (Acting): Dr. Murray Goldstein
DEPUTY DIRECTOR (Acting): Dr. Katherine L. Bick
EXECUTIVE OFFICER: Mr. Richard L. Sherbert, Jr.
EQUAL EMPLOYMENT OPPORTUNITY OFFICE (EEO)
Coordinator: Mr. Levon 0. Parker
OFFICE OF SCIENTIFIC AND HEALTH REPORTS (OSHR)
Chief: Ms. Sylvia Shaffer
OFFICE OF PLANNING AND ANALYSIS (OPA)
Chief: Mr. LeRoy Goldman
Deputy Chief: Mr. Joseph Culhane
Senior Medical Advisor: Dr. Zekin A. Shakhashiri
OFFICE OF BIOMETRY AND FIELD STUDIES (OBFS) l.A
Chief: Mr. William Weiss
Deputy Chief (Acting): Dr. Jonas H. Ellenberg
EXTRAMURAL ACTIVITIES PROGRAM (EAP) 2
DIRECTOR: Dr. John C. Dalton
DEPUTY DIRECTOR: Dr. John W. Diggs
COMMUNICATIVE DISORDERS PROGRAM (CDP) 3
DIRECTOR: Dr. Ralph F. Naunton
DEPUTY DIRECTOR: Dr. J. Buckminster Ranney
FUNDAMENTAL NEUROSCIENCES PROGRAM (FNP) 4
DIRECTOR: Dr. Eugene Streicher
DEPUTY DIRECTOR: Dr. W. Watson Alberts
NEUROLOGICAL DISORDERS PROGRAM (NDP) 5
DIRECTOR: Dr. Floyd J. Brinley, Jr.
DEPUTY DIRECTOR (Acting): Dr. Janett Trubatch
EPILEPSY BRANCH (EB) 5. A
Chief: Dr. Roger J. Porter
DEVELOPMENTAL NEUROLOGY BRANCH (DNB) 5.B
Chief: Dr. Joseph S. Drage
STROKE AND TRAUMA PROGRAM (STP) 6
DIRECTOR: Dr. Michael D. Walker
DEPUTY DIRECTOR: Dr. Donald H. Luecke
i-NINCDS
TABLE OF CONTENTS (cont'd) T^
OFFICE OF THE DIRECTOR OF INTRAMURAL RESEARCH (ODIR) 7
DIRECTOR: Dr. Thomas N. Chase
NEUROEPIDEMIOLOGY SECTION (ODIR/NES) 7. A
Chief: Dr. Bruce S. Schoenberg
LABORATORY DIRECTOR: Dr. Richard L. Irwin
NEUROTOXICOLOGY SECTION (ODIR/NTS) 7.B
Chief: Dr. Richard L. Irwin
INSTRUMENTATION AND COMPUTERS SECTION (ODIR/ICS) 7.C
Chief: Dr. Theodore R. Colburn
LABORATORY OF BIOPHYSICS (LB) 8
CHIEF: Dr. William J. Adelman, Jr.(MBL, Woods Hole, MA)
LABORATORY OF CENTRAL NERVOUS SYSTEM STUDIES (CNSS) 9
CHIEF: Dr. D. Carleton Gajdusek
DEPUTY CHIEF: Dr. Clarence J. Gibbs, Jr.
LABORATORY OF MOLECULAR BIOLOGY (LMB) 10
CHIEF: Dr. Ernst Freese
LABORATORY OF MOLECULAR GENETICS (LMG) 11
CHIEF: Dr. Robert A. Lazzarini
LABORATORY OF NEURAL CONTROL (LNLC) 12
CHIEF: Dr. Robert E. Burke
LABORATORY OF NEUROCHEMISTRY (LNC) 13
CHIEF: Dr. Janet Passonneau
LABORATORY OF NEURO-OTOLARYNGOLOGY (LNO) 14
CHIEF: Dr. Jorgen Fex
LABORATORY OF NEUROPATHOLOGY AND NEURO ANATOMICAL
SCIENCES (LNNS) 15
CHIEF: Dr. Igor Klatzo
ASSOCIATE CHIEF: Dr. Henry deF. Webster
LABORATORY OF NEUROPHYSIOLOGY (LNP) 16
CHIEF: Dr. Jeffery Barker
ii-NINCDS
TABLE OF CONTENTS (cont'd) TAB
CLINICAL DIRECTOR (Acting): Dr. Paul L. Kornblith
CLINICAL NEUROSCIENCES BRANCH (CN) 17
CHIEF (Acting): Dr. Paul Fedio
DEVELOPMENTAL METABOLIC NEUROLOGY BRANCH (DMN) 18
CHIEF: Dr. Roscoe 0. Brady
EXPERIMENTAL THERAPEUTICS BRANCH (ET) 19
CHIEF (Acting): Dr. Thomas N. Chase
INFECTIOUS DISEASES BRANCH (ID) 20
CHIEF: Dr. John L. Sever
MEDICAL NEUROLOGY BRANCH (MN) 21
CHIEF (Acting): Dr. John L. Sever
NEUROIMMUNOLOGY BRANCH (NI) 22
CHIEF: Dr. Dale E. McFarlin
ASSOCIATE CHIEF: Dr. Henry F. McFarland
SURGICAL NEUROLOGY BRANCH (SN) 23
CHIEF: Dr. Paul L. Kornblith
DEPUTY CHIEF: Dr. Barry H. Smith
Alphabetical Listing of NINCDS PRINCIPAL INVESTIGATORS page iv
Numerical Listing of NINCDS Research Projects page vi
*A detailed Table of Contents for each program area will be found
immediately following the TAB indicator.
iii-NINCDS
ANNUAL REPORT
October 1, 1981 through September 30, 1982
National Institute of Neurological and Communicative Disorders and Stroke
NAME
Alphabetical Listing of NINCDS Principal Investigators
TAB PAGES NAME TAB
Adelman, W J Jr
Albers, R W
Alkon, D L
Altschuler, R A
Anders, J J
Anderson, D W
Anderson, D W
Anderson, S
Asher, D M
Bajda, L
Bak, M J
Barker, J L
Barranger, J A
Baum, H M
Baum, H M
Blasberg, R G
Brady, R O
Brightman, M W
Broman, S H
Brooks, R A
Brooks, R A
Brouwers, P
Brown, P W
Burke, R E
Calne, D B
Cammermeyer , J
Caspary, W J
Chase, T N
Chase, T N
Chen, T C
Chen, T C
Constantopoulos, G,
Dalakas, M C
Dambrosia, J
Dambrosia, J
DiChiro, G
DiChiro, G
Drage, J S
Dubois-Dalcq,
Edelstein, S
Ehrenstein, G
Eldridge, R
Eldridge, R
Elkins, E
Ellenberg, J :
Ellenberg, J ;
Ellenberg, J :
Fedio, P
8
13
8
14
15
l.A
7. A
7.B
9
5
12
16
18
l.A
l.A
23
18
15
5.B
l.A
23
17
9
12
l.A
15
l.A
19
23
l.A
l.A
18
20
l.A
l.A
23
23
5.B
20
l.A
8
l.A
7. A
3
l.A
l.A
5.B
17
8,18
44
39
26,27
61,69
19
,10,11
10,19
13
2,3
28
47,62
25
31
29
4
8
3,4
,19,21
,46,49
67,68
23
,21,22
28,30
,22,25
56,57
22,23
6,8
29
7,12
73
31,32
58
15
23
,40,41
43,74
20
15,19
,28,60
,71,73
,20,21
22,23
18,24
24
36
14,18
60
,14,15
60,65
,51,52
,61,71
,17,27
,7,8,9
III
R C
Feinberg, R
Fex, J
Fishman, I G
Fishman, P H
FitzHugh, R
Freese, E
Freese, E B
Gajdusek, D (
Gal, A E
Garruto, R M
Gibbs, C J
Gilbert, D L
Goldstein, M
Goyco, E T
Graven, M
Gross, C
Gross, C
Harper, J S
Hawkins, N
Henneberry,
Hirtz, D G
Hirtz, D G
Hoffman, D W
Houff, S A
Hruska, R E
Jane, J
Johnson, R
Jokl, P
Jones, A E
Karniouchina,
Kase, C
Kebabian, J W
Kessler, R M
Kirino, T
Kornblith, P L
Kudrjavcev, T
Kunitz, S C
Kunitz, S C
Kupferberg, H .
Kuroiwa, T
Lasansky, A
Lazzarini, R A
Lecar, H
Lee, Y J
Lee, Y J
LeWitt, P
LeWitt, P
Li, C L
Loeb, G E
PAGES
5.B
21
14
2,3
l.A
66,72
18
10,17
8
15
10
6,7
10
5
9
29,35
18
11,15,16
9
29
9
29,35
8
16
l.A
33
l.A
55
20
16
l.A
25,26,30
l.A
31,45,65
20
20,22
l.A
70
10
4,8
l.A
52,53
5.B
16,27
14
2
20
23
7.B
33
l.A
54
17
7
l.A
33
23
23
15
19
l.A
26,27,45
19
13
23
23
15
29
23
16,17,23
7. A
18,20
l.A
24,26,29,30
l.A
65,66,72
5. A
25,28
15
11
16
6
11
4,5
8
19
l.A
34,35,37
l.A
53,58,61
l.A
73
19
16
23
24
12
11
iv - NINCDS
Alphabetical Listing of NINCDS Principal Investigators - (Cont'd)
NAME
TAB
PAGES
NAME
TAB
PAGES
Lohr, J
16
6
Reiner, B
l.A
38
London, W T
l.A
63,64
Richardson, K
l.A
36
London, W T
20
20
,21
,22,23
Rieth, K G
23
22
Ludlow, C
l.A
35,38
Sank, V J
23
22,23
Ludlow, C
3
58
,59,61
Sato, S
17
10
,11,12
Ludlow, C
3
(
54, 74
Schmidt, E M
12
9
Lust, W D
13
13,17
Schoenberg, B S
7. A
16,
,17
,18,19
Madden, D L
20
13,14
Schoenberg, B S
7. A
20
,21
,22,23
Marks, W B
12
10
Schoenberg, B S
7.A
24
,25
,26,27
Martin, A
17
6,8
Schwartz, A M
14
2
Martin, J R
15
23
Sever, J L
l.A
50,59
Martin, M R
14
3
Sever, J L
20
13
,15,19
Mar t i nez-Maldonado ,
,M l.A
55
Silbergeld, E K
7.B
35
McAndrews, J F
l.A
33
Smith, B H
3
77
McFarland, H F
22
4,7
Smith, B H
23
17,23
McFarlin, D E
22
4,5,6
Smith, T G
16
3
Mohr, J P
l.A
26
,27,45
Sofijanov, N
l.A
52
Morris, S J
7.B
32,34
Spatz, M
15
14
,15
,16,17
Moscicki, E
l.A
48
Spatz, M
15
18
,20,21
Mosinger, J L
14
2
S toner, G L
15
24
Myrianthopoulos, N
C 5.B
23
,26,28
Suzuki, R
15
10,12
Nelson, K B
l.A
51,
r52
,53,69
Talbert, A J
l.A
56
,57,61
Nelson, K B
5.B
16
,17,27
Tandon, P
l.A
54
Newmark, J
18
23
Taylor, R E
8
17,20
Newmark, M E
23
23
Ting, P
15
13
Nichols, B
l.A
32
Trams, E G
18
12,13
Nichols, P L
5.B
19
Wagner, H G
16
5, 7
Nitsch, C
15
7,8,9
Wallen, W C
20
17,18
Oldfield, E H
23
18
Walters, J R
19
14
Passonneau, J V
13
12,
rl5
,16,18
Ward, C
l.A
60
Patronas, N J
23
23
Webster, H deF
15
22
Pikus, A
3
62,
,63
,66,67
Weinfeld, F D
l.A
42,43
Pikus, A
3
68,
,69,
,70,71
Weiss, G H
l.A
56
Pikus, A
3
72,
,73,
,75,76
Weiss, W
l.A
33
,54,65
Porro, M G
5. A
26
Wells, J B
8
12
Porter, R J
19
17,18
Wolf, A P
23
23
Porter, R J
23
23
Wolf, P
l.A
28
Price, D
l.A
55
Woyciechowska, J
l.A
59
Quarles, R H
18
14
Yonekawa, W
5. A
27
Reese, T S
15
25
,26,27
Zalewski, A A
13
11,14
V - NINCDS
ANNUAL REPORT
October 1, 1981 through September 30, 1982
National Institute of Neurological and Communicative Disorders and Stroke
PROJECT NUMBER
INTRAMURAL RESEARCH PROJECTS
Numerical Inventory
TAB PAGE PROJECT NUMBER
TAB
PAGE
ZOl NS
00200-28
CN
17
6
ZOl NS
00402-26
ID
20
13
ZOl NS
00706-23
DMN
18
8
ZOl NS
00813-21
LNC
13
10
ZOl NS
00815-22
DMN
18
9
ZOl NS
00969-18
CNSS
9
35
ZOl NS
00972-11
ID
20
20
ZOl NS
01047-20
SN
23
19
ZOl NS
01163-20
NDP
5
4
ZOl NS
01195-18
SN
23
20
ZOl NS
01244-18
LMB
10
7
ZOl NS
01245-17
CN
17
7
ZOl NS
01282-18
CNSS
9
29
ZOl NS
01309-17
DMN
18
10
ZOl NS
01424-16
CN
17
8
ZOl NS
01442-16
LNNS
15
25
ZOl NS
01457-16
DMN
18
11
ZOl NS
01480-15
DMN
18
12
ZOl NS
01481-15
DMN
18
13
ZOl NS
01586-15
LNC
13
11
ZOl NS
01654-15
SN
23
21
ZOl NS
01658-15
CN
17
9
ZOl NS
01659-14
LNP
16
6
ZOl NS
01686-14
LNLC
12
7
ZOl NS
01687-14
LNLC
12
8
ZOl NS
01688-14
LNLC
12
9
ZOl NS
01731-14
ID
20
16
ZOl NS
01805-14
LNNS
15
28
ZOl NS
01808-13
DMN
18
14
ZOl NS
01881-12
LNNS
15
26
ZOl NS
01886-12
LMB
10
5
ZOl NS
01924-12
CDIR
7. A
13
ZOl NS
01927-12
ODIR
7. A
14
ZOl NS
01950-11
LB
8
9
ZOl NS
01983-11
ID
20
17
ZOl NS
01984-11
ID
20
18
ZOl NS
01985-11
ID
20
14
ZOl NS
01986-11
ID
20
21
ZOl NS
01995-10
LNNS
15
22
ZOl NS
02006-10
LNC
13
12
ZOl NS
02010-10
SN
23
24
ZOl NS
02019-10
LNP
16
3
ZOl NS
02026-10
LMG
11
4
ZOl
NS
02034-
-10
ID
ZOl
NS
02038-
-10
ID
ZOl
NS
02058-
-10
DNB
ZOl
NS
02059-
-10
DNB
ZOl
NS
02060-
-10
DNB
ZOl
NS
02062-
-10
DNB
ZOl
NS
02073-
-09
SN
ZOl
NS
02079-
-09
LNLC
ZOl
NS
02080-
-09
LNLC
ZOl
NS
02086-
-09
LNNS
ZOl
NS
02087-
-09
LB
ZOl
NS
02088-
-09
LB
ZOl
NS
02091-
-09
LB
ZOl
NS
02092-
-09
LB
ZOl
NS
02106-
-09
DNB
ZOl
NS
02107-
-09
DNB
ZOl
NS
02108-
-09
DNB
ZOl
NS
02109-
-09
DNB
ZOl
NS
02112-
-09
DNB
ZOl
NS
02114-
-09
OBFS
ZOl
NS
02136-
-08
ID
ZOl
NS
02139-
-08
ET
ZOl
NS
02142-
-08
LNC
ZOl
NS
02144-
-08
LNNS
ZOl
NS
02151-
-08
LB
ZOl
NS
02152-
-08
LNP
ZOl
NS
02160-
-08
LNLC
ZOl
NS
02162-
-08
DMN
ZOl
NS
02163-
-08
DMN
ZOl
NS
02167-
-08
ODIR
ZOl
NS
02169-
-08
DNB
ZOl
NS
02171-
-08
DNB
ZOl
NS
02185-
-08
GDP
ZOl
NS
02202-
-07
NI
ZOl
NS
02203-
-07
NI
ZOl
NS
02204-
-07
NI
ZOl
NS
02205-
-07
NI
ZOl
NS
02216-
-07
LNO
ZOl
NS
02217-
-07
LNC
ZOl
NS
02218-
-07
LB
ZOl
NS
02219-
-07
LB
ZOl
NS
02234-
-07
DNB
ZOl
NS
02236-
-07
ET
20
24
20
15
5.B
16
5.B
17
5.B
18
5.B
19
23
22
12
10
12
11
15
29
8
10
8
14
8
15
8
11
5.B
20
5.B
21
5.B
22
5.B
23
5.B
24
l.A
51
20
22
19
14
13
13
14
30
8
13
16
7
12
12
18
15
18
16
7. A
15
5.B
25
5.B
26
3
58
22
4
22
5
22
6
22
7
14
2
14
3
8
16
8
17
5.B
27
19
17
vi - NINCDS
Intramural Research Projects - Numerical Inventory (Cont'd)
PROJECT NUMBER
TAB
PAGE
PROJECT NUMBER
TAB
PAGE
ZOl
NS
02238-
-06
DBFS
1,
.A
24
ZOl
NS
02395-
-04
CDP
3
62
ZOl
NS
02239-
-06
DBFS
1,
,A
42
ZOl
NS
02396-
-04
CDP
3
63
ZOl
NS
02240-
-06
ODIR
7.
,A
16
ZOl
NS
02404-
-04
OBFS
1.
,A
43
ZOl
NS
02241-
-06
CD IF
7,
,A
17
ZOl
NS
02405-
-04
OBFS
1.
,A
47
ZOl
NS
02243-
-06
ODIR
7.
,A
18
ZOl
NS
02406-
-04
OBFS
1.
,A
46
ZOl
NS
02247-
-06
CDP
3
59
ZOl
NS
02408-
-04
OBFS
1.
,A
25
ZOl
NS
02254-
-06
LNC
13
14
ZOl
NS
02411-
-04
OBFS
1.
,A
53
ZOl
NS
02256-
-06
LNC
13
15
ZOl
NS
02414-
-04
OBFS
1.
,A
71
ZOl
NS
02257-
-06
LNC
13
17
ZOl
NS
02415-
-04
OBFS
1.
A
64
ZOl
NS
02258-
-06
ET
19
16
ZOl
NS
02423-
-03
ODIR
7.
A
26
ZOl
NS
02263-
-06
ET
19
13
ZOl
NS
02424-
-03
ODIR
7.
A
27
ZOl
NS
02264-
-06
ODIR
7.
,B
31
ZOl
NS
02429-
-03
LNC
13
18
ZOl
NS
02265-
-06
ET
19
15
ZOl
NS
02430-
-03
LNC
13
19
ZOl
NS
02269-
-06
CN
17
10
ZOl
NS
02431-
-03
CN
17
11
ZOl
NS
02271-
-06
ID
20
23
ZOl
NS
02432-
-03
CN
17
12
ZOl
NS
02273-
-06
LB
8
12
ZOl
NS
02433-
-03
DMN
18
18
ZOl
NS
02275-
-06
LNNS
15
14
ZOl
NS
02434-
-03
DMN
18
19
ZOl
NS
02286-
-06
LNNS
15
31
ZOl
NS
02435-
-03
DMN
18
20
ZOl
NS
02297-
-06
ODIR
7.
A
19
ZOl
NS
02440-
-03
CDP
3
64
ZOl
NS
02299-
-06
ODIR
7.
A
20
ZOl
NS
02441-
-03
CDP
3
65
ZOl
NS
02300-
-06
ODIR
7.
A
21
ZOl
NS
02442-
-03
OBFS
1.
A
68
ZOl
NS
02301-
-06
ODIR
7.
A
22
ZOl
NS
02443-
-03
OBFS
1.
,A
32
ZOl
NS
02305-
-06
ODIR
7.
A
23
ZOl
NS
02444-
-03
OBFS
1.
,A
34
ZOl
NS
02307-
-06
ODIR
7.
A
24
ZOl
NS
02446-
-03
OBFS
1.
,A
60
ZOl
NS
02310-
-06
OBFS
1.
,A
39
ZOl
NS
02447-
-03
OBFS
1.
,A
69
ZOl
ZOl
NS
NS
02312-
02315-
-06
-05
OBFS
1.
A
50
ZOl
NS
02450-
-03
OBFS
1.
A
33
SN
23
23
ZOl
NS
02451-
-02
ODIR
7.
B
32
ZOl
NS
02316-
-05
LB
8
18
ZOl
NS
02452-
-02
ODIR
7.
B
33
ZOl
NS
02317-
-05
LB
8
19
ZOl
NS
02453-
-02
DMN
18
21
ZOl
NS
02318-
-05
ET
19
18
ZOl
NS
02454-
-02
SN
23
18
ZOl
NS
02319-
-05
ODIR
7.
B
35
ZOl
NS
02455-
-02
LNC
13
16
ZOl
NS
02324-
-05
LNNS
15
15
ZOl
NS
02456-
-02
LNNS
15
7
ZOl
NS
02327-
-05
LNNS
15
16
ZOl
NS
02457-
-02
LNNS
15
8
ZOl
NS
02330-
-05
LNP
16
4
ZOl
NS
02458-
-02
LNNS
15
9
ZOl
NS
02332-
-05
DNB
5.
,B
28
ZOl
NS
02462-
-02
LNNS
15
19
ZOl
NS
02336-
-05
CDP
3
60
ZOl
NS
02463-
-02
LNNS
15
20
ZOl
NS
02337-
-05
CDP
3
61
ZOl
NS
02464-
-02
CDP
3
66
ZOl
NS
02339-
-05
LNP
16
5
ZOl
NS
02465-
-02
CDP
3
67
ZOl
NS
02340-
-05
OBFS
1.
,A
29
ZOl
NS
02466-
-02
CDP
3
68
ZOl
NS
02341-
-05
OBFS
1.
.A
67
ZOl
NS
02467-
-02
CDP
3
69
ZOl
NS
02357-
-04
LNNS
15
17
ZOl
NS
02468-
-02
CDP
3
70
ZOl
NS
02361-
-05
LNNS
15
18
ZOl
NS
02469-
-02
CDP
3
71
ZOl
NS
02362-
-04
LNNS
15
32
ZOl
NS
02470-
-02
CDP
3
72
ZOl
NS
02364-
-04
LMB
10
8
ZOl
NS
02471-
-02
CDP
3
73
ZOl
NS
02365-
-04
LMB
10
4
ZOl
NS
02480-
-02
OBFS
1.
,A
73
ZOl
NS
02366-
-04
DMN
18
17
ZOl
NS
02481-
-02
OBFS
1,
,A
56
ZOl
NS
02367-
-04
SN
23
16
ZOl
NS
02482-
-02
OBFS
1.
,A
57
ZOl
NS
02368-
-04
SN
23
17
ZOl
NS
02483-
-02
OBFS
1.
.A
52
ZOl
NS
02370-
-04
ODIR
7.
.A
25
ZOl
NS
02484-
-02
OBFS
1.
,A
35
vii - NINCDS
Intramural Research Projects - Numerical Inventory (Cont'd)
PROJECT NUMBER TAB PAGE
ZOl
NS
02486-02
OBFS
ZOl
NS
02488-02
OBFS
ZOl
NS
02489-02
OBFS
ZOl
NS
02490-02
OBFS
ZOl
NS
02491-02
OBFS
ZOl
NS
02492-02
OBFS
ZOl
NS
02493-02
OBFS
ZOl
NS
02494-02
OBFS
ZOl
NS
02495-02
OBFS
ZOl
NS
02496-02
OBFS
ZOl
NS
02497-02
OBFS
ZOl
NS
02498-02
OBFS
ZOl
NS
02499-02
OBFS
ZOl
NS
02500-02
OBFS
ZOl
NS
02501-02
OBFS
ZOl
NS
02502-02
OBFS
ZOl
NS
02503-02
OBFS
ZOl
NS
02504-02
OBFS
ZOl
NS
02505-02
OBFS
ZOl
NS
02506-02
OBFS
ZOl
NS
02511-02
EB
ZOl
NS
02512-02
EB
l.A
58
l.A
37
l.A
38
l.A
61
l.A
28
l.A
27
l.A
26
l.A
49
l.A
44
l.A
65
l.A
54
l.A
31
l.A
45
l.A
72
l.A
66
l.A
36
l.A
70
l.A
41
l.A
74
l.A
63
5. A
25
5. A
26
NEW INITIATIVES FOR FY 1982
ZOl
NS
02514-01
OBFS
ZOl
NS
02515-01
OBFS
ZOl
NS
02516-01
OBFS
ZOl
NS
02517-01
OBFS
ZOl
NS
02518-01
OBFS
ZOl
NS
02519-01
OBFS
ZOl
NS
02525-01
ODIR
ZOl
NS
02526-01
LB
ZOl
NS
02527-01
LMB
ZOl
NS
02528-01
LMG
ZOl
NS
02529-01
DMN
ZOl
NS
02530-01
DMN
ZOl
NS
02531-01
ID
ZOl
NS
02539-01
EB
ZOl
NS
02540-01
EB
ZOl
NS
02545-01
LNNS
ZOl
NS
02546-01
LNNS
ZOl
NS
02547-01
LNNS
ZOl
NS
02548-01
LNNS
ZOl
NS
02549-01
LNNS
ZOl
NS
02550-01
LNNS
ZOl
NS
02551-01
LNNS
ZOl
NS
02552-01
LNNS
ZOl
NS
02557-01
CDP
ZOl
NS
02558-01
CDP
ZOl
NS
02559-01
CDP
ZOl
NS
02560-01
CDP
l.A
62
l.A
48
l.A
30
l.A
40
l.A
55
l.A
59
7.B
34
8
20
10
6
11
5
18
22
18
23
20
19
5. A
27
5. A
28
15
10
15
11
15
12
15
13
15
23
15
24
15
27
15
21
3
74
3
75
3
76
3
77
vlli - NINCDS
^
o
m
o
-n
-i
X
m
o
5o
m
o
BO
O
>
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of the Director, NINCDS
National Institute of Neurological and Conmunicative Disorders and Stroke
Table of Contents
OFFICE OF THE DIRECTOR (OD) 1
EQUAL EMPLOYMENT OPPORTUNITY OFFICE (EEO) 3
OFFICE OF SCIENTIFIC AND HEALTH REPORTS (OSHR) 8
OFFICE OF PLANNING AND ANALYSIS (OPA) 14
OFFICE OF BIOMETRY AND FIELD STUDIES (OBFS) (See TAB l.A)
i - OD TAB 1
Annual Report of the Acting Director
of the
National Institute of Neurological and
Communicative Disorders and Stroke
October 1, 1981 through September 30, 1982
Fiscal Year 1982 has been characterized by (1) a continuation of the
search for an Institute Director with a resulting delay in several areas of
overall planning and program consideration, (2) more than usual difficulty
in the recruitment of key scientific staff in the intramural program and
(3) critical changes in the philosophy of extramural research funding because
of the most severe competition for available funds in the history of the
Institute.
With the retirement of the Institute Director as of February 1, 1981,
an Acting Director and Acting Deputy Director have borne the responsibility
for Institute leadership. This has included presentation of the Institute's
budget to the Congress on each of 2 years and the preparation of the Institute's
budget request to the Department for a 3rd year. Major changes in Institute
organization and in the recruitment of the management team were again postponed;
however, with the approval of the Director, National Institutes of Health
(NIH), selected critical changes were initiated. These included: the recruit-
ment of a Chief of the Office of Planning and Analysis (OPA), (formerly the
Office of Program Planning and Evaluation); discontinuation of the pilot
program to develop and implement a new all Institute program information
system (PINS) and designation of the former extramural program information
system as the overall Institute unit; a Scientific Program Advisory Committee
(SPAC) as the scientific advisory panel for extramural research planning;
forwarding a request to the Department for reorganization of the Extramural
Neurological Disorders Program into two Programs (the Convulsive, Developmental,
and Neuromuscular Disorders Program, CDNDP, and the Demyelinating, Atrophic,
and Dementing Disorders Program, DADDP); the appointment of a Director,
CDNDP, and an Acting Director, DADDP; completion of a scientific merit and
policy review of the Institute's Guam research program; completion of a
scientifc merit and policy review of the Institute's neural prosthesis program;
completion of a scientific merit and policy review of the Institute's anti-
convulsant drug development program; and completion of a scientific merit
and policy review of the Institute's Venezuelan Lake Maracaibo Huntington's
Disease research endeavor. In compliance with an order from the Secretary,
search procedures have been initiated for an NINCDS Associate Director for
Neurological Disorders and for an NINCDS Associate Director for Communicative
Disorders.
The Institute's intramural research program continues to be characterized
by a continuing high level of research productivity in some areas and an
acceptable but necessary reconsideration of research organization and operation
in other areas. The recently developed neurosurgical research program is
now well established and functioning well. After an extended search, a
Chief of the Laboratory of Neurophysiology has been appointed and is doing
well in focusing his laboratory's research activities at high levels of
scientific priority. However, recruitment for other key scientific leadership
positions have been unsuccessful; these include leaders of the Institute's
intramural endeavors for epilepsy, for clinical communicative disorders.
OD
and for positron emission tomography. The non-competitive federal salary
and the inability to offer recruitment possibilities (additional slots) are
the major reasons given by candidates for declining appointment to these
positions.
The Institute is beginning to occupy the new space assigned to it in
the NIH Ambulatory Care Research Facility. The lengthy delay for availability
of the space, and the not unexpected continuing frustrations in completing
the necessary physical moves have made the occupancy a difficult experience.
Because of several years of limitation of intramural resources (slots, other
object funds, station support contract funds). Fiscal Year 1983 will be
characterized by additional steps to decrease resources to laboratories not
of the highest productivity. A plan has been developed by the Institute's
Intramural Director and will be implemented by him. Several research prizes
of national and international renown have been won by NINCDS intramural
scientists including the Pisano Award and the Lasker Award.
Despite modest increases in the availability of research grant funds,
the NINCDS research grant program has had its most difficult year in Institute
history. The competitive funding rate has fallen to one of its lowest funding
levels; "commitments" have been reduced by formula cuts; and competing grants
have been awarded at marked reductions from levels recommended. These adminis-
trative steps have had a serious impact on the recruitment of new scientists
to areas of Institute responsibility and on the morale of the present cadre
of skilled scientists. The Institute staff is working closely with the
NINCDS National Advisory Council to identify and explore philosophical and
administrative alternatives to stabilize the research grant program for the
next decade. Unfortunately, one product of the difficult extramural funding
issues is a divisiveness developing between extramural grantees and intramural
scientists who each believe the other is receiving favored treatments; steps
are being taken to inform all parties of the total status and to encourage
closer interactions and cooperation.
In conclusion, it has been a privilege to serve the Institute as Acting
Director for Fiscal Year 1982. All Officers of the Institute and members
of the staff have my gratitude for their assistance and cooperation.
OD
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Equal Employment Opportunity Office
Office of the Director
National Institute of Neurological and
Communicative Disorders and Stroke
INTRODUCTION
The National Institute of Neurological and Communicative Disorders and
Stroke's (NINCDS) equal opportunity, affirmative action and civil rights
activities are centered in the Equal Employment Opportunity Office. This
Office serves as principal advisory to the Director of the Institute and
managers at all levels concerning positive application and enforcement of
Affirmative Action and Civil Rights policies of the Federal government. It
is responsible for coordinating, evaluating and monitoring the enforcement
of the 1964 Civil Rights Act and Executive Order 11246 in matters concerning
the Institute's contracts and grants, coordinating the implementation of
the Black College Initiatives (Executive Order 12320), and developing and
implementing programs supportive of the Minority Biomedical Research Support
(MBRS) and Minority Access to Research Careers (MARC) Programs. The Office
also manages the NINCDS Community Outreach Programs to increase the
representation of minorities and women in biomedical research, particularly
the neurosciences . The Institute has an EEO Advisory Committee that
provides advice to the Director, NINCDS, on all matters relating to Equal
Employment Opportunity, and an EEO Counselor that counsels employees and
applicants who believe they have been discriminated against, and
representatives to the NIH Federal Women's Program and the Handicapped
Employees Advisory Committee.
The Institute continues to implement a viable affirmative action
program to increase the representation of minorities and women in its work
force. The Multi-Year Affirmative Action Plan will include specific actions
and strategies that will facilitate the recruitment and placement of
minorities in the Medical Staff Fellowship Program, Research Staff
Fellowship Program, biological and physical sciences and top management
positions. The Plan will also include mechanisms to increase NINCDS'
support to Historically Black Colleges and Universities.
SIGNIFICANT NINCDS AFFIRMATIVE ACTION
ACCOMPLISHMENTS AND INITIATIVES IN FY '82
Promotions
In FY '82, fifty-six employees were awarded promotions in the
Institute. Eleven (or 23%) were minorities and thirty-six (or 64%) were
non-minority females. Twenty employees received promotions at grade levels
GS-9 and above, five were minorities and twelve were females.
3 - odCeeo)
Honors and Awards
Forty-two employees received recognition under the Federal Incentive
Awards Program in FY '82. Approximately six (or 14%) were minorities and
twenty-nine (or 69%) were non-minority females.
MINORITY BIOMEDICAL RESEARCH SUPPORT (MBRS) AND
MINORITY ACCESS TO RESERCH CAREERS (MARC) PROGRAMS
In order to increase the number of minorities undertaking research in
the neurosciences, the NINCDS within the past few years established
cooperative agreements to support components of the Minority Biomedical
Research Support (MBRS) and Minority Access to Research Careers (MARC)
Programs that relate to the overall NINCDS mission.
The funds NINCDS awards through MBRS and MARC Programs strengthen the
neuroscience research capabilities of minority institutions of higher
education. This support also helps to develop minority neuroscientists ,
and enables the NINCDS to identify and support meritorious projects that
have been proposed by minority investigators.
In FY'82, the NINCDS awarded $150,000 to support MBRS grants at the
following schools: South Carolina State College, University of New Mexico,
Howard University and City College of New York.
Under the NIH Summer Program, the Institute selected eight students (4
MBRS students and 4 MARC Honors students) for positions in the Institute's
research laboratories.
NIH SUMMER RESEARCH FELLOWSHIP PROGRAM
In FY'82, NIH initiated the Summer Research Fellowship Program, a
biomedical research training program available to medical and dental
students. Eleven medical students from various medical schools throughout
the country were selected for training positions in the NINCDS Intramural
Research Program. Six (or 55%) were minority medical students and three (or
27%) were non-minority female medical students. To correct the
underrepresentation of minorities and women in the Medical Staff Fellowship
Program, aggressive recruitment and placement of minorities and women in
this program will continue to be an affirmative action goal of the NINCDS.
SUPPORT TO HISTORICALLY BLACK COLLEGES AND UNIVERSITIES
Executive Order 12320, dated September 15, 1981, directs each Federal
agency to increase the participation of Historically Black Colleges and
Universities in Federally sponsored programs. Initiatives implemented in
FY'82 in NINCDS were:
A. Ten students from seven Historically Black Colleges were selected
for summer positions in the Institute.
4 - OD(EEO)
B. Two Minority Biomedical Research Support grants and two research
grants were awarded to Historically Black Colleges.
C. Institute staff members conducted seminars concerning NINCDS
programs and activities at Delaware State College, Dover,
Delaware; Langston University, Langston, Oklahoma; and Howard
University School of Medicine, Washington, D. C.
D. Four medical students from Howard University School of Medicine
were selected for reserch training positions under the NIH Summer
Research Fellowship Program.
E. As part of the Summer Externship Program for medical students at
Provident Hospital in Baltimore, Maryland, eight students from
Meharry Medical College and Morehouse College of Medicine were
selected for clinical research training positions in the
Institute.
COMMUNITY OUTREACH ACTIVITIES
Staff members from the Institute participated in the following
workshops and sjrmposiums to promote the participation of minorities in the
neurosciences :
A. The Minority Biomedical Research Support Symposium;
B. The Student National Medical Association Conference;
C. The National Medical Association Scientific Meeting; and
D. Graduate and Professional Opportunities Career Day Program at the
University of Minnesota, including a meeting with Black and
Hispanic medical and dental students.
NEW INITIATIVES
The Institute in FY '82 implemented the following two initiatives to
increase the representation of minorities in the neurosciences:
A. In an effort to increase participation of minority students in
the neurosciences, the NINCDS has awarded a three-year grant to
the Society for Neuroscience for the establishment of a program
that will provide funds for minority students and scientists to
attend annual meetings of the Society.
5 - OD(EEO)
B. In order to increase the participation of Hispanics in the Summer
Program and other reserch training programs in the NINCDS, the
Institute's EEO Officer and Personnel Officer conducted a series
of seminars at: (a) University of New Mexico; (b) California
State University; (c) East Los Angeles College; and (d)
University of California, San Diego. Meetings were held at each
school with MBRS and MARC students to provide information and
discussions concerning career and training opportunities in
biomedical research at the NIH.
Three Hispanic students from the University of New Mexico and a MARC
Honors student from California State University were appointed to summer
positions in the Institute's research laboratories. One student from the
University of California, San Diego accepted a position with the National
Heart, Lung and Blood Institute.
NIH EEO PROGRAM
Assisting in the development and implementation of NIH Affirmative
Action and Civil Rights Programs continues to be an important function of
the Institute's EEO Office. In FY' 82, the Office participated in the
following functions at the NIH level:
A. Mr. Levon 0. Parker, the Institute's EEO Officer, was selected to
chair the NIH Committee on Black College Initiatives. The
Committee was formed as part of the NIH Civil Rights Plan to
define and implement the NIH role in the implementation of
Executive Order 12320 concerning Historically Black Colleges and
Universities .
B. In conjunction with three other Institutes, conducted a seminar
and laboratory tour for students in the United Negro College Fund
Premedical Summer Institute; science students from Morgan State
University; participants in the North Carolina Health Manpower
Development Program; and the Prehealth Careers Program at
Benedict College, South Carolina.
C. The EEO Officer participated in the development of mechanisms to
monitor job selection at the NIH.
D. The Office and other staff members of the Institute participated
in the first NIH Affirmative Action Recruitment Conference. The
objectives of the conference were: (1) to provide a forum in
which NIH program officials could meet with representatives from
selected institutions with significant minority and female
enrollments; (2) to familiarize the academic community with the
staffing needs of the NIH, especially in the scientific areas,
with particular emphasis on those occupational categories in
which minorities and women are underrepresented; and (3) to
develop a network of resources in the academic community that
will identify potential applicants for positions at the NIH.
6 - ODCEEO)
EEO ADIVSORY COMMITTEE
The Institute's EEO Advisory Conmittee played an important role in the
development and implementation of NINCDS' EEO/Af f irmative Action Programs
in FY '82. Some activities of the Committee this past year were:
A. In conjunction with the EEO Office and the Personnel Office, the
Committee initiated a new information sheet entitled
"EEO/Personnel News Briefs." This newsletter is an effort to keep
employees abreast of current developments in EEO and Personnel.
B. Sponsored meetings in two program areas to give employees an
opportunity to discuss concerns and issues with top management.
C. Organized the Annual NINCDS All Employees' Meeting.
7 - ODCEEO)
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of Scientific and Health Reports
Office of the Director
National Institute of Neurological and Communicative Disorders and Stroke
Within the National Institute of Neurological and Communicative Disorders
and Stroke, dissemination of research information to the public is chiefly
the responsibility of the Office of Scientific and Health Reports (OSHR).
This Office advises the Director and the executive staff on ways to effec-
tively report results of research conducted and supported by the Institute.
Reporting tasks range from simply mailing a pamphlet in response to an inquiry
to writing and coordinating technical state-of-the art reports.
The OSHR consists of two main sections. Public Inquiries and Scientific
Publications, and a media liaison effort carried out by the Office deputy
chief.
OSHR staffing remained stable for most of this fiscal year, with the Public
Inquiries Section benefiting from its strongest staffing in years. Two
summer interns with previous experience in science writing also helped give
the office stronger capabilities than had been available in previous summers.
The only major staff change occurred in the Scientific Publications Section,
where Robert Hinkel, who had been with the OSHR for 17 years in a 27-year
career at NIH, retired at the end of June. Mr. Hinkel had been chief of
the Scientific Publications Section since 1971. His departure left the
Section with only one full-time writer/editor in an office that had had 3
the previous year. The impact of this severe staff shortage was mitigated
somewhat when a well-trained science writer was hired as a summer intern
for the Section, and by the continuing moratorium on Department of Health
and Human Services publications. In August, however, permission was obtained
to proceed with 3 new Hope Through Research pamphlets that were part of the
FY82 publications plan. The Acting Director, NINCDS, agreed that OSHR should
bring the Scientific Publications Section back to full staff, and the office
began taking the steps necessary to achieve this objective.
The DHHS-wide moratorium, in effect since May 1981, seriously disrupted
progress in revising outdated NINCDS publications, including the Hope Through
Research series of information pamphlets for the public. Work was allowed
to continue on five previously approved pamphlets that originally had target
publication dates in FY81 but that had fallen behind schedule. All five
were published in FY82. However, it became increasingly difficult to manage
the Section effectively, since there was no assurance that planned projects
would be approved by DHHS. As a result, all FY82 projects are being moved
to the FY83 publications schedule. In effect, then, the OSHR has "lost"
one publishing year. If the recent permissions can be seen as a return to
allowing the Institute to publish in the public interest, then it may be
possible to pick up the interrupted schedule and maintain good productivity
for the next three years or so until all outdated material has been revised.
8 - ODCOSHR)
Public Inquiries Section
The Public Inquiries Section responds to written and telephone inquiries
concerning some 600 neurological, conmunicative, and sensory disorders as
well as to questions about Institute programs and policies. Many of the
inquiries involve complex subject matter, requiring coordination with intra-
mural scientists and grantees to ensure that replies are as responsive as
possible. Inquiries concerning policies and programs sometimes must be
coordinated with Institute officials and the NIH and DHHS Secretariat.
During FY82, patients with disorders of the nervous system, and their families
and friends, were by far the largest requesters of information. They asked
primarily about effective treatment for specific disorders, where to obtain
treatment, and how to pay for it. Requests for referrals to specialists
and medical centers were received constantly. Information about drugs —
especially "orphan" drugs and the Institute's role in their development —
was also anxiously sought by patients whose conditions do not respond to
available drug therapies.
This year, 478 individually prepared responses were sent to the Institute's
lay and medical audiences. Another 161 responses were written in answer to
controlled letters from the Congress and the White House. Also, 118,710
inquiries were answered with publications; 1,440 of these were accompanied
by form responses or personal notes providing additional information. Another
137,456 publications were sent out to fill bulk requests from voluntary
health agencies, medical centers, and local and state agencies. Still another
6,453 publications were distributed to scientists and physicians at medical
meetings.
During this reporting period there was a dramatic decrease in publications
supplied to voluntary health agencies — the direct result of the printing
moratorium which prevents OSHR from reprinting publications, thereby forcing
the Office to conserve limited supplies. At the same time, the number of
publications sent to individuals increased, largely due to media interest
in several new Hope Through Research pamphlets. This change in distribution
considerably increased the workload of the Public Inquiries Section: handling
500 individual requests requires far more effort than shipping a bulk order
of 500 publications to a single address.
Public Inquiries Section personnel also plan and develop the NINCDS exhibits
program, and serve as Institute spokespersons at the medical and scientific
meetings to which the various exhibits are sent. Last year, the Section
staff worked with NIH Medical Arts on the design of 5 new picture panels
for the NINCDS exhibit. The full-color panels depicted otolaryngological
research, PETT, and basic research activities. The addition of the new
panels to the exhibit increased its overall flexibility and adaptability to
specific audiences important to Institute programs.
Plans to develop an exhibit specifically for neurosurgical meetings were
delayed by budgetary considerations and the Institute's decision to cut
back temporarily on the number of meetings to which the exhibit is sent.
However, new panels are being designed for meetings attended in support of
the Communicative Disorders Program.
9 r- ODCOSHR)
In the fall of 1981, the NINCDS exhibit was shown at meetings of the Child
Neurology Society in Minneapolis, and the Society for Neuroscience and the
American Speech, Language and Hearing Association, both in Los Angeles.
From January through September 1981, the exhibit was sent to meetings of
the Association for Research on Otolaryngology in St. Petersburg; the American
Academy of Neurology and the American Neurological Association, both in
Washington, D.C.; the Triological Society in Palm Beach; the Biophysical
Society in Boston; the American Association of Anatomists in Indianapolis;
the Association for Chemoreception Sciences in Sarasota; and FASEB in New
Orleans. The last four of the above meetings were scheduled in response to
the Institute program directors' desire to interest specific scientific
audiences in applying to NINCDS for research support.
As one way of carrying out the Institute's commitment to encouraging minority
scientists to undertake biomedical research, the OSHR in cooperation with
the NINCDS EEO Office sent exhibits to the Minority Biomedical Support meeting
in Albuquerque and the National Medical Association meeting in San Francisco.
The Public Inquiries Section also carries out a small initiative to meet
the special information needs of NINCDS employees. The chief vehicles for
conveying information via office bulletin boards is NINCDS CLIPS, a poster-
sized sheet of news clippings about the Institute. CLIPS and other materials
are distributed frequently to inform employees of research accomplishments
of NINCDS scientists and grantees, to advise them of policy changes, and to
alert them to radio and TV coverage of NINCDS work.
Similarly, news reaches internal audiences through the NIH RECORD, which
this year carried more than two dozen news and feature stories prepared by
OSHR writers. A number of these stories prompted media inquiries or were
picked up by other publications for further dissemination.
The Public Inquiries Section also continued this year to provide materials
for the Institute's Advisory Council meetings, and has updated the Council
Directory.
The head of the Section also serves as information liaison with the Extra-
mural Activities Program and with the program directors in the Federal Building;
she is responsible for identifying grantee research that is appropriate for
use in Institute reports and publications, and writes annual special reports
for Congress on cerebral palsy and spinal cord injury.
This year. Institute responsibilities under the Freedom of Information Act,
formerly centered in the Public Inquiries Section, were transferred to the
Office of Grants Management.
Scientific Publications Section
The Scientific Publications Section produces and distributes Institute
publications for a variety of scientific and professional audiences and for
the general public. The Section serves all the administrative units of the
Institute, ad hoc committees preparing reports, and, as appropriate, outside
organizations working in the neurosciences. The services cover planning,
10 - ODCOSHR)
clearance, writing, and editing of publications; securing designs, layouts,
and printing; distributing and storing publications; and subsequent revision
and reprinting according to demand.
A priority project of the Publications Section has been revising and expand-
ing the Institute's Hope Through Research pamphlet series. These pamphlets
offer information of interest and value to patients and their families, and
describe research approaches to the various neurological and communicative
disorders. During this fiscal year, new pamphlets on epilepsy, shingles,
brain tumors, hearing loss, and chronic pain were published. Work began on
new pamphlets on stroke, Parkinson's disease, and head injury, but publi-
cation was delayed because DHHS approval for these projects was not granted
until August 1982.
NINCDS fact sheets are another series of publications the Section has developed
to meet a need for information about rare and little known neurological and
communicative disorders. Thirteen fact sheets are now in print. This year,
a revised fact sheet on Friedreich's ataxia was published, as well as a new
fact sheet on torsion dystonia. A fact sheet on Joseph's disease was prepared
for possible publication in FY83.
NINCDS Extramural Research and Training Awards, a guide for grant appli-
cants, was revised and published this fiscal year. NINCDS Intramural
Research Training Programs, describing training opportunities within the
Institute's laboratories and research branches, was also revised and pub-
lished. The design of these two publications resembles that of The NINCDS
Today and the NINCDS Fact Book, so the four publications, none more than a
year old, can be recognized as a "family" with the common purpose of des-
cribing the Institute and its programs.
The NINCDS Today, a 20-page, four-color booklet describing and depicting
the work of the Institute, was published and distributed in FY82. This
publication won a first place in the Blue Pencil Awards contest sponsored
by the National Association of Government Communicators, and was also
selected by the Art Director's Club of Metropolitan Washington for display
in their annual show.
A service performed by the Section has been production of guides for health
practitioners, presenting the latest information in research and treatment
of various disorders. In FY82, the Section published Epilepsy; A Manual
for Health Workers, written originally for physicians and paramedical per-
sonnel in third world countries but adapted by the Section for worldwide
use. This manual was given international distribution.
NINCDS ' s Office of Biometry and Field Studies operates a long-term program
of hospital studies to produce authoritative statistics on incidence, pre-
valence, and costs of the major neurological and communicative disorders.
A by-product of this program is a series of short brochures presenting high-
lights of study results. The second publication in this series. National
Head and Spinal Cord Injury Survey, was published and distributed in FY82.
11 - ODCOSKR')
The NINCDS Fact Book, updated to July 1981, was produced and distributed.
Late in the fiscal year, a third edition of this publication was prepared
and readied for printing.
Two useful directories were updated but because of the moratorium were not
published: Voluntary Agencies Working to Combat Neurological and Communi-
cative Disorders and NINCDS Directory of Professional Societies.
Two periodical issuances, not publications but essential to the OSHR communi-
cation mission, are NINCDS NOTES, a monthly Institute news service to journal
editors, and RESEARCH CURRENTS, a triannual packet of lay-language science
articles which now goes to some 100 voluntary agencies sharing interests
with NINCDS. Response to RESEARCH CURRENTS has been favorable, with many
of the articles reprinted in voluntary agency newsletters.
During 1982, a summer intern assigned to the NINCDS Equal Employment Oppor-
tunity Office and working under the supervision of OSHR produced the first
issue of NINCDS EEO/Personnel News Briefs, an information page designed to
inform employees about important Personnel and EEO issues. News Briefs may
be issued periodically as needed.
Media Liaison
NINCDS research on neurological and communicative disorders continues to
attract media attention, with certain areas the focus of more than usual
interest. Among research topics that most intrigue reporters are the
dementias, brain imaging technology, and spinal cord regeneration. The
OSHR deputy chief, who has primary responsibility for media liaison, responds
to inquiries but also seeks to develop interest in areas that are crucial
to the Institute's mission.
Among the OSHR media activities reaching national audiences this year was
the radio program "Prime Time," which chose to feature an NINCDS scientist
in its show on Alzheimer's disease. Hundreds of letters were received from
listeners as a result of the show, which was broadcast nationally several
times. Similarly, NINCDS research was frequently spotlighted on the local
CBS television affiliate in brief health reports that were sometimes picked
up nationally.
Print reporters regularly turn to OSHR for information on diverse topics.
This year a major piece on the role of voluntary health organizations in
combating neurological and communicative disorders appeared in the LOS
ANGELES TIMES as a result of a story idea placed by the OSHR deputy chief.
Similarly, on OSHR's recommendation columns about research on shingles and
stuttering appeared in the WASHINGTON POST and the NEW YORK TIMES, producing
thousands of requests for new Hope Through Research pamphlets on these subjects.
Often a single research finding will be of interest to a variety of media
if presented in an intriguing fashion. This year, for example, OSHR helped
disseminate to the public findings concerning the ineffectiveness of the
TORCH test commonly used by obstetricians and gynecologists. Through the
intervention of OSHR staff, stories recommending that physicians not use
12 - ODCOSHR)
the TORCH test appeared in the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION,
WOMAN'S DAY, NIH RECORD, NEWS & FEATURES, RESEARCH CURRENTS, and locally on
WDVM-TV. It is impossible to know how many other media outlets used this
information after seeing the story in one of these publications or on
television.
OSHR also assisted with an NIH science writers' seminar on slow virus re-
search, with major stories about this research appearing in SCIENCE NEWS,
NEW YORK TIMES, U.S. MEDICINE, and other national newspapers and journals.
The results of a consensus development conference on CT scanning of the
brain were also disseminated widely through OSHR media liaison efforts.
The Media Liaison Section is expanding efforts to provide information about
NINCDS activities to professional societies concerned with the
neurosciences. Initial efforts are being made with professional groups
interested in communicative disorders, with the primary goal of mounting a
cooperative national campaign to inform the public about the problem of
presbycusis.
13 - ODCOSHR)
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of Planning and Analysis
Office of the Chief
National Institute of Neurological and Communicative Disorders and Stroke
The Office of Planning and Analysis (OPA) advises the Institute Director
and Office of the Director (OD) staff as well as components of the
intramural and extramural programs of the Institute on a wide variety of
programmatic issues and requirements. These include program
development, analysis, evaluation, the development of implementation
plans, legislation, and data coordination. The OPA provides staff
support to facilitate the integration of program planning, analysis, and
evaluation efforts in the categorical program areas. It also provides
the Director and the Executive Staff with assistance in coordinating the
development of research plans for meeting these goals.
The OPA develops, in collaboration with Program Managers and Directors,
the Institute responses on a number of issues, including analyses of
specific aspects of research programs. Staff serve in a liaison
capacity for reporting research on various subjects. An analysis of
NINCDS prevention activities involved identification of the total
Institute research matrix to extract FY 81 projects related to primary,
secondary, and tertiary prevention. Data is also coordinated and
compiled regarding NINCDS clinical trials activities as well as
activities related to technology assessments and consensus conferences.
The OPA this year initiated a series of meetings with the Program
Directors and other key Institute personnel to assess the past and
current role of the office and to elicit suggestions and reactions to a
variety of initiatives planned for the future. Following these
meetings, recommendations regarding potential future initiatives were
made to the Acting Director. One such recommendation resulted in the
OPA initiating a comprehensive review and analysis of the NINCDS
legislative charter as well as the legislative charters and histories of
several other NIH Institutes. On June 21, 1982, a meeting of key OD
staff as well as two former NINCDS Directors was convened for the
purpose of discussing relevant legislative issues. Work is now in
progress to implement the recommendations developed at that meeting.
Analysis and Reports Section (ARS)
The Section prepares and coordinates the annual Evaluation Plan for the
research programs of the Institute and develops proposals for the
recurrent assessment of the effectiveness of its research programs.
This year the Section conducted an information session for all
interested Institute staff on the procedures and requirements for
obtaining one percent set-aside evaluation funds. The FY 83 NINCDS
Evaluation Plan contains five proposals. Included among these is a
proposed project to develop research goals for the neurological and
communicative sciences. This project will build upon the previously
developed National Research Strategy. Section staff also serve as
evaluation contacts and Institute representatives in all activities
14 - ODCOPA)
related to evaluation. The Section provides to NIH material requested
by the Assistant Secretary for Planning and Evaluation regarding the
status of ongoing evaluation projects and utilization and application of
their findings.
The Section prepares and coordinates the development of the Research and
Legislative Plan of the Institute. This plan is concerned with setting
the major themes, thrusts, and tone for the discussion of budgetary
requirements for future years. Input is also solicited and obtained
from the Program Directors and from the Director and Deputy Director of
NINCDS. Budgetary projections are developed by the Budget Office in
close collaboration with the Section. Questions raised by NIH/OD are
responded to jointly by the Budget Office and the Section.
The ARS also has the responsibility of coordinating development of the
Institute Annual Report. The Section works with the Institute's Program
Areas and provides them with technical assistance to assure uniformity
of format and editorial quality of the Report. The Annual Report is a
standard formal Institute document which presents an overview of the
total scope of NINCDS research as to science, program, and budget.
Program summaries as well as contract narratives and intramural research
project summaries are included.
As a legislative focus for the Institute, we have continued to work with
appropriate staff of NIH/OD to monitor legislative developments in order
to safeguard and maintain all elements of the Institute's mission.
Legislative proposals pertaining to NIH reauthorization,
neurofibromatosis, government-industry cooperation, orphan drugs, and
other areas of vital interest to NINCDS were reviewed and
recommendations were forwarded to the Office of the Director.
The Section also participated in the development and review of the
annual Implementation Plan of the Institute. This involves setting
funding priorities within the context of program objectives, research
opportunities, and available resources. This is done in close
collaboration with the NINCDS Office of the Director.
The ARS also responds to a large number of ad hoc queries from a variety
of private and public sources regarding NINCDS research as it relates to
NHLBI, NIEHS, pain research, research on the handicapped, toxicology,
aging, and a variety of other important areas. In addition the Section
provides NINCDS representation on Interagency Technology Committees such
as Digestive Diseases, Dermatology, and Arthritis.
Information Technology Section (ITS)
This Section has been responsible for developing a Program Information
System (PINS) to combine programmatic, fiscal, and management data into
an integrated Institute-wide database. Validation of programs and
assistance has been provided by the firm of JRB Associates, Inc.
Considerable ITS staff effort during the first nine months of the year
was directed to the continuing development of the System. While
significant progress was made, the scope and complexity of the PINS
15 - OD (OPA)
effort led to the view that it was beyond the resources of the
Institute. Therefore, PINS was terminated by the Acting Director,
NINCDS, on June 24, 1983.
A concurrent effort that was concluded in mid-year was the development
of an interactive system for the storage and retrieval of drug reaction
data for both inpatients and outpatients participating in clinical
trials. This system was turned over to the Intramural Research Program
for operation. The Section served as the focal point within the
Institute for ADP coordination, preparation of the annual ADP plan, and
related activities. Due to PINS termination, ITS was abolished in July
1982, and its personnel were reassigned to other positions as
appropriate.
On September 1, the Office of Data Analysis and Reports, Extramural
Activities Program, was abolished, and its personnel were reassigned to
the newly created Management Information and Data Section, OPA. The new
Section has the responsibility for administering the Institute
information and data system which involves the collection,
classification, organization, storage, and retrieval of data for
research grants, training grants, career awards, fellowships, contracts,
and intramural research projects. It will produce special and recurring
reports and other computer-prepared documents to meet Institute and
Institute Program needs as well as developing and implementing automated
processes to facilitate reporting as it affects program administration.
16 - OD(OPA)
CONTRACT NARRATIVE
Office of Planning and Analysis, OD/NINCDS
Fiscal Year 1982
Contractor: JRB ASSOCIATES, INC., 8400 Westpark Drive, McLean, Virginia
22101 (NO1-NS-82301)
Title: Validation and Technical Support — NINCDS Program Information
System
Date Contract Initiated: November 1, 1981
Contractor's Project Director: Jacqueline Sanders
Current Annual Level : $17,000
Objectives : The contractor was expected to continue providing technical
support to the Institute by refining the program which updates the PINS
database from IMP AC, developing a program to copy ODAR classification
codes from IMP AC, revamping and installing an audit trail to record
changes to data in the files, and refining classification data entry and
modification programs to facilitate processing by ITS support staff.
Completion of an interface with the NIH organization file and data entry
of intramural research projects were also required. It also was to lay
the groundwork for ITS to complete the creation of an FY '81 frozen file
through file definition and coordination of online usage and development
of the History Maintenance Program.
Major Findings: Considerable effort was aimed at producing a working
file that could demonstrate both the usefulness and the report capability
of PINS. A file was loaded with IMPAC data and efforts were directed to
an audit trail for recording changes to data within the files. Several
programs for reports were made operational. ITS programming staff was
aided in debugging problem programs and several training sessions took
place concerning the database administration of the system.
Significance to the Program of the Institute: The scientific, budget,
and program information of the Institute is increasing in quantity and
complexity. Rapid access to pertinent facts in a timely manner is essential
for effective management. PINS is being developed as a database management
system providing online access to the data by organizational units
throughout the Institute. Data will be accessible when and where they
are needed and in a form that can be readily used. PINS will maintain
data currency, validity, and compatibility between it and existing NIH
systems such as IMPAC.
Proposed Course: The contract terminated on December 19, 1981.
17 - ODCOPA)
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of Biometry and Field Studies
Office of the Director
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-7
Bibliography 8-10
IRP Consultants 11
CONTRACT NARRATIVES
Full Phase Stroke Data Bank 12
NOl NS 2-2302
NOl NS 2-2397
NOl NS 2-2398
NOl NS 2-2399
Pilot Data Bank Network in Stroke 13
NOl NS 9-2302
NOl NS 8-2397
NOl NS 8-2396
NOl NS 8-2398
Pilot Data Bank Network in Traumatic Coma 14-15
NOl NS 9-2308
NOl NS 9-2309
NOl NS 9-2307
NOl NS 9-2306
Data Bank Maintenance Center for Pilot Data Bank 16
Network Projects in Stroke and Traumatic Coma
NOl NS 8-2390
Test of Study Design and Pilot Study for a National 17
Survey of Epilepsy
NOl NS 8-2383
Survey of Intracranial Neoplasms 18
NOl NS 4-2336
Survey of Neurological Disorders in Copiah County 19-20
Mississippi
YOl NS 7-0031
NOl NS 7-2357
National Hospital Survey of Disease 21-22
(formerly Comprehensive Disease Statistics Survey)
NOl NS 7-2379
2-YOl NS 9-0043-05
L-OBFS/OD
TAB l.A
Table of Contents (cont'd)
EGA Dementia Supplement 23
lYOl 0-0004-00
PROJECT REPORTS
Pilot Data Bank Project Network in Stroke 24
ZOl NS 02238-06 OBFS
Clinical Databanks As a Resource for Epidemiologic 25
Research
ZOl NS 02408-04 OBFS
Stroke Diagnosis: The NINCDS Data Bank Algorithm 26
ZOl NS 02493-02 OBFS
Data Support for Diagnostic Algorithms of Stroke 27
ZOl NS 02492-02 OBFS
Activities of Daily Living Following Stroke 28
ZOl NS 02491-02 OBFS
Pilot Data Bank Network Project in Coma 29
ZOl NS 02340-05 OBFS
Traumatic Coma: Epidemiological Characteristics 30
ZOl NS 02516-01 OBFS
CT Scan Observer Variability Study 31
ZOl NS 02498-02
Development of Offline Data Entry System for Stroke and 32
Coma Projects
ZOl NS 02443-03 OBFS
Spinal Manipulative Therapy as Treatment for Musculo-Skeletal 33
Dysfunction in Athletes. Formerly titled "Study of Efficacy
of Spinal Manipulative Therapy on the Performance of Athletes"
ZOl NS 02450-03 OBFS
Statistical coordinating center for the phenobarbital clinical 34
study (previously titled "Cognitive and Behavioral Effects of
Phenobarbital in Young Children").
ZOl NS 02444-03 OBFS
Statistical Coordinating Center for Communicative Disorders 35
Program projects.
ZOl NS 02484-02 OBFS
Medical Studies Database System 36
ZOl NS 02502-02
TAB l.A ii-OBFS/OD
Table of Contents (cont'd)
Interactive Computer System for Patient Entry and Randomization 37
for Clinical Study
ZOl NS 02488-02 OBFS
Evaluation of the effectiveness of information services 38
provided to specialists in communicative disorders by MEDLINE
ZOl NS 02489-02 OBFS
A Statistical Study of Sensory-Decision-Theory Method in the 39
Measurement of Experimental Pain
ZOl NS 02310-06 OBFS
Statistical Methodology for the Measurement of Pain 40
ZOl NS 02517-01 OBFS
Epidemiological Study of Pain (Formerly titled Estimation of the 41
Incidence Rate of Disabling and Severe Headache)
ZOl NS 02504-02 OBFS
Design of Health Interview Survey Questionnaire Supplements 42
(Previously titled: "Design of Convulsive Disorder Questionnaire")
ZOl NS 02239-06 OBFS
National Survey of Chronic and Debilitating Headache (Previously 43
titled: "National Headache Survey")
ZOl NS 02404-04 OBFS
Analysis of Data From the National Survey of Multiple Sclerosis 44
ZOl NS 02495-02 OBFS
Stroke Incidence in South Alabama 45
ZOl NS 02499-02 OBFS
The Frequency of Neurological Disorders Among Hospital Discharges 46
ZOl NS 02406-04 OBFS
Assessment of Strategies for Analyzing Data from Small Area Health 47
Surveys (Previously titled: "Assessment of Strategies for Analyzing
Data from Small Area Mortality Surveys")
ZOl NS 02405-04 OBFS
Study of Hearing Disorders Among the Aged 48
ZOl NS 02515-01 OBFS
The Prevalence of Multiple Sclerosis in Colorado 49
ZOl NS 02494-02 OBFS
Maternal Infection Study (previously titled "Methodology for 50
Systematic Analysis of Multiple Antibody Readings on Matched
Controlled Studies")
ZOl NS 02312-06 OBFS
-OBFS/OD TAB l.A
Table of Contents (cont'd)
Etiology and Natural History of Convulsive Disorders and 51
Cerebral Palsy
ZOl NS 02114-09 OBFS
Predictive Value of the EEC in Febrile Seizures 52
ZOl NS 02483-02 OBFS
Survey of Practice in the Management of Febrile Seizures 53
(previously titled "Survey of Management of Children with
Febrile Seizures").
ZOl NS 02411-04 OBFS
INDO-U.S. Study of Head Injury 54
ZOl NS 02497-02 OBFS
Neurological Aspects of Aging in Primates 55
ZOl NS 02518-01 OBFS
The Use of Phantom Views to Diminish an Artifact in CT Scans 56
ZOl NS 02481-02 OBFS
Optimization of Software for PET Scanner 57
ZOl NS 02482-02 OBFS
Statistical models of in vitro mutagenicity assays 58
ZOl NS 02486-02 OBFS
Case-Control Studies of Antiviral Antibodies in Multiple 59
Sclerosis
ZOl NS 02519-01 OBFS
Parkinson's Disease in Twins (previously titled "Parkinson 60
Twin Studies")
ZOl NS 02446-03 OBFS
Research in Statistics 61
ZOl NS 02490-02 OBFS
Review of Techniques for Sampling of Rare Populations 62
ZOl NS 02514-01 OBFS
Antibody Titers in Macacas on Cayo Santiago 63
ZOl NS 02506-02 OBFS
Cage Standards for Primates 64
ZOl NS 02415-04 OBFS
Preliminary Steps for a Data Bank Project in Epilepsy 65
ZOl NS 02496-02 OBFS
Myasthenia Gravis Study 66
ZOl NS 02501-02 OBFS
TAB l.A iv-OBFS/OD
Table of Contents (cont'd)
Type-Specific Stroke Mortality Trends 67
ZOl NS 02341-05 DBFS
Feasibility of a National Survey of Speech Defects 68
ZOl NS 02442-03 OBFS
A Prospective Study of Low Birthweight Infants 69
ZOl NS 02447-03 OBFS
Cerebral Palsy Bibliography of Selected References 70
ZOl NS 02503-02 OBFS
Early Stopping Rules Used in Clinical Trials previously 71
titled "Simulation of Early Stopping Rules Used in
Clinical Trials"
ZOl NS 02414-04 OBFS
Polymyositis/Dermatomyositis Study 72
ZOl NS 02500-02 OBFS
A Clinical Study of Bromocriptine and Pergolide for the 73
Treatment of Parkinson's Disease
ZOl NS 02480-02 OBFS
Headache in Pregnant Women 74
ZOl NS 02505-02 OBFS
v-OBFS/OD T^B 1^^
Annual Report
for period October 1, 1981 through September 30, 1982
Office of Biometry and Field Studies
Office of the Director
National Institute of Neurological and Communicative
Disorders and Stroke
The Office of Biometry and Field Studies (OBFS) supports a program in bio-
statistics and computer science to further medical research in the areas of
neurology and communicative disorders.
OBFS is active in a number of program areas, such as computerized clinical
data banks, national surveys of disease, and there has also been a considerable
increase in the Branch's clinical trial activities, both intramurally and in
consultation with university-affiliated groups that conduct clinical research.
A major OBFS responsibility is management of the NINCDS Stroke and Trauma-
tic Coma Clinical Data Banks. The Stroke Clinical Data Bank is a cooperative,
prospective study of hospitalized stroke patients, which is now moving into its
main five-year phase. In the pilot project, data on over 1100 cases were col-
lected at four clinical centers. Among the studies drawn from these data is
one relating post-stroke depression to location of brain injury. This work
found that among right-handed persons with ischemic infarctions, those with
lesions of the left hemisphere were more likely to be depressed than those with
lesions of the right hemisphere or with brain stem injury. Inappropriate mood
and depth of depression were also shown to be associated with location of
injury.
Another study has examined the clinical features and patient characteris-
tics associated with development of post-stroke complications. Preliminary
findings suggest that risk of complications is associated with age, sex, race,
severity and laterality of stroke, functional ability, and stroke type. Fur-
ther analysis will provide a profile of the complication-prone patient.
A third study has focused on patients with lacunar infarcts. The object of
this study, among the 100 patients found with lacunar stroke, is to delineate
subtypes, and determine the clinical outlook and risk factors for each subtype.
Histories of hypertension or diabetes were found more frequently among these
patients. Preliminary analyses indicate that functional prognosis and survival
are better for lacunar infarctions than for other stroke types.
Stroke Data Bank research includes the development of a new diagnostic
algorithm for stroke, and its use as a prognostic index, by studying its rela-
tionship to laboratory evidence and to activities of daily living. In addi-
tion, work has begun on refining the data collection forms and protocols from
the pilot for use in the main phase of the Stroke Data Bank.
The Traumatic Coma Clinical Data Bank, which is also moving into a five-
year main phase, is a collaborative effort involving five neurosurgical depart-
ments and OBFS. From January 1980 through March of 1982, the pilot project
prospectively collected information on over 680 comatose hospitzlized accident
victims. These data have undergone extensive quality assurance reviews and are
presently being analyzed for research findings. Studies in progress include
an investigation of the relationships among accident characteristics, injury
1-OBFS/OD
details, emergency care and outcome, and a study of patients with subdural
hematomas.
A study of patients whose initial post-injury condition appears not to be
serious but who swiftly deteriorate, has identified about 40 such cases from
the first 325 cases in the data bank. Analysis of data from these 40 cases has
shown an association between computerized tomographic findings of midline shift
and poor prognosis. Another study drawn from the 681 cases in the coma data
bank examined the relationships among pre-hospitalization hypotension and
hypoxia, elevated intracranial pressure and outcome. Each of these secondary
insults was shown to be associated with outcome.
OBFS personnel have provided consultation on data bank design and implemen-
tation to scientists at NIH and elsewhere. OBFS is assisting in the planning
of a Workshop on Computers in Neurology for the 1983 American Academy of
Neurology meeting, and will give a presentation on clinical data banks. OBFS
is also developing a workshop to be held in conjunction with the 1983 Stroke
Council meeting of the American Heart Association to report to the neurological
community on the methodology and findings of the Stroke Clinical Data
Bank.
The data entry, data transmission and report generating system of the
microcomputer used in the Stroke and Coma Data Banks has been substantially
improved in FY 1982. One part of this computer system creates a narrative case
summary for individual patients. A method for electronically transferring data
sets overnight without a computer operator's assistance has been developed.
This is an innovative step in data management for clinical data banks and for
other types of multicentered studies.
Another major program initiative is clinical trial research. OBFS is the
statistical coordinating center for several continuing or planned clinical
trials. With the Developmental Neurology Branch, NDP, it has established the
statistical coordinating center for a clinical trial that addresses the issue
of the potential loss of cognitive function in children who have febrile
seizures and are treated with phenobarbital.
OBFS participated in the design of a clinical trial on the efficacy of
spinal manipulative therapy as a treatment for musculo-skeletal dysfunction on
the performance of athletes, in collaboration with the Acting Director, NINCDS,
and Yale University.
OBFS has been actively consulting on a number of proposed clinical
trials. The most active area for potential clinical trials is for new thera-
pies for multiple sclerosis. OBFS has provided consultation and statistical
guidance to investigators at Albert Einstein Medical College in developing
clinical trials for COPOLYMER I. Pilot studies suggest that COPOLYMER I bene-
fits both exacerbating-remitting and chronic progressive multiple sclero-
sis.
OBFS has provided statistical consultation for other clinical trials of
therapy for multiple sclerosis, including plasmapheresis at Childrens Hospital
in Boston, and methylprednisolone and azathioprine at UCLA. There will be an
OBFS representative on the Safety Monitoring Committees of the COPOLYMER I and
the plasmapheresis trials.
2-OBFS/OD
In anticipation of further collaboration in clinical trials, for which
OBFS would provide data management, project coordination, computer support
and statistical analysis, OBFS has planned an external operations center to
support the OBFS statisticians in these collaborative projects.
In addition, an innovative computer and data management system has been
developed by OBFS staff. This system utilizes the Hewlett-Packard minicomputer
at OBFS as well as the DCRT computers, for checking eligibility of patients for
entering a trial, registering them and randomly allocating patients to treat-
ments. The system improves the efficiency of data entry and management, ascer-
tainment of patient status, data tracking and the production of charts, tables
and reports on the progress of the trial. Current OBFS activity on the system
includes enhancements in the area of quality assurance and simplifying trans-
mission of data from the OBFS mini-computer to DCRT for access to extensive
statistical software. The system currently provides support for a study of
Medline usage funded by the Communicative Disorders Program (CDP) of NINCDS,
and for the trial of barbiturate therapy and cognitive changes in chil-
dren.
Pain is the focus of a number of investigations which are under way. OBFS
has initiated a meeting of pain experts to determine whether there has been
sufficient progress in the methodology for the assessment and measurement of
pain to warrant the sponsorship and organization of a symposium on that sub-
ject. The Intramural Program and all of the Extramural programs of NINCDS are
collaborating with OBFS in planning and funding this meeting.
OBFS prepared a report based on an investigation of sensory decision the-
ory measures for deriving psychophysical measurements of pain. A study of the
statistical characteristics of the temporal patterns of persistent, episodic
pain such as migraine headache is currently being developed.
In collaboration with the Office of Analysis and Epidemiology, NCHS, OBFS
is evaluating the average and age-specific incidence rates of various chronic
pain syndromes, and investigating their association with epidemiologic factors.
For example, the relationship between incidence and prevalence rates and length
of illness due to headache has been examined, and a report has been prepared.
A study is currently being developed to evaluate the age-specific incidence of
neck-back pain and low back pain and their association with demographic,
psychological and medical care variables based on NCHS national surveys.
In collaboration with the Developmental Neurology Branch, NDP, an investi-
gation is under way to measure the relationship between migraine headache and
pregnancy, based on Perinatal Project data. Preliminary results indicate that
children of mothers with a history of migraine have a higher incidence of sei-
zures than do children of mothers free of migraine.
As a major initiative in the area of pain, the OBFS is engaged in a study
of severe and debilitating headache. The principal objectives of the study are
to (1) investigate risk and etiological factors associated with headache; (2)
develop classifications of headache; and (3) describe the magnitude and extent
of the headache problem in a geographically defined population. The survey
will be based upon telephone interviews of adults from a random sampling of
households located within the geographic area of study. In preparation for an
3-OBFS/OD
area survey of this disorder, a questionnaire, procedures for telephone inter-
viewing, and an operational classification of headache have been developed.
Several headache clinics are collaborating with DBFS in this effort. These
clinics have provided abstracts of the medical records of 400 clinic patients;
these patients are participating in telephone interviews about their headache
experience. Information elicited during the interviews will be compared with
that found in the abstracts.
Data from the National Multiple Sclerosis Survey indicate that as of
January 1, 1976, there were 123,000 reported cases of multiple sclerosis in the
conterminous United States (a rate of 58 per 100,000 inhabitants). The annual
incidence for the period 1970-1975 was estimated to be 8,800 (a rate of 4.2 per
100,000 inhabitants). Professor Robert P. Inman of the Wharton School examined
the consumption losses due to the disease. The estimated annual cost per pa-
tient, for 1976, was $6,527 or $800 million for all the reported cases. An
examination of the mobility data revealed that slightly over 50 percent of the
patients reported difficulty getting around indoors and outdoors, but 40 per-
cent reported no mobility problems. Nearing completion is an analysis of data
on the psychosocial factors that affect employment. This multiple sclerosis
study is being performed in collaboration with investigators from Albert
Einstein College of Medicine. Additionally, a brochure highlighting the find-
ings of the survey is being prepared, in cooperation with Dr. Emanuel Stadlan
of NDP.
A report on the findings from the National Survey of Intracranial Neo-
plasms is under review by the Stroke and Trauma Program and will be submitted
for publication.
An epidemiologic study of stroke incidence in three counties in southern
Alabama has been completed. The age-adjusted incidence rate for blacks was
almost twice that of whites. Two-thirds of the stroke cases had a history of
hypertension and one in five had a history of diabetes.
A study to test a three-step case-finding strategy for a national survey
of epilepsy has been completed. First, prescriptions for anticonvulsant drugs
were sampled at pharmacies. Second, physicians who wrote the prescriptions
were asked about the diagnoses of patients whose prescriptions had been selec-
ted for study. Third, some of the patients considered to be epileptic by the
physicians were interviewed briefly to find out about the number of different
anticonvulsant drugs taken and where the drugs were obtained. From preliminary
information, it appears that this case-finding strategy will have to be modi-
fied for use in a national survey since the combined nonresponse rate (phar-
macies, physicians, patients) was high. A final report on the study is forth-
coming.
A feasibility study of the Hospital Discharge Survey to develop a system
for the periodic collection of morbidity and clinical data from hospital rec-
ords has been completed. This study was conducted in collaboration with the
National Center for Health Statistics (NCHS). The study developed 15 clinical
algorithms for use in case ascertainment and classification for disorders of
interest to NINCDS, NHBLI, NCI, and NEI. The yield of acceptable cases from
the pertinent ICDA codes and the methodology for estimating the incidence and
prevalence of these disorders from the information were determined. The
4-OBFS/OD
results show that this methodology could be used for a system of collecting
periodic national data to study trends in neurologic disease rates.
The Copiah County Study, a joint effort of the OBFS, the United States
Bureau of the Census, and the University of Mississippi Medical Center, has
been completed. The study generated prevalence estimates for major neuro-
logical disorders in the biracial population of Copiah County, Mississippi. A
report has been published on the methodology of the study. Another is expected
to be the first published report on the prevalence of essential tremor for a
geographically defined population within the United States. Two other reports,
one on cerebral palsy, the other on stroke, are in preparation this
year.
The Senile Dementia Study is a collaborative effort of the OBFS, the
National Institute of Mental Health, and the Johns Hopkins University. It is
currently in the second phase of data collection, which involves reinterviewing
the cases approximately one year after their initial interview, to note changes
in their condition over the interval. During the first phase, 39 cases of
senile dementia were identified, given neurological examinations, and inter-
viewed. A control group was also interviewed.
The OBFS is working with the Division of Heart and Vascular Diseases,
NHLBI, in analyzing hearing data collected during Cycle 15 of the Framingham
Heart Study. The main objectives of this investigation are to (1) describe the
prevalence of hearing impairment in the Framingham cohort, by demographic
characteristics; (2) investigate the relationship between the severity of
hearing impairment and risk factors for hearing loss, such as noise exposure
and toxicity and (3) investigate possible relationships between hearing impair-
ment and cardiovascular risk factors and outcomes.
A study of the incidence and prevalence of multiple sclerosis in two
Colorado counties is in progress. This study involves researchers from OBFS
and the Rocky Mountain Multiple Sclerosis Center in Denver. Colorado is sus-
pected of having a higher prevalence of multiple sclerosis than would be ex-
pected, given the State's latitude. If the hypothesis of a higher prevalence
is borne out, then additional studies will be undertaken to seek possible
explanations.
The OBFS has launched an effort to publish a series of disease-specific
reports on neurological disorders. These reports will include data on the
incidence, prevalence, and mortality of the disorders, as well as recommenda-
tions for additional studies that need to be done. An investigator from the
University of Maryland is preparing the first report on Parkinson's
Disease.
A significant effort continues to be focused on the analysis of data from
the Collaborative Perinatal Project. Intensive studies are proceeding in the
areas of febrile seizures, neonatal seizures, convulsive disorders, cerebral
palsy, and maternal infection during pregnancy.
A multi-stage program is progressing to determine the optimal management
of children with febrile seizures. The consensus meeting held in 1980 delin-
eated several areas of needed research including (1) the usefulness of the EEC
in predicting later recurrence of seizures in children with a febrile seizure
5-OBFS/OD
and (2) the possible harmful side effects on cognitive function of administra-
tion of chronic phenobarbital to children with febrile seizures. In collabora-
tion with the Developmental Neurology Branch, NDP, OBFS has initiated two major
research studies to answer these questions: (1) the clinical trial of pheno-
barbital and (2) the Yugoslavian study of the predictive value of the EEG in
febrile seizures. In collaboration with the Neurological Disorders Program and
the American Medical Association, OBFS has engaged in a physicians' survey of
practice in the management of children with febrile seizures, a study which
also provides information regarding these questions.
A collaborative investigation of head injury was designed with OBFS and
the Departments of Neurosurgery at the University of Virginia and at the All-
India Institute of Medical Science in New Delhi. The proposal has been ap-
proved by the Government of India. It has been funded for three years with
PL480 rupees. The proposal will now enter the NIH peer review process. If
approved, the pilot phase will be a comparative study of the two head-injured
cohorts; the second phase will include clinical trials of therapy for head-
injured patients.
OBFS has initiated the development of a consortium of center grant and in-
dividual investigator grant proposals whose primary objective will be studies
of the neurological aspects of aging in Macaca mulatta primates. In collabora-
tion with NDP and the Grants Management Branch, OBFS is working with the pro-
posed grantees, the University of Puerto Rico, the Veterans Administration
Hospital in San Juan, and Dr. Donald Price and his colleagues at the Johns
Hopkins University, to generate a number of study proposals whose unifying
characteristic is the use of aging primates at the under-utilized Caribbean
Primate Research Center. The OBFS contribution will include the provision of a
statistical coordinating and data operations center for all of the study data
which are developed from the primate studies. A major objective of OBFS would
be to explore the association of data items across individual study boundaries.
For example, it might be fruitful to determine the association, if any, between
primate behavioral characteristics of aging as identified by the behavioral
group at the University of Puerto Rico, and pathological neurotransmitter
findings of Dr. Price and his associates. The Division of Research Resources
(DRR) is helping to identify DRR funded sources of aged primates which might be
secured and added to the present primate colony in Puerto Rico.
Intramural Program research collaboration continues to be an important
element of OBFS activities, and OBFS investigators participate fully in all
phases of the projects in which they are involved. The range and variety of
problems utilize the varied talents of the OBFS staff which, in addition to
mathematical statistics, include those of mathematics, epidemiology, demog-
raphy, survey statistics, physics and computer science. The latter two, for
example, are extensively relied upon for the work in computer-aided tomography.
There are 15 projects in which OBFS is currently collaborating with scien-
tists in the Intramural Research Program. They include a wide range of sub-
jects, such as methods for enhancement of computer-aided tomography, assessment
of regimens for Parkinson's disease, assessment of the potential teratogenic
effect of phenytoin and valproic acid, and the role of antiviral antibodies in
multiple sclerosis.
6-OBFS/OD
In the area of clinical trials, OBFS has collaborated with the Experimen-
tal Therapeutics Branch (IRP) on clinical studies of Parkinson's disease. Both
in-patient and out-patient clinical trials of new drugs or the new application
of standard drugs (e.g., lisuride, bromocriptine, pergolide) have been initi-
ated with Parkinson's disease patients. OBFS has been involved in the design
and analysis of these trials as well as in the monitoring of the accumulating
data and the analysis of adverse reactions.
Collaborative work with the Infectious Diseases Branch includes the devel-
opment of methods to account for variation for bioassay techniques, and the
determination of the role of viruses in multiple sclerosis. The latter activ-
ity includes case-control studies and a study of twins.
A study of cognitive, psychological, and clinical differences in twins,
discordant with respect to Parkinson's disease, is nearing completion. This
project is in the Section on Neuroepidemiology , with the Experimental Thera-
peutics Branch providing clinical evaluations, and OBFS is providing the sta-
tistical analysis of the data.
OBFS statisticians have also been active in the research and development
of statistical methods and theories to meet the needs of NINCDS in design of
experiments, analysis of data, and statistical modeling of biological processes
and phenomena. Current studies include methods of nonparametric regression,
determination of sample sizes for clinical trials with multinomial outcomes,
regression in Poisson data, sequential methods with early stopping, two-period
cross-over designs for Phase II clinical trials, regression methods for sur-
vival data, patient recruitment monitoring, ranking and selection methods,
case-control studies with unequal number of controls per case, and Markov
modeling of clinical features of Parkinson's disease.
OBFS maintains and fosters an active interest within NIH and elsewhere in
methodological issues in the application of statistics and computer science to
medicine. The Branch actively participates in the American Statistical Asso-
ciaion, the Biometric Society and the Association for Computing Machinery with
staff holding offices, acting as reviewers for the journals, organizing ses-
sions at meetings, making presentations at meetings, and publishing papers.
Two members of OBFS became Fellows of the American Statistical Association in
1982.
7-OBFS/OD
Office of Biometry and Field Studies
Bibliography
Anderson, D.W. , Schoenberg, B.S., and Haerer, A.F. "Racial differentials in
the prevalence of major neurological disorders: Background and methods of the
Copiah County Study." Neuroepidemiology 1: 17-30, 1982.
Bavim, H.M. and Rothschild, B.B. "The incidence and prevalence of reported
multiple sclerosis." Ann. Neurol. 10: 420-428, 1981.
Baum, H.M. "Stroke prevalence: An analysis of data from the 1977 National
Health Interview Survey." Public Health Rep. 97: 24-30, 1982.
Baum, H.M. and Goldstein, M. "A study of cerebrovascular disease type specific
mortality: 1968-1977." Stroke, in press.
Baum, H.M. and Rothschild, B.B. "Mobility restriction and multiple sclerosis."
Submitted to Arch. Phys. Med. Rehabil.
Bruckner, A., Lee, Y. J. , O'Shea, K.S., et al. "Teratogenic effects of valproic
acid and diphenylhydantoin on mouse embryos in culture." Submitted for publi-
cation.
Catane, R. , Richter, A., Lee, Y.J., et al. "Small cell lung cancer: Analysis
of treatment factors contributing to prolonged survival." Cancer, in press.
Dambrosia, J.M. and Greenhouse, S.W. , "Early Stopping for Sequential Restricted
Tests of Binomial Distributions." Biometrics, Accepted.
Eisler, T. , Dambrosia, J.M. and Calne, CD. Letter to the Editors: "Deprenyl
in Parkinson Disease." Neurology 31, 1981.
Ellenberg, J.H. and Nelson, K.B. "Recommendations for the Treatment of Febrile
Seizures: Their Efficiency vs. Epilepsy." In Febrile Seizures, edited by K.B.
Nelson and J.H. Ellenberg, pp. 97-102, Raven Press, 1981.
Ellenberg, J.H. and Nelson, K.B. "Predictions of Cerebral Palsy at Four Months
of Age." Developmental Medicine and Child Neurology, 1981, (with Editorial
comment ) .
Ellenberg, J.H. , Hirtz , D. , Nelson, K.B. "The Age of Onset of Seizures in
Young Children." Submitted for publication.
Ellenberg, J.H. Review of Clinical Trials by Schwartz, D. , Flamant, R. , and
Lellouch, J. Biometrics, December 1981.
Goldstein, M. and Chen, T.C., "The Epidemiology of Disabling Headache."
Advances in Neurology, Vol. 33, pp. 377-390, 1982.
Gross, C.R. and Dambrosia, J.M. "Quality Assurance for Clinical Data Banks."
In Proceedings of the Fifth Annual Symposium on Computer Applications in
Medical Care, November, 1981.
8-OBFS/OD
Haerer, A.F., Anderson, D.W. , and Schoenberg, B.S. "Prevalence of essential
tremor: Results from the Copiah County Study." Arch. Neurol. , in press.
Hirtz, D. , Nelson, K.B., Ellenberg, J.H. "Seizures following childhood immuni-
zations." Submitted for publication.
Kunitz, S.C., Fishman, I.G. , and Gross, C.R. "Attributes of An Optimal Data
Bank for Clinical Research: An Experience - Based Approach. " In Proceedings
of the Sixth Annual Symposium on Computer Applications in Medical Care, in
press.
Lee, Y.J. and Wesley, R.A. "Statistical Contributions to Phase II Trials in
Cancer: Interpretation, Analysis and Design." Seminars in Oncology, Vol. 8,
pp. 403-416, 1981.
Lee, Y.J. and Dudewicz, E.J. "Robust selection procedures based on vector
ranks." Accepted for publication in Statistics and Decisions.
Lee, Y.J. and Dudewicz, E.J. "Robust/Nonparametric Selection Methods in
Blocked Data: Relative Efficiency Study." Submitted for publication.
Lee, Y.J. "Interim Recruitment Goals in Clinical Trials." Submitted for pub-
lication.
LeWitt, P. A., Gopinathan, G. , Ward, CD., Dambrosia, J.M. , Durso, R. , and
Calne, D.B. "Lisuride versus Bromocriptine Treatment in Parkinson Disease" A
double-blind study." Neurology 32, 1982.
LeWitt, P., Ward, C. , Larsen, A., Dambrosia, J. and Calne, D. "Comparison of
Pergolide and Bromocriptine Therapy in Parkinsonism." Submitted for publica-
tion.
Nelson, K.B. and Ellenberg, J.H. "The Role of Recurrences in Determining
Outcome in Children with Febrile Seizures." In Febrile Seizures, edited by
K.B. Nelson and J.H. Ellenbewrg, pp. 19-25, Raven Press, 1981.
Nelson, K.B. and Ellenberg, J.H. "Apgar Scores as Predictors of Chronic Neuro-
logic Disability." Pediatrics, Vol. 68, pp. 36-44, 1981.
Nelson, K.B. and Ellenberg, J.H. "Febrile Seizures." In Childhood Epilepsy,
PSC Publishers, Littleton, Massachusetts, 1982.
Nelson, K.B. and Ellenberg, J.H. "An Epidemiologic Approach to the Problems of
Cerebral Palsy." Excerpta Medica, Neurology and Neurosurgery, 1982.
Nelson, K.B. and Ellenberg, J.H. 'Maternal Seizure Disorders, Outcome of Preg-
nancy, and Neurologic Problems in Children." Neurology, 1982.
Nelson, K.B. and Ellenberg, J.H. "Obstetric Conditions, Apgar Scores and
Neurologic Outcome." Submitted for publication.
Nelson, K.B. and Ellenberg, J.H. "Children Who Outgrew Cerebral Palsy."
Pediatri c s , May 1932.
9-OBFS/OD
Nelson, K.B. and Ellenberg, J.H. (ed.) Febrile Seizures, Raven Press, Inc.,
1981.
Nichols, B. , Rush, R. , Moss, P., Edelstein, S. , Fishman, I. and Kunitz, S.
"Data Entry for Multiple Center Data Banks - A Microprocessor Approach" In
Proceedings of the Fifth Annual S3rmposium on Computer Applications in Medical
Care, pp. 307-321, November, 1981.
Sever, J.L. , Madden, D.L. , Ellenberg, J.H. , Tzan, N.R. , Edmonds, D.M. "Toxo-
plasmosis: Maternal and Pediatric Findings in 23,000 Pregnancies." Submitted
for publication.
Simon, R. and Lee, Y.J. "Nonparametric confidence limits for survival proba-
bilities and the median." Cancer Treatment Reports, Vol. 66, pp. 37-42, 1981.
Staquet, M. , Rozencweig, M. , Lee, Y. J. , and Muggia, F.M. "Methodology for the
assessment of new dichotomous diagnostic tests." J. Chronic Diseases, Vol.
34, pp 599-610, 1981.
Ward, CD., Sanes, J.N. , Dambrosia, J.M. , and Calne, D.B. "Methods for Evalu-
ating Treatment in Parkinson Disease." In Experimental Therapeutics of Move-
ment Disorders, edited by S. Fhan, I. Shouloon, and D. Calne, Raven Press,
1982.
Weiss, G. , Talbert, A., and Brooks, R. "Use of Phantom Views to Reduce CT
Streaks." Journal of Physics in Medicine and Biology. Accepted.
Weiss, W. "Common Problems in Designing Therapeutic Trials in Chronic
Disease." Neurology, Accepted.
10-OBFS/OD
OFFICE OF BIOMETRY & FIELD STUDIES
Section on Mathematical Statistics
Consultation with IRP
Dr. John Barranger, Developmental and Metabolic Neurology Branch: Copper ab-
sorption in Menke's Disease.
Dr. Christopher Ward, Experimental Therapeutics Branch: Study of Parkinson's
Disease in Twins and Study of Objective Measurements of Movement Disorders.
Dr. Rodney Brooks, Neuroradiology and Computed Tomography Section: Surgical
Neurology Branch, Enhancement of CAT and PET scanning techniques and optimiza-
tion of PET Scanner Software.
Dr. John L. Sever, Infectious Diseases Branch: Study of Toxoplasmosis in preg-
nant women, study of relation of serological infection during pregnancy to out-
come in children.
Dr. Roswell Eldridge, Section on Neuroepidemiology: Parkinson Twin Studies.
Dr. George H. Weiss, Physical Sciences Laboratory, DCRT, the Use of Phantom
Views to Diminish an Artifact in CT Scans.
Dr. William B. Marks, Intramural Research Program, NINCDS: Statistical analy-
sis methods in neuronal spike data.
Dr. William T. London, Infectious Diseases Branch, IR, Estimation of Sample
Sizes for Testing Positive Antibody Titers in Macacas on Cayo Santiago.
Dr. Lata Nerurkar, Infectious Diseases Branch, IR, Comparison of ELISA and IHA
methods for detecting infection.
Dr. Anita Chu, Infectious Diseases Branch, IR, Reye's Syndrome Study.
Dr. Elizabeth Barbehenn, Laboratory of Neural Control, Study of Frog Retina.
Dr. Isabel Shekarchi, Infectious Diseases Branch, Evaluation of the ELISA method
of tioassay.
Dr. Christy Ludlow, Communicative Disorders Program, Jitter as a function of
fundamental frequency and other factors.
Dr. Joann^. Woyciechowska, Infectious Diseases Branch, IR, Antiviral antibodies
in Multiple Sclerosis.
Dr. Peter LeWitt, Experimental Therapeutics Branch, Clinical Trial of Pergo-
lide and Bromocriptine in Parkinson's Disease.
Dr. William London, Infectious Diseases Branch, IR, Allometric Relationships in
Four Species of Primates.
11-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry & Field Studies, OD, NINCDS
Fiscal Year 1982
1. Univ. of Maryland (NOl-NS-2-2302)
2. Univ. of S. Ala. (NOl-NS-2-2397)
3. Boston Univ. (NOl-NS-2-2398)
4. ffichael Reese Hospital & Medical Center (NOl-NS-2-2399)
Title: Full Phase Stroke Data Bank
Contractor's Principal Investigators: 1. Dr. Thomas Price
2. Dr. Jay Mohr
3. Dr. Philip Wolf
4. Dr. Louis Caplan
Current Annual Level FY' 82: 1. $185,097
2. $186,578
3. $174,029
4. $168,467
Objectives : The primary objective of this project is to implement a full phase
computerized interactive data bank network which will contain uniform longitu-
dinal data on stroke patients to aid both research and patient management. This
is a collaborative project involving four separate medical centers which collect
data, a data base management center to store and manipulate the data and staff
at OBFS who have the responsibility for data analysis.
Major Findings: This project will benefit from the experience gained in the
Pilot Data Bank Network in Stroke, which produced a uniform vocabulary of data
elements including diagnostic sub-classifications of Stroke, test results, med-
ical and surgical therapy, complications, and measures of stroke deficit and
recovery.
Significance to the NINCDS Programs and Biomedical Research: The Full Phase
Stroke Data Bank Network is important because it will provide a resource of high
quality data on the clinical course of stroke. The project serves as a proto-
type for national data bank networks for other neurological disorders.
Proposed Course of the Project: This is the first year of a five year project.
The initial course will include determination of research questions to be inves-
tigated, and design of forms to collect the data. The experience of the Pilot
Data Bank Network in Stroke will be very useful to the Full Phase Project, but
the investigators will also be innovative in their approach to the best research
use of the system.
12-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry & Field Studies, OD, NINCDS
Fiscal Year 1982
1. Univ. of Maryland (NOl-NS-9-2302)
2. Univ. of S. Ala. (NOl-NS-8-2397)
3. Duke Univ. (NOl-NS-8-2396)
4. Boston Univ. (NOl-NS-8-2398)
Title: Pilot Data Bank Network in Stroke
Contractors' Principal Investigators:
Current Annual Level FY '82;
1. Dr. Thomas Price
2. Dr. Jay Mohr
3. Dr. Albert Heyman
4. Dr. Philip Wolf
1. $ 7,500
2. no cost
3. no cost
4. no cost
Objectives: The primary objective of this project is to develop a computerized
interactive data bank network which will contain uniform, longitudinal data on
stroke patients to aid both research and patient management. This is a collab-
orative project involving four separate medical centers which collect data, a
data base management center to store and manipulate the data and staff at OBFS
who have the responsibility for data analysis. This project has met its objec-
tives and will continue into a full-phase with competitive awards.
Major Findings: This project has produced a uniform vocabulary of data elements
including test results, medical and surgical therapy, complications, and meas-
ures of stroke deficit and recovery. The collaborating hospital centers have
collected data on approximately 1,000 stroke patients.
Significance to the NINCDS Program and Biomedical Research: The Pilot Data Bank
Network in Stroke is important because it demonstrated the feasibility and util-
ity of having medical centers collaborate to provide a resource of high quality
data on the clinical course of stroke. This project will serve as a prototype
for a national data bank network for other neurological disorders.
Proposed Course of the Project: This project has achieved its primary objec-
tives and have been completed. Currently manuscripts describing the data bank
and its findings are being prepared for publication.
13-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
1 . Univ. of Texas-Galveston
and Baylor Univ. Medical
College
(NOl-NS-9-2308)
2. Univ. of Cal. in San Diego (NOl-NS-9-2309)
3. Medical College of Virginia (NOl-NS-9-2307)
4. Univ. of Virginia (NOl-NS-9-2306)
Title: Pilot Data Bank Network in Traumatic Coma
Contractors' Principal Investigators
1. Dr. Howard Eisenberg
2. Dr. Lawrence Marshall
3. Dr. Donald Becker
A. Dr. John Jane
5. Dr. Robert Grossman
6. Dr. Kamran Tabaddor
Current Annual Level FY' 82
1. $52,000
2. 43,376
3. 41,000
4. 33,000
Objectives; The primary objective of this project is to develop a computerized
interactive data bank network for traumatic coma patients. This data bank will
be used for clinical research and patient management.
Major Findings: This data bank project has developed and is utilizing a uniform
vocabulary to collect patient data which will include the details of the acci-
dents, test results, therapies and outcomes. The Glasgow Coma Scale is part
of this vocabulary. Data from 681 severely head injured patients were collected
from January 1980 to February 1982 and data analysis is continuing.
Significance to the NINCDS Program and Biomedical Research; The Traumatic Coma
Data Bank Project is important for several reasons. Longitudinal data on
severely head injured traumatic coma victims were collected at six centers using
uniform definition and procedures. This information will provide a large body
of high quality data for clinical research on the factors influencing survival
and quality of life following severe head injury. In addition, the data bank
will serve as an efficient mechanism for collecting, storing and retrieving
the information collected on a single patient and groups of patients. The
number of therapies and monitoring devices commonly utilized during the acute
phase of managing traumatic coma necessitates a highly organized data handling
capacity.
14-OBFS/OD
Proposed Course of the Project; This was a three-year collaborative pilot pro-
ject involving six centers which collected patient data, a Data Bank Maintenance
Center, and OBFS staff which provided systems support, in collaboration with
the Principal Investigators. During the first stage of its operation, effort
was focused on refining the uniform vocabulary and developing data collection
methods. The second stage was a test phase during which the vocabulary and
procedures for collection, entry and retrieval were implemented on a trial
basis. In the third stage, data were collected, entered, and subjected to a
wide variety of data quality enhancement efforts. Currently, analyses of the
data are being performed.
15-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
Stanford Univ. (NOl-NS-8-2390)
Title; Data Bank Maintenance Center for Pilot Data Bank Network
Projects in Stroke and Traumatic Coma
Contractor's Project Director: Dr. James F. Fries
Current Annual Level FY' 82: $96,000
Objectives; TOD-ARAMIS, renamed the "Data Bank Network", was the Data
Bank Maintenance Contractor (DBMC) for the Pilot Projects to establish Data
Bank Networks for Stroke and Traumatic Coma. During the three and one-half
year contract period, the Data Bank Network system provided the host computer
for these projects for data editing, storage, and retrieval, as part of the
Time-Oriented Data Base (TOD) system. Data collected at pilot centers and
entered into separately maintained Stroke and Coma data banks are available
for retrieval within and among the pilot centers.
Major Findings: The Data Bank Network has created the computer schema for the
Stroke and Coma Data Bank uniform vocabularies and developed methods for enter-
ing these data, as transmitted from the microprocessors located in each hospital,
into the central data bank. The schema is a dictionary of data elements con-
tained in the patient chart. Data entry personnel at the ten clinical centers
have been trained and several retrieval programs have been developed and uti-
lized for preliminary analyses and using standard statistical packages on the
stored data.
Significance to the NINCDS Program and Biomedical Research: The Data Bank
Maintenance Center is crucial to the success of the ten data banks which com-
prise the Pilot Data Bank Networks for Stroke and Traumatic Coma. It serves
as the central data repository, maintains data integrity and provides program-
ming and systems support to the ten centers. The availability of this database
computer software has made these data bank networks feasible without extensive
investment in new programming activity. Applying this system to stroke and
traumatic coma is a first step in the development of an optimal system for a
national data bank network for neurological disorders.
Proposed Course of Contract: The Maintenance Center is now focusing its activ-
ities on storage and retrieval for Stroke and Coma. The Coma data bank con-
tractors have recently revised their vocabulary; the coma schema has been
reconstructed to reflect the current vocabulary; and efforts are under way to
transform existing data to the new format, where possible. Data are being
entered at each center and are analyzed for errors by the automatic data check
programs. This project has been completed and data is being transferred to
DCRT.
16-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
RESEARCH TRIANGLE INSTITUTE (NOl-NS-8-2383)
Title: Test of Study Design and Pilot Study for a National Survey
of Epilepsy
Contractor's Project Director; Dr. Fred Bryan Jr.
Current Annual Level: $33,536
Objectives: This project was initiated to develop a new casefinding approach
for ascertaining the frequency of cases of epilepsy. The previously used
methods have serious deficiencies, and this proposal seeks to remedy them. The
goal is to use pharmacies which fill prescriptions for anticonvulsive drugs, to
lead to the physicians providing care and thus to the epileptics. In a national
survey, estimates of the scope of the epilepsy problem could be obtained for the
U.S. population by using techniques of probability sampling.
Maj or Findings : The design test has been completed by the Contractor. The
pilot study will be completed this year.
Significance to the NINCDS Program and Biomedical Research: Morbidity surveys
of relatively rare disorders are difficult to carry out for the U.S. population.
One fundamental problem is that adequate numbers of cases for meaningful
analyses may not be included in the sample of individuals selected for study due
to stringent requirements for sampling a population. With epilepsy, the problem
is compounded because of the perceived social stigma associated with having the
disorder. The approach being tested in this contract will, if feasible, yield a
cost-effective strategy for the sampling of epileptics who take anticonvulsive
drugs. Furthermore, the privacy of the persons included in the study will be
safeguarded to a great extent. If this strategy proves successful, a national
survey of epileptics could be undertaken which would be invaluable to NINCDS and
other organizations responsible for the planning of programs for epilepsy.
Proposed Course of the Project: The project is divided into two parts: a
design test and a pilot study. The design test is on a small scale, and its
chief purpose is to lead to the development of methodology for data collection
from pharmacies and physicians and to aid in the design of the pilot study. The
pilot study is on a larger scale, and its purpose is to resolve methodological
issues which are raised by the investigators or were apparent after the design
test. In addition, the pilot study will serve as a dry run for the procedures
of the main survey. After the report on the pilot study has been studied
carefully, a decision will be made on whether to embark on a national survey of
epilepsy.
17-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
WESTAT, INC. (NOl-NS-4-2336)
Title: Survey of Intracranial Neoplasms
Contractor's Project Director; Thomas G. McKenna
Current Annual Level: $ 0
Objectives; The primary objective of this survey is to produce national es-
timates and accompanying measures of precision for the incidence, prevalence,
and economic costs of intracranial neoplasms.
Major Findings; The main survey has been completed and the findings have been
presented to NINCDS by the contractor in the form of a final report. The report
has been reviewed and additional data have been collected from the hospitals and
certain analyses have been redone to improve the quality of the findings. The
clinical, epidemiologic and economic findings will be presented in articles
which will be submitted for publication in professional medical journals.
Significance to the NINCDS Program and Biomedical Research; This survey is
important for two reasons. First, it provides national estimates of the in-
cidence, prevalence, and economic costs of intracranial neoplasms. These
estimates are especially useful to NINCDS for purposes of program planning and
allocation of funds. Second, the survey will demonstrate to health investi-
gators the value of probability sampling as a tool in sample selection.
Probability sampling is the only general method available which can provide a
measure of the precision of an estimate. Though this method is widely used in
other areas, it is largely neglected in health studies. This survey, and the
others of the NINCDS Survey Program, will demonstrate that probability sampling
is both desirable and feasible for certain types of health studies.
Proposed Course of the Project; The main study has been completed and the final
report was submitted by the contractor. After careful examination of the final
report it became evident that certain ICDA categories needed to be examined in
order to validate the findings before publication. Some of the participating
hospitals furnished photocopies of selected patient records and the data has
been reanalyzed. The clinical and epidemiologic findings have been prepared in
an article which is ready to be submitted for publication in a neurological
journal. This study has been completed.
18-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
UNITED STATES BUREAU OF THE CENSUS (YOl-NS-7-0031)
UNIVERSITY OF MISSISSIPPI (NOl-NS-7-2357)
Title; Survey of Major Neurological Disorders in Copiah
County Mississippi
Contractor's Project Director; Mr. Robert W. Mangold
(Bureau of the Census);
Dr. Armin F. Haerer (University of Mississippi)
Current Annual Level; $0 (Bureau of the Census);
$0 (University of Mississippi)
Objectives; The primary objective of the proposal is to establish the
prevalence of six major neurological and developmental disorders
(cerebrovascular disease, convulsive disorders, cerebral palsy, psychomotor
delay, Parkinson's disease, and dementia) in a well-defined population of
southern blacks and whites. A secondary objective is to evaluate the
sensitivity and specificity of certain screening questions by means of an item
analysis at the close of the study. This analysis is needed because effective
screening questions will be used in other morbidity surveys (e.g., the Health
Interview Survey of NCHS).
Major Findings; Preparation of reports is continuing. Presentations are being
scheduled for various professional meetings.
Significance to the NINCDS Program and Biomedical Research; At present, there
are no adequate data on the prevalance of the six disorders of interest among
southern blacks and whites in the United States. A number of studies suggest
that stroke is more common among the black population. Mortality data and a few
morbidity studies suggest that Parkinson's disease is less common among blacks.
A biological explanation of this observation is that both melanin and dopamine
are involved in the same metabolic pathway. Dopamine-deficiency in the basal
ganglia has been found in patients with Parkinson's disease and is the rationale
for the treatment of this condition with L-dopa. Blacks have a higher
concentration of dopamine in the basal ganglia than whites which could explain a
lower frequency of Parkinson's disease. On the other hand, it may be that
blacks with this condition do not seek medical care or receive inadequate care.
Mortality tabulations, with all of their biases, suggest that blacks have a
predominance of epilepsy and cerebral palsy, but this requires confirmation with
morbidity data. The magnitude of the dementia problem has not been studied in
any United States population and Copiah County will provide some indication as
to whether there is a racial and sex differential in the frequency of this group
of conditions.
19-OBFS/OD
Proposed Course of the Project: The field operations for the main study were
divided into two types of operations. The first was a household screening
operation which was conducted by the Bureau of the Census. Residents of the
study area were screened in their homes by means of a questionnaire administered
by lay interviewers who were trained and supervised by the Bureau of the Census.
The second type of operation was the examination of persons suspected of having
one or more of the disorders of interest on the basis of responses given to
questions from the screening questionnaire. The University of Mississippi
provided senior, board-certified neurologists to accomplish the neurological
examinations and to record the medical findings on forms designed especially for
this study. After the close of field operations, the data were sent to the
Bureau of the Census for processing. Staff of NINCDS, with the assistance of
the Project Director from the University of Mississippi, are now analyzing the
data and preparing scientific reports.
20-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
WESTAT, INC. (NOl-NS-7-2379)
NATIONAL CENTER FOR HEALTH STATISTICS (2-YO1-NS-9-0043-05)
Title; National Hospital Survey of Disease
(formerly Comprehensive Disease Statistics Survey)
Contractor's Project Director: Westat, Inc. - Dr. Anita Schroeder
NCHS - Dr. Monroe Sirken
Current Annual Level: Contractor - $ 0
NCHS - 20,000
Objectives: The objectives are to test the feasibility of obtaining hospital
incidence and prevalence data for cases identified from abstracted hospital
records of a number of neurological and other disorders, from a redesigned
Hospital Discharge Survey of the NCHS. A key objective of a successful study
would be to develop a survey program that would permit the annual collection
of data on these disorders in order to develop trends of their incidence and
prevalence.
The national sample of short-stay hospitals would provide a stable base for
special studies. These studies would include methodological problems such as
multiplicity. It would also provide an unbiased sample of patients for periodic
studies of special interest such as costs of illness, degree of disability,
duration of illness, etc. Comparability of data collection methods, and
protocols from the same sample of short-stay hospitals, would also permit
comparison across disease lines.
Major Findings: The Feasibility Study has been conducted in a sample of 27
hospitals. The data have now been analyzed and individual disease reports
are being prepared, as well as the final report covering the methodological
issues. NCHS has been involved in this cooperative effort with NINCDS and
has worked on many methodological and statistical problems of the survey.
Significance to the NINCDS Program and Biomedical Research: NINCDS has been
conducting a program of surveys of neurological disorders. There is a need
to consider a more comprehensive approach to the collection of disease
statistics. First, there is a considerable degree of redundancy in the
present approach, both within NINCDS, and, probably, across Institute
boundaries. Redundancy leads to higher than necessary costs associated with
the collection of disease statistics data. Second, the present approach
leads to delays in obtaining current information, since there are a limited
number of surveys which can be conducted at any one time. Third, the methods
and protocols used by each contractor differ and this affects the comparability
of data across disease lines. Fourth, and perhaps most important, these data
provide planning information based on a limited time period, when in fact trend
data, obtained on an annual, prospective basis, would better serve the program
planning and program evaluation functions.
21-OBFS/OD
The development of a comprehensive system for the collection of disease
statistics on a wide variety of diseases would be of great value to NINCDS and
other NIH Institutes, for it would eliminate the four above-mentioned major
problems.
This proposal would establish a cooperative and joint relationship between NCHS
and NINCDS, and would provide for an NCHS collection of national health
statistics of considerable interest to NINCDS, and potentially, to other NIH
Institutes. It would, to the extent that incidence and prevalence data can be
obtained from records at short-stay hospitals, supplant NINCDS data collection
efforts. NINCDS would continue to analyze the data collected to meet its own
program planning needs.
Proposed Course of the Project: In the Feasibility Study the contractor was
responsible for the field work, data collection, and processing of the data.
The disease algorithms were prepared by NINCDS staff with the aid of medical
consultants and other participating NIH Institutes. The development of the
sampling plan, counting rules, and selection of the participating hospitals was
undertaken by the National Center for Health Statistics, under a separate
interagency agreement.
After the final report of the Feasibility Study has been received
and reviewed, a determination will be made as to what will be the next
steps leading to the main National Study.
22-OBFS/OD
CONTRACT NARRATIVE
Office of Biometry and Field Studies, OD, NINCDS
Fiscal Year 1982
NATIONAL INSTITUTE OF MENTAL HEALTH (lYOl-0-0004-00)
Title; EGA Dementia Supplement
Contractor's Project Director; William Eton, Ph.D.
Current Annual Level; $175,000
Objectives; The study will identify a group of demented individuals who are
non-institutionalized and the type of dementia will be ascertained by means of a
medical examination. An estimate of the social and economic costs will also be
generated.
Major Findings: None. The data are still being collected.
Significance to the NINCDS Program; As the population of this nation ages , the
dementias will become an increasing medical problem. There are currently no
reliable data on the cost of these disorders and this information is needed to
assist in future health planning efforts.
Proposed Course of the Project; This project is an add-on to an existing NIMH
program of mental health surveys. After an initial screening for cognitive
disability, the subjects who are disabled will be given a medical examination.
A close relative or friend of those with verified dementias will be used to help
establish the history of the disease and estimate the social and economic costs
to the affected individual and their friends or relatives.
23-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02238-06 OBFS
PERIOD COVEREI
QVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Pilot Data Bank Project Network in Stroke
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Selma C. Kunitz, Head, Computer Applications Section, OBFS
OD, NINCDS
Other: Cynthia Gross, Ph.D., Biostatistician, CAS, OBFS, NINCDS
Barbara Nichols, Programmer, CAS, OBFS NINCDS
Sylvia Edelstein, Systems Analyst, CAS, OBFS, NINCDS
James Dambrosia, Ph.D., Mathematical Statistician, SMS, OBFS, NINCDS
Irene Fishman, M.A. , Statistician, CAS, OBFS, NINCDS
Dr. Albert Heyman, Duke University Medical Center
Dr. Jay Mohr, University of South Alabama College of Medicine
Dr. Thomas Price, University of Maryland School of Medicine
Dr. Philip Wolf, Boston University Medical Center, School of Medicine
COOPERATING UNITS (if any)
Duke University Medical Center, Durham, NC; Univ. of Maryland School of
Medicine, Baltimore, MD; University of South Alabama, College of Medicine,
Mobile, Ala.; Boston University Medical Center, Boston MA
Lab/branch
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
2.0
OTHER:
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (a1 ) MINORS ^ (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The objectives of the Pilot Stroke Data Bank were: a.) to develop a uni-
form method of data collection utilizing standard clinical nomenclature and
data collection methods to obtain patient histories, diagnosis, treatment
and outcome data in the course of routine care; b.) to implement an inter-
active data bank network enabling the pooling of clinical data among insti-
tutions for collaborative inter-institutional studies and to provide rapid
access to large quantities of clinical data; and c.) to demonstrate the
feasibiity of such a network, including the computer aspects, collabora-
tion among a number of institutions, to serve as a model for neurological
diseases and disorders. This project has met its immediate objectives.
The collected data from this pilot on over 1100 stroke patients are being
analyzed for studies of stroke course and diagnosis. The pilot project
has been completed.
PHS-6040
(Rev. 2-81)
24-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02408-04 OBFS
PERIOD^c^o^Ef^ED^ 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Clinical Databanks As a Resource for Epidemiologic Research
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Cynthia Gross, Ph.D., Biostatistician
Computer Applications Section, OBFS, OD, NINCDS
Other: Selraa C. Kunitz, Head, Computer Applications Section,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
lab/branch . ^ „ . , . , ,
Office of Biometry and Field Studies
Computer Applications Section, OBFS, OD, NINCDS
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.3
PROFESSIONAL:
.3
OTHER:
.0
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
B (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Much has been written on the use of observational studies in epidemiolog
ical research. It will be necessary to apply many of the same epidemiologic
techniques used in conventional observational studies to the clinical data
bank. Work on determining which epidemiologic approaches are most appro-
priate for use with clinical data banks has begun in conjunction with the
Pilot Stroke and Traumatic Coma Databank Networks (N01-NS-8-2309 , 6, 7,
8; NOl-NS-9-2302, 96, 97, 98). The current focus of this project has
been quality assurance methods for use in multicentered clinical data banks.
PHS-6040
(Rev. 2-81)
25-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02493-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Stroke Diagnosis: The NINCDS Data Bank Algorithm
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.'s: Selma Kunitz, Head, Computer Applications Section, OBFS, NINCDS
Jay P. Mohr, Neurologist, University of S. Alabama College of
Medicine
Carlos Kase, Neurologist, University of S. Alabama College of
Medicine
Cynthia Gross, Ph.D., Biostatistician, CAS, OBFS, NINCDS
James Dambrosia, Ph.D., Mathematical Statistician, SMS, OBFS,
NINCDS
Other: None
COOPERATING UNITS (if any)
Departments of Neurology: Boston University, University of South Alabama,
University of Maryland and Duke University
lab/branch
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.15
PROFESSIONAL:
.15
CHECK APPROPRIATE BOX(ES)
1 (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
In conjunction with the NINCDS Pilot Stroke Data Bank Network (ZOl NS
02238-06 OBFS) a diagnostic classification schema for strokes was devised
which consisted of cerebral pathology, vascular pathology, location, diagnos-
tic source and diagnostic role. Approximately 1,100 stroke patients have been
classified by this algorithm and the results are being analyzed for publica-
tion.
PHS-6040
(Rev. 2-81)
26-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02492-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Data Support for Diagnostic Algorithms of Stroke
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J. P. Mohr, Head, Department of Neurology, University of South
Alabama
C. Kase, Department of Neurology, University of South Alabama
J.M. Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
Others: I. Fishman, Statistician, Computer Applications Section, OBFS,
OD, NINCDS
S. Kunitz, Chief, Computer Applications Section, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Department of Neurology, Boston University, Department of Neurology and Neuro-
surgery, University of Maryland; Department of Neurology, Duke University;
Dept. of Neurology, Univ. of South Alabama; Medical Center Stanford Univ.
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.20
PROFESSIONAL:
.15
,05
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Pilot Stroke Data Bank project has developed operational diagnostic
algorithms for the classification of stroke type. This study utilizes data
from the Stroke Data Bank to measure the operational uniformity and consis-
tency of the application of the diagnostic algorithms to patients entered
at the four participating stroke centers. Identification of factors common
within a stroke type as well as factors that differ between stroke types
provides a means for enhancement and verification of the algorithms.
PHS-6040
(Rev. 2-81)
27-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02491-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Activities of Daily Living Following Stroke
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: P. Wolf, Department of Neurology, Boston University
J. Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
Others: I. Fishman, Statistician, Computer Applications Section, OBFS, OD,
NINCDS
S. Kunitz, Chief, Computer Applications Section, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Dept. of Neurology, Boston University; Dept. of Neurology and Neurosurgery,
Univ. of Maryland; Dept. of Neurology, Univ. of South Alabama; Dept. of
Neurology, Duke Univ.; Medical Center, Stanford Univ.
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.25
PROFESSIONAL:
.20
,05
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study attempts to establish the scores associated with activities
of daily living as a measure of stroke outcome. This study is a component
of the Pilot Stroke Data Bank Project. The influence of factors such as
medical complications, age, site and type of lesion, on the stroke course
and subsequent level of activities of daily living and performance and
placement class of the patients will be examined at specific points in
time. Each patient is expected to have a minimum of two years of follow-
U£.
PHS-6040
(Rev. 2-81)
28-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02340-05 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Pilot Data Bank Network Project in Coma
NVESTIGATORS AND ALL OTHER
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P,I.: Selma C. Kunitz , Chief, Computer Applications Section, OBFS, CD, NINCDS
Other: James M. Dambrosia, Ph.D., Mathematical Statistician, SMS, OBFS, NINCDS
Cynthia Gross, Ph.D., Biostatistician, CAS, OBFS, NINCDS
Irene Fishman, M.A. , Statistician, CAS, OBFS, NINCDS
Sylvia Edelstein, Systems Analyst, CAS, OBFS, NINCDS
Barbara Nichols, Programmer, CAS, OD, NINCDS
Dr. Lawrence Marshall, University Hospital at San Diego, CA
Dr. Howard Eisenberg, University of Texas Medical Branch at Galveston, TX
Dr. John Jane, Univ. of Virginia, Charlottesville, VA
Dr. Donald Becker, Medical College of Virginia, Richmond, VA
Dr. Robert Grossman, Baylor University, Houston, Texas
Dr. Kamran Tabaddor, Albert Einstein Medical College, Bronx, NY
COOPERATING UNITS (if any) University Hospital at San Diego, CA; University of Texas
Medical Branch at Galveston, Texas; University of Virginia Medical Center,
Charlottesville, VA; Medical College of Virginia, Richmond, VA; Albert Einstein
School of Medicine, Bronx. N.Y. ; Baylor School of Medicine, Houston, TX
lab/branch
Office of Biometry and Field Studies
SECTION
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
2.0
OTHER:
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS 0 (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A Pilot Traumatic Coma Data Bank Project has been implemented with the
objectives of developing common data collection methods and a uniform clinical
vocabulary to insure inter-center comparability for the collection of accurate
data for multicenter studies of severe head injuries. This is a demonstration
project intended to provide guidelines and protocols for expansion to addi-
tional centers and other neurological disorders. The data collection in the
pilot has focused on refinement of measures of outcome following head trauma,
comparing primary brain injury characteristics (accident details, injury types
and location) with outcome, and exploring the impact of secondary insults to
the brain (shock, hypoxia, elevated intracranial pressure) on outcome.
PHS-6040
(Rev. 2-81)
29-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02516-01 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Traumatic Coma: Epidemiological Characteristics
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Pi's: Cynthia Gross, PhD, Biostatistician, CAS,OBFS, NINCDS
Selma C. Kunitz, Head, CAS, DBFS, NINCDS
Other: Margaret Meadows, Statistical Assistant, CAS, OBFS, NINCDS
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
SECTION
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.25
PROFESSIONAL:
.20
.05
CHECK APPROPRIATE BOX(ES)
K (a) HUMAN SUBJECTS
D (al) MINORS ^ (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The pilot Traumatic Coma Data Bank has collected information on
681 patients with severe head injuries, drawn from six centers in the
United States. These data are being analyzed to identify patterns
of injury and type of accident as they vary from center to center, by
patient demographic characteristics, season and time of day.
PHS-6040
(Rev. 2-81)
30-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02498-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
CT Scan Observer Variability Study
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Cynthia Gross, Ph.D., Biostatistician, CAS, OBFS, NINCDS
Other James Dambrosia, Ph.D., Mathematical Statistician, SMS, OBFS
NINCDS
Karlin Richardson, Programmer, CAS, OBFS, NINCDS
Dr. Thomas Gennarelli, Neurosurgeon, Univ. of Penn. School of
Medicine
COOPERATING UNITS (if any)
University of Pennsylvania, School of Medicine
lab/branch
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A study of observer variability in CT Scan reading and coding was
implemented utilizing identical sets of CT Scan polaroids and the CT
Scan Data Collection form of the Pilot Traumatic Coma Data Bank.
Readers were neurosurgeons participating in the Coma Data Bank
(ZOl NS 02340-05 OBFS). The degree of agreement among readers was
calculated by Kappa statistics and an item analysis was performed.
Severity of errors was determined by a substantive analysis.
PHS-6040
(Rev. 2-81)
31-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02443-03 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development of Offline Data Entry System for Stroke and Coma Projects
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.
Barbara Nichols, Programmer, CAS, DBFS, OD, NINCDS
Other: Selma C. Kunitz, Head, Section on Computer Applications,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
1.0
PROFESSIONAL:
OTHER:
.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A "front-end" general purpose software package was developed for the
Data-point terminals in the Data Bank Centers, which allows data to be
entered, edited and stored locally by time and date. The software
operates with menu processing, in which a nonprogrammer can choose the
options for data entry from a list. It produces screen images which repli-
cate the order of data on the data collection record. During data entry,
data are edited for valid numeric ranges, alpha-numeric checks, code lists,
and special formats such as dates. A new communication discipline is being
added to insure the accuracy of data transmission. Patient management
reports were designed and are now being implemented to serve as tools for
patient care at the Data Bank Network Centers.
PHS-6040
(Rev. 2-81)
32-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02450-03 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Spinal Manipulative Therapy as Treatment for Musculo-Skeletal Dysfunction
in Athletes. Formerly titled "Study of Efficacy of Spinal Manipulative
Therapy on the Performance of Athletes"
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Peter Jokl, Assoc. Prof, of Orthopaedic Surgery, Director of
Athletic Medicine, Yale University School of Medicine
Murray Goldstein, Acting Director, National Institute of Neurological
and Communicative Disorders and Stroke, NIH
J.F. McAndrews , President, Palmer College of Chiropractic
William Weiss, Chief, Office of Biometry & Field Studies, NINCDS
Other: James M. Dambrosia, Mathematical Statistician, Office of Biometry
and Field Studies, NINCDS
COOPERATING UNITS (if any)
Yale School of Public Health
lab/branch
Office of Biometry and Field Studies
Office of the Chief
INSTITUTE AND LOCATION NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS: Q.l
PROFESSIONAL:
0.1
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project will evaluate the efficacy of spinal manipulative therapy
for alleviating neuromuscular and musculo-skeletal problems that diminish
athletic performance. A demonstration of the effectiveness of treatment
will be provided by a randomized controlled clinical trial of student
athletes at Yale University. The OBFS role in this project's responsibility
is the design and analysis of the trial to be accomplished in close collabo-
ration with the Yale University School of Medicine.
The study design is near completion. Completion of the proposal awaits
a site visit to the proposed facilities at Yale; a meeting with officials of
the Medical School; and meetings with exercise physiologists at Yale and the
athletic trainers and other staff who will participate in the study.
PHS-6040
(Rev. 2-81)
33-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02444-03
OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Statistical coordinating center for the phenobarbital clinical study
(previously titled "Cognitive and Behavioral Effects of Phenobarbital in
Young Children").
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.
Others;
Young Jack Lee, Mathematical Statistician, Section on Mathematical
Statistics, OBFS, OD, NINCDS
Jonas H. Ellenberg, Acting Deputy Chief, OBFS, OD, NINCDS
Karin B. Nelson, Chief; Deborah G. Hirtz, Expert Consultant;
Cerebral Palsy and Other Motor Disorders Section, DNB, NDP, NINCDS
Karlin Richardson, Programmer; Kenneth A. Eisner, Systems Analyst;
Sylvia Edelstein, Systems Analyst; Section on Computer Applications,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Cerebral Palsy and Other Motor Disorders Section, DNB, NDP, NINCDS;
University of Washington
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.0
1.0
check APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Statistical design considerations for the study were developed for the RFP,
as well as the functions and organization of the statistical coordinating
center.
During this fiscal year, precoded data forms, and computer systems for data
entry and management are being developed in collaboration with the Computer
Applications Section. The system will handle patient status and data tracking.
data quality assurance, and production of simple charts and tables. Edited
data will be transferred to the DCRT , NIH Computer for statistical analyses.
**[This study is to support the DNB/NDP/NINCDS contract study entitled:
"Behavioral and cognitive side effects of phenobarbital used for prevention
of febrile seizure recurrence." The project officer is Dr. Karin B. Nelson,
DNB, NDP, NINCDS, and the contractor of the study is the University of
Washington. ]
PHS-6Q40
(Rev. 2-81)
34-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02484-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Statistical Coordinating Center for Communicative Disorders
A*
Program projects
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. Young Jack Lee, Mathematical Statistician, Section on
Mathematical Statistics, OBFS, OD, NINCDS
P.I. Christy Ludlow, Communicative Disorders Program, NINCDS
COOPERATING UNITS (if any)
Communicative Disorders Program, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.10
PROFESSIONAL:
.10
OTHER:
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
n(al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Statistical designs are being developed and sample sizes determined for
three CDP, NINCDS, project plans. They are: a study of the acquisition
of communicative skills through speech, sign or total communication in
the congenitally deaf; a study to evaluate the outcome of language learn-
ing through speech and/or sign in the congenitally deaf; and a population-
based cohort study to evaluate the impact and treatment of speech and
language disorders in children. The status of this project is indeter-
minate due to lack of program funding.
[This study is the OBFS/NINCDS portion of contract studies in communica-
tive disorders. The project officer of the contracts would be Dr. Christy
Ludlow, CDP, NINCDS. But these contract studies were not funded and thus
inactive. ]
PHS-6040
(Rev. 2-81)
35-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02502-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Medical Studies Database System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.'s: Karlin Richardson, Programmer, OBFS, NINCDS
Sylvia Edelstein, Systems Analyst, OBFS, NINCDS
Other: Ken Eisner, Systems Analyst, OBFS, NINCDS
Dr. Young Jack Lee, Mathematical Statistician, OBFS, NINCDS
Selma C. Kunitz, Chief, Computer Applications Section, OBFS, NINCDS
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
Section on Computer Applications
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS g (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of the Medical Studies Database System (MSDS) is to provide
a computerized system that facilitates data handling functions with a high
degree of automation that minimizes data collection errors and computer
programming and provides forms-tracking , data updating with automatic
audit-trail and user-friendly data retrieval. The methodology involves:
1) Entry of medical data from data collection forms onto Hewlett Packard
264 7A Intelligent Terminal screens which mirror the data collection forms;
2) The transfer of the data to a data base management system (DBMS),
Hewlett Packard's Image, on an HP-IOOO minicomputer under RTE IVB operating
system;
3) A forms-tracking system which records the validity status of the data;
4) Easy-to-use retrieval utilities.
PHS-6040
(Rev. 2-81)
36-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02488-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Interactive Computer System for Patient Entry and Randomization
for Clinical Study
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Young Jack Lee, Mathematical Statistician,
Section on Mathematical Statistics, OBFS, OD, NINCDS
COOPERATING UNITS (If any)
Laurie Burch, Programmer, Personal Service Contract
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An interactive computer system is under development. The system will
utilize the TSO of the DCRT, NIH computer. The clinical trial opera-
tions office will register patients entering clinical trials, check the
eligibility and perform random allocations of the treatment to eligible
patients, all using the interactive system.
PHS-6040
(Rev. 2-81)
37-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02489-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Evaluation of the effectiveness of information services provided to
specialists in communicative disorders by MEDLINE
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. Christy Ludlow, Communicative Disorders Program, NINCDS
P.I. Barbara Reiner, Communicative Disorders Program, NINCDS
Others: Young Jack Lee, Section on Mathematical Statistics, OBFS,
OD, NINCDS
Sylvia Edelstein, Systems Analyst, Section on Computer Applica-
tions, OBFS, OD, NINCDS
Karlin Richardson, Programmer, Section on Computer Applications,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Communicative Disorders Program, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.50
PROFESSIONAL:
.30
.20
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Five study centers are participating in evaluating the effectiveness of
MEDLINE in information services provided to specialists in communicative
disorders . User profiles and information needs are collected through
The Phase I data have been collected and entered
The Phase II
preuse questionnaires.
into the computer. The Phase II data are being collected,
data form is under development.
[This study is the OBFS/NINCDS portion of a larger contract study enti-
tled: Evaluation of the Effectiveness of Information Services Provided
to Specialists in Communicative Disorders by MEDLINE. The project officer
is Dr. Christy Ludlow, CDP, NINCDS. Project numbers are NOl-NS-0-2342,
NOl-NS-0-2343, NOl-NS-0-2344, NOl-NS-0-2345 and NOl-NS-0-2346. ]
PHS-6040
(Rev. 2-81)
38-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02310-06 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
A Statistical Study of Sensory-Decision-Theory Method in the
Measurement of Experimental Pain
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I,: Ta-Chuan Chen, Ph.D., Mathematical Statistician, DBFS, NINCDS
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0
PROFESSIONAL:
OTHER:
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project investigates statistically the nature of sensory-decision-
theory (SDT) method in determining pain components from responses of experi-
mental subjects to painful stimuli. The parametric approaches to the SDT
method were evaluated for the estimability of, and the relationship between,
sensory discriminability and response bias. Sampling behavior of these
indices was also examined. A report has been prepared and the study has
been completed.
PHS-6040
(Rev. 2-81)
39-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHAI^IGE
(Do
PROJECT NUMBER
NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02517-01 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Statistical Methodology for the Measurement of Pain
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Ta-Chuan Chen, Ph.D., Mathematical Statistician, OBFS, NINCDS
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.3
PROFESSIONAL:
.3
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project investigates the statistical problems involved in the
Measurement of experimental and clinical pain. (1) A study has been conducted
to investigate the statistical technique used in deriving psychophysical
measurements of pain. A report has been prepared for the part of work dealing
with sensory-decision-theory measures such as d' and g. Further study of the
interrelationship among other types of measurement indices, e.g., p(A), Hodo's
percent bias and MacNicol's index of response bias,B , are ongoing. (2) A
study of statistical quantification of the temporal characteristics of persis-
tent, episodic pain such as migraine headache is currently being developed. A
group of measurements for this type of pain has been selected for further
investigation. (3) A meeting is in preparation by the members of OBFS and
other program areas of NINCDS to review the current state-of-the-art of the
methodology for the measurement of pain. This meeting will justify the need
for conducting a full-scale symposium to discuss various aspects of pain measure
ment problems .
PHS-6040
(Rev. 2-81)
40-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02504-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Epidemiological Study of Pain (Formerly titled Estimation of the
Incidence Rate of Disabling and Severe Headache)
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Ta-Chuan Chen, Ph.D., Mathematical Statistician, OBFS, NINCDS
COOPERATING UNITS (if any)
Thomas F. Drury, Ph.D., Office of Analysis and Epidemiology, NCHS
lab/branch
Office of Biometry and Field Studies
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
.1
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
n (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is to evaluate the average and age-specific
incidence rates of various chronic pain syndromes, and to investigate the
relationship between occurrences of these pain conditions with various epidemi-
ological factors. (1) The incidence rates of disabling and/or severe head-
ache were evaluated with data obtained from a Mid-West non-clinical population
survey. The relationship between incidence and prevalence rates and length
of illness due to headache has been examined. A report of the results of this
study has been prepared. (2) A study is currently being developed to evaluate
the average and age-specific incidence rates of neck-back pain and low back
pain based on the data from NCHS national surveys. The association of these
pain syndromes with various demographic, psychological and medical-care
variables will be investigated.
PHS-6040
(Rev. 2-81)
41-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02239-06 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Design of Health Interview Survey Questionnaire Supplements (Previously
titled: "Design of Convulsive Disorder Questionnaires")
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Frederic D. Weinfeld
OTHERS: Dallas W. Anderson
Herbert M. Baum
Survey Statistician
Survey Statistician
Demographer
OBFS NINCDS
OBFS NINCDS
OBFS NINCDS
COOPERATING UNITS (if any)
Clint Burnham, National Center for Health Statistics; W. Alien Hauser,
Columbia University; Lee Kudrow, California Medical Clinic for Headache
lab/branch
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.10
PROFESSIONAL:
.10
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project involves the design and field testing of questionnaires to be
used as supplements to the NCHS's Health Interview Survey (HIS). The first
such questionnaire was designed to collect information on the number of
persons who had had a stroke, diagnosed or undiagnosed, and their
hospitalizations. This questionnaire was included in the 1977 HIS.
Questionnaires are being designed as supplemental modules for the HIS. One
questionnaire will collect information on those persons with convulsive
disorders. Another questionnaire will collect information on headache. The
data collected will be used to provide national estimates of the prevalence
of these disorders.
PHS-6040
(Rev. 2-81)
42-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02404-04 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
National Survey of Chronic and Debilitating Headache (Previously
titled: "National Headache Survey")
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Frederic D. Weinfeld
PI: Ta-Chuan Chen
OTHER: Dallas W. Anderson
Survey Statistician OBFS NINCDS
Mathematical Statistician OBFS NINCDS
Survey Statistician OBFS NINCDS
COOPERATING UNITS (if any)
National Center for Health Statistics; California Medical Clinic for
Headache; Cleveland Clinic; Diamond Headache Clinic; Headache Research
Foundation
lab/branch
Office of Biometry and Field Studies
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.10
PROFESSIONAL:
1.00
.10
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is to design a survey which would measure the
prevalence, and describe the demographic characteristics of, major types of
headache. The survey would also identify the clinical and environmental
risk factors which may be associated with these headaches, and determine the
impact of headaches on society. The survey questionnaire, which includes
sections on demography, medical information and history, and cost, etc., has
been developed. In the Feasibility Study (Phase 1), patients from four
well-respected headache clinics have been solicited for a telephone
interview about their headache problems. Information in the physician files
about the headaches has been abstracted, coded, and computerized. This will
be used as a basis for the investigation of validity of the telephone data.
Plans for an Area Survey (Phase 2) have also been made.
PHS-6040
(Rev. 2-81)
43-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02495-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Analysis of Data From the National Survey of Multiple Sclerosis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Herbert M. Baum
OTHERS: Karlin Richardson
Demographer
Programmer
OBFS NINCDS
OBFS NINCDS
COOPERATING UNITS (if any)
Beth Rothschild, National Analysts; Labe Sheinberg, Nicholas LaRocca, and
Alice Kornblith, Albert Einstein College of Medicine
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.70
PROFESSIONAL:
.60
.10
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The National Survey of Multiple Sclerosis (NSMS) is a probability sample of
all multiple sclerosis patients in the conterminous United States. The
Survey gathered detailed data on the disease, emplo3anent , and social history
of over 1200 cases. The Office of Biometry and Field Studies, in
conjunction with other researchers in the field of multiple sclerosis, is
undertaking a detailed analysis of these data. It is hoped that we will
obtain an understanding of how disease factors affect the lives of
individuals with multiple sclerosis.
PHS-6040
(Rev. 2-81)
44-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE,
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02499-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Stroke Incidence in South Alabama
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.'s: Cynthia Gross, Ph.D., Biostatistician, OBFS, NINCDS
Dr. Jay Mohr, neurologist, University of S. Alabama College
of Medicine
Dr. Carlos Kase, neurologist. University of S. Alabama College
of Medicine.
Other: None
COOPERATING UNITS (if any)
University of South Alabama, College of Medicine, Mobile, Alabama
lab/branch
Office of Biometry and Field Studies
SECTION
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.3
PROFESSIONAL:
.25
OTHER:
.05
CHECK APPROPRIATE BOx(ES)
g (a) HUMAN SUBJECTS
n (al) MINORS K (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
As a component of the Pilot Stroke Data Bank (NOl NS 8-2397), 1980
stroke incidence data has been collected for the population of a well-
defined geographic area located in three counties in southern Alabama.
About 160 persons hospitalized with a stroke which occurred in 1980
were identified from a population of about 100,000 persons.
These data provide incidence rates by age, sex, race, and stroke type.
The age adjusted incidence rate for blacks vjas almost twice the rate
for whites. Medical history as well as other factors were collected for
each stroke case. Two-thirds of the stroke cases had a history of hyper-
tension and one in five had a history of diabetes. These data are
presently being analyzed for a publication which will compare these
findings with other similar studies of stroke.
PHS-6040
(Rev. 2-81)
45-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02406-04 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Frequency of Neurological Disorders Among Hospital Discharges
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Herbert M. Baum
Demographer
OBFS NINCDS
COOPERATING UNITS (if any)
Donald Smith, National Center for Health Statistics
lab/branch
Office of Biometry and Field Studies
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Hospital Care Statistics Branch, of the National Center for Health
Statistics, has agreed to provide us with data on neurologically related
hospital discharges. A list of conditions, using ICDA-8 codes, of primary
interest to the Institute was prepared. By examining data on the first-
listed and on all listed diagnoses at the time of discharge we can monitor
secular trends. This will become an annual reporting effort. This project
has been terminated.
PHS-6040
(Rev. 2-81)
46-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02405-04 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less) .,. ^ , otia ui..uo
Assessment of Strategies for Analyzing Data from Small Area Health Surveys
(Previously titled: "Assessment of Strategies for Analyzing Data from Small
Area Mortality Surveys")
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Dallas W. Anderson
Survey Statistician
OBFS NINCDS
COOPERATING UNITS (if any)
W. Edwards Deming, Washington, D.C.
lab/branch
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.10
PROFESSIONAL:
.09
.01
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Studies of small areas, such as coimnunities or counties, are an important
tool of epidemiologists , who are interested in studying distributions of
diseases in populations. Many studies of this type have been reported in
the scientific literature. An assessment of techniques of analysis
frequently used in these studies was initiated to determine their adequacy
for use in the NINCDS survey of major neurological disorders in Copiah
County, Mississippi (YOl-NS-70031 , NOl-NS-7-2357).
PHS-6040
(Rev. 2-81)
47-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02515-01 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Study of Hearing Disorders Among the Aged
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Eve K. Moscicki
OTHERS: Herbert M. Baum
Earleen Elkins
Scientist
Demographer
Audiologist
OBFS NINCDS
OBFS NINCDS
CDP NINCDS
COOPERATING UNITS (if any)
Patricia McNamara, FES, NHLBI
lab/branch
Office of Biometry and Field Studies
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.30
PROFESSIONAL:
.25
.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
□ (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
3 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Hearing data collected during Cycle 15 of the Framingham Heart Study
(1978-1979) will be analyzed to estimate the prevalence of hearing
impairment among the Framingham cohort. The risk factors that might be
associated with hearing loss found in this population will also be
examined.
PHS-6040
(Rev. 2-81)
48-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02494-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Prevalence of Multiple Sclerosis in Colorado
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Herbert M. Baum
Demographer
OBFS NINCDS
COOPERATING UNITS (if any)
D. Thompson, L. Nelson, and J. Burks, Rocky Mountain Multiple Sclerosis
Center
lab/branch
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.25
PROFESSIONAL:
.20
OTHER:
.05
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Rocky Mountain Multiple Sclerosis Center is one of a few centers devoted
solely to the care of patients with multiple sclerosis, and is the only
center of its type in the State of Colorado. Using records from the Center,
local multiple sclerosis societies, and the local chapter of the National
Multiple Sclerosis Society we will attempt to estimate the incidence and
prevalence of the disease for Weld and Larimer Counties. If this effort is
successful, we might try to get an estimate for the State. Other
collaborative efforts are also anticipated.
PH 8-6040
(Rev. 2-81)
49-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02312-06 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Maternal Infection Study**
(previously titled "Methodology for Systematic Analysis of Multiple Antibody
Readings on Matched Controlled Studies") .
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Jonas H. Ellenberg, Acting Deputy Chief, OBFS, OD, NINCDS
John L. Sever, Chief, Infectious Diseases Branch, IRP, NINCDS
Other: Alan Talbert, Mathematical Statistician, OBFS, OD, NINCDS
Martha Griswold, Statistician, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Infectious Diseases Branch, IRP, NINCDS
lab/branch
office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,10
PROFESSIONAL:
.10
check APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Analysis of the Collaborative Perinatal Project (CPP) data continues in
the area of maternal infection. (The CPP is a prospective study of
approximately 60,000 gravidae and the follow-up of their children through
the seventh year of life.) The relationship of maternal infection during
pregnancy with the later status of the child is being examined using both
clinical and serologically-conf irmed infections in the mother.
**(This study is the OBFS/NINCDS portion of a larger study entitled: Peri-
natal Infections Causing Damage to the Child - Collaborative Perinatal
Project, ZOl NS 00402-26 ID. The principal investigator on the overall
study is Dr. John L. Sever, Chief, IDE, IRP, NINCDS.)
PHS-6040
(Rev. 2-81)
50-OBFS/OD
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02114-09 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Etiology and Natural History of Convulsive Disorders and Cerebral Palsy
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Jonas H. Ellenberg, Acting Deputy Chief, OBFS, OD, NINCDS
P.I.: Karin B. Nelson, Chief, Cerebral Palsy and Other Motor Disorders
Section, DNB, NDP, NINCDS
COOPERATING UNITS (if any)
Cerebral Palsy and Other Motor Disorders Section, DNB, NDP, NINCDS
lab/branch
Office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.2
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
□ (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study examines the relationship between perinatal and early postnatal
factors and the occurrence of seizure disorders and cerebral palsy in child-
hood. The project derives from the data of the Collaborative Perinatal
Project, a large prospectlvely-f ollowed population (approximately 60,000
mothers, with their children followed to seven years of age). The univariate
screen of maternal, obstetric and pediatric risk factors, and demographic
analysis have been completed. Multivariate assessment of the data bank is
In progress Including correlation and regression analysis. Selected topics
of particular clinical relevance are under examination.
** [This study is the OBFS/NINCDS portion of a larger study entitled: Convul-
sive Disorders Data Analysis Group, ZOl NS 02058-10 DNB and Cerebral Palsy
Data Analysis Group, ZOl NS 02059-10 DNB. The principal investigator for
these studies is Dr. Karin B. Nelson, Chief, Cerebral Palsy and Other Motor
Disorders Section, DNB, NDP, NINCDS.]
PHS-6040
(Rev. 2-81)
51-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02483-02 OBFS
PERIOD COVER
t?ctofeer 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Predictive Value of the EEG in Febrile Seizures
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Jonas H. Ellenberg, Acting Deputy Chief, DBFS, CD, NINCDS
Nikola Sofijanov, Pediatric Neurologist, University of
Skopje, Yugoslavia
Karin B. Nelson, Chief, Cerebral Palsy and Other Motor
Disorders Section, DNB, NDP, NINCDS
Deborah G. Hirtz, Pediatric Neurologist, Cerebral Palsy and
Other Motor Disorders Section, DNB, NDP, NINCDS
Other: Frances Canning, Forms Design, DNB, NDP, NINCDS
Sylvia Edelstein, Senior Programmer, Computer Applications
Section, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Pediatric Clinic, University of Skopje, Yugoslavia
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE and LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.20
PROFESSIONAL:
.10
.10
CHECK APPROPRIATE BOX(ES)
^ (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study will evaluate the significance of the EEG as a predictor for
recurrence of seizures in those children who have had a simple febrile
convulsion. Outcome with respect to febrile seizure recurrence and
afebrile seizure occurrence will be reported. The evolution of the EEG
pattern will be described, and patterns will be correlated with the
clinical outcome. The clinical study is being carried out in Skopje,
Yugoslavia, at the Pediatric Clinic of the University of Skopje.
The study began in FY'82 and will be completed in FY'87. Completed
during FY'82 were the data management and quality control systems.
PHS-6040
(Rev. 2-81)
52-OBFS/OD
PROJECT NUMBER
ENCf
(Do
NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02411-04 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Survey of Practice in the Management of Febrile Seizures (previously
titled "Survey of Management of Children with Febrile Seizures").
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.
P.I.
P.I.
P.I.
Young Jack Lee, Mathematical Statistician, Section on
Mathematical Statistics, OBFS, OD, NINCDS
Jonas H. Ellenberg, Acting Deputy Chief, OBFS, OD, NINCDS
Deborah G. Hirtz, Pediatric Neurologist, Cerebral Palsy and
Other Motor Disorders Section, DNB, NDP, NINCDS
Karin B. Nelson, Chief, Cerebral Palsy and Other Motor Dis-
orders Section, DNB, NDP, NINCDS
COOPERATING UNITS (if any)
Cerebral Palsy and Other Motor Disorders Section, DNB, NDP, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.30
PROFESSIONAL:
.15
.15
CHECK APPROPRIATE BOX(ES)
El (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A survey of clinical practice in the management of febrile seizures is
ongoing. The survey form has been submitted for 0MB clearance. The
survey of approximately 10,000 physicians in various specialities will
determine which medical discipline(s) treats most children with febrile
seizures, what criteria physicians use to determine therapy, the regimens
prescribed and the specific goals of therapy.
PHS-6040
(Rev. 2-81)
53-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02497-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
INDO-U.S. Study of Head Injury
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.'s: William Weiss, Chief, OBFS, NINCDS
Dr. John Jane, Chairman, Dept. of Neurological Surgery,
Univ. of VA, Charlottesville, VA
Dr. Prakash Tandon, Chairman, Dept. of Neurosurgery,
All-India Institute for Medical Research, New Delhi, India
Other: Rebecca Rimel, R.N.N.P. , Univ. of VA, Charlottesville, VA
Cynthia Gross, Ph.D., Biostatistician, CAS, OBFS, NINCDS
COOPERATING UNITS (if any)
University of VA. Dept. of Neurosurgery, Charlottesville, VA
All-India Institute of Medical Science, New Delhi, India
lab/branch
Office of Biometry and Field Studies
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,15
PROFESSIONAL:
.10
,05
CHECK APPROPRIATE BOX(ES)
[^ (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Information on head-injured persons has been collected in independent
research efforts in Charlottesville, Virginia, and in New Delhi, India. A
preliminary review of these data collection efforts has indicated significant
overlap in the type of information collected. A preliminary analysis of the
collected data is proposed to identify differences and similarities between
these head-injured populations, and to determine the feasibility of a pros-
pective cooperative association for the study of head injuries.
The Government of India has approved the research proposal and has
allocated 767,000 rupees for the three-year Indian portion of the collabora-
tive study. The proposal will now enter the NIH review process.
PHS-6040
(Rev. 2-81)
54-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02518-01 OBFS
PERIOD COVERED
October 1. 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neurological Aspects of Aging in Primates
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. Manuel Martinez-Maldonado, Chief, Medical Service & Director
Renal Metabolic Laboratory, Veterans Administration Center,
San Juan, Puerto Rico
Efran Toro Goyco, Chairman, Dept. of Biochemistry
University of Puerto Rico Medical School, San Juan, Puerto Rico
Donald Price, Professor, Dept. of Neurology
University of Maryland School of Medicine
Other: William Weiss, Chief, OBFS, NINCDS
James Dambrosia, Ph.D., Acting Chief,
Section on Math. Stat., OBFS, NINCDS
COOPERATING UNITS (if any)
Medical School, University of Puerto Rico, San Juan, Puerto Rico
Veteran Administration Center, San Juan, Puerto Rico
Johns Hopkins University
lab/branch
Office of Biometry and Field Studies
SECTION
Office of the Chief
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n {a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project will be a consortium of center grants and individual investi-
gator grants to study the neurologic aspects of aging in Macaca mulattas. The
University of Puerto Rico will provide the facilities of the Caribbean Primate
Research Center and investigators in behavioral research at Cayo Santiago and
Sabana Seca. Investigators with individual research projects from the University
of Puerto Rico and the Veterans Administration Hospital in San Juan will use
the primate facilities. Dr. Price and his colleagues at Johns Hopkins University
will map neurotransmitter pathways in the young, adult, and aging primate brain.
OBFS will provide the computer facility and a statistical coordinating center to
process the data and to collaborate on identifying associations across individual
project boundaries.
PHS-6040
(Rev. 2-81)
55-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02481-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Use of Phantom Views to Diminish an Artifact in CT Scans
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. George H. Weiss, Chief, Laboratory of Physical Sciences, DCRT
P.I. Alan J. Talbert, Statistician, OBFS, OD, NINCDS
P.I. Rodney Brooks, Physicist, Neuroradiology and Computed
Tomography Section, Surgical Neurology Branch, NINCDS
COOPERATING UNITS (if any)
Laboratory of Physical Sciences, IRP, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
PROFESSIONAL:
.2
OTHER:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An artifact in computed tomography scans which occurs with too few views
is the appearance of streaks at some distance from the image causing them.
The phantom views method consists of inserting phantom data points,
obtained by interpolation between real data points. This study shows that
the phantom views method does diminish this artifact and finds the optimum
number of phantom views. This study has been completed and a paper has
been accepted for publication.
PHS-6040
(Rev. 2-81)
56-OBFS/OD
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02482-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Optimization of Software for PET Scanner
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. Alan J. Talbert, Statistician, OBFS, OD, NINCDS
P.I. Rodney A. Brooks, Physicist, Neuroradiology and Computed
Tomography Section, Surgical Neurology Branch, NINCDS
COOPERATING UNITS (if any)
Neuroradiology and Computed Tomography Section
Surgical Neurology Branch, IRP, NINCDS
lab/branch
Office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (a1 ) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Software is being developed for a PET scanner which is being constructed
by the Neuroradiology and Computed Tomography Section. The picture pro-
cessing program is being optimized for speed and accuracy. This involves
the use of low level languages and intimate knowledge of image processing
mathematics and the computer architecture. Substantial improvements in
execution time have been achieved. Further improvements are being
developed.
'' [This study is the OBFS/NINCDS portion of a larger study entitled:
Development of a High Resolution Positron Emission Tomograph. The
Principal Investigator is Dr. Rodney Brooks, Neuroradiology and CT
Section, SNB, IR, NINCDS.]
PHS-6040
(Rev. 2-81)
.57-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02486-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Statistical models of in vitro mutagenicity assays
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. Young Jack Lee, Mathematical Statistician, Section on
Mathematical Statistics, OBFS, OD, NINCDS
P.I. William J. Caspary, National Toxicology Program,
National Cancer Institute
COOPERATING UNITS (if any)
National Toxicology Program, National Cancer Institute
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Chemically-induced genetic damages of cells (mammalian or submammalian)
in vitro are observable by allowing the cells to express their DNA
damage and the progenies with locus-specific mutation to be selected
and form colonies.
PHS-6040
(Rev. 2-81)
58-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space;
U.S. DEPARTMENT OF
I HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02519-01 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Case-Control Studies of Antiviral Antibodies in Multiple Sclerosis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Joanna Woyciechowska, Infectious Diseases Branch, IRP, NINCDS
John L. Sever, Infectious Diseases Branch, IRP, NINCDS
Other: James M. Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Infectious Diseases Branch
lab/branch
Office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH Bethesda, Md. 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Levels of antiviral antibodies from MS patients are compared to those of
matched control subjects in an attempt to establish possible alteration of
immune responses in patients with MS. One component of the study uses 24
twin pairs, and another has 99 MS patients with controls matched on age,
sex, geographic location, and migration history. This project has been
completed.
** [This study Is the OBFS /NINCDS portion of two larger studies entitled: Non
viral Antigens in Perinatal and Neurological Disease, ZOl NS 01985-11 ID,
and Combined Clinical, Viral and Immunological Investigation of Acute and
Chronic Diseases of the Central Nervous System, ZOl NS 02038-10 ID. The
principal investigator of the former project is Dr. David Madden, IDB/IRP/
NINCDS and that of the latter is Dr. John Sever, IDB/IRP/NINCDS . ]
PHS-6040
(Rev. 2-81)
59-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02446-03 OBFS
PERIOD COVERED
October 1, 1981, through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Parkinson's Disease in Twins
(previously titled "Parkinson Twin Studies")
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. R. Eldridge, Section on Neuroepidemiology, IRP, NINCDS
P.I. C. Ward, Experimental Therapeutics Branch, IRP, NINCDS
P.I. J. Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Experimental Therapeutics Branch, IRP
Section on Neuroepidemiology, IRP
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.20
PROFESSIONAL:
.15
.05
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
Q (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Twin pairs , discordant with respect to Parkinson's disease, are evaluated
for zygosity and the presence of Parkinson disease. Clinical, laboratory,
historical, and psychometric data are obtained for both the pro-band and
the co-twin. Statistical analysis of these matched pairs will attempt
to identify risk factors and examine differences between the pro-bands
and co-twins.
[This study is the OBFS/NINCDS portion of a larger study entitled:
"Genetic Epidemiology Studies in MS and Other Multifactorial Neurologic
Disorders" (ZOl NS 02167-06 ODIR). The principal investigator on the
overall study is Dr. Roswell Eldridge, NES , ODIR.]
PHS-6040
(Rev. 2-81)
60-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02490-02 OBFS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Research in Statistics
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: James M Dambrosia, Acting Chief, Section on Mathematical Statistics,
OBFS, OD, NINCDS
Young Jack Lee, Mathematical Statistician, Section on Mathematical
Statistics, OBFS, OD, NINCDS
Alan Talbert, Mathematical Statistician, Section on Mathematical
Statistics, OBFS, OD, NINCDS
Jonas H. Ellenberg, Acting Deputy Chief, OBFS, OD, NINCDS
OTHER: None
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md. 20205
TOTAL MANYEARS:
.65
PROFESSIONAL:
.65
OTHER:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
□ (a1 ) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project addresses statistical problems generated from collaboration
with scientists in other program areas and general statistical problems
of current interest. This project is a continuing activity of the Section
on Mathematical Statistics.
PHS-6040
(Rev. 2-81)
61-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02514-01 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Review of Techniques for Sampling of Rare Populations
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Dallas W. Anderson
Survey Statistician
OBFS NINCDS
COOPERATING UNITS (if any)
W. Edwards Deming, Washington, D.C.; Monroe Sirken, National Center for
Health Statistics
lab/branch
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.01
PROFESSIONAL:
.01
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
D (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Special techniques of sampling are required for surveys of rare
characteristics in populations, as ordinary approaches would be impractical.
This investigation provides a compilation and assessment of sampling
techniques used successfully in population studies of rare characteristics.
This assessment is made in light of the Institute's need for surveys of
relatively rare neurological disorders.
PHS-6040
(Rev. 2-81)
62-OBFS/OD
U.S. DEPARTMENT OF
1 HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02506-02 OBFS
PERIOD COVERED October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Antibody Titers in Macacas on Cayo Santiago
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: William T. London, Chief, Experimental Pathology Section,
IDB, IR, NINCDS
Other: William Weiss, Chief, OBFS, CD, NINCDS
COOPERATING UNITS (if any)
Infectious Diseases Branch, IR, NINCDS
lab/branch
Office of Biometry and Field Studies
Office of the Chief
INSTITUTE AND LOCATION NINCDS, NIH, Bethesda, Maryland, 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project will provide a test of four antigens on adult and juvenile
Macacas on Cayo Santiago, Puerto Rico. One problem is to determine the per-
cent of positive antibody titers that can be determined from the adult sample
for whom blood sera are presently available, and the number of juveniles
that should be sampled.
PHS-6040
(Rev. 2-81)
63-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02415-04 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cage Standards for Primates
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Dr. William T. London, Chief, Experimental Pathology Section,
IRP, NINCDS
Other: James Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Infectious Diseases Branch, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.15
PROFESSIONAL:
0.10
0.05
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Present cage assignments for primates are based solely on the animals'
weight. Variation in shape between species of primates of the same
weight indicate that the current weight-based standard may be inappro-
priate. A large number (410) of primates of four different species
have been measured (arms, legs, chest, tail, crown to rump, crown to
heel) in order to determine association of and variations in weight
as functions of shape measurements.
PHS-6040
(Rev. 2-81)
64-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02496-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Preliminary Steps for a Data Bank Project in Epilepsy
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.'s: Selraa C. Kunitz, Chief, CAS, OBFS, NINCDS
Cynthia Gross, Ph.D., Statistician, CAS, OBFS, NINCDS
William Weiss, Chief, OBFS, NINCDS
Other: Nikola Sofijanov, Visiting Scientist, OBFS, NINCDS
W. Allen Hauser, M.D. Neurologist, Sergievsky
Institute, N.Y. , N.Y.
COOPERATING UNITS (If any)
LAB^^jtie of Biometry and Field Studi(
SECTION
Computer Applications Section
']mM:' hW:%thesda, Md. 20205
TOTAL MANYEARS:
PROFESSIONAL:
.05
OTHER:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
□ (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
For a data bank to be effective in clinical research, there must be a
clear delineation of the research questions that will be addressed. An
initial step, then, in proposing a data bank is developing a list of
appropriate research questions and hypotheses. A broad set of research
questions for a potential data bank in epilepsy has been suggested.
PHS-6040
(Rev. 2-81)
65-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02501-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Myasthenia Gravis Study
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Irene G. Fishman, Statistician, CAS, OBFS, OD, NINCDS
Selma C. Kunitz, Chief, CAS, OBFS, OD, NINCDS
Other: Ken Eisner, Systems Analyst, CAS, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Christopher Clark, M.D. , Elliott Neurological Center of the
Pennsylvania Hospital, Philadelphia, PA.
lab/brwjch
office of Biometry and Field Studies
SECTION
Computer Applications Section
^'''^im(^i,''m^'
Bethesda, Maryland 20205
TOTAL MANYEARS:
.1
PROFESSIONAL:
.1
OTHER:
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The project involves consultation to a group of neurologists who are
interested in the possibility of collecting clinical information on patients
with myasthenia gravis. An initial set of parameters to be collected has
been proposed, the first version of forms has been redesigned, and data is
being collected on demographics, initial evaluation, and subsequent follow-ups.
This project is currently in progress. OBFS staff is acting only in a consulta-
tive role to this extramural group of investigators.
PHS-6040
(Rev. 2-81)
66-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02341-05 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Type-Specific Stroke Mortality Trends
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Herbert M. Baum
OTHERS: Murray Goldstein
Demographer
Acting Director
OBFS NINCDS
NINCDS
COOPERATING UNITS (if any)
lab/branch
Office of Biometry and Field Studies
SECTION
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.10
PROFESSIONAL:
.05
.05
CHECK APPROPRIATE BOX(ES)
Q (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The investigators used the NCHS mortality data tapes for 1968-1976 to
examine age-type-specific stroke mortality trends by race, sex, and
hypertension status. There are many problems inherent in arriving at
conclusions in a study based on death certificates, but the study explores
the shortcomings of the data to arrive at implications. A general decline
in stroke death rates was observed with the largest declines being observed
for hemorrhagic strokes and for nonwhites. An examination of the data by
hypertension status indicates the need for clinical studies which will
examine the relationship between hypertension and stroke mortality. This
project is now completed.
PHS-6040
(Rev. 2-81)
67-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02442-03 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less]
Feasibility of a National Survey of Speech Defects
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Herbert M. Baum
OTHERS: Eve Moscicki
Christy Ludlow
Demographer
Scientist
Speech Pathologist
OBFS NINCDS
OBFS NINCDS
CDP NINCDS
COOPERATING UNITS (if any)
Communicative Disorders Program, NINCDS
lab/branch
Office of Biometry and Field Studies
Section on Surveys and Demographic Studies
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
.00
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS Q (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
National data on the incidence and prevalence of communicative disorders are
scarce. An investigation of the feasibility for gathering such data has
been undertaken. One plan is to conduct a survey of both providers and
cases. This approach will permit us to also gather data on the cost of the
problem, type of services needed, amount of services needed, etc. This
project has been terminated.
PHS-6040
(Rev. 2-81)
68-OBFS/OD
SMITHSONIAN SCI
PROJECT NUMBER
ENC
(Do
E INFORMATION EXCHANGE
NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02447-03 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
A Prospective Study of Low Birthweight Infants
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I. J.M. Dambrosia, Acting Chief, Mathematical Statistics Section,
OBFS, OD, NINCDS
P.I. Karln B. Nelson, Chief, Cerebral Palsy and Other Motor
Disorders Section, DNB, NDP, NINCDS
COOPERATING UNITS (if any)
Children's Hospital of Washington, D.C.
Section on Cerebral Palsy and Other Motor Disorders, DNB, NDP, NINCDS
lab/branch
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
H (al) MINORS n {a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
All low birthweight (1750gm or less) infants referred to Children's
Hospital are examined, CAT scanned for hemorrhage, and evaluated by the
Hospital staff. Specified information is collected prospectively on
each child until the age of three years. The objective of the study is
to identify risk factors associated with neurological deficits, in par-
ticular CP. This project has been terminated due to the unavailability
of staff and funds at Children's Hospital.
PHS-6040
(Rev. 2-81)
69-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02503-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cerebral Palsy Bibliography of Selected References
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Naomi M. Hawkins, Technical Information Specialist, DBFS, OD, NINCDS
Other: Karin B. Nelson, M.D., Chief, Cerebral Palsy and Other Motor
Disorders Section, DNB, NINCDS
Jonas H. Ellenberg, Ph.D., Acting Deputy Chief, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Cerebral Palsy and Other Motor Disorders Section, DNB, NINCDS and
Section on Mathematical Statistics, OBFS, NINCDS
lab/branch
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,05
PROFESSIONAL:
,05
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Preparing a bibliography on cerebral palsy with selected references
covering etiology, risk, diagnosis, prognosis, prevalence and incidence
and history. This project has been completed.
PHS-6040
(Rev. 2-81)
70-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02414-04 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Early Stopping Rules Used in Clinical Trials previously titled "Simulation
of Early Stopping Rules Used in Clinical Trials".
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: James Dambrosia, Mathematical Statistician, Section on
Mathematical Statistics, OBFS, NINCDS
P.I.: Jonas H. Ellenberg, Chief, Section on Mathematical Statistics,
OBFS, NINCDS
COOPERATING UNITS (if any)
LAB/BRANCH
Office of Biometry and Field Studies
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.1
PROFESSIONAL:
.1
CHECK APPROPRIATE 80X(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project assesses the various techniques proposed for early stopping
of clinical trials in the face of unexpected evidence of the failure or
success of a particular regimen, prior to the scheduled termination of a
trial.
Distribution theory for these procedures is either mathematically
intractable or only known asymptotically. A computer simulation study for
comparison of the various procedures is being considered.
OBFS organized an invited paper session at the Spring 1981 Biometrics
meeting concerning this topic. The papers from this session have been
published and this project is completed.
PHS-6040
(Rev. 2-81)
71-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02500-02 DBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Polymyositis/Dermatomyositis Study
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Irene G. Fishman, Statistician, CAS, DBFS, OD, NINCDS
Selma C. Kunitz, Chief, CAS, DBFS, OD, NINCDS
Other: Ken Eisner, Systems Analyst, CAS, OBFS, OD, NINCDS
COOPERATING UNITS (if any)
Christopher Clark, M.D. , Elliott Neurological Center of the
Pennsylvania Hospital, Philadelphia, PA
lab/branch
Office of Biometry and Field Studies
Computer Applications Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
Xl (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The low incidence of myositis and its chronic course necessitate collab-
oration of a number of investigators. The project involves consultation by
OBFS staff to a group of neurologists who are considering the possibility of
collecting clinical information on myositis patients. An initial set of
data items for collection has been proposed, and forms were designed to
enter data on demographic information, initial evaluation, and subsequent
follow-up. These forms were distributed to interested researchers, and re-
finements were made incorporating experience with their use. The revised
set of forms will be discussed at their next meeting in the Fall of 1982.
OBFS staff is acting only in a consultative role to this extramural group
of investigators.
PHS-6040
(Rev. 2-81)
72-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02480-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
A Clinical Study of Bromocriptine and Pergolide for the Treatment
of Parkinson's Disease**
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: J.M. Dambrosia, Acting Chief, Mathematical Statistics, Section,
OBFS, OD, NINCDS
P.I.: P. LeWitt, Experimental Therapeutics Branch, IRP, NINCDS
P.I.: D. Calne, Head, Experimental Therapeutics Branch, IRP, NINCDS
COOPERATING UNITS (if any)
Experimental Therapeutics Branch, IRP, NINCDS
lab/branch
Office of Biometry and Field Studies
SECTION
Mathematical Statistics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,20
PROFESSIONAL:
.15
OTHER:
,05
CHECK APPROPRIATE BOX(ES)
2 (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project assesses the relative efficacy of Bromocriptine versus
Pergolide for the treatment of Parkinson's disease. A randomized, double-
blind, two-period crossover trial with washout periods is employed to
evaluate treatment of forty outpatients. Patient responses are measured
objectively by computer sensing equipment and clinically using a modified
Columbia rating scale. Adverse reactions are monitored throughout the
trial. This project is completed.
**(This study is the OBFS/NINCDS portion of a larger study entitled:
Therapeutic Studies in Parkinsonism and Other Movement Disorders,
ZOl NS 02258-05 ET. The Principal Investigator on the overall study
is Dr. Thomas Chase, Acting Chief, Experimental Therapeutics Branch.)
PHS-6040
(Rev. 2-81)
73-OBFS/OD
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02505-02 OBFS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Headache in Pregnant Women
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Ta-Chuan Chen, Ph.D., Mathematical Statistician, OBFS, NINCDS
Other: Karin Nelson, M.D. , Chief, Cerebral Palsy and Other Motor
Disorders Section, DNB, NDP, NINCDS
Sylvia Edelstein, Systems Analyst, OBFS, NINCDS
COOPERATING UNITS (if any)
Paul Nichols, Ph.D., Developmental Neurology Branch, NINCDS
lab/branch
Office of Biometry and Field Studies
Office of the Chief
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.4
PROFESSIONAL:
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS 1^ (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project investigates the relationship between migraine headache and
pregnancy based on the data collected from a large group of women in pregnancy
the Collaborative Perinatal Project gravidae. Subgroups of pregnant women
characterized by the absence and presence of migraine and other recurrent head
aches prior to or during pregnancy, are identified. Characteristics of these
subgroups are investigated on a variety of demographic, sociological, medical
and obstetric factors, and the association of headache with other disorders.
Seven data files were created bearing information of migraine history, use of
headache medications, and frequencies of headache during pregnancy. Preliminary
results showed pregnant women with a migraine history had more other symptoms
and illnesses during their pregnancies than women without a migraine history.
Children of mothers with a history of migraines appear to have higher incidence
of seizures than children born to mothers in the non-migraine group. More
careful statistical analyses will be carried out.
PHS-6040
(Rev. 2-81)
74-OBFS/OD
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Extramural Activities Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
ADMINISTRATIVE SUMMARY 1
RESEARCH GRANTS PROGRAM 2
MANPOWER PROGRAMS' REPORT 4
GRANTS MANAGEMENT SUMMARY 6
CONTRACTS MANAGEMENT SUMMARY 7
OFFICE OF DATA ANALYSIS AND REPORTS 8
SCIENTIFIC EVALUATION SUMMARY 9
i-EAP TAB 2
ANNUAL REPORT
October 1, 1981, through September 30, 1982
Director's Report
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
The Extramural Activities Program (EAP) , NINCDS, was organized in July, 1975,
to serve as the Institute center for science administration and fiscal manage-
ment of the grant, fellowship, and research contract programs. The structure
of EAP includes components responsible for manpower, scientific merit review,
contract management, grants management, committee management, data reporting
and analysis, and program support services including processing.
The senior staff of EAP consists of:
Director
Deputy Director
Chief, Scientific Review Branch
Chief, Contracts Management Branch
Chief, Grants Management Branch
Chief, Office of Data Analysis and Reports
Staff carries out an overall coordinating and supervisory function in regard
to the implementation of recommendations of the NANCDS Council and Contract
Advisory Committees, and the processing and issuance of proposals and awards
in the respective program areas. The Director, EAP, in consultatation with
the Director of NINCDS, works closely with the other Program Directors on
questions of policy relating to the NINCDS extramural programs.
More specifically, the Extramural Activities Program coordinates grant and
contract programs for the NANCDS Council, the Program Directors, the
Contract Review Board, the Training Board, the Program Staff, and the
Extramural Staff. The EAP studies and supervises certain program processes,
e.g., distribution of awards during the four quarters of the fiscal year;
prepares summary data, e.g., the Research Grant and Fellowship Data Books;
and provides fiscal information, e.g., Fiscal Status Reports, Percentage
Funding Rates, and develops alternate strategies for various budget levels.
One major personnel change is as follows: Dr. Marilyn Semmes, formerly
Director of Special Projects, Head Start Bureau, joined the staff of the
Scientific Review Branch as Executive Secretary, Communicative Disorders
Review Committee. Dr. Semmes replaces Dr. Ernest J. Moore, who joined the
staff of the Communicative Disorders Program, NINCDS, earlier in the year.
In summary, the Extramural Activities Program provides for the Director of
the Institute and the Directors of the Program Areas scientific, fiscal, and
administrative management support services.
1-EAP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Research Grants Program
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
The Research Grants portion of the NINCDS Annual Report provides an overall
summary of administrative developments as they pertain to research grants.
Other activities such as training awards, contracts, etc., are mentioned here
merely to provide an overview, and are discussed in more detail elsewhere.
The research grant, contract, and training programs of the NINCDS are focused
on the identification, stimulation, and support of essential research problems
aimed at the improved diagnosis, treatment, and prevention of disorders of the
nervous system, the neuromuscular apparatus, the ear, and human communication.
They include disorders affecting the development and maturation of the nervous
system (developmental disorders, motor and convulsive disorders, and demyelin-
ating and degenerative disorders) ; disorders caused by extrinsic insults (cen-
tral nervous system infections, stroke, trauma, neoplasms); and disorders in
human communication (hearing, speech, language, the vestibular system, other
senses, and behavior). Research support is also provided in the area of funda-
mental neuroscience which is appropriate to the Institute's mission, but not
related to any specific disorder. Included are nerve structure and function
studies and investigations of the development of various types of prostheses.
The administrative instruments used to accomplish these purposes include
research projects, research program projects, clinical research centers,
research career awards, research career development awards, teacher-inves-
tigator awards, institutional research fellowship awards, individual research
fellowship awards, and contracts.
The following Table shows the number of research grant applications considered
by the Council at its spring meetings over the past five years.
MAY '78 MAY '79 MAY '80 MAY '81 MAY '82
600 645 618 685 644
Over the past five years, there has been a significant increase in the number
of applications reviewed. This may be attributed partially to the effective-
ness of the research training programs of the Institute from which the output
of fully trained investigators has reached its full potential only in recent
years.
The following Table shows the number of research grants (R's and P's) awarded
and the total amounts of funds expended (in millions) each year for the past
five years.
FY '78 FY '79 FY '80 FY '81 FY '82
NUMBER 1,149 1,391 1,553 1,505 1,559
DOLLARS $106.4 $132.2 $160.7 $171.0 $181.0
Table I (on the following page) shows the number of awards and the amounts of
funds expended for each type of award within each Program Area.
2 -EAP
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3-EAP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Manpower Programs' Report
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
The Institute has four training programs. Two programs, the Individual National
Research Service Award (NRSA) and the Institutional National Research Service
Award, are funded from the $8,078 million available in the FY '82 budget
for training. The other two programs, the Research Career Development Award
and the Teacher Investigator Development Award, are funded from FY '82 funds
available in the "Other Research" category.
National Research Service Awards for Institutional Grants (Training Grants)
From FY '82 funds, the Institute provided continuation support for 42 Insti-
tutional NRSA's and made 25 new and renewal awards to support the following
number of programs, according to NINCDS Program Area:
Program Area
Communicative Disorders
Fundamental Neurosciences
Neurological Disorders
Stroke and Trauma
New
and
Continuation
Renewal
Awards
Amount*
Awards
Total
Number
Number Amount"
Number
Amount*
4
$
380
7
$ 419
11
$ 799
9
719
17
1,111
26
1,830
10
657
14
1,104
24
1,761
2
134
4
204
6
338
Total
25 $1,890
42
$2,838
67
$4,728
"Amounts in thousands
In the training grant program, funds are being provided for 44 predoctoral
trainees and 216 postdoctoral trainees. In addition, about 148 short-term
trainees were supported in summer programs.
National Research Service Awards for Individual Postdoctoral Fellows (Fellowships)
From FY '82 funds, the Institute provided continuation support for 89 fellows
and made 102 new and renewal awards. A number of supplemental awards were
also made but this did not increase the number of individuals being trained.
The National Research Service Award for Senior Fellows is now in its third
year of operation. The Institute made three awards totalling $81,000 during
this FY '82. It is expected that a larger number of awards will be made in
future years as this program becomes more visible. In total, awards were
made to support the following number of fellows, according to NINCDS Program
Area:
4-EAP
Program Area
Communicative Disorders
Fundamental Neurosciences
Neurological Disorders
Stroke and Trauma
New
and
Continuation
Renewal
Awards
Amount"
Award
s
Total
Number
Number Amount*
Number
Amount''
19
$
325
19
$
341
38
$ 666
51
889
40
688
91
1,577
20
368
18
322
38
690
12
195
12
222
24
417
102
$1,777
$1,573
191 $3,350
Total
^Amounts in thousands
Research Career Development Award Program
During the period covered by this report, NINCDS made the following number of
new and continuation RCDAs, according to the NINCDS Program area:
Program Area
Communicative Disorders
Fundamental Neurosciences
Neurological Disorders
Stroke and Trauma
New Awards
Number Amount*
Continuation
Awards
Total
Number Amount* Number Amount*
1
$ 37
7
278
2
72
1
38
15
$ 555
16
$
592
18
708
25
986
21
793
23
865
9
351
10
389
11
$ 425
63
$2,407
74
$2,832
Total
*Amounts in thousands
Teacher Investigator Development Award Program
During the period covered by this report, NINCDS made the following number of
new and continuation TIDAs, according to NINCDS Program Area:
Program Area
Communicative Disorders
Fundamental Neurosciences
Neurological Disorders
Stroke and Trauma
Total
*Amounts in thousands
New Awards
Number Amount*
Continuation
Awards
Total
Number Amount* Number Amount*
3
$
125
17
$ 707
20
$ 832
0
0
0
0
0
0
16
705
50
2,093
66
2,798
4
169
20
858
24
1,027
23
$ 999
87 $3,658
110
$4,657
5_
EAP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Grants Management Branch
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
The Grants Management Branch (GMB) consists of two sections, the Grants Admin-
istration Section and the Grants Processing Section. There are 22 people in
the branch, with 11 people in each section. The Grants Administration Section
is responsible for the administrative management of the research and training
programs which are funded through a variety of assistance mechanisms, i.e.,
research project grants, program project grants, specialized center grants,
training grants, fellowships, and career development awards. In addition, the
Grants Administration Section has the responsibility for coordinating NINCDS
responses to Freedom of Information requests. The Grants Processing Section
is responsible for processing the grant applications for research, training,
fellowship, and career development grant programs, for ensuring that funds are
appropriately encumbered, and for preparing the books for the Advisory Council
meetings .
During Fiscal Year 1982 the GMB will be responsible for a total grant budget
in excess of $198 million, of which approximately $189 million will be for
research grants and $9 million will be for training grants. The total repre-
sents a 4.8% increase over that for Fiscal Year 1981. Although there has been
an increase in the FY' 82 total grant budget, the number of awards issued prob-
ably will not similarly increase. This is because the cost of conducting
research has been increasing at a rate in excess of that of the NINCDS grant
budget. Nonetheless, approximately 2,217 applications will be reviewed at the
three NANCDS Council meetings held during Fiscal Year 1982.
During Fiscal Year 1982 the Grants Processing Section was among the first
B/I/D's at NIH to begin preparing the Notice of Grant Award for its research,
training and fellowship programs by using its own computer terminal. By
assuming this responsibility from the Division of Research Grants, the time
needed to process awards has been reduced from 14 to 5 working days. The
Notice of Grant Award can therefore be issued to the Principal Investigator
and Grantee Institutions in an even more timely fashion than had previously
been possible.
The Grants Management Branch is now responsible for coordinating responses to
Freedom of Information (FOI) requests submitted to the NINCDS. In FY '82 the
GMB will process an estimated 175 FOI requests. These requests will range from
the simple, such as copies of the minutes of meetings which can be released
generally without deletions, to the complex, such as summary statements, grant
applications, etc., which can be released only after required deletions have
been made for privacy purposes and patent issues are resolved.
&-EAP
ANNUAL REPORT
October 1, 1981, through September 30, 1982
Contracts Management Branch
Extramural Activities Program
National Institute of Neurological and
Communicative Disorders and Stroke
The Contracts Management Branch (CMB) consists of the Chief of the Branch, four
specialists, and three supporting staff.
During fiscal year 1982, the CMB was responsible for some 85 contracts and
Interagency agreements, totaling $13 million in awards. The total value of
these contracts, including amounts obligated to-date, is nearly $60 million.
There are 22 ongoing intra- and interagency agreements, some of which are
funded from other sources not included in the dollar amount above. In addition,
there are some 90 research contracts that have expired and are in the process
of being administratively closed out.
During fiscal year 1982, the CMB issued 11 Request for Proposals (RFPs) for the
purpose of soliciting new contract projects and for recompeting several ongoing
projects. It is expected that approximately 16 new contract awards will be made
during the year due to anticipated multiawards as a result of more than one of
these solicitations. Added to this workload are 45 renewals of existing
contracts with additional funding and over 80 other actions modifying contracts
in some manner but not requiring additional funding.
This year saw the introduction of a second utilization of the Master Agreement.
The Master Agreement mechanism is being implemented to add flexibility to the
Program areas and to speed the procurement process. By the end of FY 1982, it
is anticipated that 15 Master Agreements for another Program will have been
awarded.
Two members of the staff, Ms. D. Selleh and Ms. P. Davis, recieved Quality Step
Increases during FY 1982. In a special ceremony Ms. Davis also received the NIH
Award of Merit.
7-EAP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of Data Analysis and Reports
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
Personnel Activities; Two grant clerks retired. A technical information
specialist was hired to assist with disorder, scientific, and program area
classification of grant applications and data activities. A clerk-typist was
moved into a computer programmer trainee position. A new clerk was hired.
Overall staff size is unchanged — four program analysts, an accounting techni-
cian, a technical information specialist, two computer programmers, a computer
programmer trainee, and a clerk-typist. Several staff members have attended
training courses mostly in the automatic data-processing area. One employee
was promoted; one received a quality step increase.
The office continues to publish a complete series of printed fiscal and
currently active data books. These include, on an annual basis, the Training
Data Book, the Fiscal Year Summary Book Series (four volumes) , and on a semi-
annual basis the Research Grants Data Book. Quarterly and Council reports are
also produced though not sent to a printer.
During Fiscal Year 1982 ODAR implemented an automated system of tracking the
payment of grants, replacing a manual ledger system that had existed for
several years. It is operated and maintained by our accounting technician.
The data base is updated daily; preprogrammed reports are available on demand.
ODAR also developed and implemented an automated system for tracking other
object expenditures in the extramural programs. Our accounting technician,
using input provided by the extramural administrative offices, also operates
and maintains this data base. Data are input to this system the same day they
are received from the administrative offices; preprogrammed reports are pro-
duced monthly or more frequently if necessary.
ODAR is now producing about 400 computer-generated letters each Council cycle,
notifying principal investigators of Council actions. Formerly, this letter
production required someone manning a mag-card machine for about AO hours.
One of our routine responsibilities includes assigning disorder, scientific,
program area, discipline specialty field, and the principal investigators'
specialty codes to grant applications for reporting purposes. We process about
1,600 applications annually.
In addition to the above-mentioned activities, the Office of Data Analysis and
Reports (ODAR) responded again to more than 300 requests for information not
only from within the Institute, but also from other NIH Institutes and Federal
and non-Federal agencies .
- EAP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Scientific Review Branch
Extramural Activities Program
National Institute of Neurological
and Communicative Disorders and Stroke
The Scientific Review Branch (SRB) is responsible for the technical merit
review of applications for Research Program Projects, Specialized Centers,
Workshops/Conf erences, Teacher-Investigator Development Awards, and Insti-
tutional National Research Service Awards. The Branch has three standing
Committees — Communicative Disorders Review Committee (CDRC), Neurological
Disorders Program Project Review A Committee (NSP-A) , and Neurological Disorders
Program Project Review B Committee (NSP-B) . Although these three committees are
responsible for the technical merit review of the majority of grant applications,
it is necessary to convene a number of ad hoc committees to evaluate applications
not assigned to a standing committee and to evaluate all contract proposals sub-
mitted in response to a "Request for Proposal."
On September 30, 1982 the staff of the Scientific Review Branch included the
following individuals:
Ellen G. Archer, Executive Secretary, NSP-B
Mary Black, Clerk Typist
Alfred Bruner, Executive Secretary
Diane Casillas, Grants Technical Assistant
Margaret Caudle, Grants Technical Assistant
Leon J. Greenbaum, Jr., Executive Secretary, NSP-A
Frances Hisaoka, Grants Technical Assistant
Joyce Lamb, Grants Technical Assistant
Katherine Phillips, Grants Technical Assistant
Meigs L. Ranney, Lead Contracts/Grants Technical Assistant
Marilyn Semmes, Executive Secretary, CDRC
Raymond Summers, Chief
Howard Weinstein, Executive Secretary
Arthur B. White, Executive Secretary
Olga Williams, Grants Technical Assistant
The following table summarizes the number and type of grant applications that
were revievjed and it indicates the number of site visits that were made.
9-EAP
NUMBER OF APPLICATIONS REVIEWED AND SITE VISIT IIADE BY
SCIENTIFIC REVIEW BRANCH PERSONNEL ACCORDING TO TYPE OF APPLICATION
Type of Grant
Application
Program
Project (POl)
Specialized
Center (P50)
Cooperative Clinical
Research Grant (RlO/ROl)
Conference
Grant (R13)
Teacher-Investigator
Development Award
(K07)
Institutional National
Research Service
Award (T32)
TOTAL
Review by Standing NINCDS
Committees (CDRC, NSP-A and
NSP-B)
Number of Number of
Applications Site Visits
47
21
11
54
33
175
41
14
63
The table shows that 175 grant applications were reviewed and that 63 site visits
were made. It should be noted that the number of applications and number of site
visits for applications going to the January 1982 Council has been estimated.
Concerning the technical merit review of contract proposals that were submitted
in response to RFPs, 38 were received in response to 6 RFPs. Responses are due
for two additional RFPs (82-08 and 82-09) before the end of the fiscal year and
we do not know how many proposals will be received.
Personnel in the Scientific Reviev/ Branch work closely with all components of
the Extramural Activities Program and with personnel in the five NINCDS pro-
grams. It is imperative that we maintain liaison with leaders of the scientific
community for the purpose of identifying the most qualified individuals to serve
on our technical merit review committees and panels.
T-O-EAP
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Communicative Disorders Program
National Institute of Neurological and
Communicative Disorders and Stroke
TABLE OF CONTENTS
PROGRAM SUMMARY 1-13
GRANTS ACTIVITY SUMMARY
Speech and Language
Basic Studies 14
Causal and Predictive Factors in Disorders 15
Diagnosis, Treatment and Rehabilitation 16
Taste and Smell
Basic Studies 17
Structure and Function 17
Causal and Predictive Factors in Disorders 18
Diagnosis, Treatment and Rehabilitation 18
Touch
Basic Studies 19
Hearing
General Considerations 20
Peripheral Auditory System
Basic Studies 20
Causal and Predictive Factors in Disorders 21
Diagnosis, Treatment and Rehabilitation 22
Central Auditory System
Basic Studies 24
Causal and Predictive Factors in Disorders 24
Diagnosis, Treatment and Rehabilitation 25
Biochemistry, Neurochemistry and Pharmacology of Hearing
Basic Studies 25
Diagnosis and Treatment 27
TAB 3
GRANTS ACTIVITY SUMMARY (continued)
Auditory Prosthesis Research
Basic Studies 27
Diagnosis, Treatment and Rehabilitation 28
Equilibrium and Balance
Basic Studies 28
Diagnosis, Treatment and Rehabilitation 30
Disorders of the Ears, Nose and Throat
Basic Studies 31
Causal and Predictive Factors in Disorders 31
Diagnosis, Treatment and Rehabilitation 34
CONTRACT NARRATIVES
Auditory Sensitivity in Young Children
(NOl-NS-5-2313) 36
A Comprehensive Study of the Language Recovery Process in
Adults with Aphasia Following a Cerebrovascular Accident
(NOl-NS-7-2378) 37
Evaluation of a Test of Speech Perception in Noise
(NOl-NS-7-2380) 39
Decongestant/Antihistamine Therapy for Otitis Media
with Effusion (OME)
(NOl-NS-8-2384) 41
Laryngeal Carcinoma: Identification of High Risk Factors
(NOl-NS-8-2399) 42
The Acquisition of Language and Communicative Skills by
Speech and Sign in Infantile Autism
(NO1-NS-9-2305) 44
Evaluation of the Outcome of Preschool Impairment in
Language Development
(NOl-NS-9-2322) 46
Efficacy of Adenoidectomy/Tympanostomy Tubes for
Persistent Otitis Media with Effusion (POME)
(NOl-NS-0-2328) 48
Determination of Effects of Hearing Aid Amplification
on Children
(NOl-NS-0-2329) 49
TAB 3
CONTRACT NARRATIVES (continued)
Methods for Studying Phonatory and Articulatory
Control in Young Children Who Stutter
(NOl-NS-0-2331) 50
Evaluation of the Effectiveness of Information Services
Provided to Specialists in Communicative Disorders by
MEDLINE
(NOl-NS-0-2342)
(NOl-NS-0-2343)
(NOl-NS-0-2344)
(NOl-NS-0-2345)
(NOl-NS-0-2346) 52
An Analytical Study of the Auditory Effects of Noise
(NOl-NS-1-2381) 54
The Prescription of Communicative Devices for Non-
Speaking Patients
(NOl-NS-2-2305) 55
Assessment of High Frequency Hearing
(NOl-NS-2-2394) 57
PROJECT REPORTS
Characteristics of Dysarthric Speech Associated
with Neurologic Disease
ZOl NS 02185-08 CDP 58
The Characteristics and Treatment of Vocal Tics and
Language Processing in Gilles de la Tourette Syndrome
ZOl NS 02247-06 CDP 59
Cis Platinum and Early Identification of Ototoxicity
ZOl 02336-05 CDP 60
The Effects of Stimulants on the Auditory Processing
and Language Skills of Hyperactive, Language Impaired
and Normal Subjects
ZOl NS 02337-05 CDP 61
Analysis of Fluctuating Hearing Loss Associated with
Cogan's Syndrome
ZOl NS 02395-04 CDP 62
Auditory Deficits in Osteogenesis Imperfecta
ZOl NS 02396-04 CDP 63
The Development of Acoustic Measurement Tools for
Assessing Vocal Pathology
ZOl NS 02440-03 CDP 64
TAB 3
PROJECT REPORTS (continued)
Hearing Assessment in Central Neurofibromatosis
ZOl NS 02441-03 CDP 65
Audiologic Findings in Autism
ZOl NS 02464-02 CDP . 66
Hearing in Peripheral Neurofibromatosis
ZOl NS 02465-02 CDP 67
Pediatric Oncology Regimen and Ototoxicity
ZOl NS 02466-02 CDP 68
Auditory Function and Cerebral Vasculitis
ZOl NS 02467-02 CDP 69
Audiologic Findings in Wegener's Granulomatosis
ZOl NS 02468-02 CDP 70
Small Cell Carcinoma and Hearing Loss
ZOl NS 02469-02 CDP 71
Audiologic Findings in an Aging Population
ZOl NS 02470-02 CDP 72
Hearing and Neomycin Therapy for Type II Hyperlipidemia
ZOl NS 02471-02 CDP 73
The Effects of Penetrating Head Injuries on Speech
and Language Functioning
ZOl NS 02557-01 CDP 74
Audiologic Findings of Multiple Sclerosis Lymphocyte
Depletion Treatment
ZOl NS 02558-01 CDP 75
Audiologic Findings in Alzheimer's Disease
ZOl NS 02559-01 CDP 76
Evoked Potential Correlates of Neurological Disorders
ZOl NS 02560-01 CDP 77
TAB 3
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Communicative Disorders Program
National Institute of Neurological and
Communicative Disorders and Stroke
Introduction
The Communicative Disorders Program is concerned with the scientific bases of
communication between individuals (speech, voice, hearing) , with the scientific
bases of the individual's communication with his or her environment (chemosenses,
balance control) and with the disorders of those modes of communication. The
normal physiology of many of these communication systems is poorly understood, and
since, in many if not all instances, treatment or prevention of disorders is depen-
dent upon a clear understanding of the normal, clinical management of disorders is
often limited to symptomatic treatment or rehabilitation. The Program therefore
encourages basic investigations of system physiology, and investigations directed
to the application of basic knowledge in the prevention and treatment of disorders.
Communicative Disorders Program Staff
Ralph F. Naunton, M.D., F.A.C.S., Otolaryngologist, has served as Director of
the Communicative Disorders Program during the past year.
J. Buckminster Ranney, Ph.D. , has served as Deputy Director of the Program.
Earleen Elkins, Ph.D., Audiologist, directs the hearing portion of the Program
and also supervises the Audiology Service at the Clinical Center, responsible for
diagnostic clinical audiology and clinical research.
Christy L. Ludlow, Ph.D., Speech and Language Pathologist, directs the speech and
language portions of the Program. In addition to her Extramural Activities, she
maintains a clinical research program with the assistance of Ms. Celia Bassich,
Research Speech Pathologist.
Ernest J. Moore, Ph.D., Audiologist, directs the vestibular, otolaryngologic and
cochlear prosthesis portions of the Program.
Jack Pearl, Ph.D., Chemosensory Physiologist, is responsible for the chemosensory
and haptic portions of the Program.
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Communicative Disorders Program Activities
Ad hoc Advisory Committee Meetings
The Advisors have met on two occasions during the past year. Each of the following
was present at one or both of these meetings:
Dr. Robert C. Bilger Dr. Robert I. Kohut
University of Illinois Bowman Gray School of Medicine
Dr. Norman Geschwind Dr. Murray B. Sachs
Beth Israel Hospital Johns Hopkins School of Medicine
Dr. Raymond D. Kent Dr. David V. Smith
Boys Town Institute University of Wyoming
Program staff also attended these meetings together with a number of other represen-
tatives from the Institute. The Advisors have provided direction to the Program
bearing on future areas of research, in particular, identifying those calling for
special emphasis. They have also critically evaluated staff suggestions for new
or special initiatives, approving of them or suggesting modifications. The next
meeting is scheduled for October 1982.
Program Activities
In collaboration with the Office of Scientific and Health Reports a booklet was
developed and published on "Hearing Loss: Hope Through Research." It provides
current information on hearing disorders and diseases and is designed for the
lay public. (Dr. Elkins)
In order to encourage serious investigations of tinnitus, a Program Announcement
was issued for studies which would address this very common complaint of hearing-
impaired people. Applications are sought to define the auditory properties of
tinnitus as well as the possible causes and treatment of this phenomenon.
(Dr. Elkins)
Speech is used in a number of different ways to measure the hearing ability of a
listener. A conference was held to explore current clinical procedures and to
relate recent research findings to the improvement of diagnostic methods. The
participants also determined future research that is required to evaluate
peripheral and central processing of speech stimuli, - whether or not the patient
requires the use of a hearing aid. (Dr. Elkins)
Efforts to improve information services for clinicians and investigators in the
communicative sciences are continuing. The Communicative Disorders Program staff
conducted an evaluation study of Deafness, Speech and Hearing Abstracts, the
major abstracting periodical in the communicative sciences and disorders. They
recommended upgrading this publication with the use of the MEDLINE data base of
the National Library of Medicine. Consequently, an agreement was developed with
the NLM to provide current citations for dsh Abstracts and CDP staff are developing
the retrieval programs for each of the fields in the communicative sciences and
disorders. The first issue using the expanded and timely data base provided by
MEDLINE services will be published early in 1983. Since dsh Abstracts reviews
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the world literature in deafness, speech, language and hearing, these efforts will
have impact on the availability of recent research information for specialists
in these fields. (Drs. Ludlow and Reiner)
The MEDLINE evaluation project is continuing as a national study of the needs of
specialists in communicative sciences for improved information services. Over
700 professionals are participating in the study and are primarily speech-language
pathologists, audiologists and graduate students. Very few have previously had
exposure to computerized data bases; most were using individual journal subscrip-
tions and discussions with peers to keep abreast of recent developments in their
fields. Based on the first year of receiving MEDLINE services, it is becoming
evident that users prefer accessing bibliographic information with the help of a
technical information specialist with background training in communicative disorders
rather than searching independently or having a search done for them, MEDLINE
services seem most satisfactory for accessing information in subject areas beyond
a user's particular specialty.
In 1982, a five year evaluation of performance in the speech and language research
program was conducted by CDP staff. Since 1978, the number of speech and language
grant applications received has doubled from 36 to 74 (105% increase). However,
over the same time period, the number of speech and language applications funded
has increased by only 29%. Between 1978 and 1982 the rate of approval of applica-
tions has increased from 64% to 73% while the percentage of approved grants which
are funded has decreased from 57% to 35%. Hence, due to a shortage in funds in
the Communicative Disorders Program, support has been unable to keep pace with
the rapid growth and increase in quality in speech and language research applica-
tions over the last five years. An evaluation of program performance by mechanism
reveals that funding has kept pace with inflation only in the support of research
grants, even though it has not kept pace with growth in the number of applications
received as indicated above. Between 1978 and 1981, the available dollars for
research grant support increased by 31.4% over inflation. This was largely due to
the competitiveness of the grant applications received in this area, since the
increase in grant funding over inflation for the NINCDS as a whole over the same
period was 23.4%. At the same time, contract research support has been reduced in
actual dollars by 11.5% and when adjusted for inflation, this represents a reduction
of 32% in real spending. This reduction has effected a decrease in programmatic
efforts aimed at developing measurement and diagnostic tools for research in speech
and language disorders for which the contract mechanism was being used effectively.
Past accomplishments included the development of: treatment coding systems to
quantify progress during language intervention; screening tests for early detection
of delayed language development; a procedure for evaluating communicative abilities
of aphasics, hearing impaired and aging adults; methods for diagnosis of sensory
and perceptual disorders in language impaired children; and, methods for measuring
hemispheric differences in cerebral metabolism in aphasic adults following stroke.
The dollars spent on training new investigators in speech and language research
have increased over inflation between 1978 and 1981 by 12.75%. However, when the
number of trainees receiving support is examined across the 4 different training
support programs during this time there are dramatic differences. Increases
occurred in the two research career support programs; the number of Teacher Inves-
tigator Development Awards increased from two to seven while Research Career
Development Awards increased from one to three. At the same time, however, the
number of postdoctoral trainees decreased drastically in both the individual
National Research Service Awards as well as Institutional NRSA support programs.
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The total number of postdoctoral candidates was 27 in 1978 and only 10 in 1981, -
a 63% reduction in the number of candidates being trained in research. The effectsi
of these reductions will become most evident in the next five to ten years.
(Dr. Ludlow)
Subsequent to the marked reductions in postdoctoral training in speech and languagei
research a Program Announcement entitled, "Institutional National Research Service
Awards for Clinical Research Training in Speech and Language Disorders" was issued
in September 1981. Over 65 inquiries and 12 applications were received during the
first 8 months of this announcement. It is expected that some increase in post-
doctoral training in speech and language research will be effected in 1983 through
this program. (Dr. Ludlow)
In order to encourage physician involvement in research directed towards the
prevention and treatment of otolaryngologic communicative disorders, a Program
Announcement was published encouraging the formation and application for support
of Clinical Otolaryngologic Research Centers. These would comprise clinical and
basic scientists working in collaboration towards the prevention and treatment
of specific disease entities. Approximately 35 inquiries have been received by
the Program to date. (Dr. Moore)
In collaboration with the Journal of the American Medical Association an article
entitled, "Taste and Smell: The Neglected Senses" was published. This will
provide information to the medical community on chemosensory disorders and type
of preventive interventions available. (Dr. Pearl)
A Hearing, Language and Speech Voluntaries meeting was held in April 1982. Invited
representatives from ten (10) voluntary associations, councils, foundations or
institutes met to share perceptions and needs for hearing, language and speech
research. Three complementary themes were identified by the participants: Indenti
fication, Intervention and Prevention. Observers from other voluntary associations
attended the meeting as well as observers from professional associations.
(Dr. Ranney)
4-CDP
Staff Presentations at National and International Meetings
Bassich CJ, Ludlow CL. "The use of perceptual methods for assessing vocal
pathology." American Speech-Language-Hearing Association.
Elkins E, Pikus A. "Audiologic Profile in Peripheral Neurofibromatosis."
American Speech-Language-Hearing Association.
Elkins E. "NIH Support for Research in the Communicative Disorders." National
Council of Graduate Departments of Psychology.
Elkins E. "NIH Clinical Research in Hearing." National Conference on Research
Goals and Methods for Otolaryngology.
Elkins E, Dolan TR. "Review and Funding of Research Grants Pertaining to Hearing
at NIH and NSF." Acoustical Society of America.
Ludlow CL. "Objective measures for assessing speech impairments in dysarthria."
American Speech-Language-Hearing Association.
Ludlow CL, Bassich CJ. "The results of perceptual and acoustic assessment of
two types of dysarthria." Clinical Dysarthria Conference.
Ludlow CL, Insel TR, Bassich CJ. "Oral expressive language elicitation deficits
in obsessive-compulsive adults." International Neuropsychological Society.
Ludlow CL. "The brain bases for language functioning: New insights from penetra-
ting head injuries." Georgetown University Round Table on Languages and Linguis-
tics, "Contemporary Perceptions of Language: Interdisciplinary Dimensions."
Ludlow CL. "Identification and assessment of aphasic patients for language inter-
vention." National Conference on Language Intervention.
Ludlow CL, Rosenberg J, Dillon D, Buck D. "Persistent speech dysprosody following
penetrating head injuries." Speech Motor Control Conference.
Ludlow CL, Cudahy EA, Bassich CJ. "Developmental, age and sex effects on gap
detection and temporal order." Acoustical Society of America.
Ludlow CL, Coulter DC, Bassich CJ. "Relationships between vocal jitter, age,
sex and smoking." Acoustical Society of America;
Ludlow CL, Coulter DC, Gentges F. "The effects of changes in vocal fold morphology
on phonatory jitter." Voice Foundation Symposium: Care of the Professional Voice,
Juilliard School.
Moore EJ. Chairperson for session on Speech, Language and Audiological Services
at the American Speech-Language-Hearing Association meeting.
Moore EJ. "Bases of Auditory Brain Stem Evoked Responses." National Black
Association of Speech, Language and Hearing.
Naunton RF. "Funding for Research in Communicative Disorders." Society of
University Otolaryngologists.
5-CDP
Naunton RF. "Research in Otolaryngology: NTH Support and Other Considerations."
Middle Section of the American Laryngological, Rhinological and Otological Society.
Naunton RF. "Preparation of Research Grant Applications." Association for
Research in Otolaryngology.
Naunton RF. "The Communicative Disorders Program," National Conference on
Research Goals and Methods in Otolaryngology.
Pearl J. "NIH Support for Taste and Smell: Research and Training." Association
for Chemoreception Sciences.
Ranney JB. "Deafness Research Opportunities." International Convention of the
Alexander Graham Bell Association for the Deaf.
Reiner BJ. Exhibit on the Use of MEDLINE for Bibliographic Retrieval in Communica-
tive disorders. American Speech-Language-Hearing Association.
Staff Presentations at Other Meetings
Elkins E. "Federal Grants." American Speech-Language-Hearing Association.
Elkins E. "Federal Support of Research of the Hearing and Vestibular Systems as
Reported for FY 1979 and FY 1980." Committee on Hearing, Bioacoustics and
Biomechanics, National Academy of Sciences.
Elkins E. "Statistical Procedures for Analyzing Speech and Hearing Research."
Seminar for Advanced Studies, University of Maryland.
Elkins E. "Speech Recognition and Hearing Aids: 1982 State of the Art." Maryland
Speech-Language-Hearing Association.
Elkins E. "Experimental Design and Analysis of Auditory Evoked Response Data from
Adult Subjects." Washington Hospital Center, Washington, D.C.
Elkins E. "Noise-Induced Hearing Loss." D.C. Chapter of Graduate Women in Science.
Moore EJ. "Grants and Contracts." Grantsmanship Workshop, Howard University.
Moore EJ. "Rules and Procedures for Applications to NIH." Universities of
Goteborg, Karolinska, Upsalla and Malmo, Sweden.
Moore EJ. "Auditory BSER: Stimulus Parameters and Clinical Applications."
Universities of Goteborg, Karolinska, Upsalla and Malmo, Sweden.
Naunton RF. "The Hearing Impaired Child." Keynote Address. Illinois Department
of Public Health Symposium.
Pearl J. "NIH Support of Chemosensory Research." Monell Chemical Senses Center.
6-CDP
Other Staff Activities
Dr. Elkins:
- Served as Institute representative to the Committee on Hearing, Bioacoustics
and Biomechanics; National Academy of Sciences. (Member of Tinnitus and
Auditory Evoked Response Working Groups) .
- Served as chairperson. Committee on Speech Audiometry, American Speech-
Language-Hearing Association.
- Served as member. Committee on Speech Recognition, Acoustical Society of
America.
- Served as consultant, Audiometric and Tympanometric Data Collection and
Analysis, National Health Examination Survey, National Center for Health
Statistics.
- Served as member. Advisory Board for NASA/Gallaudet College project: Autocuer
Device for the Hearing- Impaired.
- Served as member, Committee on Research Facilitation, National Conference
on Research Goals and Methods in Otolaryngology.
Drs. Ludlow and Reiner:
- Served as consultants to the Executive Board, Deafness, Speech and Hearing
Abstracts.
Dr. Ludlow:
- Served as member. Consortium of Affiliates for International Programs of
the American Association for the Advancement of Science.
- Served as chairman. Scientific Affairs Committee of the American Speech-
Language-Hearing Association.
- Served as chairman. Journal Selection Committee, Deafness, Speech and
Hearing Abstracts.
- Served as Liaison Representative to the American Speech-Language-Hearing
Association to the American Association for the Advancement of Science.
- Served as member. Speech Communication Technical Committee, Acoustical
Society of America.
- Served as Associate Editor (Neuropathologies) , Journal of Speech and
Hearing Research.
- Served as member. Editorial Advisory Board, Journal of Developmental and
Behavioral Pediatrics.
7-CDP
- Appointed principal investigator of speech and language research on the
Vietnam Head Injury Program funded by the Veterans Administration and
supported by the Army, Navy and Air Force.
- Elected to membership in the Academy of Aphasia.
- Appointed member, Speech Communication Technical Committee, Acoustical
Society of America.
Dr. Moore:
- Served as NIH Tour coordinator. National Conference on Research Goals and
Methods in Otolaryngology, Bethesda, Maryland.
Dr. Naunton:
- Served as chairman, Membership and Credentials Committee, American
Neurotology Society.
- Served as member, Editoral Board, American Journal of Otolaryngology.
- Served as President, American Auditory Society.
- Served as member, American National Standards Institute (Bioacoustics) .
- Served as consultant, ENT Devices Section, FDA Panel on Dental,
Ophthalmological and ENT Devices.
- Served as member. Board of Directors, Better Hearing Institute.
- Served as member. Committee on Research, American Otological Society.
- Appointed Honorary member. Society of University Otolaryngologists.
- Presented listener call-in program on Tinnitus, WAMU Radio, Washington, D.C.
Dr. Pearl:
- Served as member, NINCDS Equal Employment Opportunity advisory committee.
- Serving as CDP representative, NINCDS Symposium on Pain Measurement and
Assessment.
- Discussed disorders of taste and smell, radio program.
- Manned Institute exhibit at Association for Chemoreception Sciences.
8-CDP
Dr . Ranney :
- Represented CDP/NINCDS at the Interagency Ad Hoc Committee on Deafness/
Hearing Impairment Research meetings, Washington, D.C.
- Served as chairman for the Scientific Exhibits Sub-Committee for the 1982
American Speech-Language-Hearing Association Program Committee.
- Served as member. Committee on the Clinical Fellowship Years, American
Speech-Language-Hearing Association.
9-CDP
Clinical Activities
Dr. Elkins
Clinical research in hearing, under the direction of Dr. Elkins and in cooperation
with Ms. Pikus and Ms. Grimes of the Clinical Center, continues to focus on hearing
losses associated with various diseases and disorders. Studies are being conducted
to identify carrier status in selected genetic diseases; detect ototoxicity related
to chemo therapeutic agents and radiation therapy; document suspected hearing im-
pairment associated with several neurological disorders; develop a profile of risk
factors for presbycusis; and develop techniques for the measurement of auditory
function in autistic children and adults. Hearing and middle ear function in
Osteogenesis Imperfecta resulted in a publication in cooperation with investigators
in the Clinical Center and the Division of Computer Research and Technology. This
study showed that a majority of the subjects (N=55) display absent acoustic reflexes
and increased compliance of the middle ear with notched tympanograms suggestive of
anomalous ossicular articulation. Similar findings in otherwise uninvolved rela-
tives (N=92) suggest a genetic basis for these defects. Details of other studies
in progress may be found in the reports of research projects.
Dr. Ludlow
Outpatient clinical research activities have increased to accommodate ongoing speech
and language research protocols under the direction of Dr. Ludlow. These protocols
are being conducted in collaboration with otolaryngological services in the Clinical
Center. Referrals of chronic undiagnosed laryngeal disorders are being received
from local and national sources. Patients are participating in diagnostic studies
of several phonatory disorders including spastic dysphonia and aphonia. New pro-
cedures for predicting the effects of recurrent laryngeal nerve section in patients
with spastic dysphonia are being developed and have potential for use in differen-
tial diagnosis of these disorders.
An automated system for measuring vibratory function during phonation for speech
is being used in assessment of phonatory abnormalities associated with changes in
vocal fold morphology. One measure is particularly sensitive to structural
asymmetries between the vocal folds and will identify when small growths occur on
one of the vocal folds such as in laryngeal carcinoma, polyps or nodules. This
analytic technique has potential for clinical application since it appears to be
insensitive to symmetric morphological changes in the vocal folds such as are
associated with smoking or age.
An acoustic analysis system containing many parameters for analyzing dysarthria
speech was completed and received well by the scientific community. It is valid
for differentiating (a) between normal and dysarthric speech and (b) between speech
symptoms associated with pathologies involving different structures within the
central nervous system. The successful completion of this analytic system will
allow investigations into the organization of the speech motor control system as
reflected by brain lesions and neuropathologies at specific locations in the CNS.
Speech motor disturbances in tardive dyskinesia, Parkinson's disease, Huntington's
chorea, and dystonia are being evaluated to determine whether the measures developed
are sensitive to differences in neuropharmacological intervention and could be
useful in treatment research.
10-CDP
Experiments involving oral and speech motor control in tardive dyskinesia and
Huntington's disease are aimed at determining whether lip and jaw movement range
and rate are affected when undisturbed by the intrusion of involuntary movements.
A unique three dimensional movement transducer for lip and jaw movements was
developed for this research to measure lip and jaw movement displacement, velocity
and acceleration during automatic, purposive and speech movements. The purpose
of this research is to determine how speech movement patterning is disturbed by
pathology at the level of the basal ganglia.
The speech and language research program is using some of the above techniques
in the study of speech motor control in penetrating head injuries in collaboration
with the Vietnam Head Injury Study at Walter Reed Army Medical Center. CT scanning
is being used to quantify the extent and location of central nervous system damage.
Experimental studies of speech motor control in patients with well defined lesions
at different brain locations will ascertain which structures are critical to the
integrity of speech motor control. Since these penetrating lesions have different
locations fronj those associated with cerebrovascular accidents, the findings thus
far provide critical new tests of hypotheses regarding neural organization of speech
programming. A syndrome of residual speech dysprosody 10 or more years following
brain injuries has indicated that frontal lobe white matter tracts from the pars
opercularis on either the left or right side have importance in the control of
rate of sequential movements in speech. Further, residual Broca's aphasia 10 or
more years following brain injury has been found only when fronto-parietal white
matter tracts from the Rolandic fissure and pre-motor regions are completely
involved, rather than Broca's region.
11-CDP
Staff Publications
Calne E, Welngartner H, Ludlow CL, Cudahy E, Wehry S. Qualitative Analysis of
scopolamine Induced amnesia. Psychopharmacologla; 74: 74-80, 1981.
Ludlow CL. Directions for the development of Improved methods for assessing
vocal pathology. ASHA Reports, 11: 3-8, 1981.
Ludlow CL, Hart MO, eds. Proceedings of the Conference on the Assessment of
Vocal Pathology. ASHA Reports, No. 11: 1981.
Naunton PvF. Research In otolaryngology: NIH support and other considerations.
Laryngoscope 1982; 92: 489-493.
Naunton RF. Tympanostomy tubes: the conservative approach. Annals of Otology,
Rhinology and Laryngology 1981; 90: 529-532.
Rapaport JL, Elkins R, Langer DB, Sceery SW, Buchsbaum MS, Gillin JC, Murphy DL,
Zahn T, Lake R, Ludlow CL. Childhood obsessive compulsive disorder. American
Journal of Psychiatry; 138: 1545-1554, 1981.
Rapoport JL, Jensvold M, Elkins R, Buchsbaum MS, Welngartner H, Ludlow CL, Zahn T,
Neims A. Behavioral and cognitive effects of caffeine in boys and adult males.
The Journal of Nervous and Mental Disease; 169: 726-732, 1981.
Reiner BJ, Ludlow CL. Using MEDLINE for literature retrelval in communicative
disorders. Asha Journal, 23: 655-661, 1981.
Calne ED, Polinsky RJ, Ludlow CL, Ebert MP, Nee LE. Heterogeneity and Variability
in Tourette's Syndrome. In Chase T, Frledhoff A, eds. Tourette's Syndrome,
Raven Press, New York, in press.
Hanson D, Ludlow CL, Bassich CJ. Vocal fold paresis in Shy-Drager syndrome. Annals
of Otology, Rhinology and Laryngology, in press.
Ludlow, CL. The brain bases for language functioning: New insights from penetrating
head injuries. In Byrnes H, ed. Proceedings of Conference on Contemporary Percep-
tions of Language: Interdisciplinary Dimensions. Washington, D.C., Georgetown
University Press, in press.
Ludlow CL. Identification and assessment of aphasic patients for language inter-
vention. In Miller J, Yoder DE, and Schief elbusch R, eds. Language Intervention.
Trenton, New Jersey, B. C. Decker, Inc., in press.
Ludlow CL, Bassich CJ. The results of acoustic and perceptual assessment of two
types of dysarthria. In Berry W, ed. Clinical Dysarthria, San Diego. College-Hill
Press, California, in press.
Ludlow CL, Coulter D, Gentges F. Differential sensitivity of frequency perturbation
to laryngeal neoplasms and neuropathologies. In Abbs J, Bless D, eds. Proceedings
of International Conference on Vocal Fold Physiology. College-Hill Press, San
Diego, in press.
12-CDP
Ludlow CL, Cudahy E, Bassich CL, Brown GL. Auditory processing skills of hyper-
active, reading and language impaired boys. In Katz J, Lasky E, eds. Central
Auditory Processing Disorders: Problems of Speech, Language and Learning. Univer-
sity Park Press, Baltimore, in press.
Ludlow CL, Polinsky RJ, Caine ED, Bassich CJ, Ebert MH. Language and speech
abnormalities in Tourette's Syndrome. In Chase T, Friedhoff A, eds. Tourette's
Syndrome, Raven Press, New York, in press.
13-CDP
GRANTS ACTIVITY SUMMARY
Communicative Disorders Program
Speech and Language
Basic Studies
Speech production research is aimed at understanding how humans plan and execute
speech, by examining to what degree the movement patterns for producing speech
sounds are fixed motor programs in adult speakers. When adults were instructed
to increase or decrease their speaking rate, the timing of muscle contractions
and articulator movements for the production of consonant sounds were invariant
relative to the length of vowel productions. Thus, constant time relationships
are maintained between different articulator movements for speech sounds regard-
less of the speaker's overall speech rate suggesting that speech production is
programmed in units containing all the movements required for producing con-
sonants and vowels together. Further examination of these issues includes
studies of coarticulation, the influence of the movements required for one speech
sound upon preceding sounds. Electromyographic studies of vowels requiring lip
rounding determined that the movement gesture associated with the vowel is
initiated at a fixed time preceding the vowel regardless of the types of sounds
preceding the vowel. These results suggest that each speech sound is preprogrammed
as a motor gesture and not dependent upon which sounds precede or follow it.
Animal studies of the organization of laryngeal motor neurons in the brain stem
are aimed at determining the neural control of individual motor units in the
larynx. The location and morphology of cell bodies which control motor units
involved in vocal fold adduction and abduction for sound production, inspiratory
gestures of the larynx and airway protection mechanisms such as coughing, are
being studied in monkeys. Determination of whether the same neurons contribute
to different functions and are recruited to varying degrees for different
functions will provide new knowledge regarding the neural control of the larynx.
Stimulation studies of single motoneuron axons in the brain stem of anesthetized
monkeys have demonstrated both expiratory and inspiratory motor units in the
cricothyroid. The expiratory units have faster conducting axons and faster
contracting muscle fibers than the inspiratory units and are derecruited during
elevated PCO or inspiratory dyspnea. The cell bodies for these units were
found in the dorsal subdivision of the nucleus ambiguous. Inspiratory units were
recruited during PCO„ or forced inspiration. Similar studies will determine
whether the same motor units have separate functions for vocalization and are
controlled by the same brainstem nuclei.
Speech perception studies of man's ability to recognize speech sounds, have
increased dramatically in recent years. Recent research has indicated that the
process is much more complicated than was originally thought. Acoustic spectra
with the same frequency components as natural speech but containing sinusoidal
replicas are perceived differently by listeners dependent upon whether they are
told that they will be hearing sound or speech, suggesting that adult listeners
use different perceptual mechanisms for perceiving speech and non-speech sounds.
Investigators are currently producing synthetic speech stimuli and varying the
acoustic cues to determine what normal adult listeners require to be able to
perceive phonetic segments.
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Neuropsychological studies of the degree of lateralization of language functions
have demonstrated differences between normal left and right-handed subjects in
the laterality of language functions. Over 300 male and female left-handers
and 250 right-handers have been administered an extensive battery of tests of
the laterality of language and non-language functions including dichotic listening,
finger tapping with concurrent naming and reading, manual preference, eyedness,
manual dexterity, handwriting posture, familial handedness, figure-ground per-
ception and manual and pedal asymmetries. The data have consistently indicated
a different, more variable, bilateral brain organization for language functions
in left banders in comparison with right banders.
The influence of sex on differences in brain organization for language have also
been examined in this research. No support has been found for the hypothesis
that there are language lateralization differences between males and females.
Causal and Predictive Factors in Disorders
The major obstacle to effective prevention or treatment of many speech and language
disorders is the lack of knowledge regarding the cause of the disorder. Examples
of this are language and learning disorders in children. Brains of individuals
known to have had specific language learning disorders such as dyslexia are being
obtained for postmortem study of the cellular structures in the brain. Previous
neuroanatomical studies of adult, fetal and infant brains have demonstrated
lateral asjnnmetries, with regions of the left temporal lobe being greater than
on the right. Scientists have postulated that the lateralization of language in
the left hemisphere in 98% of persons may, therefore, have a neuroanatomical
basis. Cytoarchitectonic studies of cellular organization in adult brains have
demonstrated that particular regions in the temporal lobe contain the cells
specific to the region in greater numbers on the left side. Possibly during brain
development a greater number of cells migrate to the left than to the right lobes.
A recent cytoarchitectonic study of a dyslexic brain demonstrated an abnormal
cellular organization of the left temporal lobe suggesting that abnormal cell
migration patterns during brain development may underlie some of these congenital
disorders.
Human geneticists are examining the family histories of stutterers and have found
a significantly greater family history of stuttering in stutterers than that
found in fluent speakers. Genetic linkage studies are proceeding in families
with a high density of stuttering over several generations in an effort to
identify loci which may have an association with the occurrence of stuttering
in these families. The identification of genetic mechanisms which may underlie
the development of abnormal brain mechanisms responsible for congenital speech
and language disorders has potential for the prevention of such disorders as
stuttering, developmental language disorders and dyslexia.
Investigators are validating a predictive screening test which can be administered
to pre-schoolers and first graders to identify those children who are at risk for
developing dyslexia on learning to read. Rapid automated naming tests were
administered to 300 children between five and six years of age along with tests
of language comprehension, non-verbal cognition and lateral dominance for lan-
guage. These children are being followed as they undergo reading training to
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determine which children later have dyslexia. It is hoped that particular patterns
of fluency and poor rhythmicity on rapid naming prior to reading will be predictive
of reading failure in schooling. If so, children at risk for developing dyslexia
can be identified early and effective intervention provided to prevent the appear-
ance of reading problems in school.
Diagnosis, Treatment and Rehabilitation
Experimental investigations are comparing the language learning characteristics
of language impaired children with normal children who are at the equivalent
stages in language development, and therefore much younger than the language
impaired group. In both groups the acquisition of new words for production is
poor when the words contain speech sounds the subject has not yet acquired. Thus
phonological development appears to play a significant role in language development
and should be focused on in language intervention.
Further, a study of the effects of participating in imitation was examined relative
to the acquisition of new words. Speech imitation was not beneficial to language
impaired children in an attempt to improve their production of new words. This
finding contra-indicates the use of speech imitation in intervention — a technique
now employed by many clinicians.
Research on the diagnosis and treatment of patients with spastic dysphonia has
continued. The recent discovery of the effectiveness of cutting one of the
recurrent laryngeal nerves to the vocal folds continues to be difficult to explain.
Continued comparisons of segments of the recurrent laryngeal nerve of patients
with spastic dysphonia and normals using light and electron microscopy yield no
significant differences, suggesting that the basis for the disorder is more central.
Diagnostic techniques which are predictive of the outcome of recurrent laryngeal
nerve section treatment for spastic dysphonia are currently being explored. Laryn-
goscopy, aerodynamics, acoustics and laryngography have not been found useful in
the diagnosis of spastic dysphonia. Rather, clinical phonatory characteristics
seem most predictive. Vocal arrests and vocal tremor have been found to be distinct
entities with vocal tremor predictive of little benefit from recurrent laryngeal
nerve surgery. A new technique of using a CO laser for thinning the body of the
paralyzed vocal fold has been found effective in treatment of those cases in which
spasticity recurs.
New treatment techniques for aphasic adults following stroke are being developed.
Lesion sites observed on CT scans have been found predictive of the outcome of
Melodic Intonation Therapy with non-fluent chronic aphasic patients. Those with
a good response to treatment had lesions primarily associated with either Broca's
area (cortical) or capsular/putamenal regions with anterior/superior lesion
extension (subcortical) . The CT scan lesion sites of poor treatment responders
were either bilateral, or unilateral with lesions including Wernicke's area
(cortical) or in the auditory radiations in the temporal isthmus (subcortical) .
Communicative aids are being developed for several groups of patients who are
non-vocal and severely physically disabled and have no means of communication
with others. Often such patients only have control remaining for eye movement
such as in the terminal stages of Amyotrophic Lateral Sclerosis. An ocular
control device has been found useful for such patients. The device fits on the
patient as a pair of eye glasses and tracks eye movement. Training the patient
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to use the device requires a minimum of two 30 minute sessions. The patient
can use the device to control other aids or to communicate through synthetic
speech. This and similar communicative devices are allowing such patients
to escape from their "locked in" condition and make their needs and thoughts
known.
Taste and Smell
Basic Studies
Understanding the trophic maintenance and regeneration of receptor cells is
important in attempting to prevent degeneration and aid recovery of impaired
neural systems. The olfactory system is unique in that the first-order neuron
is capable of regeneration, spontaneously and after insult such as bulbectomy,
axonal damage, or treatment of the olfactory epithelium with ZnSO, . The olfactory
bulbs are not required for the acquisition of olfactory tasks by mice. After
bilateral bulbectomy, discrimination was lost, but returned with the formation
of synaptic connections between regenerated olfactory receptor cells and the
cortex of the forebrain. It is not known whether the regenerated system has the
same sensitivity and range of responsiveness to odor as the undamaged system.
Results in hamsters suggest that receptor density, but not the total number of
receptors, reaches control levels after regeneration. The replacement of receptors
occurs in a thinner sheet of epithelium.
The electro-olfactogram (EOG) records the slow negative potential developed at
the surface of the olfactory epithelium. Results suggest that the EOG reflects
primarily the activity of young receptor cells that are not connected to the
olfactory bulb. Results in frogs showed a correlation between the rate and the
amplitude of the EOG and the rate of the regrowth of olfactory cilia during the
recovery from the insult of ZnSO,.
Because of its length, the garfish olfactory nerve is an ideal preparation for
studying certain aspects of axonal transport and degeneration. When crushed,
this nerve degenerates from the crush site toward the synapse. The rate of
degeneration decreases linearly with temperature. Since the rates of degeneration
are identical to the slow phase of axonal transport in regenerating fibers, it
is hypothesized that slow flow is taking place in the axons that have been
separated from their cell bodies. This slow flow would eventually cease because
the cell bodies cannot replenish the flow and the cessation of flow would induce
degeneration of the axons.
The taste buds also regenerate. Previous work with adult rats showed that bilat-
eral glossopharyngeal nerve denervation produces a loss of all the vallate
taste buds, whereas unilateral denervation produces a loss of about only 10% of
the buds because of the bilateral innervation of the buds. Studies in rat pups
show that unilateral denervation prevents many of the buds from developing and
suggests that interaction between fibers and bud precursors must occur during
early development to induce the normal number of buds.
Structure and Function
It may be necessary to revise the concept of the human olfactory epithelium to
include two morphologically distinct populations of receptor cells. One is the
well-known ciliated type. The presumptive new one is a microvilli type. These
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cells are being obtained with a recently developed tool that permits safe removal
of small biopsies of olfactory mucosa from people.
The first example of competitive inhibition of sweet taste in mammals has been
reported and results suggest that there are two types of receptor sites, a sugar
and a non-sugar site on the taste receptor cells of gerbils. Electrophysiological
results showed that a galactopyranoside did not stimulate the receptor, but inhib-
ited the response to sweetness. Sugars were inhibited competitively; artificial
sweeteners were inhibited non-competitively.
Causal and Predictive Factors in Disorders
Patients entering the clinical chemosensory centers include those with Kallmann's
syndrome, in which the olfactory bulbs fail to develop, familial dysautonomia,
in which certain taste buds fail to develop, and genetically-determined metabolic
disorders. It is being shown that the inherited ability to fully taste the bitter-
ness of phenylthiocarbamide is also associated with a greater ability to perceive
sweets and other taste qualities. There are some indications that the tasters
may be specially sensitive to certain chemotherapies. The chemical senses lend
themselves to description in terms of molecular properties. There are olfactory
studies whose results are being linked to immunological-like models where one
part of the genetic locus of the major histocompatability complex is related to
the chemical signal and another part is related to the reception of the signal.
The ability to detect the odor of a putative pheromone, androstenone, appears
to be genetically determined as indicated by results with Identical and fraternal
twins and siblings. These results were not related to the expression of the
major histocompatability complex.
The precise nature and causes of genetic variants in chemosensitivity in mice is
being determined in psychophysical studies and electrophysiological investigations
of nerve preparations for tastants.
There is concern about whether early experience with NaCl affects subsequent Na
or water intake and hypertension. Pregnant rats were fed a Na-free diet from
three days after gestation to twelve days after parturition. Their pups exhibited
a decreased preference for salt solutions as opposed to water but drank more
water and salt solutions than control pups. The difference in water intake between
the two groups can account for their preferences. Peripheral responses from the
chorda tympani were unremarkable when the salt-depleted pups were 24 days old.
Diagnosis, Treatment and Rehabilitation
Teams at two clinical chemosensory research centers are determining the advantages
and limitations of different tests for evaluating the chemical senses in a stan-
dardized way in clinical settings. Psychophysical measurements include detection,
recognition, identification and magnitude estimates of chemicals. A refinement
is cross-modality matching in which a decibel equivalent is determined for salty,
sour, sweet, and bitter tastants.
The interruption of the inhalation reflex by the inhalation of irritants through
the nose may prove to be an objective index of the status of the common chemical
sense. In comparison to non-smokers, smokers had a higher threshold for the
reflex and judged the pungency of two selected odorants as less intense. Smoking
during testing inhibited the inhalation reflex.
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Measurement of chemosensory abilities offers opportunities for non-invasive
detection of major disorders. For example, it seems possible to identify a
subgroup of people who are genetically predisposed to insulin-dependent diabetes
mellitus based on their perception of the taste of glucose. The intensity function
for the prediabetics resembled that for recruitment in that sensitivity was poor
at weak but normal at high concentrations. The prediabetics perceived fructose
normally. The recruitment of the prediabetics for glucose suggests that there
may be a separate receptor site with which glucose but not fructose interacts.
It is controversial whether zinc is effective in the treatment of chemosensory
disorders. The mean plasma and red blood cell zinc levels of patients with
chemosensory disorders were within normal limits. The levels in subgroups of
patients are being analyzed.
Most of the hyposmics and anosmics who have entered one of the clinical chemo-
sensory research centers appear to have nasal obstruction rather than disruption
of neural function. The medical status of the patients included a history of
polyps, allergic rhinitis, and periodic remission of symptoms. Viral infections
and nasal obstruction are two of the common medical conditions which are asso-
ciated with the olfactory disorders of patients who are entering another clinical
chemosensory research center.
Children with nasal obstruction exhibited deficient detection thresholds for
odorants. Associated medical conditions included adenoid hypertrophy, allergic
rhinitis, and upper respiratory infections. Adenoidectomy enhanced olfactory
sensitivity in many of the children with adenoid hypertrophy.
Touch
Basic Studies
There has hitherto been near-consensus that active touch leads to better perfor-
mance than passive touch. This view is being increasingly challenged by new
studies and reinterpretation of previous results. It was commonly believed that
the scanned mode led to better performance than the static mode when letters
were identified by the Optacon, an optical to tactile conversion instrument for
the deaf-blind. Recent results challenge this view. It is still uncertain
whether modes other than the scanned mode can improve real reading performance
with the Optacon. One implication is that the different ways of generating
tactile patterns need to be examined in the context in which they are used,
whether for reading aids, mobility aids, or speech perception.
The principles of sensory coding of spatial information are being determined by
examining somatosensory system integration of inputs from multiple points on
the skin. Cutaneous sensation magnitude, measured by reaction time, was
augmented in monkeys and people by increasing the number of stimuli points.
Electrophysiological recordings from the cortex of monkeys support the hypothesis
that there are large overlapping representations of the hand and arm rather than
separate and distinct representations. Direction-sensitive responses in the
cortex were obtained from punctuate and brush-like stimulation of the skin.
The study of sensory interactions is a natural approach to prosthesis studies.
One of the ways to improve two-point tactile acuity is to add sensory information
for temperature. This work is being extended to include interactions between
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skin temperature and pressure sensation. Results of pilot studies on thermal-
taste interactions suggest that the popularity of chile pepper could steip from
its enhancement of the flavor of foods, including salty and sweet ones. It is
known that the amount of sugar people use in their coffee depends on the tem-
perature of the coffee. Recent results suggest that for some sugars the tem-
perature effect may be linked to the nervous system of the person and for other
sugars, to the mutorotation of their isomers in solution.
It is of clinical importance to know whether a skin graft may assume the charac-
teristics of the donor or the recipient site. The temporal nature of sensory
recovery is being measured with modern psychophysical tests and instrumentation
and consideration is being given to physical metrics. Von Frey hairs yielded
unreliable results. Measurement of the depth of skin indentation is proving to
be more closely related to the intensity of tactile sensation than measurement
of force.
Hearing
General Considerations
The division of the nervous system specialized for the processing of sound is
called the auditory system. The structures outside the brain or brain stem are
classified as peripheral and include the outer, middle and inner ear. The
remainder of the system is known as the central auditory system and consists
of an ascending pathway, a descending pathway and multiple interconnections
between them. The more central portions of the system are less well understood
than the peripheral portions. Knowledge of the auditory system has progressed
from the periphery toward the cortex. Despite our incomplete knowledge of its
function, from working with the hearing-impaired population it is known that
major malfunctions of the system usually are associated with failure of the
various mechanisms which process sound from the outer ear to the auditory portion
of the cerebral cortex.
Peripheral Auditory System
Basic Studies
The major function of the middle ear is one of matching the acoustical impedance
of air to the acoustical impedance of the fluid within the cochlea. This function
is accomplished by a sound pressure transformation. A method has been developed
which incorporates a high impedance acoustic source with a computer-controlled
system for sound generation and measurement. Both magnitude and angle of acoustic
admittance can now be measured over the broad frequency range of 10 Hz to 20,000 Hz.
This work suggests that the effects of middle-ear cavities can be related to the
anatomical dimensions of the cavities and that the admittance is primarily deter-
mined by the tjmipanic membrane at frequencies about 4,000 Hz. Further study
indicates that two-tone distortion products and non-linear properties of the input
admittance, indicate that some of the non-linear behavior that occurs for stimulus
levels above 80 dB sound pressure level (SPL) results from mechanical properties
of the basilar membrane.
The sensory receptor cells (hair cells) , for hearing are located within the cochlea
which in turn is embedded within the petrous portion of the temporal bone of the
skull. The cochlea represents the first stage for processing sound in the auditory
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system. It is a highly specialized end organ and a very sensitive one. Many
studies are directed toward understanding the transformation of mechanical events
to neural patterns in the cochlea by electrical or chemical phenomena.
Central issues in the study of the auditory periphery concern the role of inner
and outer hair cells, by defining the nature of their population-specific responses
and determining how their inputs are distributed to component divisions and neural
populations within divisions of the cochlear nucleus. Studies show that the outer
hair cell system projects to the brainstem and the axons of Type II neurons are
present in the cochlear nerve at its entrance to the brainstem.
The transduction mechanism of hair cells is one of the least understood aspects
of the hearing process. Studies show that outer hair cells are almost entirely
responsible for the generation of cochlear potentials, but it is not known whether
these potentials play an important role in the process of excitation of afferent
fibers, most of which innervate the inner hair cells.
Another finding demonstrates that the receptor-potential responses of hair cells
to tone-burst stimuli show frequency selectivity, non-linear properties and
lowpass filtering. The frequency selectivity is sharper than that of the basilar
membrane displacement, but roughly equivalent to the frequency selectivity of
cochlear nerve fibers. Thus, sharp frequency selectivity is a property of
individual hair cells. Non-linearities in hair cell responses occur at low
sound pressure levels where the macromechanical properties of the middle and
inner ear are linear .
Causal and Predictive Factors in Disorders
Past work has shown that the high metabolism of the cochlea makes it susceptible
to agents in the blood stream such as drugs. The highly deleterious effects of
the aminoglycosides and some other antibiotics are now well-known. However,
the interaction of these drugs with loop inhibiting diuretics has only recently
been under investigation.
If the molecular mechanism of ototoxicity is known, then the sites on the anti-
biotic that are responsible for this toxicity can be determined. Experiments
are being conducted to modify the chemical composition of existing antibiotics
to render them less ototoxic while still retaining their antibacterial properties.
Cochlear injury caused by noise exposure continues to attract the efforts of
several investigators. One group has shown that interruptions in noise exposure
of the same total acoustic energy will partially protect the low-frequency region
of the organ of Corti, but not the more basal or high-frequency region. As a
result of such work, it is felt that different kinds of lesions may reflect
different mechanisms of acoustic injury.
Experiments in which a single exposure to noise was interrupted by inserting quiet
periods, show that although hearing damage is not eliminated completely, it is
significantly reduced by these recovery periods. This limitation of the total-
energy principle is under study at intensities somewhat below the critical
intensity. Present results indicate that when exposures are interrupted, the
total energy may be as high as ten times as great as an uninterrupted one without
producing a greater hearing loss.
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Studies of the possible potentiation of noise exposure by common drugs such as
aspirin are underway. Interestingly, aspirin is the only known pharmaceutical
agent which is ototoxic during the drug regimen but whose effects are reversible
once drug administration is discontinued.
Studies of the normal effects of aging on both the peripheral and brainstem
portions of the auditory system are being compared with results obtained from
animals with genetically-determined anomalies. This work is designed to separate
genetic and aging effects to identify key factors responsible for the respective
auditory impairments. Improved treatment of such patients is expected to result
from this work.
Studies are being conducted to identify the etiology of idiopathic sudden hearing
loss. By studying viral antibodies, attempts are being made to determine which
viral agents are likely to be responsible for the hearing loss incurred by these
patients. Current findings of work regarding the mechanisms of viral pathogenesis
indicate that the reactivation of latent herpes viruses may play an important role.
The pathophysiological mechanisms of diabetes, atherosclerosis, hypertension,
hereditary and environmental factors are under study for possible association with
sensorineural hearing loss.
The study of temporal bones from patients with documented Meniere's disease
indicates that in Meniere's attacks, the permeability of the membranous walls
of the labyrinth is altered. The tectorial membrane, and possibly the cupula also,
shrink under the influence of an increased sodium concentration of the endolymph.
The hydrostatic pressure of the endoljrmph also increases and tends to flatten the
tectorial membrane against the reticular lamina. Changes in the tectorial membrane
may be responsible for auditory dysfunction in Meniere's disease and in fluctuating
hearing loss.
Humans with identical abnormal hearing threshold levels display large differences
in performance on other auditory tasks. It has also been found that physiological
damage to the auditory systems of experimental animals can be produced by moderate
exposures to noise or ototoxic drugs without a concomitant measurable change in
hearing threshold levels at conventional audiometric frequencies. Confirmation
of this finding was obtained by exposing animals to either moderate amounts of
noise or ototoxic drugs and then measuring their threshold levels, whole-nerve
action potentials, the locus of tips of individual-nerve-fiber tuning curves and
charts of hair cell destruction as a function of position along the basilar mem-
brain. The only measure which showed any significant relationship with the
pattern of hair cell loss was the tuning-curve measures. Although the other
estimates of threshold agreed quite well with each other, all failed to reflect
even rather large areas of destroyed hair cells.
Diagnosis, Treatment and Rehabilitation
Information about the basic mechanisms of hair cell function and the factors
Influencing the production of neural responses, are being pursued to develop,
evaluate and improve techniques used for clinical diagnosis and treatment of
human hearing disorders.
In order to develop prostheses for the severely hearing-impaired such as cochlear
implants and tactile stimulators, it is increasingly important to understand
neural saturation so that channel capacity will not be wasted by presenting
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unencoded stimulation. Several experiments are providing information about the
capacity of the auditory system to process stimuli with different parameters to
separate normal performance from performance by listeners with moderate to severe
hearing losses.
Ongoing studies are testing various aspects of theories of hearing to improve
current models of cochlear function and provide insight into the process of
acoustic information coding in the cochlea. One investigator is determining
the processes involved in the coding of the temporal characteristics of low-and
medium-frequency pure tones to achieve a better understanding of how more complex
acoustic stimuli such as speech are coded and processed by the nervous system.
One of the difficulties encountered by researchers studying presbycusis is in
differentially diagnosing it from noise-induced and drug-induced hearing loss.
A unique opportunity to study inner ear changes associated with presbycusis in
aging monkeys was presented when the temporal bones from a colony of 15 animals
were obtained. The animals had not been exposed to either noise or ototoxic
drugs and had well-documented premortem hearing assessments. Preliminary findings
suggest that presbycusis is an independent phenomenon separate from the con-
founding factors experienced in the environment. Hair cell loss in the cochlea
is being examined to support these conclusions.
Another problem which is thought to have its origin in the cochlea is tinnitus
(ringing in the ears) . At the present time, it is considered to be a symptom
of a deeper underlying malfunction such as drug and noise toxicity, though it
is reported as accompanying many other types of sensorineural hearing impairments.
Few controlled experiments have studied the phenomenon of tinnitus because the
most prevalent type, subjective, is perceived only by the sufferer and is diffi-
cult to quantify objectively. A recent study attempted to quantify the annoyance
of tinnitus in patients with noise-induced hearing loss. The intensity of noise
required to adequately mask their tinnitus had to be increased by more than 40 dB
but changed significantly over time and probably indicates that the rate of
fluctuation may be an important factor in determining the annoyance of tinnitus.
Other studies are employing masking by narrow bands of noise as a means of
relieving the tinnitus annoyance.
Treatment for people with sensory hearing losses is generally limited to wearing
a hearing aid which in its basic form is a complete miniature sound system.
Besides providing louder sounds for the hearing-impaired, clinicians are also
concerned about protecting these listeners from excessively high level speech
and environmental sounds. Researchers have been able to alter the hearing aid
circuitry to compress loud incoming sounds but still preserve understanding of
speech by these patients. Another research team is exploring ways to improve
hearing aid amplification in reverberant environments which are known to create
severe hearing problems for older persons. Other studies are employing various
psychophysical methods to develop test procedures that can predict the charac-
teristics of a hearing aid that are required for each individual to optimize
his or her understanding of speech.
One team of investigators has standardized a procedure using auditory evoked
potententials (ABR) and frequency-specific stimuli in order that a graphical
representation of a young child's hearing can be obtained. They are now using
it clinically to select hearing aids for young, pre-language infants.
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Central Auditory System
Basic Studies
Spike-like signals received from the inner ear are further processed by the
auditory nerve and the auditory brain stem until they reach the the auditory
portion of the cerebral cortex. Currently, a 'method of studying the auditory
network is to find a single nerve-unit whose activity can be recorded and
present a variety of inputs to the ear and note the response of the unit for
each type of input.
Anatomical studies are providing details of the organization of efferent inner-
vation of the olivocochlear bundle in an effort to explain its functional role
in the hearing process. Current findings indicate that there are dual and
independent efferent innervations of the organ of Corti. In addition, information
about the patterns of afferent input to the neurons of origin and of the patterns
of synaptic distribution of these neurons to the cochlea are contributing to our
understanding of the auditory process.
Causal and Predictive Factors in Disorders
Electrophysiological techniques are being used in the study of auditory nerve
fibers, units of the brainstem and the auditory cortex. Components of the electro-
encephalogram that can be shown to be synchronized with sound stimuli are generally
called auditory evoked responses (ABR) . Such a technique is being employed with
premature infants who present immaturity of many organ systems including the
central nervous system. Furthermore, many such infants are exposed to ototoxic
agents and are placed in high noise environments. The very high rate (about 10%)
of peripheral auditory dysfunction defined for this population and the possibility
of more precisely determining neurologic prognosis makes the ABR a valuable method
for determining the integrity of the auditory system.
Another study of premature infants with and without intraventricular brain
hemorrhages, identified high risk factors associated with prematurity. By measur-
ing their auditory evoked responses, researchers are able to detect evidence of
hearing dysfunction in these infants between 28 weeks and term and find it related
to the occurrence of hyperbilirubinemia and hypoxia. Prevention of neurological
sequelae in the preterm Infant is the long range goal of this work which utilizes
safe technology for early detection.
A study of right-left asjmmietries in brain stem auditory evoked potentials on
normal subjects showed that no significant asymmetries were found for most of
the peaks including those representing auditory nerve activity. However, for
the significant asjraimetries identified in I(-), III(+) and IV(+) , the larger
peaks were associated with right ear stimulation. These same subjects showed
some correlation between the evoked potential results and the dominant ear as
demonstrated in a dichotic listening task.
Pharmacological studies intending to elucidate the cochlear mechanisms leading
to auditory-nerve discharges indicate that most of the ototoxic effects of the
diuretic drug, furosemlde, appear to be on responses to low-level stimuli and
can perhaps be related to changes in the endocochlear potential. Results of
another experiment show clearly that the two major functions of the binaural
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auditory system, localization (represented by interaural time discrimination) and
signal selection (represented by masking level difference) do not function opti-
mally when the auditory system is confronted by both tasks simultaneously.
Though cortical response to sound is poorly understood, it is assumed that higher-
order processing of stimuli occurs in one or more of several areas of the auditory
cortex. Studies underway show tha-t auditory recognition and discrimination are
related to task complexity, stimulus complexity and the interaction between the
task and stimulus. So far, these relationships hold true for both normal listeners
and those with hearing impairments.
Diagnosis, Treatment and Rehabilitation
Assessment of auditory dysfunction among patients with brainstem pathologies should
eventually lead to the development of new diagnostic tests for diagnosing central
auditory disorders and describing the auditory dysfunctions found in these patients.
This is being pursued by comparing auditory brainstem responses and masking level
differences in such patients to explain certain binaural phenomena.
Other studies are involved in the development of clinical tests of central auditory
processing for use with patients who have concomitant peripheral losses. Binaural
separation of sound stimuli is proving to be the most promising technique at the
current time, but progress has been slow.
Biochemistry, Neurochemistry and Pharmacology of Hearing
Basic Studies
Biochemical, neurochemical and pharmacologic studies have provided new insights
into how chemical events subserve the characteristic activity of the peripheral
and central auditory system. It has been through advances ixi quantitative
analytical approaches that the acquisition of knowledge in these most important
areas has progressed. The primary objective has been to provide a solid research
base to explain biochemical events involved in sensory and neural processes. The
information to date however, has not derived from chemical analyses alone.
Different levels of complexity in both structure and function have relied heavily
on concomitant derived data from neurobiology, neuroanatomy and neurophysiology.
As a result of this working relationship between closely-allied areas, concepts
and information which were widely dispersed have been formulated into meaningful
hypotheses.
The research to date can be segmented into that which is concerned with inner ear
cochlear tissues, cochlear fluids and Vlllth nerve neurons, and the cochlear
nucleus within the brainstem. Of interest are the mechanisms of ototoxic drugs
and their possible interaction with physical and other chemical agents. Experi-
mental preparations include chinchilla, guinea pig, mouse, rat, frog and goldfish.
Biochemical and related studies of putative neurotransmitters of hair cells are
under investigation. The afferent transmitter substance and possible associated
enzyme system is being examined through the use of a lateral line preparation.
By isolation and analysis of the synaptic vesicle fraction, the investigator
hopes to identify the presumed neurotransmitter. Another approach is to
characterize primary amines in the perili^mph that may be involved in afferent
transduction. Sound-isolated and sound-exposed animals are used and resultant
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data are analyzed using microf luorescence high performance liquid chromatography
(HPLC) . Changes in levels of aspartate, arginine, and alanine are monitored.
A similar approach tests several antagonists to glutamate receptors.
A combined biochemical and histochemical technique is used to study cochlear
homeostasis. Studies include specific activity and histochemical localization
of adenylate cyclase during development of the inner ear of the normal mouse,
and the influence of hormones and neuromodulators (e.g., B-adrenergic agonists
and blockers, vasopressin, parathyroid hormone. Prostaglandin PGE) on enzyme
activity. Cochlear microphonic, endocochlear potential and whole nerve action
potential also are measured in response to the hormones and neuromodulators.
The effects of noise as well as overstimulation on energy metabolism is
determined by 2-deoxyglucose capture. The hypothesis tested is that the
decrease in energy metabolism observed with overstimulation is caused by
vasoconstriction.
Other studies include the quantitative, electrochemical, electrophysiologic, and
histological analysis of the normal and experimentally altered inner ear. The
experimental model involves arterial perfusion of the inner ear of the guinea
pig with synthetic blood in order to control the biochemical environment.
Specific aims include: (1) evaluation of metabolic substrates in the organ of
Corti, stria vascularis, and Reissner's membrane; (2) evaluation of putative
transmitters in the organ of Corti in chinchilla; (3) evaluation of amino-acid
profile in perilymph, endolymph, CSF, and blood by HPLC; (4) study of the effect
of toxic substances on cyclic-adenosine monophosphate; (5) evaluation of the effect
of interruption of the efferent cochlear fibers upon enzymatic pathways of the
organ of Corti; and (6) evaluation of metabolism in genetic deficient inner ear and
Kanamycin treated animals (Waltzing guinea pig). These projects are important
since they may ultimately open the way to new types of pharmacologic therapy of
hearing disorders.
As a foundation for work in this area, another investigator conducts neuropharma-
cologic studies of synaptic transmitter substances in the cochlear nucleus (CN) .
Putative excitatory neurotransmitters, namely glutamate and aspartate, are
iontophoretically applied to single neurons in various regions of the CN. Since
microneurochemical studies indicate that L-glutamic acid and L-aspartic acid show
regional distributions within the CN complex, the principal investigator contends
that iontophoretic application of the excitatory transmitters will, therefore,
have differential effects in different areas of the CN. Glutamate, aspartate,
and cysteic acid are assessed in terms of relative effectiveness in altering
spontaneous activity; area specific response patterns are generated. The
heterocyclic glutamate analog, kainic acid and the aspartate analog, N-methyl
D-aspartate, are examined for their effect. Specific antagonists are also
investigated in this respect.
There is a further long-range effort to understand the synaptic chemistry of
the cochlear nucleus of the auditory brainstem, by histochemical examination
of cholinergic structures. The basic methods involve quantitative histochemistry.
Four specific aims are listed based on monitoring the levels of cholinergic enzymes.
First, the principal investigator proposes to determine the relative proportions
of choline acetyltransferase and acetylcholinesterase activities in subregions
of the rat cochlear nucleus that are related to centrifugal pathways; second, he
will determine the origin and routes of the centrifugal pathways; third, he will
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measure cholinergic enzymes in the olivo-cochlear bundle; and fourth, examine
similar regions in the cat where the anatomy is more firmly established. These
studies are designed to determine chemical efferent activity in the auditory brain
stem similar to that which has been found anatomically and physiologically.
Diagnosis and Treatment
Once symptoms of drug ototoxicity are detected, it would be beneficial to be able
to treat or alleviate the condition prior to permanent effects. A project
related to this goal is designed to detect complexes formed during inactivation
of gentamicin by carbenicillin, and to investigate its ototoxic effects in the
guinea pig model. Studies focus on three areas: (1) identification and
characterization of the gentamicin-carbenicillin reaction products (G-C) ,
(2) pharmacokinetics of G-C in patients with various degrees of renal failure who
are treated with gentamicin and carbenicillin, and (3) testing of G-C for ototoxic
potential in an animal model (guinea pigs) . The investigators isolate and
characterize G-C complexes by silica gel thin-layer chromatography, electrophoresis,
counting of radioactivity, differential binding to phosphocellulose, high-pressure
liquid chromatography, and gel-filtration. The critical goals involve the
demonstration in vivo of G-C complexes and subsequently, its ototoxicity. Base-
line vestibulometric and cochleometric testing are utilized.
Another approach to the problem of ototoxic- induced hearing loss is to explain
the molecular mechanism underlying the drug action. Cellular actions and the
structure-toxicity relationships are explored. The hypothesis tested is that
aminoglycosides interact with polyphosphoinositides in monomolecular films and
liposomes. It is thought that the aminoglycosides act at the membrane level by
lowering permeability barriers, and that this potentiates the effect to other
ototoxic drugs. Certain drugs are tested for reversibility. Data to date
support the hypothesis that a disturbance of polyphosphoinositide turnover is a
contributing factor in ototoxicity.
Auditory Prosthesis Research
Basic Studies
Profoundly deaf subjects do not for the most part benefit from a conventional
hearing aid. In order to overcome this problem, efforts have been made to
utilize electrical auditory nerve stimulating prosthetic devices. The objective
is to restore hearing for speech. Physiologic, psychophysical, and speech science
research have revealed that intelligible speech can be encoded by a nerve stimu-
lation device consisting of a series of independent stimulation channels. The
requirement for several discrete channels is not impossible. For example, if
six to eight or more sectors of the auditory nerve array can be discretely
electrically stimulated, it is quite possible to encode speech in profoundly
deaf subjects.
A number of investigators are addressing the fundamental problems involved in
auditory prosthesis research. These investigations are proceeding with the
objective of discovering effective methods for stimulation with a multichannel
cochlear prosthesis. The research involves fabrication of implantable multi-
electrode arrays, interfacing multi-electrode arrays with the auditory nerve.
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tests of these arrays In animals, determination of interelectrode interactions,
assessment of cochlear ganglion cell survival, improvement in dynamic range,
development of a transcutaneous multi-electrode driving system, and design of
a sound-processor which provides maximum speech discrimination. This latter
development will ultimately lead to fabrication of a wearable sound-processor.
Diagnosis, Treatment and Rehabilitation
The task at hand is the development of multichannel sound processor-stimulator.
Studies toward this goal include: (]) psychophysical investigations of the
reactions of profoundly deaf patients to electrical stimulation, (2) spatio-
temporal representation of speech elements, (3) special speech testing of
implant patients, (4) definition of psychophysical and electrophysiologic
patterns, (5) determination of the status of surviving auditory nerve elements,
(6) stability of implant operation over long time periods, and (7) safety factors
of implant devices. Specific consideration is given to problems inherent in
application of implant devices in deaf children.
One investigator has fabricated two multichannel printed circuit teflon ribbons
contained within a silicone rubber carrier. The aim is to produce a device
which will be frequency specific, small and flexible and contain 30 conductors
and electrodes necessary for ]5 biplar channels.
A somewhat different approach is taken by another investigator towards the
development of a multichannel cochlear prosthesis. This investigator is developing
an eight-channel, polymide, flexible thin-film electrode. All electrodes undergo
in vitro testing prior to implantation in cats, while additional ones will undergo
saline testing for as long as two years. Once electrodes pass the in vitro test-
ing period, cats will be implanted. Ultimately, profoundly bilateral deaf adults
are to be implanted. A variety of electrophysiologic and morphological studies
will be used to test for mechanical or electrical damage. This research proceeds
from the notion that the modiolar electrode array is not adequate, and that a
flexible scala typmpani electrode is the array of choice. A complete battery of
otologic, neurologic and psychological tests will be administered. After implan-
tation, extensive psychophysical, speech, electrophysiologic and other data will
be collected to determine the efficacy of the multichannel electrode array. With
these developments, the potential for continued progress of multichannel arrays
is promising.
Equilibrium and Balance
Basic Studies
Progress has been made in understanding how the peripheral and central vestibular
systems process information. This has occurred despite the complexity of the
vestibular labyrinth, its afferent pathways, central mechanisms, inputs from the
visual and proprioceptive systems, superimposition of various other sensory systems,
and the convergence of disorders that affect the peripheral and central vestibular
systems.
Contributions from the fields of neuroanatomy, neurophysiology, immunology, and
biochemistry have served as a foundation for basic vestibular research studies,
and the clinical disciplines of otology, neurology and audiology have derived
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specific information being on disease etiology and pathogenesis. Clinical
investigations on equilibrium and balance have translated fundamental knowledge
to treatment and prevention regimens, which in turn may require major testing
in clinical trials. It remains to be seen whether demonstration programs will
test the feasibility of mounting prevention, treatment and education programs in
specific settings on specific vestibular problems. Once a firm basis of knowledge
has been established its application on the clinical level becomes possible.
The Institute has a major responsibility for vestibular disorders and diseases.
The significance of this responsibility and the challenge it represents can only
be appreciated when considered in light of the devastating effect that equilibrium
and balance problems have on maintenance of posture, locomotion, social inter-
action and work environment. Specific research projects in this scientific area
include morpho-physiologic studies of secondary vestibular neurons, studies of
structure and function of afferent vestibular pathways and intracellular dye
injections of vestibular axons so as to trace peripheral and central projections.
To demonstrate vestibular efferent projections from individual christae and
maculae of the semicircular canals, the HRP-TMB histochemical technique is used
by another investigator. Transynaptic projections are studied using H-labeled
proline-fucose, and fluorescence techniques are used to investigjite catechola-
minergic neurons in reticular formation. Accurate two-plane (coronal, sagittal)
neuronal maps are constructed so that further definition of morphology accrues,
which will provide further guidance for electrophysiologic studies.
Processing of visual and vestibular signals to produce eye movements and body
postural responses relates to the fundamental studies of anatomy and physiology
discussed above. In this effort, a vestibular mechanism responsible for infor-
mation storage of slow-phase eye velocity has been implicated. Investigations
in this area are directed towards basic mechanisms responsible for producing
vestibular nystagmus, optokinetic nystagmus (OKN) and visual vestibular inter-
actions. It has been observed that stored neural activity promotes ocular-
following during OKN and is responsible for optokinetic after-nystagmus, which
lengthens the time over which compensatory eye movements are maintained. The
decay-time constant of neurons in the vestibular nuclei are longer than those
found in canal afferents. Manifestations of stored activity are found in neurons
in the vestibular nuclei of monkey. Research indicates that such a velocity
storage mechanism is present in man. While it may play less of a role in man,
the mechanism has been found to be important in mediating visual-vestibular
interactions.
The avian, amphibian and mouse embryo otocyst are being used as organ culture
models in studies of synaptic specialization in vestibular sensory epithelia,
vestibular innervation, and synaptic junction modulation of afferent and efferent
projection systems. Light and ultrastructural level studies form the basis for
analysis of successful explants. Freeze fracture analysis is used for the mature
and developing intramembrane studies. The experimental preparations selected
provide both phylogenetic comparisons and a common basis for correlation of the
various experimental studies.
Using electrophysiologic techniques, investigators are examining postural reflexes
in the neck and forelimbs which respond to otolith stimulation. Decerebrate and
semicircular canal-plugged cats are tested on a computer-driven tilt table.
Information is thus derived about the sensitivity of various muscle groups to
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tilt, sensitivity of vestibular neurons to tilt, and identification of the afferent
projection of vestibular neurons. Tonic and phasic neurons are investigated. The
function of the medial and lateral vestibular spiral tracts also are tested.
In other studies of the vestibular system, information is derived concerning the
mechanical aspects of selective filtering and transduction, and the effects of
peripheral signal integration in the inner ear. The aim is to deduce the physical
bases of various sensory properties of the inner ear. The experimental animals are
the American bullfrog and gerbil. Measurements are made of the resting potential
and response properties of single afferent fibers in the inner ear which are
sensitive to gravitational stimulation. Once the physiological properties of
fibers have been characterized, they are dye marked by iontophoretic injection of
lucifer yellow. The specimens are then examined by fluorescence microscopy in
order to determine: (1) fiber diameter, organ of origin in inner ear, number of
cells innervated by fibers and their location within sensory organs and, in
some cases, central termination of fibers; (2) examination of tectoria, cupulae
and otoconial membranes in frozen, freeze-f ractured specimens and freeze-dried
specimens. Because the vestibular nuclei have not been well characterized in
the bullfrog, Golgi impregnation and other standard neurohistologic methods are
used.
Diagnosis, Treatment and Rehabilitation
A system is under development to measure vestibular control of posture with a view
toward clinical testing of otological and neurological patients. The major goal
of this research is to determine whether a test that measures the patient's
postural system, or the ability to maintain posture, can detect a vestibular lesion.
Patients are placed on a platform which, by making changes in ankle angle, sta-
bilizes the ankle joint during rotation. Vision is eliminated by eye closure.
Motion is measured by video camera pictures of lights applied at various points
on the body surface. This study also examines a patient's ability to adapt to
perturbations in visual or somatosensory inputs. These perturbations are brought
about by varying the visual field motion relative to the patient's head or by
applying linear translation to the supporting surface. The objective is to
delineate the normal and abnormal responses to this test.
Refinement of posturographic techniques used in clinical evaluation of patients
with disorders of balance continue. Data have been obtained with patients
and normal subjects. These quantitative studies of human posture control mechanisms
use the simultaneous center of force and head trajectory recordings. Controlled
visual and galvanic vestibular inputs to vestibulo-spinal control system are em-
ployed in order to characterize time and frequency domain human postural control
responses and to study visual-vestlbular interactions. The transfer characteristics
between the human head and center of mass movements are determined. In addition
to force platform recordings, EMG responses for muscles controlling ankle-joint
positions are obtained for comparison with force platform analysis of posture
control. Selected patient groups with converging neural musculo-skeletal system
abnormalities are studied as abnormal control groups. Mathematical models
of the multi-linked human postural control systems are employed to optimize the
postural reflex control mechanisms in normal and vestibular deficient humans.
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A microprocessor-based system for vestibular function testing is under development
and a clinical trial is being prepared. A library of nystagmus records will be
developed and nystagmus tests will be standardized. If realized, an automated
system could become available to clinicians to standardize vestibular tests. The
specific instrumentation used are a microprocessor-based instrument which collects
and analyzes nystagmus recorded via electrooculography , a rotating chair and
accompanying optokinetic device, and caloric stimulators which are controlled by
the microprocessor. Prototypes for all devices have been assembled and partially
tested. Continued development of a data base of human evaluations of eye movement
data which can be compared with the computer evaluations are planned. The goal
is to define a quantitative method by which the device algorithm for nystagmus
analysis can be made to match human performance in the reading of nystagmus records.
Further aims are to improve the real-time nystagmus program for artifact rejection
and the detection of fast phase and eye blinks, and to evaluate the device in a
clinical setting. Completion of these objectives will accomplish a specific
practical goal for intervention research.
The vestibulo-toxic effects of aminoglycoside antibiotics on the dynamics of the
human vestibulo-ocular and vestibulo-spinal reflex systems are being studied, as
are the adaptive properties of these reflexes following total loss of vestibular
function. Patients receiving aminoglycoside antibiotics are tested with various
combinations of oculo-motor pursuit, optokinetic and rotational vestibular
stimuli. Upright postural control is studied by manipulation of visual and ankle
joint proprioception in patients with aminoglycoside induced vestibular ototoxicity.
The results should significantly advance the health care of patients receiving
ototoxic antibiotics by providing sensitive quantitative methods for early
detection of vestibular aminoglycoside ototoxicity, provide vestibular incidence
figures for several commonly used aminoglycoside antibiotics, and provide infor-
mation about adaptive motor reflex mechanisms. These data will be of value in
designing more effective rehabilitative treatment protocols.
Disorders of the Ears, Nose and Throat
Basic Studies
Basic studies on etiology and pathogenesis have received major attention. Studies
continue in neuro-otology, anatomy, physiology and pathophysiology of the ear,
middle ear response to otitis media, histopathology of animal and human temporal
bones, ototoxic drug interactions, and laryngeal, pharyngeal and acoustical
factors related to speech. This research has resulted in several discoveries,
theories, and significant concepts which, in turn, have served as a basis for
further research, refinement, development, evaluation and dissemination of
research findings to several relevant disciplines such as otolaryngology, speech
pathology, audiology, neurology, pediatrics and rehabilitative medicine.
Causal and Predictive Factors in Disorders
Despite the encouraging progress made by various investigators who are conducting
basic research into the biologic process prior to the onset of an ear, nose or
throat disease, much remains to be accomplished. As a result, research continues
into basic mechanisms underlying diseases and disorders which manifest themselves
in the outer, middle and inner ears.
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Related to the outer and middle ears is an investigation on spontaneous and
experimentally- induced aural cholesteatoma in an animal model — Mongolian gerbil.
Anatomic, electrophysiologic and behavioral studies are conducted so as to shed
light on the invasive and erosive characteristics of human aural cholesteatoma.
So as to determine the natural history of this ear disease, the investigator
employs auditory brain stem evoked responses (BSER) , transmission electron-
microscopy and cytocochleography. Of interest is whether spontaneous cholesteatomas
are similar to those that are surgically-induced (via ear canal ligation) . The
investigator employs a procedure of surgically-imposing semi-permeable and
impermeable barriers between the advancing front of the cholesteatoma and the base
of the middle ear. Since erosion of the middle ear bone usually takes place as a
result of the advancing mass, he will determine whether bone erosion is due to
pressure, enzymatic protease action, cellular osteoclast action, or a combination
of these factors. A related but different study is investigating cholesteatomas as
a result of skin and inflammatory granulomas in the guinea pig middle ear. Mor-
phologic and immunocyto chemical studies at the light and ultrastructural level
are used to localize and quantify a specific collageno lytic enzyme.
Attention continues to be devoted to the most common middle ear problem in children
— serous otitis media with effusion. Several investigators are examing the
immune response of the middle ear, mucociliary fluid clearance, microbiologic
factors, underlying pathogenesis, concomitant mechanical properties, and 3-D recon-
structions of the tympanic membrane in normal and diseased ears.
Immunologic aspects of the middle ear are of major importance. Whether the
bacteriostatic substances in an effusion develop tolerance for the disease,
whether the initial ear infection prevents the development of an adequate immune
system, or whether further infection is caused by the immune response are questions
that may be answered using immunologic methods.
A model of the immune response in the middle ear of the guinea pig has been
developed utilizing keyhold limpet hemocyanin (KLH) . Various related topics under
investigation include immune as opposed to systemic responses, immune expression,
identification of B- and T-cell lymphocytes, identification of specific antibody-
producing cells, and characterization of the role of immunoglobulins and immune
Ijnnphocytes. The human disease is further characterized as to cellular and
humoral response, variation in sensitization-challenge intervals, development of
chronic effusion, and contribution of the local immune response to chronic effusion
and inflammation. The pathophysiologic consequences of the middle ear response
are also being examined, together with regulation of the response by both immune
and pharmacologic inhibitors.
Related to this problem is whether muco-exudates produced by otitis media may
accumulate instead of clearing through the Eustachian tube. Previous findings
have firmly established that middle ear fluid must have the character of an
incipient gel if proper clearance by ciliary action is to take place. Not being
normally a permanently cross-linked system, mucus undergoes spontaneous structural
changes. Hence, the effectiveness of clearance can be linked to the number of
cells producing mucus, the amount produced, the rheological character of the
secretion and the nature of the muco-ciliary wave interaction. The glycoprotein
macromolecular aggregates from which mucus derives its special rheological proper-
ties are probed. The studies continue to be directed towards the structure of the
glycoprotein entity, the distribution of cross-links, the mechanics of ciliary beat
and the factors controlling mucus production.
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In summation, major investigations on various forms of otitis media include the
basic disciplines of anatomy, physiology, biochemistry, immunology, and bacteri-
ology. The role of the infectious process, Eustachian tube dysfunction, the
immune response, and the sequelae of otitis media (granulation tissue, cholestea-
toma, cholesterol granuloma, subsequent sensorineural hearing loss, etc.) are
receiving concerted and coordinated attention.
While significant progress has been made on diagnosis, identification of causal
factors and treatment of outer and middle ear disorders, the same cannot be said
of the inner ear. Further work is needed in preventing inner ear diseases.
Morphological studies using both transmission and scanning electron-microscopy
are used to provide detailed accounts of the inner ear of animals. A major goal
of this research is to correlate animal findings with normal human temporal
bones. Special emphasis is placed on the structure of the spiral ganglion cells,
nerve fibers in the osseous spiral lamina, as well as their distribution in the
organ of Corti. The concept that morphological changes of the endolymphatic sac
and ductus reuniens may play a role in controlling endolymphatic hydrops is
examined. Transport of horseradish perosidase (HRP) into frog auditory neurons
using sophisticated chromagen techniques such as tetramethyl benzidene (TMB)
continues to be explored. Studies of the acoustic ref lex-cochlear route, the
human auditory nerve potential, and the BSER continue to receive considerable
attention as diagnostic tools for both children and adults.
Research into basic fundamental mechanisms of the vestibular apparatus continues.
Development and refinement of techniques to evaluate functional alterations after
partial ablation of the vestibular system and the system's subsequent compensation
are proceeding. Work at the light and electron microscopic level on the human
saccule and utricle, otoconial membranes, and other vestibular portions of the
ear have added new insights into this difficult area. Progress has been made
in the study of proprioceptive and visual input enhancement of vestibular system-
induced imbalance. Recently, ultrastructural alterations in the vestibular
ganglion after labyrinthectomy have been confirmed. These findings are related
to the study of ultrastructure of commissural fibers of the vestibular nuclei
in the squirrel monkey. These studies are likely to become standard reference
data for other investigators in this and other closely-related areas.
Of interest in the area of laryngeal dysfunction is the brain stem control of
laryngeal muscles. Using a stimulating and recording method for intact laryngeal
motoneurons, investigators have characterized individual motor units in anesthe-
tized non-human primates. The thrust of the research is to determine function,
recruitment sequence, axon conduction velocities and muscle fiber contractile
properties. The histochemical method is used to characterized the muscle fiber
motor unit. Germane to these studies is to ascertain location and cell body
morphology in the brain stem using HRP tehniques. A final set of experiments
characterize these same motor units during vocalization.
On a more molecular level, biochemical characteristics of various muscle fiber types
are determined using quantitative histochemical reaction products. The aim is to
quantify different enzymes and substrates that may indicate relative oxidative
and glycolytic capacities of muscle fibers. Quantitative morphological parameters
are obtained using serial sections processed for electron microscopy. Morphometric
data include determination of Z-line width, volume densities of sub-sarcolemmal
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mitochondria, myofibrils and intercellular lipid. Correlational studies of
biochemical events and morphological architecture of intrinsic laryngeal muscle
will assist in relating these findings to laryngeal function. Basic studies such
as these should assist in providing a foundation for a better understanding of
peripheral action, central control and biochemical events underlying laryngeal
muscle contractions during human sound production.
The mechanism of action of ototoxic agents, singly and in such therapeutic
combinations as aminoglycoside antibiotics (eg. kanamycin) with loop diuretics
(eg. ethacrynic acid, furosemide) are being studied. In order to examine drug
interaction experimentally, an animal model was developed and is used to determine
time-dose-effect relationships. Ultrastructural sites within the cochlea at which
the earliest damage occurs have been identified. Furthermore, non-aminoglycoside
drugs have been found to have interactional effects. Sophisticated histochemical
and autoradiographic methods are used. Thus, work continues on producing time-
dose-effect relationships of several non-aminoglycosidic drugs found to interact
at a level which causes lesions of the cochlea and vestibular mechanisms. The
developing chick embryo model that is used to study ototoxic agents and their
interactions, using electron microscopic techniques, has xesulted in important
new leads.
Diagnosis, Treatment and Rehabilitation
The clinical phase of the natural history of diseases or disorders of the ear,
nose and throat also receives attention. Several of the studies noted above about
the natural course of otitis media, cholesteatoma and other outer and middle ear
disorders are directed toward alleviating the disability (and subsequent morbidity
if untreated), after these conditions have been detected.
Information is being sought concerning the pathogenesis and possible treatment for
idiopathic sudden hearing loss. Patients admitted into the study withing 10 days
of their hearing loss undergo a complete otologic examination, audiometric studies,
physical examination and evaluation for known causes of sudden hearing loss. Blood
and serum are analyzed for viral antibody, cell-mediated immunity, and quantifi-
cation of IgE, IgM and IgG. While spontaneous recovery often occurs following
sudden hearing loss, a slight beneficial effect to steroid treatment has been
documented. The determination of the relationship between virally-induced sudden
hearing loss to other pathologic, demographic, or environmental factors are
included. These studies should increase our understanding of the etiology,
classification, and treatment of sensorineural hearing loss of sudden onset.
In a number of studies human temporal bone pathology is being examined and
correlated with known audiologic, otologic, behavioral and physical findings.
One study places special emphasis on Meniere's disease and other types of endolym-
phatic hydrops. Other studies are less narrowly focussed, temporal bones from a
wider variety of clinical conditions being examined histologically and the
findings related to clinical data. At times, bones are obtained in which ear
disease may not be the primary concern; nevertheless, the cause of death and
resultant histopathologic changes (e.g. , leukemia) are of importance to oto-
pathology.
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Studies are being conducted on the s3miptomatology, etiology, cause and typology
of spastic dysphonia. The long-term goal is to evaluate the effectiveness of
surgical treatment by unilateral recurrent laryngeal nerve section, evaluate
secondary procedures for recurring spasticity, identify causative mechanisms of
spastic dysphonia, establish criteria for vocal tremor, and determine the
microanatomy of the recurrent laryngeal nerve. Acoustic, aerodynamic, glotto-
graphic, psychophysiologic, electromyographic and pharmacologic studies are
conducted. The combined efforts of researchers in speech and hearing sciences,
otolaryngology, neurology, physiology and pathology are utilized.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
UNIVERSITY OF FLORIDA (NOl-NS-5-2313)
Title: Auditory Sensitivity in Young Children
Contractor's Project Director: Donald C. Teas, Ph.D.
Date Contract Initiated: June 30, 1975
Current Level of Support: $0
Objectives: This contract was awarded to study auditory sensitivity in young
children. The goal was to develop and evaluate a battery of tests which could
be used to characterize the hearing sensitivity of young chidren not suspected
of having hearing deficits and to examine the feasibility of using such a
battery to assess the hearing of infants and young children who are suspected
of /or at-risk for hearing dysfunction. Particular emphasis was placed on the
developmental aspects of the hearing ability of this population.
Methods Employed: Auditory brain stem responses (ABR) were obtained for
infants to broadband clicks with center frequencies of 500, 1,000, 2,000, 4,000
and 8,000 Hz and intensities of 20, 40 and 60 dB (above normal adult
threshold). Blink inhibition by acoustic lead tone measures were developed for
use with patients aged 2 to 30 months. A visual reinforcement paradigm with
children under 3 years employed test frequencies of 500, 2,000 and 8,000 Hz.
Major Findings;
1. The ABR work showed that the 8,000 Hz filtered click was the most
effective stimulus for eliciting Waves I, III and V and the 1,000 Hz
stimulus was the poorest. Wave V was the most sensitive measure for
all stimuli. A clinically usable test should include stimuli at both
2,000 and 8,000 Hz.
2. Ninety percent of the infants showed significant blink inhibition by
25 msec for tones presented at 40 dB SPL.
3. Infants from 6 to IB months of age showed thresholds within 15 dB of
adult norms for all frequencies tested. Six-month-olds were
significantly less sensitive to 8,000 Hz than to either of the lower
frequency stimuli, but older infants demonstrated approximately equal
sensitivity for all frequencies tested.
Significance to Biomedical Research and the Program of the Institute:
Procedures were needed to assess hearing of young children who are incapable of
providing conventional responses. A battery of tests to determine hearing
sensitivity at different developmental stages is essential to the initiation of
a habilitation program to optimize language and psychosocial development.
Proposed Course: Contract was completed on December 30, 1981.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, I98I through September 30, 1982
MINNEAPOLIS MEDICAL RESEARCH FOUNDATION, MINNEAPOLIS, MINNESOTA (NOl-NS-7-2378)
Title: A Comprehensive Study of the Language Recovery Process in Adults with
Aphasia Following a Cerebrovascular Accident
Contractor's Project Director; Alan B. Ruben, M.D.
Date Contract Initiated; September 30, 1977
Current Annual Level of Support; $315,155
Objectives; The purpose of the research is to develop increased understanding
of the neurophysiological and behavioral bases of the language recovery process
in aphasic adults. Multidisciplinary studies will determine;
1. The relationship between outcome of aphasia and the size and location
of brain pathology and neurophysiological activity in each hemisphere.
2. The relationship between changes in neurophysiological activity of
either hemisphere, and degree of language recovery.
3. Whether cognition is associated with the degree of recovery from
aphasia.
4. Whether verbal learning/memory deficits are associated with degree of
recovery from aphasia.
Methods Employed; Aphasia patients are examined monthly between one and six
months following the onset of aphasia due to a cerebrovascular accident.
Metabolic patterns during language and non-verbal behavior in each hemisphere
are being examined with xenon inhalation cerebral blood flow and spectral
analysis of EEC recordings. CT scanning is carried out on admission to the
research and at one month post onset; speech and language, dichotic listening,
verbal learning and memory and cognitive testing are carried out at regular
intervals over the first six months.
Major Findings; Analysis of the first 24 cases on the cerebral blood flow data
indicate; no consistent changes in right hemisphere flow between 2, 6 and 12
months post onset and no relationship between right hemisphere flow or change
in flow and language recovery. In patients with good auditory comprehension,
the flow was greater in the left temporal probes than in the patients with poor
auditory comprehension. No changes were found in the degree of alpha
suppression in either the left or right hemispheres which could be associated
with language recovery. Thus far, these metabolic studies do not provide
support for the theory of increased involvement of the right hemisphere in
language functioning during recovery from aphasia.
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studies of verbal learning in aphasia indicate patients are able to acquire new
information and store it; however, those with frontal opercular lesions have
greater difficulties with list learning. Memory span, on the other hand, is
impaired independently from list learning and language recovery, and may not
be as important in aphasia recovery as list learning performance.
Significance to Biomedical Research and the Program of the Institute; Language
recovery in aphasic adults is not well understood. In most cases recovery is
rapid during the first nine weeks following the onset of symptoms. The size
and location of brain lesions, regional blood flow, and physiological response
of each hemisphere during verbal behavior will determine the association
between dominant hemisphere status and level of recovery from aphasia. If
recovery is not highly associated with changes in the left hemisphere, and the
right hemisphere is found to be involved in verbal functioning, both the right
and left hemispheres may be involved in language recovery following a CVA. The
results will be useful for developing appropriate approaches for treatment.
Proposed Course : The contract was extended for one additional year to complete
testing of close to 55 subjects. Termination date is March 31, 1983.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, I98I through September 30, 1982
UNIVERSITY OF ILLINOIS (NOl-NS-7-2380)
Title: Evaluation of a Test of Speech Perception in Noise
Contractor's Project Director; Robert C. Bilger, Ph.D.
Date Contract Initiated; September 29, 1977
Current Annual Level of Support: $0
Objectives; The purpose of this contract was to conduct experimental work to
determine the interlist equivalency, performance by signal-to-babble (S/B)
functions and validity of the Speech Perception in Noise (SPIN) Test.
Methods Employed; Interlist equivalence of all ten recorded forms of the SPIN
Test were determined on a sample of 128 hearing-impaired adults by generating
alpha coefficients, intercorrelations between all ten forms, variance estimates
for error and obtained variances for each form, and mean performance. Lack of
equivalence among forms required item analyses and generation of eight new
forms that met the equivalence criteria. All forms were administered to
subjects with other speech stimuli to determine the degree to which the SPIN
Test over- or under-estimates speech perception in noise compared to other
measures of speech recognition. The validity of the SPIN Test was determined
with 40 additional hearing-impaired subjects who were fitted with hearing aids.
A paradigm was followed to obtain validating data with a test of the relative
effectiveness of the subjects' communication via visual, auditory and combined
cues when wearing a hearing aid; a set of psychological tests selected to
measure his cognitive adaptability; tests of linguistic competency; and, a test
of Communication Ability in Daily Living. Three to four months later, the
subjects were reevaluated on several measures of communication effectiveness to
assess the efficacy of the hearing aid.
^4ajor Findings;
1. The non-auditory test developed to assess the ability of these
hearing-impaired people indicates the semantic and redundant cues
employed by them to ascertain the final words in highly predictable
sentences.
2. The eight revised forms of the SPIN Test are equivalent and can be
used interchangeably and repeatedly.
3. SPIN Test results correlate well with other selected measures of
speech recognition. Clinical applicability of the SPIN Test is
undergoing further evaluation.
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Significance to Biomedical Research and the Program of the Institute;
Assessment of supra-threshold speech perception in noise will provide a
valuable tool for the practicing clinician in managing hearing-impaired
patients. There is a high probability that the SPIN Test will have predictive
value in determining the degree of benefit that persons with acquired
sensorineural hearing impairments may appreciate from a properly selected
hearing aid.
Proposed Course; Final data analyses and reports are being prepared. Contract
completion date was August 31, 1982.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
CHILDREN'S HOSPITAL OF PITTSBURGH (NOl-NS-8-2384)
Title; Decongestant/Antihistamine Therapy for Otitis Media with Effusion (OME)
Contractor's Project Director; Charles D. Bluestone, M.D.
Date Contract Initiated; July 1, 1978
Current Level of Support; $0
Objectives; To determine if a combination of an oral decongestant and
antihistamine medication (D & A) is effective in the treatment of otitis media
with effusion.
Major Findings; A total of 6II subjects from 7 months to 12 years of age were
enrolled during the period from July, 1978 - June, 1981. Over 90? (N=553)
returned for the four-week examination. The outcome of the trial was based
primarily on the presence or absence of OME. Of the 278 (50.3?) subjects with
either unilateral or bilateral OME at entry into the program who received D &
A, 69 (24.85J) had no effusion in either ear at the four-week endpoint. A
similar figure was found for the children who received a placebo (N=67 of 275
subjects, or 24.3/^). Within the D & A group and within the placebo group who
entered with bilateral OME, both groups exhibited unilateral (or bilateral) OME
at the four-week endpoint. No significant differences were found for either
group as a function of age or duration of OME. Other possible related factors
as to outcome were analyzed, such as sex, race, bilateral vs unilateral OME,
previous history of OME, presence or absence of upper respiratory allergy,
upper respiratory tract infection, rhinorrhea, adenoid size, season and socio-
economic status. No significant differences were found between the two groups
for any of these stratified factors. Some side-effects were noticed for the
D & A group. Subsequent development of acute suppurative OME or purulent
rhinitis was similar for both groups. Drug compliance, recurrence rates and
hearing status were similar for both the experimental and control groups.
Significance to Biomedical Research and the Program of the Institute; A
combination of oral D & A failed to reveal any beneficial effect in eliminating
OME after four weeks of treatment; therefore, D & A is not an effective
treatment for OME in infants and young children.
Proposed Course; The contract terminated on June 30, 1981.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
PRESIDENT AND FELLOWS OF HARVARD COLLEGE. CAMBRIDGE. MASSACHUSETTS
(NOl-NS-8-2399)
Title; Laryngeal Carcinoma: Identification of High Risk Factors
Contractor's Project Director: Kenneth J. Rothman, M.D., Ph.D.
Date Contract Initiated: September 29, 1978
Current Annual Level of Support: $0
Objectives: To identify individual health, environmental, and occupational
factors which will delineate persons at high risk of laryngeal carcinoma in the
United States today. The following objectives will be met:
1. An integration of data available on factors associated with a high risk
of laryngeal carcinoma in the United States;
2. An examination of mortality, incidence data and time trends to identify
regions with significantly high rates of laryngeal cancer over the last
10 years; and,
3- Investigations of occupational factors and their relationship with
laryngeal carcinoma.
Methods Employed: Data from the Commission of Professional and Hospital
Activities, an organization which gathers information on about MO per cent of
the country's hospital discharges, were analyzed to determine regional
differences in the incidence of laryngeal carcinoma. Time trends were examined
across 1970 -1978 by region and sex. Data from the Third National Cancer
Survey (TNCS) were evaluated to determine the interaction between alcohol and
tobacco in laryngeal cancer. Interview data from the TNCS were also examined
to determine which occupations had rate ratios greater than one.
Case control studies were conducted in Augusta, Georgia and New Haven,
Connecticut to examine the risk ratios of different occupations for laryngeal
carcinoma.
Major Findings: In the case control study conducted in Augusta, Georgia, rate-
ratio estimates were greater than one for the following occupations: workers
who separated filtered or dried textile fibers (RR=2.6); grain farmers (corn
and soybeans) (RR=4.9); laborers and maintenance personnel (RR=5.4); mechanics
(engine, electric motor, miscellaneous mechanics, millwrights, and repairmen
(RR=1.M) and truck drivers, taxi drivers and chauffeurs, bus drivers and
deliverymen (RR=1.1).
Significance to Biomedical Research and the Program of the Institute: The
chances of survival following laryngeal carcinoma can be significantly enhanced
with early treatment and the vocal mechanism may be spared when surgical
intervention is not necessary. Screening programs are needed of persons at
high risk of laryngeal cancer (such as industrial male workers who are heavy
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smokers and drinkers between 60 and 65 years of age). Before such programs oan
be initiated, a clearer understanding is needed of what factors could delineate
persons at high risk for this disease. The final report of this project will
indicate what further research is needed for delineating persons who are at
high risk as well as what is currently known about the relative risk for this
disease in various sections of the population.
Proposed Course; Both Phase II and III of the research have been completed by
the contractor; a case control study of the relationship between occupational
histories and the occurrence of laryngeal carcinoma will be completed by June,
1982.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 1981 through September 30, 1982
UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL, NORTH CAROLINA (NOl-NS-9-2305)
Title: The Acquisition of Language and Communicative Skills by Speech and Sign
in Infantile Autism
Contractor's Project Director: Thomas Lay ton, Ph.D.
Date Contract Initiated: March 31, 1979
Current Annual Level of Support: $51,092
Objectives; To conduct an experimental study of the development of
communicative skills by autistic children when training involves only speech
stimuli, only sign stimuli, speech and sign stimuli presented simultaneously,
or speech and sign presented independently. The research will determine after
six months of training which method of language training results in greater
expressive and receptive language skills; greater use of language skills for
communication; and greater retention of language skills following training.
The study will also determine whether autistic children evidence cross-modality
transfer of information learned in speech or sign to the other modality;
whether simultaneous presentation of stimuli in two different modalities
interferes with learning; and whether autistic children show similiar language
learning difficulties in both the speech and sign modalities.
Methods Employed; Children with infantile autism are randomly assigned to
different language training methods: with speech alone, with sign alone, with
alternating instruction between speech and sign and with speech and sign
combined.
Major Findings: A total of 36 children have completed the training program with
six more included and nearly finished. The results of initial language
development testing on admission to the study, are related to performance in
language training. Children whose expressive language is initially superior to
their receptive language, are most difficult to predict in their language
training results while two other groups are more predictable. The group with
relatively good overall performance on expressive and receptive testing and
better performance in receptive items demonstrated a more rapid learning rate
than those with generally poor performance on all language testing and only
slightly better receptive language.
Significance to Biomedical Research and the Program of the Institutes;
Impaired speech and language development is common to all children with
infantile autism although the degree of impairment varies among children. The
etiology of these disorders is not known and the bases for these children's
specific difficulties in learning language is not well understood. Some have
proposed auditory and speech processing difficulties which could account for
these impairments. Recently, there have been clinical reports of marked
success with some of these children in learning language using signs or
gestures. Further reports indicate that once such children begin to use signs
to communicate they may vocalize spontaneously and develop speech for
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communication more readily. This research will examine these issues experi-
mentally and have significance for the development of improved speech and
language training for autistic children.
Proposed Course; The final phase is being extended without additional funds to
allow time for report writing to March 31, 1983.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
UNIVERSITY OF CALIFORNIA, SAN DIEGO (NOl-NS-9-2322)
Title: Evaluation of the Outcome of Preschool Impairment in Language
Development
Contractor's Project Director: Paula Tallal, Ph.D.
Date Contract Initiated: September 30, 1979
Current Annual Level of Support: $64,200 (forward funded, annual support
approximately $260,000)
Objectives: To determine, through a longitudinal intensive study, the outcome
of preschool impairments in language development. In particular, the research
will determine:
1. Whether the patterns of development of language, speech, listening and
learning skills found in four-year-old, language-impaired children
differ from those of normal children when both groups are examined
annually between four and nine years of age.
2. Whether preschool children impaired in language development have
greater difficulties in acquiring reading and writing skills than
normal children at six, seven, eight and nine years of age.
3. Whether preschool children impaired in language development are
impaired in their verbal learning, memory and scholastic achievement in
comparison with normal children at five, six, seven, eight and nine
years of age.
4. Whether certain familial and language, speech, listening and learning
characteristics of language-impaired children at four years of age, are
predictive of their language, reading, writing and scholastic abilities
at five, six, seven, eight and nine years of age.
Methods Employed: One hundred language-impaired children are being examined
annually between four to nine years of age with multidisciplinary inves-
tigations into their patterns of development of language, learning and memory,
cognition, reading and writing. Two control groups, one chronologically
similar and the other at an equivalent mental age, are also being followed for
comparison of their developmental patterns with those of the experimental
group.
Major Findings: The contractor is close to completing the selection and first
year of testing of the language-impaired subjects for the investigation.
Subject acquisition has been difficult since many subjects referred as
language-impaired do not meet the rigorous subject selection criteria.
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Subsequent to completion of the pilot testing, the testing battery was reduced
to include items sensitive to age and which differentiate between normal and
language-impaired subjects. A new language assessment battery was developed
for this project which is far superior to any currently available and will be a
significant new tool for the assessment and study of language-impaired
children. The research will examine the validity of the assessment battery for
assessing language development in language-impaired children and for discrimi-
nating normal and language-impaired children at each age level.
Significance to Biomedical Research and the Program of the Institutes; The
research will provide critically needed information for treatment of children's
language disorders. It will determine whether language-impaired children
differ from normal in their language acquisition process or are simply delayed
in the normal sequence of language acquisition. Until information is obtained
on the language development process in language-impaired children, appropriate
treatment approaches cannot be developed.
The research will also determine whether preschool impairments in language
development are precursors of difficulties in learning to read and write. The
research will provide a detailed analysis of the types of difficulties these
children have when learning to read. With improved understanding of the
reading deficits of children who have a linguistic difficulty, remedial
procedures for this segment of the reading-disabled population can be improved.
Proposed Course: A contract was awarded for the first three years to include
the developmental phase, subject selection and the first eighteen months of the
longitudinal study. A Technical Merit Review site visit will be held in
September 1982 before extending the contract for the final four years of the
study.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER (NOl-NS-0-2328)
Title: Efficacy of Adenoidectomy /Tympanostomy Tubes for Persistent Otitis
Media with Effusion (POME)
Contractor's Project Director: George A. Gates, M.D.
Date Contract Initiated: January 1, 1980
Current Level of Support: $424,447
Objectives: To conduct a controlled clinical trial to determine the efficacy
of various treatment modes for persistent otitis media with effusion (POME).
The treatment consists of myringotomy (MX) without or MX with tympanostomy
tubes (MXTT), adenoidectomy (AD) and a combination of all three treatment modes
(MXADTT). The primary aim is to determine the most effective treatment for
improved hearing and prevention of recurrent middle ear effusions.
Major Findings: A total of 1,080 screening evaluations have been completed
(12/31/81). This number represents 815S of a predicted load of 1,340 for this
time period. The attrition rate, however, has been higher than expected.
Approximately 40/J of the children have been disqualified prior to
randomization. Approximately 30^ of the remaining children were cleared
medically and, therefore, were not randomized. Thus, a total of 124 patients
(24?) have been randomized. Preliminary analyses of these data indicate that
MXTT and MXADTT offer the best treatment for POME. Questions which have not
been answered are the extent to which surgical retreatment might occur for each
treatment group, surgical complications (e.g., drainage, cholesteatomas)
experienced for the MXTT and MXADTT groups, number of treatment failures, and
number of months with consecutive or intermittent effusion.
Significance to Biomedical Research and the Program of the Institute: Otitis
media with effusion (OME) is one of the major health problems in children.
Currently, there is no consensus as to the most efficacious treatment of this
vexing problem using the four treatment modes. Preliminary information points
to the effectiveness of two of the four treatment procedures.
Proposed Course: This contract is due to terminate on January 31, 1985. Due
to the longitudinal nature of the study, and the problem of accumulating a
sufficient number of patients to be randomized, the study should continue for
the full five-year period.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 1981 through September 30, 1982
PURDUE RESEARCH FOUNDATION (NOl-NS-0-2329)
Title; Determination of Effects of Hearing Aid Amplification on Children
Contractor's Project Director: Carl A. Binnie, Ph.D.
Date Contract Initiated; March 31, 1980
Current Annual Level of Support: $109,287
Objectives; The purpose of this contract is to determine the possible effects
of hearing aid amplification on the residual hearing of children with
sensorineural hearing loss. It will relate hearing changes to the
electroacoustic characteristics of the hearing aids, amount of hearing aid use,
degree of hearing impairment, earmold or coupling system, etiological
information and amount of progressive hearing deterioration.
Methods Employed; Baseline audiometric and tympanometric measures have been
made. Changes in threshold are measured at predetermined intervals along with
dosimetry and recordings of environmental noise exposure. Complete medical
genetic evaluations are obtained as necessary. Function-gain measures are made
in the soundfield for both aided and unaided conditions using computer-
generated narrow bands of noise centered at the octave frequencies from 250-
4,000 Hz.
Major Findings; Preliminary results indicate that hearing aid amplification
has not significantly changed the hearing capabilities of any of the youngsters
under study.
Significance to Biomedical Research and the Program of the Institute: The
possibility of acoustic trauma produced by prolonged use of a powerful hearing
aid has serious implications for the moderate to severely impaired listener.
If such deterioration does occur, it will be essential for clinicians to take
steps which will protect the inner ear from further damage and still provide
the benefit of hearing aid amplification.
Proposed Course: Data will continue to be collected. Expected completion date
is March 30, 1983.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 198I through September 30, 1982
SYRACUSE UNIVERSITY. SYRACUSE, NEW YORK (NOl-NS-0-2331)
Title; Methods for Studying Phonatory and Articulatory Control in Young
Children Who Stutter
Contractor's Project Director; Edward Conture, Ph.D.
Date Contract Initiated; July 31, 1980
Current Annual Level of Support; $260,867
Objectives;
1. To develop measurement techniques and testing procedures for assessing
the speech production skills of young children between four and six
years of age which are noninvasive, objective and reliable.
2. To determine which aspects of phonatory and articulatory control during
speech production differ in fluent and stuttering children between four
and six years of age.
Methods Employed ; The following procedures are being adapted for use with
young children;
1. Surface electromyography is used to record from the orbicularis oris
inferior (001) and the depressor labii inferior.
2. Voice onset time is measured from the electroglottograph and the sound
spectrograph.
3. Vocal fold adduction is being measured from the glottal duty cycle of
the electroglottograph.
4. Chest and abdominal components of respiratory movements are being
measured from the Respitrace system.
5. Lower lip and jaw movements are being measured from strain gauges.
Speech is being sampled during rapid repetition of syllables, words and phrases
and all signals are recorded simultaneously and digitized with time coding to
allow for cross-correlations between different measures aligned for time.
Major Findings; In initial pilot studies, fluent utterances in normal
speaking children and young stutterers were compared. The initiation of
electromyographic activity in the 001 and the duration of 001 contraction
synchronous with voice onset during syllable productions indicate that muscle
contractions for labial closing gestures are synchronous with phonatory onset
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in stuttering children during fluent speech rather than preceding phonation as
occurred in the normally speaking children. Further, the stuttering children
have shorter durations of 001 muscle contractions overall. These pilot data
suggest that the bilabial contact gestures are too short in the fluent gestures
of stuttering children and provide evidence that the temporal organization for
speech differs from normal in stuttering children in other articulators besides
the larynx.
Significance to Biomedical Research and the Program of the Institute: There is
a critical need to stimulate research on stuttering; NINCDS is the prime BID
within the U.S. Government for the support of stuttering research and only
supports one grant in this area. Recent research on adults has indicated some
differences in phonatory control between normal and stuttering adults. This
project will examine the hypothesis of whether or not children who become
persistent stutterers show differences in phonatory control during the normal
developmental period of non-fluency.
Objective methods of assessing speech-timing control in young children who
stutter will provide the necessary tools for research on the developmental
period of non-fluency and the development of stuttering in young children.
These methods of assessment may lead the way to early identification of young
children who are at risk of developing speech dysfluencies and may indicate
appropriate intervention techniques for improving the development of speech
timing control and preventing stuttering.
Proposed Course; The contract is expected to terminate in July 1983.
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CONTRACT NARRATIVE
Communicative Disorders Program
October 1, 1981 through September 30, 1982
OHIO UNIVERSITY. ATHENS, OHIO (NOl-NS-0-2342)
Contractor's Project Director: William Seaton, Ph.D.
Current Annual Level of Support: $31,9^7
FATHER FLANAGAN'S BOYS HOME, OMAHA. NEBRASKA (NOl-NS-0-2343)
Contractor's Project Director: Ronald Netsell, Ph.D.
Current Level of Support: $21,996
LOYOLA UNIVERSITY AT CHICAGO, CHICAGO, ILLINOIS (NOl-NS-0-2344)
Contractor's Project Director: William A. Yost, Ph.D.
Current Annual Level of Support: $21,16?
UNIVERSITY OF CONNECTICUT. STORRS. CONNECTICUT (NOl-NS-0-23^5)
Contractor's Project Director: Jay Lerman, Ph.D.
Current Annual Level of Support: $17,178
UNIVERSITY OF HAWAII AT MANOA, HONOLULU, HAWAII (NOl-NS-0-23^6)
Contractor's Project Director: James Yates, Ph.D.
Current Annual Level of Support: $11,^430
Title: Evaluation of the Effectiveness of Information Services Provided to
Specialists in Communicative Disorders by MEDLINE
Date Contracts Initiated: September 15, 1980
Objectives: Data will be provided to the NINCDS on MEDLINE users who are
specialists in communicative disorders to answer the following questions:
1. What are the information needs of various communicative disorders
specialists?
2. Whether various types of specialists in communicative disorders learn
to use terminals for interacting directly with MEDLINE and developing
individualized literature searches?
3. Whether MEDLINE provides adequate coverage of research literature in
each of the communicative disorders specialities?
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4. Which service models (direct access or technical assistance) are most
satisfactory for serving the needs of various types of specialists in
communicative disorders?
5. Which information needs in various communicative disorders specialties
are not met by MEDLINE?
Methods Employed; Professionals were recruited for involvement as user
participants at each MEDLINE center. On admission to the study, each
participant completed a pre-use questionnaire. The results of the pre-use
questionnaire will indicate the current practices of various professionals and
their perceived information needs. User participant training workshops were
conducted prior to providing services at each MEDLINE center. Users have
unlimited free access to MEDLINE services for l8 months. With each use, users
may choose to access information through one of three modes: direct access
operating the terminal themselves; working with the technical information
specialist at the terminal; or filling out a search request with no involvement
in the search process. Data are kept at each center on the modes of access
used and corresponding levels of satisfaction. After l8 months of free access,
each user participant will complete a post-use questionnaire evaluating their
use, level of satisfaction, and preferred search mode of MEDLINE, any changes
in their information accessing habits and perceived unmet information needs.
Major Findings; Over 700 user participants are enrolled in the study. The
majority of these are speech-language pathologists, audiologists and graduate
students. Few had used computerized databases before the project. Personal
journal subscriptions and discussions with peers were the most common methods
of accessing information prior to the study.
Preliminary data indicate the preferred search mode is conducting a search with
the technical information specialist. MEDLINE retrieval results are most
satisfactory when users are less familiar with the topic and want to survey a
body of literature which they have not been following closely.
Significance to Biomedical Research and the Program of the Institute; The
Scientific Information Program of the NINCDS has supported activities aimed at
providing the rapid transfer of research and technological advances to
specialists in communicative disorders. The Communicative Disorders Program
has focused on meeting the objectives of its Scientific Information Program by
upgrading MEDLINE services in communicative disorders. A User's Manual and
Specialized Thesaurus were published and workshops developed and videotaped to
train scientists and clinicians on how to use MEDLINE and enabling users to
have direct access to MEDLINE. The new service model developed by the GDP is
much less costly than specialized Information Centers since users learn to
access the information directly and are charged only for the online time
required and hard copy printout.
Proposed Course; All five contracts wil terminate on March 14, 1983.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 1981 through September 30, 1982
MEDICAL UNIVERSITY OF SOUTH CAROLINA (NOl-NS-1-2381)
Title: An Analytical Study of the Auditory Effects of Noise
Contractor's Project Director: John H. Mills, Ph.D.
Date Contract Initiated: July 1, I98I
Current Annual Level of Support: $34,000
Objectives; The purpose of this contract is to conduct a detailed analysis of
the auditory effects of noise and to identify areas in need of further
investigation.
Methods Employed : With the contributions of 14 scientific experts, a written
analysis of completed national and international studies will be made in the
following areas: differential diagnosis and measurement of noise-induced
hearing loss; individual differences in susceptibility; protection and
conservation of hearing; anatomy, physiology and biochemistry; temporary,
permanent and asymptotic threshold shifts; noise and other ototraumatic agents;
and continuous, intermittent and impulse noise. Areas in need of additional
research will be identified in a document with suggested methodologies and
procedures for studying the problems.
Major Findings: Over 3,000 studies have been analyzed and ordered according to
importance to the scientific knowledge of auditory effects of noise.
Significance to Biomedical Research and the Program of the Institute: Noise-
induced hearing loss (NIHL) is one of the few hearing disorders that can be
prevented in the American population. This project is intended to identify
promising avenues of research that can profitably be pursued to alleviate NIHL.
Proposed Course: Contract is expected to be completed by April 30, I983.
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CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, 1981 through September 30, 1982
TUFTS-NEW ENGLAND MEDICAL CENTER (NOl-NS-2-2305)
Title: The Prescription of Communicative Devices for Non-Speaking Patients
Contractor's Project Director: Cheryl Goodenough-Trepagnier
Date Contract Initiated: June 30, 1982
Current Annual Level of Support; $248,000
Objectives;
1. To design procedures for determining: a) the cognitive abilities of
non-speaking patients with severely handicapping physical and
neurological disorders to operate various types of communicative
devices, b) the communicative augmentative needs of such patients,
c) the cognitive and motor requirements of users for operating various
types of communicative devices, and d) the communicative augmentative
features of various types of communicative devices;
2. To develop a prescriptive system for selecting the optimal device for
an individual patient; and,
3. To conduct a validation study of the prescriptive accuracy of the
system for selecting a device which will maximally augment a patient's
communicative abilities.
Methods Employed; During the development phase,
1. Objective and reliable patient assessment procedures will incorporate
device interface simulators for measuring: the force, range accuracy
and speed of movement of the tongue, lips, jaw, fingers, hands, head,
etc.; and the range and control of airflow, sucking, blowing, etc.
Objective procedures will assess visual and auditory acuity, symbol
recognition, language comprehension, scanning, selection and encoding
skill, and speech intelligibility.
2. Administration and scoring procedures will be developed for determining
patients' augmentation needs including environmental demands, required
communication modes and references.
3. Objective and reliable procedures will measure the requirements of
users for various types of communicative devices. Formal testing
procedures will be applied to determine; the motoric operating require-
ments including force, range, resolution, duration, latency, and
accuracy of various body movements and functions and the sensory,
perceptual and cognitive requirements to operate each device.
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4. A scoring inventory and procedures for determining the functions of
different types of communicative devices will include items parallel to
those in the patients' augmentation needs assessment battery.
Major Findings: Not applicable since the contract was just recently initiated.
Significance to Biomedical Research and the Program of the Institute: New
communicative devices for the non-vocal are being developed at a rapid rate due
to advances in microprocessors. For non-vocal patients to benefit from these
advances, patient and device evaluation procedures are required. Objective
measurement procedures are needed to initiate research in this field as well as
to enable appropriate prescription of devices even when they are not available
to the clinician or patient for trial. The system will provide a framework for
future device development and should stimulate future research on the needs and
treatment of non-vocal patients.
Proposed Course: Phase I will require 27 months for development and pilot
testing of the prescription system, while Phase II, the validation study, will
require 12 months and should be complete in September 1985.
56-CDP
CONTRACT NARRATIVE
Communicative Disorders Program, NINCDS
October 1, I98I through September 30, 1982
BOLT. BERANEK AND NEWMAN (NOl-NS-2-2394)
Title; Assessment of High Frequency Hearing
Contractor's Project Director; Kenneth N. Stevens, Sc.D.
Date Contract Initiated; December 8, 198I
Current Annual Level of Support; $159,000
Objectives; The purpose of this contract is to develop and evaluate an
electroacoustical device which will reliably and validly measure hearing
thresholds in the frequency range of 8,000-20,000 Hz. The ultimate aim will be
a system capable of assessing high frequency hearing impairment in humans.
Methods Employed ; Measurements are being made on a simple tube with small
microphones at both ends to simulate measurements of pressure at the entrance
to the ear canal and at the eardrum. Similar measures are being taken on real
ears. The measured standing wave patterns are being compared with those
obtained from the model system to determine the influence of such factors as
non-rigid walls and terminal impedance. Pulses are applied to earphone
terminals to obtain samples of pulse response so that preliminary calibration
algorithms can be developed. The feasibility of different transducers,
microphones and calibration techniques are being explored. Decisions are being
arrived at for the calibration signal, transducer position and measurement of
canal impedance.
Major Findings; Preliminary results are not yet available.
Significance to Biomedical Research and the Program of the Institute; A
reliable and valid means of assessing high frequency hearing in humans will
provide a valuable clinical measure for early detection of cochlear damage due
to noise-induced and drug-induced trauma. Close monitoring of hearing
deterioration is expected to provide evidence for altering the dosage of the
damaging agent, either noise or drug, in an effort to protect the patient from
further hearing loss.
Proposed Course; Transducers will be developed along with appropriate
calibration procedures. A microprocessor-controlled audiological testing
system will be designed and constructed. Normative data will be collected on a
population of young subjects and a reevaluation of the prototype instrumen-
tation will be conducted. Contract completion date is August 7, 1984.
57-CDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02185-08 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Characteristics of Dysarthric Speech Associated with Neurologic Disease
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHERS :
C, L, Ludlow Speech Pathologist CDP NINCDS
C. J. Bassich Speech Pathologist CDP NINCDS
R. F. Naunton Otolaryngologist, Director CDP NINCDS
R. Eldridge Neurologist IRP NINCDS
COOPERATING UNITS (if ar
Intramural Research Program, NINCDS
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
35
PROFESSIONAL:
,25
,10
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The distinctive patterns of speech motor control disturbances (dysarthrias)
associated with neuromotor diseases/disorders affecting different regions of the
central nervous system are being studied.
An objective system of acoustic analysis has been developed which measures the
coordination, timing and rate of different speech gestures, and control of
fundamental frequency and speech intensity level. The analysis system was
demonstrated valid for differentiating between normal and dysarthric speech and
between speech disorders associated with pathologies at different locations in
the central nervous system. Measures are being made with a three-dimensional
movement transducer of the displacement, velocity and acceleration of lip and
jaw movements. The maximum range, rate and onset and offset timing during oral
gestures and speech production is being studied in normal speakers and patients
with Tardive Dyskinesia, Parkinson's disease, Huntington' s Chorea, and Dystonia.
58-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02247-06 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Characteristics and Treatment of Vocal Tics and Language Processing in Gilles
de la Tourette Syndrome
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHERS :
C. L. Ludlow
C. J. Bassich
R. Polinsky
Speech Pathologist
Speech Pathologist
Neurologist
CDP NINCDS
CDP NINCDS
LCS NIMH
COOPERATING UNITS (if any)
Intramural Research Program, NIMH
lab/branch
Communicative Disorders Program
SECTION
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
,35
PROFESSIONAL:
,25
OTHER:
.10
CHECK APPROPRIATE BOX(ES)
B (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Ihe vocal tics in Gilles de la Tourette Syndrome are being analyzed to determine
the differences in timing control and production between vocal tics and the same
productions in normal prepositional speech. The relationship between the pro-
ductions of vocal tics and language formulation deficits in Tourette Syndrome
are being examined in an effort to develop an explanatory model for expressive
language deficits seen in some of these patients. The family histories and
speech and language characteristics of family members of patients with Tourette
Syndrome are being examined to develop pedigrees of the familial patterns of
speech and language disorders found to occur in 50% of these patients.
PHS-6040
(Rev. 2-81)
59-CDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02336-05 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cis Platinum and Early Identification of Ototoxicity
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHERS :
E. Elkins
A. Pikus
A. Grimes
Audiologist
Audiologist
Audiologist
CDP NINCDS
CC
CC
COOPERATING UNITS (if any)
Clinical Center Audiology
Radiation Oncology Branch
Division of Cancer Treatment, NCI
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,02
PROFESSIONAL:
.02
.00
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Cisplatinum used in the treatment of testicular and ovarian cancer is known to
have ototoxic effects. Cochlear damage is manifest by a high-frequency hearing
loss and general difficulty in understanding normal conversational speech.
Periodic assessments of pure tone thresholds and suprathreshold speech
perception are being conducted to evaluate and relate degree and progression of
ototoxicity to drug dosage and frequency of administration.
60-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02337-05 CDP
PERIOD COVERED
October 1.
1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Effects of Stimulants on the Auditory Processing and Language Skills of
Hyperactive, Language Impaired and Normal Subjects
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHERS ;
C, L. Ludlow
J. L. Rapoport
G. L. Brown
C. J. Bassich
Speech Pathologist
Psychiatrist
Psychiatrist
Speech Pathologist
CDP NINCDS
IRP NIMH
IRP NIMH
CDP NINCDS
COOPERATING UNITS (if any)
Intramural Research Program, NIMH
lab/branch
Communicative Disorders Program
SECTION
INSTITUTE AND LOCATION
NTWCnS. NTH, Bethesda,
Maryland 20205
total MANYEARS:
.50
PROFESSIONAL:
.25_
.25
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A series of studies are being conducted to determine the following
1
2.
The relationships between auditory processing deficits, speech
perception skills, attention disorders, and speech and language
development in hyperactive boys, with and without learning disorders;
The effects of stimulants on the speech, language and communicative
skills of language disordered hyperactive boys;
Whether auditory processing disorders in hyperactive boys with and
without disorders in speech, language and reading respond similarly to
the administration of dextroamphetamine; and
Whether the effects of stimulant drugs on auditory processing disorders
in language impaired children are related to the effects of stimulants
on language processing and speech fluency.
61 -CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02395-04 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Analysis of Fluctuating Hearing Loss Associated with Cogan's Syndrome
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
A.
Pikus
Audiologist
OTHERS :
B.
F. Haynes
Staff Physician
E.
Elkins
Audiologist
cc
LCI NIAID
CDP NINCDS
COOPERATING UNITS (if any)
Clinical Center Audiology
Laboratory of Clinical Investigation, NIAID
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
,00
check APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
□ (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Cogan's Syndrome (CS) is characterized by acute nonsyphilitic interstitial
keratitis and acute episodes of vertigo, tinnitus and hearing loss. Within 1 to
2 weeks after initiation of corticosteroid therapy, all patients demonstrated
improved hearing thresholds for pure tones and supra-threshold speech discrimi-
nation results. These patients have been followed an average of 2.5 years; all
have only mild-to-moderate hearing impairment in the mid and low frequencies.
Three of the patients have been tapered off steroids completely with no
subsequent permanent decrement of hearing. Thus, early corticosteroid
administration to patients with sudden hearing loss associated with Cogan's
Syndrome may preserve auditory function.
PHS-6040
(Rev. 2-81)
62-CDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
TITLE OF PROJECT (80 characters or less)
Auditory Deficits in Osteogenesis Imperfecta**
PI:
A.
Pikus
OTHERS :
E.
Elkins
E.
Gross
J.
W. Hansen
S.
Levin
K.
Rosenbaum
D.
Rowe
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02396-04 CD?
PERIOD COVERED
October 1, 1981 through September 30, 1982
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Audiologist
Audiologist
Chief, Molecular
Structure Section
Pediatrician, Develop-
mental Biology &
Clinical Nutrition Section
Dept. of Otolaryngology
Dept. of Genetics
Dept. of Pediatrics
CC
CDP NINCDS
ERKB NICHD
NPMB NICHD
Johns Hopkins University
Children's Hospital,
Washington, D.C.
University of
Connecticut
COOPERATING UNITS (if any)
LDBA NIDR; CC, NIH; Molecular Structure Section, ERRB, NICHD; Developmental
Biology & Clinical Nutrition Section, NPMB, NICHD; Johns Hopkins University;
University of Connecticut; Children's Hospital, Washington, D.C.
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,10
PROFESSIONAL:
,10
OTHER:
,00
check APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Methods are being developed to delineate the types of hearing losses associated
with Osteogenesis Imperfecta (01) . Measurement of middle ear function by
tympanometry and acoustic reflexes are being developed to classify penetrance
and types of auditory deficits associated with differing forms of this disease.
**[This study is the NINCDS portion of a larger study (CC) entitled:
"Collagen Metabolism in Osteogenesis Imperfecta (01)" , of which
Dr. Jay R^ Shapiro is the Principal Investigator. ]
63-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02440-03 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Development of Acoustic Measurement Tools for Assessing Vocal Pathology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: C. L. Ludlow
OTHERS: R. F. Naunton
C. J. Bassich
R. Eldridge
Speech Pathologist CDP NINCDS
Otolaryngologist, Director CDP NINCDS
Speech Pathologist CDP NINCDS
Neurologist IRP NINCDS
COOPERATING UNITS (if any)
Intramural Research Program, NINCDS and National Naval Medical Center
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,50
PROFESSIONAL:
,25
,25
CHECK APPROPRIATE BOX(ES)
H (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Acoustic measures for the assessment and analysis of phonatory functioning in
various types of laryngeal pathology are being developed. Objective noninvasive
assessment techniques which can differentiate between normal function and varying
degrees of pathology have been completed. Various signal processing algorithms
for analyzing frequency and amplitude components of speech waveforms are being
evaluated for differential sensitivity to morphological and neurological changes
in the larynx. Nasopharyngolarynscopic videotape recordings during connected
speech are examined for interpretation of phonatory pathology in various types
of disorders Including spastic dysphonia and extrapyramidal disorders. Explana-
tory models of the effects of different laryngeal disease processes on phonatory
function are sought to further understanding of the phonatory mechanism.
64-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02441-03 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Hearing Assessment in Central Neurofibromatosis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. Elkins
OTHERS: A. Pikus
R. Eldridge
Audiologist
Audiologist
Head, Clinical
Neurogenetics Study
CDP NINCDS
CC
NES NINCDS
COOPERATING UNITS (if any)
Clinical Center Audiology
Clinical Neurogenetics Studies, NES, ODIR, IRP, NINCDS
Cancer Epidemiology Branch, NCI
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.10
PROFESSIONAL:
10
,00
CHECK APPROPRIATE BOX(ES)
1 (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This autosomal dominantly inherited form of neurofibromatosis (NF) usually
occurs without the visible stigmata of peripheral NF and is characterized by
bilateral acoustic tumors. Complete families are being studied, including
children, in order to provide earlier and more accurate diagnoses of tumors.
Appropriate and timely medical and audiological management plus counseling
are considered for each patient individually.
6 5 -CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE Of
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02464-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Audiologic Findings in Autism**
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
cc
cc
NIMH
NIMH
CDP NINCDS
PI:
A.
Pikus
Audiologist
OTHERS :
A.
Grimes
Audiologist
J.
Rapoport
Physician
J.
Rumsey
Psychologist
E.
Elkins
Audiologist
COOPERATING UNITS (if any)
Clinical Center Audiology
Biological Psychiatry Branch, NIMH
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,20
PROFESSIONAL:
,20
OTHER:
,00
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Peripheral auditory function is being evaluated in children and adults with
Autism. For this difficult-to-test population, differential audiologic
assessment is a prerequisite to appropriate long term educational and
psychological nianagement. Additionally, the occurrence of auditory deficits in
this population has not been clearly defined.
**Part of a cooperative study with NIMH
66-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this spacej
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
i ZOl NS 02465-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Hearing in Peripheral Neurofibromatosis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. Pikus
OTHERS: E. Elkins
A. Grimes
J. Bader
Audiologist
Audiologist
Audiologist
Clinical Associate
CC
CDP NINCDS
CC
Epidemiology Branch
NCI
COOPERATING UNITS (if any)
Clinical Center Audiology
Clinical Neurogenetics Studies, NES, ODIR, IRP, NINCDS
Cancer Epidemiology Branch, NCI
lab/branch
Communicative Disorders Program
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
,10
PROFESSIONAL:
,10
OTHER:
,00
CHECK APPROPRIATE BOX(ES)
^ (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
□ (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An interdisciplinary clinic has been staffed for the evaluation of patients with
peripheral neurofibromatosis (NF) and their families. Due to the dominant
inheritance pattern of the disease, the probability of involvement of offspring
is 50-50. The nature and extent of auditory deficits associated with the
disorder have not previously been defined in this population. This patient
population is being evaluated to provide recommendations for treatment and
follow-up by the referring primary-care physicians.
6 7 -CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02466-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Pediatric Oncology Regimen and OtotQ:xjLclty
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. Pikus
OTHERS: A. Grimes
E. Elkins
P. Rizzo
Audiologist
Audiologist
Audiologist
Head, Infectious Disease
Section
Chief, Pediatric
Neurological Branch
CC
CC
CDP NINCDS
COP CDT NCI
COOPERATING UNITS (If any)
Clinical Center Audiology
Pediatric Oncology Branch, NCI
lab/branch
Communicative Disorders Program
SECTION
INSTITUTE AND LOCATION
NINCDS. NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
,20
PROFESSIONAL:
.20
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
.00
D (b) HUMAN TISSUES
D (c) NEITHER
VIMARY OF WORK (200 words or less - underline keywords)
All pediatric oncology patients on the "fever" protocol are given periodic
complete audiological analyses to ascertain if certain antibiotics used in
prevention or treatment of infection have damaging effects on hearing.
68-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
TITLE OF PROJECT (80 characters or less)
Auditory Function and Cerebral Vasculitis
PI: A. Pikus
OTHERS: A. Grimes
E. Elkins
R. Roberts
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02467-02 CDP
PERIOD COVERED
October 1, 1981 through September 30. 1982
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Audiologlst
Audiologist
Audiologlst
Clinical Associate
CC
CC
CDP NINCDS
LCI NIAID
COOPERATING UNITS (if any)
Clinical Center Audiology
Laboratory of Clinical Investigation, NIAID
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,15
PROFESSIONAL:
.15
,00
CHECK APPROPRIATE B0X{ES)
g (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This auto- immune disease is associated with auditory and vestibular symptoms.
Incomplete information is available on its manifestations in the auditory
system. This investigation studies the auditory system deficits in an attempt
to identify the most common sites of lesions and to profile the course of this
disease within the auditory system.
69- CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHAN
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02468-02 CDP
PERIOD COVERED
October 1, 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
Audiologic Findings in Wegener's Granulomatosis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. Plkus
OTHERS: E. Elkins
A. Grimes
A. Fauci
Audiologist
Audiologist
Audiologist
Chief, Laboratory of
Immunoregulation
CC
CDP NINCDS
CC
LIR NIAID
COOPERATING UNITS (if any)
Clinical Center Audiology
Laboratory of Clinical Investigation, NIAID
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH. Bethesda. Maryland 20205
TOTAL MANYEARS:
ML
PROFESSIONAL:
JSL
JKL
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This auto-immune disease is often manifest by intractable middle ear diseases
in addition to cochlear involvement. The current study evaluates the nature
and extent of auditory deficits associated with Wegener's Granulomatosis to
determine any effects of treatment on hearing and middle ear function.
70-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02469-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Small Cell Carcinoma and Hearing Loss
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
A.
Pikus
Audiologist
CC
OTHERS :
A.
Grimes
Audiologist
cc
E.
Elkins
Audiologist
CDP
NINCDS
A.
Lichter
Chief, Radiation Section
ROB
NCI
COOPERATING UNITS (if any)
Clinical Center Audiology
Radiation Therapy, NIH
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
.05
PROFESSIONAL:
.05
.00
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Patients with Small Cell Carcinoma of the lung are often treated with
chemo therapeutic agents and radiation therapy in combination or sequence.
Concern has developed over hearing loss in some patients. Project is designed
to help identify which (if either) factor may be causally related to hearing
deficits in this patient population.
71-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02470-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Audiologic Findings in an Aging Population*
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PI:
A.
Pikus
Audiologist
CC
OTHERS :
A.
Grimes
Audiologist
cc
E.
Elkins
Audiologist
CDP
NINCDS
M.
Schwartz
Staff Psychiatrist
LNS
NIA
R.
Duara
Senior Staff Fellow
LNS
NIA
COOPERATING UNITS (if any)
Clinical Center Audiology
Laboratory of Neurosciences, Gerontology Center,
National Institute on Aging
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
.20
PROFESSIONAL:
.20
OTHER:
,00
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An assessment of auditory function of "normal" (healthy aging) subjects is
being obtained through an Institute on Aging protocol investigating regional
brain metabolism. Subjects are given audiologic assessment test batteries to
develop a profile of risk factors for presbycusis.
*Part of larger study with Institute on Aging
72-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
TITLE OF PROJECT (80 characters or less)
Hearing and Neomycin Therapy for Type II Hyperlipidemia**
PI:
A.
Pikus
Audiologist
CC
OTHERS:
A.
E.
J.
Grimes
Elkins
Hoeg
Audiologist
Audiologist
Research Associate
cc
CDP
MD
NINCDS
NHLBI
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02471-02 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
COOPERATING UNITS (if any)
Clinical Center Audiology
Molecular Disease Branch, NHLBI
lab/branch
CnTiminnlcative Disorders Program
INSTITUTE AND LOCATION
NTNCnS, NIH. Bethesda, Maryland
20205
TOTAL MANYEARS:
JiQ_
PROFESSIONAL:
.30
OTHER:
.00
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A double-blind study of the effects of neomycin on hearing is being conducted
in patients with Tyne II Hvperlipidemia. Patients are receiving oral neomycin
and dietary regulation^n rotation and/or combination. Audiologic examinations
establishing baseline data are followed at predetermined increments to be
related to the other study variables.
**Part of larger study on Type II Hyper lip idemia and Neomycin Therapy
73-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02557-01 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Effects of Penetrating Head Injuries on Speech and Language Functioning
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
C. L. Ludlow
Speech Pathologist
CDP NINCDS
COOPERATING UNITS (if any)
Vietnam Head Injury Project, Walter Reed Army Medical Center, Clinical
Investigation Service including D. Dillon, D. Buck, J. Rosenberg and C. Fair
lab/branch
Communicative Disorders Program
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
10
PROFESSIONAL:
.10
OTHER:
.00
check APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The goal is to better understand the brain bases for speech and language func-
tioning. This research is part of a multidisciplinary investigation into the
long-term functional and anatomical sequelae of penetrating craniocerebral
trauma . Data collection began in 1967 with type of wound, initial neurological
presentation, therapy and follow-up examinations. The present phase includes
study of (a) anatomical deficits with the use of CT scans and (b) neurological,
sensory-motor, hearing, speech, language, and cognitive function. The purpose
is to determine (1) whether particular locations of brain lesions following
penetrating head injury are associated with specific residual deficits of:
strength and range of motion of the articulators; isolated and sequenced oral
volitional movements; oral movement and speech syllable repetition; word, phrase
and sentence imitation; categorical and temporal order perception for speech
sounds; meaningful word and syllable articulation and discrimination; auditory
and reading comprehension of lexical, semantic and syntactic information and
spoken and written expression of names, phrases, semantic relations and
syntactic structures.
74-CDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space;
TITLE OF PROJECT (80 characters or less)
Audiologic Findings of Multiple Sclerosis Lymphocyte Depletion Treatment
PI:
A.
Pikus
Audiologist
CC
OTHERS :
E.
Elkins
Audiologist
GDP
NINCDS
A.
Grimes
Audiologist
CG
H.
MacFarland
Assistant Chief,
Neuroimmunology
Branch
NIB
NINCDS
D.
McFarlin
Chief, Neuroimmunology
NIB
NINCDS
Branch
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02558-01 GDP
PERIOD COVERED
October 1. 1981 through September 30, 1982
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
COOPERATING UNITS (if any)
Clinical Center Audiology
Neuroimmunology Branch, NINCDS
lab/branch
Communicative Disorders Program
SECTION
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
,10
PROFESSIONAL:
,10
OTHER:
.00
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
There is inadequate understanding of 8th nerve dysfunction in multiple sclerosis
This study will determine the role of lymphocyte depletion treatment m the
fluctuations of the auditory deficit associated with multiple sclerosis.
75-GDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02559-01 CDP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Audiologic Findings in Alzheimer's Disease*
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
A.
Pikus
Audiologist
CC
OTHERS :
E.
Elkins
Audiologist
CDP NINCDS
A.
Grimes
Audiologist
CC
S.
Rapoport
Chief, Laboratory of
Neurosciences
NIA
L.
Sokoloff
Chief, Laboratory of
Cerebral Metabolism
NIMH
COOPERATING UNITS (if any)
Clinical Center Audiology
Laboratory of Neurosciences, NIA
lab/branch
Communicative Disorders Program
SECTION
INSTITUTE AND LOCATION
S. NIK. Bethesda, Maryland 20205
TOTAL MANYEARS: 1 PROFESS I ONAL:
JSL
■ 10
,00
CHECK APPROPRIATE BOX(ES)
2 (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Changes in cognition as well as other neurologic involvement occur during aging
and in organic dementia of the Alzheimer type. The changes in the auditory
system have not previously been delineated or defined. This study plans to
describe the nature and extent of auditory deficits associated with Alzheimer's
disease in this population.
*Part of a larger study entitled: Regional Cerebral Glucose Utilization in
Organic Dementia of the Alzheimer Type (ODAT)
76-CDP
PHS-6040
(Rev. 2-81)
TITLE OF PROJECT (80 characters or less)
Kynked Pntpnrial rnrr/^l af-pg nf WpiirnlngiVal Dignrrlpr'a
PI: Barry H. Smith
OTHERS: Ernest J. Moore
Dan Stowens
Susumu Sato
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02560-01 CDP
PERIOD COVERED
July 1. 1982 through September 30. 1982
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Deputy Chief, SNB NINCDS
Surgical Neurology Branch
Staff Scientist CDP NINCDS
Staff Fellow DMNB NINCDS
Neurologist NDP,EB NINCDS
COOPERATING UNITS (if any)
Surgical Neurology Branch
Clinical Neurosciences Branch
Developmental and Metabolic Neurology Branch
lab/branch
Communicative Disordergr Program
NSTITUTE AND LOCATION
NINCDS, NIH. Bethesda, Maryland 20205
TOTAL MANYEARS:
-XLA.
PROFESSIONAL:
0.4
,00
CHECK APPROPRIATE BOX(ES)
1 (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The aim is to investigate various evoked potential correlates of neurologically
normal, and neurologically impaired individuals who exhibit Central Nervous
System (CNS) dysfunction as a result of neoplasms and metabolic disorders. A
combined evoked potential paradigm is used, capitalizing on short and long
latency auditory, somatosensory and visual evoked potentials.
7 7 -CDP
PHS-6040
(Rev. 2-81)
o
o
TO
>
ANNUAL REPORT
October 1, 1981 - September 30, 1982
Fundamental Neurosciences Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
INTRODUCTION 1
GENERAL FUNDAMENTAL NEUROSCIENCES
Research Grants, Program Project Grants, New Investi-
gator Research Awards 1-4
The Neurochemistry of Learning and Memory 5
Neuroanatomical Asymmetry in the Human Temporal Lobes 6
Neurophysiology of Cognitive Processes 6
Integration of Autonomic and Somatic Divisions of the
Nervous System 6
NEURAL PROSTHESIS PROGRAM 6
BIOMEDICAL ENGINEERING 7
SCIENTIFIC INFORMATION EXCHANGE
The Neurosciences Research Program 7_8
CONTRACT NARRATIVES
Studies of Urinary Bladder Evacuation by Electrical
Stimulation
NOl NS 3-2307 9
Safe Procedures for Electrical Stimulation of the
Nervous System
NOl NS 9-2315 10
Electrochemical Studies
NOl NS 9-2316 H
Safe Methods of Electrical Stimulation
NOl NS 0-2319 12-13
Study of Intramuscular Electrical Stimulation of Muscle
NOl NS 0-2330 I4
Study of the Effects of Electrical Stimulation of the
Cerebellum
NOl NS 0-2332 I5
i-FNP TAB 4
Transducer Development and Evaluation of Sensory
Feedback
NOl NS 0-2335 16
Development of Multichannel Stimulating Electrodes
NOl NS 0-2336 17
Development of Multichannel Stimulating Electrodes
NOl NS 0-2337 18
Transdermal Stimulation Electronics for Auditory
Prostheses
NOl NS 1-2354 19
Development of Improved Capacitor Stimulating
Electrodes
NOl NS 1-2356 20
Biomaterials for Neural Prostheses
NOl NS 1-2382 21
Multichannel, Multiplexed, Intracortical Recording
Electrode Arrays
NOl NS 1-2384 22
Adhesion Studies
NOl NS 1-2391 23
Development of Improved Capacitor Stimulating
Electrodes
NOl NS 2-2392 24
Neural Control of the Urinary Bladder
NOl NS 2-2396 25
TAB 4
ii-FNP
ANNUAL REPORT
October 1, 1981 - September 30, 1982
Fundamental Neurosciences Program
National Institute of Neurological and
Communicative Disorders and Stroke
INTRODUCTION
Basic research in the neurosciences is supported by all four Extramural
Programs. However, the Fundamental Neurosciences Program is primarily concerned
with those projects which are not obviously disease-related and serve to expand
the store of scholarly information in the classic disciplines of neuroanatomy,
neurophysiology, neurochemistry , neuropharmacology and neuropsychology. This is
the base upon which clinical research is ultimately dependent, not only for in-
formation, but for the development of instruments, techniques and methodologies
which make applied research possible. The basic research laboratory not only
provides the tools for clinical investigation but often the training in scien-
tific methodology as well.
The Neural Prosthesis Program, directed by Dr. F. T. Hambrecht, is an im-
portant aspect of FNP activities. It is primarily oriented toward the study and
solution of basic problems at the interface between electrodes and nervous
tissue, issues which must be satisfactorily resolved before the chronic implan-
tation of devices to compensate for lost sensory or motor capacities. These
involve electrode toxicity and materials, parameters of stimulation, corrosion
by body fluids, electronic pack encapsulation, and the design and construction
of multiple electrodes. This program, one of the few of its kind in the world,
is primarily supported through research contracts at the level of about 2.6
million dollars a year.
GENERAL FUNDAMENTAL NEUROSCIENCES
On June 14, 1982 there were 460 regular research grants, 6 new investigator
research awards and 12 program project grants in the program (see tables).
Neurophysiology and neurochemistry together accounted for about 80% of FNP
grants. Twelve percent of the regular research grants supported studies in
neuroanatomy with smaller numbers of grants in neurobiology, neuropsychology,
neural prostheses and biomedical engineering. Six program projects were in the
area of neurophysiology, three were in neurochemistry, two were in neuroanatomy
and one in biomedical engineering. It should be emphasized that the FNP only
includes basic studies that are not disease or disorder-related and thus consti-
tutes only a fraction of NINCDS support for basic science.
1-FNP
FUNDAMENTAL NEUROSCIENCES PROGRAM
ACTIVE REGULAR RESEARCH GRANTS
JUNE 1982
Neuroanatomy
Neurophysiology
Naur ochemis try
Neurobiology
Neuropsychology
Neural Prostheses and
Biomedical Engineering
Scientific Information
% of
% of
Number
Total
$
Total $
58
12.6
4.4M
12.6
194
42.2
14. IM
40.3
167
36.3
12. 8M
36.6
21
4.6
1.7M
4.9
13
2.8
l.OM
2.8
6
1.3
.5M
1.4
1
.2
.5M
1.4
TOTALS
460
100.0
35. OM
100.0
2 - FNP
FUNDAMENTAL NEUROSCIENCES PROGRAM
ACTIVE PROGRAM PROJECT GRANTS
JUNE 1982
Neuroanatomy
Neurophysiology
Neurochemistry
Biomedical Engineering
Number
% of
Total
$
% of
Total $
2
17
l.OM
24
6
50
1.5M
36
3
25
1.2M
28
1
8
.5M
12
TOTALS
12
100
4,2M
100
3 - FNP
FUNDAMENTAL NEUROSCIENCES PROGRAM
ACTIVE NEW INVESTIGATOR RESEARCH AWARDS
JUNE 1982
Number
Neuroanatomy
Neurophysiology
Neurochemistry
Neural Prostheses
53K
97K
38K
112K
TOTALS
300K
4 - FNP
The Neurochemistry of Learning and Memory
One of the strongest attractions of young investigators to the neurosciences
resides in the underlying hope that ultimately higher behavioral processes such
as learning and memory can be explained in neurophysiological, neurochemical or
neuroanatomical terms. Affective behavior, apparently modulated by neurotrans-
mitter and neurohormonal activities, is primarily associated with intrinsic
mechanisms that are activated by suitable stimuli and are sometimes identified
with certain phylogenetically old brain areas.
"Event-related potentials" recorded from the scalp appear to be correlated
with conscious behavior such as attention, decision-making and anticipation.
However the origin and underlying neurobiology of these recordings are unknown.
Since potentials can be elicited in both humans and animals, there is reason to
believe that the relevant brain areas and mechanisms will eventually be identified.
An encouraging report on research grant support of these studies is found below.
There is no question that alterations in neural activity are accompanied by
metabolic changes, and that the latter are often predominately localized in the
areas involved. The use of the 2-deoxyglucose method in conjunction with pro-
duction of evoked potentials has neatly shown this correspondence which had been
assumed for many years. However, energy is required for a great multitude of
processes and the role of metabolic change with functional activity may be quite
unspecific - perhaps merely a restoration of the status quo ante - replenishment
of neurotransmitters and reestablishment of various ionic gradients. Analogously,
it is difficult to assess the real meaning of neurochemical changes which occur
with "learning" in animals. Over the course of the last 20 years, many experi-
ments have shown an enhanced incorporation of precursors into ribonucleic acid
or protein in particular brain regions during and following training. Furthermore,
drugs which inhibit ribonucleic acid or protein synthesis, administered just
before training, apparently prevent acquisition of the task. However, before the
significance of these observations can be evaluated in terms of the chemistry of
learning or of the "engram," a number of exacting criteria must be met: changes
in the level or turnover of a substance should be anatomically localized, match
the time course of the specific phase of memory formation, and not occur when
memory formation is inhibited. Removal of the anatomical locus ought to inter-
fere with memory formation and/or recall and neurophysiological recording from
the locus of change should detect some form of altered cellular response. Finally,
it is desirable to show that observed chemical changes are not related to stress,
motor activity or numerous other concomitant processes. Learning may result
primarily in a remodeling of synaptic connectivity.
These complex methodological difficulties have led investigators to examine
the neurochemical aspect of learning in simpler nervous systems where experimental
conditions are more controllable and fewer neurons are involved. Thus, in Aplysia,
the sensitization or conditioning of the gill withdrawal reflex is accompanied
by increased synthesis of cyclic adenosine monophosphate (cAMP) in the sensory
nerve, followed by phosphorylation of the calcium channel and ultimately leading
to augmented release of neurotransmitter from the sensory nerve on to the motor
nerve. The duration of the conditioned or sensitized response is temporally
correlated to the period of higher cAMP levels and increased phosphorylation.
Thus, one potential basis for a neurochemical mechanism of learning has been
established.
5-FNP
Neuroanatomical Asymmetry in the Human Temporal Lobes
The investigation of neuroanatomical asymmetry in the human temporal lobes
and related psychological characteristics continues at McMaster University.
Seventy-seven volunteers with cancer have been given psychological tests and,
despite some losses, 35 brain specimens have now been obtained. Preliminary
results with 12 specimens, correlating macroscopic anatomical variation with
some of the cognitive test results and handedness, were presented at a scien-
tific meeting near the end of 1981. Histological analysis has begun on selected
cortical areas and some correlations with the microscopic variation now seem
possible. A grant proposal to extend this research was submitted recently.
This unique research data should provide new clues about the nature of hemi-
spheric specialization in the human brain.
Neurophysiology of Cognitive Processes
Over the past two years, 55 applications have been received in response to
this program announcement. By the close of this fiscal year, it is anticipated
that 17 awards will have been made in this important area. It is planned to re-
issue this program announcement during the next fiscal year in order to emphasize
the program's continuing interest in promoting research on the biological basis
of higher brain functions.
Integration of Autonomic and Somatic Divisions of the Nervous System
In October 1980, FNP issued a Program Announcement "Integration of Autonomic
and Somatic Divisions of the Nervous System." Stimulation of this research area
was enthusiastically endorsed by the FNP Advisory Committee to remedy a long-
standing, unfortunate dichotomy in neurophysiological studies. The separation
of the nervous system into somatic and autonomic divisions has obfuscated and
neglected constant intimate interrelationships in support of tissue function.
During FY 1982, 26 proposals were received of which four were funded.
NEURAL PROSTHESIS PROGRAM
The fruits of past years' efforts were visible on several Neural Prosthesis
Program research contracts. Multichannel electrodes designed and fabricated for
implantation into the cochleae of human subjects were completed, and under a
separate grant in the Communicative Disorders Program were successfully
implanted into two deaf individuals. The electrodes were easily inserted,
have performed flawlessly, and appear to be well tolerated by the cochlear
tissue. Intensive psychophysical testing is now being carried out and the
results of this testing will be used to design speech processors which will
convert the acoustical waveform of speech to the most appropriate electrical
signals to drive the implanted stimulator and electrode arrays. The principal
goal of the multichannel cochlear prosthesis is to permit sensory deaf
individuals to understand ordinary speech.
Significant progress has also been made on research contracts involving
the use of functional electrical stimulation for rehabilitation of quadriplegic
individuals. A nine-channel, computer controlled stimulator has been designed
and is now operational. This permits control of up to nine separate muscles
and is being used to study restoration of both key grasp and pinch grasp in
6-FNP
patients with spinal cord injuries at the C5 and C6 levels. The patients like
the computer-controlled system because it reduces the amount of mental
concentration that they must exert to utilize the system and because all joint
braces are eliminated. The system also permits smoother muscle control with
less muscle fatigue. The development of artificial sensory transducers for
partial replacement of force and position sensation in the hand has successfully
completed feasibility studies and prototype transducers are being fabricated.
Over the next few years, these artificial sensors will be incorporated into a
closed loop feedback system with microcomputers in the loop. This should
permit even more sophisticated control of paralyzed upper extremities by spinal
cord injury victims.
Basic research studies for application to neural prostheses have also been
productive. For example, research contracts on new materials for electrode
construction have demonstrated that iridium metal has a greater margin of
safety with respect to electrochemical reactions than platinum which has been
the standard noble metal used in most prostheses. High dielectric materials
have been deposited on metal substrates and promises a new generation of safe,
effective, capacitor electrodes. The adhesion of Parylene to metals has been
improved by the use of a new glow-discharge deposited biomaterial.
BIOMEDICAL ENGINEERING
The Biomedical Engineering Program is closely related to the Neural
Prosthesis Program. If a contract involves essentially instrument or device
development without a significant component of basic or applied research, it
is placed in the Biomedical Engineering Program. At the present time, there
are two such contracts, one for the development of implanted transdermal
stimulators for auditory prostheses, and one for the development of multichannel
single unit recording arrays. Progress on the transdermal stimulator has been
in the area of increased yields of titanium hermetic packages. The multichannel
electrode array contract has just begun, and they are initially studying
various substrate materials to form the foundation for the electrode probe.
Pure silicon appears to have the strength to pass through brain tissue but
may not be strong enough to penetrate the meninges.
The Biomedical Engineering Program also has several projects supported
by the grant mechanism which are not monitored as closely as the contracts.
Included under grant support is a device to determine axoplasmic flow in vivo ,
an intracranial pressure monitoring system, a printed circuit electrode array
for monitoring neuronal activity in cell cultures, and an instrumentation
system for quantitatively measuring changes in motor performance in humans
during various treatment modalities.
SCIENTIFIC INFORMATION EXCHANGE
The Neurosciences Research Program
The Neurosciences Research Progran (NRP) , until recently part of the Massa-
chusetts Institute of Technology, has transferred its operations to the campus
of the Rockefeller University in New York City. For more than 20 years, the NRP
has worked to fuse the various disciplines of neurobiology into a single field
of neurosciences. Recently a new program has been inaugurated to allow 6-12
7-FNP
scientists at a time to visit the Rockefeller facility for periods from several
days to several months and interact with each other and with the University's
faculty in the neurosciences. The first activities will be in the areas of the
modular organization of the brain, the mechanisms of control of cortical output,
the relation between the chemistry and neurophysiology of photoreceptors and the
theoretical analysis of functioning nerve networks. Dr. Vernon Mountcastle,
Dr. Gerald Edelman, and Dr. Maxwell Cowan will serve as leaders in these new
programs.
8-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO (NOl-NS-3-2307)
Title: Studies of Urinary Bladder Evacuation by Electrical Stimulation
Contractor's Project Director: Emil Tanagho , M.D.
Date Contract Initiated: March 12, 1973
Current Annual Level of Support : $0
Objectives and Methods Employed: Studies are being conducted in animals with
upper motor neuron lesions to determine the feasibility of urinary bladder
evacuation by electrical stimulation of the sacral spinal roots. Studies
are also being carried out on methods of preventing urinary incontinence.
Major Findings: This contract expired in March 1982 and major effort was
placed on summarizing data from animal studies over the last nine years and
preparing a final report.
Significance to Biomedical Research and to the Program of the Institute: The
restoration of the ability of persons with neurogenic bladders to empty their
bladders voluntarily is a long-range goal of this work and would reduce urinary
tract infections that are a major cause of death in paraplegics and quadriplegics.
The problem of urinary incontinence is of both social and medical significance,
especially in the geriatric population.
Proposed Course of Contract: This contract terminated in March 1982. The
Project Director was successful in obtaining a NINCDS grant to evaluate the
techniques of bladder evacuation and control of incontinence by electrical
stimulation in humans. This grant started April 1, 1982.
9-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: ETC LABORATORIES (NOl-NS-9-2315)
Title: Safe Procedures for Electrical Stimulation of the Nervous System
Contractor's Project Director: Barry Brummer, Ph.D.
Date Contract Initiated: August 28, 1979
Current Annual Level of Support: $0
Objectives and Methods Employed: The electrochemical processes that occur at
the electrode-electrolyte interface and methods of reducing undesirable reactions
are being studied. Techniques such as atomic absorption spectrophotometry,
and cyclic voltammetry are used to analyze the simulated extracellular fluid
in which electrodes have been pulsed with the goal of developing electrodes
and stimulus regimens to reduce undesirable electrochemical reactions.
Major Findings: Studies of the corrosion resistance of iridium compared to
platinum and platinum-iridium alloys continues to show the superiority of
pure iridium. This is due to the high charge carrying capacity of the
activated iridium surface. Biphasic pulsing of iridium in saline solutions
for periods up to seven days has little or no effect on the stability of
activation. Initial results indicate that activation of the iridium surface
extends the useful charge injection limits for anodic pulses as much as tenfold.
These tests were repeated with the same results in human cerebrospinal fluid.
Significance to Biomedical Research and to the Program of the Institute:
Development and evaluation of safe stimulating techniques for use in neural
prostheses are major goals of the Neural Prosthesis Program of the Institute.
Proposed Course of Contract: This contract will expire during this fiscal
year. Proposals for competitive renewal have been received and negotiations
for a new contract are presently in progress.
10-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: ELECTROCHEMICAL TECHNOLOGY CORPORATION (NOl-NS-9-2316)
Title: Electrochemical Studies
Contractor's Project Director: Dr. Theodore Beck
Date Contract Initiated: December 1, 1979
Current Annual Level of Support: $120,000
Objectives and Methods Employed: New stimulation electrodes based on ion
selective membranes are being developed and fabricated.
Major Findings: The pH changes which result from biphasic pulsing of small
electrodes at high charge and current densities were evaluated. At a current
density of 1 ampere/cm , pH values of 6-10 can be produced at the surface of
an electrode immersed in extracellular fluid. A technique has been developed
for applying ion selective membranes to electrodes that is based on dipping
electrodes in a viscous, partially polymerized solution. MMA/MAPTAC polymers
were found to maintain their transference numbers and physical properties when
submitted to aging in normal saline for 154 days. The conductivities of these
polymers decrease slowly with age but are still well above their required
minimum. A mathematical analysis of the temperature elevation that might
occur with miniature intracortical metal stimulating electrodes was completed.
In essence, electrodes as small as 5-10 microns in diameter and exposed
length produce no significant temperature elevation in the extracellular
fluid at distances greater than about 1 micron from the electrode.
Significance to Biomedical Research and to the Program of the Institute:
Neural prostheses that utilize functional electrical stimulation require safe
techniques for long-term neuronal activation and inhibition. This work will
provide a better understanding of the electrochemical factors involved and will
develop new electrodes based on these findings.
Proposed Course of Contract: This contract will expire in December 1982.
A renewal contract has been advertised and proposals received.
11-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: HUNTINGTON MEDICAL RESEARCH INSTITUTES (NOl-NS-0-2319)
Title: Safe Methods of Electrical Stimulation
Contractor's Project Director: William Agnew, Ph.D.
Date Contract Initiated: March 1, 1980
Current Annual Level of Support : $283,381
Objectives and Methods Employed: The histopathological effects of long-term
electrical stimulation of the nervous system in animals are being studied with
various electrode designs, stimulus wave forms, and stimulus parameters. Major
emphasis is on intracortical electrodes and peripheral nerve stimulating
electrodes. During stimulation, ion-sensitive electrodes are used to monitor
changes in extracellular ion concentrations. When long-term stimulation is
completed, the tissues surrounding the electrodes are examined using both light
and electron microscopy.
Major Findings: Ion-selective microelectrodes are used to monitor changes in the
concentration of potassium and calcium in the extracellular compartment of the
cerebral cortex during up to four hours of continuous electrical stimulation of
the cortical surface. At stimulus charge densities that induce minimal
localized histological changes in the tissue, extracellular potassium underwent
only a transient increase at the beginning of stimulation followed by a rapid
return to the prestimulation concentration. The extracellular calcium was
unaffected. At a higher charge density that is known to produce histological
damage, there was a rapid transient increase in extracellular potassium followed
by a more gradual return to a plateau level, slightly above the prestimulus
value. Extracellular calcium decreased then increased at a depth 100 microns
below the surface of the cortex but underwent an increase followed by a slow
decrease in the middle layers (750 microns) . Studies of the effects of
intracortical electrical stimulation of the cerebral cortex of cats with
charge balanced, rectangular pulses for a continuous period of 24 hours have
shown that moderate to severe neural damage only occurs after stimulation with
charge densities of at least 400 microcoulombs/cm per phase. There was no
evidence of erosion of electrode tips following stimulation at this level as
assessed by scanning electron micrographs of the electrodes. Histological
evaluation of electrode tracts indicated that implantation of passive electrodes
induced the formation of a connective tissue sheath, and in some instances,
minimal neural damage at the exposed tip. Studies of the Avery cuff electrode
implanted around sacral nerve roots in dogs have indicated, following ten
months of implantation, that there is essentially no change in function, and
histopathological evaluation revealed normal appearing nerves. This is true
for both control nerves and nerves stimulated at levels which produce bladder
evacuation in dogs.
12-FNP
significance to Biomedical Research and to the Program of the Institute:
These studies are important for determining the safety and efficacy of various
forms of neural stimulation utilized in neural prostheses for the neurologically
handicapped. In addition, new surgical and neurophysiological techniques are
being developed which are proving valuable to neurosurgeons and neurophysiologists
in other laboratories and clinics.
Proposed Course of Contract: This contract is in the third year of a three-
year contract. A competitive renewal is expected.
13-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: CASE WESTERN RESERVE UNIVERSITY (NOl-NS-0-2330)
Title: Study of Intramuscular Electrical Stimulation of Muscle
Contractor's Project Director: J. Thomas Mortimer, Ph.D.
Date Contract Initiated: June 27, 1980
Current Annual Level of Support: $333,702
Objectives and Methods Employed: The use of electrical stimulation of the
neuromuscular system in animals and humans for artificial control of muscle
and generation of purposeful movements is being studied. The ultimate goal
is to restore function to the upper extremities in patients paralyzed as the
result of spinal cord injuries.
Major Findings: (1) A nine-channel, computer controlled stimulator has
been developed and is now in regular use in the patient laboratory. The
hardware development was supported by the National Institute of Handicapped
Research (NIHR) and the software development by this contract. (2) Piece-
wise, linear modulation of stimuli are used to generate single axis control
for both of two hand-grasping modes and for implementing a finer control of
palmar prehension grasp. (3) A digital controller has been designed to
provide regulated compliance of stimulated muscle. (4) Second generation
force transducers have been fabricated and successfully passed sensitivity
and stability tests. (5) Relationships between stimulus parameters and
excitation of different diameter myelinated nerve fibers in peripheral nerves
have been determined.
Significance to Biomedical Research and to the Program of the Institute: The
techniques being investigated are restoring lost function to paralyzed
individuals.
Proposed Course of Contract: This is the third year of a three-year contract.
A competitive renewal is anticipated.
14-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF MINNESOTA (NOl-NS-0-2332)
Title: Study of the Effects of Electrical Stimulation of the Cerebellum
Contractor's Project Director: Dr. James Bloedel
Date Contract Initiated: September 29, 1980
Current Annual Level of Support : $92,769
Objectives and Methods Employed: The effects of cerebellar stimulation on
primate models of spasticity and movement disorders are being evaluated. The
neurophysiological mechanisms and anatomical pathways associated with these
effects are also being examined.
Major Findings: Unilateral decortication encompassing the left motor cortex
(area 4 in the left premotor cortex and area 6 in Rhesus monkeys) results in
extensive co-contraction of the biceps and triceps of the right arm during
trained voluntary movements, but the trajectories in individual components of
the movements have remained the same. Electrical stimulation through four
bipolar electrodes implanted in the right interposed and dentate nuclei modifies
the trajectory of the movement. Specifically, stimulation of the anterior
interposed nucleus during the turnaround period in the movement results in
the animal missing the start position on the return path which is evidence of
stimulation-induced dysmetria. New data indicate that the effects of dentate
stimulation on the characteristics of the stretch reflex recorded in the
gastrocnemius and tibialis anterior muscles can be graded over a range of
stimulus intensities and that the threshold for effecting the stretch reflex
of the extensors occurs at a slightly lower threshold than the stimuli required
to effect the stretch reflex of the flexor muscles. These effects were
dependent on the phase of the stretch during which stimuli were applied.
Significance to Biomedical Research and to the Program of the Institute:
These studies should provide information on the neurophysiological mechanisms,
if any, by which cerebellar stimulation modifies normal movement and movement
disorders.
Proposed Course of Contract: This investigation is in the second year of a
three-year contract.
15-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF UTAH RESEARCH INSTITUTE (NOl-NS-0-2335)
Title: Transducer Development and Evaluation of Sensory Feedback
Contractor's Project Director: Andrew A. Schoenberg, Ph.D.
Date Contract Initiated: August 1, 1980
Current Annual Level of Support : $220,849
Objectives and Methods Employed: The possibility of providing artificial
pressure, force, slip, and position information to quadriplegic patients has
not been explored because of lack of suitable transducers. This research
will develop such transducer systems and evaluate them in a simulated model
of a paralyzed hand that is controlled by functional neuromuscular stimulation.
Major Findings: For finger location sensing, longitudinal mode vibration of
the PVF material is now used instead of the thickness mode vibration to get
a higher transmission power and receiver sensitivity. Electronic circuitry has
been developed for the force transducers.
Significance to Biomedical Research and to the Program of the Institute:
This research is part of a multidisciplinary approach to the restoration of
lost function in paralyzed individuals. Restoration of sensation could also
be useful to individuals with congenital absence of sensation or with severe
burns.
Proposed Course of Contract: This work is in the second year of a three-year
contract.
16-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: STANFORD UNIVERSITY (NOl-NS-0-2336)
Title: Development of Multichannel Stimulating Electrodes
Contractor's Project Director: Robert White, Ph.D.
Date Contract Initiated: September 15, 1980
Current Annual Level of Support: $214,860
Objectives and Methods Employed: State-of-the-art microelectronic techniques
are being applied to the design and development of second generation multi-
electrode arrays for stimulation of the eighth nerve. These electrodes will
be used for the evaluation of the feasibility of multichannel auditory
prostheses.
Major Findings: Metal-polyimide adhesion has been successfully achieved by
vacuum-evaporating titanium and platinum onto the activated surface of the
polyimide. These have survived 14-hour boiling in deionized water followed by
a tape test. A stiff ener wire embedded into the Silastic carrier of a
thin-filmed scala tympani electrode has improved the mechanical properties.
Using such a configuration, a number of non-traumatic scala tjraipani implants
have been made in cat cochleae.
Significance to Biomedical Research and to the Program of the Institute:
Multichannel electrode arrays for stimulation of the eighth nerve may provide a
means of communication for sensory deaf individuals. The NINCDS is committed to
determining the feasibility of auditory prostheses for the deaf.
Proposed Course of Contract: This investigation is in the second year of a
three-year contract.
17-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO (NOl-NS-0-2337)
Title: Development of Multichannel Stimulating Electrodes
Contractor's Project Director: Michael Merzenich, Ph.D.
Date Contract Initiated: September 1, 1980
Current Annual Level of Support: $188,083
Objectives and Methods Employed: The electrical and mechanical properties of
the scala tympani are being studied and on the basis of these results, multi-
channel stimulation electrode arrays are being developed which are suitable for
stimulation of the eighth nerve in humans.
Major Findings: Two sixteen electrode, eight-channel scala tympani electrode
arrays which were designed and developed under this contract have been fabricated
and inserted into two human volunteers (with the support of a separate grant
in the Communicative Disorders Program) . Special instruments were designed
for implantation of these devices and include a special forked cup forcep,
a depth limited trephine, and a cable passer for quickly passing the electrical
cable from the electrode array beneath the scalp to the percutaneous connector.
Also designed is a novel surgical disconnect plug which is being patented.
Significance to Biomedical Research and to the Program of the Institute:
Multichannel electrode arrays for stimulation of the eighth nerve in the scala
tympani may provide a means of communication for sensory deaf individuals.
This Institute is committed to determining the feasibility of auditory
prostheses for the deaf.
Proposed Course of Contract: This investigation is in the second year of a
three-year contract.
18-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: STANFORD UNIVERSITY (NOl-NS-1-2354)
Title: Transdermal Stimulation Electronics for Auditory Prostheses
Contractor's Project Director: Robert L. White, Ph.D.
Date Contract Initiated: July 1, 1981
Current Annual Level of Support: $211,367
Objectives and Methods Employed: Design, development, and fabrication of
transdermal stimulators to be used in the evaluation of multichannel cochlear
implant auditory prostheses.
Major Findings: For over one half of the contract year, the integrated circuits
laboratory at Stanford University was not in operation due to remodelling and
the need for changes to meet government regulations. During this down period,
considerable effort was expended on designing and fabricating the next generation
eight-channel implantable stimulators, A stagger-tuned system was developed
to reduce the dependence of transmission voltage gain upon coil coupling. This
has been completed and a model fabricated. Results indicate that a voltage
gain of .71^12 percent can be maintained over a variation of coupling coefficient
from 0.2 to 0.6 and over a variation in load resistance from 260 ohms to 5000
ohms. Measurements of tissue loss at 20 megahertz were completed. The losses
were found to be negligible. A new design of the voltage regulator section
of the implant was completed and is compatible with the proposed CMOS processing
planned. It has a low current consinnption (100 microamps) and can produce
regulated current and output voltage with only one volt dropped across the
regulator itself. A minor change in the transmission coding scheme makes it
possible for new transmitter units to operate as either an eight-channel
monopolar or four-channel biopolar stimulator without hard-wire changes.
Redesign of the oscillator-transmitter system has brought the power consumption
down from 500 milliwatts to 160 milliwatts. A technique has been developed
for attaching miniature platinum- iridium wires to tantalum feedthroughs based
on microwelding.
Significance to Biomedical Research and to the Program of the Institute: The
Institute is presently supporting, under the grants mechanism, the evaluation
of multichannel auditory prostheses. This contract will provide electronic
stimulators to several of these grantees.
Proposed Course of Contract: This work is in the first year of a three-year
contract.
19-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: EIC LABORATORIES (NOl-NS-1-2356)
Title: Development of Improved Capacitor Stimulating Electrodes
Contractor's Project Director: Barry Brummer, Ph.D.
Date Contract Initiated: September 1, 1981
Current Annual Level of Support: $176,919
Objectives and Methods Employed: Improvements in the charge storage capability
per unit volume and the current density output capability of capacitor electrodes
suitable for intracortical stimulation of neural tissue are the major objectives.
Prototype capacitor electrodes will be fabricated and supplied to other
investigators.
Major Findings: Films of BaTiO were made by RF sputtering. Using Auger
spectra, they were compared with the polycrystalline BaTiO target and shown
to have a similar stoichiometry. Preliminary ac bridge measurements of the
capacitance of the as-deposited and heat treated films showed that the dielectric
constant of the heated films was increased by an order of magnitude over non-
heated films. The increase is expected if the heat treatment converts the
amorphous BaTiO„ film to the polycrystalline modification. Titanium capacitor
electrodes which were fabricated under this contract were supplied to NIH
for in vivo testing in monkeys. During stimulation, the titanium oxide
dielectric became very leaky. Although this tended to reverse itself between
stimulation periods, the electrodes were considered unacceptable. Because of
this and the fact that the titanium electrodes showed no significant advantages
over tantalum capacitor electrodes, no further work on titanium capacitor
electrodes will be carried out. Emphasis will be placed on high dielectric
constant materials such as BaTiO_ .
Significance to Biomedical Research and to the Program of the Institute: The
capacitor stimulating electrode is the safest method presently available to
stimulate neural tissue. Improvement in its stimulating capabilities and methods
of reducing its physical size will permit the development of more sophisticated
and safer neural prostheses which utilize stimulation of neural tissue.
Proposed Course of Contract: This work is in the first year of a three-year
contract.
20-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF MISSOURI (NOl-NS-1-2382)
Title: Biomaterials for Neural Prostheses
Contractor's Project Director: Allen Hahn, Ph.D.
Date Contract Initiated: September 30, 1981
Current Annual Level of Support: $217,930
Objectives and Methods Employed: Development of new biomaterials for use as
implant encapsulants, primers, and lead insulators. In a single reactor,
glow discharge polymers are being used as primers for insulators such as
Parylene.
Major Findings: Attempts to use argon cleaning of substrates have failed
because the argon causes sputtering of polymers deposited on the chamber walls.
This resulted in a thin layer of polymer being deposited on substrates rather
than the surface being removed from the substrates. This is also true for other
materials within the chamber such as aluminum as demonstrated by Auger spectro-
scopy in the first few angstroms of the substrate. Studies of the degree of
completeness of polymerization of Parylene films have shown that there is less
than 1 percent of dimers and other oligomers in the synthesized Parylene.
Tensile pull tests have shown that plasma treatment of exposed Parylene surfaces
can provide enhancement of epoxy adhesion. Studies on mechanical flex testing
of both smooth and roughened surfaces substantiate the fact that adhesion of
Parylene is improved with an increase in substrate surface roughness. As the
temperature of Parylene C synthesis chamber is lowered, there is a deterioration
of the mechanical properties and the morphology of the polymer chains.
Preliminary biocompatibility studies with glow discharge polymerized methane
show minimal reactions except for some minor movement artifact effects.
Significance to Biomedical Research and to the Program of the Institute: Many
implanted devices that are presently available or are planned for the future
are adversely affected by water and sodium ions in extracellular fluid.
Development of improved encapsulation and sealing systems to prevent their
access to the implants will be useful not only to neural prostheses, but to
other artificial organs that involve implanted electronics.
Proposed Course of Contract: This work is in the first year of a three-year
contract.
21-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: UNIVERSITY OF MICHIGAN (NOl-NS-1-2384)
Title: Multichannel, Multiplexed, Intracortical Recording Electrode Arrays
Contractor's Project Director: Dr. Ken Wise
Date Contract Initiated: September 25, 1981
Current Annual Level of Support: $189,000
Objectives and Methods Employed: Develop miniature, multichannel, multi-
electrodes for recording single-unit electrical activity from the cerebral
cortex at precisely known depths. State-of-the-art photolithographic and
electron beam lithographic techniques will be used in conjunction with
custom-designed, monolithic integrated circuits to produce the electrode arrays.
Major Findings: This contract has just begun and emphasis has been placed on
determining the best substrate material for the electrode array. Design of the
electronic circuitry that will be part of the probe structure has been initiated.
Silicon has been evaluated as a substrate material. It has the mechanical
strength to pass through cortical tissue but does not appear to be strong
enough to penetrate the meninges.
Significance to Biomedical Research and to the Program of the Institute; The
ability to record simultaneously from different single neurons in a cortical
column will provide information as to the functional significance of cortical
columns in the cerebral cortex. Eventually, it is hoped that single-unit
activity can be recorded for long periods of time and utilized as command
signals for neural prostheses.
Proposed Course of Contract: This work is in the first year of a three-year
contract.
22-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: HUGHES AIRCRAFT COMPANY (NOl-NS-1-2391)
Title: Adhesion Studies
Contractor's Project Director: Ms. Danute Basiulis
Date Contract Initiated: September 30, 1981
Current Annual Level of Support: $159,983
Objectives and Methods Empr&y%"d: A study is being carried out on adhesion
of various insulators to substrates which are being considered for use in
neural prosthetic implants. The goal is to improve adhesion and prevent
water condensation between sealants and substrates.
Major Findings: Measurements of the moisture barrier capabilities of
chemically vapor deposited films of PHOTOX SiO^, PHOTONITRIDE PLASMA-NITRIDE
on interdigitated, double tract, parallel, serpentine pattern of aluminum
films was completed. An additional influence of a 20 volt dc bias between
parallel films during humidity exposure was also monitored. After ten days
of exposure to humidity, all the bias test vehicles failed by having an open
circuit develop in one or the other of the aluminum films. The test vehicles
that were not subject to bias had an 80 to 100 percent survival rate. A new
method of removing Parylene from electrode tips has been developed which is
based on plasma etching.
Significance to Biomedical Research and to the Program of the Institute:
Many implanted devices that are presently available or are planned for the
future are adversely affected by water and sodium ions in extracellular fluid.
Development of improved sealing systems to prevent the access of water and
sodium ions to the implants will be useful not only to neural prostheses,
but to the development of all artificial organs which involve implanted
electronics.
Proposed Course of Contract: This work is in the first year of a three-
year contract.
23-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: GINER, INC. (NOl-NS-2-2392)
Title: Development of Improved Capacitor Stimulating Electrodes
Contractor's Project Director: Harry Lerner, Ph.D.
Date Contract Initiated: November 1, 1981
Current Annual Level of Support: $141,030
Objectives and Methods Employed: Research on methods of increasing the charge
storage capability per unit volume and the current density output capability
of capacitor electrodes that are suitable for stimulation of neural tissue is
being carried out.
Major Findings: Small, porous, sintered tantalum electrodes 100 microns in
diameter and conically tipped were successfully fabricated using a modified
slurry dipped method. These electrodes have a specific capacitance of over
250 nanofarads/mm compared to electrolytically roughened electrodes which had a
specific capacity of 150 nanofarads/mm . The porous structure occupies about
60 percent of the total volume based on scanning electron microscopic analysis.
Studies of a tantalum-titanium alloy indicate that it does not offer any
advantage over pure titanium in terms of both capacitance and leakage current.
Attempts to electrolytically etch tantalum wires to increase surface roughness
were limited by the fact that only the superficial surface (less than 5 microns
deep) of the electrode was roughened by this technique.
Significance to Biomedical Research and to the Program of the Institute: The
capacitor stimulating electrode is the safest method presently available to
stimulate neural tissue. Improvement in its stimulating capabilities and methods
of reducing its physical size will permit the development of more sophisticated
and safer neural prostheses which utilize stimulation of central nervous system
tissue.
Proposed Course of Contract: This work is in the first year of a three-year
contract.
24-FNP
CONTRACT NARRATIVE
Fundamental Neurosciences Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: MCMASTER UNIVERSITY (NOl-NS-2-2396)
Title: Neural Control of the Urinary Bladder
Contractor's Project Director: Andrew Talalla, M.D.
Date Contract Initiated: April 26, 1982
Current Annual Level of Support: $121,500
Objectives and Methods Employed: The feasibility of sacral root stimulation
for evacuation of the urinary bladder in human subjects with neurogenic bladders
will be determined. Electrodes will be placed on the appropriate sacral nerves
and connected to implanted stimulators. Urologic status of these patients will
be determined and any complications noted.
Major Findings: There are no major findings as this contract has just been
initiated.
Significance to Biomedical Research and to the Program of the Institute: The
restoration of the ability of persons with neurogenic bladders to empty their
bladders voluntarily is a long-range goal of this work and would reduce
urinary tract infections that are a major cause of death in paraplegic and
quadriplegic individuals.
Proposed Course of Contract : This work is in the first year of a three-year
contract.
25-FNP
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Neurological Disorders Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
ORGANIZATION OF REPORT 1
PROGRAM SUMMARY STATEMENT 1
REPORT OF THE OFFICE OF THE DIRECTOR
Contract Narrative
Establishment of a Research Roster for 3
Huntington's Disease Patients and Families
NOl-NS-9-2320
Research Project
Selected Maternal Risk Factors and 4
Congenital Cardiovascular Anomalies
ZOl NS 01163-20 NDP
Extramural Grants Activities
Degenerative Neurological Disorders of Adult Life 5
Demyelinating and Sclerosing Disorders
Infectious Diseases of the Nervous System
Muscular and Neuromuscular Disorders
Other Neurological Studies
REPORT OF THE EPILEPSY BRANCH
REPORT OF THE DEVELOPMENTAL NEUROLOGY BRANCH
16
24
29
34
TAB 5.
A
TAB 5.
B
i - DIR/NDP TAB 5
ANNUAL REPORT
October 1, 1981 - September 30, 1982
NEUROLOGICAL DISORDERS PROGRAM
NATIONAL INSTITUTE OF NEUROLOGICAL
AND COMMUNICATIVE DISORDERS AND STROKE
NATIONAL INSTITUTES OF HEALTH
ORGANIZATION OF REPORT
The Annual Report has four sections. The first section is a brief administrative
summary of the program. The second section is a report from the Office of the
Director, NDP with eight subsections. The third and fourth sections are reports
from the Epilepsy and Developmental Neurology Branches respectively.
PROGRAM SUMMARY STATEMENT
The Neurological Disorders Program (NDP) of the National Institute of
Neurological and Communicative Disorders and Stroke (NINCDS) consists of the
Office of the Director, the Developmental Neurology Branch and the Epilepsy
Branch. The Program has responsibility for the support of research directly or
indirectly related to all of the medical neurological disorders except for
stroke. The eight categories into which these disorders are grouped for
administrative purposes are as follows:
Convulsive and Related Paroxsymal Disorders
(administered within the Epilepsy Branch)
Demyelinating and Sclerosing Disorders
Infectious Diseases of the Nervous System
Muscular and Neuromuscular Disorders
Neural Aspects of Learning and Behavior
Neurological Disorders of Aging
Other Neurological Studies
Neurological Disorders of Early Life
(administered within the Developmental Neurology Branch)
Grant Activity
The major mechanism of Program support is the investigator-initiated research
grant application. During FY 1981, the Program initiated seven program
announcements designed to encourage research in areas where it was felt that
additional effort was appropriate.
Four of the announcements were to strengthen further the Program' s emphasis on
neurological disorders of the pediatric age group; i.e., Neurological
Abnormalities associated with Learning Disorders, Neural Tube Defects, Neonatal
Brain Disorders, and Neurobiology of Autism.
Research momentum in the Epilepsy Branch has been maintained with three program
announcements to encourage investigation into basic mechanisms of
epileptogenesis, relation of hormones to epilepsy, and development of small
animal models for screening of antiepileptic drugs.
1 - DIR/NDP
Highlights of grant supported research findings are presented in the subsections
of the reports of Office of the Director and the Branches.
Contract Activity
The bulk of the Program' s contract funds are used by the Epilepsy Branch to
support their continuing program to develop more effective antiepileptic drugs-
Promising compounds are moving through the Epilepsy Branches Chronic Toxicity
Screening Program. These activities are described more fully in the report of
the Epilepsy Branch.
The analysis and publication of the National Collaborative Perinatal Project
(NCPP) data by the Developmental Neurology Branch nears completion with the
publication of one monograph and numerous articles in FY 1982. Four additional
monographs are in various stages of preparation. An RFP has been issued to
create a users guide to the NCPP files so that interested members of the general
biomedical public may have free access to the original data. These activities
are more fully described in the report of the Developmental Neurology Branch.
Direct Operation Activities in FY 1981
1) Program Advisory Committee
The Neurological Disorders Program has an Ad Hoc Advisory Committee of outside
experts to provide guidance for its activities. The Committee members are:
Baylor College of Medicine
St. Paul-Ramsey Medical Center
The Johns Hopkins University
New York Medical College
Massachusetts General Hospital
Albert Einstein College
Yale University
St. Louis Children's Hospital
Robert G. Grossman, M.D.
Robert J. Gumnit, M.D.
Richard T. Johnson, M.D.
Seymour Levine, M.D.
Joseph B. Martin, M.D. , Ph.D.
Dominick P. Purpura, M.D.
J. Murdoch Ritchie, Ph.D., F.R.S.
Joseph J. Volpe, M.D.
One meeting was held in FY 1982.
3) NDP Sponsored Workshops and Conferences
In addition to several workshops and conferences for which the Neurological
Disorders Program provided financial support by the grant mechanism, the Program
also provided substantial staff input into organizing and conducting a meeting to
explore the need for support of antibody or tissue banks.
4) Study of Huntington's disease in Venezuela
In March 1982, the Program sponsored a field trip to Maracaibo, Venezuela, in
order to obtain family histories as well as tissue samples from families with
Huntington's disease. One extensive genealogy was constructed, and about 150 new
tissue samples were returned to the United States for storage at the
Massachusetts General Hospital and the Camden National Repository. This project
is described further in the "Neurological Disorders of Aging" report.
2 - DIR/NDP
CONTRACT NARRATIVE
Neurological Disorders Program
October 1, 1981 - September 30, 1982
NOl-NS-9-2320
Title: A Research Roster for Huntington's Disease Patients and Families.
Contractor's Project Director; P. Michael Conneally
Current Annual Level of Funding: $118,997
Objectives: To establish a National Research Roster of patients with
Huntington's disease (HD) and their families. This roster will serve as a
national source of information for physicians and scientists interested in
locating Huntington's disease patients and families willing to participate in
experimental studies into the diagnosis, etiology and treatment of this
disease. Also to furnish statistical and demographic data on families
collected.
Major Accomplishments: The HD Research Roster was established at Indiana
University in September, 1979. Its contractor has developed two
questionnaires: A family history form for entering pedigrees and an in-depth
questionnaire for affected individuals. A third data form for those at risk
is being developed.
Roster personnel have made an intense effort to contact families across the
country. In the United States, 548 separate families (comprising 855
individuals living and dead) have been entered, representing 47 states. 705
Affected Questionnaires have been received. Families from Canada, Greece, and
Venezuela add more than an additional 2,000 people to the Roster data base.
A brochure has been developed for distribution at scientific meetings.
Notices in journals, booths at professional society meetings, and other forms
of advertisement are being used to stimulate increased scientific utilization
of the roster now that families are available. Issues of confidentiality have
been sensitively handled and the response to the Roster from scientists and
families has been positive. A growing list of investigators are utilizing the
Roster to retrieve statistical data or make contact with research subjects.
Roster data have led to a major new hypothesis for understanding age of onset
and the inheritance pattern for juvenile HD, developed in a paper now in
press .
The Roster has also computerized over 2,000 individuals belonging to an
exceedingly complex HD kindred in Venezuela and is serving as a data clearing-
house for molecular geneticists using tissue samples from pedigree members.
Proposed Course of the Contractor: This program is under the surveillance of
an NINCDS project officer and performance is under continued review. The
original Roster contract expires September 30, 1982. A Justification for
Noncompetitive Procurement was submitted and approved, and a new Roster
contract will be negotiated for an additional three years of support.
3 - DIR/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 01163-20 NOP
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Selected Maternal Risk Factors and Congenital Cardiovascular Anomalies
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
L. Bajda
A. Nay lor
Medical Consultant (Pediatrician) OD NOP NINCDS
Research Geneticist DNB NOP NINCDS
COOPERATING UNITS (if any)
Birth Defects and Genetic Disorders Section, DNB, NDP, NINCDS
lab/branch
Office of the Director, Neurological Disorders Program, NINCDS
INSTITUTE
NINCDS,
IND LOCATION
NIH, Bethesda^
Maryland 20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
1.0
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
C (a) HUMAN SUBJECTS
)tl (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study, using data from the NINCDS Collaborative Perinatal
Project, investigates the relation of selected factors which may affect the
mothers during pregnancy, and possibly cause congenital heart defects in the
children. Observations on about 47,000 pregnancy records provide case and
control data for analysis. Some 486 children have been identified as having
definite congenital cardiac anomalies. These include cardiac conditions which
are part of known syndromes but exclude children suspected of having ventricu-
lar septal defects who are reported without cardiac defect at the one-year
examination and thereafter. Preselected maternal risk factors noted in the
pregnancy records for the mothers of 392 children with definitely defined con-
genital heart anomalies are compared with control data matched for maternal age,
race, date of LMP, and geographical location (institution).
This project has been discontinued.
PHS-6040
(Rev. 2-81)
DIR/NDP
DEGENERATIVE NEUROLOGICAL DISORDERS OF ADULT LIFE
The program supports research in the neurobiology of degenerative diseases such
as Parkinson's disease, Huntington's disease, Alzheimer's disease, Related
Disorders, such as tardive dyskinesia, and General Studies. Grants on
Parkinson's disease primarily follow a biochemical strategy (34 grants,
$4,400,000). A broadbased approach ranging across genetics, biochemistry, and
psychology is being pursued in the Huntington's disease program (14 grants,
$2,400,000). Research on Alzheimer's disease and other dementias of aging, which
pose major public health problems, is gradually increasing (20 grants,
$2,000,000). The program in General Studies includes work on the structural and
functional alterations of the normal and pathological aging nervous system, (10
grants, $600,000). The Related Disorders program research projects, which have
pharmacological implications, (4 grants, $300,000) focus especially on tardive
dyskinesia. The total program contains 82 active research grants totalling
$9,800,000.
Parkinson's Disease and Parkinsonism
Parkinson's disease, the most common form of Parkinsonism, is a common illness of
middle life. About one-half million people in the United States or about 1% of
the population over age 50, are affected by this disease. Prevalence and
incidence rates are about the same in all races and throughout the world where
good epidemiological studies have been conducted. Men and women are equally
affected.
The primary cause of Parkinson' s disease remains a mystery. Dopamine (DA)
containing neurons in the substantia nigra die, causing a depletion of this
important neurotransmitter. Gradually, clinical signs of tremor, rigidity, and
bradykinesia begin to appear, becoming more severe as time passes. Many patients
suffer gradually diminished intellectual faculties. The symptoms of Parkinsonism
can also result from neuroleptic administration, as a postencephalitic sequelae,
from arteriosclerosis and from a variety of diseases and intoxications.
The majority of grants on Parkinson's disease focus on the biochemistry of the
illness and the ways in which neurotransmitter systems transmit messages in the
brain areas most affected. It is not surprising that the biochemistry of this
disorder should preoccupy scientific attention since discovery of the
deficiencies of dopamine in Parkinson's disease patients led to breakthroughs in
our understanding of neurochemistry and pharmacology in brain disorders in
general.
Clinical Studies
Now that the initial excitement of discovering that decreased dopamine stores
leads to Parkinsonian symptomatology has subsided, it has become increasingly
apparent that administration of L-dopa to increase endogenous dopamine stores is
not sufficient to treat the disease completely. Unpleasant side effects and an
erratic effectiveness of the treatment, known as the "on-off" phenomenon, have
pushed scientists to seek new treatments. Many of these compounds act in concert
with L-dopa to increase its potency; others mimic its action.
5 - DIR/NDP
Investigators at New York University have had a long-standing research program
dedicated to discovering new treatments for Parkinsonism, They have had some
success using dopamine agonists such as bromocriptine and lergotrile. Both drugs
were effective in relieving tremor in Parkinsonian patients and also in VMT-
lesioned monkeys, but lergotrile was shown to have significant hepatotoxic
effects. Several ergoline derivatives were evaluated for their dopamine agonist
activity in animals, but only two drugs, pergolide and lisuride, were shown to be
potent DA agonists and long acting agents in the experimental animal models.
Preliminary clinical studies with pergolide are positive. Studies suggest that
pergolide has a high affinity for pre- and postsynaptic DA receptors, while its
partial ergoline analogue has a high affinity for the presynaptic, but not for
the postsynaptic DA receptors. The data also suggest that dopamine synthesis j^
vitro and in vivo may be regulated by different presynaptic DA receptors. The
nigral graft model and the possible role of epinephrine systems in DA-mediated
behaviors is also being explored.
New compounds will hopefully be added to the drug armamentarium currently
available for treating Parkinsonism. An investigator at St. Louis University has
identified a group of carboxylic acid derivatives of tetrahydroisoquinoline
compounds which have important pharmacologial effects on an endogenous opiate
system on neuroendocrine systems, and on the neurotransmitters dopamine and
epinephrine. Working on a theory that the adverse side effects of L-dopa
treatment, including the debilitating "on-off" phenomena, stems from the
conversion of dopamine to o-methyldopamines, investigators at the Columbia
Presbyterian Hospital propose to study the action of catechol-o-methyl
transferase (COMT) inhibitors to prevent this conversion and serve as an adjunct
treatment in Parkinsonism.
Pharmacological tools are not the only resources available for the clinical
treatment of Parkinson's disease. A scientist at the University of Wisconsin is
examining the clinical efficacy of a combined program of stress management and
EMG biofeedback relaxation techniques to reduce Parkinsonian symptoms.
Biofeedback training will enable the patient to manage specific problems, such as
rigidity, tremor, and "freezing", while learning to manage stress will help the
patient minimize situations which exacerbate symptoms. The study promises to
develop useful adjunct therapy with no pharmacological side effects to
interfere.
Centers
At the University of Colorado a "Center for the Study of Basal Ganglia Disorders
and Neurotransmitter Function" has had a continuing and productive history and
serves as an example of the work pursued in these projects.
Neuropharmacological, neurochemical, electrophysiological and immunocyt ©chemical
techniques are used to explore normal and abnormal functioning of the basal
ganglia. The major thrust of the program is a multidisciplinary study of
neurotransmitters and neuromodulators in the central nervous system (CNS) with
major emphasis on the basal ganglia and the nigrostriatal dopamine pathway. Four
research programs examine the neurochemical and electrophysiological changes in
basal ganglion function brought about by acute and chronic nerve stimulation and
agonist or antagonist drug administration. Special attention is given to the
roles of presynaptic and postsynaptic receptors. The effects of chronic drug
administration and, as a related theme, neuronal plasticity are the focus of a
number of research projects. Studies include aspects of neuronal growth,
6 - DIR/NDP
differentiation and regeneration, and the influences of calcium dependent
regulator proteins, glycoproteins and growth factors on these processes.
Neurotransmitter biosynthetic enzymes are viewed as indices of neuronal growth
and development.
Tyrosine hydroxylase from rat pheochromocytoma has been purified to homogeneity
and its physical and kinetic properties have been characterized by the
investigator at this center. The holoenzyme has a molecular weight of
approximately 240,000 daltons and consists of four subunits which appear to be
identical or nearly identical. The enzyme is phosphorylated by cyclic AMP-
dependent protein kinase and enzyme activation is well correlated with
phosphorylation. An immunocytochemical procedure was developed for localizing
tyrosine hydroxylase in brain and peripheral tissues. Nerve stimulation is not
associated with a shift in the subcellular distribution of this enzyme in
chromaffin cells of the adrenal. While most of the enzyme appears to be located
in the cytosol, a small fraction is associated with chromaffin granules. The
proportion which is associated with granules does not increase during stress and
adrenal secretion. This group has made the interesting finding that brain
transplants in oculo and in situ manifest good viability and make functional
connections with host brain or subsequent grafts. The development of appropriate
histological and functional organization can be readily demonstrated. Chromaffin
cells in oculo or in the lateral ventricle alter their morphology to a neuronal
phenotype and can provide functional catecholamine input to host brain in the
latter case.
Biochemistry and Pharmacology
Considering the need for better pharmacological tools to treat movement disorders
such as Parkinsonism, Huntington's disease, Tourette's syndrome, and tardive
syskinesia, the discovery of the clinical efficacy of apomorphine has aroused
considerable interest. An investigator at the University of Texas is continuing
a program of basic research on the metabolism of apomorphine (APO) and N-n-
propylnorapomorphine (NPA). These two drugs have shown definite promise as
clinically useful anti-Parkinsonian agents. His work has shown that
apomorphine' s clinical efficacy may be related to its dopaminergic activity. The
investigators will continue their work developing analytical methods for studying
these drugs and their analogs and in metabolites in biological material, and will
pursue ways to overcome the deleterious side effects of the drugs, particularly
azotemia.
A number of substances that are strong candidates for neurotransmitters in the
mammalian CNS are found in high concentrations in the basal ganglia. These
include acetylcholine (ACh), dopamine (DA), serotonin (5HT), gamma-aminobutyric
acid (GABA), substance P and taurine. Little is known about the effect of these
substances and other putative neurotransmitters on the responsiveness of neurons
of the globus pallidus. Other researchers at Texas are studying the
responsiveness of primate pallidal neurons to neurotransmitters. GABA, glycine,
taurine and beta-alanine depressed the spontaneous firing of neurons located in
all pallidal segments. GABA was the most powerful depressant and stopped
spontaneous firing of many neurons with currents less than 5 nA. Cells located
in the internal pallidal segment were generally more responsive to the depressant
action of GABA than cells located in the external segment of laminar region. In
general, glycine was not as effective a depressant as was GABA.
7 - DIR/NDP
Work at the University of Michigan may provide a better clinical understanding of
the spasticity associated with Parkinsonism as well as giving insight into the
fundamental mechanisms underlying basic spinal cord neuropharmacology.
Experiments will measure neurochemical changes and synaptic function within the
spinal cords of rats and cats with spinal cord transections as the animals
develop generalized spasticity. This laboratory has developed a technique for
studying GABA turnover by high pressure liquid chromatography. Preliminary work
show a 100% increase in GABA turnover in flaccid paraparesis compared to sex-
matched, litter-mate, sham-operated controls.
Neurophysiology and Neuroanatomy
Scientists at the University of Washington are examining the neurons of the
entopeduncular nucleus (ENT) and describing efferents to and afferents from this
area, as well as the synaptic actions of ENT cells of several brainstem sites
which may link the ENT to the globus pallidus. The investigators seek to clarify
what drives the high tonic firing rate characteristic of pallidal and nigral
basal ganglia output neurons in awake animals. This laboratory has shown that
microstimulation of the globus pallidus with 100 uA pulses at 300 per second
interfere with the performance of a monkey in a button-pushing task in a manner
somewhat analogous to the bradykinesia syndrome. Lesions of the same area
produced by injection of kainic acid also produced slowing of movement in this
task. This group has also shown reciprocal connections between the globus
pallidus and the pedunculopontive nucleus.
Investigators at the Johns Hopkins University are utilizing electrophysiological
and anatomical methodology to explore the motor functions of the basal ganglia.
In normal and lesioned monkeys, they are seeking to clarify further the normal
functions of the basal ganglia in the regulation of movement and posture and to
unravel the pathophysiologic mechanisms underlying movement disorders in man.
Trained monkeys are given visuomotor tracking tasks while neurons in key brain
areas are monitored as the monkeys perform a limb movement. This work comprises
some of the best and most exciting single unit analyses of basal ganglia activity
in awake monkeys .
They have shown that the activity of the majority of cells in the globus pallidus
and subthalamic nuclei are modulated by movements of individual body parts.
However, the majority of this cellular activity was related to arm and leg
movements. In the pars reticulata of the substantia nigra, however, neuronal
activity was rarely related to limb movements, but many discharged physically in
relation to licking and chewing movements. Other studies indicate that the major
determinant of neuronal discharge during a limb movement for basal ganglia (BC)
neurons is the direction of movement. While changes in neural activity occur
during the reaction time period, the majority of cells change their activity
during the period before the onset of movement, but after the first change in EMG
activity. These data thus suggest that the BG may not play a role in the
initiation of limb movements, but rather in the control of ongoing limb
movements. Moreover, their role may be more related to the selection or
energizing of muscles than in the specification of movement parameters.
Huntington' s Disease
Huntington's disease (HD), a fatal degenerative hereditary condition, is a
disorder of the basal ganglia closely related to Parkinson's disease. While
8 - DIR/NDP
Parkinsonism produces tremor and rigidity, Huntington' s disease causes
uncontrollable chorea, and gradual loss of the capacity to walk, talk, swallow,
and maintain oneself independently. The majority of patients show some degree of
dementia, beginning with loss of short-term memory and organizational skills and
progressing to a severe incapacity toward the end of the illness. Profound
emotional disturbances mimicking schizophrenia and manic depressive disorders may
also occur. Huntington's disease is transmitted as an autosomal dominant gene
and usually manifests itself between the ages of 35 and 45 years. Children
comprise 10% of cases. Treatment is merely palliative and most often entails the
administration of dopamine blockers or antagonists. There is no test to
determine if a child of a Huntington's disease patient is carrying the lethal
gene before symptoms of the illness appear. Patients generally live 10 to 20
years following symptom onset. Biochemically, the disease is characterized by
reduced stores of GABA, glutamic acid decarboxylase (GAD), acetycholine (ACh),
substance P, angiotensin II converting enzyme and variety of other
neurotransmitters and neuromodulators. There is almost total loss of the small
neurons of the caudate nucleus and putamen as well as cortical atrophy, giving
rise to a typical picture of enlarged ventricles and sulci on GAT scans.
Genetic Studies
A number of investigators are continuing laboratory work to identify the abnormal
gene that is responsible for the host of physical and mental symptomatology that
characterizes Huntington's disease. In a disorder as relatively uncommon as
Huntington's disease, and with family members so widely dispersed geographically,
a centrally located data bank of pedigrees is an invaluable aid to research. A
contract for a Huntington's Disease Roster was given to the University of Indiana
to develop such a roster, in response to a recommendation of the Commision for
the Control of Huntington's Disease and Its Consequences. The Roster can match
together family members with different names and from disparate states, thus
creating much larger pedigrees It can also select specific families needed for
particular research projects and serve as an intermediary between the scientist
and the subject.
Studies of Non-neural Tissues
An investigator at Duke University is pursuing his preliminary data which
indicate alterations in cell attachment and protein glycosylation in HD
fibroblasts. In particular, glutamine was found to be toxic to HD fibroblasts
leading to changes in morphology and eventual cell death; these effects are
partially reversed by glucosamine. On the basis of these and other observed
abnormalities, the investigator suggests that HD fibroblasts express a membrane
defect due to abnormal glycosylation of proteins and that this impaired
glycoprotein synthesis may be correctable by a diffusible factor in serum. His
work proposes to characterize these differences further, and to pursue the
hypothesis that the enzyme responsible for glucosoamine synthesis, fructose-6-
phospate glutamine transaminase, is the defective metabolic step in producing the
disease. At this point the enzyme has been purified from fibroblasts 1300
fold. Preliminary analysis indicates that nutritional modulation of this enzyme
by sugar and serum concentration are important biological variables in tissue
culture.
9 - DIR/NDP
Biochemical and Structural Studies
Animal models have always been important in the understanding of the etiology,
pathogenesis, and possible treatment of disease. HD is no exception. Recently,
a new animal model was created by the injection of kainic acid, a highly toxic
glutamate analogue derived from seaweed, into the striatum of rats. The kainic
acid produces a selective degeneration of striatal intrinsic neurons, and
neurochemical and histologic alterations in the nigro-striatal circuit that
closely mimic those found in HD. Fibers of passage are less affected by the
kainate, and the chemical has no effect if cortical-striatal glutamatergic
pathways are served.
An investigator at The Johns Hopkins University School of Medicine is continuing
his work of elaborating the lesioning effects of kainic acid. In vitro
measurements are being made of the specificity of receptor binding of kainic acid
and kainic acid-induced release of labeled neurotransmitters from prelabled
slices of hippocampus, striatum, and cerebellum. In vivo studies focus on the
effects of kainic acid injections on local brain energy metabolism. Studies have
been completed on the acute metabolic effects of kainic acid and related
excitotoxins within the striatum; and considerable progress has been made in the
characterization of excitatory acidic amino acid receptors using ligand-binding
techniques. Recently, they have developed preliminary data for the existence of
a presynaptic receptor for kainate on reputed glutamatergic neurons and of the
existence of endogenous peptides that interact with a high degree of specificity
and high affinity with the glutamate receptor.
Interdisciplinary Workshops
A crucial need in Huntington's disease research is to recruit new investigators
to the study of this relatively little known disorder, and to generate new
research hypotheses. The Hereditary Disease Foundation has had a ten year
program of sponsoring interdisciplinary workshops on Huntington's disease and
other degenerative disorders to achieve these ends. Participants range from
postdoctoral and medical students to department chairmen and span a wide variety
of scientific expertise in basic and clinical areas. Four workshops a year are
being supported through a grant to the Foundation.
Huntington's Disease Center
One of the most exciting initiatives in Huntington' s disease research was the
award of two grants in FY80 to establish "Centers Without Walls", as recommended
by the Congressionally mandated Commission for the Control of Huntington's
Disease and Its Consequences. Each Center supports clincial and basic research
aimed at uncovering the etiology and pathogenesis of Huntington's disease and
developing new physiological and sociopsychological treatments for the
disorder. One Center is located at The Johns Hopkins University and is composed
of a number of different departments within the Medical School, such as
psychiatry, neurology, genetics, and the School of Public Health. The program
consists of nine clinical and basic research projects. Clinical studies range
from case-finding and epidemiological studies, and research on genetic
counseling, to the exploration of eye movements as clues to early disease process
and diagnosis, and the amelioration of swallowing difficulties. Basic science
projects include the localization and measurement of neurotransmitters,
10 - DIR/NDP
neuropeptides, and enzymes in the brain, and the detailed elaboration of the
structure and function of the basal ganglia, an area of the brain affected by
Huntington's disease, Parkinson's disease, Tourette's syndrome and many other
movement disorders. A survey of Huntington's disease in Maryland has been
completed. Using the clinical and genealogical data collected from patients and
persons-at-risk in the Maryland survey, a number of studies have been
completed. These are: 1) the genetics of HD, 2) psychiatric research on
affective disorder and at risk offspring, 3) neurology, 4) diagnosis and 5)
neuropathology. An educational and counseling course has been established and a
newsletter published.
The other "Center" represents a consortium of departments within different
institutions, including Massachusetts General Hospital, McLean Hospital, Boston
University, Tufts New England Medical School, the Boston Veterans Administration
Hospital, and the University of Massachusetts, and supports 10 scientific
investigations in participating institutions. Patients and their families are
being seen at clinics in the different Centers. A total of 225 different
individuals from 100 apparently unrelated HD families have been seen. The
standard collection of information included the completion of 100 Family
Histories containing a total of 3,699 individuals both living and dead. Age of
onset has been specified for 211 of the 520 designated HD gene carriers in the
stored families. The most striking finding is that in early onset 70% inherit
the gene from an affected father, this reduces to 48.5% for mid-life onset and
20% for late-life onset. The sex of the affected parent has a profound influence
on age of onset. Patients and their families are being seen at clinics in the
different Centers. A number of the projects focus on mapping and measuring
levels of neuroendocrines and neuropeptides. These investigators are developing
new procedures for analyzing brain tissues which will be of value for looking at
all brain disorders. In addition, they are examining tissues from patients dying
of other devastating brain diseases such as schizophrenia, Alzheimer's disease,
Parkinson's disease and others. Studies have been completed in a series of brain
extracts from patients with Huntington' s disease and compared with those of
controls. Results have demonstrated definitively the preservation of neuronal
elements containing somatostatin in the caudate and putamen as well as in the
external and internal segments of the globus pallidus in patients with
Huntington's disease. Studies have confirmed previous reports that the same
areas of brain have diminished concentrations of substance P, indicating that the
selective preservation of somatostatin is accompanied by reduction of another
neuropeptide. A team of molecular geneticists at Massachusetts General Hospital
is using recombinant DNA techniques to try to determine the exact chromosomal
location of the abnormal Huntington's disease gene. These scientists are in the
process of mapping the human genome, uncovering "markers" on chromosomes which
will greatly advance the localization of other genetic diseases. They use tissue
samples from families with special pedigrees, particularly from Venezuela.
Arbitrarily chosen single copy DNA segments have been cloned and used as
hybridization probes against restriction enzyme digested DNA from 6 or more
unrelated individuals. A procedure has been established for isolating clones
containing only single copy DNA.
Venezuela Project
A major project of the NDP Huntington's Disease Program has been the study of a
unique population of Huntington's disease families living on the shores of Lake
11 - DIR/NDP
Maracaibo. In July, 1980, a contract was signed with the University of Zulia, in
Maracaibo, to enable a team of Venezuelan and U.S. scientists to study the
families neurologically, genetically, psychologically and sociologically. The
Venezuelan focus is particularly valuable for research purposes for the following
reasons: 1) a single founder means that all patients have inherited an identical
HD gene. 2) Families are extremely large with many members both affected and
unaffected. 3) The families are interrelated, with a relatively high frequency
of two people "at risk" for the disorder, marrying and producing children who
have a higher probability of being homozygotic, if a "double dose" of the gene is
not lethal rn utero. 4) None of the patients are taking any medications so that
drug effects do not confound the data.
Geneticists from the Boston "Center Without Walls" are analyzing the tissue
collected using recombinant DNA techniques to identify DNA polymorphisms linked
to the HD gene. Transformed lymphocyte lines and fibroblasts are available for
any qualified investigator to use and may be obtained from the Institute of
Medical Research, Camden, New Jersey. The Venezuelan pedigrees have been
computerized and are part of the Huntington's Disease Roster at the University of
Indiana. Preliminary analysis of the pedigrees obtained in the study of
Huntington's patients in the Lake Maracaibo area has identified one individual in
the remote fishing village of Lagunetas who may have inherited the Huntington's
disease gene from both parents. If confirmed, this homozygosity, not known to
have occurred previously, may aid in precise localization of the Huntington's
disease gene on a specific chromosome.
Alzheimer's Disease and Other Dementias of Aging
The problem of the dementias in the United States has assumed alarming
proportions. At least two-thirds of elderly people with advancing dementia
suffer from Alzheimer's disease (AD). In recent years, many scientists have
argued that distinctions between presenile dementia and Alzheimer's disease are
arbitrary and meaningless.
The classical neuropathology of AD is characterized by abnormalities of the
cerebral cortex. The three pathological hallmarks of the disease are: neuritic
plaques consisting of abnormal neurites associated with extracellular amyloid;
perikaryal neurofibrillary tangles comprised of accumulations of paired helical
filaments; and granulovacuolar degeneration.
Structural Studies
The majority of the research supported is aimed at clarifying the structural and
biochemical abnormalities which characterize Alzheimer's disease. A number of
studies focus on cytoskeletal changes, the neurofibrillary tangles and senile
plaques. These tangles appear in the neuronal soma as aggregates of paired
helical filaments approximately 200 A in cross section, with a twist
approximately 80 A along their length. Both neurofibrillary tangles and their
normal, unpaired, and nonhelical neurof ilamentary counterparts have been
identified as proteins with a molecular weight of around 50,000 daltons. Several
different laboratories are investigating paired helical filaments in the
presenile and senile dementias as well as in Down's syndrome. Twisted tubules
have been partially purified by investigators at New York University Medical
Center. The relationships among various neurofilaments and between these
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filaments and tubulin are being explored. Another investigator at Boston
Biomedical Research Institute is characterizing the chemistry and function of
neurofilament proteins with regard to their sequencing, immunoreactivity,
comparability with other glial fibrillary proteins, and tendency to proliferate
in neurons treated by neurolathyrogens. Neurofibrillary degeneration induced by
spindle inhibitors and aluminum salts have been previously studied as a model of
human neurofibrillary degeneration seen in senile dementia of Alzheimer type and
other neurological disorders. Recent studies suggest that the formation of
neurofibrillary tangles in neuronal perikarya is not caused by new synthesis of
neurofilament proteins, but rather by retrograde transport and relocation of
these proteins in the perikarya.
Recently, investigators have succeeded in labeling tubulin, brain microtubule
accessory proteins (MAP) and clathrin with the fluorescent compound
dichlorotriazinylamino fluorescein (DTAF). This work suggests a very high
specificity of the MAPs and suggests that they may be controlling elements in
determining the type of cytoskeletal array which is formed.
Researchers are immunochemical ly isolating and characterizing the Alzheimer
neurofibrillary tangle (ANT), crossreacting antigens from normal young human and
animal brains. They are studying the presence of normal neurofibrillary proteins
and of serum proteins in ANT by immunocytochemical techniques, to identify ANT-
crossreacting antigens in normal neurofibers, and to compare ANT with
neurofibrillary tangles in other human conditions. Previously, they demonstrated
the presence of an ANT-crossreacting antigen/ s in normal young human and animal
brains by immunocytochemical labelling of the tangles with an antiserum raised
against an in vitro assembled microtubule preparation. In order to elucidate the
question if~ormal neurofibrillary proteins are an integral part of the ANT, they
studied the reactivity of ANT with antisera against different neurofibrillary
proteins using the peroxidase anti-peroxidase technique. The findings suggest
that paired helical filaments might contain more than one antigen. It appears
that the ANT-crossreacting antigens present in normal brain are different from
the known microtubule or neurofilament polypeptides.
Recent studies by NINCDS grantees strongly suggest that the neurons in the
nucleus basalis of Meynert (nbM) selectively degenerate in AD. On the basis of
these observations, it has been hypothesized that a selective lesion in the nbM
is, in substantial part, responsible for the cholinergic abnormalities in the
cortex.
Biochemical Studies
Other research sponsored by the Institute is aimed at characterizing the
biochemical alterations in SDAT. The acetylcholine muscarinic receptors of the
cortex are maintained even though there may be a 75% to 95% loss of cortical
choline acetyltransf erase (ChAT). Localization of this synthetic enzyme and its
receptor is being pursued in human and animal brain tissue by enzyme
immunohistochemistry and radiography. Microscopic, histologic and biochemical
techniques will be used to compare young and old brains and normal and senile
dementia of the Alzheimer's disease type brains.
Investigators have shown a close correlation between _in vivo synthesis of
acetylcholine (ACh), glucose oxidation, and behavior during hypoxia; similar
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effects of hypoxia on ACh synthesis and glucose oxidation could be demonstrated
with brain slices or isolated synaptosomes making it likely that the observed J^
vivo effects on ACh synthesis were not a secondary effect mediated by other
neurotransmitters. There is evidence for impaired Ca-dependent release of ACh
from the nerve ending under hypoxic conditions, and this is thought to provide a
feedback inhibition on ACh synthesis.
Animal models of dementia are hard to come by since dementia involves the loss of
a capacity we cannot be sure animals ever had. Mutant mice can be excellent
systems for studying degenerative processes. An investigator at Indiana
University is studying the Purkinje cell degeneration (PCD) mutant as a model of
selective cell loss in the nervous system. One model of both normal and
pathological aging holds that there is genetically programmed cell death which
gives rise to the characteristic signs of aging. In the PCD mutant, all Purkinje
cells irreversibly degenerate. Preliminary work by the investigator on tissue
culture explants of PCD cerebellum indicate that degeneration occurs at postnatal
day 17. The laboratory has performed a quantitative analysis of the molecular
layer of the Purkinje cell degeneration (PCD) mutant mouse. The results have
shown that between control and 6 month old affected PCD's, there is a significant
difference in number of parallel fibers. The parallel fibers in 6 month old
affected mice are 57% of the control. Further loss occurs in the 9 and 12 month
old animals. At 12 months of age, the parallel fibers in the strip of molecular
layer are reduced to 17% of the control. The selective degeneration of a
particular cell type allows the researcher to look at neurotransmitter
functioning in the cerebellum, focusing on GABA which is a primary
neurotransmitter for Purkinje, Basket, and Golgi cells. They have completed
studies of the effect of the Purkinje cell loss on the noradrenergic system. The
purpose of such study was to determine whether the loss of the Purkinje cell
affects the amounts of norepinephrine or cyclic AMP in the cerebellum of mice
between 25 and 280 days of age. No changes in norepinephrine content were
detected during or after the Purkinje cell degeneration.
Clinical Studies
A large program project on "Senile Dementia: Alzheimer and Vascular Disorders" at
Albert Einstein College of Medicine takes an interdisciplinary approach to
studying the dementias. Clinicians, biochemists, neuropathologists and
neurophysiologists, psychologists, mathematicians and many others turn their
talents toward discovering the origin of these diseases and developing
appropriate treatments. Investigators are interested in the nature, incidence,
prevalence and course of senile dementias. The identification of risk factors
and prevention will receive considerable attention.
The program has three major sections. Section I consists of laboratory studies
relating to the etiology and pathogenesis of senile dementia, particularly of the
Alzheimer type (SDAT). One project will attempt to grow paired helical filaments
in culture. Another explores the possibility that a persistent virus infection
may cause SDAT. Two other projects will focus on the localization (through
immunocytochemistry) and regional distribution of five peptides in normal and
senile human brains and explore the possible relationships of these peptides to
the composition of neuritic plaques and tangles. They have observed reductions
in somatostatin like iramunoreactivity (SLI) and showed direct correlations to
CHAT in AD and SDAT. They found that neurofibrillary tangles share common
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immunological properties with elements present in normal brain and have developed
new neuropsychological studies.
Section II continues several clinical and psychological studies of SDAT now in
progress. A longitudinal study of 500 residents of a nursing home has generated
a wealth of biological and psychological data. As residents die, approximately
40 brains a year are available for correlations of postmortem biochemistry with
premortem clinical parameters.
The third section consists of a large prospective study of about 400 people drawn
from two nursing facilities and "normal" elderly volunteers drawn from the
community. The prospective study will identify risk factors in dementia produced
primarily by multiple cerebrovascular infarcts. They have recently found a high
incidence of ventricular arrythmia and bradycardia but a lower incidence of high
density lipoproteins than in another large study.
New Directions
The NINCDS is actively seeking to increase the level of research effort directed
at Alzheimer's disease and other diseases of aging. In concert with the National
Institute of Aging, a Program Announcement was released soliciting grant
applications on research into the etiology, pathogenesis, treatment and
prevention of these devastating disorders.
General Studies
The primary neuronal cell type in the striatum is the striatal spiny efferent
neuron (SENS). It receives presumed monosynaptic input from both cortex and
thalamus and is reciprocally connected with the substantia nigra. Stimulation of
various striatal afferent systems produces different synaptic actions on SENS.
An investigator at Michigan State University is attempting to explain these
different actions by morphological studies of synaptic inputs which he will
correlate with physiological studies of these same afferents to intracellularly
labeled striatal spiny neurons. A major thrust of this work has been the
analysis of postsynaptic potentials evoked in neostriatal spiny neurons by
stimulation in substantia nigra. This complex postsynaptic potential, which has
both excitatory and inhibitory components, has been the subject of considerable
study and controversy since it was first described by Hull and his associates in
1973. This laboratory's analysis has demonstrated this potential results
primarily from inadvertent stimulation of axons in the vicinity of substantia
nigra, rather than from substantia nigra neurons and their processes. The
earliest excitatory component has been shown to be a monosynaptic axon reflex of
collaterals from rapidly conducting brainstem-projecting neurons of neocortex.
This was the first demonstration of the postsynaptic action of intrastriatal axon
collaterals of pyramidal tract neurons by thalamic or cortical stimulation. This
group has recently demonstrated that the underlying mechanism is disfacilitation
of striatal neurons, rather than intrinsic inhibition as previously believed.
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DEMYELINATING AND SCLEROSING DISORDERS
The demyelinating and sclerosing disorders grant portfolio includes research
relevant to Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and the
Ataxias. As of May 1982 there are 96 active grants, including 5 MS , 1 ALS, and 2
ALS-MS research program project centers. Total funding of this research is
approximately $14.2 million from FY 1981 and 1982 funds. In FY 1982 a total of
104 applications were received and 83 were approved, of which approximately 13
new and 15 competing renewals were funded at a total cost of approximately $1.2
million for new research grants and approximately $1.9 million for competing
renewal grants.
Multiple Sclerosis
As of May 1982, there are 37 active grants in the Multiple Sclerosis (MS)
subprogram, including 5 MS and 2 ALS-MS research program project "centers".
Total funding in support of these activities is approximately $9.1 million from
FY 1981 and 1982 funds. A total of 45 applications were received, and 35 were
approved of which 5 new and 4 competing renewals were funded for a total cost of
approximately $700 thousand for new research grants and approximately $800
thousand for competing renewal grants.
1. Etiology and Pathogenesis
The most promising and active research efforts currently are directed toward
putative immunological and/or viral etiologies and/or pathogenesis of MS. There
is, for example, accumulating evidence that perturbations of T-lymphocyte
function, particularly alterations of suppressor T-cell activity, occurs in MS
patients. A recent finding is a decrease in T-suppressor (Ts) lymphocytes and an
alteration in the ratio of T-helper (TH) to Ts cells preceding and during an
acute attack of MS. It is expected that new research thrusts may further
elucidate the role of the immune system in modulation or expression of
neurological disease.
Studies are currently underway to: 1) investigate factors which cause genetically
susceptible individuals to develop MS, 2) detect changes in immunological
responses in relation to clinical changes, 3) determine immunologic responses to
viruses, particularly myxoviruses, and 4) compare survival, rate of progression
and disability among patients in high and low prevalence areas.
2. Immunology, Virology, and Research Models
Animal models of virus-induced demyelination are used to investigate the
morphological and immunopathological features of myelin injury. Theiler's virus
encephalomyelitis is one such model which is characterized by viral persistence
in central nervous system (CNS) tissue. Studies demonstrate that demyelination
in this model is probably immune-mediated.
The possibility that MS may be due to a dysimmune state continues to be a prime
consideration in the pathogenesis of the disease. A good parallel may be drawn
between MS and animal models of experimental allergic encephalomyelitis (EAE), in
particular, chronic relapsing EAE. EAE can be produced in a variety of different
species of animal hosts. Following injection of whole CNS tissue (or some of its
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components, especially myelin basic protein) combined with an appropriate
immunopotentiating agent, the sensitized host elaborates inflammatory immunologic
responses leading to demyelination.
Acute MS is characterized in part by a perivascular inflammatory reaction which
may simulate the inflamatory lesions of acute EAE. A main distinctive feature of
MS is the extensive injury to the myelin sheath (and axons to a lesser degree)
which results in large, grossly evident, plaques of demyelination. Chronic
relapsing EAE resembles this characteristic MS feature rather closely.
Investigators at Northwestern University studing immune regulatory mechanisms in
EAE in Lewis rats have found that splenocytes collected from rats sensitized to
myelin basic protein together with complete Freund's adjuvant (CFA), cultured
with concanavalin-A and later in MBP, enhance their EAE transfer capacity to
syngeneic recipients. Some splenocyte preparations after more intense
sensitization held little or no EAE transfer activity following culturing. They
believe that this occurs because these splenocytes contain large numbers of
monocytes (macrophages) with very potent suppressor activity. Removal of these
macrophages allows the remaining splenocytes to be fully activated in vitro with
concanavalin-A or MBP and to exhibit strong EAE transfer activity.
They found also that daily treatment of rats per os with indomethacin, from the
seventh through the twelfth day after sensitization to spinal cord-CFA, resulted
in a marked potentiation in the severity of EAE. It can be seen that with some
further sophistication this system can be very useful in transferring EAE among
allogenic rats and hamsters. The explanation of these observations would appear
to lie in rapid proliferation of monocytes (probably macrophages).
EAE supernate transfer activity, released from briefly cultured lymph node cells
of a donor sensitized to spinal cord-CFA, but not MBP-CFA, elicits the typical
histopathologic changes of EAE in recipient rats but is never accompanied by
clinical signs of the disease. This is under study in the laboratory, and the
goal is to define in biochemical terms the "transfer" factor and to identify its
specific function.
Some oligoclonal bands in the CSF of patients with MS and subacute sclerosing
panencephalitis appear to contain antibodies which react with both measles virus
and myelin basic protein. Because of the serological and epidemiological
evidence linking measles virus to MS, evidence for persistence of the virus
genome in MS tissue is sought. Very recent efforts have succeeded in identifying
measles virus genome in brain tissue of two of six cases of MS using new, highly
sophisticated hybridization techniques.
3. Selected Examples of Research Activities
Since proteolipid protein (PLP) was discovered, very little information has
accumulated about it because of its insolubility in aqueous solvents and its high
degree of association with lipids. Attempts to isolate PLP usually leads to
aggregation and denaturation. An investigator at Washington University in St.
Louis overcame many of these difficulties and is making progress toward PLP
characterization.
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This antiserum can be also used in other animals indicating a lack of species
specificity of proteolipid protein. Antisertim to PLP from various animals does
not demyelinate spinal cord cultures nor cause inhibition of myelin synthesis in
culture. However, antisera to PLP from animals injected with galactocerebroside,
or CNS myelin, does demyelinate cultures.
Although MBP and PLP proteins are present in oligodendrocytes, neither protein
was observed in oligodendrocytes until substantial differentiation of these cells
had occurred, and oligodendrocytes were positive for MBP before PLP was
visible. These studies indicate that the MBP is added to the myelin prior to
PLP, and there is a shift in priority of synthesis from MBP to PLP in individual
oligodendrocytes during the process of myelination. Moreover, very small fibers
contain low concentrations of MBP relative to PLP, and conversely, very large
fibers contain a high concentration of MBP relative to PLP. Thus, the relative
concentration of these proteins in myelin is not constant but varies as a
function of the size of the myelinated fiber.
An investigator at Johns Hopkins University in Baltimore, Maryland, studies
proteins and glycoproteins found in oligodendroglial plasma membranes in a cell
culture system. Oligodendroglia can be purified by bulk-isolation techniques
from bovine, lamb, or human subcortical white matter tissue. The preparation is
up to 95% homogeneous. Purified oligodendroglia can be maintained as suspension
cultures for several days, and some cells can be maintained for several weeks.
The maintained cells are viable as indicated by the rapid incorporation of
radiolabeled precursors into specific product. These cells synthesize lipids and
proteins, especially lipids found enriched in myelin. After a short time in
culture the oligodendroglia elaborate whorls of myelin lamellae, having the
characteristics of mature compacted myelin.
An investigator at the Temple University in Philadelphia analyzes the biochemical
aspects of myelination. He has shown that thyroid hormone (T3) stimulates
oligodendrocyte to produce myelin.
The MS center at the Albert Einstein College of Medicine in New York City has
demonstrated that non-IgG immunoglobulins as well as IgG mediate complement-
dependent demyelination in CNS cultures, immunoglobin-binding to myelin and
oligodendrocytes, and IgG caused myelin swelling and oligodendrocyte
proliferation. Parallel investigations of serum from MS patients have
demonstrated that some factors other than immunoglobulins may be the
demyelinating factors. The work with sera from MS patients indicate that, unlike
acute EAE, in chronic progressive multiple sclerosis patients most of serum
demyelinating activity is due to complement-dependent non- immunoglobulin factors
and that serum immunoglobulins play at most a minor role in the in vitro
demyelination. It appears that the demyelinating factors in EAE sera are
immunoglobulins and the demyelinating factors in MS sera may be enzymes.
Investigators at Duke University at Durham, North Carolina, have found extensive
cross-species interactions of myelin basic protein that suggest that the antibody
response is restricted to specific portions of the molecule which have been
carefully preserved during evolution. They suggest that failure of antibodies to
myelin components to affect myelinogenesis might relate to neutralizing serum
factors; if sufficient antibodies are given, a positive effect may be achieved.
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At the MS center at the Veterans Administration Medical Center associated with
the University of California in San Francisco, a research team studies
inmunological activity of oligoclonal immunoglobulins in CSF, in extracts from
nervous tissues of animals developing EAE, and in patients with multiple
sclerosis using a relatively new technique called imprint
electroimmunof ixation. Using imprint electroimmunof ixation they have found that
approximately 50 percent of MS patients have CSF antibodies to MBP and measles
confined to the oligoclonal region.
Studies have also been carried out in rabbits sensitized with MBP and complete
Freund's adjuvant. Rabbits with herpes simplex encephalitis developed bands in
CSF specific for herpes antigen. These findings are helpful in elucidating
whether viral infection, or an autoimmune reaction, can reactivate latent clones
of antibody-forming cells in the CNS, and produce an oligoclonal pattern as seen
in MS.
The MS-ALS Center at La Jolla, California, is involved in studies of the cause
and pathogenesis of demyelinating and degenerative disorders of the CNS. They
have provided evidence that antibody can initiate and maintain virus persistence
in vitro and that an antibody signal to a viral determinant expressed on the
surface of infected cells can initiate unique changes in the cytoplasm of such
cells. For example, the antibody to measles virus can strip viral antigens from
the surface of infected cells and render these cells resistant to lysis by
cytotoxic lymphocytes or antiviral antibody and complement. Further, experiments
are in progress to establish whether the defect in the measles virus
polypeptides, in antibody initiated virus persistence, is at the level of viral
transcription or translation.
An investigator at the Medical University of South Carolina in Charleston, South
Carolina, previously reported that MS patients suffering from active MS often
exhibit high response to pokeweed mitogen driven IgG production, a T-cell
dependent process. In contrast, new data show that MS patients' responses to the
T-independent B-cell activator (salmonella paratyphi) are lower than observed in
normal individuals. These preliminary findings indicate an abnormally low
response to T-independent antigens which might be determined by a gene associated
with the Ig structural gene.
The results obtained so far indicate that the changes in T-cell subsets in MS are
actually related to simultaneous modifications of regulatory properties with
regard to IgG production. This may be relevant to the disease process since an
increase in intrathecal IgG synthesis during exacerbations has been reported.
An investigator at Washington University, in St. Louis, has shown an anomaly of
multiple sclerosis T-cells when allogeneic T-cells and B-cells were co-
cultured. Allogeneic normal T-cells and B-cells from HLA mismatched subjects and
cultures of normal T-cells and multiple sclerosis B-cells generated about the
same percentage of plasma cells. In contrast, allogeneic combinations of
multiple sclerosis T-cells and normal B-cells generated a several-fold-increased
percentage of plasma cells. This data supports the theory that T-cell
lymphocytes from patients with active MS are deficient in a subset of cells that
negatively modulate allogeneic B-cell activation. The deficient subset could
conceivably be a suppressor or cytotoxic cell. Suppressor cytotoxic T-cells are
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radiosensitive and helper T-cells are radio-resistant. The investigator has
found that irradiating normal T-cells increased the percentage of generated
plasma cells much higher than irradiating MS T-cells. This data supports the
recent report that patients with active MS have a diminution of suppressor
cytotoxic T-cells called 0KT5.
4. Laboratory Assessment
No definitive diagnostic laboratory tests for MS are known. Progress has been
made in the early diagnosis of MS utilizing visual, auditory, and sensory evoked
responses and computerized tomography. Clinically unsuspect lesions may be
identified by these and other new methods.
The oligoclonal immunoglobulin assay is helpful in confirming the diagnosis of MS
in 90-95% of the cases. A highly sensitive radioimmunoassay is being used to
assess demyelination and myelination using nucleotide rich material (NRM) found
in the CSF which is unique to MS patients. Further, an attempt is being made to
verify the presence of neuroelectric blocking f actor (s) reportedly found in serum
obtained from patients with MS.
A group at Johns Hopkins University, and others, have reported that basic protein
appears in the cerebrospinal fluid (CSF) of MS patients undergoing an acute
attack. The presence of myelin basic protein in the CSF of MS patients
undergoing acute attacks may have practical significance in assisting in the
early diagnosis of MS and permitting monitoring of the activity of the disease in
patients with confirmed MS. Myelin basic protein assay in CSF may also prove to
be a useful tool for measuring response to therapy.
5. Treatment and Clinical Trials
There is no wholly safe and effective treatment for MS. ACTH and steroids
continue to be used in ttie treatment of exacerbations of MS. Clinical trials are
exploring immunosuppressive therapy with azathioprine, prednisone with
azathioprine, and cyclophosphamide in chronic progressive MS. A study of the
efficacy of co-polymer I on recent bouts of MS at the Albert Einstein College of
Medicine is showing promising results. A multicentered collaborative study of
plasmapheresis in the treatment of exacerbating-remitting MS is underway.
6. Summary and Future Trends
The application of new techniques has resulted in the identification of two
different viruses in MS brain tissues but these observations remain to be
confirmed. In addition, blood and spinal fluid of MS patients have antibodies to
a variety of viruses. Studies are continuing in an effort to uncover the
possible relationship of infectious agents to MS. Research on mechanisms of
persistence of viruses in tissues has been ongoing and although a number of
mechanisms have been identified, others remain to be confirmed. The NINCDS
continues to support studies defining the immunological abnormalities of MS
patients and the causes and mechanisms for their development. The most important
results thus far relate to a significant reduction of cells whose function is to
suppress immunological reactions prior to and during acute attacks of MS. The
most intensive research currently is in the immunological area. Progress has
been made in improving the reliability of diagnosis in MS. Clinical trials are
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supported by NINCDS and by other agencies here and abroad. Genetic studies have
uncovered an association between MS and patterns of histocompatibility
antigens. Factors which may have an influence upon the course of MS are being
studied. Recently, evidence has been uncovered which suggests that location
and/or frequency of change in the patient's residence may be important in the
development and course of MS. Techniques for growing oligodendroglial cells
(which form and maintain myelin) in tissue cultures have been developed and a
variety of studies are in progress using this system.
Amyotrophic Lateral Sclerosis
The human motor neuron disorders (MND), of which amyotrophic lateral sclerosis
(ALS) is one, are a group of neurological disorders characterized by weakness,
muscle atrophy, and widespread denervation. There is evidence that the MND's
represent a spectrum of diseases with common clinical and pathological
features. Genetic studies suggest a variety of modes of inheritance: autosomal
recessive, dominant, and polygenic. The infantile spinal muscular atrophies are
inherited as an autosomal recessive trait, and some of the familial cases of ALS
appear to be inherited as an autosomal dominant. In many other families the mode
of inheritance is less well defined. Most of the cases, however, are sporadic.
As of May 1982 the Amyotrophic Lateral Sclerosis (ALS) subprogram had 11 active
grants which included one ALS research program project center. The total cost
expenditure from FY 1981 and 1982 funds for these research activities is
approximately $1 million. This includes 1 ALS "center". When the additional two
ALS - MS "centers" are also included, the number of active grants is 13 for a
total cost of approximately $2.9 million. In FY 1982 19 applications were
received, and 15 were approved, of which 2 new and 4 competing renewals were
funded at a cost of approximately $90 thousand for the new and approximately $0.5
million for the competing renewal grants. In FY 1980 the Neurological Disorders
Program issued a Program Announcement (PA) calling for grants on the Motor Neuron
Diseases, Spinocerebellar and System Degenerations. The response to this PA,
which also embraced grants on ataxias, has been modest.
1. Etiology and Pathogenesis
The etiology of the motor neuron diseases remains unknown. One theory holds that
ALS is due to accelerated aging of the motor neuron, which is genetically
programmed. ALS has been thought to be associated with secondary factors such as
prior poliomyelitis, neoplasia, or excessive athletics. That ALS is due to
multiple etiological factors is supported by the following: familial cases can
be either autosomal recessive or dominant; genetic and environmental interaction
is seen in familial and nonfamilial clusters in Guam; and dizygotic male twins
developed ALS in the sixth decade. There is some variability both in the
duration of illness and in the pathology of the familial forms of the illness.
Variations are also noted in the sporadic form of ALS where 20% of afflicted are
alive after five years. ALS has been reported in association with dementia and
degeneration of other systems.
2. Virology, Immunology, and Animal Models
Attempts to transmit MND to chimpanzees (Gibbs and Gadjusek) by the inoculation
of brain and spinal cord tissue from patients with ALS have so far been
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negative. Despite the expectation of uncovering a latent or persistent virus
infection in ALS, the search for the presence of virus has been unrewarding.
There are only vague suggestions of immune dysfunction in ALS, which require
additional study.
Animal models are important in the study of MND. Several have been identified
and are being studied intensively including an hereditary canine spinal musclar
atrophy (HCSMA) of Brittany Spaniels which was found by investigators at Johns
Hopkins. Other models include Wobbler mouse, Swedish Lapland dogs, Stockard's
paralysis in large dogs, and murine retrovirus poliomyelopathy. Toxic models are
also being investigated.
3. Selected Examples of Research Activities
At the ALS center at St. Vincent's Hospital in New York City, a research team is
actively engaged in studies of several aspects of ALS etiology and the
pathogenesis of ALS. Their study of the distribution of HLA-A, -B, and -C in
patients with ALS found no statistically significant deviation. They found a
trend, however, toward a decrease in HLA-A9, and toward an increase in HLA-Bw35
and -Cw4.
In the past year, by employing modern analytical equipment, scientists at the
center detected abnormal levels in ALS brains of CNS gangliosides, and their
ratios to each other, perhaps due to defective synthetic pathways. These
findings, when confirmed, could become a part of a diagnostic battery for ALS and
may help in establishing the etiology of ALS.
An investigator at the University of Southern California, at Los Angeles, is
studying the effects of neural differentiation on viral replication,
dif ferencesin viral replication in the neural, glial, and non-neural cells,
effects of cell division on viral replication, and the effect of viral clonal
variation on viral replication in the neural or glial cells.
Theiler's murine encephalomyelitis virus related to human poliomyelitis, has a
particular affinity for motor neurons and causes neuro-degenerative disease in
mice.
Using this model, these scientists have found that cellular differentiation and
the arrest of cell division can alter Theiler's virus replication. The
preferential replication of Theiler's virus in dividing cells in vitro, as well
as in neurons, reflects age and cellular specific changes.
4. Treatment
At present, there is no effective treatment for ALS. Symptomatic relief of
excessive salivation may be achieved pharmacologically. Past treatments which
have proven ineffective include neurotoxin, corticosteroids, immunosuppression,
immunostimulation, transfer factor, and plasmapheresis. No clinical trials in
ALS are presently supported by the Institute.
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5. Summary and Future Trends
\ Motor neuron diseases constitute a host of disorders about which little is
known. New ideas and research initiatives are needed which will lead to a better
(Understanding of these disorders and thus to effective management, treatment, and
prevention.
The Program has stimulated research interest in ALS by issuing a program
announcement in May, 1980. Grantees supported by NINCDS are continuing the
search for possible viral causes of the disease utilizing the most sophisticated
techniques. The search for nutritional and metabolic abnormalities in ALS
continues. The Intramural Program has identified a condition resembling
poliomyelitis, which occurs in families in which ALS occurs. The possible cause
of this illness and its relationship to ALS is being explored. A dog model for
ALS has been identified and studies of its pathology, clinical course and
genetics are progressing. Unsuccessful therapeutic trials for ALS utilizing
various modalities have been conducted.
Future trends in ALS and related research are expected to concentrate on animal
models, axonal transport, and toxic neuropathies, and the possible effects of
target organs on motor neurons.
Ataxia
As of May 1982, the Ataxia subprogram had 5 active grants. The total cost from
FY 1981 and 1982 funds for these research activities is approximately $300
thousand. In FY 1982, 6 applications were received and 2 were approved. Two new
grants were awarded at a cost of over $100 thousand. No awards were issued for
the competing renewal grants. In the FY 1980, the Neurological Disorders Progam
issued a Program Announcement calling for grants on Motor Neuron Diseases,
Spinocerebellar and System Degenerations; that is, ataxias and motor neuron
diseases.
Estimates of people afflicted with ataxia range from 5,000 up to 20,000, in the
United States. The ataxias include a variety of disorders, primarily
heredofamilial, currently classified on the basis of clinical and pathological
features. Although ataxia may be a part of the clinical picture of a whole host
of disorders, the primary interest of this subprogram is in those in which
uncoordinated movement, due to involvement of the cerebellum and/or its pathways,
is a principle feature.
1 . Etiology and Pathogenesis
The symptoms of ataxia may begin during childhood, adolescence, young or mid-
adulthood, depending upon the disorder. The causes of cerebellar ataxia include
developmental defects, such as cerebellar agenesis and hypoplasia, progressive
degenerative disorders, such as familial spino-cerebellar degeneration,
Friedreich's ataxia (most common form), and ataxia telangiectasia.
Friedreich's ataxia is a progressive degenerative disorder affecting the nervous
system, heart, and certain enzyme systems. An abnormality of pyruvate
decarboxylation was observed in some patients, but still needs further
confirmation. Recent data suggests a reduction of activity of mitochondrial
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malic enzyme, an enzjmie involved in regulation of carbohydrate metabolism. In
general, however, we must state that no specific biochemical defect has been
found in the majority of the patients with clinically and pathologically defined
hereditary ataxias such as cerebello-olivary ataxia, olivo-ponto-cerebellar
atrophies (OPCA), and spastic ataxia.
2. Research Models
An investigator at Johns Hopkins University in Baltimore, Maryland, is studying
canine inherited ataxia in the Gordon setter dog. The pathological changes,
especially in older dogs, resemble those of the familial human cerebellar
cortical atrophies. There are significant clinical and histological
similarities, as well as some pathological differences, between the animal and
human ataxias. Clinical, morphological and genetic studies, currently in
progress, will hopefully demonstrate the significance of this potentially
valuable animal model.
3. Selected Examples of Research Activities
An investigator at Mount Sinai School of Medicine in New York City found that
patients with adult-onset olivopontocerebellar atrophy (OPCA) that was either
sporadic, or genetic recessive, had a significant reduction in leukocyte
glutamate dehydrogenase (GDH) activity. The defect was found to be specific for
this form of OPCA since patients with the dominant form of OPCA as well as other
types of spinocerebellar degeneration were found to have normal enzymatic
activity in leukocytes.
An investigator at University of Mississippi Medical Center at Jackson,
Mississippi, attempts to determine the genetic linkage relationships of
autosomally dominant inherited spinocerebellar ataxia. A determination of
antigens at the HLA A and B loci within the histocompatibility complex on human
chromosome 6 have formed the major basis for the linkage studies. Additional
genetic markers thought to be located on human chromosome 6 near the HLA complex
are currently the subject of additional investigation,
4. Summary and Future Trends
The ataxias, like motor neuron diseases, constitute a heterogeneous group of
disorders about which relatively little is known. New ideas and research
initiatives are needed. Of the current research efforts, measurements of
selected enzyme activities and study of animal models appear to be the most
promising.
INFECTIOUS DISEASES OF THE NERVOUS SYSTEM
The Infectious Diseases subprogram supports investigations of viral, bacterial,
and parasitic infections, and research on any infectious agent that might be
suspected to be the cause of a degenerative disease of the nervous system.
In fiscal year (FY) of 1982, 31 grants were active in the infectious diseases
subprogram. This includes two program project centers. Total costs from FY 1981
and 1982 funds for these research activities is approximately $3.5 million. In
FY 1982 a total of 19 applications were received and 17 were approved, of which 3
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new and 5 competing renewals were funded at a total cost of approximately $450
thousand for new research grants and approximately $500 thousand for competing
renewal grants.
It is suspected that many neurological diseases or disorders are caused by
viruses, although a particular virus has not been identified. These include:
Reye's syndrome, Guillain-Barre syndrome, multiple sclerosis, amyotrophic lateral
sclerosis, Creutzfeldt-Jakob disease, some forms of Parkinson's disease, and
congenital defects.
The programmatic aims of this subproject are: 1) to determine the etiology of
degenerative diseases of the nervous system of man by experimental transmission
of diseases to animals; 2) to develop animal models for characterization of the
isolated etiological agents of these diseases; 3) to uncover therapeutic regimens
for the prevention and/or control of these diseases in animals and to determine
their safety and efficacy for use in man: 4) to study viral, bacterial and
parasitic diseases of the nervous system; 5) to provide support for research
activities relevant to MS, ALS, and other neurodegenerative diseases; 6) to
provide support for research relevant to the dementia subprogram.
1. Creutzfeldt-Jakob disease
Clustering of cases of Creutzfeldt-Jakob disease (CJD) has not been found in the
U.S. although it does occur in other countries. About 15% of the cases are of the
familial type which may suggest a genetic susceptibility to infection. It
remains to be determined whether the agent of CJD is maintained only by patient
to patient transmission, is shared by man with lower vertebrates, or whether it
is a latent infection of man that is rarely activated. The CJD agent may turn
out to be very similar to the scrapie agent, which is believed to be a very small
molecule of genetic material.
An investigator at Yale University in New Haven, Connecticut, studies the
pathogenesis of experimental Creutzfeldt-Jakob disease in guinea pigs, hamsters
and mice. Light and electron microscopic (EM), virological, tissue culture and
biochemical techniques are utilized. The leading hypothesis is that the CJD
agent is composed of various viral strains with distinct incubation periods, or
that it is a variant of scrapie.
2. Scrapie
Research is directed toward understanding the nature of the scrapie agent which
affects sheep. Because the present assay for scrapie requires determination of
an endpoint by titration in mice over a nine-month period, it is especially
tedious to purify the scrapie agent and use this preparation to study its
chemical and immunological properties.
An investigator at the University of Wisconsin in Madison, Wisconsin, was unable
to adapt scrapie to grow in cell cultures, but has found that inhibiting cell
growth allowed cultured virus to maintain infectivity for longer periods J^
vitro. Recent results suggest that scrapie is caused by a small naked virus
bound to a protein molecule. Another investigator at the University of
California in San Francisco reported recently that the scrapie agent is a protein
molecule without a nucleic acid, or so small that it is not detectable.
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3. Herpes Viruses
The importance of HSV-neural interaction lies in the critical role of infection
in determining latency and reactivation in recurrent HSV-1 (cold sores,
keratitis), HSV-2 (genital herpes) disease, as well as in the encephalitides
caused by these viruses in both the adult (HSV-1) and neonate (HSV-2).
An investigator at the University of Utah School of Medicine studies the role of
macrophages in CNS demyelination of athjmiic mice after corneal HSV infections.
Previous studies have shown that after infection the immune competent animals had
more extensive demyelination that the athymic mice. Recent studies show that as
more cells respond to the lesion in the immune competent animals, the
demyelinative lesions become more extensive. Electron microscopy demonstrates
that macrophages may have a role in the demyelination. After infectious virus
disappears from the chronically infected animals, the mouse can remyelinate CNS
axons with Schwann cells. Since the virus is usually confined to the trigeminal
nerve and tract, and does not spread to other parts of the brain, studies are
underway to elucidate this phenomenon.
An investigator at the University of Minnesota is also studying Herpes simplex
virus infections of the nervous system. He has largely defined the progression
of the infection as it moves from a peripheral site of infection through the
peripheral nerves, via nerves into the spinal cord, and finally to the brain.
This progression can be stopped in the nerves where the virus can establish a
latent infection.
4. Marek' s Disease Virus
An investigator at the University of Georgia, in Athens, studies genetic and
immune mechanisms underlying the susceptibility of chickens inoculated with
Marek' s disease virus (MDV) to the development of transient paralysis. They try
to determine which factors are responsible for the appearance of B blood group
histocompatibility complex restriction of clinical transient paralysis to line G-
B2 chickens. Previous findings indicate that the susceptibility to transient
paralysis is controlled by a major histocompatibility complex.
To explore the immunological basis of transient paralysis (TP) caused by Marek' s
disease virus, the investigators suppressed B-cells by cyclophosphamide.
Genetically susceptible chicks were given cyclophosphamide for four consecutive
days after hatching. None of the cyclophosphamide-treated birds developed
transient paralysis after infection with the Marek' s disease virus while seven of
the twelve cyclophosphamide untreated birds displayed symptoms of the disorder
after the virus infection.
Since cyclophosphamide treatment has been found to transiently diminish T-cell
dependent immunity, he performed a similar experiment with surgically
bursectomized birds. None of the bursectomized birds developed transient
paralysis after viral infection while seven out of nine control birds were
affected. These results suggest the possibility that transient paralysis might
be antibody-mediated. On the other hand, removal of the bursa, which is one of
the sites of viral replication, might have lowered the virus load and
consequently prevented expression of symptoms.
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Results of the neurologic and electrophysiologic examinations that have been
performed indicate that MDV-induced TP in chickens may provide a useful model for
studying certain virus-caused central nervous system disorders that occur in man
and other species. The finding that suppression of the humoral immune system
prevents TP suggests that this disease may be an immune-complex or autoimmune
type of disorder. This is an important finding which should by further studies
lead to a better understanding of the mechanism responsible for the transient
nature of this disease. The results which show that only certain strains of MDV
will cause TP in chickens having certain genotypes indicate that there may be an
essential, and perhaps complex, virus-host cell interrelationship for
manifestation of disease symptoms.
5. Measles
One of the basic mechanisms by which viruses persist is the generation of
defective interfering virus. In order to define the morphologic biology and
pathogenetic mechanisms associated with defective interfering virus infection, a
study of the natural or experimentally induced lymphocytic choriomeningitis virus
infection in its natural host in the mouse is conducted.
An investigator at the University of Connecticut Health Center, in Farmington,
Connecticut, studies the phenomenon of lymphocytes properties to adherence to
virus infected cells. The investigator observed that blood lymphocytes attach to
measles virus infected cells. Peripheral blood lymphocytes from MS patients
adhere to measles infected cells in significantly increased numbers than control
cells. The increased adherence of cells from MS patients appears to be due to a
prostaglandin mediated event. This event is sensitive to inhibition by aspirin,
and it is monocyte-dependent.
6. Demyelinating Viruses: Canine Distemper Virus and Visna
Canine distemper virus (CDV) causes persistent, demyelinating disease in dogs.
By studying interferon levels in the serum of dogs, after infection with
different CDV strains, it may be possible to differentiate between infection with
an attentuated (no interferon) versus virulent (injected with interferon) CDV.
It is known that interferon is present in the CSF of dogs with persistent brain
infection. As of now, however, it is not known whether this phenomenon
represents a cause or is a result of persistent infection.
A research team at the Ohio State University, Columbus Ohio, is working on canine
distemper virus infection in germ-free dogs with associated demyelinating
encephalitis, a viral model of MS. Canine distemper is a highly contagious,
natural viral disease, whose pathogenesis involves a lympholytic phase followed
by viral dissemination to epithelial tissues such as the lung, gastrointestinal
tract, and other organs. Virus invasion of the CNS is a frequent occurrence and
fatal encephalitis usually results. The team was fortunate to isolate viral
strain R1521 which is unique in that although the virus is neurotropic, it causes
a persistent infection and demyelinating encephalitis of the CNS in three week
old germ-free dogs instead of the usual acute fatal disease. A number of studies
associated with this new model are now underway.
Visna is a demyelinating disease in Icelandic sheep caused by a virus. One of
the most interesting aspects of persistent visna infection is the phenomenon of
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generating variants (antigenic drift), different from the original infecting
virus. Among several tentative conclusions is one that the variants could play
an important role in the occurrence of lesions and clinical disease.
Recent light microscopic studies by investigators at the University of
Pennsylvania have clearly indicated that the pathological lesions of clinical
visna are markedly different from those seen in subclinical infections. When
clinical disease appears there are severe focal lesions of spinal cord and brain
stem, in which tissue destruction, scarring, and demyelination are prominent.
Since the Icelandic sheep model is the only one in which clinical visna disease
occurs, it offers a unique opportunity to describe the demyelinating lesion
caused by visna virus at an ultrastructural level.
Studies at Johns Hopkins University have shown that the macrophage is an
important target cell in this infection. The investigator studies the possible
role of proteolytic enzymes and phagocytosis of infectious virus-antibody
complexes to establish the macrophage properties which may enhance infectivity of
the virus and determine tissue tropism. The ability of infected monocytes to
respond to chemotactic stimuli are also studied because of their importance in
disseminating virus in vivo.
7. Summary and Future Trends
The size of this subprogram, and the level of research activity supported, from
the point of view of its relevance to major neurological disorders, appears to be
adequate. Research on latent and slow viruses is of high quality and is well
represented in this subprogram.
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MUSCULAR AND NEUROMUSCULAR DISORDERS
The Neurological Disorders Program supports research in basic nerve and muscle
function and dysfunction with special emphasis on Muscular Dystrophy, Myasthenia
Gravis and Peripheral Neuropathies. In May 1982, 149 grants were active at a
cost of nearly $14,593,000. There are four program projects: one for basic
research in neuromuscular diseases, one for research in muscle regeneration and
two clinical research centers for neuromuscular disorders and for peripheral
neuropathies. In addition, a collaborative clinical trial on the use of
plasmapheresis for the treatment of Guillain-Barre syndrome is underway.
Basic Studies on Nerve and Muscle
Nearly 50% of the funds of the grant portfolio are devoted to basic research on
nerves, muscles and their interactions. This included 92 grants, costing
$7,539,155 as of May 1982. These studies utilize a wide variety of preparations
from simple invertebrate organisms through amphibia, mammals and humans.
Physiological, biochemical, anatomical, and molecular biological techniques are
being used to determine the macromolecular basis of muscle contraction, the
mechanism of excitation contraction coupling, and the function of the muscle
spindle system. Studies on nerve are underway to specify the channels, gating
mechanisms and ion selectivity involved in nerve conduction. In addition, the
program supports work on nerve-muscle interaction. These investigations are to
determine both the pre- and post-synaptic events involved in neuromuscular and
synaptic transmission. They include the mechanism of transmitter action,
storage, release and recycling of synaptic vesicles. The activity of
acetylcholine receptors and the enzyme cholinesterase are being examined as well
as the changes that can be induced in the efficiency of synaptic transmission.
Finally the trophic effects exerted by nerve and muscle upon each other are under
investigation.
Invertebrates, with simple nervous systems, large neurons and stereotyped
behaviors are exceptionally useful for physiological, anatomical and biochemical
studies to determine the cellular and eventually the molecular basis of
behavior. The crayfish is an ideal preparation in which to examine the response
to stretch. The tips of the dendrites in this crustacean's stretch receptor
undergo distinctive morphological changes under stretch in comparison with the
relaxed state. These changes are described as "beading" and involve alterations
in the distribution of the intramembrane particles seen in freeze fracture
replicas. Furthermore, the dendrites of the sensory neurons in the stretch
receptor have been shown to receive only GABA mediated inhibitory synapses.
These receptors are an ideal structure in which to unambiguously identify GABA
synapses and to anatomically characterize the pre- and post-synaptic membranes.
Tissue and organ culture is another way of simplifying the nervous system for
easier analysis. Studies of development of neuromuscular junctions of the toad
and rat in tissue culture are designed to elucidate the roles and mechanisms of
synaptic connections. Functional synaptic transmission has been demonstrated to
precede and in fact to be prerequisite for the accumulation of receptor molecules
on the post-synaptic membrane. There are definite species differences. Toad
nerves do not induce receptor accumulation on rat muscle, and neither do rat
nerves. Finally, no loss of extrajunctional sensitivity is seen with
innervation, but the junctional sensitivity increases further.
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In different but related studies, immunocytochetnical methods have shown that a
form of actin (one of the muscle contractile proteins) is highly concentrated at
the neuromuscular junction. It is present in developing muscle before the post-
synaptic fold forms and may play a role in the receptor aggregation during the
formation of the neuromuscular junction. Investigations on the role of calcium
in muscle contraction continue to yield new information. Electrical stimulation
of skeletal muscle fiber leads to the release of calcium stored in the
sarcoplasmic reticulum which then activates muscle contraction. This work
utilizes frog muscle, and the investigators have shown that the sarcoplasmic
reticulum senses the tubular membrane potential by charge movement alone. New
optical dyes are being designed to measure both membrane potentials and the
amount of free calciiom present in muscle cells during activation. Previous
optical measurements have been demonstrated inaccurate due to the interaction of
the dyes with the living system.
Although it has been known for some time that both nerve and muscle are affected
in many ways when their normal interaction is interrupted, the causes of these
changes are still being documented. Evidence suggests that trophic influences of
nerve on morphologic, physiologic and metabolic properties of skeletal muscle are
mediated in part by muscle activity and in part by trophic substances which are
carried by axonal transport. In order to investigate the mechanism of both of
these processes, a model system for the study of protein turnover in cultured
muscle has been set up for the investigation of trophic influence and muscle
activity on protein synthesis and degradation. A trophic protein, sciatin,
purified from nervous tissue, has been shown to enhance the morphological
development and to promote the maintenance of skeletal muscle cells growing in
tissue culture. In addition, this protein has been demonstrated to increase both
the number and density of acetylcholine receptors incorporated into the membranes
of these muscle cells.
The overall objective of the muscle transplantation and regeneration project is
to learn about mechanisms by which a grafted muscle becomes reintegrated with the
nervous and vascular system of the host. Studies during the past year have shown
that any muscle precursor cells that may be present in the central ischemic zone
of muscle grafts do not undergo DNA synthesis. Investigators have demonstrated
that better anatomical distribution of nerve fibers accounts for improvement in
nerve-intact grafts compared to standard grafts. A histochemical procedure has
been developed to distinguish between the arterial and venous ends of capillaries
during the revascularization of free muscle grafts. The major problems in
clinical grafting of skeletal muscle are to determine how muscle can best adapt
to ischemia during the early post-transplantation period and what mechanisms are
important for subsequent revascularization and reinnervation of transplanted
muscle. These investigations are directly targeted to such problems and the
results obtained can be quickly translated into modifications of current surgical
techniques for transplanting skeletal muscle tissue.
Muscular Dystrophy
Muscular dystrophy is a group of chronic, progressive, genetically determined
diseases characterized by weakness and wasting of the voluntary muscles. The
rate of progression varies markedly from type to type. It is estimated that some
200,000 men, women, and children in the United States are suffering from some
form of this disease. Nearly two-thirds of the known victims are children
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between the ages of 3 and 13. There is no effective treatment for muscular
dystrophy itself. To date, none of the wide variety of diets and drugs
administered to patients has shown a significant or lasting effect on the course
of the disease. Physical therapy has limited value in delaying contractures but
does not otherwise affect the course of the dystrophic process. Antibiotics may
prolong the lives of children who would otherwise succumb to respiratory
infections. In fiscal year May 1982, 28 grants providing nearly $3,628,533 were
awarded in the Muscular dystrophy sub-program, including one program project.
In Duchenne dystrophy, the affected striated muscle is characterized by the
presence of scattered foci of degenerating myofibers. Within these foci,
numerous myogenic cells in various stages of regeneration represent the potential
of the muscle for repair. In older patients, the process of muscle regeneration
becomes abnormal and eventually has no influence on the clinical progress of
dystrophic degeneration. Studies initiated to test the hypothesis that later
regenerative failure is due to a direct effect upon the myogenic stem cell
revealed that, contrary to established opinion, induction of muscle competence in
somites is a two-phase process. First the myotome is induced and gives rise to a
postmitotic contractile rudiment. Then proliferatory stem cells (myoblasts)
arise which ultimately develop into musculature. These latter cells are derived
from the dermatome. A myoblast-fibroblast modulation is proposed to account for
the characteristic loss of regenerating stem cells and simultaneous increase in
interstitial fibrosis. Developmental studies to verify this are underway.
Hereditary muscle disorders closely resembling human muscular dystrophy, have
appeared in a number of animal species, including hamsters, chickens and rats.
These animal models allow scientists to perform controlled experiments which
cannot be carried out in human beings.
Hereditary muscular dystrophy in chickens has been postulated to be the result of
a primary intrinsic defect in the differentiation of fast twitch skeletal muscles
due to the absence, reduction or alteration of a muscle cell membrane receptor
for a thymus derived secretory product. The subsequent blockage in muscle cell
differentiation or inherited immune abnormalities would then result from a
secondary development of autoimmune pathology.
The genetically dystrophic chicken is also being utilized to develop
chemotherapeutic drugs. Muscle cells from embryonic chickens are grown in a
culture to provide an in vitro assay system in which to study the potential
efficacy of specific classes of drugs with various modes of action upon muscle
growth, protein turnover and cytochemistry. Inherent practical problems which
have impeded the intensive description of muscle growth and protein turnover with
drug intervention in whole muscle from intact animals are circumvented with these
cultured cells.
Myasthenia Gravis
Myasthenia Gravis (MG) is a chronic neuromuscular disorder characterized by
progressive weakness and abnormally rapid fatigue of the voluntary muscles.
Twenty years ago about 30% of the patients died within 2-4 years of the onset of
the disease and many of those that lived were severely disabled. Today mortality
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is less than 5%, and many patients can live relatively normal lives despite the
presence of the disorder. In fiscal year 1982, 13 grants were active providing
$1,261,075.
The objectives of most of the projects relevant to myasthenia gravis are to
determine mechanisms governing the synthesis and assembly of the acetylcholine
receptor, to understand the structural basis of acetylcholine receptor function
and to elucidate the pathological mechanisms of the disease.
Basic research on KG has utilized such diverse animals as electric fish whose
electroplaques contain relatively large quantities of acetylcholine receptors,
snakes that produce toxins which specifically bind to these receptors, and rats
immunized against purified acetylcholine receptors that develop symptoms much
like humans having the disease. A radioimmunoassay was developed for detecting
antibodies against acetylcholine receptors and utilized to find these antibodies
in animals immunized against purified acetylcholine receptor. Using this assay,
it was possible to detect antibodies against human acetylcholine receptor in sera
from patients with myasthenia gravis. These studies have demonstrated that
myasthenia gravis is an autoimmune disease in which circulating antibodies
against a person's acetylcholine receptor molecule have arisen and damaged
neuromuscular conduction resulting in muscle weakness and fatigability.
There are still several outstanding problems with understanding this disease.
The causative factor in the production of circulating antibodies is not
understood. In addition, the relation between the presence of antibodies and
impairment of neuromuscular transmission is not a simple one. It is not
understood why some patients with severe sjrmptoms of the disease lack or have a
low level of circulating antibodies and why the effects of the antibodies vary
from one muscle to another.
A syndrome quite analogous to myasthenia gravis can be produced in several
strains of mice which show significant variation in the incidence of paralysis.
The difference between species, known as high and low responders, has been shown
to involve the immune system rather than reflect a difference in the target
neuromuscular junctions. Examination of these different strains of mice may help
to understand the factors which lead to manifestation of the human disease.
Moreover, these studies may shed light on the genetic mechanisms underlying
myasthenia, degradation of acetylcholine receptors and the manner in which
receptor binding results in paralysis.
The recently developed technique for making monoclonal antibodies offers an ideal
tool with which to investigate the relation between antibody specificity and
pathogenic effect. With monospecific antibodies it is possible to define the
antigenic sites that mediate receptor modulation, and test the ability of these
antibodies to induce experimental autoimmune myasthenia gravis in animals.
Several relatively successful treatments to relieve the symptoms of myasthenia
gravis are presently in use. These include drugs which block cholinesterase
activity, immunosuppressants, thymectomy, which prevents production of
antibodies, and plasmapheresis, which removes antibodies from the blood.
However, the specific information being obtained on the etiology of the disease
should yield not only far more precise and effective treatment, but may even lead
to the prevention of MG, as well as other autoimmune diseases.
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Peripheral Neuropathies
The peripheral neuropathies are common and serious health problems often
associated with prolonged morbidity. The majority of the affected population are
diabetics. There are approximately three and a half million diabetics in the
United States and 10% of them have symptoms of painful burning, numbness,
weakness or paralysis of the extremities. Male diabetics often become impotent,
a defect which may be due to autonomic neuropathy or angiopathy. The direct
cause of these neurological disorders is not known, and no therapeutic measures
are available. The Neurological Disorders Program especially encourages research
in this area. In addition to diabetic neuropathy, the Program supports research
in steroid and toxic neuropathy and in Guillain-Barre' syndrome. During May
1982, twelve regular grants and one clinical research center program project in
the general area of peripheral neuropathy were awarded at a cost of $1,931,614.
Diabetic rats kept normoglycemic showed no significant difference in the rate of
fast axoplasmic transport compared to controls. In severely hyperglycemic
animals, the downflow rate was significantly reduced. In addition, a selective
staining technique for the smooth endoplasmic reticulum in nerve fibers was
developed. Combining this staining technique with high voltage electron
microscopy allows the examination of the 3 dimensional structure of the smooth
endoplasmic reticulum. This work is important for correlating changes in the
presumed morphologic substrate for axoplasmic transport with the abnormalities
identified in hyperglycemic rats.
Idiopathic polyneuritis, known as Guillain-Barre syndrome, is presently the most
common cause of acute severe generalized paralytic disease in people. Although a
relatively uncommon condition, affecting the population at a reported annual
prevalence of 1-1.6 cases per 100,000 population, it has recently come to public
attention in the United States as a presumed complication of vaccination against
"swine flu".
Investigations on Guillain-Barre'' syndrome have demonstrated that rats are far
more suitable animals in which to study experimental allergic neuritis, a model
for the disease, than are rabbits, guinea pigs or monkeys. Furthermore, a
protein of peripheral nerve myelin has been identified as the neuritogenic
antigen when present as a lipid-protein complex. These studies should eventually
provide the insight needed to elucidate the induction and possible suppression of
the Guillain-Barre'' syndrome in humans. Finally, a collaborative clinical trial
on the use of plasmapheresis to treat acute Guillain-Barre^ syndrome is underway
and the results should be available by 1983.
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OTHER NEUROLOGICAL STUDIES
This section consists of three main categories of research projects:
Neural Aspects of Learning and Behavior
Disorders of Other Senses with Emphasis on Pain Research
Neuroendocrine Studies
The research activities in these three categories are described in the following
reports .
NEURAL ASPECTS OF LEARNING AND BEHAVIOR
In this category there are 4 projects. These projects are directed towards the
identification of anatomic and morphological substrates in the central nervous
system that influence behavioral alterations. Investigations are conducted to
assess possible behavioral consequences of genetically determined traits as
related to structural organizations in several strains of animal models, A
question is being tackled of whether, or not, in children, the degree of
lateralization of handedness is related to intelligence. Towards this end, the
correlation of degree of handedness with learning ability is being
investigated. The other aspect of learning and behavioral processes is related
to the identification of raacromolecules and biochemical markers that may be
important in establishing long-term memory. In these studies changes in specific
proteins during acquisition of new behavior have been observed. It is hoped that
eventually such studies may help explain the mechanisms of learning, memory and
behavioral manifestations.
DISORDERS OF OTHER SENSES
WITH EMPHASIS ON PAIN RESEARCH
In this category there are 28 projects. About two-thirds of these projects are
related to pain and pain mechanisms. A narrative on this subject is also
included. Other projects in this area are related to motor control, neural
mechanisms subserving position sense, and sensory coding. The emphasis is upon
ascending spinal pathways conveying static position signals, the identification
of the types of receptors that contribute to these signals and the central
representation of these signals within the brainstem, thalamus and sensory
cortex. The hypothesis is being tested about the nature of segmental and
supraspinal motor control systems and the variables that are controlled by
segmental reflex areas. Studies are also designed to investigate the neural
processes underlying the initiation and guidance of voluntary limb movement to
answer questions, such as, what parameters of movement are specified by central
programs and how are these parameters expressed in the neural activities of the
major motor systems. Also, what role does afferent information play in the
initiation and control of movement and how can this information be used by the
nervous system to alter existing programs to better achieve the behavioral
responses .
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PAIN
Neuropeptides and Receptors
Our knowledge of synaptic transmission in the spinal dorsal horn is extremely
limited both in terms of agents and biophysical features. It is suggested that
at least part of the reason is the difficulty in recording _in vivo from the
relatively small cells of the region intracelluarly for long enough to do
systematic biophysical and pharmacological studies because of movements due to
respiration and cardiovascular pulsations. This project is designed to overcome
these difficulties through the use of a slice preparation of the dorsal horn that
theoretically would permit study under the physically more stable conditions of a
bath. The long-term aim is to determine the transmitter identity and synaptic
circuitry of neurons in the spinal cord that are involved in central mechanisms
of pain. Both biophysical and pharmacological studies are outlined. The former
would be used to determine general characteristics of cells such as input
resistance. The pharmacological manipulations are being used to test for the
effects of peptides (substance P, vasoactive intestinal peptide (VIP),
cholecystokinin, enkephalin) and other agents such as opiates.
The demonstration of stereospecif ic binding of morphinoid opiates to receptors in
the brain suggested the presence of endogenous ligands for these receptors. This
presence was confirmed and two closely related, endogenous ligands, Met-
enkephalin and Leu-enkephalin were isolated from porcine brain and sequenced. A
series of conformationally restricted analogs of Met - and Leu - enkephalin are
being synthesized, tested for biological activity, and studied by various
physical techniques to elucidate their conformations in aqueous solution.
Comparisons of conformational features within the series and correlation with
receptor binding affinities and other in vivo and in vitro activities are being
used to isolate the key conformational requirements for binding and/or
transduction. Since it is becoming increasingly clear that multiple opiate
receptors exist and since these receptors can be expected to have different
conformational requirements, the information derived from the conformationally
restricted analogs of this study will be used in the design of more potent and
more specific analogs. These enkephalin analogs are being tested for their
opiate activities using rat brain receptor binding, guinea pig ileum, rat tail
flick, and other assays.
Pharmacological Studies of Pain Systems
Stress-induced Analgesia: several projects are directed towards psychophysical
analysis of stress-induced analgesia. For example, it has been noted that acute
exposures of a severe stressor can result in analgesia. Repeated exposures result
in a progressive decline of the analgesic responses, in much the same manner that
the pituitary-adrenal responses to stress show adaptation. Virtually every
physical stressor increases plasma levels of B-endorphin as well as ACTH and
corticosterone however, not all stressors produce analgesia Some stressors
induce an analgesic response that is sensitive to opiate receptor blockade by
naloxone, others cause a nonnaloxone sensitive analegsia. The proposed
psychophysical experiments will assess whether the sensory changes induced by
various stressors are specific to the modality of pain or whether they are
accompanied by deficits in auditory and/or visual acuity as well.
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Another study is concerned with stress analgesia and the possibility that stress
is a physiological trigger to endogenous analgesia systems. Much evidence is
cited to support the conclusion that such analgesia systems do exist in the
central nervous system. Far less information is available concerning the
circumstances that normally call this system into action. Stress seems to be
such a trigger, but its opioid basis has been in doubt. The thrust of this work
has been to show that both opioid and nonopioid analgesia systems occur. Using a
single stressor, footshock, the investigators have obtained reliable naloxone-
sensitive and naloxone-insensitive stress analgesia. By applying other criteria
for opioid involvement (sensitivity to low dose naloxone antagonism, tolerance
development with repeated application of stress, and cross-tolerance with
morphine), they found a consistent pattern of results. According to all criteria
used so far, the one form of stress analgesia is opioid, the other not. It is
concluded that some forms of stress are adequate triggers for an opioid analgesia
system. Other forms appear to make use of some parallel system whose
neurochemical basis remains unknown.
Pharmacological studies of descending spinal pathways involved in the modulation
of pain sensations are being pursued. Evidence exists showing that neurons in
the raphe magnus, many of which are serotonergic, are activated by acetylcholine
and inhibited by noradrenalin. These observations are extended by determining
the functional significance of these connections and their relevance to
analgesia. The hypothesis is tested that cholinergic neurons project to the
nucleus raphe magnus (NRM) and this connection produces analgesia. Tail flick
and hot plate tests are being used to assess analgesia after microinjection of
one of a series of cholinergic agonists or cholinesterase inhibitors. In some
cases , either nicotinic or muscarinic antagonists will be injected to determine
the specificity of the effect and the receptor type.
Peripheral neural mechanisms of pain adaptation and of primary and secondary
hyperalgesia are being studied in monkeys and humans. Small increments and
decrements in skin temperature are superimposed on different base temperature
before, during, and after mild skin injury consequent to a single heat
stimulus. Test stimuli are applied either within the area of injury or to a
nearby area. Incremental and decremental detection thresholds will be measured
in both monkey and human subjects, using a two-alternative forced choice
procedure and an escape-tolerance detection task. In addition, human subjects
will make repeated magnitude estimations during the course of evoked pain
sensations. Responses to the same heat stimuli of mechanothermal nociceptive A
and C fibers will be recorded from peripheral nerves of anesthetized monkeys and
of awake human subjects. Objective measures of thermal sensitivity
(e.g. , detection thresholds) in monkeys and humans are being compared with
subjective measures of pain in humans and, in turn, with response sensitivities
of nociceptive A and C fibers in both monkeys and humans during pain adaptation
and during the development of primary and secondary hyperalgesia.
Neural Pathways in Transmission of Pain
Studies of neurochemical neuroanatomy in the brainstem nuclei critical in
nociceptive perception in the spinal cord are being pursued. It has been clearly
demonstrated that serotonergic and enkephalinergic neurons located in the nucleus
raphe magnus of the brainstem project downward into the dorsal horn of the spinal
cord and modulate nociceptive thresholds. Using neuroanatomical techniques the
36 - DIR/NDP
investigators are determining retrograde transport and iramunohistochemical
localization to know which neurons are serotonergic, which are enkephalinergic
and which co-secrete serotonin and enkephalin. They are particularly interested
in the neurochemical coding at the EM level in the cord, and also propose to
define the location of opiate action in the periaqueductal gray by similar
approaches.
Several projects are directed towards mapping the sensory conducting fibers in
the spinal cord, brainstem and other parts of the nervous system. For example,
one investigator is analyzing in detail the afferent and efferent connections of
spinal and brainstem somatosensory systems by sorting processes that occur as
fibers from the dorsal column nuclei (DCN), spinal trigeminal nerve, and lateral
cervical nucleus diverge and reassemble upon entering the diencephalon. This
strategy is providing data on individual neurons with the DCN regarding each
neuron's response properties, its precise location, its shape and size.
Another investigator is continuing his electrophysiological, morphological, and
immunocytochemical studies on spinal cord sensory processing systems. These
studies are designed to refine our knowledge of the small fiber afferent system
in its early stages of processing within the spinal cord. This work is important
for health-related problems because it attempts to establish the synaptic
arrangements associated with pain and related mechanisms. Now that the
signalling of tissue damage and tissue disturbing stimulation is established to
come from specialized sense organs (nociceptors), the central connections of such
neurons take special importance. Understanding both the symptomatology and the
pathophysiology of pain requires understanding of the neural circuitry
involved. From the standpoint of therapy, the synaptic stations and chemical
intermediaries at synapses have a special significance since it is at the points
of synaptic transfer that most potent, neurally-acting drugs produce their
effects. The possibility of selective drug therapy for pain and its disorders
will be greatly enhanced if we understand the pathways and synaptic mechanisms
peculiar to the sensation.
Neurophysiological and Psychophysical Studies of Pain
There has been considerable interest in central mechanisms of pain sensation.
The fact is, however, that pain in the vast majority of cases arises from lesions
outside the central nervous system. These diseases include causalgia, reflex
sjnnpathetic dystrophy, neuromas, chornic degenerative disc disease, nerve
entrapment, and tic douloureaux. Studies of peripheral neural mechanisms are
addressing the question of how and why pain signals are generated in patients.
The ultimate aim of this research is to learn how to prevent the abnormal pain
signals from being generated in the first place. The investigators have laid the
groundwork on mechanisms of cutaneous pain in normal and injured skin. They are
now studying how pain signals are produced in injured nerves. The injuries at
first will consist of nerve transections with and without resuture, and nerve
crush. In this way they are trying to understand how and why neuromas, nerve
crush and nerve regeneration cause pain. They are also attempting to simulate
other types of nerve injury that appear to be associated consistently with
chronic pain. A final objective of this work is to determine the basis for how
electrical stimulation relieves pain. This therapeutic intervention represents
one of the most significant tangible advances in pain therapy of the past
decade. It works well, however, in a small number of patients. Better
37 - DIR/NDP
understanding of how it relieves pain may lead to improvement and wider
utilization of this technique.
NEUROENDOCRINE STUDIES
Currently this program supports 73 projects related to steroid hormones,
neuropeptides and interaction of these endocrine systems with monoamine
neurotransmitters. Most of these projects deal with the identification of
hormone receptors and neurosecretion. Also included are related phenomena such
as synthesis, storage, release, transport, conversion, inactivation, regulation,
and characterization of the neuroendorine peptides in the brain, hypothalamus and
pituitary. Some projects study neuroendocrine functions as related to behavior,
thirst, hunger, body weight regulation, circadian rhythms, stress, temperature
regulation, etc. The total expenditure in this subprogram is $5,561,358.
During the past few years many separate peptide substances have been structurally
identified and shown to be present in significant quantities in the brain.
Almost without exception, the highest concentration of these substances is in the
hypothalamus, with particularly high concentrations in the neurovascular zone of
the median eminence. Several of these peptides have clear functions in relation
to anterior pituitary control; others, although shown to influence hormone
secretion, may function primarily in other regions of the brain related to
sensory conduction, pain mechanisms, and behavioral responses. Receptors for
many of these substances are now being searched for in the brain. Pathways
linking peptidergic systems are currently under investigation using neuro-
anatomical tracing techniques and immunocyto-chemistry.
Occurrence of Neuropeptides
Several projects are investigating the distribution of several biologically
active peptides in the brain, spinal cord, and pituitary gland. The following
peptides are being be studied: Substance P, neurotensin, thyrotropin releasing
factor, gonadotropin releasing factor, somatotropin releasing factor or
somatostatin, melanotropin release inhibiting factor, alpha-melanocyte
stimulating hormone, the opioid peptides: enkephalins and endorphins, etc. The
peptides are being localized with the help of specific antibodies. Thus the
sensitivity and specificity of the immunochemical binding is combined with the
structural resolution of light and electron microscopy. This permits precise
topographical localization and mapping of the peptide-containing cells, pathways
and synaptic contacts in the brain. Most of the peptides to be studied have been
discovered only recently. Initial work indicates their widespread distribution
throughout the body, but especially in the nervous and endocrine systems. They
may function as neurotransmitters, modulators of neurotransmission, regulators of
hormone release from the pituitary gland, or as neurohormones released directly
into the blood stream. In order to conduct meaningful physiological studies with
these peptides, knowledge on their precise cellular and subcellular localization
as well as topographical distribution in the central nervous system will be
essential .
Peptide Receptors
The role of peptides in neurobiological function has received increasing
attention in recent years. It appears that most peptides are distributed widely
38 - DIR/NDP
throughout the brain and act by attachment to peptide receptors to initiate
neurobiological events; these effects result in neurophysiological, biochemical,
and behavioral manifestations. The presence of peptides in the CNS has
stimulated intense interest in uncovering cellular receptors for them. Current
studies are directed at determining whether such receptors exist, the nature of
their localization (i.e., presynaptic, postsynaptic, or in blood vessels),
whether their distribution coincides with that described for the peptide, and
whether more than one type of receptor is present for a given peptide form or
forms. At present, save for the opioid receptors, this field remains in its
infancy. Identification of two types of opiate receptors according to binding
characteristics and by bioassay has occurred in parallel with the demonstration
of multiple types of opiate substances present within the nervous system. These
observations have served to illuminate the diverse physiologic functions of the
endogenous opioids. It appears that there are at least two types of opiate
receptors, called mu and delta. It is likely that mu receptors are involved in
mediating analgesic responses, whereas delta receptors are involved in eliciting
seizure activity and in certain behavioral responses. Endorphin appears to bind
to both types of receptors; the enkephalins bind only to mu receptors. Morphine
binds predominantly to mu receptors, and it has been suggested that dynorphin,
which is vastly more potent, may be the endogenous ligand for the mu receptors.
It has been possible to characterize the differential distribution of delta and
mu opiate-receptor localization within the CNS by autoradiography and with the
light microscopy.
The functional significance of specific prolactin binding sites on ependyma of
the rat choroid plexus is being investigated with emphasis towards a possible
role for prolactin in the regulation of electrolyte balance between blood and
cerebrospinal fluid (CSF). A preliminary electron microscopic autoradiographic
analysis of prolactin movement relative to ependyma cytology indicates initial
binding of prolactin to ependyma plasmalemma within a very short time. These
results suggest that ependjmia may be the final target cells rather than a
component of blood to CSF transport system for prolactin.
Brain cells are protected from the effects of circulating peptides by the brain
endothelial wall, i.e., the blood-brain barrier (BBB). The available evidence
indicates specific transport systems in the BBB, similar in nature to carrier
systems known to transport nutrients and thyroid hormones, do not exist for
peptides. There is evidence, however, that specific receptors for circulating
peptides such as insulin do exist on the luminal side of brain endothelia.
Peptide binding to the BBB may generate the production within endothelia of
second messenger compounds that are released to brain extracellular space. In
this way mechanisms would exist for the rapid modulation of brain cell function
by circulating peptides, without the peptide actually crossing the BBB. Studies
are examining peptide binding and action at the BBB using the isolated cerebral
capillary as the primary model system. Three major areas will be investigated.
The specific binding to isolated capillaries of such peptides as insulin,
enkephalins, vasopressin, somatostatin, angiotensen II, and prolactin are being
studied, and second messengers such as cyclic AMP, cyclic GMP, glycine,
glutamate, aspartate, or GABA will be investigated which affect the peptide-
mediated release of these substances into the brain.
39 - DIR/NDP
Neurotransmitters and Neuropeptide Secretion
Although it is well known that neurotransmitters play a prominent role in the
regulation of hypophyseal hormone secretion, their site of action is unclear.
The neurotransmitter effect may be a direct one with the neurotransmitter itself
stimulating or inhibiting hormonal release from the pituitary gland.
Alternately, its effect may be an indirect one by modulating the release of
specific hypothalamic releasing or inhibiting hormones. Studies are being
conducted to determine the actions of the neurotransmitter dopamine on pituitary
hormone secretion with emphasis on prolactin (PRL) and growth hormone (GH)
release and to ascertain whether hormonal secretion is affected by direct
(peripheral) action on the pituitary gland, by hypothalamic or higher center
actions (central) or by actions at both levels.
There is a great deal of evidence that the biogenic amine, dopamine (DA), affects
pituitary function in the human. This effect is more pronounced on PRL and GH
secretion. DA has recently been shown to also blunt LH secretion in healthy
women and men. An effect on corticotropin (ACTH) and thyrotropin (TSH) in normal
subjects is more subtle, but under extreme endocrinologic perturbations it is
readily apparent.
Peptide Processing and Degradation
The control of neuropeptide activity by specific peptidases both to regulate
production of active fragments from larger precursors and to specifically degrade
the active products is an important central issue in neuropeptide function. A
promising line of investigation of this phenomenon is proposed for purification
of cation-sensitive neutral endopeptidase and partial purification of prolyl
endopeptidase. Both enzymes have been characterized in terms of molecular
weight, cation sensitivity, pH optimum, sensitivity to inhibitors, regional brain
distribution, and peptide bond specificities. Even at this rather early stage of
the work, several possibilities of specific biological functions of these enzymes
have been suggested. Neutral endopeptidase is enkephalinogenic when tested on
alpha-endorphin. Prolyl peptidase cleaves substance P specifically at the single
peptide bond that generates two active fragments (C-terminus is much more
potently bound to synaptic membranes than sub-P itself; N-terminus is a neurite
growth factor). The facts that angiotensin converting enzyme and prolyl
endopeptidase have some overlapping specificity and that angiotensin converting
enzjrme inhibitors given to rats increase brain levels of substance P may indicate
the prolyl endopeptidase does function physiologically to control levels of this
hormone. The studies designed to produce specific endopeptidase inhibitors using
peptide aldehydes may provide both a useful probe of the physiological function
of these enzymes and a new class of neuroactive drugs.
Another study is concerned with the investigation of conversion and inactivation
of peptide hormones. Two separate series of experiments are planned: (l) those
concerned with enzymes involved in conversion as defined by the production of
smaller fragments from precursor materials; and, (2) enzymes involved in the
breakdown and inactivation of active peptides. Several systems will be
studied. In the first, angiotensin(s ) will be studied with respect to the two
enzymes involved in conversion, namely, renin and the angiotensin- 1 converting
enzyme. The second group of polypeptides are the lipotropins. The enzymes
involved in the cleavage of beta-lipotropin to its individual fragments will be
40 - DIR/NDP
investigated. Other experiments will investigate the inactivation of LHRH where
considerable progress for purification of inactivating enzyme has been
achieved. Other studies of a similar type are being conducted with somatostatin
and the opioid peptides. Data obtained will be useful for basic knowledge on the
formation and metabolism of brain hormones, and for developing analogs with
higher potency and longer action which may be important in clinical implication.
Behavioral Responses to Neuropeptides
Learning and Memory
Research on the neurochemical basis of learning and memory has been one of the
major concerns in the neurosciences. The theoretical implications of the
functions of brain peptides in higher processes of the central nervous system is
of considerable interest. Clinical implications of research on neurochemistry of
learning and memory are appreciated when it is realized that there is no adequate
therapy for memory derangements found in clinical neurology and geriatrics.
Vasopressin (VP), a neurohypophyseal hormone, has been implicated in memory
processes of the CNS both in humans and in rats. A large body of data implicates
VP in memory processes for active and passive shock-avoidance tasks. Oxytocin
(OT), another neurohypophyseal hormone, has been shown to have effects opposite
to those of VP on avoidance behavior in normal animals. Indeed, it has been
suggested that OT is an endogenous "amnesic peptide". The alleged effects of VP
on memory processes in normal rats may be unrelated to its endocrine actions
because a VP analog, desglycinamide -lysine-8-vasopressin which has minor
antidiuretic, pressor and adrenocorticotropin (ACTH) releasing activities, has
effects on avoidance behavior similar to those of VP.
Discovery of the Brattleboro strain of rats (HODI ) which exhibits congenital
hypothalamic diabetes insipidus allowed another possible test of the hypothesis
that VP is involved in CNS processes. These rats lack VP in the brain. These
rats are also inferior in acquiring and maintaining active and passive shock-
avoidance behavior when compared with normal heterozygous DI rats. The
behavioral differences could be obliterated by injections of VP into HODI rats.
Studies have found that HODI rats actually show better retention of the aversive
component in an approach-avoidance behavioral task than normal animals. The
interpretation, based on data gathered on HODI rats, that VP is involved in
memory needs a more complete characterization than is presently available.
Feeding Behavior
The central nervous system is known to play an important role in body weight
regulation through its control of behavioral, hormonal, and metabolic events.
Recent studies in animals have implicated several peptides in the regulation of
feeding behavior. CCK, TRH, and insulin are reported to be satiety factors,
decreasing food intake, whereas beta-endorphin has been implicated in states of
increased food ingestion. The site of action of these peptides in affecting
feeding behavior has been presumed to be within the CNS, with controversy over
whether this effect is mediated through the ventromedial hypothalamus;
interaction with the noradrenergic system has been proposed. Suppression of
feeding by CCK has also been reported to be mediated through a parenteral
abdominal site.
41 - DIR/NDP
Another line of investigation suggests that central monoamine system controls the
body weight regulation. These studies are based upon an animal model. In
genetically obese mice in which abnormalities have been uncovered in
catecholaminergic system, the relationship of spontaneously occurring obesity to
monoamine function is being investigated. In the diabetes mouse, reduction of
central norepinephrine levels improves the obesity syndrome. Experiments are
being conducted to explain this phenomenon. And, the question of the effector
mechanisms in the central control of body weight regulation is being examined.
In the most widely studied models of abnormal weight regulation, rats with either
ventromedial or lateral hypothalamic lesions, altered autonomic function is
apparent. Data are accumulating to suggest that a change in the sympathetic
nervous system may be important in weight changes that follow the lesions. These
studies will examine the contribution of central catecholamines to disturbances
in autonomic function related to feeding and body weight.
Cholecystokinin (CCK) peptides are present in brain in high concentrations, and
CCK and its specific receptors have been shown to be localized in such areas as
cortex and hypothalamus. Recent evidence strongly suggests a role for brain CCK
in the control of feeding behavior. CCK, when injected into the cerebral
ventricles of sheep, acts as a highly potent agent in suppressing feeding
behavior. Of real physiological significance is the finding that satiety can be
blocked by injection of CCK antiserum into the CSF. It is hypothesized that CCK
is released in the brain during feeding, possibly secreted into the ventricular
system and transported via CSF, and acts on CNS receptors involved in the
elicitation of satiety. Investigations are being conducted that will determine
rates of release of CCK into CSF during hunger and satiety and determine sites of
release as well as sites of action of brain CCK in causing satiety. Thus, these
experiments will provide additional information necessary to establish the
physiological role of CCK in brain in the control of feeding behavior.
In another study the neuroanatomical organization of areas of the nervous system
are being traced which are responsible for the control of food intake and body
weight regulation. Although it has been known for some time that damage to
certain areas of the hypothalamus can lead to obesity in an otherwise normal
experimental animal, the neuroanatomical organization of these areas, which
include the ventromedial (VMN), arcuate (ARC) and dorsal premammillary (DP)
nuclei, is not well understood. Recent biochemical evidence based on chemical
stimulation and measurement of catecholamine levels has also implicated the
paraventricular nucleus (PVN) and the median eminence (ME). The present series
of experiments are aimed at 1) elucidation of hypothalamic organization in
normal rats and 2) determination of possible anatomical and biochemical
abnormalities in the brains of genetically obese rats. Normal cytoarchitectonic
features as well as neural connections of VMN, ARC, DP, PVN and ME will be
studied. In humans a relationship exists between obesity and certain diseases.
Elucidation of the neuroanatomical pathways involved in the control of food
intake and body weight regulation as well as demonstration of abnormalities in
the brains of genetically obese animals may be of use in therapeutic approaches
to obesity.
Temperature Regulation
Temperature regulation represents a complex interplay of several causative agents
and/or pathological conditions. Circadian temperature cycle may occur as a
42 - DIR/NDP
result of hypothalamic injury (tumors, cysts, etc), imbalance of neuropeptides in
the brain affecting thermoregulatory system, transport of pyrogens in cessation
or induction of fever, hormones and neurotransmiter release, calcium/sodium
imbalance in the hypothalamus, etc.
Hypothalamic lesions produce devastating effects in man. Many of these lesions
are caused by tumors or cysts arising from tissue at the base of the brain or the
floor of the cranial vault and can be successfully treated if detected in time.
The classic signs of hypothalamic injury are useful in making the diagnosis, but
many of them occur late in the history of the injury. In the course of these
studies on fever mechanisms in patients and subhuman primates with neurological
injury, the hypothesis was developed that the disruption of the circadian
temperature cycle may be a useful diagnostic sign of hypothalamic dysfunction.
The plan is proposed to test this idea by observing circadian temperature cycles
in monkeys in which hypothalamic lesions are progressively produced, as an
analogue of the progressive injury that occurs in man. Temperature cycles will
be recorded in patients with known or suspected hypothalamic injury to correlate
the temperature cycles with evidence of central lesions. Information from these
studies may be useful in the diagnosis of hypothalamic disorders.
Previous research on this project has shown that the study of clinical cases of
dysthermia can provide information that is directly useful to the clinician, and
it can serve as a guide to important research problems. Patients are being
studied to learn whether, as described above, circadian temperature cycles are
altered by hypothalamic lesions. Also other patients have been tested with CNS
sarcoid disease, Wernicke's encephalopathy, Frohlich's syndrome, fever of unknown
origin, accidental hypothermia, heatstroke, drug fever, and CNS disorders due to
perinatal anoxia. These studies may provide a great deal of return in terms of
direct applicability of the data to health sciences, and clinical application.
43 - DIR/NDP
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Epilepsy Branch, NDP
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
OVERVIEW 1
GRANT SUPPORTED RESEARCH 3
CONTRACT NARRATIVES
Studies of Toxicology and Selected Pharmacology
of Potential Anticonvulsants 7
NOl NS 0-2327
Early Pharmacologic Evaluation of Anticonvulsant
Drugs 9
NOl NS 0-2335
Progabide in Partial Seizures 10
NOl NS 1-2371
NOl NS 1-2367
Epilepsy Information Transfer 12
NOl NS 80-2341
Comprehensive Epilepsy Program 14
NOl NS 76-2340
NOl NS 76-2341
NOl NS 80-2332
Publication of Epilepsy Abstracts, Volume 14 18
NOl NS 3-2303
Treatment of Infantile Spasms 19
NOl NS 9-2321
Investigation of Pharmacologic Posttraumatic
Epilepsy Prophylaxis 21
NOl NS 2-2313
Study of Experimental Anticonvulsant
Drugs in Primates 23
NOl NS 1-2349
i - EB/NDP
TAB 5. A
RESEARCH PROJECTS
Development of Analytical Methods of Analysis for
Potential Anticonvulsants 25
ZOl NS 02511-02 EB
Inhibition of Microsomal Primidone Metabolism
by Phenytoin 26
ZOl NS 02512-02 EB
HPLC Analysis for ADD 67003 (Progabide) and Its Major
Metabolite in Plasma 27
ZOl NS 02539-01 EB
In Vitro Inhibition of Phenytoin Metabolism by
Carbamazepine 28
ZOl NS 02540-01 EB
TAB 5, A ±1 _ EB/NDP
ANNUAL REPORT
October 1, 1981--September 30, 1982
Epilepsy Branch
Neurological Disorders Program
National Institute of Neurological and Communicative Disorders and Stroke
National Institutes of Health
The Epilepsy Branch committment to the prevention, diagnosis, and treatment of
epilepsy continues as its goal. Through its Antiepileptic Drug Development
Program, the Branch supports drug development in selected areas where there is
minimal commercial interest and where reasonable prospects for successful develop-
ment of effective agents exist. These activities were highly recommended for
continuation by an ad hoc review committee in February 1982. They are supported
by the contract and direct operations mechanism although the Branch proposes to
launch a major new clinical trial (Prevention of Posttraumatic Epilepsy) by the
Cooperative Agreement mechanism. The Branch also intends to broaden the range of
the drug development program by utilization of the grant mechanism.
Several personnel changes occurred among the Epilepsy Branch professional staff
during this year. Lawrence D. Smith, M.S., retired from his position as Pharmacy
Consultant after many years of service with the Branch. This position was filled
by Frank Nice, M.S., who recently completed graduate work at the University of
Arizona. Qu Zhiping, M.D., a WHO Neurosciences Fellow, returned to Shanghai at
the end of the year. He will apply many of the techniques learned at the Branch
in setting up the first intensive monitoring system of epilepsy in China.
Dr. Qu Zhiping will be replaced by Yu Liyun, M.D., also of Shanghai. Also during
the year, Salvatore Piredda, M.D. joined the Branch as a guest worker to study
neurochemical mechanisms of anticonvulsants.
The NINCDS Antiepileptic Drug Development Program has continued to be effective
in interesting pharmaceutical companies to pursue the development of new drugs
for the treatment of seizures. The screening project received nearly 1,000
chemicals to determine possible anticonvulsant activity. These chemicals were
evaluated by its contractor, the University of Utah. Ninety day rat and dog
toxicity studies continued at Southern Research Institute under contract, with
compounds from six firms having been evaluated to date. The first compound
submitted by an academician was also evaluated this year. In continuing a major
effort. Epilepsy Branch staff worked closely witL_ the Contracting Officer, NINCDS,
to utilize a master agreement with task orders for clinical trials of antiepilep-
tic drugs. This support mechanism provides the opportunity to evaluate new drugs
in any of the seizure classifications without the lengthy procedures normally
associated with awarding research contracts. Last year, a task order was awarded
for the pharmacokinetic evaluation of Progabide in addition to two task orders
for the clinical evaluation of this drug in partial seizures. This year, two
task orders were awarded for the clinical evaluation of two new antiepileptic
drugs. This major undertaking in clinical evaluation of a new drug represents
the reinstatement of the clinical thrust of the Antiepileptic Drug Development
Program.
The Epilepsy Branch is involved in a multicenter collaborative study, sponsored
by Hoffmann-La Roche, Inc., designed to evaluate the relative short-term safety
and efficacy of Nitrazepam and ACTH in infantile spasms. This study is intended
to serve as the basis for a New Drug Application designed to make Nitrazepam
1 - EB/NDP
available in the United States for the treatment of this disorder. Also,
Flupirtine, one of the first compounds to be successfully screened through the
Antiepileptic Drug Development Program, is presently under clinical evaluation as
a potential antiepileptic drug at the Clinical Center, NIH.
The pharmacology laboratory of the Epilepsy Branch continues to provide support
for the Antiepileptic Drug Development (ADD) Program and to study the metabolism
of anticonvulsant drugs. The laboratory has developed a method of analysis for
Progabide and its active metabolite by high pressure liquid chromatography (HPLC) .
This method is being used in the Branch's clinical efficacy studies for this
drug. There are also efforts underway in developing new in vivo and in vitro
models for evaluating the pharmacologic activity of new anticonvulsant drugs.
The endogenous receptors, benzodiazepine and GABA, are being investigated as
possible in vitro epilepsy models. The chemical and electrical bonded seizure
model is also being investigated for use in screening potential antiepileptic
drugs. Data derived from these potential models will be correlated with the
results obtained from the standard Maximal Electroshock and subcutaneous Metrazol
epilepsy models. In vitro models are being used in studying both metabolic
pathways and potential drug-drug interactions. Studies examining the interaction
of phenytoin-primidone and phenytoin-carbamazepine are underway using rat micro-
somal enzymes. The rat will be useful in delineating the mechanism of the inter-
actions .
Through many different means, the Epilepsy Branch in FY82 has remained actively
involved in all aspects of epilepsy activities. Contracts have been awarded or
are already ongoing to evaluate antiepileptic drug actions in small animal and
monkey models as well as part of clinical trials involving human volunteers and
patients with epilepsy. Comprehensive Epilepsy Programs have supported applied
research as well as having coordinated research and teaching with health care
services related to persons with all types of epileptic seizures within defined
geographic areas. The Branch is currently aiding in the planning and organizing
of the Epilepsy International Symposium to be held in Washington, D.C. in 1983.
Many national and international visitors participated in exchange of ideas and
concepts with Branch personnel during the year. Also, the Branch has maintained
and broadened relationships during the past year with drug companies to foster
the development of new and novel antiepileptic drugs and also with national and
international epilepsy societies to assist in the dissemination of information on
epilepsy.
EB/NDP
GRANT SUPPORTED RESEARCH
While substantive efforts continue in the development of new antiepileptic
drugs, major advances were made in FY82 in understanding the role of
GABA and the benzodiazepine receptor complex in neuronal activity.
Hopefully, these developments will provide more insights for the treatment
of more than two million Americans suffering from epilepsy.
In FY82, the NDP received 136 applications for research and support of
convulsive and related parxysomal disorders, of which 108 were approved
and 18 funded for a total of $2,488,558. Of the funded applications, 12
were new or supplemental awards for $1,279,656. There are currently 93
active grants totaling $9,943,510.
Four-fifths of the grants supported by the Epilepsy Branch involve basic
research on processes responsible for generation, spread and control of
abnormal discharge in animal tissues. The remaining grants are dedicated
specifically to the study and control of seizures in humans.
Approximately half of the grants have as their primary objective to
understand the basic mechanisms which are responsible for the generation
and spread of epileptiform discharges. A basic question to be answered
is whether the neurons involved in epileptiform discharges are normal
neurons in an abnormal aggregate or if the cells in such an aggregation
which produce epileptiform discharges are themselves abnormal. How
these cells connect and intercommunicate with each other to produce
these discharges is not known. The attention in basic physiology research
is focused on excitatory post-synaptic potentials (EPSP) , which is the
initial event of an epileptiform discharge, and the inhibitory potential
(IPSP) responsible for control of the EPSP. It has been shown that a
normal cell can produce a "burst" or EPSP. Other cells, which have been
shown to be inhibitory, can also produce bursts. Experiments on hippocampal
slices have shown the IPSP, which is an important control mechanism, can
be blocked with agents such as picrotoxin. If this blocked neuron is
then stimulated to produce an EPSP, the impulse is transmitted to the
axon with inhibition. With repeated EPSPs, it has been shown that there
is a change in the shape of the dendritic spike, resulting in a facilitation
of transmission of these impulses to the axons. Other studies have
shown that penicillin works on synapses, blocking the IPSP, producing
synchronous activity of cells.
Single cell physiology is inadequate to explain the spread of an epileptiform
discharge. Investigators are currently studying different pathways for
cellular communication of nervous activity. What makes a combination of
cells, which are apparently normal, act together to produce an abnormal
discharge? There are two aspects to the answer: the number of connections
between the cells and the strengths of coupling between cells. There
are at least four ways that neurons can conduct electrical activity. In
addition to conducting impulses by chemical neurotransmission, cells may
be coupled electroton^cally by so called "gap junctions." In addition, cells
can excite their neighbors by the field potential of apposing membranes.
Finally it is also known that accumulation of extracellular cations,
such as potassium and barium, contribute to synchronization of cell
3 - EB/NDP
activity. Investigators have shown that few cells can be coupled electro-
tonically. This electrotonic coupling exists in both the neocortex and
the CAl region of the hippocampus. Although research indicates that the
number of such connections are relatively small, electrontonic coupling
does contribute to the synchronization process. Further research has
shown that there is a much higher percent of cells electrotonically
coupled in the newborn cortex, indicating that such coupling may be very
important in the development of neuronal activity in the cortex.
Histopathological studies on tissues from epileptic foci show a loss of
dendritic spines, with development of nodules which gradually spread to
other cells. In addition, there is a collapse of the dendrite system
around a single stalk. Other investigators have observed a development
of large nodules around shafts of glia, with glial shortening resulting
in glial scars. In addition, the mossy tufts of neurons in the CA3
region in kindled rats have a strikingly different appearance than in
normal rats. The dendritic shafts from seizure-prone gerbils show fewer
dendritic spines than animals that are not seizure prone. Vascular
changes have been noted in patients with epilepsy whose tissues have
been examined after surgical removal. In up to a third of all tissue,
there have been microaneurysms or some other abnormality in the vascular
tree with extravasation of blood into normal nerve tissue.
Other investigators are attempting to determine the role of astroglia
and their relationship to seizure activity. It is thought by some
observers that astroglia act as a potassium buffer, but this research is
in its early stages. It is known, however, that astroglia swell in the
presence of brain edema and therefore take up water. This function is
mediated by carbonic anhydrase and the sodium-potassium ATP pump. Other
studies on the neurochemistry of epilepsy have shown that in the presence
of seizures, there is an accumulation of glutamate with ammonia intoxication
resulting in a decrease in GABA content, high intracellular potassium,
and C0„ imbalances.
Inhibition of excitatory activity within the neuron is mediated by
chloride permeability. Cells which are principally inhibitory in nature,
the so-called interneurons, have been shown to have higher concentrations
of glutamic acid decarboxylase (GAD) . There are a variety of ways that
inhibitory control can be lost. Investigators have shown that there can
be a decrease in the number of inhibitory cells following injury, hypoxia,
or other insults such as freezing, etc. Other investigators have shown
that GABA S3mthesis can be decreased by biochemical means such as pyridoxine
deficiency and hyperbaric oxygen. GABA release can be diminished by
toxins, and GABA receptors can be inactivated by drugs such as bicuculline,
penicillin, and picrotoxin. Alterations of the chloride gradient, for
example, by replacing chloride with barium, can interfere with the
chloride pump and result in loss of inhibition. Investigators have
shown that in the alumina cream model , the amount of GAD and the number
of GABA releasing terminals in the cortex are significantly reduced.
Other studies have shown that cells with a high GAD content seem particularly
susceptible to injury, hypoxia and necrosis. In a strain of rats susceptible
to seizures when exposed to white noise, it has been shown that GABA
binding is markedly reduced in certain areas of the brain. Also in some
patients it has been noted that there are large decreases in GAD content
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as well as in GAD binding.
Neuropeptides probably play a significant role in the generation or
control of abnormal discharges. For example, somatostatin increases the
excitability of CAl cells in the hippocampus similar to the effect of
glutamate. More often, it has been shown that there is a change in the
pre-synaptic terminals which may be an indirect effect of the hormone.
The peptides arginine-vasopressin and oxytoxin increases cortical excit-
ability and can induce seizures. Arginine-vasopressin in the hippocampus
can evoke increases in excitation of CAl neurons. Clinically, it has
been shown that arginine-vasopressin may be involved in febrile convulsions.
In the presence of enkephalin, IPSPs are diminished considerably and may
be reversed. It appears that the change due to enkephalin is an increase
of incoming potentials. Substance P produces membrane hyperexcitability
causing depolarization and decreasing potassium conductance.
Considerable effort is being made toward understanding the nature and
role of the GABA/benzodiazepine/ionophore receptor complex. This receptor
complex plays an important role in conductance of the inhibitory chloride
ion. GABA, a major inhibitory neurotransmitter, appears to exert its
effects through an increased post-synaptic permeability to chloride
ions. It now appears that there are several well-defined, independent
but interacting binding sites contained in this membrane-bound complex;
a binding site for benzodiazepine-like substances, ionophore binding
sites, a GABA recognition site, and a barbiturate/picrotoxin binding
site. It is postulated that these sites surround the chloride channel
and activate or open the channel to allow an increase in chloride
conductance. A number of drugs and chemicals can bind to each of these
sites, with either agonist or antagonist activity. GABA-related depressants
such as valproic acid, or GABA itself can bind to the GABA site increasing
permeability of the inhibitory chloride ion. GABA related excitants
such as bicuculline, pencillin or strychnine may bind to the GABA site
to prevent chloride conductance. Barbiturates and many related antiepileptic
drugs bind to the receptor complex and enhance GABA activity, while a
number of chemicals, such as picrotoxin, or pentylenetetrazol prevent
barbiturate binding and decrease inhibition.
Other investigators are examining indirect ways to increase GABA content.
Drugs are being designed which will inhibit GABA-transaminase , the
enzyme responsible for degradation of GABA, and drugs which enhance the
activity of GAD, the enzyme responsible for production of GABA.
Other investigators have shown that GABA and benzodiazepines can modify
the flux of calcium ions across cell membranes. Benzodiazepines have
been found to inhibit a Ca -calmodulin stimulated protein kinase in
brain membranes.
The relationship of the benzodiazepine/GABA/ion receptor complex and
anticonvulsant drug mechanism of action is also under active investigation.
Barbiturates increase GABA-mediated inhibition probably by enhancing
GABA binding to the receptor, resulting in a decrease in presynaptic
calcium entry. Phenobarbital thus appears to have a direct GABA -mimetic
action; enhancement of GABA binding by phenobarbital results in an
increase in the mean channel open time, with an increase in current and
5 - EB/NDP
enhanced inhibitory response. At high concentrations, phenobarbital
shortens action potentials due to a decrease in calcium entry resulting
in a decreased transmitter release. Since this effect occurs at
concentrations higher than those required to prevent epileptiform discharges,
this probably represents a sedative/hypnotic action. Phenytoin, on the
other hand, appears to act on repetitive firing of neurons. Studies
indicate that phenytoin acts on the sodium channel, resulting in an
accumulation of sodium channels in the activated (open) state.
A small number of grants is devoted to the study and treatment of epilepsy
in patients. Studies on surgical resection of the temporal lobe in
patients with partial epilepsy continue with emphasis on the development
of criteria for selection of patients and neuropsychological evaluation
of patients following surgery. Two investigators are performing clinical
trials in patients; one in infantile spasms and one in complex partial
seizures. Other researchers are developing new methodology for detection
prevention and treatment of seizures as well as assessment of the effects
of seizures and their treatment on learning and behavior.
The Epilepsy Branch of the Neurological Disorders Program now supports a
growing team of very talented young investigators. This team is composed
of investigators whose aim is the elucidation of the basic mechanism of
initiation of seizure discharges at cellular, tissue and organic levels.
This information is being incorporated by other investigators in the
areas of molecular pharmacology and medicinal chemistry in the design of
exciting new antiepileptic drugs. Clinical investigators play a vital
role with studies in humans which provide for improved patient care as
well as feedback for basic scientists.
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CONTRACT NARRATIVE
Neurological Disorders Program--Epilepsy Branch
October 1, 1981--September 30, 1982
SOUTHERN RESEARCH INSTITUTE (NOl-NS-0-2327)
Title: Studies of Toxicology and Selected Pharmacology of Potential
Anticonvulsants
Contractor's Study Director: Robert G. Meeks , Ph.D.
Contractor's Study Supervisor: Keith Obrosky, Ph.D.
Date Contract Initiated: March 1, 1979
Current Annual Level: $513,000
Objectives :
1) Oral toxicity of candidate anticonvulsant compounds in beagle dogs and rat:
This portion of the toxicity evaluation exposes potential toxicologic effect of
candidate anticonvulsant compounds on a variety of organ systems in the dog
(beagle) and rat. Initial 14 to 28-day studies are to establish a dose-range for
the longer 91-day oral toxicity studies. Changes in body weight and food con-
sumption are presumptive indices for a toxicological effect. A gross necropsy is
performed at the end of study and any remarkable changes in tissues are examined.
Various hematological and biochemical parameters are determined also. The results
of the dose-range finding studies are transmitted to the NINCDS Project Officer
within 21 working days following termination. The 91-day oral toxicity studies
in either rat or dog (beagle) are larger in scope than the dose-range finding
studies. Hematologic, biochemical, and urinary parameters are monitored several
times. Histopathologic examination of tissue is carried out on all animals in
order to evaluate cellular changes. A final written report of all aspects of
these studies is completed within 100 days of completion of the study.
2) Synthesis of additional amounts of candidate compounds: The contractor shall
synthesize and characterize additional amounts of test compounds for the toxicity
studies as directed by the project officer. The number shall not exceed three
per year when funds are available. The synthesis and characterization of the
compounds must meet Good Laboratory Practices (GLP) requirements.
Methods Employed: Over 40 compounds which have completed the early pharmacologic
evaluation of the anticonvulsant drug screening contract have been reviewed by
the Subcommittee on Anticonvulsant Drugs during the last two years. The Com-
mittee has established priorities for the toxicologic evaluation of the com-
pounds. Supplies of several compounds (2-5 kg) were requested from the supplier,
received by NINCDS, and sent to the contractor. A study number was assigned to
each compound and a protocol was written by the contractor describing in detail
each aspect of the study. The contractor must then follow the approved protocol.
Any deviations or changes must be approved by the Project Officer.
Significance to Biomedical Research and the Program of the Institute: The study
data provided by this contract are vital and necessary to advance potential
compounds through the Antiepileptic Drug Development Program in order that they
might be used by patients with epilepsy. During the past year, two 13-week oral
toxicity studies in rats were completed (ADD 40016, ADD 03055). In addition,
three dose-range-finding studies were finished (ADD 40016, ADD 40037, ADD 03046).
7 - EB/NDP
Proposed Course of Contract: Four 13-week oral toxicity studies in rats have
been scheduled (ADD 54001, ADD 03055, ADD 40037, ADD 09004). Two dose-range-
finding studies are contemplated (ADD 17014, ADD 50016). The contract has the
capability of doing two additional 13-week oral toxicity and four to five addi-
tional dose-range finding studies. The third year of the contract ends
February 28, 1983, with a Technical Merit Review scheduled for October 1982.
Publications: None
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CONTRACT NARRATIVE
Neurological Disorders Program--Epilepsy Branch
October 1, 1981--September 30, 1982
UNIVERSITY OF UTAH (NOl-NS-0-2335)
Title: Early Pharmacologic Evaluation of Anticonvulsant Drugs
Contractor's Project Director: Ewart A. Swinyard, Ph.D.
Date Contract Initiated: November 1, 1980
Current Annual Level: $548,000
Objective: To determine the anticonvulsant properties of novel organic compounds
at various levels of testing from preliminary screening to extensive activity and
toxicity profiles.
Methods Employed: Compounds are received by NINCDS from academic and industrial
medicinal chemists and then are sent to the University of Utah for evaluation.
The initial phase of the contract is to test all compounds for anticonvulsant and
neurotoxic activity over a wide dose range. The median effective dose (ED ) and
the median toxic dose (TD -) are determined for those compounds which possess
significant activity in the initial evaluation. These parameters are determined
at time of maximal pharmacologic activity following intraperitoneal administration.
The compounds are evaluated for their ability to raise seizure threshold and/or
prevent seizure spread. The data is analyzed and reviewed by the NINCDS staff
and the results are transmitted to the suppliers of the compounds. Additional
supplies of the most promising candidate compounds are obtained for advanced
testing. A complete profile of acute neurotoxicity in mice following intraperi-
toneal administration of the candidate compound is determined, of which the
median hypnotic dose (HDc--) and median lethal dose (LD ) are included in the
third phase of evaluation. The fourth phase includes the estimation of the
median effective anticonvulsant dose and the median neurotoxic dose following
oral administration. The fifth phase evaluates the median effective dose (ED )
of candidate compounds for the ability to inhibit threshold seizures induced By
bicuculline and picrotoxin and tonic seizures induced by strychnine. Phases 6
and 7 are carried out in rats. In Phase 6, the median effective anticonvulsant
dose (ED^f.) and the median neurotoxic dose (TD^-) are determined following oral
administration. In Phase 7, the minimal lethal dose following chronic administra-
tion (five-day) is established along with its effect on anticonvulsant activity.
The effect of candidate compounds on drug metabolizing has been included into
Phase 7.
Significance to Biomedical Research and the Program of the Institute: This
contract provides for the evaluation of the anticonvulsant activity and antiepi-
leptic potential of new chemical compounds. For the year beginning October 1,
1981, 860 compounds were screened for Phase 1. Sixteen compounds have been
completed through Phase 6 and seven through Phase 7 . This work level exceeds
that specified in the contract.
Proposed Course of Contract: The contract ends October 31, 1983, with a Technical
Merit Review scheduled for summer 1983.
Publications: None
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CONTPACT MPRATIVK
Neurological Disorders Program — Ft)ilepsy Branch
October 1, 1 9B1 —September ''^O, 1 QB?
UNIVERSITY OF MINNESOTA (N01 -NS-1 -2371 ) ; UNIVERSITY OF VIRGINIA
(N01-NS -1-2367)
Title: Progabide in Partial Seizures
Contractors' Projject Directors: University of Minnesota, Robert Gumnit , M.D.
and Ilo Leppik-, ^'.D.
University of Virginia, Fritz F. Dreif uss , M.D.
Date Contracts Initiated: September '^0, 19^1
Current Annual Level; ,*211,000 (University of Minnesota ?1?6,000;
University of Virginia ?^ 85,000)
Objectives; To characterize the efficacy and safety of a new CAEA agonist,
progabide, in the treatment of refractory partial seizures. To confirm the
efficiency of the two-period crossover trial design in testing drug effi-
cacy in partial seizures.
Methods Employed: The main study covered by these contracts is a random-
ized, double-blind, two-period crossover study comparing prof?abide with
placebo when given as an add-on medication to patients with partial
seizures refractory to therapy with two standard drugs, phenytoin and car-
bamazepine. Contracts have been let to two centers in order to recruit
adequate numbers of patients. Methodology includes on-line analyses of
plasma concentrations of the standard antiepileptic drups and the investi-
gational drug and its metabolites. Methodology also includes collection
of individual patient data at each center site on micro-com.-outers with
recording of data on floppy disks programjned in advance at the Epilepsy
Branch. The main study was preceded by a pilot study of four patients at
each of the two centers.
Major Findings: T'he pilot study has been successfully completed. Five of
the initial eight patients have reported some subjective improvement in
their seizure disorder. In some patients, seizures which previously
progressed to full complex partial seizures, vrith decreased levels of
consciousness, now under the effect of the investigational drug appear to
be experienced as sim.ple partial seizures, without impairment of consci-
ousness. Drug toxicity has manifested itself as dizziness and irritability
of mood in approximately half of the patients in the Dilot study. One
patient suffered mild, transient cholestatic jaundice.
10 - EE/NDP
Significance to Biomedical Research and the Program of the Institute;
This study is intended to provide definitive evidence on the therapeutic
potential of a new drug in the treatment of refractory partial seizures,
the most important therapeutic problem in epilepsy. The study is important
as a reinitiation of previous clinical drug efficacy studies, a major
component of the Fpilepsy Branch's Antiepileptic Drus Development Program.
The study is also intended to promote methodological advances in the area
of antiepileptic clinical drug testing.
Proposed Course: Contract is intended to -nrovide for data on ^0 completed
patients by August "^0, 1 Q83 at the University of Minnesota and 30 completed
patients by August 30, 1 QR4 at the University of Virginia. Contracts are
completed as of one month following the date of completion of the final
patient.
Publications: None
11 - EB/NDP
CONTRACT NARRATIVE
Neurological Disorders Program--Epilepsy Branch
October 1, 1981--September 30, 1982
UNIVERSITY OF MINNESOTA (NOl-NS-80-2341)
Title: Epilepsy Information Transfer
Contractor's Project Director: Robert J. Guranit, M.D.
Date Contract Initiated: 9/30/80
Current Annual Level: $208,674
Objectives : The objective of this contract is to transfer information being
generated from the Minnesota Comprehensive Epilepsy Program to all appropriate
audiences. The materials and information being developed for all phases of epi-
lepsy in this research program need to be rapidly transmitted to improve treat-
ment for people with seizures. The contractor is providing support and coordi-
nation to established clinical and laboratory research programs by virtue of
interdisciplinary interchange through methods such as inhouse conferences. The
contractor is training and educating physicians and other professionals in the
newest advances in epilepsy research and treatment in an effort to specifically
increase and quicken the flow of information from clinical research. The con-
tractor is establishing a broad program for public education to help disseminate
the newest advances in epilepsy treatment.
Methods Employed: This project began September 30, 1980. The contractor is
developing, testing, and implementing a broad program for professional education
for the purpose of demonstrating to physicians and other professionals the newest
in advances in epilepsy research and treatment. All types of epilepsy and all
age groups are included. Efforts are being made to develop, implement, and
scientifically evaluate programs to train those who serve patients with seizures.
The contractor is also developing, testing, and implementing a broad program of
public education for the purpose of improving public and patient knowledge about
epilepsy. Efforts are being made to develop, test and implement public education
programs and materials in cooperation with appropriate lay organizations; develop,
test and implement educational programs for the patient; and use methods for
interdisciplinary exchange to provide support and coordination to established
clinical and laboratory research programs.
Significance to Biomedical Research and the Program of the Institute: This
program is designed to rapidly transfer information being developed from all
phases of epilepsy research to individuals delivering health care services and to
individuals and families of those with epilepsy. In addition, this contractor
can obtain feedback information from individuals delivering health services and
from consumers which may point the way to future areas of research.
Proposed Course of Contract: This project will continue until September 29,
1983.
12 - EB/NDP
Publications:
Gates JH, Whalen SM: Epilepsy and sports participation. Inst Athletic Med,
Sideline View 3(3):l-4, 1981.
Gumnit RG (Ed): Epilepsy. A Handbook for Physicians. Fourth Edition.
University of Minnesota Press, Minneapolis, 1981, 64 pp.
Sells MA (Ed): Epilepsy: A Guide to Services . University of Minnesota Press,
Minneapolis, 1982, 76 pp.
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CONTRACT NARRATIVE
Neurological Disorders Prograin--Epilepsy Branch
October 1, 1981--September 30, 1982
Contractor
MED COLL GEORGIA
(NOl-NS-76-2340)
UNIV OF WASHINGTON
(NOl-NS-76-2341)
UCLA
(NOl-NS-80-2332)
Title
Initiation
Date
Comprehensive 6/30/76
Epilepsy Program
Project Director
D. Smith, M.D
Comprehensive 6/30/76 A. Ward, Jr., M.D.
Epilepsy Program
Annual
Level
$1,198,712
1,140,764
Comprehensive 6/30/80
Epilepsy Program
A. Delgado-Escueta, M.D. 1,267,580
Objectives: The objective of the Comprehensive Epilepsy Program is to facilitate
applied research and to coordinate research and teaching with health care ser-
vices related to persons with all types of epileptic seizures within a defined
geographic area.
Methods Employed: Each contractor is conducting clinical and laboratory research
in the diagnosis, treatment, prognosis and prevention of epilepsy. Each contrac-
tor is demonstrating to physicians and other professionals the newest advances in
epilepsy research and treatment and is establishing a broad program for public
education. In addition, each contractor is establishing the required procedures
to assure, in a research setting, the availability to the person with epilepsy of
complete and up-to-date preventive medical and rehabilitative psychological,
vocational, educational, and social services.
Major Findings: All of the contractors showed evidence for the feasibility of
establishing a program in their geographic area by a detailed description of
clinical research capability, health care delivery capabilities, rehabilitation
resources, etc., for the person with epilepsy. Clinical research projects encom-
pass etiology, epidemiology, diagnosis, and treatment of epilepsy conducted in a
multidisciplinary setting.
Significance to Biomedical Research and the Program of the Institute: Epilepsy
is a significant national health problem. Despite recent advances, much remains
to be learned about the causes and mechanisms of seizures in order to more effec-
tively prevent, diagnose, and treat patients with seizures. These contracts are
designed to increase the understanding of epilepsy by developing improved tech-
niques for prevention, diagnosis, and treatment with the ultimate aim of substan-
tially reducing the number of people who suffer from epilepsy and of controlling
seizures to ameliorate their impact so that affected individuals may attain as
much as possible a normal life. These studies, by studying an abnormal brain,
may provide new insights into the normal functioning of the brain and may provide
clues as to why the brain functions abnormally.
Proposed Course of Contract: Contracts NOl-NS-76-2340 and NOl-NS-76-2341 are
scheduled to expire on 6/30/82. Contract NOl-NS-80-2332 will undergo peer review
during FY 83.
14 - EB/NDP
Publications:
MEDICAL COLLEGE OF GEORGIA
Aly MI, Abdel-Latif AA: Studies on the effects of Acetylcholine and antiepileptic
drugs on P, incorporation into phospholipids of rat brain synaptosomes .
Neurochem Res 7:155-165, 1982.
Green JB, Walcoff M, Lucke JF: Phenytoin prolongs far-field somatosensory and
auditory evoked potential interpeak latencies. Neurology (N.Y.) 32:85-88, 1982.
King DW, Gallagher BB, Murvin AJ, Smith DB, Marcus DJ, Hartlage LC, Ward LC III:
Pseudoseizures: diagnostic evaluation. Neurology (N.Y.) 32:18-23, 1982.
Nosek TM: Depression of axonal excitability by valproate is antagonized by
phenytoin. Epilepsia 22:641-650, 1981.
Nosek TM: How valproate and phenytoin affect the ionic conductances and active
transport characteristics of the crayfish giant axon. Epilepsia 22:651-665,
1981.
Swift TR, Gross JA, Ward LC, Crout BO: Peripheral neuropathy in an epileptic
population. Neurology (N.Y.) 31:826-831, 1981.
UNIVERSITY OF WASHINGTON
Bowdle TA, Patel IH, Levy RH, Wilensky AJ: The influence of free fatty acids on
valproic acid plasma protein binding during fasting in normal humans. Eur J Clin
Pharmacol (in press).
Dodrill CB: Psychological assessment in epilepsy. In: Sands H (Ed), Epilepsy.
A Handbook for the Mental Health Professional. New York: Brunner/Mazel, 1982,
pp 111-132.
Dodrill CB: Psychosocial characteristics of epileptic patients. In: Ward AA Jr
(Ed), Proceedings of the ARNMD. New York, Raven Press (in press).
Eraser RT: Rehabilitation strategies for serving the client with epilepsy. In:
Dam M, Gram L, Penry JK (Eds), Advances in Epileptology: Xllth Epilepsy
International Symposium. New York: Raven Press, 1981, pp 229-235.
Eraser RT: Epilepsy. In: Pan E, Backer T, Vash C (Eds), Annual Review of
Rehabilitation. New York: Springer, 1981, pp 147-172.
Eraser RT, Smith WR: Adjustment to daily living. In: Sands H (Ed), Epilepsy.
A Handbook for the Mental Health Professional. New York: Brunner/Mazel, 1982,
pp 189-221.
Hermann B, Dikmen S, Schwartz MS, Karnes WE: Interictal psychopathology in
patients with ictal fear: A quantitative investigation. Neurology 32:7-11,
1982.
Hermann BP, Dikmen S, Wilensky AJ: Increased psychopathology associated with
multiple seizure types: fact or artificial? Epilepsia (in press).
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Lovely MP, Ozuna J: Status epilepticus. In: Nikas D (Ed), Continuing Issues in
Critical Care Nursing. New York: Churchill Livingstone (in press).
Ozuna J: Compliance with therapeutic regimens: Issues, answers, and research
questions. J Neurosurg Nurs 13:1-6, 1981.
Ozuna J, Hawken M: Learning needs of the epilepsy patient. In: Van Meter M
(Ed), Neurologic Care: A Guide for Patient Education. Appleton-Century , 1982,
pp 133-151.
Ozuna J: Nursing role in management of chronic neurological disorders. In:
Lewis S, Palmer P, Collier D (Eds), Medical-Surgical Nursing: Assessment and
Management of Clinical Problems. McGraw Hill, (in press).
Ozuna J: Assessment related to the neurological system. In: Lewis S, Palmer P,
Collier D (Eds), Medical-Surgical Nursing: Assessment and Management of Clinical
Problems. Place: McGraw Hill, (in press).
Patel IH, Venkataramanan R, Levy RH, Viswanathan CT, Ojemann LM: Diurnal
oscillations in plasma protein binding of valproic acid. Epilepsia (in press).
Wilensky AJ, Friel PN, Levy RH, Comfort CP, Kaluzny SP: Phenobarbital kinetics
in normal subjects and epileptic patients. Eur J Clin Pharmacol (in press).
UCLA
Cereghino JJ: Why Comprehensive Epilepsy Programs? Urban Health 11:30-33, 45,
1982.
Cornford E, Braun L, Oldendorf W: Developmental modulations of blood-brain-
barrier permeability as an indicator of changing nutritional requirements in the
brain. Pediatr Res 16:324-328, 1982.
Cornford E, Crane P, Braun L, Bocash W, Nyerges A, Oldendorf W: Reduction in
brain glucose utilization rate after tryptophol (3-indole ethanol) treatment.
J Neurochem 36:1758-1765, 1981.
Cornford E, Braun L, Oldendorf W, Hill M: Comparison of lipid mediated blood-
brain-barrier penetrability in neonates and adults. Am J Physiol (in press).
Goldberg MA: Pharmacologic strategies in the treatment of epilepsy. Semin
Neurol 1:81-86, 1981.
Greenberg D, Lange K: A maximum likelihood test of the 2-locus model in Coeliac
Disease. Am J Med Genet (in press).
Greenberg D, Hodge S, Rotter J: Evidence for recessive and against dominant
inheritance at the HLA "linked" locus in Coeliac Disease. Am J Hum Genet (in
press) .
Hsu A, Byrd S: Diagnosis and management of epilepsy. Urban Health 11:34-37,
1982.
16 - EB/NDP
Lund G, Mittan R: The urban epilepsy program at King/Drew Medical Center. Urban
Health 11:28-29, 1982.
Mclntyre HB, Goldberg AS: The knowledgeable use of the EEG in seizure disorders.
Semin Neurol 1:77-80, 1981.
Mittan R, Locke G: The other half of epilepsy: psychological problems. Urban
Health 11:38-40, 1982.
Nuwer MR: Indications for surgical treatment of epilepsy. Semin Neurol 1:103-
109, 1981.
Shields WD, Lubens P: Seizures in childhood. Semin Neurol 1:95-102, 1981.
Walter RD: Evaluation of the patient with a suspected seizure disorder. Semin
Neurol 1:61-64, 1981.
Wasterlain CG: Status epilepticus. Semin Neurol 1:87-94, 1981.
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CONTRACT NARRATIVE
Neurological Disorders Program--Epilepsy Branch
October 1, 1981--September 30, 1982
EXCERPTA MEDICA FOUNDATION (NOl-NS-3-2303)
Title: Publication of Epilepsy Abstracts , Volume 14
Contractor's Project Director: Pierre Vinken, M.D.
Date Contract Initiated: December 15, 1972
Current Annual Level: $55,000
Objectives: To scan serial publications and periodicals from approximately 3500
world biomedical journals and select appropriate articles to be included in
Epilepsy Abstracts in accordance with the guidance of the Project Officer and his
editorial advisors; prepare abstracts with appropriate translations into English
from foreign languages; classify, index, and store the abstracts in a computer-
retrievable form; and produce a 9-tract, 1600 bpi computer tape for use at NIH.
The text is automatically set by computer-operated photocomposition. The Excerpta
Medica Foundation produces camera-ready copy for each monthly issue of Epilepsy
Abstracts , which includes an index of subjects and authors, and prints and distri-
butes the journal monthly with a cumulative index at the end of the volume. In
order to pay for the production of the camera-ready copy, printing, and distribu-
tion, the Excerpta Medica Foundation sells subscriptions to recover these costs.
Methods Employed: Subscriptions to Epilepsy Abstracts , each at annual cost of
$77.00, have been acquired from interested persons by Excerpta Medica. Computer
tapes were delivered to NIH bimonthly in accordance with the contract. These
tapes comprise the EPILEPSYLINE data base retrievable throughout the country from
B.R.S., Inc.
Proposed Course of Contract: The current contract expired in February 1982.
Efforts are underway to secure another contract to insure the maintenance of the
publication of Epilepsy Abstracts.
Publications: None
18 - EB/NDP
COr':"PACT NAPP.ATIVF
Neurological Disorders Vvoeram — 'Epilepsy Branch
October 1, 19*^1 --^epteinber '^0, IPf?
THE T^THODIST H05PTIAL (HOUSTON) - (N01 -NS-q-2?21 )
Title: Treatment of Infantile Spasms
Contractor's Project Director: Peter Kellaway, Ph.D.
Date Contract Initiated: September ^0, 1 OTP
Current Annual Level: ?24,66o
Objectives; To conduct a double-blind controlled crossover evaluation of
corticotropin and prednisone in 25 patients with infantile spasms.
Children who fail to respond to either treatment will be administered
clonazepam in an ODen trial. Precise quantitation methods were developed
in a predecessor contract.
Methods Employed: A request for proposals was issued in FYVQ gnd resulted
in the avrard of the present three year contract to The T'^ethodist HosDital.
After appropriate testine of the nlacebos, of corticotronin and nrednisone,
patients were admitted to this double-blind, two-period crossover trial.
This clinical evaluation is a response-conditional crossover trial, i.e.,
patients who have ^00'r reduction in seizure frequency during the first
treatment period are not crossed over to the alternative therapy.
Major Findings: Under the present contract the comparative efficacy of
corticotropin and prednisone in infantile spasms vras studied. As of this
date, 20 patients have entered into the study; 1^ patients have completed
the protocol, 4 patients are currently in som.e phase of the protocol. One
hundred and three (10'^) twenty-four hour monitoring sessions have been
completed. In addition, eight infants have been monitored who did not
prove to have spasms. Four patients responded to the initial drug, five
patients responded to the crossover drug, and four did not respond to
either treatment. Four patients entered the open clonazepam, trial, none of
whom responded. Five patients developed hypertension, a common side effect
of corticotropin. One patient developed continuous herpes. All patients
will com^plete the study by July 1 9B2 . A comparison of the three
drugs — corticotropin, prednisone, and in failures, clonazepam — may be made
when the study is ujiblinded and completed in July 19B2.
Significance to Biomedical Research and the Program of the Institute:
This contract will end with the completion of the 25 patients in July IPP?.
At this time, a definitive clinical statement can be made about the
relative efficacy of corticotropin and prednisone in this severe disorder.
The methodology employed to evaluate the treatment of infantile spasms
(video recordings, F^G, and accellerometry) were adapted -^or use in another
19 - EB/NDP
multi-center trial. Hoffman-La Roche Inc. is sijpr)ortin/' a clinical
evaluation of nitrazepam in infantile spasms. Dr. Kellaway is serving as a
consultant to that study; the Epilepsy Branch is cooperating in protocol
development, data interpretation and analysis.
Proposed Course of Contract; The contract will end with the comnletion of
25 patients in July 19B2.
Puhlication; Hrachovy, R.A., Frost, J.D., Jr., Kellaway, P., Zion, "". , A
controlled study of ACTH therapy in infantile spasms. Epilepsia
21:631-6^6, IQ'^^O.
20 - EB/NDP
CONTPACT i^TARPATTVT^
Neurological Disorders Program — f^-Dilepsy Branch
October 1, 1 9P1 —September '^O, 1 9P2
UNIVERSITY OF KANSAS MEDICAL CENTER (N01 -NS-2-231 •^)
Title: Investigation of Pharmacologic Posttrauinatic ^pileDsy Prophylaxis
Contractor's Project Director: Charles E. Prackett, M.D.
Date Contract Initiated: June 28, 1972
Current Annual Level; ?;^B,000
Objectives; The main objective of the study was to determine the
effectiveness of therapeutic treatment with phenytoin and phenobarbital in
persons who suffer severe head injury and are thus liable to posttraumatic
epilepsy. This study was preceded by a pilot study with prophylactic
doses. The patients admitted to the severely injured protocol are being
followed for an additional 18 months to provide information about the
occurrence of "late" seizures.
Methods Employed: The current double-blind controlled clinical trial
com.pared therapeutic doses of phenobarbital and phenytoin versus placebo.
Patients were randomly assigned to either treatment group in each of two
strata. The first stratum consisted of severe closed head injuries and the
second consisted of severe dural penetrating injuries.
Major Findings: In the completed pilot study, 125 patients were
accessioned to the protocol in which either phenobarbital, 60 ms, and
phenytoin, 200 mg, or placebo were given to head injured patients daily for
IB months. These patients were then followed an additional 18 months.
Eleven patients experienced seizures while on the study and four had
seizures after completion of drug therapy. No significant difference in
seizure incidence was found between the active and placebo groups on the
low drug doses used.
The pilot study results led to the second phase of the contract work.
Forty-nine patients were accessioned to the revised protocol in which
patients random.ized to active drug received higher, individualized
therapeutic doses of phenytoin and phenobarbital for six months.
Therapeutic range was achieved and maintained by freauent blood level
analysis and dose adjustment. These patients were then followed an
additional 12 months for seizure frequency. Ten patients experienced
seizures while on the study (two, active; and eight, placebo). Analysis of
the 4P patients in this series indicates that those patients with phenytoin
and phenobarbital in therapeutic doses had a significantly lower incidence
of posttraumatic epilepsy than those patients on placebo for the period of
treatment.
21 - EB/NDP
Significance to Biomedical Pesearch and the Program of the Institute:
Using a conservative five percent incidence rate of posttraumatic epilepsy,
the at-risk population of 500,000 serious injuries annually yields an
annual incidence of posttraumatic epilepsy of 25,000 in the United States
due to iTi.otor vehicle accidents alone. The Commission for the Control of
Epilepsy and Its Consequences reported approximately !'^5,000 per person as a
conservative but reasonable figure for the average cost to society and to
the patient with epilepsy. Multiplying this by the annual incidence of
posttraumatic epilepsy ('25,000), an estimated ??1 25 ,000,000 annually could
be saved by the elimination of posttraumatic epilepsy subsequent to motor
vehicle accidents alone. More importantly, the prevention of posttraumatic
epilepsy in adults can relieve these individuals from the tremendous
social, psychological as well as medical, burdens associated with the
acquisition of a seizure disorder.
Proposed Course of Contract: The result of the pilot study and the
treatment period are in publication. Because of the very protracted neriod
of time during which posttraumatic epilepsy may occur, and the highly
variable incidence of seizures occurring with the different types of
severely head injured, the patients in the Phase II study are being
followed for an additional 18 months. This follow-up will end in FY82.
This additional information will provide for the collection of sufficient
data to allow for inferences to be made regarding the occurrence of "late"
seizures.
Publications; (l) Penry, J.K. , Vlhite , B.C., Brackett, C.F., A controlled
prospective study of the pharmacologic prophylaxis of posttraumatic
epilepsy (abstract). 'fJeurology (nj) ?O:fi00-601 , 1970.
(2) White, E.G., Pharmacological prophylaxis of posttraumatic epilepsy
reconsidered. Epilepsia (in publication).
(?) White, B.C., Penry, J.K., Brackett, C.E., et al. Pharmacological
prophylaxis of posttraumatic epilepsy. Prophylatic and therapeutic doses.
Epilepsia (in publication).
22 - EB/NDP
CONTRACT NARRATIVE
Neurological Disorders Program — Epilepsy Branch
October 1, 1981 September 30, 1982
UNIVERSITY OF WASHINGTON (NOl-NS- 1-2349)
Title: Study of Experimental Anticonvulsant Drugs in Primates
Contractor's Project Director: Joan S. Lockard, Ph.D.
Date of Contract Initiated: February 16, 1981
Current Annual Level: $548,000
Objectives: To evaluate the anticonvulsant efficacy of drugs in primates
with chronic partial seizures. Seizure frequency and behavioral toxicity
are compared with drug dosage and drug blood concentration. Metabolic
and pharmacokinetic studies are conducted prior to efficacy determination.
Methods Employed: A request for proposals was issued in FY80 and resulted
in the award of the present three-year contract to the University of
Washington. A series of studies were performed or being performed during
the present year. These were assay and pharmacokinetic studies, efficacy
studies, and metabolic studies involving three anticonvulsants. The
results will provide the scientific basis for decisions regarding appropriate
clinical trials.
Major Findings: Under the present contract the efficacy of progabide
and pharmacokinetics of stiripentol were studied. Progabide seems to
reduce seizure frequency by a small to moderate amount in the majority
of animals. There is evidence of reduced seizure rates for considerable
time after its withdrawal although this may be more related to the
method of administration. The bioavailability of stiripentol appears to
be limited by an extensive first pass effect. Kinetic behavior presents
a prolonged terminal distribution phase. The drug is eliminated mostly
by biotransformation with one-third of the dose found in the urine as a
glucuronide.
Significance to Biomedical Research and the Program of the Institute:
The availability of this model for selected drug candidates provides the
potential scientific basis for decisions regarding appropriate clinical
trials, thus conserving both time and funds as new drugs are developed.
Such studies serve as an incentive to the pharmaceutical industry in
developing new drugs.
Proposed Course of Contract: A change in the projected research includes
the development of a model to evaluate the efficacy of a delivery system
for insoluble, short half-life drugs. The development of such a model
would expand the types of drugs that could be studied. The contract
expires January 15, 1984, with a Technical Merit Review scheduled for
July 1983.
23 - EB/NDP
Publications:
Lane EA, Levy RH: Metabolite to parent drug concentration ratio as a function
of parent drug extraction ratio: cases of nonportal route of administration.
J Pharmacoklnet Biopharm 9(4): 489-496, 1981.
Patel IH, Levy RH: Intramuscular absorption of carbamazepine in rhesus monkeys.
Epilepsia 21(1): 103-109, 1980.
Patel IH, Levy RH, Neal JM, Traser, WF: Simultaneous analysis of phenobarbital
and p-hydroxyphenobarbital in biological fluids by GLC-chemical-ionization mass
spectrometry. J Pharm Sci 69(10) : 1218-1219, 1980.
Pastel IH, Wedlund P, Levy RH: Induction effect of phenobarbital on the carba-
mazepine to carbamazepine - 10, 11 - eposide pathway in rhesus monkeys.
J Pharmacol Exp Ther 217(3): 555-558.
Stella VJ, Yamaoka K, Levy RH: An added complication in the estimation of
apparent hepatic blood flow in vivo by pharmacokinetic parameters.
Drug Metab Dispos 9(2): 172-173, 1981.
Viswanathan CT, Levy RH: Plasma protein binding interaction between valproic
and salicylic acids in rhesus monkeys. J Pharm Sci 70(11): 1279-1281, 1981.
24 - EB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRADURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02511-02 EB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development of Analytical Methods of Analysis for Potential Anticonvulsants
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Harvey J. Kupferberg
Others: Wayne Yonekawa
Jill Shaw
Pharmacologist
EB NDP NINCDS
Pharmacologist EB NDP NINCDS
Medical Technician EB NDP NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Epilepsy Branch, NDP, NINCDS
SECTION
INSTITUTE AND LOCATION
NTNCnS, NTH, Re.thesda, , MP 20205
TOTAL MANYEARS:
0.7
PROFESSIONAL:
0.5
OTHER:
0.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
£] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Analytical methods for the quantitation of drugs are needed for the various
phases of drug development. These methods must have specificity and sensitivity
to quantitate drugs in dosage forms of the toxicology study, and in body fluids
for human pharmacokinetic and efficacy studies. Chromatographic methods are
most useful for this purpose. Drugs are extracted. The physical and chemical
characteristics of each compound is evaluated in order to determine the suitable
chromatography and detection. Volatile compounds are subjected to gas-liquid
chromatography (GLC) . Polar compounds are quantitated by high pressure liquid
chromatography (HPLC) . Extraction procedures for a variety of compounds were
developed using a preferential solvents systems theory. The final methods were
found to be suitable for a variety of both animals and humans.
25 - EB/NDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02512-02 EB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Inhibition of Microsomal Primidone Metabolism by Phenytoin
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Maria G. Porro
Others: Harvey J. Kupferberg
Pharmacologist
Pharmacologist
EB NDP NINCDS
EB NDP NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Epilepsy Branch, NDP, NINCDS
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
0.5
PROFESSIONAL:
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
£] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Phenytoin has been reported to cause an elevation of plasma phenobarbital in
epileptic patients. Phenytoin has been shown in patients to 1) stimulate the
metabolism of primidone to phenobarbital and 2) inhibit the hydroxylation of
phenobarbital. The concomitant rise in phenobarbital levels can cause sedation
in epileptic patients. The use of an in vitro system of hepatic microsomes can
be of benefit in elucidating the mechanism of this drug-drug interaction. Micro
somes will be obtained from adult male phenobarbital-treated Holtzman rats. The
rate of phenobarbital production from primidone and the hydroxylation of pheno-
barbital will be followed at 37°C in a NADPH and NADP system. The Michaelis
constant (K ) Maximal Velocity (V ) will be determined for the conversion of
primidone to phenobarbital and for the conversion of phenobarbital to hydroxy-
phenobarbital. The inhibition constant (K ) will be determined for phenytoin in
this system.
26 - EB/NDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02539-01 EB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
HPLC Analysis for ADD 67003 (Progabide) and Its Major Metabolite in Plasma
of Epileptic Patients
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Wayne Yonekawa
Others: Harvey J. Kupferberg
Pharmacologist
Pharmacologist
EB NDP NINCDS
EB NDP NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Epilepsy Branch, NDP, NINCDS
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
0.75
PROFESSIONAL:
0.75
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Progabide (ADD 67003) has been shown to be an effective anticonvulsant in
various animal models of epilepsy. It is metabolized to 4-[ (4-chlorophenyl) (5-
fluoro-2-hydroxy phenyl)methylene] butanoic acid. This acid metabolite has
anticonvulsant activity similar to that of Progabide. Progabide is now under-
going a NINCDS-sponsored clinical efficacy trial. Plasma level measurements of
both parent drug and active metabolite are an integral part of these studies.
A high pressure liquid chromatographic (HPLC) method has been developed that is
sensitive enough to simultaneously quantitate both drug and metabolite in plasma
of epileptic patients receiving orally administered drug. This method uses an
electrochemical detector for specificity and sensitivity. Both drug and meta-
bolite can be quantitated to levels of 10 ng/ml of plasma and the assay is
presently being used in the NINCDS clinical studies.
27 - EB/NDP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02540-01 EB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
In Vitro Inhibition of Phenytoin Metabolism by Carbamazepine
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Harvey J. Kupferberg
Others: Wayne Yonekawa
Pharmacologist
Pharmacologist
EB NDP NINCDS
EB NDP NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Epilepsy Branch, NDP, NINCDS
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
0.25
PROFESSIONAL:
0.25
OTHER:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
Q (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Carbamazepine has been shown to increase plasma phenytoin levels in epileptic
patients receiving both drugs. The rise in phenytoin plasma levels can lead to
nystagmus, sedation, and other central nervous system side effects. The use of
an in vitro system of hepatic microsomes can be used in elucidating the biochemi--
cal mechanism of this drug interaction. Microsomes will be obtained from rats,
mice, and rabbits. The Michaelis-Menton (K ) and maximal velocity (V ) will
be determined for each species by following the rate of formation of HFPH, the
major metabolite of phenytoin. This enzymatic process will be followed at 37°C
in a NADPH-NADP system. The species which appears to have a similar K , V anc|
metabolic profile to humans will be used for this study. The type of inhibition
(competitive, noncompetitive) and the inhibition constant (K ) for carbamazepine
will then be determined.
28 - EB/NDP
PHS-6040
(Rev. 2-81)
dd
a
m
<
m
o
l—
o
en
-<
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Developmental Neurology Branch, NOP
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
^ ■
RESEARCH SUMMARY
I. Overview 1
II. Reye's Syndrome Initiative 1
III. Section Reports 2
IV. Additional Activities 7
CONTRACT NARRATIVES
Behavioral and Cognitive Side Effects of Phenobarbital
Used for Prevention of Febrile Seizure Recurrence
NOl NS 2-2395 8
Combined Neuropathologic and Epidemiologic Study
NOl NS 3-2312 9
Physical Growth Analysis
NOl NS 5-2308 10
Analysis of General and Placental Pathology Data
NOl NS 7^2376 ]2
A Prospective Cohort Epidemiologic Study of Learning
Handicaps in Children Attending School
NOl NS 7-2377 ]3
Comprehensive Study of Labor and Delivery Effects
on Offspring
NOl NS 8-2381 14
RESEARCH PROJECTS
Convulsive Disorders Data Analysis Group
ZOl NS 02058-10 DNB 16
Cerebral Palsy Data Analysis Group
ZOl NS 02059-10 DNB 17
BirthweightTrGestational Age
ZOl NS 02060-10 DNB 18
i - DNB/NDP TAB 5.B
Table of Contents (cont'd)
Minimal Brain Dysfunction
ZOl NS 02062-10 DNB 19
Developmental Factors Associated with Mental
Retardation
ZOl NS 02106-09 DNii 20
The Study of Visual Abnormalities in the NINCDS
Collaborative Perinatal Project
ZOl NS 02107-09 DNB 21
Developmental Factors Associated with Learning Disorders
ZOl NS 02108-09 DNB 22
Comprehensive Analysis of the NCPP Data on Congenital
Malformations
ZOl NS 02109-09 DNB 23
Neonatal Hyperbilirubinemia
ZOl NS 02112-09 DNB
Compendium of Heritable Disorders of the
Nervous System
ZOl NS 02171-08 DNB
24
Obstetrical Medication and Development in Infancy
and Early Childhood
ZOl NS 02169-08 DNB 25
26
Febrile Seizures Study
ZOl NS 02234-07 DNB 27
Analysis of NCPP Twin Data
ZOl NS 02332-05 DNB 28
TAB 5.B ii - DNB/NDP
ANNUAL REPORT
For Period October 1, 1981 through September 30, 1982
Developmental Neurology Branch, Neurological Disorders Program
National Institute of Neurological and Communicative
Disorders and Stroke
National Institutes of Health
GENERAL SUMMARY
OVERVIEW
The Developmental Neurology Branch (DNB) develops and implements a pro-
gram of research on the neurobiological aspects of the developmental
disorders of children including cerebral palsy and other motor disorders,
autism and behavioral disorders, mental retardation and learning disorders,
and central nervous system birth defects and genetic disorders. The DNB is
formally organized into sections which correspond to these four subprogram
areas. During this year the DNB administered about 195 grants classified as
Disorders of Early Life, a major disorder category within the extramural
grant program.
New initiatives through program announcements have been issued by the DNB
in Reye's sjmdrome, neonatal brain disorders, neural tube defects, and neuro-
physiology of learning disorders. A new contract study designed to measure
the possible effects of phenobarbital therapy on the cognitive and neuro-
logical status of the treated child who has experienced febrile seizures
has been awarded.
The DNB has continued a major effort during this fiscal year to meet the
objectives of the Comprehensive Plan for Analysis and Interpretation of
NINCDS Collaborative Perinatal Project (NCPP) Data. A major area of the
Comprehensive Plan was completed during the year: a book dealing with
neuropathology is in press. Also, during the year a total of 53 papers
were published or are in press; these papers are cited in the body of the
report. As the NINCDS will soon complete its use of the Collaborative
Perinatal Project data, an RFP has been issued which requests proposals
for the production of a "Users Guide" to the NCPP data to facilitate the
long-term management of the microfilm and computer tape files as a national
data resource by the National Archives. The awarding of this contract is
anticipated in this fiscal year.
Other activities of the DNB include primary responsibility for administer-
ing the Privacy Act within the NINCDS and conducting reviews of NINCDS re-
search contract proposals to assure the protection of human subjects.
REYE'S SYNDROME INITIATIVE
A program announcement on Reye's syndrome was sponsored by NINCDS and pub-
lished on May 16, 1980 which requested individual and program project
1 - DNB/NDP
research grant applications. This program announcement was cosponsored by
three other Institutes. There have been six grants funded by NINCDS under
this program announcement. One, a large program project, is investigating
in Reye's syndrome cerebral circulation, metabolism, and electrophysiology;
cerebral ammonia metabolism; lipid metabolism and hepatic energy states;
virologic and immunologic problems; and developing an animal model. Other
new grants are investigating metabolic coma and cerebral energy metabolism,
mitochrondial function, metabolic patterns during disease; and muscle
metabolism after recovery.
The DNB served as the focal point within the NINCDS in the planning of a
Consensus Development Conference on the Diagnosis and Treatment of Reye's
Syndrome which was held on March 2-4, 1981. The Consensus Conference
focused on the criteria for diagnosis and on the treatments in use, with
particular attention to the treatment of the syndrome as a function of the
severity of the syndrome. The Consensus Statement was published in the
Journal of the American Medical Association, November 27, 1981.
III. SECTION REPORTS
Section on Cerebral Palsy and other Motor Disorders
A program announcement was published on January 2, 1981 which requested
program project grant applications on clinical research on neonatal
brain disorders focusing on the pathogenesis, diagnosis, treatment, and
outcome of intraventricular hemorrhage in low birthweight neonates, hypoxic-
ischemic encephalopathy in full-term infants, neonatal seizures, and meta-
bolic disorders relevant to neonatal brain function. Six program project
applications were received, but none were funded. Amended applications
are expected.
Current activities on febrile seizures include several invited presenta-
tions and chapters for books. An NIH Consensus Development Conference
on Long-term Management of Children with Febrile Seizures was held in
1980. Results of the consensus meeting have been published in lay and
professional journals, and the papers have been edited for a monograph,
published in 1981. Results of the meeting are available in a DHHS
publication Febrile Seizures, a National Institutes of Health Consensus
Development Conference Summary, Vol. 3, No. 2.
The effect of anticonvulsant medication, particularly phenobarbital, on
the developing nervous system has been a major concern of the DNB. The
Consensus Conference on Febrile Seizures also emphasized this concern, and
a contract has been awarded which will study development of cognitive and
neurological function relative to long-term phenobarbital therapy in chil-
dren who have experienced febrile seizures. A Request for Contract Proposal
(RFP) was issued on March 13, 1981 entitled "Behavioral and Cognitive Side
Effects of Phenobarbital Used for Prevention of Febrile Seizure Recurrence,"
and an award was made to the University of Washington, Seattle, on May 1,
1982.
A study of the EEC as a predictor of febrile seizures has begun in Yugoslavia
in pursuance of another of the recommendations. The Section has also
2 - DNB/NDP
participated in establishment of a group to investigate time trends in CP
incidence in the United States in an effort to assess the results of changes
in newborn care in this country.
In the cerebral palsy analysis of NCPP data, a univariate screen has been
performed to evaluate maternal and pediatric conditions most strongly asso-
ciated with cerebral palsy. Four of five regression analyses have been
run. Cerebral palsy at 7 years is found more frequently in boys than girls,
and among whites than blacks. Twelve per cent of cerebral palsy is apparent-
ly caused by events occurring after the first month of life, most often in-
fection or trauma. Clearly handicapping cerebral palsy was present at age
7 in 22-33/10,000 children, the range being related to race and sex. Studies
have been completed and published demonstrating the relationship of birth-
weight and gestational age to cerebral palsy, and the relationship of
physical findings in the newborn period, at four months, and at one year,
to chronic motor handicap.
Another published study concerns low Apgar scores as predictors of long-
term morbidity. Associated handicaps have been investigated in children
with cerebral palsy, and natural history described in children who "outgrew"
cerebral palsy, i.e., those children who showed signs of cerebral palsy at
an earlier age but at the 7-year examination were free of motor handicap .
The major multivariate analyses relating to the antecedents of cerebral
palsy are now in progress. Several analyses are underway to clarify asso-
ciations revealed in the regression analyses.
In the convulsive disorders analysis of NCPP data, major findings are that
approximately one in 20 children (57/1000) at age seven years have had at
least one seizure. About 1/10 of that number (4.8/1000) had active epilepsy
by the age of seven. In the NCPP population, epilepsy in childhood is approx-
imately equal in prevalence in blacks and whites. Two-thirds of children who
had seizures between one month and seven years of age had febrile seizures
only. Data on prevalence of specific seizure disorders in early childhood
are now available and were presented at an international meeting on child
neurology. Approximately a quarter of children with epilepsy in early child-
hood have another major neurological handicap — either mental retardation or
cerebral palsy, or both. Seizures occurring in the first months of life were
associated with a relatively high rate of death or subsequent disability in-
cluding cerebral palsy. Neonatal seizures were found to be a major marker of
risk for subsequent neurologic morbidity, and neonatal seizures in full term
infants with very low Apgar scores appeared to be an important predictor
of chronic neurological disability. Predictors of neonatal seizures are
under investigation. A manuscript on neonatal seizures in the NCPP has
been prepared under contract, and is in press. Low birthweight, short
gestation, and low Apgar scores were not important risk factors for seizure
disorders in children who did not also have cerebral palsy. The major multi-
variate analyses concerning the antecedents of convulsive disorders are now
in progress. Mothers with noneclamptic seizure disorders have been reported
by others to be at increased risk for certain problems in their pregnancies
or progeny. These associations and possible intermediary factors have been
explored in the population of the NCPP, and a paper on this topic is in press.
3 - DNB/NDP
A study of febrile seizures has been a major focus of the convulsive dis-
orders area. Of 1706 children with febrile seizures followed to the age
of 7 years, 2% had become epileptic by the age of 7 and another 1% had
had at least one nonfebrile seizure not meeting the definition of epilepsy.
Comparison of 431 children who have had febrile seizures only with their
seizure-free siblings indicates that febrile seizures do not "cost" the
child a loss in IQ or increased vulnerability to learning disorders.
Three risk factors were identified which served to mark children at
special risk of subsequent epilepsy among children who have had febrile
seizures. The best predictor of recurrence of febrile seizures was
early age of onset.
Section on Mental Retardation and Learning Disorders
A program announcement encouraging the submission of research grant appli-
cations on brain neurophysiology and/or neurochemistry in learning dis-
orders, and related research supporting this effort, was published on
January 1, 1982. Of particular interest are studies using evoked potential
and EEC measures. Other areas of Interest include neuroendocrine, meta-
bolic and neuroradiologlcal studies. The two primary goals are: (1) to
develop objective and reproducible diagnostic criteria for identifying
homogeneous subgroups of children with learning disorders; (2) to re-
fine neurophysiological techniques for evaluating cortical functions in
these LD subgroups and in normal comparison groups. The reliability and
validity of measures of brain electrical activity need to be Investigated
in both study and normal control groups by age, sex, type of learning task,
and hemispheric specialization. Research should be directed at developing
knowledge of the neurophysiology of learning disorders, and expanding the
capability for accurate diagnosis. This research would require a multi-
disciplinary approach involving participation from such areas as neuro-
physiology, developmental neuropsychology and pediatric neurology. Approxi-
mately 100 inquiries and requests for additional information have been re-
ceived from members of the research community.
The Section has participated in the scientific meetings of the Association
for Children with Learning Disabilities, the American Psychological Associa-
tion, and the Child Development Research Group. The Section also partici-
pated in the meetings of the American Psychological Association and the
Behavior Genetics Association.
In the mental retardation analysis of NCPP data, tabular displays of the
data have been completed, and a monograph reporting on 37,000 children is
in preparation. Risk factors were examined separately for severely and
mildly retarded children, and for subgroups without an identified cause or
major neurological abnormality. The incidence of mild retardation (1% in
whites and 5% in blacks) and to a lesser degree, of severe retardation (0.5%)
was inversely related to socioeconomic status. Among the severely retarded,
25% of whites and 50% of blacks had no major genetic or neurological abnor-
mality. Perinatal risk factors for the severely retarded group as a whole
include Down's syndrome, major CNS malformations, neonatal seizures and
clinical signs of perinatal hypoxia. For the subgroups of severely re-
tarded with unknown etiology, perinatal risk factors include non-CNS mal-
4 - DNB/NDP
formations, peripheral nerve abnormalities, signs of hypoxia, and maternal
urinary tract infection during pregnancy. Special studies of drugs taken
during pregnancy and of the incidence of mental retardation in relatives
were conducted.
In the learning disorders area, a monograph has been reviewed for publi-
cation and a revised version is in preparation. The findings show that
among children with at least average IQ scores but below average achieve-
ment test scores, socioeconomic status and family size were better pre-
dictors of unexpected school failure than were indices of physical or
neurological status. Beginning in the preschool period, low achievers
had higher frequencies of cognitive and behavioral problems, and neuro-
logical soft signs than did their IQ-matched controls. Hyperactive low
achievers had an increased frequency of obstetrical complications. Sex
differences were found in the predictors as well as in the incidence of
unexpected academic failure. A summary of results is being published in
a chapter on the methods and findings of the Collaborative Perinatal Project
to be included in a book on longitudinal research in the United States.
Analyses in the area of obstetric medication and later physical and cog-
nitive development in a cohort of normal births are completed and a re-
port is in preparation. The findings suggest that inhalants are inde-
pendently associated with deficits in psychomotor functioning in infancy,
and that some drugs given during labor and delivery are associated with
lower scores on cognitive tasks at later ages.
The final report of the study of symptoms of minimal brain dysfunction has
been published (Nichols, P.L., and Chen, T.C.: Minimal Brain Dysfunction:
A Prospective Study, Erlbaum, 1981) .
Section on Birth Defects and Genetic Disorders
A program announcement was published on neural tube defects on December 12,
1981. The research goals of this program are the attainment of knowledge
and understanding about normal and abnormal neural tube formation, specific
etiologies of neural tube defects, the mechanisms which these etiologies
initiate, the molecular and gross events which lead to neural tube defects,
individual and population differences in incidence and in susceptibility
to the forces which produce neural tube defects, and the nature of such
susceptibility; and the utilization of this knowledge to develop measures
for the prevention and treatment of neural tube defects. The scope of this
program encompasses research in developmental aspects, natural history, and
prevention of neural tube defects, utilizing a variety of subjects, approach-
es and methods .
The Section has been responsible for the administration of some 90 research
grants mainly in the areas of developmental neurology and genetic disorders
of lipid metabolism. Among other activities is a compilation of a compre-
hensive list of all known heritable disorders of the nervous system which
to date numbers about 900.
The Section Chief took an active part in the 9th World Federation of Neurol-
ogy Workshop on Huntington's Chorea, participated as an invited speaker
5 - DNB/NDP
in the 9th International Congress of Neuropathology, lectured to medical
students at George Washington University as an Associate Clinical Professor
of Neurology, and to various other scientific and lay groups. He also
participated in the NIH Interinstitute Medical Genetic Conferences and
engaged in genetic counseling.
Two parts of the 11-part program plan for the comprehensive analysis of
NCPP data in the area of congenital malformations remain to be completed:
the analysis of minor and multiple malformations, and the analysis of
the 7-year malformations. The analysis of minor and multiple malforma-
tions has been designed, input variables have been selected and defined,
and preliminary tabulations have been produced. The analysis of the
7-year malformations updates the malformation finding in a cohort of
children originally followed through the first year of life. Of those
alive at 1 year 77.8% were examined at 7 years, and a further 14.7% were
followed for some time from 1 to 7 years, though they were not examined
at 7 years. Only 7.5% were completely lost to study. Findings from the
analysis of 7-year malformations indicate that the proportion of children
with malformations at 7 years is higher than that at 1 year mainly due to
newly identified eye, mouth and genitourinary malformations and tumors. A
large number of verifications and corrections has been undertaken before
final tabulations are made.
Epidemiologic analysis of neural tube defects has shown that increased
risk for these defects is associated with diabetes mellitus and organic
heart disease in the mother, diuretics, antihistamines, sulfonamides and
thyroxin taken during the first trimester, and short immediately previous
pregancy interval. The last finding supports the hypothesis of fetus-
fetus interaction as an etiologic factor in the occurrence of neural
tube defects.
Studies of twins are in progress to assess and interpret the influence
of maternal socioeconomic, neonatal, medical and other environmental fac-
tors on survival, growth and development, and on abnormal outcome of NCPP
twins .
Section on Autism and Related Behavioral Disorders
A new chief for the Section on Autism and Related Behavioral Disorders,
Martha Bridge Denckla, M.D., assumed duties on December 28, 1981. A
series of meetings with counterpart extramural program administrators from
NIMH and NICHD have advanced and focussed the NINCDS-DNB specific mandate
to investigate the neurobiologic basis of autism and related behavioral
disorders. With NIMH representatives, the Section Chief co-founded a
Child Development Research Study Group, inviting interested professionals
from NINCDS-DNB, NICHD and NIMH to attend monthly meetings. At the monthly
meetings, the specific research activities and interests of each of the
twenty participants are shared. Discussion of common research concerns
has led to plans for collaborative initiatives and program announcements.
Research liaison-collaboration with the intramural unit on Childhood Mental
Illness has been established (e.g., planning studies of evoked potentials
6 - DNB/NDP
and cerebral blood flow in autistic, learning-disabled, and normal children).
The Section Chief met with the National Society for Autistic Children Board
of Directors and Medical Advisory Board chairman on March 4, 1982, and gave
an address on "Research Initiatives on Autism" on July 6, 1982 at the NSAC
national conference in Omaha, Nebraska.
Collaborative Perinatal Section
The Unit for Data Collection is responsible for maintaining the NINCDS
Collaborative Project files in accordance with a system designed to facili-
tate data retrieval. During the fiscal year major efforts were concentrated
on editing the NCPP microfilm, setting up the completed microfilm file,
supplying data to DNB professional staff, outside investigators and consult-
ants, providing research assistance to on-going studies, and preparing
NINCDS microfilmed records for Federal Storage. Approximately 27,000
records are now at the Federal Records Center and the balance of the NCPP
file, approximately 32,000 records, are awaiting pick-up for delivery to
the Federal Records Center. The master copy of the NCPP microfilm and the
computer tape files will be transferred to National Underground Storage
Inc. in Bayers, Pa. An RFP for creation of a "Users Guide" was issued and
a contract award is anticipated in this fiscal year. Research assistance
via computer tapes, computer printouts or microfilm was provided to 20
investigators (8 in-house and 12 outside investigators) .
The Unit for Production of Data Analysis has as its basic mission the proc-
essing and storage by digital computer of the medical research data collect-
ed by the NCPP. All research files have been completed. A financial
system that audits all computer funds spent by the Branch and an automated
bibliography of all NCPP publications are now operational.
IV. ADDITIONAL ACTIVITIES
The Office of the Chief, DNB, continues as the NINCDS focal point for
implementation of the Privacy Act. The Chief, DNB, continues to serve
as NINCDS Privacy Act Coordinator. Activities for this fiscal year in-
clude the following: (1) advice to NINCDS personnel regarding Privacy
matters; (2) determination of the applicability of the Privacy Act to
each new NINCDS contract involving human subjects; (3) required annual
report prepared and submitted to the NIH Privacy Act Coordinator; (4)
reviewing requests for access to or amendment of grant records; (5)
attending orientation sessions regarding changing regulations in
implementation of the Act; and (6) revising NINCDS System Notices to
comply with new regulations.
The Office of the Chief, DNB, continues to administer the Clinical Research
Panel, NINCDS Contract Review for the Protection of Human Subjects, and
the Chief, DNB, serves as Chairman. This panel has the responsibility for
reviewing NINCDS contracts for adherence to DHHS and NIH rules and regula-
tions regarding the protection of human subjects in research and recommend-
ing approval or disapproval to the Director, NINCDS.
7 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NDP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
UNIVERSITY OF WASHINGTON, SEATTLE, WASHINGTON (NOl-NS-2-2395)
Title: Behavioral and Cognitive Side Effects of Phenobarbital Used for
Prevention of Febrile Seizure Recurrence
Contractor's Project Director: Jacqueline R. Farwell, M.D.
Current Annual Level: $183,992.00
Objectives: The University of Washington will conduct a randomized, placebo-
controlled study to determine the effects of long-term phenobarbital treatment
in children aged one to five years who have had febrile convulsions. The
primary objective is to assess the effects over a two-year period of treatment,
and six months after treatment termination, of phenobarbital on behavior and
cognitive function. A secondary objective is to evaluate the effects of febrile
seizure recurrence on behavior and cognitive function, and to compare these with
the effects of prophylactic treatment.
Significance to the Program: This contract results from recommendations of the
NINCDS Consensus Panel on Febrile Seizures. Febrile seizures are a common
occurrence in early childhood, and uncertainty exists whether the benefits of
treatment for prevention of recurrence outweigh its risks. In addition, pheno-
barbital is the most commonly used anticonvulsant in infancy and childhood, and
information on its behavioral and cognitive side effects on the developing child
will be of great value in other neurologic disorders.
Course of Contract: May 1, 1982 through April 30, 1985. (A TMR will take place
before the two final years.)
8 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NDP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
CHILDREN'S HOSPITAL MEDICAL CENTER, BOSTON, MASSACHUSETTS (NOl-NS-3-2312)
Title: Combined Neuropathologic and Epidemiologic Study
Contractor's Project Director: Floyd H, Gilles, M.D.
Current Annual Level: $ 0.00
Objectives: The contract has analyzed the neuropathology collection of the
NINCDS Collaborative Perinatal Project (NCPP). An estimate of the quality of
the material and a catalogue of gross brain abnormalities has been prepared.
Plots of fetal brain weight of grossly normal brains against estimated gesta-
tional age, utilizing a Gompertz function, were made and an analysis completed
relating events of pregnancy, labor, and delivery. A comparison was made of
rate of brain weight acquisition in utero to rate of brain weight acquisition
after birth as a function of total (gestational plus survival) age. A study
was made of intracranial hemorrhage including topography of hemorrhage. Risk
factors associated with perinatal telencephalic leucoencephalopathy were
studied. A cerebral necrosis study included criteria of necrosis in the peri-
natal brain, and an evalution of selected risk factors in relation to sub-
classification of neuronal and white matter necrosis.
Major Findings: Review and classification of pathology material are complete.
Data analysis is complete and a 27-chapter monograph has been completed,
reviewed, and approved for publication.
Course of Contract: June 1, 1973 through December 31, 1976. The contract is
terminated; and the monograph is being published.
Publications: Gilles, F.H., Leviton, A., and Dooling, E.C.: Developing Human
Brain: Growth and Epidemiologic Neuropathology. Littleton MA: Wright-PSG
(in press) .
9 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NOP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
UNIVERSITY OF MICHIGAN (NOl NS 5-2308)
TITLE: Physical Growth Analysis
Contractor's Project Director: Stanley M. Gam, Ph.D.
Current Annual Level: $ 00.00
Objectives: To develop the physical growth measurement data on the 50,000 chil-
dren examined within the framework of the NINCDS Collaborative Perinatal Project
CNCPP). Specifically:
1. Develop for body weight, length, chest circumference and head circumference,
a set of tabular, percentile, normative tables of (a) size-for-age, (b) incre-
ments of size for age-interval, (c) size-for-size for age and size for gestation
length for whites, blacks and Puerto Ricans separately and for boys and girls
separately. This set of tables is largely intended as a reference document for
the NINCDS Collaborative Perinatal Project.
2. Develop a set of summary tabulations and reports, directed to the major
pediatric and growth-related users, complete with narrative and graphs, with
the purpose of providing in the professional literature both an account of
major substantive findings, and an in-the-literature account of the major data.
3. To correlate the incidence and prevalence of dental and facial abnormalities
with neurological defects, congenital abnormalities and other disorders of
childhood.
Major Findings: The tables, with accompanying graphs, as outlined in 1. , above,
are complete. Findings are reflected in approximately 27 publications to date.
Significance to the Program: The findings are important to the pediatric commu-
nity as well as to physical anthropologists and nutritionists in that they repre-
sent results from the largest longitudinal data base yet studied in the U.S.
Course of Contract: Terminated April 30, 1980. Dr. Gam continues to analyze
and publish NCPP data with support from sources other than the NINCDS. The
planned series of publications is being completed and a final, comprehensive
report has been requested.
Publications:
Gam, S.M., Ryan, A.S., and Abraham, S. : New values defining "low" and "defi-
cient" hemoglobin levels for white children and adults. Ecol. of Food and
Nutr. : 11:71-74, 1981.
10 - DNB/NDP
Contract No. NOl NS 5-2308
Garn, S.M. : Noninvasive measurements of bone mass and their clinical applica-
tions. Ecol. of Food & Nutr; 10:195-197, 1981.
Garn, S.M.: Aging Students? Physical Anthropology News: 1(1):9-10, 1981.
Garn, S.M. , Ryan, A.S., Owen, G.M. , and Falkner, R. : Developmental differences
in the triceps and subscapular fatfolds during adolescence in boys and girls.
Ecol. of Food & Nutr.: 11:49-51, 1981.
Garn, S.M. : The growth of growth. Am. J. Phys. Anthropol: 57(2): 191, 1982.
Garn, S.M. , Ryan, A.S., and Higgins, M.W. : Abstract: Implications of fatness
and leanness. Am. J. Phys. Anthropol.; 57(2): 191, 1982.
Garn, S.M. , Johnston, M. , Ridella, S. , and Petzold, A.S.: In reply: to
Dr. Cunningham and smoking and pregnancy. Am. J. Dis. Child.: 136:82, 1982.
Garn, S.M. : Review: Radiology of the pediatric elbow. Radiology: 142:366, 1982.
Lamb, M.E. , Garn, S.M. , and Keating, M.T.: Correlations between sociability and
motor performance scores in 8-month-olds. Infant Behavior and Development :
5:97-101, 1982.
11 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NDP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
THE PENNSYLVANIA STATE UNIVERSITY, UNIVERSITY PARK, PA. (NOl-NS-7-2376)
Title: Analysis of General and Placental Pathology Data
Contractor's Project Director: Richard L. Naeye, M.D.
Current Annual level: $ 0.00
Objectives: The objectives of the last extension of the contract were (1) to
complete the determination of the effects of smoking on the fetus, (2) a
further explanation of the relationship between prepregnancy weight for height
and placental growth as related to fetal growth and pregnancy outcome, and (3)
a determination if selected factors thus far examined have an independent in-
fluence on long term psychomotor development in NCPP children.
Major Findings: Findings are reflected in approximately 44 publications to date.
Course of Contract: The contract terminated July 31, 1979; extra time is
allowed to complete the planned series of publications, and a final, compre-
hensive, report is expected. Dr. Naeye continues to analyze and publish NCPP
data with support from an NINCDS grant (1 ROl NS 16403-01) .
Publications:
Naeye, R.L. : Coitus and antepartum haemorrhage. Br. J. Obstet. Gynaecol.; 88:
765-770, 1981.
12 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NDP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
CHILDREN'S HOSPITAL MEDICAL CENTER, BOSTON, MASSACHUSETTS: (NOI-NS-7-2377)
TITLE : A Prospective Cohort Epidemiologic Study of Learning Handicaps in
Children Attending School
Contractor's Project Director; Alan Leviton, M.D.
Current Annual Level: None
Ob jectives : Conduct analyses of antecedents of school behavior and school
achievement at age 9 in an identified sample of children in the Boston
component of the NINCDS Collaborative Perinatal Project (NCPP) for the
purpose of identifying risk factors for learning disorders.
Major Findings : Five learning handicaps in boys and six in girls have been
identified as outcomes of interest. Antecedents are being analysed by epoch--
e.g. — pre-pregnancy, pregnancy, delivery, early postnatal. An interactive
multiple logistic regression procedure is being used to analyse the data.
Risk factors for learning handicaps include low family income, large family
size, prior abortions, and some complications of pregnancy.
Course of Contract; The contract which began on September 30,1977 terminated
November 14, 1980. Additional time has been allowed for completion of a
monograph. Although progress has been slowed because of the consulting
statistician's move to Dartmouth, the Project Director estimates that the
monograph should be completed before the end of calendar 1982.
13 - DNB/NDP
CONTRACT NARRATIVE
Developmental Neurology Branch, NDP, NINCDS
Office of the Chief
October 1, 1981 through September 30, 1982
BETH ISRAEL HOSPITAL, BOSTON, MASSACHUSETTS (NOl-NS-8-2381)
Title: Comprehensive Study of Labor and Delivery Effects on Offspring
Contractor's Project Director: Emanuel A. Friedman, M.D.
Current Annual Level; $0.00
Objectives: The objectives are (1) to determine the effects on the fetus and
the surviving infant of clinically definable labor factors, labor disorders
and the spectrum of delivery procedures, and thus to identify and quantitate
the specific risk factors in labor and delivery that contribute to perinatal
mortality and to the development of long-term neurological and developmental
disorders in children, and (2) to determine relationships between the various
types of maternal anesthesia-analgesia and development of the child; specifi-
cally, to examine in detail the time-dose relationships and drugs used in com-
bination during the course of labor and delivery, in relation to long-term
neurological outcome in the child.
Major Findings; Work on the contract has progressed and the required report
following Phase 9 has been received. The monograph is now being written.
The contractual requirements for the ninth phase of this contract include
completion of all foregoing efforts so as to define the high-risk labor and
delivery constellations, and to proceed further by categorizing possible
predictor variables in the maternal background so as to characterize the
gravida-at-risk.
All data from the original index population (vaginal delivery with fully
defined labor progression pattern) have now been integrated with data from
the distinctive subgroups made up of patients delivered by cesarean section
and those who delivered stillborn infants.
Stratified by parity, there were 2,642 nulliparas and 3,261 multiparas.
When examined by the level of cervical dilatation that had been achieved at
the time the arrest occurred, nulliparas averaged 6.48 cm. (standard devia-
tion 1.76, standard error 0.03, modal value 5.0 cm.); multiparas averaged
6.60 cm. (standard deviation 1.70, standard error 0.03, modal value 8.0 cm.).
In the course of examining the distribution of data according to the level
of dilatation, we encountered the now-familiar zero end-digit clustering
phenomenon that we have come to expect in these analytic studies. Arrest
prior to 4 cm. is a rarity (192 cases or 1.06 percent of the index popula-
tion and 3.25 percent of all documented arrest cases). Moreover, the
frequency remains at rather a constant level regardless of the degree of
dilatation at which the arrest occurred beyond this point (averaging 15.2
percent for each centimeter increment subgroup from 4 to 9 cm. ) .
14 - DNB/NDP
Contract No. NOl-NS-8-2381
The distribution of levels of dilatation at which arrest occurred has been
stratified by parity. In general terms, multiparas arrested labor at more
advanced cervical dilatation than nulliparas, but the range was broad in both
subgroups. Of greater interest in this regard was the duration of the arrest
according to the level of dilatation achieved. In nulliparas, for example,
the mean duration was 1.57 hour (standard deviation 0.34, standard error 0.01
hour) , as contrasted to the much shorter average period of arrest in multiparas
of 0.93 hour (standard deviation 0.55, standard error 0.01 hour).
This was further elaborated by the level of dilatation to show that the dura-
tion of arrest "tolerated" by the physicians managing the patient was in
general much longer at lower dilatations than at more advanced dilatations by
a factor of more than 2.5 times in nulliparas and more than 6.5 times in
multiparas. This is illustrated by a 3.02 hours of arrest in nulliparas at
3.0 cm. of dilatation versus 1.17 hour of arrest at 9.0 cm. dilatation (2.58-
fold difference); at the same levels of dilatation in multiparas, the durations
of arrest were 3.71 and 0.57 hour, respectively (a 6.51-fold difference).
We may conclude from these data and the preceding observations relating to
outcome that arrests of short duration are innocuous both with regard to
delivery prognosis and fetal/infant prognosis. This is reflected in the low
neonatal and perinatal mortality data as well as the rare cesarea section
performed among them. The data also permit us to conclude, with considerable
reliance, that prolonged durations of arrest at any level of cervical dilata-
tion is ominous with regard to both the probability of cesarean section and
the likelihood of a bad outcome for the infant.
Course of Contract; March 13, 1978 through September 12, 1982. A six-month
extension has been approved for preparation of the monograph.
Publications: None
15 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
1 HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02058-10 DNB
PERIOD COVERED
Oc tober 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Convulsive Disorders Data Analysis Group
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: K.B. Nelson
PI: J.H. Ellenberg
PI: D.G. Hirtz
Pediatric Neurologist DNB NINCDS
Mathematical Statistician OBFS NINCDS
Expert Consultant DNB NINCDS
COOPERATING UNITS (if any)
Dr. J. Freeman, Johns Hopkins
Dr. K. Holden, Johns Hopkins
OBFS, CD, NINCDS
lab/branch
Developmental Neurology Branch
SECTION
Section on Cerebral Palsy and Other Motor Disorders
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.9
PROFESSIONAL:
0.6
0.3
CHECK APPROPRIATE BOX(ES)
K (a) HUMAN SUBJECTS
m (al) MINORS D (a2) INTERVIEWS
gl (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study examines the relationship between perinatal factors and the occur-
rence of seizure disorders in childhood in a large, prospectively studied
population. In addition to the central question of etiology, it investigates
frequency, prognosis, demographic characteristics, and a number of other
aspects of these disorders. Univariate screen of maternal, obstetric, and
pediatric risk factors, and demographic analysis, have been completed. File
creation for multivariate analysis is now complete, and regression analyses
are in progress. Selected topics of particular clinical relevance are under
examination.
PHS-6040
(Rev. 2-81)
16 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02059-10 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cerebral Palsy Data Analysis Group
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: K. B. Nelson
PI: J. H. Ellenberg
Pediatric Neurologist
Mathematical Statistician
DNB NINCDS
OBFS NINCDS
COOPERATING UNITS (if any)
OBFS, OD, NINCDS
LAB/BRANCH
Developmental Neurology Branch
Section on Cerebral Palsy and Other Motor Disorders
INSTITUTE AND LOCATION
NINCDS, NIHj Bethesda, Maryland 20205
TOTAL MANYEARS:
1.2
PROFESSIONAL:
0.8
0.4
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
H (al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This large prospective study attempts to add to available knowledge of the
perinatal factors associated with motor handicaps in childhood, the primary
goal being to identify areas for possible preventive efforts.
Studies on the prevalence, on perinatal factors and neonatal signs in the
early recognition of cerebral palsy have been published. Data on demographic
analysis and a univariate screen of maternal and pediatric factors associated
with cerebral palsy are available. Studies on early recognition of cerebral
palsy, and on natural history of children with early motor abnormalities,
have been published. Multivariate analysis is nearing completion.
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02060-10 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Birthweight-Gestational Age
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J. S. Drage
Chief
DNB, NINCDS
COOPERATING UNITS (if any)
J. B. Hardy, The Johns Hopkins University
E. D. Mellits, The Johns Hopkins University
lab/branch
Developmental Neurology Branch
SECTION
Collaborative Perinatal Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.10
PROFESSIONAL:
0.05
0.05
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
[^(al) MINORS D (a2) INTERVIEWS
H (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The final analyseb, including a rerun of parts of Phase II and all of
Phase III have been completed. Phase II, a multivariate analysis to determine
relationships with birthweight, included analyses of primigravida only, as
well as all gravida. Analyses were run utilizing information prior to delivery
and separately at delivery (for example, placenta weight). Phase III examines
events subsequent to birth as a function of information available at birth.
These results are summarized in the form of Empirical Risk Tables which describe
the empirical probability of the negative outcomes within the first year of life
as a function of birthweight, gestational age, race, sex and placenta weight.
The structure of the manuscript has been formed into four sections: 1. Descrip
tion, 2. Concomitant Events, 3. Antecedents, 4. Subsequent Risk. Emphasis
for the text material over the past year has been on finalizing figures and
tables. Virtually all are completed. The writing of the monograph is in prog-
ress.
PHS-6040
(Rev. 2-81)
18 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space;
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02062 - 10 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Minimal Brain Dysfunction
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI : P. L. Nichols
Other: Ta-Chuan Chen
Research Psychologist
Sr. Math. Statistician
DNB NINCDS
OBFS NINCDS
COOPERATING UNITS (if any)
OBFS, OD, NINCDS
lab/branch
Developmental Neurology Branch
SECTION
Mental Retardation and Learning Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.00
PROFESSIONAL:
00
OTHER:
.00
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
(al) MINORS D (a2) INTERVIEWS
g (b) HUMAN TISSUES
□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been completed.
PHS-6040
(Rev. 2-81)
19 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02106 - 09 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Developmental Factors Associated with Mental Retardation
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: S. H. Broman
Other: P. L. Nichols
E. C. Bien
Acting Chief, MRLDS
Research Psychologist
Research Psychologist
DNB NINCDS
DNB NINCDS
DNB NINCDS
COOPERATING UNITS (if any)
Dr. Peter Shaughnessy, University of Colorado Medical Center
Dr. Wallace Kennedy, Florida State University
lab/branch
Developmental Neurology Branch
SECTION
Mental Retardation and Learning Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
.5
.2
check APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
H (al) MINORS n (a2) INTERVIEWS
K (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this study is to identify predictors of mental retardation in a
population of 37,000 children followed from the prenatal period to age 7. Risk
factors were examined separately for severely and mildly retarded children, and
for subgroups without an identified cause or major neurological abnormality.
The incidence of mild retardation (1% in whites and 5% in blacks) and to a
lesser degree, of severe retardation (0.5%) was inversely related to socio-
economic status. Among the severely retarded, 25% of whites and 50% of blacks
had no major genetic or neurological abnormality. Perinatal risk factors for
the severely retarded groups as a whole include Down's syndrome, major CNS mal-
formations, neonatal seizures and clinical signs of perinatal hypoxia. For the
subgroup of severely retarded with unknown etiology, perinatal risk factors
include non-CNS malformations, peripheral nerve abnormalities, signs of hypox-
ia, and maternal urinary tract infection during pregnancy. Special studies of
drugs taken during pregnancy and of the incidence of mental retardation in rel-
atives were conducted. This investigation is completed and a monograph is in
preparation.
PHS-6040
(Rev. 2-81)
20 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02107-09 DNB
PERIOD COVERED
October 1, 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
The Study of Visual Abnormalities in the NINCDS Collaborative Perinatal
Project
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. Feinberg
Research Psychologist
(retired)
DNB, NINCDS
COOPERATING UNITS (if any) w.R. Baldwin, New England College of Optometry; R.E. Hoover,
Baltimore, Md.; R.P. Kling, Georgetown Univ. Hosp.; M.A. Whitcomb, Nat. Acad
of Sc; S.Z. Wood, Washington, D.C.; F.A. Young, Wash. State Univ.
lab/branch
Developmental Neurology Branch
SECTION
Collaborative Perinatal Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.1
PROFESSIONAL:
0.1
OTHER:
0.0
CHECK APPROPRIATE BOX(ES)
[?(a) HUMAN SUBJECTS
S(al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project includes the analysis between visual abnormalities in NCPP
children and predictor variables; anecdotal treatment based on case histories of
unusual visual abnormalities; special studies of high- incidence disorders; case
studies of the blind children; and, preparation of a monograph encompassing
these subjects. Basic data analysis is complete and a draft manuscript of the
findings was prepared and is currently being revised.
PHS-6040
(Rev. 2-81)
21 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02108 - 09 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Developmental Factors Associated with Learning Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
S. H. Broman
E. C. Bien
Acting Chief, MRLDS
Research Psychologist
DNB,NINCDS
DNB,NINCDS
COOPERATING UNITS (if any)
Dr. Peter Shaughnessy, University of Colorado Medical Center
lab/branch
Developmental Neurology Branch
Mental Retardation and Learning Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.7
PROFESSIONAL:
OTHER:
.2
CHECK APPROPRIATE BOX(ES)
^ (a) HUMAN SUBJECTS
^ (al) MINORS □ (a2) INTERVIEWS
^ (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) . , , ^ ., , . . c
This study identified early behavioral, physical and family characteristics ot
children with average IQ scores and below average school achievement, approx-
imately 3% of the NCPP population. Low achievers were compared with their IQ-
matched academically successful controls on prospectively ascertained indices
of cognitive and physical development and family environment. Cognitive deficitii
and behavioral problems in the preschool period were associated with low achieve-
ment at age 7. Socioeconomic status (SES) and family structure were better pre-
dictors of low achievement than were indices of physical development or medical
status. Low achievers were born into low SES, large families, and two-thirds of
them were boys. As preschoolers, they had more language difficulties and lower
IQ scores than controls. At age 7, deviant behavior, verbal and non-verbal
cognitive deficits, and neurological soft signs were present. Hyperactive low
achievers had an increased frequency of obstetrical complications
Sex differences
were found in predictors of unexpected academic failure. A monograph has been
reviewed for publication and the revised version is in preparation.
PHS-6040
(Rev. 2-81)
22 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02109-09 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Comprehensive Analysis of the NCPP Data on Congenital Malformations
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: N.C. Myrianthopoulos
Research Geneticist
DNB NINCDS
COOPERATING UNITS (if any)
C.S. Chung, Univ. of Hawaii; H. Lubs and M.L. Lubs, Univ. of Miami, Fla. ;
J. Frias, Univ. of Florida; M. Melnick, Univ. of S. California, Los
Angeles; P. Koslowe, Johns Hopkins Univ., Baltimore
lab/branch
Developmental Neurology Branch
Birth Defects and Genetic Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.00
PROFESSIONAL:
2.00
1.00
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
Kl (al) MINORS n (a2) INTERVIEWS
gl (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This long-term project is a primary area within the program plan for analysis
of NCPP data. The objectives are to study the epidemiologic characteristics
of congenital malformations in singletons and twins; to assess and interpret
the influence of maternal, socioeconomic, neonatal, medical and other environ-
mental factors on the occurrence of congenital malformations; to determine the
risk of familial occurrence and to elucidate the role of genetic factors and
the mode of inheritance of certain malformations; to determine the severity
and clinical signficance of congenital malformations and their associations
with neurological, psychological and sensory handicaps; and to assess the
long-range effects of malformations on survival, growth and development.
PHS-6040
(Rev. 2-81)
23 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02112-09 DNB
PERIOD COVERED
October 1. 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neonatal Hyperbilirubinemia
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
J. S. Drage
Chief
DNB, NINCDS
COOPERATING UNITS (if any)
P. C. Scheldt, USUHS, Department of Pediatrics
J. B. Hardy, The Johns Hopkins University
E. D. Mellits, The Johns Hopkins University
lab/branch
Developmental Neurology Branch
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
0.03
PROFESSIONAL:
0.01
OTHER:
0.02
CHECK APPROPRIATE BOX(ES)
nx(a) HUMAN SUBJECTS
q^(al) MINORS D (a2) INTERVIEWS
a(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The neonatal hyperbilirubinemia study has been designed to assess the rela-
tionship of intermediate levels of serum bilirubin on the subsequent neurologi-
cal and mental development of NINCDS Collaborative Perinatal Project children.
There has been increasing concern that neonatal serum bilirubin levels between
10-20 mg% may be damaging to the central nervous system, not in the classical
sense of 'kernicterus' associated with levels above 20 mg%, but rather damaging
in more subtle yet clinically significant ways. Neonates have been studied in
five birthweight-gestational age categories, by three socioeconomic classes, for
a variety of outcome measures, including mental and motor assessment at age 8
months, and a spectrum of neurological findings at age one year which will in-
clude motor performance, reflexes, tone, abnormal movements, eye findings and
the overall neurological classification of normal, suspect or abnormal. The
analysis of Phase I of this study has been published. The analysis of Phases II
and III, which include data obtained at ages four and seven years, has been
completed. A report on findings is being prepared.
PHS-6040
(Rev. 2-81)
24 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02169 - 08 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Obstetrical Medication and Development in Infancy and Early Childhood
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
S.H. Broman
Acting Chief, MRLDS
DNB , NINCDS
COOPERATING UNITS (if any)
Dr. Peter Snaugnnessy, University of Colorado Medical Center
Dr. Yvonne Brackbill, University of Florida
lab/branch
Developmental Neurology Branch
Mental Retardation and Learning Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
.08
PROFESSIONAL:
.06
.02
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
(al) MINORS □ (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This study investigated relationships between obstetric medication and physical
^ cognitive development through age seven. Subjects were full term infants
born to mothers with uncomplicated pregnancies and deliveries. The cohort was
drawn from two hospitals in the NCPP. Pharmacological agents evaluated were in-
halation anesthetics and six other drugs administered during labor and deliveT^T
Outcomes in the first year of life included items from pediatric and psychomotor
assessments. Later outcomes were scores from psychometric examinations, and itens
from a pediatric neurological examination. Univariate associations between out-
comes and drugs were identified, and the significant relationships were examined
m multiple logistic regression analyses with other risk factors included. The
results suggest that inhalants are associated with deficits in early psychomotor
and neuromotor functioning, and that oxytocin is also associated with psychomoto
. ^^^^'^^ Scopolamine and secobarbital are related to respiratory difficulties
m the newborn, and inhalants, scopolamine, and secobarbital are associated with
palpable liver at 4 months. At older ages, scopolamine is associated with sligh
lower scores on some cognitive tasks, and oxytocin is associated with lower
achievement test scores. A repnrf i.< '
ly
preparation.
PHS-6040
(Rev. 2-81)
25 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02171-08 DNB
PERIOD COVERED , ^„ ,^„„
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Compendium of Heritable Disorders of the Nervous System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: N.C. Myrianthopoulos Research Geneticist DNB NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Developmental Neurology Branch
Birth Defects and Genetic Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.10
PROFESSIONAL:
0.05
0.05
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
Kl (al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose is to prepare and maintain a comprehensive list of all knovm heri-
table disorders of the nervous system, including disorders and malformation
syndromes which, though not primarily neurological, have neurological involve-
ment.
PHS-6040
(Rev. 2-81)
26 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this spacej
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02234-07 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Febrile Seizures Study
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: K.B. Nelson Pediatric Neurologist DNB NINCDS
PI: J.H. Ellenberg Mathematical Statistician DBFS NINCDS
PI: D.G. Hirtz Expert Consultant DNB NINCDS
COOPERATING UNITS (if any)
DBFS, OD, NINCDS
lab/branch
Developmental Neurology Branch
SECTION
Section on Cerebral Palsy and Other Motor Disorders
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.6
PROFESSIONAL:
0.4
0.2
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
g(al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The NINCDS Collaborative Perinatal Project has provided a large prospectively
defined pediatric population, unselected for level of risk, in which to in-
vestigate the prevalence and natural history of the most common convulsive
disorder of childhood, febrile seizures. A series of papers has delineated
the natural history of febrile seizures, identified risk factors for unfavor-
able outcome, and reviewed the effect of sample selection on outcome. An NIH
Consensus Development Conference on Long-term Management of Children with
Febrile Seizures was held. Results of the consensus conference have been
published in professional and lay journals, and the papers were edited for a
monograph, published in 1981. A major study to evaluate the effects of medi-
cations and of recurrent seizures is soon to begin under contract. We have
collaborated in designing a study on the EEC as a predictor in febrile
seizures, and in a survey on management of febrile seizures.
PH 8-6040
(Rev. 2-81)
27 - DNB/NDP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02332-05 DNB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Analysis of NCPP Twin Data
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: N.C. Myrianthopoulos
Research Geneticist
DNB NINCDS
COOPERATING UNITS (if any)
NHLBI; M. Melnick, University of Southern California, Los Angeles
lab/branch
Developmental Neurology Branch
SECTION
Birth Defects and Genetic Disorders Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARSi
0.50
PROFESSIONAL:
0.40
OTHER:
0.10
CHECK APPROPRIATE BOX(ES)
S (a) HUMAN SUBJECTS
K (al) MINORS D (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This is a secondary area within the program plan for analysis of NCPP data
The objectives of the project are to assess and interpret the influence of
maternal, socioeconomic, neonatal, medical and other environmental factors on
survival, growth and development, and on abnormal outcome of twins.
PHS-6040
(Rev. 2-81)
28 - DNB/NDP
>
en
eo
o
CD
>
ANNUAL REPORT
October 1, 1981 — September 30, 1982
Stroke and Trauma Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
INTRODUCTION 1-3
CEREBROVASCULAR DISEASE 3-5
Clinical Trials 5-6
Research Grants __-__-__------________ 5
POSITRON EMISSION TOMOGRAPHY 7-8
SPINAL CORD INJURY 8-10
HEAD INJURY 10-12
CNS NEOPLASMS 12-14
NEURAL REGENERATION AND PLASTICITY 14-15
PAIN 15-16
CONTRACT NARRATIVES
Comprehensive Stroke Centers ---------------- 17-18
NOl-NS-8-2385 University of Rochester
NOl-NS-8-2386 American Heart Association, N.C. Affiliate, Inc.
NOl-NS-8-2387 University of Oregon Health Science Center
Comprehensive Central Nervous System Trauma Centers ----- 19-20
NOl-NS-9-2312 University of California, San Diego
NOl-NS-9-2313 Albert Einstein College of Medicine
NOl-NS-9-2314 University of Texas Medical Branch
Safety and Efficacy of Cingulotomy for Pain and Psychiatric
Disorders -------------------------- 21-22
YOl-NS-9-0044 National Institute of Mental Health
Standardized Reproducible Spinal Cord Injury Model ----- 23
NOl-NS-2-2307 Hahnemann Medical College and Hospital, Philadelphia
NOl-NS-2-2310 Georgetown University School of Medicine, Washington
i-STP TAB 6
ANNUAL REPORT
October 1, 1981 — September 30, 1982
Stroke and Trauma Program
National Institute of Neurological and Communicative Disorders and Stroke
INTRODUCTION
The Stroke and Trauma Program (STP) of the NINCDS is responsible for research in
the areas of stroke, cerebrovascular disease, brain, spinal cord and peripheral
nerve trauma, nervous system regeneration, primary and metastatic brain tumor,
pain, positron emission tomography and other related subjects. These areas and
neurologic disease entities in terms of their high incidence, prevalence, morbidity
and mortality, exact an enormous toll in human suffering. Included are the vast
number of head, spinal cord and peripheral nerve injuries, the considerable
number of strokes and their sequelae, the problems of preservation and regeneration
of neuronal function following these diseases, brain tumor and chronic pain.
High priority, therefore, is given to applied and clinical investigations with
direct relevance to the pathogenesis, diagnosis and treatment of these diseases.
With prevention of such diseases as the ultimate goal, understanding of the
basic pathophysiologic processes is fundamental to such achievement. The program
contains discrete, as well as overlapping components of basic, applied and clinical
research and utilizes the several administrative instruments of program support
(i.e., research project grants, program project grants, clinical research center
grants, cooperative clinical trials, resource contracts, and service contracts).
The allocation of research funding within STP during FY 81 was:
Stroke and Cerebrovascular Disease 34%
Positron Emission Tomography 15%
Cerebral, Spinal Cord and PNS Trauma 23%
Regeneration and Plasticity 20%
CNS Neoplasm 4%
Other 3%
During that year, 227 applications were assigned to STP as being relevant to its
mission. Of those, 71% were approved by initial review groups with concurrence
from the NANCDS Council and 40% were funded. Of the total number of grants
assigned to STP, 29% were funded as opposed to 40% in the preceding year. STP
is served by several study sections and special review committees. The median
priority score of all approved grants during the year was 229 versus 222 in the
previous year. This numerical increase in median priority of some 7 points
occurred while the median score for NINCDS as a whole decreased by 7 points.
During the year, the approval rate of grants improved significantly presumably
as an indication of better scientific merit, while the funding rate decreased to
an effective level which was only 73% of the prior year.
The Cerebrovascular Research Centers are major interdisciplinary research and
teaching efforts within STP and constitute a significant segment of the Stroke
Program. The thirteen current centers serve as a focal point for research on
etiology, natural history, diagnosis, treatment and pathophysiologic events
related to cerebrovascular disease. These individual research programs are
broad, multidisciplinary and only interrelated in a general sense. They all,
1-STP
however, focus on specific studies of either a basic or applied nature, designed
to provide a better understanding of the biochemical and pathophysiologic events
secondary to ischemia and hypoxia.
The Comprehensive Stroke Center Program is completing its final phase with the
write-up of the individual as well as composite data generated by each of the
centers. Intercomparative information in some 2,000 patients will provide
important research hypotheses for future studies.
Positron Emission Tomography (PET), an Institute-sponsored effort, is beginning
to generate important research information as newly acquired equipment within
the PET centers comes on-line. Early studies are verifying cerebral blood flow,
metabolism and physiology, both in normal patients at different ages as well as
in others with a variety of pathologic conditions. Newer compounds with either
qIIj- pis tracers are being evaluated, particularly from the point of view of
short half-life isotopes which allow multiple studies. During the course of the
next two years, the Positron Emission Tomography Program will be developing and
presenting massive amounts of useful information to the research community as a
result of these early efforts.
Trauma to the head and spinal cord remains a major therapeutic entity. The bulk
of cerebral trauma research is carried out in the Head Injury Clinical Research
Centers with more highly targeted efforts in the Comprehensive Central Nervous
System Trauma Centers. Currently, the management of severely injured patients in
highly sophisticated intensive care units with extensive diagnostic and monitoring
equipment has reached a plateau. Scientists are now turning to the cellular and
molecular events occurring within traumatized tissue in order to understand the
biological basis of injury. The same thrust is being taken in spinal cord injury
research to provide additional information on the secondary and cascading events
related to the immediate time period around the spinal cord injury. Clinical
trials in the spinal cord injured patient are examining the value of high dose
corticosteroid. A new clinical trial is being developed to evaluate the efficacy
of high doses of barbiturates in the treatment of severe head-injured patients
with uncontrolled increased intracranial pressure. While prevention of these
injuries remains an ultimate goal, it nonetheless is imperative that the head
and spinal cord-injured patient must receive prompt attention both to minimize
and/or correct injury as well as to avoid long-term disability.
Emphasis is placed on research in central nervous system regeneration and plastic-
ity as a complement to the head and spinal cord injury programs. Much of the
information derived from either lower invertebrates or the head-injured patient
may be applied directly to spinal cord injury or vice versa. While the basic
properties of regeneration and plasticity must be unravelled in the laboratory
setting, the clinical events surrounding spinal cord injury and its subsequent
effects can be studied through the activities of the Comprehensive CNS Trauma
Centers as well as the Spinal Cord Injury Clinical Research Centers. A careful
evaluation of this patient population will allow development of appropriate
stratification and prognostic factors which will aid in the design of future
clinical trials.
Clinical investigators with advanced training in a scientific discipline remain
in short supply. Yet, as research becomes more complicated, the equipment more
sophisticated and the area of concern more molecular in nature, the need for
training astute clinical investigators becomes more critical. Great emphasis
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must be given to the recruitment and development of scientifically trained
clinicians through the use of traineeships , fellowships and teacher-investigator
development award mechanisms.
The NINCDS Stroke and Trauma Program, utilizing the funds and other resources made
available to it, has served as the institutional focal point for the planning and
operation of research endeavors in cerebrovascular disease, brain and spinal cord
trauma, brain tumors, regeneration and other related research. This encompasses
applied approaches, as well as efforts directed toward understanding basic disease
processes, with the expectation of eventually preventing or ameliorating these
diseases and their sequelae. The limited resources available, now and in the for-
seeable future, require a continuing re-evaluation of program goals and objectives
to obtain the best possible research in all areas of endeavor so as to improve
the quality of patient care with these diseases, and eventually prevent them.
I. CEREBROVASCULAR DISEASE
The 13 Cerebrovascular Research Centers are designed to foster interdisciplinary
research, to maximize the sharing of stroke research resources, to attract young
investigators to research in stroke related areas, and to provide a framework for
collaborative discussion and interaction.
Studies at Cornell University Medical College during the past year 'illtlstrate ' ' *
the variety of approaches being used to investigate human and experimental stroke
and related problems. Clinical studies include development of a large computer-
ized data base with information on natural history, determining effect of early
damage on outcome, and assessing effects of early treatment. Quantitative techni-
ques are being developed to estimate brain water content by computerized tomography
scan. A prospective study using Doppler ultrasound technique has been initiated
to examine the carotid arteries of hypertensive and non-hypertensive industrial
populations with asymptomatic bruits. Neuropsychological evaluation of auditory
recognition and extinction in stroke patients continues as part of a long-term
investigation of parietal lobe function. Quantitative histochemical and blood
flow studies are being conducted in animals to characterize changes in brain
following several types of controlled ischemia. Damage to the blood-brain barrier
appears to be critical in determining whether or not edema follows cerebral
ischemia. Permeability studies are in progress employing biochemical, radionuclide,
and ultrastructural techniques. Hematologic studies in the laboratory have
demonstrated a strong anti-platelet effect of indomethacin and prostacyclin
(PGI2) in a carotid thrombosis animal model. Studies in rat neonates of remote
brain lesion effects on locus ceruleus is providing information potentially
relevant to cerebrovascular injuries in infants and which, may yield possible
mechanisms for recovery. Detailed maps of noradrenergic and adrenergic neurons
in the brain which subserve cardiovascular control are being constructed in a
search for a neurochemical basis for hypertension.
The Cerebrovascular Research Center at the Mayo Foundation has access to a unique
data resource which provides a record of long-term trends indicating the frequency
and distribution of the various categories of stroke, survival, and other aspects
of the natural history of stroke. This record system assures nearly complete iden-
tification of all residents of Olmstead County, Minnesota who receive any form of
medical care either as an in-patient, out-patient, in the emergency room or even
when seen at home or in a nursing home. Because of the standard methods of continu-
ing to update the record system, and because of the long history of neurologic
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expertise in the community, long-term observation of trends in the occurrence of
stroke in this community has been assured. Investigators at the Mayo Foundation
are also interested in proton nuclear magnetic resonance (NMR) as a practical
medical imaging modality. They are determining the sensitivity and specificity
of NMR in detecting cerebrovascular disease and comparing the results with
those obtained from CT. The findings from NMR are being correlated with cerebral
biochemical alterations, particularly those involving water, lipids, and proteins
in cerebral infarction. It is hypothesized that NMR imaging is more sensitive
than CT in the detection of cerebral ischemia and infarction during the early
stage, and that the alteration seen with NMR during the early stages of cerebral
infarction results from a change in water content, whereas the alterations in
later stages are from a change in the lipid or protein content.
During the past year, investigators in the Center at Washington University, St.
Louis, Missouri, have begun regular studies of surgical candidates for superficial
temporal artery-middle cerebral artery (STA-MCA) anastomosis using techniques
developed by them for the measurement of local cerebral blood flow, blood volume,
and oxygen utilization employing positron emission tomography (PET). As a result
of these studies, new insight has been gained into the hemodynamic consequences
of stenotic lesions in the internal carotid as well as the middle cerebral artery.
In such patients (often asymptomatic at the time of the study) they have now
observed significant reductions in blood flow accompanied by the reductions in
oxygen consumption and rather striking increases in local cerebral blood volume.
They interpret such findings to mean that viable tissue exists in this area of
threatened infarction, but that normally operative autoregulatory processes
have been exhausted. This latter observation is strikingly underscored by the
presence of the increased blood volume indicating substantial post-stenotic
dilation of the cerebral vasculature. In conformation with their working
hypothesis, they have seen such changes totally reversed by the STA-MCA anasto-
mosis procedure. These data clearly indicate the potential efficacy of pre-
surgical studies to identify individual patients who would be appropriate
candidates for the anastomotic procedure.
An operational model has been developed in the St. Louis Center for in vivo
analysis of dopamine receptors using PET. The strategy is based on the ability
to simultaneously measure tracer behavior in brain areas rich in receptors (e.g.,
caudate nucleus) and an area with no receptors (i.e., cerebellum). Using data
collected sequentially from these two regions, investigators can estimate the
density and the permeability of the blood-brain barrier to spiperone. This
model has been tested using ^^C-spiperone and direct tissue sampling in animals.
Results of these studies have been extremely encouraging to date. They are now
awaiting the synthesis of l^F-spiperone to begin actual in vivo studies.
Studies at the Massachusetts General Hospital have demonstrated the potential
usefulness of positron imaging in stroke disease and the volume of the O2
equilibrium- imaging technique in providing quantifiable indices of blood flow and
metabolism. On the basis of tomographic blood flow and oxygen metabolism images,
patients with stroke have been classified as: (1) relatively free from evidence
of damage; (2) with substantial evidence of ischemia but without necrosis; and
(3) with necrosis. The impetus for these studies stems from the realization
that acute stroke can be treated in a rational way only if one can reliably
determine the physiological status of the injured tissue, both at rest and,
after a therapeutic challenge.
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At the University of Miami, research has traditionally been oriented toward better
understanding the metabolic consequences of cerebral ischemia. More recently, the
areas of interest have been extended to include the disciplines of neurophysiology,
neuropsychology, neuropharmacology, and hematology. A report from this Center on
"Mechanisms of Irreversible Injury in Cerebral Ischemia" was presented at the
Princeton Conference.
Current interest has centered around two major areas concerned with pathogenetic
mechanisms of ischemic brain injury: (1) the factors responsible for heterogeneity
of ischemic injury within graded ischemic foci; and (2) the contribution of lipid
peroxidative processes to the production of ischemic brain injury. A reproducible
model for focal cerebral hemispherical ischemia containing consistent gradients of
hemodynamic severity has been developed which makes it possible to assess separate-
ly the mechanisms of ischemic injury in the central versus marginal portions of an
ischemic focus. Other studies in this laboratory suggest that lipid peroxidation
by free radical reactions may be a factor restricting the post-ischemic recovery
of energy metabolism in brain and that lipid-soluble antioxidants in brain may
act to mitigate the extent of eventual brain damage.
A new program has been established at Rush Presbyterian St. Lukes Medical Center
with the overall objective of enhancing knowledge concerning the role of pros-
taglandins in the pathogenesis, prevention, and treatment of stroke. This inter-
disciplinary effort includes investigators with expertise in coagulation, cell
culture, radioimmunoassay, biochemistry, neuropathology, pharmacology, and
medicinal chemistry. Preliminary studies have demonstrated the presence in
human serum of an active component which binds prostacyclin (PGI2) and prolongs
its biological activity. This active compound has been found to be markedly
reduced in patients with thrombotic stroke and attempts are being made to purify
this factor so that its physical and chemical properties can be determined. The
ultimate objective is to apply these investigations to the early diagnosis and
prophylaxis for patients who are predisposed to stroke because of abnormalities
in PGI2 stability. Other projects include the use of long-term cultures of
endothelial cells to study a prostacyclin-stimulating factor and the development
of a model of thrombosis to clarify the roles of prostacyclin and thromboxane in
experimental vascular thrombosis.
Clinical Trials
The Extracranial/Intracranial Arterial Anastomosis Study (EC/IC) was initiated
five years ago with the objective of determining whether this surgical procedure
would reduce by 50% or more, the incidence of first or recurrent completed
strokes in patients with certain forms of cerebrovascular disease (as detailed
in the clinical and radiological entry criteria for the study). As of July 31,
1982, patient accrual is expected to close, at which time there will be a total of
approximately 1,450 patients from more than 60 centers in North America, Europe,
and Japan. Years six, seven, and eight will provide for necessary patient follow-
up. Year nine will be the year for final data accumulation, analysis, and publi-
cation.
The high patency rate of about 90% following the surgical procedure speaks to
the quality of the participating surgeons as well as the feasibility of the
procedure. The considerable difficulties inherent in a multi-center study
have been successfully met to a great extent by this diligent and sophisticated
group. The NINCDS Monitoring Committee selected for this study continues to
meet regularly and is completely satisfied with the conduct of the study.
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Another cooperative study was initiated at the University of Iowa with the
objective of decreasing the morbidity and mortality from ruptured intracranial
aneurysms by determining the optimal time for surgical obliteration of the aneurysm.
Over 2,000 cases have been entered from seventy-five Centers and projected com-
pletion of case registration is March, 1983.
Research Grants
A new research project grant has been awarded to Boston University to expand the
Framingham Stroke Study. There will be a detailed risk factor evaluation for
stroke during the next two Framingham cycle examinations, approximately two
years apart. This will extend the prospective findings of the Framingham Study
on stroke up to 30 years of follow-up and will include the age group 75-84. A
number of precursors will be evaluated about which little has been previously
available. These include the role of arrhythmias documented by 1-hour ECG monitor-
ing, echocardiographic findings of valvular and myocardial dysfunction, lipid
profiles including HDL and LDL cholesterol, physical activity status, menopausal
status, psychosocial factors including Type A behavior, carotid bruit, ecolyzer-
confirmed smoking history and glucose tolerance based on a blood glucose load
and other variables. Also to be done are two methods of measuring carotid artery
stenosis. A more careful delineation of type of stroke will also be accomplished
by using CT scan information as well as the clinical findings.
There is a paucity of information about vasogenic brain edema, the most commonly
encountered form of brain edema in clinical practice which is generally seen in
association with ischemic and hemorrhagic strokes, trauma, infections, or tumors,
and involves primarily cerebral white matter. A project has been initiated at
Washington University to evaluate the hypothesis that the polyamines and their
rate-limiting synthetic enzjmie ornithine decarboxylase play an important role in
the pathogenesis of vasogenic brain edema and the break down of the blood-brain
barrier.
A new investigator at Henry Ford Hospial is studying a frequently neglected
aspect of stroke, the neuropyschological functioning of patients with transient
cerebral ischemia, and progressive or complete cerebral infarction after carotid
endarterectomy and extracranial/intracranial arterial bypass surgery. A neuro-
behavioral battery including psychological tests, neurological data, and behavioral
sampling, are being employed to assess patients preoperatively and post-operatively
over eighteen months. The results of neuropsychological assessment are correlated
with data from serial angiography and Doppler sonography. Medical and neuro-
psychological results are being studied for their relationship to demographic or
health history factors.
Metabolic regulation of cerebral blood flow is a widely accepted hypothesis, but
the mechanisms whereby the brain regulates its own blood flow is obscure. A
recent addition to the list of possible factors linking blood flow and metabolism
is the purine nucleoside adenosine, which has been proposed as a metabolic regulator
of coronary blood flow. In order to test this hypothesis, investigators at the
University of Virginia are using a multi-faceted approach to study the cerebro-
vascular physiology and metabolism of adenosine in whole brain, in cerebrospinal
fluid, and in pial vessels in situ. A comprehensive understanding of the control
of cerebral blood flow will allow a more rational treatment of its alterations
in disease status.
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II. POSITRON EMISSION TOMOGRAPHY
Cerebral blood flow is a critical variable linked to metabolism and physiology
in a wide variety of normal and pathological conditions. lodoantipyrlne labeled
with the positron-emitting radionuclide ^^C has been synthesized by Investigators
at the University of Miami School of Medicine who have validated the suitability
of this product for the measurement of regional cerebral blood flow in the rat
as a prelude to its possible application as a blood flow tracer in human studies
involving emission tomography.
For functional studies, a method has been developed for producing ^^C-2-deoxy-
glucose as a replacement for ^°F-2-deoxyglucose as a tracer. The shorter half-
life of the •'■■'•C compound lowers radiation exposure to subjects and makes it
possible to perform sequential studies in a subject on the same day.
Normal brain homeostatic mechanisms regulate intracellular pH within narrow
limits. Deviations from normal are associated with many neuropathological
processes, both structural and metabolic in nature. Since cerebral pH affects
important processes, e.g., blood flow, it is desirable to be able to assess the
acid-base status of the brain using non-invasive methods applicable to human
conditions. An evaluation has been made of the potential applicability of
5, 5-dimethyl-oxazolidine-2,4-dione (DM0) for PET studies of cerebral acid-base
balance. Results from animal studies indicate that this biochemically inert
and non-toxic compound may be a useful agent for investigating cerebral acid-
base balance using PET techniques.
At the University of California, Los Angeles, studies of aphasics using
^°F-Fluorodeoxyglucose positron emission computed tomography have shown areas
of metabolic depression in the left hemisphere larger than the area of infarction
noted on x-ray computed tomography. To evaluate the relationship between language
abnormalities and metabolic depression, 11 patients had f luorodeoxyglucose meta-
bolic scans, the Boston Diagnostic Aphasia Examination (BDAE), and the Porch
Index of Communicative Ability (PICA). Local cerebral metabolic rates for glucose
were determined for 13 brain areas as leftto-right ratios. Performance on
several of the BDAE tests (auditory comprehension, naming, oral reading, and
repetition) correlated significantly (p <0.01) with altered metabolic ratios in
the parietal and posterior middle inferior temporal areas; neither Broca's nor
Wernicke's areas showed such correlations. The findings suggest that areas
posterior, inferior, and superior to the traditional Wernicke's area (in and
around area 22) are important in the language abnormalities in this group of
aphasics .
While a number of neurological disorders are primarily or entirely manifested in
white matter, myelinated brain regions are relatively inaccessible to current
clinical imaging techniques. Although transmission computer tomography has
proven invaluable in the clinical neurosciences , its use in the selective Imaging
of myelin is limited by the minimal difference in intrinsic electron densities
of white and gray matter. Furthermore, in some disease of white matter there
may be little or no alteration in tissue density, thus minimizing the diagnostic
value of transmission tomography techniques. In order to overcome these problems,
some property other than tissue density must serve as the basis for a myelin
imaging technique. The development of positron emission tomographic techniques
facilitates the design of a suitable method, since PET permits measurement of
the regional distribution of administered radiotracers rather than of tissue
electron density.
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The PET Center at the University of Michigan has employed a test probe, iodoben-
zene, labeled with iodine ^^^ to image myelin non-invasively in the monkey.
Myelin imaging will be useful in evaluating various therapeutic regimens which
may be proposed in the future to halt or to reverse the demyelinating process.
Myelin imaging will also be useful for the detection of space-occupying lesions
confined to white matter which are currently not visible by other techniques.
At Brookhaven National Laboratory research continues on the preparation of posi-
tron emitters, particularly carbon^-*-, nitrogen^^, and oxygen ■'•^ as well as the
radionuclide fluorine^". This research is focused on development of new method-
ology involving targetry and precursor production utilizing a small "medical
cyclotron" which was recently installed. New synthetic methods for introducing
fluorine-'-" into organic molecules are being explored along with new syntheses
of labeled sugars for studying glucose metabolism, neuroleptics for in vivo
receptor studies and compounds for probing specific enzyme activity. The "pro-
drug" concept is used to improve delivery across the blood-brain barrier and
studies on animals are performed to determine bio-distributions, radiation dosi-
metry, as well as the toxicity of the proposed radiopharmaceuticals in the brain
and other organs. The Brookhaven group has led in the development of new positron-
emitting radiotracers and has done much to disseminate this technology to other
institutions.
III. SPINAL CORD INJURY
Spinal cord injury remains an extremely costly biomedical problem. As a result
of accidents, war-related injuries, and a variety of disorders, an unacceptable
number of young adults, young men in particular, are relegated to limited and
dependent futures as paraplegics. It is estimated there are 10,000 new cases of
spinal cord injury each year and a population of about 200,000 paraplegics in
the United States.
Injury to the spinal cord may be followed by a succession of secondary effects
that appear responsible for much of the ensuing disability and mortality. Most
often, paralysis follows, at some distance in time, the causative injury, since
severing of the spinal cord directly from a penetrating object is relatively
rare. More often, the spinal cord is "bruised" by a transmitted mechanical
force as might occur in an automobile collision. Neural tissue response to
trauma includes swelling, diminished blood flow and/or bleeding within the spinal
cord. It is anticipated that when the factors leading to these secondary effects
are better understood, more effective treatment of spinal cord injury will result
and disabilities such as paraplegia kept to a minimum or reversed. Thus, spinal
cord injury research is being directed at several major questions. These include
(1) explanations for the secondary (and presumably reversible) "self-destructive"
reactions of the injured spinal cord to mechanical injury; (2) the development
of sensitive diagnostic procedures to assess the extent of spinal cord dysfunction
(as well as retained function); and (3) the adoption of appropriate therapeutic
interventions to minimize the structural and functional sequelae of spinal cord
trauma.
The five Spinal Cord Injury Research Centers, supported by the NINCDS , continue to
be major contributors to fundamental and clinical research in the area of central
nervous system trauma. The centers are located at Yale University, Medical
University of South Carolina, New York University, University of Texas, San
Antonio, and Ohio State University. While a common goal binds the centers, and
while some research themes are common to several centers, each has developed
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unique interests which serve to give the broadest coverage to the problems
associated with spinal cord injury.
The research programs at Yale, South Carolina and New York University combine
both clinical and basic science studies while the programs at Ohio State and
Texas are devoted specifically to fundamental aspects of the spinal cord injury
problem.
The research team at Yale is exploring the nature of physical forces impacting
on the vertebral column and its enclosed spinal cord, the effect of the initial
injury on subsequent blood flow within the cord, and control of urinary bladder
function after injury (paraplegics often die of kidney infections related to
poor bladder control).
Investigators at the Medical University of South Carolina are refining the use
of electrical stimulation techniques and electrical recording from the central
nervous system to improve upon existing diagnostic techniques. This should allow
physicians the opportunity to better understand the extent of injury and permit
initiation of more appropriate modified therapy. Since most spinal-cord injured
patients are in a state of "spinal shock" for days after the injury, it is very
important to develop laboratory measures for ascertaining the extent of the
injury as early as possible in the shock period. This group is also determining
the effects of various tissue constituents, e.g., calcium and potassium ions,
on the injured nervous system since these substances may well contribute to the
cord's degeneration after injury.
The research group at NYU continues to pursue basic studies of the tissue environ-
ment, including chemical interactions and the generation of potentially harmful
by-products following injury. Blood clotting factors are under scrutiny as are
factors that may destroy the membranes of the spinal nerves. Refined diagnostic
procedures, e.g., evoked potential methods, developed in the laboratories are
being introduced into the clinical research and care facilities. The group has
also proposed several clinical studies of drugs reputed to minimize the conse-
quences of spinal injury in experimental animals, such as naloxone, steroids
and thyrotropin releasing hormone (TRH).
Researchers at The University of Texas are studying the degree of disability
(and recovery) as a reflection of the components of the spinal cord that are
injured (and spared) following trauma. They are also searching for the cause
and pharmacological modification of exaggerated muscle reflexes that appear in
affected muscles following injury.
The research center at Ohio State University focuses on a very fundamental approach
to the biological manifestations of spinal cord injury. Efforts are underway to
discern the effects of trauma on cellular energy systems and the enzymes that
degrade the insulating membranes of nerve tissue.
Whereas, the aforementioned studies reflect different approaches to a common
problem, a number of the centers are addressing similar questions. These include
changes in metabolism, blood flow and clotting factors, and characterization of
intact neural circuits following injury.
The NINCDS and other federal and private agencies support a number of spinal
cord injury individual research projects throughout the country. These studies
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provide insight into fundamental aspects of the disorder which when better defined
should serve as a basis for novel therapeutic interventions. Reports from two
of these laboratories in the past year have implied potential therapeutic effects
for several commonly available pharmacological agents. Studies conducted at the
Walter Reed Army Medical Center suggests that administration of naloxone immedi-
ately after injury may significantly improve recovery. However, a major problem
associated with use of naloxone in the treatment of severe spinal cord injury
relates to the fact that it also blocks the action of pain killers frequently
needed by the injured patient. As a result, investigators are now seeking pharma-
cologically related substances that are capable of reversing the effects of
injury which will not interfere with the alleviation of pain. A recent study
from the Uniformed Health Services Medical School has suggested thyrotropin-
releasing hormone (TRH) , a naturally occurring substance, as a potentially useful
alternative, and additional research is being carried out in this area. Although
these findings have stirred considerable interest within the research community,
additional efforts are required to substantiate these early findings, to ascertain
possible adverse effects, to optimize the treatment regimen, and to more fully
understand the mechanisms of the drug's actions. The NINCDS plans further studies
to corroborate the initial findings.
The National Spinal Cord Injury Study (a Yale University-based, multi-insti-
tutional, clinical program encompassing several of the spinal cord research
centers and other clinical facilities throughout the country) is in the final
phase of evaluating two steroid dosages for possible therapeutic use in acute
spinal cord injury.
IV. HEAD INJURY
The principal effort of clinical research groups, until recently, has been to
demonstrate the capability of specialized treatment centers to effect reductions
in mortality following severe head injury. More contemporary attempts to delineate
prognostic indicators of survival and quality of life are now well advanced.
While there may be small variations from clinic to clinic, it is now possible to
show that a generally agreed upon hierarchy of indicators is being established.
Non-invasive multimodal evoked potentials and the electroencephalogram are found
to be exceptionally effective in predicting outcome during the acute phase follow-
ing brain injury. Furthermore, they allow subsequent frequent monitoring of
critical changes in brain function to rapid adjustment of therapeutic activities
in relation to such changes. One research group has reported that multimodal
evoked potentials are accurate predictors of outcome in 80% of all cases and
closer to 90% when non-neural complications are excluded. The certainty is
reputed to grow still further if the following factors are taken into consideration
in descending hierarchical fashion, i.e., surgical mass lesions, age, intracranial
pressure, pupillary response, extraocular motility and motor posturing.
Another clinical correlation with important implications for the patient, the
community and clinical practice is the finding that recovery from surgical intra-
cranial decompression is a function of the time from injury to surgery. Delay
from injury to operation of less than four hours results in a mortality rate of
30%, whereas surgery performed after four hours is characterized by as much as a
90% mortality rate. In this instance, other relevant prognosticators include
the results of the initial neurologic examination, sex, multimodal evoked
potentials and post-operative intracranial pressure.
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The future management of head-injured patients may change significantly as a
result of recent additional findings. One such case in point is the perceived
need for monitoring intracranial pressure. There is now evidence to suggest
that acutely head-injured patients with normal CT (computerized tomograms) need
not have intracranial pressure monitoring routinely, since the pressure is
probably not elevated. However, repeat CTs at 24-48 hours are important in
sustaining this assurance, particularly if the clinical status of the patient
deteriorates.
Although brain injury has received considerable research attention, considerable
differences of opinion still remain regarding the pathophysiological sequelae.
At least one investigative group has indicated that the concept of diffuse post-
traumatic brain edema in the acute phase may have been overemphasized. This group
proposes that greater emphasis be placed on changes in cerebrovascular tone or
cerebrovascular volume, and on intracranial pressure. Adoption of these percep-
tions would necessitate associated changes in therapeutic regimens, i.e., control-
ling vascular tone and responsiveness, rather than edema in the acute phase.
Prostaglandins have been implicated in the damage sustained by cerebral arterioles
via arterial hypertension after brain injury. Their mechanism of action is
dependent upon generation of free oxygen radicals. Research into the factors
contributing to neural injury following ischemia indicate that the advent of
recirculation may further jeopardize neural tissues, since the generation of pros-
taglandins in blood vessel walls requires recirculation. Thus, further insight
into the vascular mechanisms associated with blood stasis may result in the
implementation of more effective therapeutic measures subsequent to trauma.
Earlier clinical studies and therapeutic trials were often initiated with patients
exhibiting varying degrees and locations of injury. However, a number of research
opportunities have illustrated the need for better discrimination in the selection
of patient cohorts for specific therapeutic studies. For instance, at least two
types of comatose patients have been described on the basis of differences in
cerebral blood flow and oxygen utilization. Another categorizing approach yields
two subgroups of severely brain-injured, discernible on the basis of early death
(within 48 hours) or not. These two cohorts are divided between those with severe
homogenizing necrosis and/or direct brain stem damage (and concomitant oculovestib-
ular alterations) versus those with hematoma and attendant symptoms. The former
derive in large measure from high speed auto accidents and appear to represent
the current irreducible mortality associated with severe head injury. The latter
derive from falls and blows and include many individuals who are ultimately
salvageable. Therefore, only by careful analysis of neurological, patho-
physiological and neuropatho logical factors can series of patients be compared
effectively and treatments evaluated meaningfully.
Several years ago, questions arose as to whether indiscriminate release of neuro-
transmitters, including epinephrine, occurred following injury to the brain, and
whether the transmitter release was responsible for deleterious secondary effects
(e.g., ischemia, edema and hypoxia of the brain) subsequently observed. While
the latter concept has yet to be substantiated, an increase in norepinephrine
has been shown and that increase is found to be inversely related to the Glasgow
Coma Scale. Alert patients, after brief loss of consciousness, have normal
levels, while those in coma have as much as seven times the normal level. Blood
pressure, pulse and temperature are elevated proportionally to elevations in
plasma norepinephrine in patients with head injury. The questions raised now are
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the possible broad range, adverse effects of sympathetic hyperactivity In patients
having sustained severe head Injury. These repercussions could Include hyper-
metabolism, cardiovascular abnormalities, as well as direct effects of catechol-
amines on the damaged brain. This line of inquiry is in keeping with a new
found emphasis on the contributions of other organ systems and local homeostatic
mechanisms (e.g., acid-base balance) to recovery from severe brain injury.
A variety of investigative methods and diagnostic techniques continue to be
developed and refined. New laboratory methods of imparting injury to the brain
have evolved, including approaches that cause graded damage due to acceleration
and torque. Thus, injuries commonly sustained by humans now can be rather faith-
fully reproduced in experimental animals, including primates. These models
enable better definition of the injury, and will permit the testing of potential
therapeutic interventions in much more meaningful contexts than hitherto possible.
The CT scan continues to be explored for its full potential. For instance, one
recent study suggests that the variations in the CT number in edematous brain are
directly related to the protein content of the edema fluid. Such findings greatly
extend the interpretative capability of these already valuable instruments.
A number of pharmacologic agents are reputed to protect the injured brain from
secondary adverse effects. Several clinical trials to evaluate the protective
effects of barbiturates are currently underway or nearing completion. The acqui-
sition of appropriate data is necessarily slow and deliberate and detailed results
will not be available for some time. Dimethyl-sulf oxide (DMSO) is also suggested
as an aid in reducing post-injury brain damage. Several research groups have
manifested interest in and proposed the conduct of trials using this agent.
However, problems related to toxicity of the substance and/or protocol of the
study remain to be overcome before definitive results will be forthcoming.
A broad spectrum of clinical and fundamental investigations are performed at the
five head injury research centers supported by the NINCDS. The centers are located
at the Virginia Commonwealth University, University of Pennsylvania, University
of Texas at Galveston, Albany Medical College and New York University. The
results of a number of the studies performed at these centers have been cited
earlier. Program projects at the University of California at San Francisco and
the University of Texas at Houston are engaged in somewhat more focused fundamental
and clinical research. The former program concentrates on brain edema, while the
latter is concerned with respiratory control, blood coagulation and psychological
indicators as they relate to the pathopysiology of brain injury and recovery
therefrom. The NINCDS also supports eight individual research programs devoted
to such topics as quantitative characteristics of computerized tomography, compen-
sation in rehabilitation, pathology of minor head injury, behavioral alterations
as a result of specific lesions and changes in neurotransmitter and receptor
function following injury.
V. CNS NEOPLASMS
Research related to brain tumor, biology and metabolism, as well as related
diagnostic and therapeutic research, remains a primary thrust within STP. Progress
has been made in determining the fine structure of a series of virus-induced
experimental brain tumors (RG2, 9L, H-54, AVM sarcoma, etc). Utilizing horse-
radish peroxidase as an experimental marker, studies have delineated permeability
characteristics, the interrelationship of subcutaneous brain tumors with
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intracerebral tumors and the variabilities observed in the growth and biology of
these systems. Quantitative autoradiographic studies will be used to more speci-
fically define fine structure relationships. The CT scan has also been utilized
for demonstrating presence of tumor in animal models as well as for more specifi-
cally defining the areas in and adjacent tumor. During the forth coming year,
greater emphasis will be placed in determining the capillary and endothelial
defects which occur in experimental gliomas.
Utilizing two types of monoclonal antibody unequivocal identification of neuro-
blastoma cells has been demonstrated in bone marrow of patients harboring this
disease. Increased efforts toward staging patients and learning more of the
tumor biology are underway. The interrelation of the mouse neuroblastoma C1300
with that in the human is being defined.
Radiation sensitizers have the potential of increasing the efficacy of radiation
therapy. Research in experimental models has attempted to establish a dose-
response curve versus comparative neurotoxicity for a series of these sensitizers
and, in addition, develop quantitative functional tests. The concentration X time
and exposure characteristics for the development of neurotoxicity in relation to
electron affinity and lipophilicity are being determined. Thus far, the metabolic
product of misonidazole (desmisonidazole) is approximately two times less toxic
than misonidazole itself. The location of peripheral nervous system lesions and
the types of axonal degeneration are being defined. Further goal of research in
this area is to develop protectors that might avoid the development of neurotoxic-
ity.
Basic research into nerve growth factors (NGF) as they may pertain to tumor
growth and differentiation provides important insight into regulatory mechanisms.
During the course of the year, investigators examined the sensitivity of NGF
receptor sites, mechanisms of controlling the affinity of NGF binding and promoter
substances to several different compounds. Specific cell lines sensitive,
resistant and unresponsive to NGF are being examined to determine their morpho-
logical and biochemical differences.
Specific effects of adenosine include induction of neurite extension. However,
adenosine also prevents proliferation when it is delivered in lesser concentra-
tions. Adenosine has been shown to mimic three of the effects of NGF. The
demonstration that the major site for adenosine activities occur extracellularly,
has led investigators to use genetic approaches to better understand its mechanism
of action.
Utilizing the neuroblastoma cell line, the interaction of NGF, growth rates,
maturation, culture and tumor-age relationships have been examined. Sensitive,
resistant and unresponsive neuroblastoma lines have been identified and thus
provide the nidus for further research. Utilizing the same cell line, other
researchers examine the functions of methyltransferase and its subcellular distri-
bution. Further research into the regulation of growth and differentiation will
be undertaken utilizing a tumor model which is highly reproducible, demonstrates
constant growth rates, metastasizes, secretes markers (catecholamines) and is
eventually lethal.
Scientists are producing monoclonal antibodies with high specific activity that
are designed to recognize and differentiate tumor from normal brain. Such
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antibodies can then be utilized for the study of the early development of tumors
and biochemical analysis of antigens involved in these antibody reactions.
Patients with neuroblastoma, for whom monoclonal antibodies have been developed,
are now able to be studied in greater detail. Utilizing the athymic nude mouse,
investigators are analyzing the predictive potential of direct subcutaneous
transplants of human brain tumors.
VI. NEURAL REGENERATION AND PLASTICITY
Current results of experimental work related to regeneration and plasticity
represent the broadest and fullest expression, to-date, of research in this
area. Using a wide variety of approaches, a critical mass of investigators has
uncovered fundamental concepts that promise to absorb the efforts of numerous
researchers seeking to unravel the enigma of regeneration in the central nervous
system.
A fuller realization of the heterogeneity of neural and non-neural tissues within
the normal central, peripheral and autonomic nervous systems has led to major
reassessments of the complexities involved in reconstituting essential neural
components in damaged tissues.
Although there has been a suggestion that some recovery of function through
regeneration may be observed in mammals, e.g., following lesions of long tracts
in neonatal rats, recent findings reveal that the observed returns of postural
and locomotor function are a reflection of either redirection of evolving tracts
over uninjured substrates, or reflexes intrinsic to the spinal cord below the
level of the lesion. In non-mammals, e.g., goldfish and sea lamprey, the
most common repair following spinal injury appears to involve regeneration,
collateral sprouting and synapse formation over relatively short distances. An
exception to the latter is reassertion of the long spinal tracts of amphibians
after cord transection during metamorphosis. Obviously, a wide range of experi-
mental models is helping establish the principles of neural development and
repair. The worth of these models for regeneration research is evident.
The nature of the research questions posed and the methodologies employed are
changing drastically. Earlier years were characterized by the search for
appropriate experimental models and the use of relatively uncomplicated morpho-
logical and electrophysiological methods to describe experimentally-induced
alterations of the nervous system. However, current studies, while dependent
upon the same survey techniques, have become increasingly more discriminating,
permitting evaluation as far as the molecular and ionic levels. Discrete
localization of specific cells, their membrane receptors, neurotransmitters,
and biosynthetic processes has been achieved through such techniques as cell
injection, freeze-fracture, immunocytochemical labeling, histochemical reactions,
microchemical assays and molecular probes. The physiological properties of
cells and their environment are explored by ion-selective electrodes, fluor-
escent markers and optical detectors. These and other powerful analytic methods
are permitting exploration at a heretofore unimagined level of detail.
Several laboratories are looking at "growth associated proteins" in the regener-
ating optic nerve-tectal system of the goldfish. They are also using radio-
labeled glucose and amino acids to study the nature and speed of the retrograde
message and biosynthetic turn-on observed in neurons following axonal injury.
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Interest continues to grow regarding the macromolecular changes occurring in
cell membranes during neurite extension, e.g., following the application of
Nerve Growth Factor to responsive neurons and related cells. The progression of
events is leading toward investigation of cellular reprogramming at the level of
gene function.
An intricate picture of neurotrophic functions and interactions is currently
emerging. Trophic factors appear to run from the relatively non-specific to the
very specific, and their sources seem to vary considerably. Thus, a battery of
bioassays appear necessary to discern the functional capability of potentially
active trophic substances. For example. Ciliary Neuronotrophic Factor (from
chick eye) has no significant trophic activity for lumbar cord neurons, while
trophic factors for the latter are present in conditioned media of Schwann or
muscle cells. The complexity of trophic function may be exemplified by the
observation that ciliary ganglion neurons cultured on polyornithine substrate in
media containing Ciliary Neuronotrophic Factor (and serum) will grow neurites
only if the polyornithine substrate is presented with Polyornithine-binding
Neurite Promoting Factors; these released into the medium by several types of
cells or exuded by explanted ciliary ganglia themselves.
There is growing recognition that the central nervous system undergoes intrin-
sic changes beyond those of the acute phase of injury. Dendrite and synaptic
reorganization may result in significant changes in sensory, motor and reflex
or effector function. The significance of these alterations to the organism and
their relative reversibility remain to be more fully explored.
Attempts to restore function following injury to the nervous system must, of
necessity, take into account a broad array of biological factors virtually un-
imagined a few brief years ago. An initial momentum has been achieved in our
attempts to understand the repair of neural systems. This impetus must be
sustained and strengthened in the effort to overcome the ravages of injury and
disease of the central nervous system.
VII . PAIN
Pain is one of the most prevalent and costly national health problems. When it
persists beyond the usual course of a disease, or normal healing time for an
injury, or is associated with progressive disease, pain may be termed chronic.
Investigators at the University of Washington have conducted research on the
effectiveness of relaxation and biofeedback, and more recently, directed attention
toward determining the efficacy of operant conditioning, hypnosis and cognitive
behavioral therapy approaches in alleviation of chronic pain. Both, biofeedback
and muscle relaxation training have been shown to reduce tension and migraine
headache activity. Biofeedback appears to be no more efficacious, is far cost-
lier than relaxation training and has been of limited value in the treatment of
chronic pain. Lengthy in-patient operant treatment programs appear to increase
physical activity levels and decrease medication use, at least while the patient
is in a controlled hospital environment. Cognitive-behavioral treatment approaches
have also been shown to alleviate pain in a variety of pain syndromes. In order
to explore the potential for therapy involving combined approaches, these investi-
gators have devised a comprehensive multidimensional assessment of patient,
process, and outcome variables which should enhance conclusions that can be
drawn from the results.
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At the University of Kansas Medical Center, a clinical trial is being conducted
to study the overall comparative efficiency of propranolol and amitriptyline in
prophylaxis of migraine and the clinical and psychological variables associated
with the therapeutic effect for each drug. During the past year, the effective-
ness of propranolol in migraine prophylaxis has been correlated with measure-
ments of physiological effects and plasma levels. In twenty-six migraine patients
there was a highly significant relationship beteen the prophylactic effect of
the drug and its beta-adrenergic blocking effect, with no such relationship to
plasma drug levels. Two statistical studies of the headache-prone population
utilizing a headache questionnaire instrument have been completed. Both studies
utilized factor analysis to investigate the natural grouping of variables occur-
ring in headache patients.
Interest in the spinal cord gray matter surrounding the central canal (lamina X)
stems from the recent demonstration that the region receives a projection from
primary afferent nociceptors and contains several pain transmitters known to be
related to pain transmission. Electrophysiological studies at the University of
Minnesota have revealed that a significant neuron population in this area is
responsive to nociceptive stimuli delivered to highly restricted receptive fields.
Furthermore, these neurons within lamina X are capable of coding information
regarding the location of a noxious stimulus on the body surface and transmitting
such information to several brainstem nuclei.
Investigators at the University of Texas are investigating the possibility that
Zoneperiac, a prostaglandin synthesis inhibitor might affect nociceptive responses
of spinothalamic cells. Preliminary studies indicate that there may be a central
action of the substance in addition to any peripheral local action.
Ongoing studies at the University of Massachusetts are directed toward defining
the mechanical sensitivity of afferent neurons innervating joint capsules. A
recently developed technique allows the measurement of afferent responses while
simultaneously measuring regional strain of the joint capsular material.
Two additional investigations have been initiated this year. One, at the Univer-
sity of Iowa, will pursue studies designed to confirm or deny the hypothesis
that acute stress-induced elevations in arterial blood pressure, resulting from
exposure to either conditioned or unconditioned adversive stimuli, may become
sustained because changes in the baroceptor reflex arcs reduce the aversiveness
of environmental stimulation. The second, at Harvard University, is aimed at
understanding mechanisms of activation of pain sensory endings and sensitization
of the endings, by use of tissue culture techniques which will allow direct
visualization of pain neurons and response to pain-specific stimuli.
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CONTRACT NARRATIVE
Stroke and Trauma Program, NINCDS
October 1, 1981 — September 30, 1982
Institutions
1. University of Rochester (NOl-NS-8-2385)
2. American Heart Association, N.C. Affiliate, Inc. (NOl-NS-8-2386)
3. University of Oregon Health Sciences Center (NOl-NS-8-2387)
Title: Comprehensive Stroke Center
Contractor's Project Directors; 1. John H. Feibel, M.D.
2. James E. Toole, M.D.
3. Frank M. Yatsu, M.D.
Current Level of Support: 1. $ 73,300
2. $150,000
3. $ 50,000
Objectives: The objectives of these Centers are to:
a. Conduct a program of applied clinical research in which fundamental
advances are utilized in the development of specific approach for the
prevention, diagnosis and management of cerebrovascular disorders.
b. Develop integrated and coordinated community resources to evaluate the
results of research on the prevention, diagnosis, and treatment of
cerebrovascular disorders.
c. Demonstrate to physicians, other professionals and the public, by a
broad public education program, the significant advances in cerebro-
vascular research and management.
Major Findings:
The Comprehensive Stroke Center Program, currently in its fourth year as a
cooperative undertaking is directed toward developing and evaluating treatment
models for stroke patients in three geographically distinct areas, the northwest
(Oregon), northeast (Monroe County, NY) and the mid-southeast (North Carolina).
Investigators in these centers have generated base-line patient data information
in an attempt to demonstrate that the transfer of currently employed therapeutic
modalities into the community does have an effect on outcome, morbidity, and
mortality of the stroke patient and that uniform data and observation techniques
are feasible.
A large amount of comparable data including demographic, diagnostic, and out-
come factors is being authenticated. Cross-center comparison tables of this
data have been prepared and a preliminary analysis of survivorship across the
three centers is in progress.
17-STP
Significance to NINCDS Program and Biomedical Research; As research in the
Stroke Clinical Research Centers has progressed, questions have arisen regarding
the applicability of their efforts. Do any of the techniques developed at a
particular clinical research center reach the surrounding community hospitals?
If so, does their application there produce the same results as it does at the
Center? Does the presence of a Center affect the distribution of care of the
stroke community? Does the care given in the Center affect mortality or morbid-
ity for a given type of stroke? Will intensive rehabilitation efforts help in
some cases? The Comprehensive Stroke Centers are attempting to find answers to
these questions.
Proposed Course: The three Centers have developed certain research areas which
are somewhat independent, while retaining programs with a certain degree of over-
lap. During the fourth year, the collection and analyses of patient data have
been done in accordance with guidelines established jointly by the three Centers.
Contractor Termination Date
University of Rochester 6/28/83
North Carolina Health Association, Inc. 5/31/83
(now Am. Heart Assoc, N.C. Affiliate, Inc.
University of Oregon Health Sciences Center 6/14/83
The completion of this work and the publication of Its results Is expected during
FY 82-83.
18-STP
CONTRACT NARRATIVE
Stroke and Trauma Program, NINCDS
October 1, 1981 — September 30, 1982
Institutions
1. University of California, San Diego (NOl-NS-9-2312)
2. Albert Einstein College of Medicine (NOl-NS-9-2313)
3. University of Texas Medical Branch (NOl-NS-9-2314)
Title: Establishment of a Comprehensive Central Nervous System Trauma Center
Contractor's Project Directors; 1. Lawrence Marshall, M.D.
2. Kamran Tabbador, M.D.
3. Ralph F. Frankowski, Ph.D.
Current Annual Level of Support; 1. $220,000
2. $220,000
3. $240,000
Objectives: This program is intended to evaluate the availability and the efficacy
of the care of patients with CNS trauma, and to develop guidelines for optimal
care of these patients in the setting of their community resources. Beyond
these broad goals, specific objectives will be to;
1. Develop coordinated community resources by means of which developments in
CNS trauma research can be evaluated on a community basis.
2. Foster clinical research on improved diagnosis and treatment of patients
with CNS trauma.
3. Bring results of research on CNS trauma rapidly and effectively to the general
community and especially to those segments of the community with a high
incidence of CNS trauma.
It is anticipated that such centers will serve as a general guide to the develop-
ment of improved facilities for patients with CNS injury in other communities
with similar geographical and population characteristics.
Major Findings; The three geographically distinctive centers have completed
gathering much of their comparative epidemiological data on CNS trauma and are
collaborating on a number of manuscripts intended for publication in appropriate
national and international journals. Further evaluation Is underway regarding
development of optimal interactions between the emergency medical services and
the trauma treatment centers. A number of publications intended to alert and
inform the public, with respect to nervous system injury, have already appeared.
The three centers are actively engaged in the implementation of a number of
research projects, interest and need for which derive from their earlier studies.
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Significance to NINCDS Program and Biomedical Research: A survey of CNS trauma
in the United States revealed approximately 400,000 new cases of head injury,
severe enough to be hospitalized. Approximately one half of these cases were
24 years old or younger. Due to the youth of those incapacitated, the impact on
national health and productivity is evident. Because of this, the NINCDS has had
special interest in the problem of CNS trauma, and is supporting research, both
in basic studies aimed at clarifying the pathophysiology of brain and spinal
cord injury and in clinical studies designed to improve diagnosis and treatment,
particularly in the period immediately following the injury. Through its programs
of head injury and spinal cord injury research, information important to patient
care is being obtained. New diagnostic techniques and new forms of treatment are
being evaluated in specialized clinical research units. In view of the increasing
amount of research in this field, it is now appropriate to evaluate this new infor-
mation at the community level and to contribute to its utilization.
Proposed Course: It is expected that two additional years of support (at a reduced
level) will be needed to complete existing and already planned research, demon-
stration and education projects. Irreversible functional deficits, including coma,
are not infrequent consequences of head injury, cardiac arrest, and other medical
problems leading to a compromised blood supply to the brain or its components.
Barbiturates are reputed to suppress the sequelae of cerebral ischemia and hypoxia
when given soon after insult. Suggestions have been made that when given in
appropriate amounts and at the proper time the drugs appear to (1) afford pro-
tection from focal infarction, (2) permit resuscitation from global ischemia-
anoxia, and (3) control intracranial hypertension. The direct barbiturate effects
involved in the protective mechanism may include reduction of metabolism, cell
membrane stabilization, free radical quenching, and anesthesia. A prospective,
randomized clinical trial on the efficacy of barbiturates in moderating the
effects of severe head injury, specifically increased intracranial pressure,
is being initiated. Physiological and clinical paramaters will be evaluated
during barbiturate treatment for otherwise uncontrollable increased intracranial
pressure. Since great uncertainty remains concerning the effect of barbiturate
treatment on the injured and ischemic brain, this cooperative clinical study
holds promise for establishing the value of a pharmacologic intervention that is
being practiced in a number of locales without well-established proof of efficacy.
20-STP
CONTRACT NARRATIVE
Stroke and Trauma Program, NINCDS
October 1, 1981 — September 30, 1982
Institutions
National Institute of Mental Health (YOl-NS-9-0044-04)
Title: Safety and Efficacy of Cingulotomy for Pain and Psychiatric Disorders
Contractor Project Director; Herbert Pardes, M.D.
Current Annual Level of Support; $83,128
Objectives: The research will assess therapeutic outcome, neurologic status, and
behavioral test performance in consecutive patients who have undergone bilateral
stereotaxic anterior cingulotomy for the relief of persistent pain or for the
alleviation of severe psychiatric disease. The purpose is to interview and
examine such patients both before and after operation to permit evaluation of
the postoperative findings in relation to the preoperative baseline for each
patient. In this way it should be possible to specify which diagnostic groups
are helped by cingulotomy and which are not, and one can document the duration of
any palliative effects. The proposed work, will also permit the investigators
to describe the neurological and behavioral effects of the surgical procedure,
whether transient or lasting, in quantitative terms.
Major Findings: After cingulotomy, patients with chronic pain rated the intensity
of their clinical pain significantly lower than they had before operation, and
matched their clinical pain to significantly lower temperatures delivered by the
Hardy-Wolf f-Goodell dolorimeter. They also had superior discrimination performance
after operation as compared with before, indicating that the improvement in their
clinical pain was not attributable to a decrement in pain perception. In contrast,
no such changes in clinical pain were seen after subcaudate tractotomy. In
fact, the subcaudate tractotomy group had significantly elevated temperature
matches after operation. Nevertheless, their postoperative discrimination scores
showed significant improvement, suggesting a dissociation of mechanisms underlying
clinical and experimental pain. Patients who received noninvasive treatments for
chronic pain matched their pain after treatment to lower temperatures than they
had before. At the same time, they were more willing to call hot or mildly
painful experimental stimuli painful than were patients in the other two treatment
groups. It is surprising that this tendency to give many reports of pain did not
preclude a successful outcome. The investigators are inclined to predict that
the benefits for this group will be transient.
Significance to NINCDS Program and Biomedical Research: Pain is the most common
symptom of disease which compels patients to seek medical counsel. In its acute
form pain has an important biological function. It prepares the individual to
cope with Injury or disease, and is a diagnostic tool for the physician. The
acute form is usually self-limiting due to the acute nature of the pathologic
process. Chronic pain, however, may have no biological function yet cause
extreme hardship for the affected individual, the family, community and workplace.
The costs to the American public have been estimated to be as much as $50 billion
21-STP
annually. This study analyzes the efficacy of a surgical method of last resort
that is employed to alleviate otherwise intractable chronic pain-
Proposed Course: To continue to follow the protocol of the on-going longitudinal
study.
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CONTRACT NARRATIVE
Stroke and Trauma Program, NINCDS
October 1, 1981 — September 30, 1982
Institutions
1. Hahnemann Medical College and Hospital, Philadelphia (NOl-NS-2-2307)
2. Georgetown University School of Medicine, Washington (NOl-NS-2-2310)
Title: Standardized Reproducible Spinal Cord Injury Model
Contractor's Project Directors: 1. Perry Black. M.D.
2. Jean R. Wrathall, Ph.D.
Current Annual Level of Support: 1. $568,000
2. $470,700
Objectives: This program, initiated September 29, 1982, is intended to
(1) develop an animal model of reproducible spinal cord injury and (2) use the
model to test drugs and other means purported to minimize the consequences of
injury to the spinal cord.
Major Findings: This program has just been funded.
Significance to NINCDS Program and Biomedical Research: There are approximately
200,000 spinal injured in the United States, with approximately 10,000 more
individuals sustaining these injuries each year. The physical, emotional, and
financial drain is enormous, especially so in light of the youth of those
incapacitated. "Novel" therapies, to minimize the disability (paraplegia and
quadriplegia) , are proposed periodically. The NINCDS is seeking an appropriate
animal model to permit well controlled trials of reputed treatments for spinal
cord injury.
Purpose Course: The two phases of study require (1) validation of a reproducible
model(s) of spinal cord injury and (2) use of the model(s) to test those therapies
considered most promising at the time the model is established.
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Office of the Director, Intramural Research Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
OFFICE OF THE DIRECTOR, IRP
NEUROEPIDEMIOLOGY SECTION (NES)
NEUROTOXICOLOGY SECTION (NTS)
INSTRUMENTATION AND COMPUTERS SECTION (ICS) 7.C
TAB
PAGES
7
1-4
7. A
5-27
7.B
28 - 35
7.C
36 - 43
i - ODIR/IRP TAB 7
Annual Report of the Scientific Director
of the
National Institute of Neurological and
Conmunicative Disorders and Stroke
October 1, 1981 through September 30, 1982
The Intramural Research Program (IRP) conducts research in the neurosciences
through the direct operation of its laboratories and clinics on the main NIH
campus as well as at off-site locations in Rockville and Frederick, Maryland; at
Woods Hole, Massachusetts; and on the Island of Guam. In these facilities.
Federal Government scientists and support personnel continue to make major
contributions to the field's explosive growth. Ranging from basic neurobiologic
probes to clinical trials of new therapeutic agents, this work continues to
advance our ability to prevent, ameliorate or cure neurologic and communicative
disorders. The impressive accomplishments of Program scientists are summarized
in subsequent sections of this report. This section will primarily address
managerial issues impacting on current and future IRP operations.
Maintenance of the Program's creative vigor and breadth of scientific inquiry,
despite fluctuating and generally shrinking resources, remains as the principle
challange to IRP management. Not only must existing, high quality, programati-
cally relevant investigations obtain adequate support, but some new initiatives
must also be launched if the Program is to exploit critical methodological and
conceptual advances and remain at the forefront of neurosciences research. An
approach to these objectives includes rigorous quality assessments of current
activities, careful restructuring of priorities, timely reallocation decisions,
and vigorous efforts directed towards the retention and/or recruitment of
scientific talent. Unfortunately, fiscal and personnel constraints, some unique
to agencies of the Federal Government, not infrequently complicate the rational
operation of these processes.
Notwithstanding claims from some in the Extramural community, the IRP is not
growing at the expense of the Institute's grants program. As in the past, IRP's
financial situation reflects that of the NIH generally and of the NINCDS
specifically. Since 1979 approximately 11-12% of the total NIH appropriation
went for the support of all intramural operations; for NINCDS this proportion
has remained essentially level at 13-14%. At the same time, grant support
increased from 61 to 66% for all of NIH and from 66 to 72% of total
appropriations for NINCDS. A decline in the Institute's research and
development contracts, from 10% in 1979 to about 5% in the current fiscal year,
provided the bulk of funds for the expansion of the grants program.
In terms of actual total dollars allocated, IRP received approximately $38
million in fiscal year 1982, an increment of $3 million above the preceding
year. When computed in constant dollars, however, the Program's total allo-
cation has remained essentially unchanged during the past two years and is now
about 4% less than in 1979. Moreover, a steadily rising proportion of this
total is now channeled towards such uncontrollables as personnel costs (up from
30 to 36% of total expenditures since 1979 due to manditory salary increases)
and overhead changes (up from 30 to 33% during the same period). As a result,
while the amount of residual "other objects" dollars available for the purchase
1 - ODIR/IRP
of laboratory equipment and supplies has remained virtually constant since 1979,
actual purchasing power has fallen by more than 25%. This decline has forced a
reduction in the overall size of IRP operations, as well as deferrals of planned
equipment replacements and laboratory renovations. Relief from this trend
towards increasing budgetary stringencies is not expected in the immediate
future.
IRP research contracts, by funding such critical activities as reagent synthesis
and off-site primate holding, provide essential support for high priority in-
house investigations. As mentioned previously, the Institute's total
expenditure on research and development contracts declined sharply during the
past two years. The reduction in the IRP contract portfolio, while less
drastic, still amounted to over 10% during the past three years. This cutback,
compounded by the effects of inflation, compelled a shift in direction for some
research projects and a curtailment in the size of overall Program operations.
Unless the IRP is to undergo major alterations in the nature and scope of its
investigative efforts, research contracts must be protected against further
erosions in their funding levels.
During the past year, IRP operated without any formal ceiling on the total
number of employees or periods in which the hiring of new staff was prohibited.
In response to these rather unique circumstances. Program size largely reflected
budgetary and spatial constraints. The net effect was that the number of IRP
scientific and support personnel remained essentially constant. At the end of
May 1982 the Program had 500 employees: 210 were in full-time-permanent and 186
in other-than-full-time-permanent positions; another 104 occupied ceiling free
positions (54 Visiting Fellows, 36 Guest Workers, and 6 Intergovernmental
Personnel Act employees). Considering this total group, 49% are classified as
scientists, 37% as technical support personnel, and 14% hold administrative
positions. In the scientific group, 32% have Government tenure (22% occupy
Civil Service positions and 10% are in the Public Health Service), while 68% are
nontenured (32% Visiting Program, 21% Fellows, and 15% in various other
categories such as Inter-governmental Personnel Act and special expert
programs) .
The number of individuals occupying IRP training positions also continued at
essentially stable levels. During the past year 179 promising young investi-
gators took advantage of opportunities to train here as Staff Fellows (63);
Visiting Fellows, Associates or Scientists (74); Guest Workers (36); and Inter-
governmental Personnel Act investigators (6). In addition, a newly instituted
program of elective courses for medical and dental students attracted 13
students during the past year. Since most who apply for one of the four 8-week
sessions offered each year seek maximum exposure to neurosciences research, a
major component of their experience is an involvement with an on-going clinical
or laboratory project. This is usually handled on a tutorial basis arranged by
the chief of the laboratory or branch that has selected the student. Another
training activity deserving special mention is the EEC Summer Employment Program
for high school, undergraduate, and graduate students. This program provides
on-the-job training with a view towards encouraging talented students to pursue
research careers in the neurosciences. During the past summer IRP employed over
80 young people in this program, with the proportion of minorities exceeding
that of any other NIH Institute.
2 - ODIR/IRP
The relative constancy in overall Program size disguises a continuing problem in
the retention and recruitment of senior scientists. During the past year Dr.
Donald B. Calne, who for the past seven years served ably as both Clinical
Director and Chief of the Experimental Therapeutics Branch, resigned to accept a
substantially higher paying academic post in Canada. Efforts to replace him
have as yet been unsuccessful. Strenuous attempts to recruit a chief for the
newly created Communicative Disorders Branch from a list of highly qualified
candidates recommended last year by an external search committee have also been
unrewarding. Similarly, long standing efforts to recruit leadership for the
Program's positron emission tomography and epilepsy research activities have yet
to be successfully concluded. These difficulties in no small measure reflect
the inadequacies of current salary and fringe benefit packages offered by NIH to
its highest level employees. For example, all four candidates interviewed for
the Communicative Disorders Branch position reported earnings from their current
academic positions 30 to 60% higher than the maximum NIH can pay.
The amount of on-campus space available for IRP use increased by nearly 7%
during the past year as a result of the opening of the laboratory half of the
fifth (NINCDS) floor of the Ambulatory Care Research Facility (ACRF). Much of
this facility, which conveniently adjoins the NIH Clinical Center, has been
assigned to the Experimental Therapeutics Branch, allowing consolidation of
operations previously scattered about Buildings 10 (Clinical Center) and 36.
Remaining ACRF laboratory areas have been dedicated to meet urgent Program needs
for cold rooms, animal rooms, and a conference room. The clinical half of the
ACRF, yet to be made available for Institute use, will house a greatly expanded
range of outpatient research activities as well as provide facilities for the
communicative disorders, epilepsy, and clinical neurophysiological activities.
Program operations will soon be further benefited by the implementation of long
standing plans to consolidate most IRP branches conducting patient research on
the fifth floor of the Clinical Center. Leading off a complicated series of
moves, the Neuroimmunology Branch will soon transfer from Building 36. Space
vacated in Building 36 as a result of all these changes will permit the
expansion of several preclinical laboratories, particularly the newly organized
Laboratory of Molecular Genetics.
As a result of current operating stringencies, no major new research initiatives
were undertaken during the past fiscal year. On the other hand, the shut down
or size reduction of some IRP components enabled important shifts in Program
emphasis. For example, the Neuroimmunology Branch received additional means to
start a new section which will focus on disorders of the neuromuscular system;
the Laboratory of Molecular Genetics received resources to augment recombinant
genetic studies; the Laboratory of Molecular Biology began a new Section on
Molecular Neurobiology; and support for Institute cerebral imaging studies
involving positron emission tomography and nuclear magnetic resonance expanded.
Investigator initiated research by Program scientists continued to flourish
during the past year. During this period 13 projects were initiated, 16 were
completed or terminated, and 130 remained active. The most extensively
supported disciplines in the basic neurosciences were physiology, chemistry,
microbiology, and pharmacology. Investigations of demyelinating, dementing,
and neoplastic disorders of the nervous system received the most support in the
clinical research area. During the past year 37 new clinical research protocols
were approved, 28 were terminated, and 87 remained active. Many of these
studies involved tests of novel therapeutic agents, most of which are now
categorized as drugs of little commercial value.
3 - ODIR/IRP
More than 300 scientific articles were published by IRP staff members during
calendar year 1981. Journals publishing most IRP authored papers during this
period included in the pre-clinical areas Brain Research, Journal of
Neurochemistry, Proceedings of the National Academy of Science, Experimental
Neurology, Science, Journal of Biological Chemistry, Nature, and in the clinical
areas Neurology, Archives in Neurology and Advances in Neurology. An IRP-
sponsored study of papers published between 1970 and 1976 by NINCDS intramural
investigators compared with NINCDS extramural grantees found that in the basic
neurosciences the number of times other authors cited articles written by
members of the former group averaged 15.6 in contrast with 13.4 for the latter
group. In the clinical neurosciences, intramural papers averaged 6.5 cites per
article as compared with 5.6 for the extramural papers.
Each year a number of IRP scientists receive special recognition for the
sustained excellence of their scientific contributions. These accolades include
invitations to lead a major professional organization, present a prestigious
lecture, serve on the editorial board of an influential journal, or to receive
an important prize. Among those so honored during the past year Roscoe Brady,
Chief of the Developmental and Metabolic Neurology Branch, deserves special
mention. He received the Passano Foundation Award for "highly original contri-
butions to our understanding of the inborn errors of lipid storage diseases
known as Sphingolipidoses".
4 - ODIR/IRP
■pa
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5
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o
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Neuroepldemiology Section, ODIR
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 5-12
PROJECT REPORTS
Clinical, Genetic, Pathophysiologic Study of 13
Hereditary Movement Disorders
ZOl NS 01924-12 ODIR
Clinical, Genetic, Pathophysiologic Study of 14
Hereditary Nervous System Tumors
ZOl NS 01927-12 ODIR
Genetic Epidemiology Studies in MS and Other 15
Multifactorial Neurologic Disorders
ZOl NS 02167-08 ODIR
Epidemiology of Dementia 16
ZOl NS 02240-06 ODIR
The Epidemiology of Cerebrovascular Disease 17
in Adults
ZOl NS 02241-06 ODIR
Pediatric Neuroepldemiology 18
ZOl NS 02243-06 ODIR
Mortality from Neurologic Disorders: National 19
and International Comparisons
ZOl NS 02297-06 ODIR
Reviews of Epidemiologic Aspects of Neurologic 20
Disease
ZOl NS 02299-06 ODIR
Clinical Course and Medical Care for Neurologic 21
Disorders
ZOl NS 02300-06 ODIR
i - ODIR/IRP (NES) TAB 7. A
Table of Contents (cont'd]
Collaborative Studies of Less Common or Less 22
Debilitating Neurologic Disorders
ZOl NS 02301-06 ODIR
The Epidemiology of Intracranial Neoplasms 23
ZOl NS 02305-06 ODIR
Educational Resources in Neurological Epidemiology 24
ZOl NS 02307-06 ODIR
Racial Differentials in the Prevalence of Major 25
Neurologic Disorders and Surveys in Developing
Countries
ZOl NS 02370-04 ODIR
Development of Data Resources for Neuroepidemiology 26
ZOl NS 02423-03 ODIR
Standardized Nomenclature and Coding of Neurologic 27
Diseases
ZOl NS 02424-03 ODIR
TAB 7. A ii - ODIR/IRP (NES)
Annual Report
for Period October 1, 1981 through September 30, 1982
Neuroepidemiology Section
Office of the Director
Intramural Research Program
National Institute of Neurological and Communicative
Disorders and Stroke
Bruce S. Schoenberg, M.D., Dr.P.H., Chief
The Neuroepidemiology Section is responsible for the development and
implementation of epidemiologic and genetic programs to investigate the
cause, prevention, and treatment of neurologic disorders in human
populations. Emphasis has been placed on major neurologic diseases in
which the diagnoses can be clinically verified to the satisfaction of
skilled neurologists.
The Section is unique in being the only unit devoted exclusively to
research in the epidemiology of diseases of the nervous system. These
research studies require collaboration of many individuals. However, since
there is a severe shortage of available manpower in neuroepidemiology, the
Section developed an active teaching program for current and future
collaborative investigators. A series of four videotapes produced by the
Section are distributed on a loan basis without charge. A textbook,
entitled NEUROLOGICAL EPIDEMIOLOGY: PRINCIPLES AND CLINICAL APPLICATIONS,
was prepared, and a scientific quarterly journal entitled NEUROEPIDEMIOLOGY
began publication in 1982. A symposium on the solutions to methodologic
problems in neuroepidemiology was held in conjunction with the Society for
Epidemiologic Research and the World Federation of Neurology. In co-
operation with the World Health Organization and the World Federation of
Neurology Research Committee on Neuroepidemiology, formal courses were
conducted in Beijing, the People's Republic of China, Madrid, Spain,
Florence, Italy, and Lima, Peru. Additional courses will be held in Mexico
City, Mexico, Quito, Ecuador, and Caracus, Venezuela. A workshop on
controlled clinical trials in neurology was held in conjunction with the
American Academy of Neurology. Future symposia are planned in collaboration
with the World Health Organization, the World Federation of Neurology, and
the International Epidemiological Association. These sessions serve as a
stimulus for neuroepidemiologic research on a worldwide basis. We are also
providing opportunities for fellows to spend from six months to one year
working with members of the Section in order to learn the techniques of
neuroepidemiology. During the past two years we have had physicians from
Great Britain, Nigeria, Mexico, Turkey, India, Spain, Italy, and Peru, and
have received inquiries from Kenya, the People's Republic of China, and
Israel for future opportunities. There is considerable neuroepidemiologic
interest among senior neurologists (two of the physicians working in the
Section are professors and chairmen of their own units abroad). Finally,
current individual and institutional research training grant programs have
been expanded to include neuroepidemiology. With the initiation of an
educational program, the Section has focused on research investigations.
5 - ODIR/IRP (NES)
Epidemiologic studies have two basic requirements: uniformity and
accuracy of data collection. This necessitates the use of a standardized,
internationally accepted classification and coding system. The most recent
scheme generated by the World Health Organization is seriously deficient
with regard to neurologic disorders. The Section is therefore collaborating
with the World Health Organization Neurosciences Program, the World
Federation of Neurology, and the American Academy of Neurology to revise
this system of classification and improve its usefulness for neuroepi-
demiologic research.
Another important problem for the neuroepidemiologist is the enormous
cost of maintaining neurologic surveillance on a large number of patients.
Therefore, we have attempted to utilize existing registries of neurologic
disease, such as in a study of presenile dementia based on the Israeli
National Neurologic Disease Registry. In addition, we have assisted
British investigators in organizing information routinely collected through
the British National Health Service on all neurologic inpatients in a
section of London with a population of 3-1/2 million inhabitants. The
utility and accuracy of these data have been demonstrated in a study of the
Guillain-Barr^ syndrome. A similar registry has been organized for the
population of northeastern Italy.
There have been a number of neuroepidemiologic case-control studies
which have suggested associations between a given factor and a particular
disease, but the number of patients has been inadequate for meaningful
conclusions. We are working in collaboration with a number of multiple
sclerosis clinics to establish a uniform protocol and data base to enable
us to explore several hypotheses of interest which require a large number
of cases. Similar arrangements are being made to initiate analytic
epidemiologic studies of Alzheimer's disease. These several projects in
support of research activities, have been initiated in conjunction with a
very active research program.
With regard to neurologic problems in children, the Section documented
the frequency of primary intracranial neoplasms in the pediatric population
of Rochester, Minnesota, and the State of Connecticut. In addition, we
investigated cerebrovascular disease in infants and children. The
magnitude of this problem was documented for the first time. The study
demonstrated that neonatal intracranial hemorrhage is relatively common
(1.1 cases/1,000 live births), that it is strongly associated with
prematurity and hyaline membrane disease, and that it is difficult to
recognize clinically. For pediatric cerebrovascular disease unassociated
with birth, trauma, or infection, the incidence rate was 2.5/100,000/year.
These cases were further characterized by survival, residual disability,
and cause (whenever possible). The clinical and angiographic features of
children with moyamoya disease were examined in detail. This condition
appears to be more common than suggested by early case reports. The
Section is also investigating the epidemiology of cerebral palsy (CP). A
study of temporal trends in the incidence rate of CP for Rochester,
Minnesota, addressed the concern that advances in perinatal care, by
rescuing the compromised neonate, are increasing the rate of neurologic
handicap. It was gratifying to learn that in the population studied,
coincident with a period of change in perinatal care, the incidence rate of
CP declined. In a CP outcome study, a decreased survival was limited to
6 - ODIR/IRP (NES)
individuals who needed custodial or total nursing care. For the remainder
of the case sample, a 100% 10-year survival prevailed, and resolution of
the motor handicap was shown not to be an exceptional event. Case-control
studies of the identified CP cases and of concurrent neonatal deaths are
being initiated in search of maternal, fetal and obstetric risk factors of
CP.
The Section has conducted extensive investigations of primary
intracranial neoplasms. First, problems with nomenclature and disease
definition were resolved. After this, two patterns of age-specific
incidence emerged. Analyses of most population-based data worldwide
revealed a small childhood peak, followed by a later peak between ages 50
and 80. Data for Rochester, Minnesota, however, showed the childhood peak,
followed by an increasing incidence rate with increasing age. Careful
study of this discrepancy showed 1) that the greater percentage of cases
first diagnosed at autopsy in Rochester accounted in large part for this
difference, and 2) that a substantial number of brain tumors remain
undiagnosed in the elderly during life. Studies have just been completed
to evaluate the role of computerized tomography in the diagnosis of brain
tumors and to explain the recent increase in the incidence of pituitary
tumors among women of childbearing age. The introduction of computerized
tomography has not resulted in any increase in the reported frequency of
these tumors in the Rochester, Minnesota population, while the apparent
rise in the incidence of pituitary tumors seems to be the result of more
sophisticated neuroendocrine diagnostic procedures. An exhaustive,
critical review of a survey strategy to measure the national incidence and
prevalence of intracranial neoplasms has been completed. In addition,
racial differentials in the frequency of certain intracranial tumors
(meningiomas and pituitary adenomas) are being examined. Investigations of
the relationship between intracranial neoplasms and extracranial tumors
have been especially rewarding. An association was found between the
occurrence of breast cancer and meningioma in women. This result raises
interesting etiologic possibilities when considered with other evidence:
1) meningioma is the only common intracranial neoplasm with a higher
incidence in females; 2) the abrupt clinical appearance or enlargement of
this tumor during pregnancy has been described; and 3) the finding of
estrogen receptor protein in meningioma has been reported.
At the present time, there is little to suggest that improved medical
management of the completed stroke will substantially affect the
cerebrovascular disease problem. It would appear that greater benefit
could be achieved by dealing with the precursors of stroke rather than
delaying treatment until after the event has occurred. Therefore, a non-
concurrent, prospective study of a cohort of 2,000 elderly individuals was
undertaken to determine the role of heart disease and hypertension as risk
factors for both transient ischemic attacks and completed stroke. When the
case-control approach was applied to these data, different patterns of risk
factors were demonstrated for transient ischemic attacks and completed
ischemic stroke. While hypertension, diabetes mellitus, definite
hypertensive heart disease, and valvular heart disease are important risk
factors for completed ischemic stroke, these disorders have a substantial
effect on the subsequent risk of TIA. When these data were analyzed in the
format of a prospective study, it was possible to calculate the absolute
risk of stroke as a function of the presence or absence of specific forms
7 - ODIR/IRP (NES)
of cardiovascular disease. The following types of cardiovascular disease
yielded the highest ischemic stroke incidence rates (given in cases/1,000/
year): myocardial infarction (15.5); congestive heart failure (20.5); and
TIA (42.0). In considering risk factors for TIA, both angina/coronary
insufficiency and congestive heart failure yielded the highest rates (10.4
and 10.9, respectively). Once etiologic precursors of stroke have been
identified, medical intervention before the occurrence of long-lasting
disability requires that there be an interval of time between the onset of
the risk factor and the development of completed stroke. Analysis of data
from this non-concurrent prospective study revealed that those developing
borderline hypertension, valvular heart disease, or ischemic heart disease
remained stroke-free for the initial one and one-half years after the first
occurrence of each specific form of cardiovascular disease. This finding
implies that there is an interval of time following the onset of these
conditions when it may be possible to intervene medically to reduce the
risk of stroke.
Other investigations in the area of stroke involve a careful analysis
of unusual patterns of cerebrovascular disease (e.g., more than 20
TIA's/day).
Alzheimer's disease/senile dementia, despite its high apparent clinical
frequency among the elderly, has not been well studied in a U.S. population.
Because of this, we have launched three investigations. One is derived
from a review of detailed clinical records utilizing a population-based,
records-linkage system; the second utilizes a two-stage survey consisting
of a questionnaire and clinical examination; and the third (in collaboration
with the National Institute on Aging) is based on a questionnaire survey.
In the records-linkage study, a neurologist using fixed diagnostic criteria
reviewed records from all medical facilities serving the residents of
Rochester, Minnesota. This made it possible for the first time to determine
the incidence of dementia coming to medical attention in a well-defined
U.S. population. For those age 30 plus, the incidence rate was 110 new
cases/100,000 population/year. The rates increase with age, and the
age-specific rates were higher in women. To confirm the reduced survival
of demented patients reported on the basis of individuals hospitalized at
specific medical centers, we examined the survival of all demented
individuals identified through our records-linkage study. Dealing with an
entire population minimizes any possible selection bias that may be present
for a series of patients seen at a particular medical institution. The
survival rates generated for all demented patients in the defined
population were significantly reduced compared to age- and sex- matched
survival statistics derived from life-tables for residents of the northwest
central region of the U.S., thereby documenting in a community study
previous observations based on hospitalized patients.
The two-stage survey permitted us to estimate the prevalence of
dementia in a bi racial community. For each race, prevalence ratios were
higher for females. For each race and sex, the prevalence figures rise
dramatically with age. This morbidity study indicates that dementia
represents a major health problem for both racial groups.
There has been some debate as to whether Alzheimer's disease is a
single disease entity regardless of its age at presentation. Since the
8 - ODIR/IRP (NES)
frequency of Alzheimer's disease is relatively low before age 60, an
enormous population is required for surveillance in order to obtain an
adequate number of patients for study. We are therefore utilizing the
resources available through the Israeli National Neurologic Disease
Registry to identify all potential cases among the population of Israel.
These cases will be intensively reviewed to determine the accuracy of
diagnosis and to explore a number of epidemiologic studies of the
distribution and risk factors for this disease. A similar sex-ratio for
patients with onset before and after age 60, and a steadily increasing
age-specific incidence in the elderly would argue in favor of a single
disease entity.
The Section is also interested in accurately documenting possible
racial differentials in the prevalence of major neurologic disorders. A
number of early investigations suggested possible differences by race, but
were based on hospital or clinic experience and could not identify a
well-defined population from which cases were derived. Population-based
studies followed, but questions concerning the results centered on possible
racial differentials in access to expertise in neurologic diagnosis and
treatment. We reinvestigated (in conjunction with the Surveys and
Demographic Studies Section, DBFS, OD, NINCDS) this problem of possible
racial differentials in the prevalence of major neurologic disorders by
surveying a well-defined population (approximately 25,000, almost equally
divided between blacks and whites). We developed a strategy which
eliminated the requirement that persons must have entered the health-care
system for detection of disease. The disorders investigated included
cerebral palsy, dementia, psychomotor delay, epilepsy, Parkinson's disease,
essential tremor, and cerebrovascular disease (both transient ischemic
attacks and completed stroke). The basis of the investigation was a
door-to-door survey which utilized a detailed questionnaire inquiring not
only about diagnoses, but also about signs and symptoms suggestive of
neurologic dysfunction. Over 99% of the households agreed to the
interview. Those household members suspected of having one of the
disorders of interest were then asked to have a neurologic examination
conducted by a senior, board-certified neurologist. The interviews and
examinations have been completed, and the data are being edited and
analyzed. Data currently available for Parkinson's disease indicate that
in the population studied, parkinsonism is more common in whites but the
difference between races is not as great as suggested by earlier studies.
The same survey yielded information on essential tremor, thereby providing
the first data on the prevalence of this condition in a defined U.S.
population. For either race, the prevalence ratios were slightly greater
in women, and for either sex, the figures were slightly higher for whites.
In this same population, it was also possible to measure the prevalence of
cerebral palsy. Prevalence ratios of cerebral palsy were higher in males
than in females, and greater in blacks than in whites.
Similar strategies are being developed for application in developing
countries (e.g., Nigeria, Mexico, the People's Republic of China, Peru,
Ecuador, and India), in collaboration with the World Health Organization.
Preliminary results from pilot studies in Nigeria and the People's Republic
of China have already revealed interesting findings. For example, migraine
9 - ODIR/IRP (NES)
is as common among a rural black African population as among urban popula-
tions of Western Europe. Furthermore, epilepsy is a major problem in
Nigeria, with a prevalence considerably higher than reported in developed
countries. In an area of Beijing in the People's Republic of China, the
prevalence of cerebrovascular disease is higher than anywhere else in the
world where this problem has been studied.
We currently have very little information on the patterns of medical
care received by all individuals with neurologic disease in a given
community. The Section is, therefore, studying this problem in Rochester,
Minnesota. Although the findings of this investigation will not necessarily
be applicable to other regions of the U.S., the City of Rochester does
offer particular advantages. Cases of neurologic disease among residents
have already been identified through previous studies. Medical encounters
are easily documented through a records-linkage resource. In addition,
Rochester residents have access to high-quality medical care, and physicians
with neurologic expertise are available within the community. Thus, the
Rochester experience may provide some estimate of the pattern of medical
care in the ideal situation in which the population has ready access to
neurologic expertise, and in which there is little financial restraint to
such care. The study for patients with brain tumor is being prepared for
publication, and similar data are being analyzed for completed stroke.
Although death certificate data are limited by possible misdiagnosis,
incomplete case ascertainment, errors in coding, etc., detailed morbidity
information on neurologic diseases for the entire U.S. and for other
countries is not available. The Section has analyzed mortality data for
selected neurologic disorders by country and by county in the U.S. The
overall patterns which emerge may be useful in evaluating trends over time
and in formulating etiologic hypotheses. Among the most interesting
findings is that the mortality from cerebrovascular disease has decreased
in most developed countries over a 20-year period. This trend is not
universal, however. For multiple sclerosis, countries initially reporting
high mortality rates have generally reported declines, so that more recent
mortality data for multiple sclerosis by country show less of a differential
than previously reported. United States mortality rates for motor neuron
disease and anencephaly were analyzed by county. For anencephaly, counties
in the Mississippi River region and in the Appalachian Region had the
highest rates. With regards to motor neuron disease, counties in the west
(especially the northwest) had the highest rates and there was a positive
association with rural farming. These leads will be pursued in more
definitive studies.
A number of other collaborative projects include the investigation of
space/time clusters of neurologic disease (with the Center for Disease
Control and the Government of Colombia), the development of survey
strategies (with the World Health Organization and the Section on Disease
Statistics Surveys), a study of myasthenia gravis and multiple sclerosis in
the same patient (with the Mayo Clinic), an investigation of neurologic
disorders during pregnancy and the postpartum period (with the Mayo
Clinic), a study of the epidemiology of eye tumors (with the Connecticut
State Department of Health), the effect of weather on the incidence of
stroke (with the Mayo Clinic), and international comparisons in the
incidence of brain tumors. Finally, extensive reviews have been prepared
10 - ODIR/IRP (NES)
on the epidemiologic aspects of Huntington's disease, otitis media,
Alzheimer's disease, cerebrovascular disease, primary intracranial tumors,
Tourette's syndrome, peripheral neuropathy, neurologic diseases in the
elderly, controlled therapeutic trials of motor neuron disease, epilepsy,
descriptive, analytic, and experimental methods in neuroepidemiology, and
statistical methods for calculating confidence intervals, and procedures
for neuroepidemiologic investigations in developing countries.
The clinical neurogenetics component of the program involves three
areas: 1) genetic-epidemiologic studies of movement disorders (e.g., the
dystonias); 2) genetic-epidemiologic studies of multifactorial neurologic
disorders (e.g., Parkinson's disease and multiple sclerosis); and
3) genetic and biochemical studies of hereditary nervous system tumors.
Collaborative studies are in progress to explain our earlier
observations of altered dopamine beta hydroxylase and norepinephrine levels
in blood and biopterin in CSF in a genetic subset of dystonia patients.
Members of selected families are being brought to the Clinical Center, NIH,
for trial of several new pharmacological agents.
In the area of multifactorial disease, we have now ascertained over 175
twin pairs and one set of quadruplets with parkinsonism. Clinical and
genetic study of 41 monozygotic twin pairs and 79 dizygotic twin pairs,
selected on the basis of at least one member being diagnosed as having
Parkinson's disease, revealed only one monozygotic twin pair and none of
the DZ group concordant for the disease. Although the unaffected co-twin
in each case remains at risk, this very low concordance suggests that
neither typical environmental nor genetic factors are critical determinants.
Data on smoking support an earlier impression that there is a decreased
risk for Parkinson's disease in smokers. Analysis of clinical and psycho-
logical observation and interview data on 21 MZ twin pairs discordant for
Parkinson's disease is underway. If life-long differences in personality
are present in affected versus unaffected twins, as our preliminary study
suggested, a very early determinant for Parkinson's disease is indicated.
Three surviving quadruplets, one of whom has Parkinson's disease, have
been extensively evaluated neurologically and psychologically. They, too,
show the same life-long differences in personality as do the discordant
monozygotic twins.
Over 140 MS twin pairs have been ascertained. Genetic-epidemiologic
analysis of 51 pairs personally examined reveals higher, but not absolute,
concordance in MZ twins. This suggests a significant genetic contribution
as well as an environmental component. The fact that of 11 twin pairs
concordant for MS, all are female, suggests that genetic factors may be
sex-influenced. Early events found to be more frequent in affected MS
twins include birth anoxia, frequent childbirth, serious infection, and
surgery.
An apparently undefined leukodystrophy simulating MS with onset at
about age 35 is under study in a kindred with over 20 affected. Tentative
genetic linkage assignment has been made.
11 - ODIR/IRP (NES)
studies in the area of hereditary tumors of the nervous system have
focused recently on neurofibromatosis with bilateral acoustic neuroma.
Efforts have been directed at improving and simplifying screening of
high-risk individuals confirming diagnosis and establishing criteria for
intervention. Audiologic studies, including evaluation of auditory-evoked
response and acoustic reflex decay, appear to be a useful means for early
documentation of acoustic neuroma and for following their effects.
12 - ODIR/IRP (NES)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01924-12 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Clinical, Genetic, Pathophysiologic Study of Hereditary Movement Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Rosv^ell Eldridge Medical Geneticist NES ODIR
Other:
Thelma Koerber
Peter LeWitt
Statistical Assistant
Clinical Associate
NES
NES
Walter Lovenberg Chief
Biochemical
Pharmacology
Section
ODIR
ET IRP
HE
NINCDS
NINCDS
NINCDS
NHLBI
G. Constantopoulos Research Biochemist Clinical DMN IRP NINCDS
Investigations
& Therapeutics
Section
COOPERATING UNITS (if any)
ET, DMN, IRP, NINCDS; HE, NHLBI; and Department of Neurology, University
of Helsinki
lab/branch
Of'fice of the Director, Intramural Research Program
SECTION
Clinical Neurogenetics Studies, Neuroepidemiology Section
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.75
PROFESSIONAL;
0.25
0.5
CHECK APPROPRIATE BOX(ES)
^ (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
In this project, we seek to 1) clarify and expand the nosology of the
hereditary movement disorders; 2) contribute to the understanding of the
underlying biochemical basis; 3) determine the most effective treatment for
each disorder; and 4) suggest guidelines for counsel ing individuals at risk.
General syndromes under study include the dystonias, tic disorders,
Huntington's chorea, and myoclonus. Approaches include standard epidemiologic
and clinical genetic studies together with collaborative efforts in evaluating
the role of neurotransmitters such as dopamine, their precursors, and
metabolites, and their necessary cofactors.
PHS-6040
(Rev. 2-81)
13 - ODIR/IRP (NES)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space j
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01927-12 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Clinical, Genetic, Pathophysiologic Study of Hereditary Nervous System
Tumors
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Roswell Eldridge Medical Geneticist
Other
NES ODIR
NINCDS
Thelma Koerber Statistical Assistant NES ODIR NINCDS
Anita Pikus Audiologist OPD CC
Barry Smith Deputy Chief SN IRP NINCDS
COOPERATING UNITS (If any)
OPD^CC; SN, IRP, NINCDS
Department of Surgery, Beth Israel Hospital
Department of Neurosurgery, Massachusetts General Hospital
lab/branch
Office of the Director, Intramural Research Program
SECTION
Clinical Neurogenetics Studies, Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.75
PROFESSIONAL:
0.25
0.5
CHECK APPROPRIATE BOX(ES)
[3 (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
l%{b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 .jords or less - underline keywords)
In this project we seek to define and classify hereditary tumors of the
nervous system; to add to the clinical description and natural history of
these diseases; to suggest methods for early diagnosis; evaluate present modes
of treatment; and develop methods for preclinical detection and screening.
14 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02167-08 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Genetic Epidemiology Studies in MS and Other Multifactorial Neurologic
Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
Roswell Eldridge Medical Geneticist
NES
Thelma Koerber
Henry McFarland
James Dambrosia
Christopher Ward
Statistical Assistant NES
Assistant Chief
Mathematical OBFS
Statistician
Visiting Scientist
ODIR
ODIR
NI
OD
LCS
NINCDS
NINCDS
IRP NINCDS
NINCDS
NIMH
COOPERATING UNITS (if any)
NI, IRP and OBFS, OD, NINCDS; LCS, NIMH; Department of Neurology, University
of Oregon; Department of Neurology, Rutgers University; and Department of
Medical Genetics, University of Indiana
lab/branch
Office of the Director, Intramural Research Program
SECTION
Clinical Neurogenetics Studies, Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
0.5
check APPROPRIATE BOX(ES)
[3 (a) HUMAN SUBJECTS
□ (al) MINORS 1X1 (a2) INTERVIEWS
(b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
In this project we are coupling genetic study with epidemiologic,
immunologic, serologic and neurochemical studies in selected families and
twin pairs with disorders due to multiple factors such as multiple sclerosis,
Parkinson's disease, and Alzheimer's disease.
To date, 14 presumptive "Multiple Sclerosis" families and 51 twin pairs with
this condition have been the subject of three publications. Sixty-five twin
pairs with Parkinson's disease have been the subject of two reports. Seven
twin pairs with Alzheimer's disease have been ascertained.
15 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02240-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Epidemiology of Dementia
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg
Chief
NES
ODIR
NINCDS
COOPERATING UNITS (if any) Epi demi ol ogy , Demography, and Biometry, NIA; W.
Massey, M.D., Duke University; E. Kokman, M.D. and J. P. Whisnant, M.D., Mayo
Clinic; B. Jordan, Harvard Medical School; M. Alter, Temple Univ.; E. Kahana,
Hadassah Hospital, Jerusalem, Israel
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
3.0
CHECK APPROPRIATE BOX(ES)
CX (a) HUMAN SUBJECTS
D (al) MINORS [^ (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A number of different approaches are being utilized to estimate the mortality
and morbidity of Alzheimer's disease/senile dementia in several population
groups in the U.S. and to measure the distribution of this disease in segments
of the population.
16 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02241-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Epidemiology of Cerebrovascular Disease in Adults
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI
Bruce S. Schoenberg
Chief
NES
ODIR
NINCDS
COOPERATING UNITS (if any)
J. P. Whisnant, M.D., Mayo Clinic; D.G. Schoenberg, M.S., Bethesda, Maryland;
A. Lilienfeld, M.D., Johns Hopkins University
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.3
PROFESSIONAL:
2.3
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
£l (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This investigation is aimed (1) at evaluating the effect of heart disease
and hypertension as potentially treatable precursors of completed stroke~and
transient ischemic attacks; (2) at documenting unusual patterns of
cerebrovascular disease; (3) at determining the autopsy patterns for patients
dying with cerebrovascular disease in a defined community; and (4) at
examining if v>/eather parameters have any effect on stroke incidence.
17 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02243-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Pediatric Neuroepidemiology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief NES ODIR NINCDS
Tatiana Kudrjavcev Neurologist NES ODIR NINCDS
COOPERATING UNITS (if any) D. Schoenberg, M.S., Research Epidemiologist,
Bethesda, Maryland; J.F. Mellinger, M.D., M.R. Gomez, M.D., and R.V, Groover,
M.D., Department of Neurology, Mayo Clinic; B.W. Christine, M.D., M.P.H.,
Connecticut State Department of Health
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
3.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) neither
SUMMARY OF WORK (200 words or less - underline keywords)
The project documented the frequency of primary intracranial neoplasms in
the pediatric populations of Rochester, Minnesota, and the State of
Connecticut. In addition, using the records-linkage system available for
residents of Rochester, Minnesota, we investigated the magnitude and risk
factors for cerebrovascular disease in infants and chi Idren. Temporal trends
in the incidence rate of cereFral palsy as well as distribution of clinical
subtypes and survival by clinical subtype were determined for the population
of Rochester, Minnesota, for the years 1950-1976.
18 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do MOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02297-06 OOIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Mortality from Neurologic Disorders: National and International Compariso*is
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS ANO ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg
Other: Nadir E. Bharucha
Roberta H. Raven
Chief
NES
ODIR
NIWCDS
Visiting Scientist
NES
ODIR
NIWCDS
Guest Worker
NES
ODIR
NIWCDS
COOPERATING UNITS (if any)
W. Massey, M.D., Duke University; D.G. Schoenberg, M.S., Bethesda, Maryland
LAB/BRANCH
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH. Bethesda, Maryland 20205
TOTAL MANYEARS:
3.7
PROFESSIONAL:
3.7
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
[J (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Although death certificate data are limited by possible misdiagjiosis,
incomplete case ascertainment, errors in coding, etc., detailed morbidity
information on neurologic diseases for the entire U.S. and for other
countries is not available. The Section has analyzed mortality data for
selected neurologic disorders by country and by county in the U.S. The
overall patterns which emerge may be useful in evaluating trends over time
and in formulating etiologic hypotheses.
19 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02299-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Reviews of Epidemiologic Aspects of Neurologic Disease
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief NES ODIR NINCDS
Tatiana Kudrjavcev Neurologist NES ODIR NINCDS
COOPERATING UNITS (if any)
W. Massey, M.D., Duke University; D. Schoenberg, M.S., Bethesda, Maryland
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.4
PROFESSIONAL:
2.4
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
□((c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Development of ne\N neurologic studies requires thorough historic and
methodologic reviews of prior investigations. These yield important
unexplored etiologic clues that may be investigated using current technology.
Major emphasis has been given to cerebrovascular disease, otitis media,
inherited ataxias, Huntington's disease, febrile" seizures, Tourette's
syndrome, peripheral neuropathy, neurologic disease in the elderly,
control fed therapeutic trials of motor neUron disease, epilepsy, descriptive,
analytic, and experimental methods in neuroepidemiology, statistical methods
for calculating confidence intervals, and procedures for neuroepidemiologic
investigations in developing countries.
20 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02300-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Clinical Course and Medical Care for Neurologic Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI
Bruce S. Schoenberg Chief
NES
ODIR
NINCDS
COOPERATING UNITS (if any)
J. P. Whisnant, Dept. of Neurology, Mayo Clinic, Rochester, Minnesota
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.0
PROFESSIONAL:
2.0
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The study uses a review and abstraction of data from records for a selected
group of neurological disorders. It obtains the items of data necessary to
determine onset of the disorder, duration, date and cause of death, or current
status. These data will be used to construct modified 1 ife tables to estimate
the expectation of life after diagnosis, the survival curve and morbidity and
severity estimates. It will also include analysis of type and duration of
medical care received by patients with neurologic disorders derived from a
wel 1-def ined population.
21 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02301-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Collaborative Studies of Less Common or Less Debilitating Neurologic Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief NES ODIR NINCDS
Other: Tatiana Kudrjavcev Neurologist NES ODIR NINCDS
COOPERATING UNITS (if any)
M, Zack, M.D., Atlanta, Georgia; Neurosciences Program, WHO, Geneva,
Switzerland; D. Duane, M.D., B. Sandok, M.D., Mayo Clinic
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
2.5
OTHER:
1.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
a (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A number of collaborative efforts involve the investigation of the
characteristics of unusual or less debilitating (e.g., headache) neurologic
disease phenomena. Unusual associations or space/time clusters of neurologic
disorders may provide leads to etiology or therapy. These may be tested
through more formal approaches.
22 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02305-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Epidemiology of Intracranial Neoplasms
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief NES ODIR NINCDS
Other: Tatiana Kudrjavcev Neurologist NES ODIR NINCDS
COOPERATING UNITS (if any) B.W. Christine, M.D., M.P.H., Connecticut State
Dept. of Health; J. P. Whisnant, M.D., and R.J. Campbell, M.D., Mayo Clinic;
L. Mahalak, M.D., Jackson, MS; A. Heck, M.D., Univ. of TN; R. Simon, M.D.,
Berkeley, CA; B. Jordan, B.A., Harvard Medical School
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
1.3
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Section has conducted extensive investigations on the descriptive
epidemiology of primary intracranial neoplasms using data derived from
population-based registries worldwide. Analytic studies were carried out to
investigate the relationship between intracranial neoplasms and tumors
occurring at other sites. These studies included careful review of tumor
nomenclature, disease definitions, and survey strategies.
23 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02307-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Educational Resources in Neurological Epidemiology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief
NES
ODIR
NINCDS
COOPERATING UNITS (if any)
D. Schoenberg, M.S., Research Epidemiologist, Bethesda, Maryland
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
2.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
[2 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A series of four videotapes on the p
produced by the Section. A tv^o-day
epidemiology was held in 1977; a one
symposium was held in 1979; a three
Republic of China in 1980; a one-wee
1981; an international advanced cour
a three-day symposium will be held i
symposium will be held in Kyoto, Jap
planned for the United States in 198
Epidemiology: Principles and Clinic
1978, and a new international journa
1982.
rinciples of neuroepidemiology were
international conference on neurb-
-day course was held in 1977; a one-day
day course was held in the People's
k course was held in Madrid, Spain in
se was held in Florence, Italy in 1981;
n Edinburgh, Scotland in 1981; a one-day
an in 1981; and a one-day course is
1. A textbook entitled Neurological
al Applications was published during
1 entitled Neuroepidemiology was begun in
24 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02370-04 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
*Racial Differentials in the Prevalence of Major Neurologic Disorders and
Surveys in Developing Countries
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI
Bruce S. Schoenberg
Dallas Anderson
Chief NES ODIR NINCDS
Survey Statistician OBFS OD NINCDS
COOPERATING UNITS (if any)OBFS, OD, NINCDSj A, Hacrer, M.D., Univ. of Mississippi; U.S.
Bureau of the Census; C.L. Bolis, M.D. (WHO); B.O. Osuntokun, M.D. (Nigeria); F.
Garcia-Pedroza, M.D. (Mexico); Wang Chung .. ^ >- - . ~
E. Bharucha, M.D. (India); M.C. Gutierrez
M.D. (Spain); J. Cabrera.M.D. (Peru) ;P. Ponce
iu ) ; ti.u. usuntoKun, I'l.u. (Nigeria;; t-.
-Cheng. M.D. (People's Republic^of China);
del Olnio, M.D.. & A. PoKera-Sanchez, /
:e, M.D. (Venezuela) ,& Dr.M.Cruz(Ecuador)
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
8.5
PROFESSIONAL:
5.5
3.0
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
(al) MINORS Kl (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this study is to accurately document possible racial
differentials in the prevalence of major neurologic disorders by surveying an
entire county, v^ith a biracial population of approximately 25,000. The
disorders investigated include cerebral palsy, dementia, psychomotor delay,
epilepsy, Parkinson's disease, essential tremor, and cerebrovascular disease.
In addition, research protocols for neuroepidemiologic studies in developing
countries have been prepared for Nigeria, Mexico, the People's Republic of
China, Peru, Spain, Ecuador, and Venezuela. Pilot investigations have been
successfully carried out in Nigeria and the People's Republic of China.
*[Former title: Racial Differentials in the Prevalence of Major Neurologic
Disorders
25 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02423-03 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development of Data Resources for Neuroepidemiology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief
NES
ODIR
NINCDS
COOPERATING UNITS (If any) F. Clifford Rose, M.B., F.R.C.P., B. Benjamin, Ph.D.,
S. Haberman, M.A., F.I. A., and R. Capildeo, M.B., B.S,, Charing Cross
Neuroepidemiology Unit, London, England; W. Sibley, M.D., Univ. of Arizona,
Tucson, Arizona.
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.1
PROFESSIONAL:
1.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
To develop 1 ) a registry of hospitalized patients with neurologic diseases in
a well-defined population of 3.5 million people, and 2) resources for
case-control studies of multiple sclerosis using uniform methods of data
collection.
26 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH- AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02424-03 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Standardized Nomenclature and Coding of Neurologic Diseases
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Bruce S. Schoenberg Chief
NES
ODIR
NINCDS
COOPERATING UNITS (if any) L. Kurland, M.D., Mayo Clinic. Rochester, MN; J.F. Kurtzke,
M.D., Georgetown Univ., Washington, D.C.; F. Clifford Rose, M.B., F.R.C.P.,
B. Benjamin, Ph.D., S, Haberman, M,A., F.I. A., and R. Capildeo, M.B., B.S.,
Charing Cross Neuroepidemiology Umt, London, England; L. Schut, M.D.,
Minnpapnljq, MN ; and K. Kondo. M.D.. Tokyo, Japan
innpapr
B/BRANCH
LAB/BRANCH
Office of the Director, Intramural Research Program
SECTION
Neuroepidemiology Section
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.1
PROFESSIONAL:
2.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
To develop an internationally acceptable standard of nomenclature,
classification, and coding of neurologic disorders.
27 - ODIR/IRP (NES)
PHS-6040
(Rev. 2-81)
70
I
8
-<
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Neurotoxicology Section, ODIR
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 28 - 30
PROJECT REPORTS
Animal Models of Neurological Disease 31
ZOl NS 02264-06 ODIR
Cellular and Molecular Approaches to Neurotoxicology 32
ZOl NS 02451-02 ODIR
Hormones and Central Neurotransmitter Function 33
ZOl NS 02452-02 ODIR
Exocytosis Modelling: Kinetics of Membrane Aggregation and Fusion 34
ZOl NS 02525-01 ODIR
Analytic Electron Microscopy in Neurochemistry 35
ZOl NS 02319-05 ODIR
1 - ODIR/IRP (NTS) TAB 7.B
Annual Report
for period October 1, 1981 through September 30, 1982
Neurotoxicology Section
Office of the Director
Intramural Research Program
National Institute of Neurological and Communicative
Disorders and Stroke
Richard L. Irwin, Chief
SUMMARY
In Vitro Studies of Erythrosin B Neurotoxicity
We have previously demonstrated that erythrosin B (tetraiodof luorescein,
U.S.F.D. & C. Red No. 3), a commonly-used artificial food and drug color: 1)
blocks synaptosomal uptake of dopamine; 2) inhibits ATP catalysis by brain
Na,K-ATPase; 3) inhibits the high affinity binding of the cardiac glycoside,
ouabain, to brain Na,K-ATPase; and 4) binds to rat brain cortical membranes.
We have recently demonstrated that subcellular distributions of [-^H]ouabain
and [^^C]erythrosin B binding in fractionated cortical tissue preparations
are equivalent and parallel ATPase activity. The dissimilar response of
[%]ouabain binding and [ •'■^Clerythrosin B binding to changes in tissue
preparation, incubation temperature, and partial solubilization of binding
sites by deoxycholate (DOC) suggests two separate binding sites for erythrosin
B and ouabain to rat cortical membranes. Although characterization of a model
for a classical receptor for erythrosin is incomplete, current evidence
indicates that in crude cortical membrane preparations specific binding of
erythrosin B is composed of a saturable and a non-saturable component.
Whether the non-saturable component is removable without loss of enzyme
activity and [^^C] erythrosin B binding remains to be clarified. Recent
studies demonstrate that the potency and specificity of the non-competitive
inhibition of [-^H]ouabain binding to Na,K-ATPase and ATP catalysis is
influenced by glycoside concentration, monovalent cation concentration, and
incubation time. Preincubation of the tissue with erythrosin B and other
variations in assay conditions result in the inhibition of not only high
affinity ouabain binding to Na,K-ATPase but also low affinity ouabain binding
and the catalytic activity of non-sodium dependent ATPases.
The cellular toxicity of erythrosin B and some structural analogs were
examined for their ability to inhibit the growth of neurites of chick dorsal
root ganglia in culture. Inhibition of NGF-stimulated differentiation is due,
in part, to the direct photo-oxidation of nerve growth factor by erythrosin B
and Rose Bengal. However, there are other light-insensitive actions of
erythrosin on both neurons and fibroblasts which were also observed in these
studies.
In collaboration with the Department of Biochemistry, University of Miami
Medical School, we have shown that the calcium-translocating ATPase of muscle
sarcoplasmic reticulum is inhibited by erythrosin B with an IC50 of lym.
The dye also inhibits calcium transport (IC50 = 500nM) and binds to a
specific site with a Kj of 300 nM. These effects are light-insensitive and
distinct from any glycoside-like effect since this tissue contains no enzyme
that is sensitive to ouabain, nor specific glycoside binding sites. Blue
dextran inhibits dye binding suggesting that the dye binding site is near to
but distinct from the nucleotide binding site.
28 - ODIR/IRP (NTS)
In Vivo Studies on Erythrosin B Neurotoxicity
In chronically implanted, free-moving rats and in lightly anesthetized
animals, fluorescein and a series of halogenated fluorescein derivatives were
infused in an anterograde manner through the common carotid artery. The
distribution patterns of these dyes through the brain and other body organs
were visualized and analyzed macro- and microscopically as a function of dose
and time after injection. These analyses were performed for fluorescein,
erythrosin B, eosin B, eosin Y, rhodamine B, phloxine B, rose bengal, and
merbromin.
Investigations of Variable Sensitivity to Neurotoxins
Variation in nervous system anatomy, function, and/or neurochemistry can
be used not only to identify individuals who may be predisposed to increased
risk from neurotoxic insult but also as a research tool useful in elucidating
mechanisms of action of neurotoxins. The Neurotoxicology Section has been
investigating the neurotoxic actions of erythrosin B (tetraiodof luorescein,
U.S.F.D. & C. Red No. 3) on Na,K-ATPase. In order to elucidate the mechanisms
of action of this neurotoxin we have searched for variation in rodent brain
Na,K-ATPase. We have found large changes in cortical Na,K-ATPase catalytic
activity during neonatal development and aging as well as both quantitative
and qualitative variation in ouabain binding during development. Arrhenius
plots indicate age-dependent variation in the lipid environment surrounding
Na,K-ATPase of cortical membranes. The development of myelin and diverse
lipid composition are both probable sources of the age variation in brain
Na,K-ATPase we have observed. We have also found reduced ATPase catalytic
activity in cortical tissue preparations from rat brains of LA/N cp/cp rats,
which have an autosomal recessive mutation for obesity. This difference is
consistent with the reduced red blood cell Na,K-ATPase activity found in
idiopathically obese humans. These age-dependent and genotypic variations in
brain Na,K-ATPase are being examined further with emphasis on what this
diversity in Na,K-ATPase can reveal about the interactions of erythrosin B
with Na,K-ATPase.
Chromaffin Granules and Chromaffin Cells
The chromaffin cell provides a well-studied system for investigating
molecular and cell-surface mediated mechanisms of neurotoxin action. Since
several neurotoxins of interest to neurology are divalent cations (lead,
manganese, copper) and since storage granules, such as chromaffin granules,
synaptic vesicles, and platelet granules contain high concentrations of
calcium, these preparations have been investigated to determine the effect of
toxic cations on calcium storage and calcium-mediated processes of fusion and
exocytosis.
Nuclear magnetic resonance studies performed in collaboration with Dr.
J.L. Costa, CN, NIMH, demonstrate that at physiological osmotic pressures the
catecholamine and AZP are unhindered. However, if the granules are dehydrated
in high sucrose, the spectra resemble the gel-like mobility pattern seen in
pig platelet granules.
Chromaffin granules will aggregate and fuse in the presence of calcium.
This reaction is independent of ATP and is not inhibited by a
phosphodiesterase inhibitor, theophylline. Rapid freeze fracture electron
microscopic studies demonstrate that membrane-associated particles move prior
to fusion. Aggregation studies by light scattering readout from a
stopped-flow apparatus have been extended using fluorescent energy transfer.
29 - ODIR/IRP (NTS)
Results have provided the first demonstration of the fluid mosaic structure of
the membrane of a subcellular organelle. Granule-granule recognition and
aggregation is mediated by protruding proteins; however, labelling studies
indicate that these proteins contain no free sulfhydryls or that no
significant detectable energy transfer occurs because of the geometry of these
particles.
Hormones and Central Neurotransmitter Function
We have shown that exposure of male rats to elevated levels of
17fi-estradiol for 6 days produced changes in the striatum. The density of the
striatal dopamine receptors was increased, as were the behaviors associated
with these receptors. Estrogen administration increased the density of the
striatal dopamine receptors, increased the stereotype behavior after dopamine
agonist administration, increased catalepsy after dopamine antagonist
administration, and increased rotation after dopamine agonist administration
in unilaterally lesioned rats. Estrogen had no effect in vitro, demonstrating
a specific iji vivo response to the drug. The change in receptors is specific
since other receptors in the striatum are not altered and dopamine receptors
in other areas of the rat brain are not increased in density. The increase in
striatal dopamine receptor density is to one specific population of receptors
since the increase can be prevented by prior destruction of the neuronal cells
originating in the striatum by the neurotoxin, 6-hydroxydopamine. The
biochemical response to estrogen is similar in male and long-term
ovariectomized female rats. The behavioral responses in the male and female
rats are quite different. The biochemical effects of estrogen can be
prevented by hypophysectomy , suggesting a pituitary factor such as prolactin
may be responsible. The increase in the density of striatal dopamine
receptors, produced by the chronic administration and acute withdrawal of
haloperidol, can also be attenuated by hypophysectomy, again suggesting the
importance of a pituitary factor in the development of an increase in receptor
density. Accordingly, prolactin by itself in normal male and hypophys-
ectomized male rats can increase the density of the striatal dopamine
receptors. These studies possess relevance in neurologic, psychiatric, and
neuroendocrinologic disorders.
Neurobehavioral Analysis of Psychotropic Drugs
We have analyzed neurochemical codes of cataleptic states, which are
behaviorally similar to opiate and neuroleptic catalepsy, and their specific
relationships to other psychotropic-drug-induced behaviors, including
stereotypy, locomotor hyperactivity, distinct epileptic seizures, coma, and
death. To this end, the Na-K ATPase inhibitor ouabain was microinjected into
the ventricular system, hippocampal formation and/or neocortex. Finally, the
contrasting reflex mechanisms underlying opiate versus neuroleptic catalepsy
were studied. To that end, a new technique of labyrinthectomy was developed
in and applied to rats.
Exocytosis Modelling: Kinetics of Membrane Aggregation and Fusion
Methods have been developed to label the granule membrane with fluorescent
lipids, allowing studies of the kinetics of the fusion of the bilayers of
these particles. A multichannel, computer controlled stopped-flow rapid
mixing spectrometer has been constructed in collaboration with Dr. Paul Smith
and Mr. Carter Gibson, of BEIB, to study these reactions.
30 - ODIR/IRP (NTS)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02264-06 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Animal Models of Neurological Disease
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other;
Sally M. Anderson
Roger Weir
Expert
Guest Worker
NTS
NTS
NINCDS
NX NCOS
COOPERATING UNITS (if any)
NONE
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neurotoxicology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.25
PROFESSIONAL:
1.0
OTHER:
1.25
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is investigation of basic mechanisms associated
with neurological disease using animal models that have been produced by
exposure to synthetic or naturally occurring neurotoxins. The interactions of
various toxins with neurotransmitters and hormones in the CNS have provided
the focus for combined behavioral and neurochemical studies emphasizing basic
mechanisms of action of proposed neurotoxins. Two major interests of this
project are: 1) to define populations of individuals that may be at increased
risk to neurological disease resulting from exposure to neurotoxins and 2) to
use naturally occurring variability in central nervous system function,
anatomy and/or neurochemistry , to elucidate mechanisms of actions of neuro-
toxins. The primary emphases this year have been: 1) the interaction of
artificial food colors with neuronal membranes and neurotransmission; 2) the
investigation of genetic and age variation in brain Na,K-ATPase (an enzyme
previously demonstrated to be inhibited by artificial food color); and 3)
neuronal interactions between neuropeptides and dopamine in the basal ganglia.
31 - ODIR/IRP (NTS)
'PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02451-02 ODIR
PERIOD COVERED , , ^„ ,„„„
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cellular and Molecular Approaches to Neurotoxicology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Stephen J. Morris
Others: Bibie M. Chronwall
Jonathan L. Costa
Robert Blumenthal
Duncan H. Haynes
J. David Robertson
Joseph M. Costello
Thomas M. Jovin
Victor P. Whittaker
Thomas C. Sudhof
Ward F. Odenwald
Michael K. Ho
Expert Consultant NTS NINCDS
Fogarty Fellow SNB NINCDS
Staff Physician CNB NIMH
Section Chief LTB NCI
Assoc. Prof., Pharmacology, Univ. of Miami
Chairman, Anatomy, Duke University
Assoc. Professor, Anatomy, Duke University
Chairman, Molecular Biology, Max Planck Inst.
Chairman, Neurochemistry , Max Planck Inst.
Graduate Student, Neurochem. , Max Planck Inst.
Microbiologist NTS NINCDS
Biologist NTS NINCDS
COOPERATING UNITS (If any)
University of Miami Medical School, Miami, FL 33101; Duke University Medical
School, Durham, NC 27706; Max Planck Institute for Biophysical Chemistry,
D-3400 Goettingen, F,R. Germany; SNB, NINCDS, CNB, NIMH
lab/branch
Office of the Director, Intramural Research Program
SECTION
Neurotoxicology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.3
PROFESSIONAL:
1.7
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
S{(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Several in vitro systems were explored for their applicability to the
testing of (suspected) neurotoxic substances, such as Erythrosin B (FD and C
Red 3) (EB) an artificial halogenated fluorescein derivative. The dye can be
used to trace solubulization and partial purification of rat brain cortex
ATPase. It also inhibits ATPase and calcium transport activity of rabbit
muscle sarcoplasmic reticulum. EB inhibits axonal outgrowth from chick dorsal
root explants by photo-oxidizing NGF. General in vitro toxic effects are also
seen.
Storage and release of catecholamines from adrenal medullary cells are
affected by a variety of heavy metals, partially through interference with
calcium-specific mechanisms involved in release of the neurotransmitter. The
calcium-promoted fusion of isolated chromaffin granules, and its inhibition by
various heavy metals, is being studied as a model process for exocytotic
release of catecholamines in vivo. The kinetics of calcium-promoted
aggregation and fusion of the granules have been studied using fluorescence
energy transfer techniques. 32 _ ODIR/IRP (NTS)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02452-02 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Hormones and Central Neurotransmitter Function
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Robert E. Hruska
Others: Marc De Ryck
Roger Weir
Karen Pitman
Diane Bradley
Lynn Ludmer
Senior Staff Fellow
NTS
NINCDS
Visiting Fellow
NTS
NT NCOS
Guest Worker
NTS
NINCDS
Biologist
NTS
NINCDS
Biological Aid
NTS
NINCDS
Biological Aid
NTS
NINCDS
COOPERATING UNITS (if any)
NONE
lab/branch
Office of the Director, Intramural Research Program
Neurotoxicology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.7
PROFESSIONAL:
0.9
OTHER:
1.8
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
20 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) Hormones, such aS estrogen or
prolactin, affect cerebral neurotransmitter receptors. Estrogen increases the
following: (1) the density of striatal dopamine (DA)receptors ; (2) stereotypy
induced by DA agonists; (3) catalepsy produced by a DA antagonist; and (4) DA
agonist-induced rotation in unilaterally lesioned rats. The increase in DA
receptor density is specific and restricted to one population. In the striatum,
this increase is prevented by hypophysectomy , suggesting involvement of a
pituitary factor. The increase in DA receptor density after chronic haloperidol
is also attenuated by hypophysectomy, again suggesting a pituitary factor, such
as prolactin, which by itself increases the density of striatal DA receptors.
We have also analyzed neurochemical codes of cataleptic states, behaviorally
similar to opiate and neuroleptic catalepsy, and their experimental relationship
to other psychotropic-drug-induced behaviors , including stereotypy, locomotor
hyperactivity, distinct epileptic seizures, coma, and death. Other experiments
show that contrasting reflex mechanisms (i.e. , vestibular controls) underlie
opiate vs. neuroleptic catalepsy. These findings may be relevant to neurologic ,
psychiatric , neuroendocri no logic disorders, and drug-induced side-effects.
PHS-6040
(Rev. 2-81)
33 - ODIR/IRP (NTS)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this spacej
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02525-01 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Exocytosis Modelling: Kinetics of Membrane Aggregation and Fusion
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Others:
Stephen J. Morris Expert Consultant
NTS
NINCDS
Paul D. Smith
Carter G. Gibson
Duncan H. Haynes
Alan Malvino
Orhan K. Oz
Visiting Scientist BEIB DRS
Electronics Engineer BEIB DRS
Assoc. Prof., Pharmacology Department, Univ. of
Miami Medical School
Technician, Pharmacology Department, Univ. of
Miami Medical School
Biologist NTS NINCDS
COOPERATING UNITS (if any)
Department of Pharmacology, University of Miami Medical School
lab/branch
Office of the Director, Intramural Research Program
Neurotoxicology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.8
PROFESSIONAL:
0.5
0.3
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
Jig (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Neurotransmitter release from synapses and neurosecretory cells involves
exocytosis: the fusion of the synaptic vesicle membrane with the cell plasma
membrane.
The kinetics of the reactions involved in membrane fusion in a model system
consisting of sonicated phospholipid vesicles are being studied using a
computer-controlled multisignal stopped-f low rapid mixing apparatus.
34 - ODIR/IRP (NTS)
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02319-05 ODIR
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Analytic Electron Microscopy in Neurochemistry
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
Ellen K. Silbergeld
C. Fieri
Chief
Physicist
NTS NINCDS
BEIB NIH
COOPERATING UNITS (if any) Department of Neuropathology, Johns Hopkins Hospital,
Baltimore MD; Department of Neurology, Tufts Medical School, Boston MA;
Department of Neurology, Univ. of Michigan Medical School, Ann Arbor, MI;
BEIB. NIH
lab/branch
Office of the Director, Intramural Research Program
Neurotoxicology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS 0 {a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been discontinued.
35 - ODIR/IRP (NTS)
PHS-6040
(Rev. 2-81)
>
W
■X)
cz
m
z
H
>
H
O
ANNUAL REPORT
October 1, 1981 - September 30, 1982
Instrumentation and Computers Section
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
ORGANIZATIONAL STRUCTURE AND SERVICES 36
INSTRUMENTATION 37 - 39
COMPUTERS 39 - 42
DISTRIBUTION OF ENGINEERING, COMPUTER AND FABRICATION SERVICES 43
i - ODIR/IRP (ICS) TAB 7.C
Annual Report of Instrumentation and Computer Section
National Institute of Neurological and Communicative Disorders and Stroke
October 1, 1981 - September 30, 1982
The Instrumentation and Computer Section provides technical support for in-
vestigators by (1) assessing the instrumentation and computer needs of the in-
vestigator; (2) designing, developing and constructing special-purpose electronic
and mechanical instrumentation and systems not commercially available; (3) de-
signing, specifying and managing laboratory computer systems for data acquisition
and processing.
Additional services provided by the Section include consultation on measure-
ment techniques, signal processing, noise and electro-magnetic interference in
data measurement systems, and equipment purchases. Several formal and informal
courses for investigators are taught by Section personnel; topics include elec-
trical circuit theory, operational amplifier applications, digital logic design,
and computer applications.
Due to manpower limitations and economic considerations, the Section is un-
able to provide the following services: repair of commercial instruments, dupli-
cation of off-the-shelf commercially available equipment, and fabrication of non-
instrument items (shelves, bookcases, etc.).
When an investigator requires the services of the Section, he first meets
with the Section Chief and other personnel as needed to discuss his requirements.
On the basis of this meeting, a decision is made as to whether ICS (Instrumenta-
tion and Computer Section) will take on the project. If a commercially produced
instrument will satisfy the investigator's requirements, he is advised to purchase
it. If custom instrumentation is needed, ICS will accept the project unless we
lack the appropriate expertise, or our current work backlog is excessive. In
these cases the project may be contracted to a private firm, or the investigator
may be directed to the Biomedical Engineering and Instrumentation Branch (BEIB).
When the Section Chief or the Assistant to the Chief agree to accept a pro-
ject, the investigator submits a standard work request form (available from ICS),
signed by his Lab Chief. This form will state the nature of the instrument or
service requested, and will contain as many details and specifications as the
investigator can provide.
The project is then assigned to an engineer, who will confer with the in-
vestigator to formulate a set of engineering specifications and a timetable and
cost estimate for the project. The ICS does not charge for services, but the
investigator will be billed for the cost of the components used. Upon delivery
of the completed instrument, a memo is sent to the investigator listing the
component costs and asking permission to have the Administrative Officer transfer
funds from his CAN to the Section's CAN.
36 - ODIR/IRP (ICS)
INSTRUMENTATION
The Section has a staff of six engineers and six technicians to design,
develop and fabricate electronic and mechanical instruments. The major effort
is in the production of electronic instruments for basic neurophysiological
research, and for clinical studies involving affective disorders. The following
are brief descriptions of representative projects, chosen from a total of 310
projects completed this year.
(1) Patient Activity Monitoring System. The Section has continued to de-
velop the Patient Activity Monitor (PAM) and the support hardware and software
which forms the system. The standard PAM, which provides 54 hours of data at
15 minute intervals, was redesigned to use batteries which have 18 months capacity.
The software has been expanded, and a provision has been made to acquire and store
data from a commercially available temperature monitor which utilizes the same
data storage principal as the PAM.
A program was written to allow activity or temperature data to be stored
in continuous files of unlimited length; this simplifies long-term data analysis.
Numerous other programs, including automatic sleep recognition and various graph-
ical data presentation techniques, were added this year. An extensive users guide
to the PAM software was written.
The major hardware advance this year has been the development of a PAM
to replace the hybrid monitor. The hybrid, which stores over 10 days of data
and is much smaller than the standard PAM, was based on the technology of con-
necting integrated circuit dies to thick-film printed substrates by micro-
miniature wire bonds. These hybrid PAMs were fabricated by a private contractor.
Unfortunately, they proved to be very failure-prone, and the devices cannot be
repaired. We have abandoned this technology, and are completing development of
a PAM with all the characteristics of the hybrid, but much more reliable and less
expensive. It is easily fabricated, using pre-tested parts, and can be repaired
if necessary. It will become our standard device, and will eventually replace
all the older PAMs.
The PAM is being evaluated for use in determining sleep stages, without
taking sleep EEG recordings. PAMs are placed on the head, trunk, and wrist or
ankle; algorithms are being developed to determine sleep stage as a function of
relative activity at the three sites. If successful, this technique would greatly
expand the possibilities for outpatient sleep research.
(2) EEG Amplifier System. A 32-channel EEG amplifier system was designed
for use in several ongoing research projects involving topographic brain mapping.
The design incorporates several new electrical components which permit construc-
tion of a compact, low cost-per-channel unit. The system consists of a pre-
amplifier, located next to the subject, joined to a main amplifier by a flat cable.
The signal gain in the preamplifier is 1,000 and, in the main amplifier, 30, for
an overall gain of 30,000. An important part of the amplifier design is the fil-
ter section. The filters were designed to prevent aliasing errors when the sig-
nal is digitized; to eliminate any phase distortion in the passband region that
would interfere with time-series average evoked response analysis; and to have a
good step response, to minimize "ringing" resulting from stimulus artifacts. The
design also includes a sample-and-hold module on each channel to prevent any
"skewing" errors associated with A/D conversion.
37 - ODIR/IRP (ICS)
(3) Computer-Controlled Trapezoid Generator. A torque motor position con-
trol system was previously developed by ICS for research on the mechanisms which
produce the tremor of Parkinson's disease and also for general neuromuscular re-
search. A signal with a trapezoid timecourse which could be synchronized with
the data collection computer was thought to be a very useful command input to
the torque motor system. To satisfy this need, a precision, computer-controlled
trapezoid generator has been developed. A PDP-11 minicomputer loads the trapezoid
parameters (up time, hold time, down time, and amplitude and polarity) into the
generator via a parallel digital interface. A fifth parameter from the computer
starts the trapezoid waveform and sets the duration of the control signals for
the torque motor system. By allowing synchronization between stimulus and com-
puter data acquisition, this trapezoid generator has greatly facilitated use of
the position control system.
(4) Tissue Culture Voltage Clamp System. A voltage clamp system has been
developed for investigating the membrane properties of electrically and chem-
ically excitable tissue culture cells. This low voltage system was designed for
use with two high impedance glass microelectrodes to clamp slow-to-medium speed
neuronal voltage changes but not action potentials. Two identical headstage
amplifiers are provided so that after electrode placement in the cell, either
electrode may be used to measure the membrane potential. These headstage ampli-
fiers also may be used as constant current sources for current clamping experi-
ments. A dual sensitivity/speed virtual ground current monitor is also provided.
(5) Discriminator and Iontophoresis Systems. The ICS amplitude/time window
discriminator system continues to be an important signal processing tool in neuro-
physiological studies. The versatility of this system has been increased and the
design simplified by implementing the circuitry with CMOS logic. Six of these
new discriminator systems were completed this year and two modified units for
processing post-synaptic potentials are under construction. Although micro-
pressure ejection of drugs from mul tibarreled pipettes has become, in many cases,
the preferred method of drug application, the use of microiontophoresis is still
widely used. Four of the ICS 5-channel iontophoresis systems are presently near-
ing completion and will be used in neuropharmacological studies in the IRP.
(6) Data Acquisition System for Isolation Rooms. Two isolation rooms are
being designed to permit the study of biological rhythms and the cyclic nature of
certain mental illnesses. Each room will be occupied by one human subject who
will be isolated from all time cues. ICS is designing a computerized data acqui-
sition system for these rooms so that activity and temperature data can be peri-
odically recorded. Recording mood self-ratings and limited subject-staff communi-
cations will be provided by special touch-input CRT terminals.
(7) Resistance Monitor and Shutter Controller. In order to view a freeze-
fractured sample of tissue with an electron microscope with greater resolution,
a thin layer of metal is first deposited on the sample. The resulting resolution
will be dependent on the amount of metal deposited and the length of exposure
time of the sample to the heat of the ion gun. A controller has been developed
that monitors the amount of metal being emitted by the ion gun by measurement of
resistance changes as metal is being deposited between two terminals separated
by a fixed length and width of non-conducting fiberglass board. A shutter,
which can be opened and closed at variable resistance limits, is used to control
the amount of material deposited and to make the exposure time of the sample to
the heat of the ion gun as short as possible.
38 - ODIR/IRP (ICS)
(8) Visual Evoked Response Stimulus System. A visual evoked response
stimulus system has been built, that will randomly select one of the eight 35mm
slide images and project it on to a 35cm X 50cm opaque screen. The projection
system uses a wery fast electromechanical shutter (2.3 msec, opening time) for a
fast rise time in presenting the image. The slides are mounted on a circular
disc, which is rotated by a direct-drive stepper motor. The maximum random access
time for any slide is 125 msec. The stepper motor is controlled by a special-
purpose processor that can be linked to either a computer or a terminal through
a standard RS232 serial interface.
(9) Neuro PET Scanner Chair and Gantry Controller. A controller is being
designed for the Neuro PET Scanner which was developed by NINCDS in conjunction
with BEIB. This controller will facilitate the positioning of the patient's head
into the scanner through control of an electromechanical chair. This device will
insert the patient's head a fixed distance into the aperture of the scanner from
a predetermined setup position. The controller will provide a digital readout
of the patient's position and will include various safety stops to prevent col-
lision of the chair and the gantry.
(10) Programmable Infusion Pump. A microprocessor-based instrument was de-
veloped to control a motor driven syringe platform (infusion pump). The pump is
used to maintain a constant arterial concentration of infused substances during
absorption studies with laboratory animals. The pump delivers an initial bolus
followed by an exponentially decreasing infusion pumping rate. A calibration
mode is available for generating syringe and motor calibration coefficient. Ini-
tially the instrument prompts the operator for pumping schedule parameters, cal-
culates necessary variables, and executes the pumping schedule. An on-line pump-
ing schedule listing is available or a pre-pumping listing of the programmed
schedule may be requested. The listing provides the pumping rate/volume per
delta time for the infusion schedule and the total volume delivered.
(11) 4-Arm Radial Rat Maze. An elevated multi-level 4-arm radial rat maze
is being constructed and instrumented to assess the effects of neuropeptides on
learning, memory, and perception in experimental animals. Audible and/or visual
cues will be presented at the end of a randomly selected arm. The path of the
animal is monitored by detectors located at selected positions throughout the
maze. When an animal traverses the proper path to the cues, a programmable
liquid reinforcement will be dispensed. At the end of the testing period, statis-
tical data will be printed regarding the animal's performance. An 8-bit micro-
processor single board computer is used to monitor and control the maze and per-
form the necessary statistical calculations.
COMPUTERS
The Instrumentation and Computer Section (ICS) continues to support the use
of the computer as a laboratory instrument. Small computers are used in the
individual laboratories for on-line, real-time interaction, process control and
data acquisition. ICS maintains support computers in Buildings 10 and 36. These
systems provide means for program preparation, bulk storage, printing and plotting,
and mathematical and statistical processing. Experimental data may be trans-
mitted from the laboratory computers, via these systems, to the DCRT facilities
for further processing. The support computers also serve to develop prototype
39 - ODIR/IRP (ICS)
systems and to test the feasibility of the use of a computer in specific labor-
atory applications. The latter capability allows an investigator, once he deter-
mines that the computer will do the job, to purchase an efficient system at mini-
mal cost. The Section also maintains an image processing system, described below.
The Section provides software support for the individual investigators. A
library of procedures has been developed that is tailored to the needs of the
Intramural Program. Individual training is available for investigators with no
prior experience in using or programming the computer. Computer specialists are
available for consultation in all areas of computer use, programming, interfacing,
real-time applications, time series analysis, data presentation, systems con-
figuration and computer procurement. Although ICS does not provide an applica-
tions programming service, systems have been developed in collaboration with
individual laboratories. Examples are included in the list of computer projects.
Program maintenance is an important function of the Section. Programs used
in a real-time interactive laboratory research environment often produce new
information which calls for modification of the program before the next exper-
iment. In addition to the software library and research related projects de-
veloped by ICS, much work is caused by the turnover of scientific and support
personnel. Many systems developed by these persons prove useful to the labor-
atory. After they leave, maintenance of such systems becomes the responsibility
of ICS. Structured programming techniques and standardization on PASCAL have
enabled the Section to provide these services without an increase in personnel.
There are currently more than 50 minicomputers in the Intramural Research Program.
The Section also maintains a microprocessor development system for software
and hardware development of microprocessor-based instrumentation at both the chip
level and the single board computer level. The system currently supports three
common microprocessors; one 16-bit processor, and two 8-bit processors. Various
utility programs and two high level language compilers are available (FORTRAN
and PLM) for application programming.
The support computer in Building 35 was upgraded this year, and with the
acquisition of two laboratory systems for program development, much of the burden
on this facility has been somewhat relieved. However, increasingly sophisticated
mathematical algorithms are being developed in the areas of image processing, cell
membrane analysis, and digital signal processing. These techniques require an
increasing amount of processor time, and the existing single user systems are not
the most cost effective method of handling these problems.
A Digital Equipment Corp. VAX-750 32-bit computer has been installed in
Bldg. 36. Space for this facility is furnished by the Laboratory of Cerebral
Metabolism, NIMH. This computer processes mathematical data more efficiently
than any of the existing 16-bit computers and has a time shared, virtual memory
operating system. It has a compatibility mode in which programs written on the
existing computers will run with little or no modification. Programs may be
written and compiled on this system to be run on the laboratory computers. The
two existing image processing systems will be linked directly to this computer,
via a high-speed communication linkage. Future plans call for connecting labor-
atory computers to the facility and developing a true distributed network. This
will provide increased capability for the laboratory satellite, at less cost to
the user.
40 - ODIR/IRP (ICS)
Image Processing System
The Instrumentation and Computer Section maintains a general purpose image
processing system. This system consists of a high-speed rotating drum scanner,
an image array processor and display, and a PDP-11/60 computer. The drum scanner
can digitize transparencies up to 10x10 inches with spatial resolution of 12,5
microns. The image array processor can simultaneously store, display and manipu-
late up to three 512x512 digitized images. Images may be compared, superimposed,
translated, zoomed or color coded at video rates. Images to be processed may be
obtained by scanning autoradiographs , x-ray film, or photographic negatives, or
by using previously digitized images generated by CAT or ECAT scanners. A
camera station is being added this year.
An interactive, menu-driven, software system provides an extensive and
expandable repertoire of basic image processing and input/output functions.
Special purpose functions can be developed to meet specific user requirements.
The facility is useful for numerous applications involving evaluation and quanti-
fication of biomedical images. Two applications, however, are primary analysis
of two-dimensional electrophoresis gels and analysis of autoradiographs of brain
or tissue sections.
The autoradiographs are used for measurements of glucose utilization in
brain tissue using the Sokoloff deoxyglucose method of glucose substitution.
Analysis of the autoradiographs involves displaying the digitized image on a TV
monitor and outlining areas of interest. The average optical density is then
computed and automatically converted to glucose utilization. Glucose utilization
of brain regions as small as 100 microns in diameter can be computed. A color
coded glucose utilization map may also be produced.
Measurement of amino acid concentrations can be made using two-dimensional
electrophoresis gels. The gels, which have been prepared by the appropriate
stain and fixer, are photographed; or if radioisotopes are used, an autoradio-
graph is obtained. The film is scanned and digitized into an array of optical
density within a defined boundary. A test gel may be compared with a standard
gel using the image array processor to determine the presence or absence of a
particular substance.
Additional examples of computer projects include:
(1) Fine Motor Control Evaluation Project. Programs have been developed
for evaluating fine motor control movements in Parkinson patients using a periph-
eral device called the Bit-Pad I (Summographics Corp.). It consists of a magnet-
ostrictive surface sensitive to the position of a pen-like stylus. The device
transmits the position of the stylus through a standard computer interface. The
program determines, over a series of trials, how well the subject can move the
stylus through a series of positions on a pattern, in a connect-the-dots fashion.
Each trial consists of at least five successive repetitions. Evaluation is based
upon speed and accuracy. The reaction time of the subject is measured at the
start of each trial; it is thought that this can be related to the number of posi-
tions in the pattern that the subject must subsequently traverse. The test should
be a sensitive indicator of the amount of fine-motor dysfunction in Parkinson
patients.
41 - ODIR/IRP (ICS)
(2) Cell Culture Analysis. This system is designed to provide an on-line
analysis of tissue culture neurons. The first phase, to study the excitatory or
inhibitory post-synaptic potentials of these cells, has been completed. A unique
feature of this system is the on-line control of artifacts introduced by the
measurement system and the properties of tissues in culture and to control the
threshold levels and amplification level as the experiment is in progress. Visual
displays of amplitude, integral and latency are available, as well as averaged
evoked response. In addition, on-line monitoring of post-synaptic potentials
elicited by stimuli presented in pairs or in trains of pulses are available. The
system also studies spontaneously occurring miniature potentials. This system is
being extended to allow analysis of the cells by other techniques such as voltage
clamping and the iontophoretic injection of neuroactive substances on the surface
of the cell .
(3) Neurophysiological Data Analysis System. This system was initially
developed for the Laboratory of Neurophysiology, NIMH, and has found widespread
use. It is a versatile system for the collection and analysis of neurophysio-
logical data, such as cortical unit events, lever position, EMG, etc., with
behavioral events, and allows the presentation of this data in its relation to
any time locked variable. The data are displayed as rasters and histograms of
the neural events, centered on behavioral criteria, with the ability to mark
selected events, and also the analog sweeps associated with these trials. Ex-
tentions are being made to this system to enhance its utility; these include the
ability to select groups of trials within a unit, the selective deletion of sweeps,
and the shifting of individual rasters in time. In addition, the individual
trials may be sorted on a number of variables included in the data. A time window
may be selected and a sort made on the pulse count (neural events) or selected
criteria from the analog data such as the integral, slope, maximum amplitude or
the latency to the first derivative.
42 - ODIR/IRP (ICS)
ENGINEERING, COMPUTER AND FABRICATION SERVICES
This table shows the distribution of the Section's workload among the
various laboratories and branches.
LABORATORY OR BRANCH
Clinical Science, NIMH ---------------
Neurophysiology, NINCDS --------------
Neurophysiology, NIMH ---------------
Biological Psychiatry, NIMH ------------
Clinical Psychobiology, NIMH ------------
Cerebral Metabolism, NIMH -------------
General and Comparative Biochemistry, NIMH - - - - -
Biophysics, NINCDS -
Neuropathology and Neuroanatomical Sciences, NINCDS
Molecular Biology, NINCDS -
Neurochemistry, NINCDS ---------------
Surgical Neurology, NINCDS -------------
Experimental Therapeutics, NINCDS ---------
Neuropsychology, NIMH ---------------
Psychology and Psychopathology, NIMH --------
Adult Psychiatry, NIMH
Molecular Genetics, NINCDS - --------
Infectious Diseases, NINCDS ------------
Neurochemistry, NIMH ----------------
Brain Evolution and Behavior, NIMH ---------
Neuroimmunology, NINCDS --------------
Clinical Neurosciences, NINCDS -----------
Neural Control, NINCDS -
Central Nervous System Studies, NINCDS -------
Other Laboratories and Branches, NIMH -------
HOURS PERCENT
2543
9.49
2511
9.37
2475
9.23
2428
9.06
1902
7.09
1738
6.48
1541
5.75
1403
5.23
1312
4.89
1096
4.09
1012
3.77
987
3.68
710
2.55
594
2.22
509
1.90
438
1.63
359
1.34
270
1.01
175
.65
159
.59
158
.59
150
.56
121
.45
101
.38
98
.37
NIMH (Total) 14,600 54.45
NINCDS (Total) 10,190 38.01
NICHD (Total)* 2,019 7.54
26,809 100.00
*NICHD loans the Section one position, and is thus entitled to 1700 hours of
service.
43 - ODIR/IRP (ICS)
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Biophysics
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1_8
PROJECT REPORTS
Excitable Membrane Characteristics: Voltage Clamp g
and Impedance Measurements
ZOl NS 01950-11 LB
Function and Structure of Ionic Channels: Ion
Interactions and Gating Mechanisms
ZOl NS 02087-09 LB
10
Subcellular and Extracellular Structure Associated ^2.
with Nerve and Muscle
ZOl NS 02092-09 LB
An Investigation of Electro-Mechanical Coupling 12
in Excitable Tissues
ZOl NS 02273-06 LB
Information Processing in Simple Nervous Systems I3
ZOl NS 02151-08 LB
Function and Structure of Membrane Ionic Channels: 14
Pharmacology and Ionic Selectivity
ZOl NS 02088-09 LB
Mathematical Modeling I5
ZOl NS 02091-09 LB
Effect of Drugs on Voltage-Dependent Ionic Conductance I5
in Membranes
ZOl NS 02218-07 LB
Structure and Function of the Perineurium I7
ZOl NS 02219-07 LB
Comparison of Different Modes of Axonal Stimulation 18
ZOl NS 02316-05 LB
Excitable Membranes and Ion Channels in Tissue-Cultured 19
Nerve and Muscle Cells
ZOl NS 02317-05 LB
Grated Ionic Channels in Membranes 20
ZOl NS 02526-01 LB
i - LB/IRP TAB
Annual Report
October 1, 1981 thru September 30, 1982
National Institute of Neurological and Communicative
Disorders and Stroke
Laboratory of Biophysics
William J. Adelman, Jr., PhD, Chief
INTRODUCTION
The research program of the Laboratory of Biophysics is concerned with
investigating molecular and cellular mechanisms responsible for excitation,
membrane potentials, the generation of the nerve impulse, synaptic activity, the
biophysical basis for the functioning of simple nervous systems, and the cellular
basis for such integrative neural functions as behavior and learning. The
laboratory is composed of two units. One of these units operates on a year-round
basis at the Marine Biological Laboratory in Woods Hole, Mass. The Woods Hole
Unit is composed of 2 sections: the Section on Neural Membranes and the Section
on Neural Systems. The Bethesda unit of the laboratory is made up of the Section
on Molecular Biophysics.
Acceptance of the idea that excitability in neurons results from the opening
and closing of ion-specific membrane channels is widespread among neuroscientists.
Much of the evidence that has led to this acceptance has been based on measure-
ments of current flow through these transmembrane channels. These channels have
been described in terms of their individual unit conductances or their conduc-
tances in ensemble. Therefore, it is now apparent that any rational description
of excitable membrane behavior must be consistent with the behavior of single
channels both individually and in the large ensembles found in neurons and muscle
cells.
One of the major directions of the Laboratory of Biophysics has been to
focus attention on channel behavior as the basis for neuronal function and thus
logically as the basis for the function of ensembles of neuronal cells or neural
systems. The overall program of the Laboratory of Biophysics (LB) has been
conceived with this basis in mind. The program, while having its origin, in
part, in the 1950' s, was broadened in the 1970 's by considering that the overall
approaches used to study the biophysics of axon and artifical bilayer membranes
could be applied to the study of neural systems. The core of this approach has
been the adoption of biophysical methods integrated with modern ultrastructural
and biochemical approaches to produce an understanding of complicated mechanisms
at fundamental levels. The organizational restructuring of LB in 1974 and the
eventual establishment of two sections of LB at the Marine Biological Laboratory
in 1975 was a direct outcome of this thinking.
At present, one sees this main thread within the individual programs of the
three sections of LB. The predominant approach of the Section on Molecular
Biophysics is to study individual channels and their unit conductances. This
section also studies membrane conductances or the behavior of channels in ensem-
ble. The Section on Neural Membranes predominantly studies membrane conductances
with a strong emphasis on structure at resolutions approaching the molecular or
atomic level. Both skeletal and cardiac muscle systems are included within this
program. The Section on Neural Systems studies mechanisms by which simple neural
1 - LB/IRP
systems process information with a major emphasis on learning mechanisms. The
Section's main thrust has been cellular electrophysiology with lateral integra-
tions to membrane conductances, microscopic anatomy, integrative behavior and
neuronal biochemistry.
Considered as an entity, the Laboratory of Biophysics is now operating over
the broadest range of basic interests in neuronal function. The insights gained
at the channel level give direction to the membrane studies and the membrane
studies give impetus to the neurophysiological and behavioral investigations.
These all receive strong input from the Laboratories' investigations in ultra-
structure science and biochemistry. These interrelations are not strictly concep-
tual as methods, techniques, equipment and personnel also develop in parallel and
become part of the direction of LB. It is hoped that the following summary of
highlights of LB's recent accomplishments give evidence that this integrative
approach is fruitful.
Section on Neural Membranes.
The Section on Neural Membranes uses modern electrophysiological, electron
optical, mathematical biophysical, and computer science techniques to investigate
the function and structure of neural cells and tissues at limits approaching the
molecular level. The general approach is to examine mechanisms that underlie all
neural function. Emphasis is placed on membrane ionic channel structure and
function. Model systems are derived, tested and used to simulate neuronal func-
tion under a variety of natural and experimental conditions. Subcellular struc-
tures supportive of axoplasmic transport and membrane ionic channel formation are
sought. The physical mechanisms involving the structures of muscle and nerve
responsible for contraction and mechanoelectrical transduction is probed and
these are related to both the biochemical and structural elements underlying
these mechanisms.
It has been clear for many years that electrical excitability involves a
mechanism whereby ionic channels in the neuronal membrane make transitions from
normally closed states to open states and vice versa. These transitions occur in
time in a manner that is dependent on the membrane potential. The measurable
phenomena (conductance, charge transfer, flux, etc.) are kinetic in the sense
that their time and spatial variations are measurable functions of voltage.
These kinetics are usually considered to be the result of channel gating mechanisms.
"Gating" is descriptive of the manner and form of opening and closing of the chan-
nel gates, accessible traffic through the opening being limited to open times,
the characteristics of the unit channels and the nature of the charge carriers.
To a large extent, the study of voltage-dependent channel gating has been a major
theme in LB.
The Section on Neural Membranes carried on several "gating" investigations
during the year. One of these studies examined the kinetics of the gating of the
sodium channel with regard to the nature of the channel molecular states involved.
Abrupt (microsecond) transitions were observed in the sodium conductance during
certain voltage clamp steps. Extended "tail" currents also were observed upon
repolarization to the holding potential following other specific clamp pulses.
These phenomena have been modeled by including an (energetic) excited molecular
state in the activation gating kinetics in parallel to the classical Hodgkin-
Huxley kinetics.
2 - LB/IRP
Another research effort dealt with calcium binding to (and the distribution
of) membrane surface sites in the vicinity of the squid axon potassium channel
molecule. The calcium binding constant was found to be 30 M"-*-, much larger than
previously thought, and implying a much lower surface potential (-15 mV) in
normal sea water than had been imagined. Surface charge appears to be distrib-
uted in such a way that its electric field component influences the channel
gating charges much more than the ion flux. This finding implies that the ionic
channel is separated from the gating charges by >_ 8 Angstrom units on the basis
of the Debye (reciprocal) length theory.
The effects of previous membrane voltage history on potassium channel gating
was another study carried out by the section. While activation kinetics were
found to be delayed by previous hyperpolarization of the membrane in a manner
similar to that found originally by Cole and Moore, translation on the time axis
of the delayed responses did not result in superposition of these with the control
responses. The disparity between delayed and control depolarizing responses
occurred during the first few milliseconds of the rising phase of the potassium
current. These results could be described by incorporating a time dependence
into the rate constant of activation of potassium channel gates in the Hodgkin-
Huxley model of the potassium conductance. Since tail currents could be fit with
a single exponential (after taking the effects of ion accumulation into account),
the lack of superposition of activation kinetics is not attributable to a second
population of potassium channels. That is, potassium current kinetics in squid
axons can be modeled by a homogeneous channel population.
The influence of channel blockers such as cesium, rubidium and barium on the
current-voltage relations of potassium channels was also studied. The results
of this study suggested that an external Cs or Rb ion can be swept into a
potassium channel both by membrane potential and by external K ions. The binding
of these ions to a binding site some distance from the external mouth of the chan-
nel was also suggested. While blockage is apparent primarily when the net channel
current is inward, a finite probability for either external Cs or Rb to enter the
channel mouth when the net channel current is outward was shown to exist. However,
such an effect is only apparent when the blocking ion concentration is relatively
large.
In keeping with the overall theme of the Section, a method was developed for
simulating single channel openings and closings as a basis for predicting excita-
ble membrane voltage changes, particularly the action potential. It was possible
to simulate the behavior of a small population of channels under a variety of
conditions. This study is important in that it provides support for the general
idea that the spatial summation and temporal variation of single channel unit
events is the primary basis for electrical activity in nervous tissue.
In a comparative study involving embryonic heart cells, the general problem
of spontaneous and rhythmic behavior of excitable cells was investigated. Voltage
clamp experiments were run on these cells which showed that atrial cells have a
time-dependent potassium ion repolarization current. The currents for these
channels are similar to nerve except that the time constants are about 50 times
longer than nerve. Perturbations of spontaneous activity in these cells were
achieved and these produced results which provided an explanation for the time
bifurcation of interrupted cyclic activity. Implications were drawn from these
heart cell studies which might be applied to understanding spontaneous activity
in nerve.
LB/IRP
A major research effort of the Section continued to be the investigation of
mechanoelectric transduction mechanisms in squid giant axons. The following
similarities in general responses between this preparation and mechanoelectric
transducer organs were observed which relate this model system to general trans-
duction mechanisms. The "primary" response to stretch (axon membrane depolariza-
tion) corresponds to the "local" or pre-potential response observed from trans-
ducer organs. The primary response is graded and dependent on mechanical stimu-
lus parameters as is the local response. The primary response, if large enough,
will lead to a membrane threshold response which is regenerative in nature and
produce a spike potential. Evidence suggests that nonconventional sodium channels
are involved in the primary response to stretch and that conventional potassium
channels are involved in the recovering repolarization.
In additional work, emphasis was placed on a detailed description of the
viscoelastic and other mechanical properties of the isolated axon preparation.
Thus, mechanical transients produced by rapid stretch of the axon were represented
in an analog circuit delay line and, with the use of certain Hodgkin-Huxley formula-
tions, a model was established. Computer simulation of stretches applied to the
model yielded electrical responses that were similar to experimental observations.
It is now apparent that there is an intimate relationship between the func-
tion of membrane channels in excitable tissues and the structure of both the
channels themselves and the neurons and muscle cells in which they are found.
It is also apparent that the internal structure of neurons, particularly axons,
has many functions. Among these are axoplasmic transport and flow. Therefore,
one of the major aims of the Section continues to be an investigation of the fine
structure of axoplasm, particularly of the neuroplasmic lattice and its relation-
ship to other cytoplasmic components and the axolemmal surface. To this end
heavy use has been made of TEM and STEM techniques using the Philips EM400 electron
microscope which, because of its "achromatic" electron optical characteristics,
is particularly useful for stereographic examination of relatively thick sections
(0.1-0.5 ym) . Such thick sections are usually only usefully examined in high
voltage electron microscopes. Considerable emphasis has been and continues to be
placed on determining the effects of the procedures usually required for electron
microscopy, that is, fixation, dehydration, embedding and sectioning.
Computer processing of scanning transmission (STEM) video signals and the
application of Fourier analytical methods to the video line signals comprising
the picture raster continued to be a convenient and objective method for the
characterization of periodic structure in many nerve and muscle subcellular
arrays. These image enhancement and analytical methods were greatly expanded by
adding energy dispersive x-ray analysis (EDAX) and electron energy loss spectro-
scopy (EELS) capabilities to the EM400 electron microscope. Much effort has gone
into generating computer programs so as to make full use of both digital image
processing and analytical techniques now being implemented in conjunction with
the EM400. All of these methods are being applied to axons and neurons from
several different species, both invertebrate and vertebrate. Several different
classes of muscle cells are being examined. The structures of both nerve and
muscle cells as seen in the electron microscope are being compared with the
protein chemistry of their constituents and with suitable light microscopy
imaging of these cells while they are active. These studies are beginning to
indicate the general lattice array of neurofilaments, neurotubules, cross-bridges,
and which of these elements are characteristic of certain classes of neurons and
certain species. All of this has been made possible by an integrative approach
LB/IRP
involving electron optics, analytical biophysics, electronic and optical
engineering and applied mathematics and computer science (primarily programming
and systems engineering) .
Section on Molecular Biophysics.
The main goal of the Section on Molecular Biophysics is to determine the
molecular mechanisms underlying the behavior of membrane ionic channels and of
drugs that interact with these channels.
A major theme of the Section this year has been the use of various chemical
agents to determine channel properties or to determine the role of the chemical
agents themselves. The chemicals used were batrachotoxin (which opens sodium
channels) , yohimbine and amioderone (which block sodium channels) , dipicrylamine
(which is a charged hydrophobic molecule) , acetylcholine and other cholinergic
agonists and partial agonists, TEMPO (a spin label), and bungarotoxin (which
blocks acetylcholine channels) .
Another major theme was the use of patch clamp both to observe single ionic
channels and to allow voltage clamping of small cells.
Previously, the method of radioactive flux measurement was used to determine
some of the properties of batrachotoxin-bound sodium channels in neuroblastoma
cells. The method of suction pipet voltage clamping now has been used to deter-
mine the voltage dependence of these properties and to obtain faster time resolu-
tion. It was found that batrachotoxin opens sodium channels because it shifts
the activation conductance-voltage curve about 50 mV in the hyperpolarizing
direction and also eliminates both fast and slow inactivation. Thus, at the
normal resting potential, when batrachotoxin is present, activation is turned on,
inactivation is turned off, and the channels are open. It was found that batra-
chotoxin also caused several changes in the kinetics of the sodium channel. In
particular, the activation process was changed to first order and was considerably
slowed. A likely explanation for these changes is that the addition of batracho-
toxin slows one of the conformational changes which normally occurs during the
opening of sodium channels, and that consequently this event becomes rate-limiting.
There are numerous drugs that act to block sodiiim channels. In order to
determine what features of the blocking molecule are important, a large number of
analogs of the use-dependent blocking drug, yohimbine, have been synthesized.
These analogs were then tested for activity in experiments on voltage clamped
squid axons. The use-dependent blocking action of the analogs correlates well
with the presence of a negative charge at a particular region of the molecule.
Experiments are planned to subject to further tests our tentative conclusion
that binding of yohimbine requires a negative charge at the appropriate position.
Amioderone is another drug which has been found to block sodium channels.
Interesting features of blocking by this drug are the long delay before the drug
acts and the lack of use-dependence. One motivation for studying this drug is
that it is now widely used as an antiarrythmic agent.
An important aspect of channel gating is the role of membrane lipids.
Dipicrylamine has been incorporated into axonal membranes in order to compare
the normal gating current with an analog gating current produced when dipicryl-
amine dissolved in a membrane is subjected to a strong electric field. The
5 - LB/IRP
dipicrylamine gating current was found to be strongly influenced by the presence
of chloroform in the membrane, presumably because chloroform changes membrane
viscosity. The normal gating current, on the other hand, was not significantly
influenced by chloroform. This strongly suggests that channel gating is essen-
tially independent of the lipid environment.
Gating current observations have so far been limited to the sodium channel.
It has not been possible to observe potassium gating current, in part because of
the relatively slow rate of channel activation. Working at elevated temperature,
a component of gating current has been observed which has the kinetics and steady
state properties of the potassium channel, and which we tentatively call the
potassium gating current.
Patch clamp measurements have been primarily directed towards determining
the amplitudes and durations of currents through single ionic channels. An
important conclusion from this work is that, for cholinergic channels, the conduct-
ance amplitude is about the same for all agonists. Partial agonists cause smaller
macroscopic conductances than do full agonists because partial agonists cause the
channels to be open for a smaller fraction of time.
Another experimental generalization is that cholinergic channels tend to
have two separate open-state lifetimes. A likely explanation for this is that
there are two open states - one corresponding to one bound agonist and the other
corresponding to two bound agonists.
Single-channel measurements have also been made on voltage-dependent channels.
A complete analysis was made of the characteristics of the calcium-dependent
potassium channel in tissue-cultured pituitary cells. The opening rate for this
channel was found to depend on both membrane potential and on the concentration
of calcium ions at the membrane interior surface.
In order to improve our ability to detect single channels, a method is being
developed to extract information about channel durations in the presence of noise
and low-pass filtering. This approach consists of two steps. First, the filter-
ing effect is estimated and appropriate corrections made. Then a square wave is
extracted from the corrected noisy signal on the basis of Bayesian inference.
The patch clamp has also been used to observe action potentials in developing
cells, and hence to monitor changes that occur during development. We found that
during the first two weeks of development of embryonic mouse spinal cord cells,
there was a rapid increase in spontaneous electrical activity. The time course
of this change parallels biochemical changes that had previously been observed.
In addition to the various electrical measurements on channels, several
spectroscopic measurements have been made as well. In particular, the binding of
agonists to cholinergic receptors was found to cause changes in electron spin
resonance of specially prepared spin labels and also causes changes in fluores-
cence. These spectroscopic changes result from conformational changes of the
receptor complex and are antagonized by the same agents that antagonize acetyl-
choline binding.
A complementary method has been used to study channel structure and function
making use of a theoretical analysis of individual channel proteins. Methods
were developed to predict three-dimensional protein structures from knowledge
6 - LB/IRP
of primary amino acid sequences. These methods (along with other information,
such as the structure of drugs that bind to a channel) were used to model specific
channels. Work has now been completed on a method to use calculated partition
energies of amino acid side chains to determine certain channel structures.
Section on Neural Systems.
The major focus of the Section is an integrated multidisciplinary effort to
determine a neural and a biochemical basis for associative learning. The nudi-
branch mollusc Hermissenda crassicornis has proven to be a most opportune prepara-
tion. Hermissenda has made it possible to define a model of associative learning
with the same defining features used for vertebrate associative learning. Move-
ment of Hermissenda toward a light source is markedly reduced after repeated
pairing of a light stimulus with rotation. This behavioral change is truly
associative (i.e., random light and rotation do not produce the effect), persists
for at least several days after training and increases with practice. Stimulus
specificity for this behavioral change is indicated by the fact that trained
animals do not show changes in responsiveness to food or gravitational stimuli.
Other features of vertebrate associative learning such as requirement for contin-
gent stimuli and extinction have also been demonstrated for Hermissenda associa-
tive learning.
Three sensory pathways essential to the associative learning model, the
visual, statocyst, and chemosensory pathways, have been studied. Synaptic rela-
tions of identified neurons which mediate this behavior have been described.
With knowledge of sensory, interneurons, and motorneurons involved in this neural
integration, membrane changes of specific neurons were implicated as primary
steps in a causal sequence responsible for the conditioning. Repeated stimulus
pairing (but not unpaired or randomized paradigms) results in short-term cumula-
tive membrane depolarization of the Type B photoreceptor resulting in long-term
inactivation of an early voltage-dependent outward K"*" current. This causes
enhanced depolarizing responses of the Type B cell and, sequentially, increased
inhibition of ipsilateral Type A cells, ipsilateral hair cells, interneurons and
motorneurons, and ultimately, retarded positive phototaxis. Duing cumulative
depolarization produced by repeated pairings of light and rotation, intracellular
Ca is elevated. Elevated intracellular Ca in turn causes enhanced activity
of a Ca''~'"-calmodulin-dependent protein kinase and thereby increased protein
phosphorylation. Increased phosphorylation of specific proteins ultimately
results in a decreased I^ and the sequence of neurophysiologic and behavioral
changes necessary for associative learning.
Intracellular recordings from sensory receptors together with interneurons
and central motorneurons have made it possible to define input-output relations
of the visual pathway. Intracellular and extracellular recordings have been made
in behaving animals. So as to assess individual neuronal activity as it affects
behavior, the neural network consisting of peripheral sensory interactions between
photoreceptors, hair cells and optic ganglion cells and the visual-statocyst
convergence on cerebropleural interneurons (IN) and MNl cells, was shown to
provide a basis for Hermissenda associative conditioning. This system was sug-
gested for conditioning networks in other animals.
Voltage clamp studies of the soma membrane of isolated Type B photoreceptors
were shown to have several light- induced conductances (Na"*", Ca"^ and K"*") . In
addition, two voltage-dependent outward K conductances, a large, fast, early
7 - LB/IRP
current and a slow, late current, were found. The early outward K current, I^,
was found to be greatly reduced in associatively trained, but not control, animals.
The kinetics of inactivation of this current were also increased for only the
trained animals. This decrease of a specific dark K current with learning was
used to explain the increased input resistance of Type B cells (after the somata
were isolated from their axons and synaptic endings) from trained animals. A
decreased I^ specific to conditioned animals was suggested as the basis for the
enhanced Type B voltage response (during and following light steps) which in turn,
via known synaptic interactions, can be put forth to account for the learned
behavior.
The two voltage-dependent outward potassium currents in the dark, I^ and Ig
(a delayed current) , have now been described by a quantitative channel model of
the Hodgkin-Huxley type. A mathematical model of these conductances together
with the light-dependent inward currents sodium channels was used to predict ob-
served responses of the Type B photoreceptor to light stimuli and current injec-
tion.
In the Type B cell, under voltage clamp, a single iontophoretic injection
of Ca"*"^ (0.5 nA, 1 min) was shown to cause prolonged inactivation of I^ but not
Ig. Elevation of intracellular Ca"*"*" was shown during the steady-state phase of
the light response as well as the LLD after light offset by means of differential
absorption spectrophotometry after Arsenazo III injection into the cell. These
findings suggest that elevation of cytoplasmic Ca during the LLD is voltage-
dependent and thus should also be enhanced when light is paired with rotation
during the conditioning procedure.
Prolonged inactivation of I^ was shown to occur when light steps were paired
with depolarizing command steps. These results were correlated with changes in
intracellular Ca"^. All of these results were used to put forth a membrane chan-
nel model for acquisition and retention of associative learning.
A series of biochemical studies were performed which suggested that elevated
intracellular Ca"^ together with depolarization cause prolonged I^ inactivation
by increasing Ca"^-calmodulin protein kinase activity.
Numerous refinements in characterization of associative learning have been
achieved during the past year. These include a dramatic extension of the dura-
tion of learning retention from days to weeks, the demonstration of contingency
and extinction, and the specification of a change in visual discriminatory
behavior as the basis for decreased positive phototactic movement following
associative training.
The overall program of the Section was productive in several other areas
which were supportive of the main thrust of the Section.
8 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01950-11 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Excitable Membrane Characteristics: Voltage Clamp and Impedance Measurements.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
W.
J.
C.
R.
R.
J.
J.
A.
L.
M.
J, Adelman, Jr.
Pohlmeister
Tyndale
Waltz
Mueller
Sasner,
R. Clay
Shrier
Glass
Guevera
Jr.
Chief LB NINCDS
Assistant Professor U. of Minnesota
Electronic Engineer MBL
Mathematician Programmer MBL
Research Assistant MBL
Professor U. of New Hampshire
Staff Fellow LB NINCDS
Assistant Professor McGill Univ.
Associate Professor McGill Univ.
Graduate Student McGill Univ.
COOPERATING UNITS (if any)
Marine Biological Laboratory, Woods Hole, MA 02543; Univ.
Univ. of New Hampshire; McGill Univ.
of Minnesota;
lab/branch
Laboratory of Biophysics, IRP
section
Section on Neural Membranes (located at MBL, Woods Hole, MA 02543)
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
4.0
PROFESSIONAL:
3.8
OTHER:
0.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The general aim of this project has been to study excitable membrane character-
istics by a variety of physical methods. One aspect has been to improve elec-
trical measxirements of excitable membrane characteristics consistent with
physical and chemical methods for the study of nerve and muscle membrane ionic
channels. Two major approaches are used. The first involves the development of
methods for analysis of ionic channel admittances and/or conductances by means
of voltage clamp techniques. Programs for carrying out this analysis are devel-
oped. Voltage and current clamp experiments are employed to characterize the
ionic currents underlying excitability in squid giant axons and chick embryonic
heart cells. The contributions of the various currents to voltage oscillations,
pacemaker potentials and action potentials are determined by computer simulation
based on the voltage clamp measurements.
PHS-6040
(Rev. 2-81)
9 - LB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02087-09 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or It
0
Function and Structure of Ionic Channels;
Mechanisms .
Ion Interactions and Gating
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
W.
J.
Adelman, Jr.
Chief
LB NINCDS
Other:
J.
R.
Clay
Staff Fellow
LB NINCDS
L,
J.
DeFelice
IPA Fellow
LB NINCDS
M.
F.
Shlesinger
Assistant Professor
Univ. of Maryland
J.
F.
Fohlmeister
Assistant Professor
Univ. of Minn.
J.
T.
Neary
Biochemist
MBL
COOPERATING UNITS (if any)
Marine Biological Laboratory, Woods Hole,
University of Minnesota
MA 02543; University of Maryland;
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section on Neural Membranes (located at MBL, Woods Hole, MA
02543)
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
3.3
PROFESSIONAL:
3.3
0.0
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Voltage clflTnp experiments are employed to determine functional and structural
characteristics of ionic channels in the squid giant axon. Information con-
cerning these characteristics of the ionic channels is gained by studying
the interaction of ions which block the passage of normal charge carriers
and by studying the effect of voltage upon the opening and closing ("gating")
of channels. Computer simulations are performed of discrete openings and
closings of single potassium and sodium ionic channels in nerve and heart using
results from probability theory and a random number generator. The gating
kinetics of stochastic single K-channels are related to the kinetics of conven-
tionally defined conductances. The effects of known potassium conductance
blockers on protein phosphorylation in squid axons is studied. Measurements of
channel current-voltage relations are made in the presence of channel blockers,
such as Rb'^, Cs+ and Ba"^
PHS-6040
(Rev. 2-81)
10 - LB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02092-09 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Subcellular and Extracellular Structure Associated with Nerve and Muscle.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS,
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: W. J. Adelman, Jr.
Other: A. Hodge
R. Mueller
P. Roslansky
R. V. Rice
R. Lasek
R. Waltz
C. Tyndale
R. D. Allen
C. K. Govind
C. R. Worthington
J. Metuzals
AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
Chief
Senior Scientist
Research Assistant
Guest Worker
Guest Worker
Professor
Mathematician Programmer
Electronic Engineer
Professor
Investigator
Professor
Professor
LB NINCDS
MBL
MBL
LB NINCDS
LB NINCDS
Case West. Res.
MBL
MBL
Dartmouth College
MBL
Carnegie-Mellon
U. of Ottawa
COOPERATING UNITS (if any)
Marine Biological Laboratory, Woods Hole, MA 02543; Case Western Reserve;
Dartmouth College; Carnegie-Mellon University; University of Ottawa
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section on Neural Membranes (located at MBL, Woods Hole, MA
02543)
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
3.9
PROFESSIONAL:
3.7
0.2
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
H (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is to examine the subcellular and extracellular
structure of nerve and muscle and relate such structure to function. Electron
microscopy in TEH, STEM and analytical electron beam probe modes, such as EELS
and EDAX, determination of proteins contributing to these structures and struc-
tural modeling are methods used in this study. The following structures are
probed: 1) Neuroplasmic lattice, 2) neur of ilament s , 3) microtubules, 4)
axolemma, 5) glial cell membranes, and 6) myofilaments. Methods developed
and used in this study are: 1) Stereoscopic imaging, 2) Optical autocorrela-
tion, 3) fast Fourier transformation (PFT) of STEM video images, and 4) STEM
Tfideo image filtering and image enhancement using reverse Fourier transformation
Video Imaged light microscopy is used to study living neurons in dark field or
differential interference contrast.
PHS-6040
(Rev. 2-81)
11 - LB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02273-06 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
An Investigation of Electro-Mechanical Coupling in Excitable Tissues.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
J. B. Wells
D, E. Goldman
Research Physiologist
Guest Worker
LB NINCDS
LB NINCDS
COOPERATING UNITS (if any)
Marine Biological Laboratory, Woods Hole, MA 02543
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section on Neural Membranes (located at MBL, Woods Hole, MA 02543)
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1.0
PROFESSIONAL:
1.0
0.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The major portion of the research effort was concerned with mechanoelectric
transduction mechanisms in squid giant axons. An input-output relationship
was observed and present studies will further define and quantitate this
relationship.
PHS-6040
(Rev. 2-81)
12 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02151-08 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Information Processing in Simple Nervous Systems.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS,
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI.: D.L. Alkon
Other: J. Shoukimas
J. Acosta-Urquidi
Y. Goh
A. Kuzirian
J. Harrlgan
I. Lederhendler
J. Neary
S. Leighton
J. Buchanan
W. Richards
S. Senft
AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
Medical Officer
Staff Fellow
Visiting Fellow
Visiting Fellow
Staff Fellow
Mariculturist
Behaviorist
Biochemist
Guest Worker
Graduate Student
Graduate Student
Graduate Student
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
LB
LB
LB
LB
LB
MBL
MEL
MBL
LB NINCDS
Northeastern U.
Princeton U.
Washington U.
COOPERATING UNITS (if any)
Marine Biological Laboratory, Woods Hole, MA 02543; Northeastern University;
Princeton University; Washington University, St. Louis, MO.
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section on Neural Systems (located at MBL, Woods Hole, MA 02543)
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
9.0
PROFESSIONAL:
8.5
0.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n(al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The principle objective is to study the mechanisms by which simple neural
networks process information with particular emphasis on mechanisms of
learning. The nervous system of Hermissenda crassicornis has proven to be
a good model for information processing at several levels: sensory transduc-
tion by photoreceptors and hair cells, analysis of synaptic circuitry, changes
in synaptic circuitry produced by conditioning paradigms administered to
intact animals, as well as to isolated nervous systems, membrane properties
modified by conditioning, identification of critical developmental stages for
the neural networks of interest, as well as stages critical for learning.
Techniques employed thus far to pursue these questions include simultaneous
intracellular recording from multiple neural elements, paired stimulation of
the visual and vestibular pathways using a rotating table, iontophoresis of
fluorescent dyes and electron dense materials, automated behavioral monitoring
of intact Hermissenda, voltage clamp of identified neural elements. Other
methods include mariculture, subcellular fractionation, protein phosphoryla-
tion analysis, and uptake of neurotransmitter precursors.
PHS-6040
(Rev. 2-81)
13 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02088-09 LB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Function and Structure of Membrane Ionic Channels
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI;
Other:
G. Ehrenstein
L.M. Huang
Nava Mo ran
H. Robert Guy
Research Physicist
Staff Fellow
Visiting Fellow
Research Physicist
LB NINCDS
LB NINCDS
LB NINCDS
LB NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section on Molecular Biophysics
INSTITUTE AND LOCATION
NTH, Rethesda, Maryland 20205
4,3
PROFESSIONAL:
0.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
"E (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Sodium channels that are modified by the addition of batrachotoxin
(BTX) differ in many ways from normal sodium channels. For example, the
modified channels activate with first-order kinetics and activate more
slowly than do normal sodium channels. These results suggest that BTX
slows down one of the conformational changes which occur during channel
opening, and that this conformational change becomes rate-limiting.
A theory was developed to calculate partition energies of all amino
acid side chains as a function of the distance of the a-carbon from a water-
protein, a water-lipid, and a protein-lipid interface. This theory was used
to develop a program that predicts the manner in which amphipathic g-helices
with specific sequences will stack side by side to form a tight protein bar-
rier between water and an apolar lipid phase. The program, in turn, was used
to predict molecular conformations for apo lipoproteins and for several mem-
brane channel proteins.
PHS-6040
(Rev. 2-81)
14 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02091-09 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Mathematical Modeling
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. FitzHugh
Research Physicist
LB NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Biophysics, IRP
section
Section on Molecular Biophysics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.2
PROFESSIONAL:
1.0
0.2
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
E (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Mathematical modeling for the following phenomenon was continued:
Signal detection and analysis of the square wave currents from single
channel opening and closing in a membrane, distorted by noise and low-
pass filtering.
PHS-6040
(Rev. 2-81)
15 - LB/ IRP
PROJECT NUMBER
ENCI
(Do
NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02218-07 LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Effect of Drugs on Voltage-Dependent Ionic Conductance in Membranes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
D.L. Gilbert
G. Ehrenstein
Research Physiologist
Research Physicist
LB NINCDS
LB NINCDS
COOPERATING UNITS (if any)
R. J. Lipicky, Food and Drug Administration; E. Wenkert , Dept .
of Chemistry, Univ. of California at San Diego; H. Pant, National
Institute on Alcohol Abuse and Alcoholism
lab/branch
Laboratory of Biophysics
SECTION
Section on Molecular Biophysics
INSTITUTE AND LOCATION
NINCDS. NIH, Be thesda, Maryland 20205
TOTAL MANYEARS:
2.6
PROFESSIONAL:
2.1
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is to better understand how drugs affect
the mechanisms of the ionic conductance in membranes which are voltage-
dependent and excitable. These studies involve the use of the squid giant
axon and the nerve bundles from the garfish. We have continued studies on
the mechanism of drug-channel interactions in the squid axon membrane. In
particular, we have studied yohimbine and its analogs . In addition, we have
studied amiodarone , an antiarrhythmic drug. We have shown that amiodarone hai
an acute effect on the electrical properties of the squid giant axon. This ik
one of the very few acute effects observed for amiodarone.
PHS-6040
(Rev. 2-81)
16 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02219-07 LB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Structure and Function of the Perineurium
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
R.E. Taylor
S.I. Rapoport
N . Shinowara
H. Levitan
Research Physiologist LB NINCDS
Medical Officer, Researcher LN NIA
Staff Fellow LN NIA
IPA LN NIA
COOPERATING UNITS (if any)
Laboratory of Neurosciences, NIA
lab/branch
Laboratory of Biophysics, IRP
SECTION
Section of Molecular Biophysics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.2
PROFESSIONAL:
0.2
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
We demonstrated the multilayer nature of the perineurium and the role of inter-
cellular tight junctions in maintaining structural and functional integrity.
Passing AC current across the perineurium demonstrated that its electrical
properties could be represented by two resistances and two capacitances. A
high capacitance, which could be ascribed to polarization of charge, probably
represents the properties of the intercellular tight junctions.
This project has been temporarily discontinued, pending the expected return
during Fiscal Year 1983 of Dr. Ananda Weerasuriya.
PHS-6040
(Rev. 2-81)
17 - LB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02316-05 LB
PERIOD COVERED Qctober 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Comparison of Different Modes of Axonal Stimulation
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
G. Ehrenstein
B . Wong
Research Physicist
Staff Fellow
LB NINCDS
LB NINCDS
COOPERATING UNITS (if any)
G. Ganot, Technion Medical School, Haifa, Israel
LAB/BRANCH
Laboratory of Biophysics , IRP
SECTION
Section on Molecular Biophysics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.2
PROFESSIONAL:
0.1
0.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
]□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Reversal potentials for two different current components in Myxicola. were
measured . One component is that induced by mechanical stimulation, of the axon
and the other component is the leakage current . Both components had reversal
potentials of about -45 mV, suggesting that they have a common pathway. Work
this year has consisted of writing up and publishing the results of this research
The reference for this publication is:
Ganot, G., Wong, B.S., Binstock, L. and Ehrenstein, G,; Reversal
potentials corresponding to mechanical stimulation and leakage current in
Myxicola giant axons. Biochim. Biophys. Acta 649: 487-491, 1981.
PHS-6040
(Rev. 2-81)
18 - LB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02317-05-LB
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Excitable Membranes and Ion Channels in Tissue-cultured Nerve
and Muscle Cells
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
H.
Lecar
Other:
B.
Wong
G.
Ubom
Research Physicist
Postdoctoral Fellow
Postdoctoral Fellow
LB NINCDS
LB NINCDS
LB NINCDS
COOPERATING UNITS (if any)
M. Adler, Laboratory of Preclinical Studies, NIAAA; C.E. Morris, Univer-
sity of Ottawa, Otta, Ontario; Laboratory of Developmental Neurobiology,
IRP, NICHD.
lab/branch
Laboratory of Biophysics
SECTION
Section on Molecular Biophysics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
2.9
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Single-channel currents are measured in isolated areas of excitable-cell
membranes using the patch electrode method . Channel gating is studied as a
stochastic process in cultured rat muscle, mouse spinal cord neurons, and
anterior pituitary cells. Gating kinetics are determined for various synaptic
agonists and partial agonists acting on the postsynaptic receptors, for elec-
trically excitable channels and for the calcium-induced potassium channel.
Electron spin resonance and fluorescence measurements are done on ace ty Icho line -
receptor protein isolated from electroplax in order to develop a molecular probe
for the conformation changes induced by agonists.
PHS-6040
(Rev. 2-81)
19 - LB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02526-01 LB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Gated Ionic Channels in Membranes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. E. Taylor
Research Physiologist
LB NINCDS
COOPERATING UNITS (if any)
F. Bezanilla, J.M. Fernandez, UCLA Dept . of Physiology
lab/branch
Laboratory of Biophysics
Section on Molecular Biophysics
INSTITUTE and LOCATION
NINCDS. NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.4
PROFESSIONAL:
1.0
OTHER:
0.4
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
g] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Gating currents corresponding to axonal potassium current have been
observed .
When dipicrylamine is incorporated into squid axons, large polarization
currents can be produced. Comparison of the effect of chloroform on these
currents and on "gating currents" leads to the conclusion that the gating
process is not sensitive to the properties of the lipids in the axonal mem-
brane .
PHS-6040
(Rev. 2-81)
20 - LB/IRP
i
is
s
o
CO
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Central Nervous System Studies
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-28
PROJECT REPORTS
Neurobiology of Population Isolates: Study of
Child Growth and Development, Behavior and Learning,
and Disease Patterns in Primitive Cultures
ZOl NS 01282-18 CNSS (12 Subprojects) 29-34
Chronic Central Nervous System Disease Studies:
Slow, Latent and Temperate Virus Infections
ZOl NS 00969-18 CNSS (37 Subprojects) 35-42
PUBLICATIONS:
In Print 43-48
In Press 49-54
CONTRACTS 55
LCNSS/IRP TAB 9
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Central Nervous System Studies
National Institute of Neurological and Communicative Disorders and Stroke
The Laboratory of Central Nervous System Studies comprises two major
projects: (1) Neurobiology of Population Isolates--the Study of Child Growth
and Pevelopment, Behavior and Learning, and Disease Patterns in Primitive
Cultures; and (2) Chronic Central Nervous System Disease Studies--Slow, Latent
and Temperate Virus Infections. Both projects are an outgrowth of the Study of
Child Growth and Disease Patterns in Primitive Cultures. It was this parent
project that gave rise to the discovery of kuru, a heredofamilial subacute
progressive degenerative disease of the central nervous system of the Fore
people and their neighbors in the Eastern Highlands of Papua New Guinea, and led
to the demonstration that kuru is caused by a serially transmissible virus which
possesses unconventional biological and biochemical properties. This was the
first demonstration that chronic degenerative disease in man could have virus
etiology and directly stimulated the research that led to the discovery of
several other slow virus infections of man. The successful transmission of kuru
and the isolation of its virus provided the necessary techniques for the
subsequent discovery of a viral etiology for some forms of presenile and senile
dementias of man, particularly the Creutzfeldt-Jakob type (CJD), and it was this
study that has led to the discovery that the agents causing these diseases form
a group of transmissible virus-like agents new to the field of microbiology.
These are the only known virus infections without examples of recovery and
are unique in their total failure to evoke any immune response to the causative
virus. Moreover, familial forms of CJD appear to be the first examples of virus
disease of man with genetic (single gene) control of pathogenesis.
During the past year, we have focused much of our attention on
high-incidence foci of motor neuron disease with associated parkinsonian
syndromes in the western Pacific, specifically, the amyotrophic lateral
sclerosis (ALS) and parkinsonism-dementia (PP) complexes among the Jakai and
Auyu people of West New Guinea, the Chamorro people of Guam, and residents of
the Kii Peninsula of Japan. It now appears that these are determined by
exposure during infancy and childhood to isolated environmental deficiencies of
calcium and magnesium. The resulting hyperparathyroidism causes deposition of
calcium and magnesium in soft tissues and brain cells; absorption and metabolism
of other metallic cations are also altered. Many years later this causes
formation of neurofibrillary tangles and cascading early neuron death resulting
in ALS, PD, and mixed neurological syndromes seen in these foci. In all three
foci, enormous calcium and magnesium deficiencies of local soil and water have
been demonstrated; residents of all three areas obtained all food and water
locally. Deposition of calcium, magnesium, and other metals in brain tissue of
patients with ALS and PD from Guam and the Kii Peninsula has been confirmed.
Now, using electron-probe X-ray microanalysis, we have further demonstration of
the presence of enormous deposits of aluminum, iron, magnesium, and calcium.
Recent economic changes have brought in imported food and water sources to Guam
and the Kii Peninsula where the diseases are disappearing, but this has not
1 - LCNSS/IRP
occurred in the West New Guinea focus where the incidence in some villages is
over 1000 times that in the United States.
During the past year a great deal of effort has centered on the
investigation of the newly-recognized worldwide distribution of hemorrhagic
fever with renal syndrome (HFRS). This was the most significant disease among
the peacekeeping forces in Korea during 1951-53 and remained largely unexplained
during that period. It is now known, largely from the efforts of our group, to
occur in much of the Eurasian landmass, carried to man by the respiratory route
from wild rodents which are silent reservoir hosts that remain unaffected by the
infection. Three strains of this bunyavi rus-1 ike virus have been identified:
(1) an Asian strain, usually of high virulence, which causes HFRS with up to 20
percent mortality in Korea, the Soviet Far East, Japan, and 19 provinces of the
People's Republic of China; (2) a European strain which causes nephropathica
epidemica (NE) in Scandinavia and some of the outbreaks of Balkan nephritis in
Yugoslavia, Greece, Hungary, and Czechoslovakia; and (3) a strain in wild
American rodents in the Frederick, Maryland area identified by presence of
antibody in sera and specific antigens in lung tissue (a similar strain not yet
known to cause human disease has been found in wild rodents in Virginia,
California, and Alaska). Recently, two new forms of this nephropathy have been
discovered: (1) a milder form, clinically resembling influenza, occurring in
Asian cities from commensal rats; and (2) a more severe form occurring in
laboratory workers in contact with infected laboratory rodents in Japan and
Belgium. This has greatly widened the interest and concern about HFRS. We have
now found the Korean hemorrhagic fever (KHF) form of the virus in urban-dwelling
commensal rats in the United States, and antibodies to the virus in native-born
Americans. A search is underway to determine whether mild and severe
nephropathies caused by these viruses in the United States may have been
misdiagnosed, as they have been until recently in Asia.
In the rapidly evolving story of the hemorrhagic fevers with renal syndrome
(HFRS), major findings have been made, particularly with regard to the detection
of antibody against Hantaan virus in domestic rats and in wild rodents of three
genera (Microtus, Clethronomys, and Pleomyscus) captured in the United States.
Pursuing this lead, we have recently demonstrated antigen in lung tissues of a
high percentage of seropostive voles (Microtus pennsyl vaniacus) trapped in
Frederick County, Maryland. Cross-immunofluorescent antibody tests suggest that
the agent in native meadow voles represents a new member of the HFRS virus
group. Efforts are currently underway to propagate this novel agent in cell
culture and in laboratory animals and to further characterize its serological
relatedness to and antigenic differentiation from the other known viruses of
HFRS.
We list the foci of high incidence of disease of great general importance
to all of medicine that have been recently located together with the 15 foci
reported in our previous annual report; and studies on all of these are
underway. These include: (1) focus of high-incidence chronic inflammatory
disease of the CNS called Viliuisk encephalomyelitis which appears to be
communicable among lakut people of the lakut ASSR of Soviet Siberia; (2) high
incidence focus of spastic paraplegia (called spastic paraparesis of the
Pacific) as seen in half of the Pacific and Colombia; (3) focus of high
incidence of ALS and PD in West New Guinea among the Auyu and Jakai peoples
resembling similar foci on Guam and the Ki i Peninsula in Japan; (4) focus of
high incidence of motor neuron disease among Australian aborigines on Groote
2 - LCNSS/IRP
Eylandt and adjacent Arnhem Land; (5) focus of high incidence of self-limiting
epilepsy as a newly recognized form of cerebral cysticercosis in West New
Guinea; (6) focus of high incidence premature aging in certain highland
populations in New Guinea; (7) focus of unusually high incidence and early age
of appearance of amyloid plaques and neurofibrillary tangles characteristic of
neurological aging in certain isolated populations; (8) foci of very much
delayed menarche and male and female puberty in isolated Melanesian populations;
(9) foci of high incidence spinocerebellar ataxias of diverse types in very
isolated highly inbred populations on la Reunion Island in the Indian Ocean;
(10) foci of high incidence Huntington's disease in several isolated Amerindian
(Venezuelan) and Melanesian (Papua and New Britain) populations; (11) focus of
high incidence male pseudohermaphroditism in isolated Melanesian and Australian
aborigines; (1?) foci of high incidence of presenile dementias of a slow virus
etiology in several population isolates; (13) focus of high incidence of
familial parkinson's disease in the Agaun Papuan population; (14) foci of
extremely high incidence of goitrous cretinism with congenital CNS defects
including deafness, mental and motor defects in New Guinea highland populations;
(15) focus of congenital Still's disease on Satawal Island, Western Caroline
Islands; (16) foci of abnormally high incidence of chronic lung disease, the
leading cause of death, and associated with an extraordinarily high incidence of
bronchial asthma in childhood on Micronesian islands; and (17) foci of high
incidence hyperuricacidemia including juvenile gout on Micronesian islands.
These studies have continued from their roots in the investigation of kuru,
which has been detailed in the Monograph published in 1981: "Kuru: Letters and
Field Notes from the Collection of P. Carleton Gajdusek", dealing with the first
year of kuru investigation. The field journals (32 volumes) and research cinema
documents dealing with our work in isolated and primitive populations over the
past 25 years are now being used extensively in the studies of child behavior
and neuromuscular development, age and speed of puberty, age of menarche, and
patterns of aging; different culturally determined patterns of learning,
language acquisition, memory, cognition and symbolic representation; differing
time, numerical and other quantitative senses and unusual forms of psychosexual
development; development and patterns of psychiatric breakdown, juvenile
suicide, violence, outbursts of unusual mass hysterias, use of drugs, and other
fad-like stereotype behavior patterns in diverse, isolated, primitive social and
cultural settings.
Once again other studies of man in isolated and primitive groups as
opportunistic investigations of importance to medicine on a worldwide basis were
highlighted in the Hitchcock Lectures in January of 198? at the University of
California (DCG), which summarized the results of such research:
MAN IN ISOLATION
1. Infectious Diseases in Isolated Populations
2. Genetic, Toxic, and Deficiency Diseases in High Incidence in
Isolated Populations
3. Unique and Unusual Patterning of Behaviour as a Consequence of
Isolation
4. Paradoxes of Unconventional Viruses: Host-specified yet viral
n-mers, where n is often large
5. Infectious Disease in Primitive Societies
LCNSS/IRP
THE NEW GROUP OF MICROORGANISMS CAUSING THE SSVEs
Following the convening of a series of international workshops on the
"Subacute Spongiform Virus Encephalopathies and the Structure of the
Unconventional Viruses Which Cause Them" held in the latter part of 1978, the
staff of LCNSS participated in an international symposium on "Slow Virus"
sponsored by NIAID and held at the Rocky Mountain Laboratory, Hamilton, Montana.
Eleven papers were presented and have been published (Academic Press); they
covered the origin of studies on slow infections in humans, the worldwide
lepldemiology of these diseases, the pathogenesis and molecular biology of the
viruses, the biological, physical and chemical properties of the viruses
including the evidence for strain variations and their unusual resistance to
gamma and ultraviolet radiation.
The most challenging outcome of the discovery that some chronic progressive
non-inflammatory CNS diseases (sporadic, as most cases of Creutzfeldt-Jakob
disease (CJP); epidemic, as kuru; or familial, as familial CJP and kuru) are
"slow infections" caused by viruses with incubation periods measured in years or
decades, has been the realization that the etiologic agents of these infections
are new kinds of microorganisms. The absence of antigenicity and their
unusual resistance to ultraviolet and ionizing radiation, to formaldehyde and
other disinfectants such as 6-propiolactone, ethylene oxide, and to heat place
them in a group unique among viruses. Their ability to produce fatal CNS
disease without eliciting inflammatory responses, the failure of the course of
disease or incubation period to be influenced by immunosuppression, and failure
to demonstrate any antigenicity in high titer infective virus preparations, or
to find any evidence of humoral or delayed hypersensitivity reactions in the
diseases, as well as an absence of response to interferon, stimulation of
interferon, or interference with interferon production, and absence of
interference with known viruses, form the series of atypical biological
properties which likewise differentiate these agents from any other group of
microorganisms. On the other hand, classical virus properties, such as
adaptation to new hosts, broadening of host range and reduction of incubation
period, dependence of pathogenic effect on the genetic breed of the host, the
presence of strains of differing virulence in wild stock viruses selected by
limiting dilution, and the interference of fast-growing by slow-growing strains
of scrapie, are all indicative of a complex host-virus genetic interaction
characteristic of more classical viruses. Attempts to delineate the chemical
nature of the replicating agents, especially to determine whether they are
replicated from introduced genetic information or by the induction, derepression
or activation of pre-existing genetic information in the host, are the major
thrusts of current investigation.
The elucidation of the structure and molecular configuration of the
infectious agent of scrapie, CJD, and kuru remains the first goal of this
laboratory. For two decades this frustrating problem has been a challenge to
molecular biologists, biochemists, and virologists in many laboratories.
In the past year we have made advances in our attempts to characterize the
scrapie agent:
A. Cesium chloride fractionation of the infectivity. The general trend of
the infectivity distribution in the first sedimentation to equilibrium from
homogeneity of the mouse scrapie agent from a mouse brain homogenate has been
determined. The infectivity is banding in a broad peak centered around density
4 - LCNSS/IRP
l.?4. The broadness of the peak indicates a considerable heterogeneity in
density. Due to the steepness of the gradient we have achieved a marked
separation from other components assayed, i.e., RNA, PNA, protein and lipid.
The preliminary infectivity data also indicate that the cesium chloride gradient
has concentrated the infectivity relative to a sample stored in cesium chloride
and not banded. Purification of 500x with respect to total brain DNA has been
achieved.
Individual or combined fractions from these gradients have been assayed
analytically for scrapie specific DNA, RNA and proteins by gel electrophoresis
but as yet without detecting a new species of macromolecule. The highly complex
protein patterns are virtually identical in normal and affected brain except for
several protein deficiencies in the affected animal.
Study of the behavior of scrapie infectivity with exposure to high energies
of sonication with rise in infectivity titer and fall even on frozen storage
thereafter, indicate "sticky" clumping of the infectious units. Theoretical
reinterpretation of much of the scrapie inactivation data in the light of the
newly proved association or aggregation of infectious units indicates that even
the aberrant behavior to UV and ionizing radiation may still be consistent with
a larger virus than we previously suspected.
B. Adaptation and development of the hamster 263-K strain of scrapie with
high virus yields, shorter doubling time and shorter incubation periods than in
mouse scrapie. Scrapie-infected hamster (strain ?63-K) is a more suitabTe
source of virus for purification studies. It is associated with a short
incubation period and high initial titer of infectivity. The disease can be
detected behavioral ly only 55 days after a high titer passage, compared with a
minimum of 180 days in the mouse system. Several titrations of hamster 263-K
brain homogenates have consistently shown initial brain titers of ?-5 x 10^'^
infectious units/gram of brain, over 100 times the titers obtained from mice.
In a detailed analysis for biochemical studies and titration purposes, the
hamster system is at least two times and, for some purposes, over 500 times more
efficient with respect to titration time and required animal space than is the
mouse system. In terms of macromolecular distributions the hamster brain has
fractionated much the same as the mouse brain. There is also a pronounced
dependency of incubation time in the hamster on the dose of the agent, and this
feature of the disease can be exploited to give an early indication of the
distribution of the agent in fractionations, if not a quantitative assessment of
infectivity.
C. The possibility of obtaining infectious nucleic acids from extracted
braih tissue"! In order to enhance the potential infectivity of any naked
nucleic acid recovered by our procedure we coupled the infectious assay with a
transfection procedure which we had shown to be effective for herpes simplex
virus, OX-174. The experimental approach was to fractionate infected mouse
brain homogenate following a heat inactivation step (80°C for 30 minutes)
designed to inactivate any enzymes that might interfere with the recovery of
infectious material. Following heat inactivation the homogenate was digested
with Protease K, then extracted with phenol in the presence of 1% sodium dodecyl
sulfate (SDS). The resulting three fractions (aqueous, phenol and heavy
interphase) were further extracted under conditions designed to preserve the
molecular nature of the material finding its way to that fraction. The aqueous
phase was further extracted with organic solvents and alcohol precipitated. The
5 - LCNSS/IRP
phenol phase was buffer extracted to recover any material and the interphase was
buffer extracted to remove the phenol. The resulting fractions were assayed for
infectivity in NIH Swiss Webster mice. The results of this experiment clearly
indicated that there was no infectivity associated with the nucleic acid
fraction. The conditions used in these experiments yielded infectious HSV-1 DNA
from infected cells but provided no scrapie infectivity. The heat and Protease
K treatment had no effect on the infectious titer, however the subsequent steps
destroyed virtually all of the infectivity. The only possible infectivity
should have been in the highest concentrations of the buffer extracted
interphase from the phenol extraction; the presence of infectivity in this
fraction has not been confirmed by pathology. These results suggested to us
that the viroid model, at least in its simplest forms, is not valid for the
unconventional agents. Further studies on the scrapie system have focused on
our impression that an essential, very hydrophobic protein is intimately
associated with the scrapie agent and that new procedures are necessary for its
isolation.
P. Attempt to detect double-stranded scrapie-specific PNA by molecular
hybridization. "Rore recent studies reported in the literature indicate that at
least a small percentage of the scrapie population has a PNA component of low
molecular weight that is DNAase sensitive which is eluted at 0.48M phosphate
buffer from hydroxyapatite columns. This would suggest that the PNA molecule
could be double stranded. During this year we tried to detect double-stranded
scrapie-specific PNA by molecular hybridization experiments since analysis of
the kinetics of DNA reassociation has proven to be a very sensitive means of
detecting the presence of specific PNA sequences in mammalian genome. As a
probe we used the DNA extracted from concentrated enriched scrapie labeled with
ll25 and annealed to total DNA extracted from infected and uninfected
brains of the same and different species. No difference was observed between
the extent of reassociation of the probe with DNA of scrapie or normal animals.
Our levels of detection indicate that if the scrapie agent were a
double-stranded DNA molecule its presence in infected brain tissue is below the
level of 50 molecules of DNA per infective unit. We have sought also to repeat
the work of others claiming to have isolated a scrapie-specific PNA. However,
our attempts to reproduce this much discussed procedure are disappointing with
less than a 1% recovery of infectivity in the high speed supernatant as opposed
to the 10-90% indicated by Marsh and Mai one. When this high speed cell -free
virus was placed on a ?.5% polyarylamide-O.B"' agar rose gel (9. 5x0. 6cm tube) at
6 mA of voltage for 2 hours, all of the infectious virus entered the gel and was
recovered (4.8xlo6). Fnzyme treatment of these infectious units was not
interpretable due to the total inactivation of the virus at 37°C after 3 hours.
These studies are being continued.
E . Comparison of neurotransmitter concentrations in brains of
scrapie-affected an'3~normal mice and hamsters in the hope of TcTentifying a_
particular neuronal system as the target for the infection in the brain.
Comparing late scrapie mice with same age controls we have observed normal
levels of catecholamines and most amino acids, but a two-fold increase in GABA
levels and a nearly 100-fold decrease in 5-hydroxytryptamine (5-HT) levels.
This finding prompted us to look at 5-HT levels in the blood. In the case of
late hamster scrapie we observe a somewhat variable but significant decrease in
blood serotonin of almost two-fold. At present these findings are being
vigorously pursued: (1) to discover the time course of these changes and
correlate them with behavioral changes and histopathology ; (?) to narrow down by
behavioral neuropharmacology, and brain microassay of neurotransmitters and
6 - LCNSS/IRP
enzymes the specific lesion(s) involved; (3) to identify other non-CNS
indicators of these changes which may be of clinical use; and (4) to test the
efficacy of 5-HT analogs as a therapy.
Our studies on the therapeutic benefits of the serotonin agonist, quipazine
maleate, and the serotonin precursor, L-5-hydroxytryptophan methyl ester, on
scrapie infectious hamsters have shown that both drugs effect small but
statistically significant improvements on ataxia and action jerks within a
rather narrow dose range. At higher doses we observed a dramatic
hypersensitivity in the scrapie infected animals to the toxic effects of both
drugs. This hypersensitivity syndrome is an intensively studied phenomenon in
the rat and has been shown to originate in that system from neuropharmacological
destruction of serotonergic nerve terminals. The hypersensitivity that we have
observed in the hamster is even more than that which can be induced by
neurotoxic agents in the rat. Thus we may support that the scrapie infection in
the hamster results in the destruction or degeneration of the axon terminals of
the serotonergic nerves. This is the first example of a serotonin
hypersensitivity arising as the consequence of a natural disease state.
In our studies of the biochemical levels of serotonin in the brains and
blood of scrapie infected hamsters and mice we have observed the following:
(1) a highly significant 2.5-fold decrease in the blood serotonin levels in
scrapie infected hamsters but no similar change in mice; (2) a highly
significant 20% reduction in mouse brain serotonin levels but no similar change
in hamsters. This change in mouse brain concentrations is seen only in the late
clinical stage of disease; and, (3) a much larger 10-fold decrease in mouse
brain serotonin levels after frozen storage for a prolonged period. Our
observation of a 2.5-fold decrease in blood serotonin levels in scrapie infected
hamsters is the first major change in blood chemistry noted in the subacute
spongiform virus encephalopathies.
F. Jj]^ £ continuing effort both to characterize scrapie vi rus and find ways
to inactivate and/or stabilize it we have performed the following inactivation
experiments: (1) sensitivity of scrapie to shear forces; (2) sensitivity of
scrapie to osmotic shock; (3) sensitivity of scrapie to exhaustive protease
treatment; and (4) sensitivity of scrapie to chlorine dioxide. Results of these
studies show: (1) overall scrapie infectivity in brain homogenates can be
increased at least 17-fold by exhaustive sonication immediately prior to
titration. This quantifies to some extent the level of aggregation of scrapie
virus in the usual preparations. We have extended these studies to determine
whether or not the high intensities of sonic radiation used in these experiments
are inactivating infectivity as well as dissociating aggregates as well as
investigating the kinetics of reaggregation. (2) Much of the infectivity loss
often associated with exposure to high ionic strength buffers is apparently due
to enhanced aggregation under these conditions. (3) If scrapie is inactivated
at all by powerful proteases this occurs at a much slower rate than for brain
homogenate proteins in general. (4) A kinetic analysis of the inactivation of
scrapie infectivity by sodium hypochlorite and chlorine dioxide, show both
chemicals to be equally effective inactivating 99.9% of the population in the
first few minutes of exposure.
A critical analysis of ionizing radiation data and electrophoresis of
scrapie has been undertaken during this past year. The conventional wisdom is
that the infectious agents of the subacute spongiform virus encephalopathies
7 - LCNSS/IRP
(SSVE) are very small, probably even subviral in size. A favorite hypothesis is
that they may represent examples of animal viroids. This expectation is based
upon the well established resistance of the SSVE to inactivation by ionizing
radiation and, more recently, the observation that scrapie infectivity will
comigrate with a viroid marker in some electrophoretic gel system. Pr. Rohwer
in our laboratory has now offered intriguing alternative interpretations for
both of these findings. He has shown that if the SSVE are highly aggregated, as
his sonication data indicate (see above), then the traditional first order
analysis of the ionizing radiation data is inappropriate. If aggregation is
taken into account in the analysis of the inactivation kinetics, the actual size
of the scrapie agent must be much larger than that deduced previously from a
first order inactivation constant and, in fact, is consistent with the molecular
weight of ordinary viruses. He has also shown that, in the electrophoretic
systems used to characterize the mobility of the scrapie agent, viruses
fractionate on the basis of their charges whereas nucleic acids fractionate on
the basis of their molecular weights. In these same systems simple
bacteriophages comigrate with much smaller nucleic markers and in fact the two
species cannot be used to calibrate one another and separations such as these
cannot distinguish viruses and viroids.
FAILURE OF SCRAPIE INFECTION TO INDUCE AN IMMUNE RESPONSE AND LACK OF
ANTIGENICITY OF SCRAPIE VIRUS IN HIGH INFECTIVITY TITER
A. During the period covered by this report major efforts have been made to
study the interaction of scrapie with the immune system of infected animals.
These studies have been done in three parts. First, the search for a new
antigenic component on the surface of spleen cells at various times following
infection. Second, a systematic examination of the interaction of scrapie with
a C3H/HeJ mouse line reported to be unique. Thirdly, the identification and
culture of the infectious cell population in the mouse spleen.
The search for a new antigenic component of the surface of spleen cells was
based on the possibility that a new cell surface component would not be detected
by the humoral immune response but would be detected by the cellular immune
system. To examine this possibility, mixed lymphocyte cultures were utilized
using two inbred strains of mice, Balb/C and C57BL/6. Two large groups of
animals were studied with cultures at weekly intervals over the early and late
stages of infection. In every case controls inoculated with normal mouse brain
were included on a 1:1 ratio. Data during the early post infection period
included spleen weights to check for the enlargement reported by others.
Throughout this study the results were uniformly negative with respect to both
the splenomegaly and to the presence of any new cell surface component. Several
cultural combinations were included to examine the scrapie-infected cells as
both target cells and responder cells. It seems clear from this work that: (1)
there is no new cell surface component on scrapie-infected spleen cells that can
be detected in mixed lymphocyte culture; (2) scrapie-infected spleen cells
retain the capacity to respond to the mitogens Con A and LPS as well as respond
to a heterologous H-2 determinant in mixed lymphocyte culture. These responses
are identical in magnitude to those animals inoculated with normal mouse brain;
(3) there is no detectable splenomegaly in scrapie infected mice within the
first three months of infection and there is no splenomegaly throughout most
infections.
LCNSS/IRP
Extensive studies with the C3H/HeJ strain of mouse have not confirmed the
published report of other investigators that this strain of mouse, when infected
with scrapie, loses its ability to mount a mitogenic response to the endotoxic
protein component of E^. cbli LPS. This animal is genetically unable to respond
to the Lipid A moiety. These studies were carried out at weekly intervals from
weeks 2 through 7, since previous reports indicated the peak depression to occur
at week 4. It has been reported that a marked spleen enlargement occurred, a
finding also not confirmed in this work. There are only two possible
explanations for the lack of agreement--one is a difference between the Chandler
and C506 strains of scrapie, or that other investigators had a contaminating
virus in their inocula. The plan for the future is to attempt to determine
which of these is the explanation and to attempt to clarify completely if there
is or is not a measurable change in the immune response of C3H/HeJ mice with
scrapie.
The results of the spleen cell sub-population studies have been completed.
It is clear that strain C506 gives extremely low spleen titers and that only as
very small number (less than 1 in 10^) spleen cells are infectious, whatever
sub-population they are in. Extensive studies on splenic macrophages in culture
have been disappointing from the point of view of continued infectivity.
We have also explored the ability of scrapie to grow in Vitrio in well-
established, 'T', 'B' and macrophage cell lines of murine ongin. Two questions
are being investigated: (1) does the cell have a receptor for scrapie on its
cell surface?; and (?) if it does not have a receptor (assuming that scrapie
agent is the free nucleic acid bound to lipid membranes), do other methods have
to be used to get the agent in the cell so that it could replicate? Inactivated
Sendai virus and lysolecithin were used as membrane-fusing agents; DEAE-Dextran,
which alters the permeability of the membrane and is used for assay infectivity
of other viral nucleic acids in cell culture, was also used. Cell culture
harvests from these experiments have been titrated in mice for infectivity and
the results from these experiments will help us answer the two questions. Since
most of the murine cell lines used in the study have endogenous C-type viruses,
it will also be interesting to see if these viruses act as helper viruses for
the growth of scrapie. Attempts to grow scrapie in mosquito cells: Aedes
albopictlis mosquito-cell lines have been used to grow several groups of
arboviruses. In such cells these viruses grow at ??.°C without producing
cytopathic effect, and infected cells become chronically infected by the virus.
Virus is released from these chronically infected cells into the medium. We
have inoculated these cells with the scrapie agent, and cell lysates at
different passage levels have been inoculated into mice for the assay of
infectivity. Results were discouraging since unlike some members of the
togaviruses, scrapie infectivity was not recovered from inoculated insect cell
lines. An SV-40 transformed cell line that contained scrapie virus at the 12th
passage level was serially passaged to higher levels; none of 50 pooled and
cloned cultures was infectious for mice at the 30th passage level or higher.
The scrapie-infected SMB line of Clarke and Haig was imported from England; five
lots of this line have been prepared and aliquots stored; mutants of the cells
are being prepared. A line of cells was derived from the brain of a hamster
infected with the 263-K strain of scrapie; this line is also under study.
B. Since conventional immunological techniques have thus far failed to
elicit an antigen-antibody reaction in kuru, Creutzfeldt-Jakob disease or
scrapie, we have been attempting to produce specific antibody to scrapie by the
9 - LCNSS/IRP
hybridoma technique of Kohler and Mil stein since it has been shown that cells
from a mouse myeloma could be fused with splenic cells from mice stimulated with
an antigen, and such fused cell clones produce specific antibody which is
monoclonal for individual antigenic determinants. Such a technique facilitates
antigenic analysis of complex antigens. In our studies spleen cells from mice
immunized with scrapie infected mouse or hamster brain scrapie specific antibody
has not yet been obtained; however, 30 monoclonal antibodies were derived which
are reactive to antigens in hamster or mouse nervous system tissues. Of the 30
clones analyzed, specificity included clones reacting with grey matter of mouse
and hamster brain, one clone reacting with axons in animal brain, several clones
reacting with cytoskeletal proteins (intermediate and micro-filaments) and 19
clones which produced antibody reactions with both neural and non-neural tissue
components.
C. We also measured the general immunocompetence of splenic lymphocytes in
an attempt to detect alterations of the immune system of scrapie affected
animals. In general splenic activation by Concanavalin A, phytohemagglutinin
and 1 ipopolysaccharide of control and scrapie inoculated mice were compared.
Mitogen-induced responses of splenocytes from infected and control cultures were
not significantly different. The PHA response of scrapie-infected mouse spleen
cells was slightly depressed over a period of ?9 to B6 days post-inoculation.
Additional efforts to induce scrapie specific antibody are underway and indeed
the use of several different preparations of high-titering scrapie infected
hamster brain that has been subjected to (a) chemical tissue membrane modifers,
(b) purified by density gradient banding, and (c) tied up with haptens. Such
mitogens are being assayed in animals rendered immunotolerant to uninfected
hamster brain.
As a control for the scrapie studies, somatic cell hybridization to produce
monoclonal antibody against a major glycoprotein (Pp 30,000 MW) associated
with human peripheral nervous system myelin was carried out. Thus far we have
produced two clones both of which react with peripheral nerve myelin; only one
produces antibody specifically reactive with the Pp low molecular weight
glycoprotein.
D. Since the demonstration of cell-fusing activity in the majority of brain
extracts of scrapie mice and CJD patients (see ANNUAL REPORT: October 1, 1977
through September 30, 1978), additional studies have been carried out using two
different techniques. One involved the formation of multinucleated cells and
the other the formation of somatic hybrid cells. Heterokaryons were measured at
18 hours and hybrid cells after an average of 25 days. The studies employed
three scrapie cases, 3? cases of transmitted CJD, two cases of untransmitted
CJD, 26 cases of other neurological diseases, three transmitted cases of other
than CJD and 17 patients without neurological disease. The results show a
significantly higher proportion of CJD brains (61%) was positive than other
neurological diseases (31.4%) or the control group (6%). Thus our earlier
observations have been clearly confirmed and although the assay does not
separate CJD from other neurological diseases to warrant its use as a specific
diagnostic test we hope that such discrimination can be improved to the extent
that the detection of cell-fusing activity might be possible utilizing serum,
urine and CSF from patients and their family members as a biological marker of
this disease. We shall continue to study the phenomena of cell fusing activity
in an effort to elucidate the mechanism in CJD and other neurologic diseases as
well as the application of this technique as a rapid means of more quickly
10 - LCNSS/IRP
measuring inf activity in experimentally derived fractions from purification
procedures employed for scrapie and CJD.
Recently study of the appearance of this cell fusing activity in brain of
hamsters infected with scrapie has shown peak fusing activity attained early in
incubation (4 weeks) instead of during clinical disease (8 to 9 weeks). This
may indicate the desirability of studying hamster brain early in the incubation
period for possible biochemical markers of scrapie virus or scrapie activity.
E. Resistance to high concentration of formaldehyde, to heat up to 85°C,
and to ultraviolet radiation at ?54 nm, and an ultraviolet sensitivity at 237 nm
greater than at 254 nm have been found for kuru and CJD viruses as for scrapie.
These very unusual physical properties greatly emphasize our current contention
that the viruses of the human diseases are closely related to the scrapie virus,
great relevance to the etiology of the plaque of Alzheimer's disease. Similarly,
the two human agents have been shown to have the same enormous resistence to
ionizing radiation (gamma rays from Cobalt CO50 as is found for scrapie
virus. The most direct inference from this enormous resistance is an effective
size of under 100,000 daltons molecular weight. Although many possible
explanations, including atypical fine structure for a nucleotide configuration
and unusually efficient nucleic acid repair mechanisms have been suggested to
account for such anamolous properters, the simplest explanations namely, that in
fact the agents are of such small size, may be true; or, the new data of
extensive "sticky" clumping or aggregation of infectious units may account for
much of the anomalous behavior.
REVISION OF SURGERY AND AUTOPSY ROOM TECHNIQUES
FOR DEALING WITH DEMENTIA PATIENTS
A. Precautions for handling CJD patients in hospitals and in operating and
autopsy rooms and laboratories. The discovery that the worldwide-distributed
Creutzfeldt-Jakob disease is caused by a serially transmissible,
self-replicating agent that passes through bacteria-, protozoan- and
fungus-retaining membrane filters, the demonstration that the virus is widely
distributed in non-CNS tissues and fluids of affected patients and possesses
great resistance to usual antiseptics, has also resulted in a growing concern
among medical and paramedical nursing and laboratory personnel, particularly
neurologist, neurosurgeons, pathologists, and anesthesiologists, about the
potential hazards involved in caring for patients with presenile dementias and
handling their tissues. Concern comes largely from recent reports documenting
transmission of Creutzfeldt-Jakob disease by corneal transplant, the accidental
inoculation of two patients in neurosugery with CJD-contaminated electrodes used
in stereotactic electroencephalographic recording and stimulation, the suspicion
that a neurosurgeon and two general practitioners may have contracted CJD from
patients and the characteristic greatly over-represented among patients with CJD
of a history of brain or eye surgery in the previous two years before onset of
clinical disease. These concerns have further been hightened by the recent
transmission of CJD to a chimpanzee by implantation of the same silver
electrodes that caused disease in the two human patients after more than two
years storage in formaldehyde vapors ued for sterilization. In response to
these concerns we have published precautions for conducting biopsies and
autopsies and have more recently, presented a summary on the current knowledge
of the pathogenicity and communicability of CJD and related subacute spongiform
11 - LCNSS/IRP
encephalopathies of man and animals which are caused by similar unconventional
viruses. We have also made recommendations on the rational precautions that
should be taken in caring for these patients and in handling their tissues and
helped establish guidelines for safe handling of the SSVE viruses in
laboratories.
B. Studies on the inacti viation of the SSVF viruses. During the last year,
inactivation studies were made with disinfectants using mouse scrapie agent.
Mouse scrapie, kuru and CJP agents seem to have similar properties.
Disinfectants used were clorox, organic iodine (Wescodyne), potassium
permanganate, hydrogen peroxide, and Zepharin. Since ethylene oxide gas is
commonly used in hospitals, ethylene oxide was also used. The data showed that
after chlorox, a 1:2B0 dilution of KMNO4 was the most effective disinfectant,
followed by Wescodyne and ethylene oxide, which reduced infectivity by 99
percent. Under the experimental conditions used in the study hydrogen peroxide
did not affect the titer of the scrapie agent at concentrations used in the
hospital environment. Residual toxicity of Zepharin for mice was high. Further
studies are in progress on the CJD agent, with ethylene oxide autoclaving used
for sterilization in the hospital setting. Finally, chloride dioxide has been
examined in parallel with potassium permangenate for inactivation activity
against a guinea pig-adapted strain of CJD virus; and chlorine dioxide, sodium
hypochlorite, potassium permangenate, hydrogen peroxide, and lysol® have been
tested for activity against a hamster-adapted strain of scrapie. Time-dose
experiments are on titration at this time, and should be completed within the
year. Depending upon the results further recommendation will be made to the
medical community. However, it is already apparent that some scrapie virus
infectivity remains in hamster brain tissue of high titer after autoclaving and
after eythlene oxide sterilization and that chlorox remains the most effective
disinfectant.
NATURAL HISTORY OF TRA^^SMISSIBLE VIRUS DEMENTIA
The Search for the Source of Infection in Man
In an effort to determine the method of spread of CJD virus in man, we
have recently completed a comprehensive worldwide epidemiologic survey of CJD.
It is shown that in the United States the average annual mortality is at least
0.26 deaths per million population. Temporal -spatial clustering of cases was
found in the United States, but reports from other countries indicate that this
occurs. Fifteen percent of the cases were of the familial type, suggesting a
genetic susceptibility to infection. In this survey, some evidence was found
that previous surgery of pre-existing neurologic disease may be associated with
an increased risk of developing CJD.
A systematic investigation of all cases of CJD dying in France during the
decade 1968-1977 was completed last year and updated through 1980 this year in
collaboration with Dr. Francoise Cathala and members of the French Neurological
Society, with a view towards clinical definition of a large and unselected case
series, and to obtain some clue as to the natural mode of disease transmission.
One hundred and seventy cases were discovered, of which 124, confirmed by
autopsy or biopsy, were the subject of multifactor statistical analysis. The
disease forms a clinical spectrum from nearly acute encephalitic type illness
with a few weeks' rapid progression and death, to lingering illness of years'
duration, impossible to diagnose in the absence of neuropathological
verification. Types of clinical onsets, range of symptoms during the course
12 - LCNSS/IRP
of illness, and symptom combinations with the highest frequencies were analyzed
in detail. In addition, epidemiological data on all 170 cases were examined for
the possibility of iatrogenic or case-contact types of human-to-human
transmssion. Apart from the approximately 10% of familial cases, no contact
could be established between any two patients in France during a 10-year period,
medical profession, and those cases in paramedical professions did not occur at
a higher rate than in the general population. Close examination of familial
cases established that even in such families, personal contact between two
subsequently affected members does not always occur, suggesing ever more
strongly the participation of predominantly genetic factors in the familial type
of CJD. Our epidemiologcal studies have already indicated that an annual
incidence of nearly one case per million can be expected when newly occuring
cases are actively searched out. The frequency of the disease continued to be
highest in the densely populated center of Paris, raising further speculation
about human-to-human modes of natural transmission. On the other hand, study of
exceptionally isolated cases, which could simplify examination of the number of
possible routes of acquiring the disease, still has not yielded any clues to
this problem. A full-scale study of any possible association of COD and scrapie
in sheep is also under way.
A detailed analysis of the clinical features of the first 100 transmissible
cases of CJD has been performed, and the results compared to the clinical
features of a similar number of cases of Alzheimer's disease. There is a
considerable overlap in the clinical spectrum of both diseases, and a group of
patients with Alzheimer's disease with myoclonus has been delineated for further
clinical and pathological evaluation. In addition, the clinical syndrome of
"amyotrophic" CJP and a group of cases of "untransmissible" CJD are being
studied.
Other clinical features of CJD which may be related to different strains of
the virus are bein examined. A manuscript is in preparation describing a small
number of cases of CJD with the clinical features of progressive supranuclear
palsy. The differences between the acute and chronic forms of CJD have already
led to the discovery of a virus strain from a Japanese case that takes readily
in non-primates and causes both gray and white matter spongiform lesions. The
possibility that the virus also causes previously unrecognized childhood
encephalopathies is also being investigated.
In a continuing investigation on the possible modes of natural transmission
of the CJD virus, we are intensively evaluating the familial occurrence of the
disease. To date, we have identified 37 families with a total of 155 affected
members. CJD occurs in a pattern suggesting autosomal dominant transmission.
Compared with the sporadic form of CJD, in familal CJD the age at death is
slightly earlier and there is a female preponderence. The clinical and
pathological features are otherwise indistinguishable. No maternal effect was
found. There was some evidence for anticipation. An analysis of temporal and
spatial separations between affected family members suggest that if contact
transmssion were occurring, incubation periods up to four decades might be
expected. However, the available data do not yet allow us to distinguish
between a genetic susceptibility to infection or some form of vertical
transmission. Studies are in progress determing genetic markers, such as the
HLA type, of both sporadic an familial CJD, which might give us an indication of
the genetic component of susceptibility to infection.
13 - LCNSS/IRP
NEUROPATHOLOGICAL SURVEILLAMCE OF CJD AMP KURU
A major part of our experimental studies on CJD include the routine
screening of the brains of all animals dying after inoculation with various
chronic neurologic diseases, since it is now known that in the case of the
squirrel monkey at least, approximately 15% of the animals die without showing
clinical signs of neurological disease. The topography of the spongiform change
has recently been analyzed in more than 200 squirrel monkey brains, where the
results indicate that considerable variation in the severity and distribution of
the lesions occur. The differences between CJD, kuru and scrapie are being
examined in both primate and non-primate hosts. The unusual white matter change
produced by a Japanese strain of CJD in mice is being examined.
A re-evaluation of the spongiform change in human kuru is being performed to
see if the same general features as seen in human CJD also occur. The peculiar
amyloid plaques that occur in 60% of kuru patients and approximately 10% of CJD
patients is being investigated both structurally and at a biochemical level.
The occurrence of these amyloid plaques in a virus-induced encephalopathy has
SCRAPIE AND CJD VIRUS ALTERATIONS IN INTER-SPECIES PASSAGE
With our demonstration of the transmissibil ity of scrapie disease from
American sheep and English goats to several species of non-human primates,
manifested by a disease in the experimental monkey that is indistinguishable
from the transmissible virus dementia originating from man, we are confronted
with the urgent question of the possible relationship between scrapie of sheep
and the spongiform encephalopathies of man. The scrapie virus is capable of
infecting all species of monkeys tested. However, the Compton (English goat)
strain after passage through non-human primates no longer induces disease when
inoculated back into sheep or goats. Of tremendous importance has been the
discovery that although these same strains of non-human primate-adapted scrapie
virus did not induce clinical disease in mice during the more than two years
they were observed, such mice did in fact have neuropathological lesions of
spongiform encephalopathy in their brains and sub-inoculation of this material
did induce disease in other mice. A similar observation has now been made on
CJD in mice wherein transmission occurred on primary passage of human brain but
on the first mouse to mouse passage animals remained asymptomatic for over 2-1/2
years yet when killed histopathological evidence of spongiform encephalopathy
was observed in their brains. Thus, we have evidence that infected animals can
remain asymptomatic and that in these animals the incubation period before onset
of clinical disease may exceed the life span of the host.
The same exceptionally long incubation periods are evidenced in those few
cases of kuru that have occurred in the Fore of Papua New Guinea during the
past five or six years; new cases occur only in patients over 20 years of age.
PATHOGENESIS OF CJD IN MICE
The biological properties of scrapie appear to be altered after passage
through the primate host--behavior, not unlike classical viruses; such altered
biological properties may account for the failure of CJD and kuru viruses to
induce disease in mice routinely. We have experienced difficulty in adapting
14 - LCNSS/IRP
the virus of CJD to mice and guinea pigs, but in recent experiments some passage
lines of CJD have caused spongiform encephalopathy in both guinea pigs and mice,
and we have recently completed studies on the pathogenesis of the Japanese
strain of the virus in Balb-C mice. The findings were strikingly similar to the
pathogenesis of scrapie in the mouse with a few notable exceptions. Initially,
characteristic spongiform degeneration of the brain was first noted
pre-clinically at 9 weeks following inoculation. Clinical signs did not become
apparent until 16 weeks with the geometric mean incubation period being 112
days. Infectivity assays of various tissues of inoculated mice resulted in
recovery of virus from brain and spleen as early as one week after inoculation.
Furthermore, the average incubation period of mice inoculated with spleen was
markedly less than that of mice injected with brain material from the second
through the sixteenth weeks of incubation indicating that the concentration of
virus is higher in the spleen than in the brain during the asymptomatic period.
Lesser amounts of virus were detected in thymus, lung, and kidney. In the
kidney the virus appeared late in the pre-clinical period and the incubation
period for recipient mice were prolonged. Virus was not detected in the liver
in contrast to its presence in this tissue in human patients. Viruria was not
demonstrable. However, we did confirm the presence of a viremia in CJD infected
animals beginning during the sixth week after inoculation. Concentrations of
virus in the blood at the 14th and 18th weeks were estimated to be appreciable
since the incubation periods in recipient mice ranged from 4 to 5 months. The
clnical disease was confirmed histologically.
ORAL TRANSMISSION OF KURU AND CJD
We have now proven the transmissibil ity of the spongiform viruses by the
oral route through feeding of virus-infected whole tissues. Two of two squirrel
monkeys fed CJD-infected chimpanzee tissues and two of two squirrel monkeys fed
scrapie infected whole tissues developed clinical disease and had typical
pathological lesions of the spongiform enceohalopathy in their brains. One of
two monkeys fed kuru-infected chimpanzee tissues developed spongiform
encephalopathy. The asymptomatic incubation period in the one monkey exposed to
kuru was 36 months; those in the two monkeys exposed to CJD virus were 23 and 27
months, respectively; and those in the two monkeys exposed to scrapie virus were
25 and 32 months, respectively. The one additional animal similarly exposed to
kuru has remained asymptomatic during the 45 months it has been under
observation.
ANTI-NEUROFILAMENT ANTIBODY
The discovery of an heterogeneic autoantibody in the sera of kuru and
Creutzfeldt-Jakob disease patients to neurofilament protein (Sotelo, Gibbs, and
Gajdusek, SCIENCE 2in:4466(0ctober 10), 190-193, 1980) using mature neurons of
murine origin in culture as antigens (Sotelo, Gibbs, Gajdusek, Toh, and Wurth,
PNAS USA 77: 653-657, 1980), has initiated a series of in-depth studies to
characterize the autoantibody and to determine whether or not it in any way
shows specificity to the viruses causing the subacute spongiform
encephalopathies. To date this does not on the surface appear to be the case
since this autoantibody has been found in lower frequency in the sera of
patients with other human neurological diseases. However, the possibility that
our "unconventional viruses" utilize a host cytoskeletal protein in their
structure as do some other viruses demands that this "non-specificity" be not
too glibly dismissed. Already it is evident that its presence is not diagnostic
15 - LCNSS/IRP
of the subacute spongiform virus encephalopathies and its presence in high titer
in the sera of Guamanian patients with amyotrophic lateral sclerosis and
parkinsonism-dementia, patients with Alzheimer's disease, and other neurological
diseases warrants this conclusion. However, the detection of this heterogenic
autoantibody has led to the particularly intriguing observation that it is
remarkably specific for a small filament only in the axon of the cell unlike
that of experimentally prepared antisera to neurofilament protein which reacts
with filaments in both the axon and the dendritic processes of neurons.
Finally, although unencumbered neurons of murine embryos in our in vitro test
provide the best method for the detection and study of this immune reaction, its
detection in mass screening has been much facilitated by the use of the indirect
fluorescent staining of frozen and fixed sections of rat embryo spinal cords
(Bahmanyar et al . , NEUROLOGY 1981). Already to our surprise the antibody has
not been found in a large series of sera from patients with autoimmune
collagenous diseases which were positive for anti -rheumatoid factor and anti-PNA
antibody. The possibility that these unconventional viruses use a filamentous
cytoskeletal protein of the host in their structure as do some bacteriophages
and plant viruses must be considered.
NEWLY EXTENDED RANGE OF CLINICAL DISEASE ASSOCIATED WITH CREUTZFELDT-JAKOB
DISEASE DIAGNOSIS
In a paper in press in BRAIN (Masters, Gajdusek and Gibbs) we are presenting
data of the transmission of spongiform encephalopathy to non-human primates
inoculated with three atypical cases of CJD. They were atypical because of the
presence of an unusually long course, the early clinical appearance of ataxia
and other cerebellar symptoms, the very slow and only moderate degree of
dementia, and neuropathological ly revealing extensive distribution of amyloid
plaques resembling those observed in kuru patients. These cases show a
remarkable similarity both clinically and pathologically to New Guinean kuru,
much more so than does the more classical CJD patients we have studied. In an
extensive review of the world literature we have found a large literature
reporting this type of disease not usually diagnosed as CJD and often occurring
in heredofamilial clusters. In such families many of the affected members have
little or minimal dementia. Thus, the strong possibility that we must now
search for the CJD virus in a wider group of patients than those with the
presenile dementia of classical CJD has been demonstrated. Specifically,
patients with spinocerebellar degeneration are called to question. In our
report in press we are calling the cases comprising this syndrome, not
previously brought together, the Gerstmann-Straussler syndrome.
LONG-TERM INCUBATION PERIODS OF KURU, CREUTZFELDT-JAKOB DISEASE AND SCRAPIE IN
NON-HUMAN PRIMATES
The year-to-year surveillance of the occurrence of kuru in Papua New Guinea
by direct clinical observation has shown that the incubation period in the human
population at risk can be as long as 20 to 30 years following exposure. A
recent analysis of our laboratory transmission data from non-human primates
maintained longer than thought reasonable by investigators in the field of
infectious diseases clearly supports the clinical observation made in New
Guinea. Nine non-human primates developed experimental kuru following
incubation periods which have ranged from 6 to more than 12 years. Of
16 - LCNSS/IRP
particular importance among this group were two chimpanzees that had been
injected by peripheral routes only (i v,ip,sc,im) and a spider monkey which had
been injected intracerebral ly and intravenously with a pool of visceral tissues
(liver, kidney, spleen) and developed disease 142 months, 82 months, and 123
months, respectively, following inoculation. Similar long incubation periods
have been observed in animals inoculated with CJD infected tissues
(7? months- 117 months) and scrapie infected tissues (72-74 months). In
addition to the intracerebral route we have now conclusively demonstrated that
these diseases can be transmitted by the following individual routes of
inoculation: intravenous, intraperitoneal, subcutaneous, intramuscular,
interdermal, intranasal, and oral. The later findings coupled with the
extremely long incubation periods, particularly noted following peripheral
inoculations since this is the most likely route of natural infections, have
great impact on our epidemiological studies and research into the etiology of
other degenerative neurological diseases.
SUMMARY
The elucidation of the etiology and epidemiology of a rare, exotic disease
restricted to a small population isolate — kuru in New Guinea--has now brought us
to worldwide considerations that have importance for all of medicine and
microbiology. For neurology, specifically, we have considerable new insights
into the whole range of presenile dementias, and, in particular, to the larger
problems of Alzheimer's disease, familial and senile dementias, and the
processes of CNS aging. The implications of vertical transmission of slow virus
infections, of conjugal transmission of these diseases, and of host genetic
control of disease expression for all genetic diseases, and the relationship of
these slow virus infection processes to those which may lead to neoplastic
transformation are obvious.
The major problem among the degenerative diseases of multiple sclerosis,
Alzheimer's diseae, amyotrophic lateral sclerosis, and Parkinsonism remain
unsolved, although there are tantalizing laboratory and epidemiological data
pointing to the possible role of virus-like agents in these diseases. Perhaps
the masked and defective slow infections with conventional viruses such as are
seen in PML and SSPE may provide the best leads for studying these diseases.
AMYOTROPHIC LATERAL SCLEROSIS AND PARKINSONISM DEMENTIA IN HIGH INCIDENCE FOCI
Our scientific direction of the amyotrophic lateral sclerosis (ALS) studies
at the Guam laboratory of NINCDS for the study of the ALS-PD complex in high
incidence among the Chamorro people, has resulted in some 12 publications which
have already appeared, or are in press, and many promising ongoing studies.
These are summarized below, but they indicate our conviction that the answer to
the perplexing problem of motor neuron disease (ALS) and Parkinsonism-dementia
(PD) are to be found in these ethnically and geographically limited foci.
Our study of the similarly intense focus of ALS and Parkinsonism and
dementia among the isolated Jakai and Auyu people of Western New Guinea,
discovered during our field studies (New England Journal of Medicine, 1963), and
with two recently updated reports just published (Ciba Symposium, 1977;
Symposium on ALS, February 2-3, Tokyo, 1978) (Neurology, in press) is proceeding
with further field work this year. This year's work has proven that the disease
is fully environmental and that ALS and PD are related as evidenced by (1)
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husband and wife with classical /^LS; (2) husband with pure PP, wife with
classical ALS, simultaneously; (3) next door neighbor to (2) above with
classical PP; and (4) two women with classical ALS in 1974 in same village and a
neighbor with PD. It appears that the "rule" is that people living or drinking
exclusively from small springs and rivers originating in the "red-soil" lowland
plain get ALS/PD. People of the same cultural and linguistic groups as these
suffering from ALS and PP but living on tidal flats and on big rivers
originating from the high mountains do not get ALS/PP. The water and soil
analyses indicate extremely low calcium in garden soils and drinking water and
the pattern of occurrences seem, as in endemic goiters to follow geological
features of the environment rather than the patterns of ethnic and cultural
demographic distribution. With this in mind, we are covering possibilities of
mineral metabolism, imbalances and trace metal toxicity as well as those of an
endogenous virus in an isolated population in our studies on Guam and West New
Guinea.
We have increased our collaborative research with the Japanese
investigators, who have been helping us on Guam by providing us each year with a
young neurologist to assist in the clinical neurological surveillance and care
of our patients there and in collaborative pathological, biochemical and
pharmacological studies. Puring this reporting period, Pr. Takao Makifuchi, of
the Brain Research Institute, Niigata City, Japan, took up residence on Guam as
a Visiting Scientist; and now Dr. Kiyomitsu Oyanagi has arrived to replace him.
Also, Pr. Richard Yanagihara was recruited for Guam, and after three months of
intensive preparation and developing protocols here at NIH proceeded to Guam
where he initiated a study of calcium, phosphorus, magnesium, and trace metal
metabolism including CAl calcium trace studies on ALS, PP and control subjects.
The Japanese are themselves concerned with their own foci of high incidence
of ALS and PP on the Ki i Peninsula of the main island of Japan. The series of
meetings and conferences on ALS in Japan held in March 1978 resulted in the
confirmation by Pr. Hi rano of the pathological identity of the Kii Peninsula PD
cases with those on Guam (both demonstrating neurofibrillary tangles), and the
final agreement that the two disease foci represent the same disease complex.
During his 1979 field studies in West New Guinea, the Chief, LCNSS, has obtained
definitive evidence that classical Guamanian ALS, PD, and ALS/PD does occur in
the high incidence foci he discovered in West Irian and is very excited about
resolving this problem. In addition, Pr. Gajdusek noted the occurrence in West
New Guinea of a subacute progressive paralysis that looks like
"slow-poliomyelitis" vitamin B deficiency. He has seen many cases this year and
recognized it as the same disease he first saw in 1974-1976 field trips. The
disease is not ALS; it can be "acute", it is often fatal, but remissions and
recurrences do occur. A few cases have had beriberi -like edema with onset but
most have not. That this very severe paralytic disease should occur within the
ALS/PP focus is amazing. International collaboration and, most importantly,
more original and innovative research concepts and more imaginative and cautious
study of the various Western Pacific foci have continued and been expanded.
Those studies which are underway in our collaborative project, and a
bibliography of recent publications (1975-1980 in press) resulting from studies
of these foci are included as an appendix to this annual report. The ongoing
studies include:
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(1) Clinical variations in ALS-PP complex in Chamorros;
(2) Human biology of ALS-PD complex and other chronic diseases in
Chamorros of the Mariana Islands;
(3) Chronic CNS disease and disability survey of Cuamanian Chamorro
migrants to the mainland United States;
(4) Genetic studies of the Chamorro population, both normal and ALS-PD
afflicted;
(F) Petection of sedimentable reverse transcriptase activity in the
brains of patients dying with ALS-PD;
(6) Search for biochemical defects in ALS-PP brains by gel diffusion
chromatography;
(7) Search for nucleic acid repair mechanism defects in transformed
leucocyte cell lines derived from ALS-PD patients;
(8) Search for an ALS or PD specific antigen in brain tissues by clonal
myeloma cell hybridization with spleen cells of ALS and PD from hyperimmunized
animals and resultant monoclonal antibody production;
(9) Trace aluminum and other heavy metal studies in brain, CSF, blood and
other tissues of ALS-PP patients;
(10) Evaluation of the precise nature of the cognitive and affective
defects and the progression of dementia in the PD patient;
(11) Evaluation of liver function and pathology;
(12) Development of techniques for the unmasking of an infectious agent
by in vitro techniques;
~Tl3) Assessment of the immunological competence of patients;
(14) Attempts to transmit ALS-PD to non-human primates and non-primate
hosts;
(15) Major virus group seroepidemiology of the Mariana and Caroline Islands,
Japan, and West New Guinea populations with relation to ALS-PD;
(16) Pharmacologic studies of ALS-PP;
(17) Elucidation of osteoporosis, osteoarthritis, and bone deformities in
the Chamorros; and
(18) Evaluation of the growth and development of normal Guamanian children
and adolescents--a 30-year follow-up study.
The genetic studies, already well advanced, include blood group factors, red
cell enzymes, serum proteins, HLA typing, and mixed leucocyte agglutinins,
dermatoglyphics, anthropometry and other gene markers.
Epidemiology of ALS and PD in Migrants to and Immigrants from Guam
Since World War II, there has been an extensive migration from Guam of at
least 15,000 Chamorros, primarily to the United States. This represents nearly
one-third of the total Chamorro population of 47,000 residing on Guam.
Amyotrophic lateral sclerosis has developed in 14 Chamorro migrants from Guam to
the United States, Japan and Korea after periods of one to 36 years of absence
from Guam. Nine of these cases have been previously reported. In another eight
subjects ALS has developed within 1 to 14 years of their return to Guam after
absences of many years from the islands. Parkinsonism dementia, a high
incidence presenile dementia peculiar to Chamorro Guamanians, has developed in
one subject 46 years after his departure from Guam. It appears that the onset
of ALS in these patients after long absences from Guam will demonstrate the
lower limit for the incubation period in each case if a toxic or infectious
exposure occurring only on Guam is the cause of the disease.
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Additionally, during the past two decades there has been an increasing
number of cases of Guamanian ALS in long-term Filipino migrants to Guam. The
average annual incidence rate of ALS in these migrants is approximately
five-fold higher than the rate of ALS in the United States. Parkinsonism
dementia-like disease has been clinically identified in five Filipino patients
and one case with autopsy verified pathologically. Because of the high degree
of genetic similarity between the Chamorro and Filipino peoples, which we have
recently demonstrated, a detailed epidemiological survey for ALS and a clinical
search for PP in the Philippine Islands is currently being conducted by members
of this laboratory.
The clinical and pathological characteristics of long surviving cases of
Guamanian ALS, that is of more than ten years duration, are currently under
study. Long surviving cases of ALS in Guam are younger, have a familial
occurrence, have a different sex ratio, and show a different pattern of disease
progression than those with a normal duration of disease.
Immunology of ALS and PD on Guam
Additional studies on HLA, dermatoglyphics and other gene markers, on
osteoporosis and osteoarthritis, on heavy metals and other environmental toxins
and on a ten-year follow-up study of the descriptive epidemiology of ALS and PD
are close to completion. Further studies based on these data are in the
planning stages or already underway.
Previous studies in our laboratory have shown that ALS and PP patients from
Guam had diminished levels of cellular immunity as determined by diminished
response to skin test antigens, lymphopenia, diminished number of 'T' cells, and
decreased mitogenic response, than those of age- and sex-matched Guamanian
controls. Further, ALS patients with HLA BW-35 had diminished cellular immunity
and shorter mean duration of the disease. This association was found to a
lesser degree among PP patients and no association was detected in the controls.
Using C^g binding techniques, Oldstone et a_l_. have shown high frequency of
immune complexes in the sera of ALS patients in the continental United States.
There was evidence of immune complex deposition in some of the kidneys of the
ALS patients. The nature of these immune complexes was not determined. Studies
of hepatitis B in the South Pacific reveal that hepatitis B virus is endemic in
most of the Pacific Islands. There is high prevalence of hepatitis B surface
(HBsAg) antigenemia, and most of the population has either HBsAg or antibody to
HBsAg. It is common to have found both HBsAg and anti -HBsAg in many individuals
in the population. Since immune complexes are known to cause immunosuppression,
we investigated the prevalence of HBsAg, anti-HBsAg, and the immune complexes
due to HBsAg and anti -HBsAg in the sera of ALS and PP patients from Guam and
healthy controls. Additionally, we also tested sera for the presence of
hepatitis A antibody. The data showed that ALS patients have lower levels of
anti-HBsAg than PP patients or controls. There was no signficant HBs
antigenemia or immune complexes in ALS and PP patients and controls. Almost all
sera tested had antibodies to hepatitis A. These studies show that HBsAg and
anti-HBsAg complexes were not responsible for the immunosuppression observed.
The lower rates of HBsAg in this population may be due to sampling of older
individuals.
In other areas of Micronesia, human biological field and laboratory studies
continue. Studies of chronic respiratory diseases indicate that 75% of the
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children under five years of age were found to have asthma, while over 50% of
the adults over 40 years of age were affected by chronic bronchitis, often with
an asthmatic component, and typical chronic obstructive airway disease occurred
in almost one-third of the male population over 50 years of age. As a result,
pulmonary airway diseases constitute the most important cause of morbidity and
mortality in the Western Caroline Islands.
CHRONIC ENCEPHALITIS AND EPILEPSY
Since chronic inflammatory neurological disease is known to follow togavirus
(arbovirus) encephalitis infections of humans in Europe and Asia, sera from more
than twenty American patients with chronic epilepsy and inflammatory brain
disease were examined by hemagglutination for all togaviruses known to cause
encephalitis of humans in North America. None had antibodies. It seems
unlikely that togavirus encephalitis is an important cause of chronic
inflammatory brain disease in the United States.
A survey of togaviral antibodies in several Pacific populations confirmed
earlier studies of the geographic distribution of several viruses. A possible
correlation between susceptibility to Ross River Virus and one red cell Rh
subtype was found in a population of Papua New Guinea. Plaque and microtiter
tests have been developed for groups A and B togaviruses, and neutralization
tests are being performed on selected sera.
SCHIZOPHRENIA AND JUVENILE AUTISM
Serum and CSF specimens from schizophrenic patients and age- and sex-matched
controls were obtained from Doctors Torrey and Wineberger of St. Elizabeth's
Hospital, Washington, D.C. and Constantine Sakkles of the University of Maryland
Hospital, Baltimore. These specimens were tested for group A and group B
arboviruses using the hemagglutination inhibition test. Viral antigens used in
the test were Eastern and Western Encephalitis, St. Louis encephalitis, and
California encephalitis. There was no significant association of arboviral
antibodies to schizophrenia. In the light of recent reports by Tyrell, et a1 .,
of detection of cytopathic agents from the CSF and some controls, attempts will
be made to do similar studies with the CSF samples on hand.
The work on the development of animal models for the study of persistent
infections has continued. A foamy virus of chimpanzees (Pan 1, also called
foamy virus 6) was isolated in this laboratory over ten years ago. In the
chimpanzee it appears to be a latent virus, and can at times be isolated from
brain explants of healthy animals. The mechanism of viral latency has been
impractical to examine, however, due to the expense and scarcity of the
chimpanzee for experimental purposes. Therefore, experiments were conducted to
adapt Pan 1 virus to a more convenient laboratory host, and after several
preliminary studies, we succeeded in adapting the virus to the mouse. Using
kidney and spleen explants from mice-infected neonatally, infectious virus has
been isolated up to one month following inoculation, viral antigen has been
demonstrated in the explants, and serum CF antibody has been detected. However,
in no animal has it been possible to detect infectious virus or viral antigen
directly in the organs themselves. We are currently studying the possibility of
viral persistence for up to a year following inoculation, and evaluating the
mice for any signs of disease during their natural lifetime. Integration of
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viral genome in the host cells is also under investigation in collaboration with
Dr. Chev Kidson in Australia.
The model of lysogenicity and of subviral genetically active macromolecular
structures from the study of bacterial viruses and bacterial genetics supply
ample imaginative framework for an expression of our ideas of possible
pathogenic mechanisms for kuru and CJD in man. The unconventional viruses of
the spongiform encephalopathies tax even our imagination in relation to
molecular biology gained from these studies in bacteria.
For a now-disappearing disease, kuru, in a small primitive population to
have brought us this far is ample reason for pursuing intensively the challenges
offered by the still inexplicable high incidence and peculiar profusion of
different neurological syndromes, pathologically distinct yet apparently related
to each other, which have been discovered in the several small population
enclaves we have investigated. Thus, the high incidence of ALS, ALS-PD on Guam
and among a small population of people in West New Guinea, coupled with the high
incidence of ALS on the Ki i Peninsula of Japan, may indeed offer the best
opportunity of solving the problem of this sclerosing disease which in the
United States has an incidence as high as that of multiple sclerosis.
The delineation of infection as the etiology of heredofamilial and presenile
and senile dementias of man was made possible only through the concomitant
studies on the neurobiology of population isolates. In this area we have been
engrossed in the investigation of deaf-mutism, mental subnormality and other
congenital central nervous system defects associated with endemic goiter in the
Central Highlands of Western New Guinea, as well as patterns of delayed puberty,
slow growth rates, and of early aging in isolated Melanesian groups. Ethnic
drug abuse (particularly of kava), strange patterns of psychosexual development,
pseudohermaphroditism, and culturally-determined responses to pain, and roots of
aesthetic expression, have all been under study. Foci in primitive population
isolates of familial periodic paralysis, progressive muscular dystrophy (both
the pseudohypertrophic type of Duchenne and the non-pseudohypertrophic distal
type), amyotrophic lateral sclerosis and Parkinsonism, are also being
investigated. Genetic studies on human evolution led to the discovery of new
genetic factors among haptoglobin, hemoglobin, and red cell enzyme pleomorphisms
and the definition of their biochemical structure.
A NEW FORM OF CYSTICERCOSIS EPILEPSY IN MAN AND A NEW SEROLOGICAL TEST FOR
CYSTICERSOSIS
The further significance of scientific investigations of small population
enclaves of remote populations was even more dramatically apparent during recent
field trips of the Chief of LCNSS, with his re-evalaution of what may turn out
to be one of the largest "epidemics of epilepsy" ever recorded. This continues
to occur in the Wissel Lakes area of West New Guinea and is the result of
cysticercosis, an infestation with the larvae of Taenia solium, the pig
tapeworm, newly introduced into New Guinea. Our recent studies have led us to
conclude that the natural history of this cysticercosis epilepsy is not a result
of death of the worm, scarring and calcification of lesions, as much of the
literature suggests, but is an early sign of inflammation from new invasion of
the brain by the Taenia larvae. After one, two or three grand mal seizures no
further convulsions occur and most patients are left without sequellae. Two
patients who have died had the most heavily infected brains ever seen, still had
22 - LCNSS/IRP
fresh uncalcified cysts, further confirming the thesis that the sel f -limited
seizures result from primary invasion of the larvae and not from old calcified
cysts breaking down. Convulsions often occur even before the first subcutaneous
nodules appear, and as the nodules increase in number, additional seizures
occur. The high incidence of severe third-degree burns, which may even result
in death, is a direct result of cysticercosis-induced seizures that occur during
sleep, throwing the patient into the house fire. The unclothed people, living
at a 2000 meter elevation, need to sleep close to the home fires on cold nights.
We are able to date the first introduction of Taenia solium into the area and to
plot the spread of taeniasis in pigs and man, and of cysticercosis and
associated epilepsy in man, to other previously Taenia-free areas. During this
year, we have learned that the cysticercosis has spread both in swine and man
throughout the West New Guinea Highlands and is now in the Baliem region. With
Dr. Budi Subianto, the local Indonesian medical officer, a visiting scientist in
our laboratory, we have planned a neuroepidemiologic study aimed at elucidating
the natural history of the epilepsy and acute psychoses and other neurological
complications that have occurred concomitantly with the emergence of
subcutaneous cysticercosis nodules.
Recently, we developed an enzyme-linked immunoabsorbent (ELISA) serological
test for diagnosis and seroepidemiological surveillance of cerebral
cysticercosis. Sera collected from adjacent populations prior to the
introduction of ]_. solium and in 1974 and 1977 from patients with epileptic
seizures, subcutaneous nodules, and other manifestations of cysticercosis at the
Enarotoli hospital were studied. Positive control sera and cerebrospinal fluid
(CSF) were from patients with neurocysticercosis in Mexico: their clinical
disease had been previously confirmed by the presence of complement-fixing
antibodies to cysticercus antigens. For the FLISA test cysticercus antigens
were high speed supernatant of a sonicated 20% suspension of cysticerci
dissected from Balinese pigs killed in Jakarta; control antigens were similarly
prepared from normal pig tissues. The ELISA procedure was that of Voller and
Bidwell (1975) and Yolken et_al. (1977) for rota virus assays. Titers were
expressed as ratio of highest^Jilution of serum bound by cysticercus antigen to
that bound by control antigen of same protein content. Standardization was done
using antisera prepared in rabbits injected with cysticercus antigen in complete
Freund's adjuvant. In symptomatic patients 5 of 6 (8370 with skin nodules, 7 of
9 (78%) with convulsions and skin nodules, and 7 of 16 (44%) new epileptics
without skin nodules had antibody while among non-symptomatic residents of the
Wissel Lakes area 4 of 52 (8%) had antibody. None of the 281 sera collected
from people outside of the Wissel Lakes area had cysticercus antibody. Among
the specimens from Mexican patients with neurocysticercosis 11 of 14 (79%) of
the sera and 20 of 25 (80%) of CSF had antibody with geometric mean titers of
580 and 1600, respectively.
Higher percentage of positive patients with systemic cysticercosis may
possibly be due to exposure to a larger antigenic mass. The lower positive
rates observed among cerebral cysticercosis patients may be due to lack of
antibody response due to direct massive infection of the brain by the parasite
and short incubation period prior to detection of convulsions. The importance
of cerebral cysticercosis in the third world countries cannot be underestimated.
The ELISA test provides a simple, sensitive technique adaptable to field use for
determining the presence and magnitude of human infections with cysticercus.
However, cross reactivity has been observed to occur with antibodies to other
parasitic diseases. This has led to studies on the development of techniques to
23 - LCNSS/IRP
produce purified cysticercosis antigens for enhancement of the specificity of
the reactions. Column-purified and unpurified antigens prepared from either
cyst or whole-worm specimens have been tested on a battery of sera from patients
with cysticercosis, other parasitic diseases, and normal controls. The results
indicate that unpurified whole worm preparations, which are easily available,
are satisfactory for most screening purposes, but that purified cyst
preparations should be used in situations where schistosomiasis (and, to a
degree, echinococcosis) needs to be eliminated from diagnostic consideration.
Collaborative studies with physicians in India, Bolivia, and Bali, Indonesia are
in progress.
From the standpoint of basic immunology column chromatofocusing and
isoelectrofocusing techniques have revealed the identity of a group of proteins
responsible for the immunogenic properties of both the cyst and whole worm
preparations, and these are currently being further characterized.
VILYUISK ENCEPHALOMYELITIS IN lAKUT PEOPLE OF THE SOVIET SIBERIA:
An Old Chronic Infective Degenerative Disease of the CNS New to Western Medicine
As previously reported, the Chief of LCNSS was invited by the Soviet
investigators to participate in the investigations in the U.S.S.R. of a unique
degenerative disorder of the nervous system, Vilyuisk encephalitis. This
disease occurs only in the lakut region of Eastern Siberia and has many features
of a slow virus disease. In 1978 he finally saw and examined patients flown to
Moscow. In August 1979 a field study in lakutia was completed, the first by any
western investigator, and many patients with VE were seen throughout the lakut
area. Pathological specimens have been obtained and extensive case records and
photographic documents are being analyzed. The diseases of Siberia and the last
two decades of Soviet work on the disease, which is clearly infectious, were
reviewed. We shall continue our collaborative study of this disease with our
Soviet colleagues and we are in the process of writing for publication extensive
reports on our field studies and laboratory investigations.
SPINOCEREBELLAR DEGENERATIONS IN HIGH INCIDENCE IN lAKUT PEOPLE OF SOVIET
SIBERIA AND IN LES PETIT BLANCS DES HAUTS OF ILE PE LA REUNION, INDIAN OCEAN
In 1981 the Chief of LCNSS completed a second field visit to He de la
Reunion in the Indian Ocean where we have encountered foci of high incidence
spinocerebellar diseases, including a variant of Friedreich's ataxia, another of
Marie's spinocerebellar degeneration, and a third of Ramsey Hunt disease
occurring exclusively in the "les petits blancs des hauts", very highly inbred
descendents of the first French settlers on this previously uninhibited island
some three centuries ago.
Among lakut people of Soviet Siberia there is a huge collection of
genetically determined Marie's type of spinocerebellar degeneration which we
(DCG) have had a chance to see and study in the field with Dr. Prokopii Petrov
and Dr. Lev Gertsovich Goldfarb.
In view of the transmissibil ity to laboratory primates of familial,
apparently dominant genetically determined forms of CJD and of the
Gerstmann-Straussler syndrome, we are very interested in these other
spinocerebellar degenerations. They are being studied for possible
transmissibility and from the possibility of providing a series of pleomorphic
24 - LCNSS/IRP
alleles determining cerebellar degenerations of differing forms at various times
of life. We hope to parallel some of the studies of the Barbeau Canadian group
studying Friedreich's ataxia in Quebec, which differs somewhat clinically from
the syndrome on la Reunion.
HEMORRHAGIC FEVER WITH RENAL SYNDROME
During the period covered by this report significant progress has been made
on our studies begun in 1953 on the hemorrhagic fevers with renal syndrome that
severely affected United Nations troops during the Korean War and for which an
etiologic agent had not been isolated in spite of enormous efforts on the part
of the Walter Reed Army Institute of Research of which we were then a part. The
isolation by Lee and Lee in 1978 of the viruses responsible for HFRS has
provided us the opportunity to reinvestigate this disease, characterize the
virus and carry out collaborative studies with colleagues in China, the USSR,
Finland, Sweden, Yugoslavia, Japan and Korea. In our first review of
hemorrhagic fever with renal syndrome Gajdusek in 1953 indicated that clinical
severity, particularly hemorrhagic manifestations, of this chronic viral
nephropathy varies from one geographic region to another. We suggested that
nephropathia epidemica (NE) of Scandinavia was a mild form of HFRS or Korean
hemorrhagic fever (KHF) with no or very minimal hemorrhagic manifestations.
Mortality in the Far East (China, Korea, USSR) ranges from 5-30%, in European
USSR it is lower, while NE is rarely fatal. The sylvatic reservoir for the
virus in Scandinavia and European USSR is in wild voles (Clethribhbmys sp.),
whereas in Eastern Asia it is in the field mouse (Apodemus agrarius). The rat,
Rattlis riattus, appears to be the reservoir in Japan and in urban foci in Korea.
Laboratory rats in Japan and Belgium are infected and have caused HFRS in
laboratory workers. The seasonal occurrence varies. Thus, cases are most
frequent in the late fall and winter in Scandinavia at a time when wild voles
enter dwellings and granaries. In southern and central China cases are more
frequent in the autumn, during threshing season, and epidemiology has
incriminated the respiratory route of infection. In both East and West sporadic
cases occur yet epidemic outbreaks are frequent. This seems to be determined by
the particular circumstances of exposure to the rodent reservoir. The military
experiences in the Soviet Far East, Manchuria, and Korea of the Russian,
Japanese, and United Nations armies, respectively, indicated two epidemic peaks,
the first in late spring and early autumn, and the second in late summer and
early fall; this was taken to suggest mite- or chigger-borne infection, as is
the case with Tsutsugamushi disease. Lee, however, has not found virus in
ectoparasites collected from infected rodents. The virulence, as evidenced by
hemorrhagic manifestations, systemic reaction and mortality varies as one moves
from Far Eastern Asia to eastern and northern Europe. This parallels the shift
of virulence of tick-borne encephalitis across the Eurasian landmass. However,
Japanese cases are less severe, resembling NE more than KHF; possibly, the virus
in rats is less virulent for man. Detailed serological comparisons of strains
isolated in different regions are necessary to establish the closeness or
divergence of the etiological viruses in various foci, and recent adaptations of
the virus to laboratory rats, athymic nude mice, and tissue culture have now
made this possible.
The first clear-cut evidence that hemorrhagic fever with renal syndrome
virus infections were occurring by the respiratory route stems from the large
outbreak of laboratory infections in Moscow in 1962 with 83 affected laboratory
25 - LCNSS/IRP
workers. /^ more recent epidemiological study of infections in medical research
laboratories in Japan and Belgium have indicated a respiratory route of
infection of laboratory workers working in animal experimental rooms in contact
with enzootically silently infected commercially reared white rats.
Epidemiological studies in outbreaks in China (Xu et_a_l_., 1979) also led to the
conclusion that most infection was by contaminated aerosols. Clinical and
epidemiological studies in Scandinavia, Hungary, the Soviet Far East and Korea
failed to directly incriminate the respiratory route of infection. But exposure
to urine and feces contaminated foodstuffs and aerosols, or arthropod vectors,
and ectoparasites such as mites and chiggers, on infected rodents were usually
thought to be the source of human infection. However, it is now evident that
infection occurs most often by the respiratory route from contaminated aerosols
produced by the asymptomatical ly infected reservoir rodents. Whether saliva and
respiratory droplet infection--the only secretions from which virus has been
isolated--is the only source of such aerosol contamination remains to be proved.
Finally, high titer antigen has been found only in the lungs in infected wild
mice (Apodemus agrarius), voles (Clethrionomys glareolus), wild urban rats
(Rattus rattlis), and laboratory rats of the Wistar strain in Japan; other
tissues contain lower concentrations of antigen as demonstrated by
immunofluorescence. In experimentally infected white rats (Wistar and Fischer
strains) and athymic nude mice the virus also appears in highest concentration
in the lungs. The virus has to date been isolated only from lung, saliva,
throat washings and blood of human patients, and no other tissue or secretion
has yet been found to be infectious. In naturally and experimentally infected
rodents the virus has not to date been isolated from feces or urine, but it has
been obtained regularly from lung, saliva, and acute phase blood.
Until recently, the serological relationship between Scandinavian
nephropathia-epidemica (NE) and Korean hemorrhagic fever (KHF) has been
established (Svedmyr, 1978; Lahdevirta, 1979). This was first done using only
as antigen KHF virus propagated in the lungs of naturally and experimentally
infected Apodemus agrarius mice. We have recently confirmed this antigenic
relationship by demonstrating specific neutralizing antibody to KHF virus in
convalescent sera from patients with NE. Similar relationships have been shown
for HFRS in European Russia with KHF virus. However, until the European virus
was isolated from NE in Finland, it was previously impossible to check for
immunological crossings in both directions. This has now been done and it is
clear that NE sera react with Korean antigen in the immunofluorescent tests at
almost the same titers with the homologous antigen from naturally infected or
experimentally infected Clethrionomys lung. KHF human sera, on the other hand,
give much higher titers with the homologous Korean virus in Apodemus lung than
with the Finnish virus in Clethrionomys lung. Sera from patients convalescent
from HFRS in southern and central China react by immunofluorescence similarly to
KHF sera as sera from HFRS patients in the Soviet Far East and in Japan. All
these Asian sera (Chinese, Soviet, Korean and Japanese) from HFRS patients as
well as Scandinavian NE sera neutralize several logs^Q of KHF virus but
qua'litative cross neutralization tests have not yet been possible since the NE
agent is only propagated with difficulty in Clethrionomys voles. Thus, the
serological crossing is a partially one-way cross, with KHF sera reacting at 10-
to ?0-fold lower titer with NE antigen than with the homologous antigen, while,
in contrast, Scandinavian NE sera show only a 2-fold reduction in titer with
lung from Apodemus or nude mice infected with KHF than with the homologous
antigen in Clethrionomys lung. Where in crossing Soviet Eurasia the shift to
the NE from the KHF serological type occurs, remains to be determined. Sera
26 - LCNSS/IRP
from Balkan (Czechoslovakia, Hungary, Bulgaria, Rumania, and Yugoslavia) cases
of HFRS are now available for such study. We have demonstrated closer
serological relationships with ME than with KHF in Yugoslavia sera from HFRS
patients, in keeping with the geographic shift of the serotype from Asia to
Europe.
In a previous report (XIV Pacific Science Congress, 1979) we conjectured
about the possible presence of unrecognized hemorrhagic fever with renal
syndrome (HFRS) in North and South America and other areas of the world wherein
the disease had not previously been recognized. The natural host of HFRS in
northern and eastern Furope, Clethrionomys sp., is indigenous across northern
North America in Canada and the United States from Maine to Alaska. The murine
host of the virus of Korean hemorrhagic fever (KHF), Apodemus sp., is not found
in the Americas. Clethrionomys-borne disease in Europe has proved to be less
severe clinically, and demonstrates fewer hemorrhagic symptoms than the
Apodemus-borne disease in eastern Asia (China, USSR, and Korea). Thus, a milder
form of nephropathy associated with little or no hemorrhagic diasthesis, as in
nephropathia epidemica (NE) in Scandinavia, might be expected in the Americas.
Using the indirect immunofluorescence test for demonstrating specific
antigen-antibody reactions in KHF infections we have tested sera from Alaska,
South America, Iran, and India. In the first 100 sera we studied from Alaska we
reported no antibodies to KHF virus; however, when this series was extended to
600 specimens a single serum had specific antibody to KHF virus at titer 1:1?8.
We also tested 4 cerebrospinal fluids (CSF) and 16 convalescent sera from
children with an undiagnosed acute febrile illness in Santa Cruz, Bolivia.
Although none of the 4 CSF reacted, 2 of the 16 sera had antibody titers to KHF
virus of l:2Fi6 and 1:1?8, respectively. Of 251 sera from residents of remote
rural villages in India, 2 had antibodies to KHF virus; a 35-year old male
gardener and a 27-year old female with titers of 1:256 and 1:640, respectively.
Casals has found (personal communication) that high titering specific antibody
to KHF virus failed to react in the HAI test against Japanese B, Murray Valley,
Omsk hemorrhagic fever, and Chikungunya antigens. We found that high titering
rabbit antisera or mouse ascitic fluids to more than 30 arboviruses, including
Rift Valley fever and Junin viruses, and antisera to simian hemorrhagic fever
virus did not react with KHF virus in the IF test. No other viruses are known
to cross react with HFRS by the IF test. Neutralization tests on the few
positive sera we have found from Alaska, Bolivia and India are in progress.
These preliminary data suggest a possible wider distribution of HFRS viruses
than is now known and further seroepidemiological screening from other parts of
the world is clearly needed.
GENETIC EFFECTS ON SUSCEPTIBILITY TO ARBOVIRUS INFECTION
Continuing our more than three decades on work on the arthropod-borne
viruses we have this year completed a study on human variation and infection
with these viruses in humans in New Guinea. Antibodies to group A (Chikungunya,
Getah, Sindbis, Ross River) and group B (dengue 2 and 4, Murray Valley
encephalitis, Japanese encephalitis, Yellow fever, Zika) arboviruses were
measured by hemagglutination inhibition and neutralization in sera from selected
aboriginal populations of New Guinea. Antibodies to Murray Valley encephalitis
and Ross River viruses were highly prevalent in most of the lowland populations.
For each population the presence of antibodies was correlated with 12 genetic
polymorphic systems: 7 blood groups (ABO, MN, Ss, Rh, P, Kidd, Puffy), 3 red
27 - LCNSS/IRP
cell enzymes (acid phosphatase, 6-PGD, PGM), and ? serum proteins (haptoglobin
and immunoglobulin Gm).
There were no significant associations between any marker system and Murray
Valley encephalitis virus infection. For one population, two blood group
systems, Rh and Kidd, showed statistically significant associations with
antibodies to the Ross River virus. Among individuals with the Rh phenotype
R^Rp (CcDee), the relative risk of infection with Ross River virus was five
times less than that for other members of the population. The relative risk of
Ross River virus infection in individuals with Kidd phenotype Jka- was
approximately three times less than that of the Jka+ individuals.
The reasons for those associations are unknown. Hypothetical explanations
include differences in cell membranes of some Rh and Kidd phenotypes impeding
attachment of virus, hereditary impairment of immune responses to the virus,
shared antigens between the virus and blood-group substances resulting in immune
tolerance, and decreased biting by mosquitoes of individuals with particular
phenotypes. It is also possible that some genetically related social subgroup
of people with less exposure to mosquitoes exists in the population. The
associations between Rh and Kidd phenotypes and susceptibility to group A or
other arthropod-borne infections must be confirmed by studies of larger
populations living where such infections are endemic.
The development and maturation of the two major projects of this laboratory
have resulted from cross-fertilization of each since their origin, and both have
grown from the basic studies on child growth and development and disease
patterns in primitive cultures. Although the two projects, each composed of
many subsections, differ markedly in the questions they address and the
techniques of investigation they employ, much of the field data collected from
one project is also requisite for the studies in other projects. Both are
served by the same investigators, who function as a team. These scientists
derive their creative stimulus, dedication and enthusiasm to a great extent from
the atypical and exotic biological, social and cultural materials presented, and
the diverse, frequently unconventional, approaches of the two projects.
Principal Investigators: D. Carleton Gajdusek, M.D.
Clarence J. Gibbs, Jr., Ph.D.
Paul W. Brown, M.D.
28 - LCNSS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
701 MS 01?«?-1ff rNSS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neurobiology of Population Isolates: Study of Child Growth and Pevelopment
Behavior and Learning, and Disease Patterns in Primitive Cultures
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PRINCIPAL INVESTIGATORS: 0. Carleton Gajdusek, M.D., Chief, LCNSS; and
Clarence J. Gibbs, Jr., Ph.D., Deputy Chief, LCNSS; David M. Asher, M.D. ,
Paul W. Brown, M.D. and Ralph M. Garruto, Ph.D.
OTHERS: Michael Alpers, M.D.; Judith Farquhar, M.A.; Peter Fetchko, M.A. ;
Dmitry Goldgaber; Klaus Mannweiler, M.D.;. Steven Ono, M.S.; Robert G. Rohwer,
Ph.D.; Donald Rubinstein, Ph.D.; Vincent Zigas, M.D.; Francoise Cathala, M.D.;
Kwang-Ming Chen, M.D.; Olivia Cruz, M.D.; Richard Feinberg, Ph.D.; Robert
MacLennan, M.D.; Father David Gallus; Fusahiro Ikuta, M.D.; Jesus Raglmar; John
Runman.
COOPERATING UNITS (if any) AUSTRALIA: Dr. Timothy Asch, Australian National
University, Canberra; Dr. Cyril Curtain, CSIRO, South Melbourne; Dr. Eric
French, Mt. Eliza: Dr. Chev Kidson, Oueensland Institute of Medical Research,
Brisbane; Dr. Louis Herzberg, Perth Medical Center, Nedland^;; (rnni-imipH)
lab/branch
Laboratory of Central Nervous System Studies, Intramural Rp<;parrh Prngram
SECTION
NSTiTUTE AND LOCATION National Institute of Neurological and Communicative Disorders
and Stroke, National Institutes of Health, t^^ethesda, Maryland ?0?ns
TOTAL MANYEARS:
12
PROFESSIONAL:
_8
OTHER:
1_
CHECK APPROPRIATE BOx(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords )Studi eS Of human biology Of
vanishing primitive societies focus on neurological development and learning
patterns in diverse cultural experiments in the human condition found in such
isolated groups. Laboratory studies by molecular biology, immunology, virology,
and biochemistry on specimens and field epidemiological work in these
genetically isolated primitive bands give less complicated bare-line data than
obtainable from civilized societies. Data and specimens collected over years on
expeditions to Micronesia, Polynesia, Solomon Islands, New Hebrides, New Guinea,
Indonesia, S. America, Asia and Africa are used. Studies on nutrition,
reproduction, fertility, neuroendocrine influences on age of sexual maturation
and aging, genetic polymorphisms, genetic distance, unusual and odd employment
of the higher cerebral CNS function of language learning, cognitive styles,
computation (calculation without words or numbers) and culturally modified
sexual behavior elucidate alternative forms of neurologic functioning for man
^hich we would be unable to investigate once the natural cultural experiments in
primitive human isolates were amalgamated into the cosmopolitan community of
nan. Foci of high incidence prevalence of kuru, ALS/PP, epilepsy, other neuro-
logical degenerations, hysterical disorders, schizophrenia, neoplasms, goiter,
:retinism, rheumatoid diseases, diabetes, asthma, chronic lung disease, malaria,
Filariasis, leprosy, cysticercosi s and other infections are investigated.
PHS-6040
(Rev. 2-81)
29
LCNSS/IRP
ZOl NS 01282-18 CNSS
COOPERATING UNITS: continued
Pr. Louis Herzberg, Perth Medical Center, Nedlands; Pr. Chev Kidson, Oueensland
Institute of Medical Reseach, Brisbane; Dr. Robert L. Kirk, Australian National
University, Canberra; Pr. Robert MacLennan, University of Sidney, Sidney;
Dr. Colin Masters, University of Perth, Perth; Dr. John Sheridan, Queensland
Institute of Medical Research, Herston; Pr. Fiona Stanley, Perth Medical Center,
Nedlands; Dr. Neville Stanley, University of Western Australia, Nedlands;
Dr. Stephen Wurm, Australian National University, Canberra.
BOLIVIA: Dr. Mario Michael Zamora, Department of Neurologic y Neurocirugia, La
paF;:
BRAZIL: Prof. Helio L. de Oliveira, Universidade de Sao Paulo, San Paulo.
CANADA: Dr. Kenneth Dresser, Toronto; Dr. Jack Hildes, University of Manitoba,
Winnipeg; Dr. Otto Schaefer, National Health and Welfare, Edmonston.
CHINA: Dr. Chin-min Hsiang, Virus Research Institute, Hupeh Medical College; Dr.
Hung Toa, Department of of Electron Microscopy, Peking University, Peking; Dr.
Zhi-Yi Xu, Department of Epidemiology, Shanghai 1st Medical College, Shanghai;
Dr. Zheng, Virus Research Institute, Hubei Medical College, Hubei.
ENGLAND: Mrs. Elisabeth Beck, Institute of Psychiatry, London; Dr. M.C. Clarke,
Agricultural Research Council, Compton; Prof. P.M. Daniel, Royal College of
Surgeons, London; Dr. A.J. Duggan, Wellcome Museum of Medical Science, London;
Dr. George Nurse, London.
FIJI : Mr. Ron Crocombe, University of South Pacific, Suva.
FINLAND: Dr. Juhani Lahdevirta, University of Finland, Helsinki.
FRANCE : Prof. Jacques Bert, Centre Hopital et Universite, Marseille;
Dr. Francoise Cathala, Hopital de la Salpetriere, Paris; Dr. Maurice Godelier,
L'Ecole Pratique Des Hautes Etudes, Paris; Dr. Jean Guiart, Paris.
GERMANY: Dr. Freidrich Deinhardt, Max-van-Petteenkoffer Institute, Munich;
Dr. Klaus Mannweiler, Henrich-Pette-Institut fur virologie und Immunologie,
Hamburg; Dr. Wulf Schiefenhovel , Max-Planck Institut fur Verhaltensphysiologie,
Percha; Dr. Heinz Stephan, Max-Plank-Institut fur Hi rnforschung, Frankfurt-am-
Niederrad.
INDONESIA: Father David Gall us. Mi si Katolik, Jayapura; Dr. Surjadi Gunawan,
Public Health Department, Jayapura; Dr. B.A. Kawengian, Dr. Soewahjudi, Public
Health Department, Jayapura; Bishop Alphonse Sowada, Catholic Mission, Jayapura;
Dr. Budi Subianto, Public Health Department, Jayapura;
Dr. Julie Sulianti Saroso, Public Health Department, Jakarta;
Father Frank Trenkenkshuh, Catholic Mission Asmat, Jayapura;
Dr. Laode P. Tumade, Department of Public Health, Jayapura; Mr. Jeff Verstegen,
Associated Mission Aviation, Jayapura.
30 - LCNSS/IRP
201 NS 01282-18 CNSS
COOPERATING UNITS: continued
ITALY: Marek and Allison Jablonko, Perugia.
KENYA: Dr. Leendert C. Vogel , University of Nairobi, Nairobi.
MEXICO: Pr. Reinhart Ruge, Cernavaca.
NETHERLANDS: Father Ben van Oers, Missiehuis, Tilburg; Dr. Jaap Goudsmit,
University of Amsterdam.
NEW HEBRIDES: Capt. John Barley, Treasury/Customs Department, Port Vila;
Dr. Kirk Huffman, Cultural Centre, Port Vila; Dr. Rabi Ramdoyal, World Health
Organization, Port Vila; Dr. Ratard, French Hospital, Port Vila.
NEW ZEALAND: Dr. R.W. Hornabrook, Wadestown.
PAPUA NEW GUINEA: Dr. Michael Alpers, Institute of Medical Research, Goroka;
Dr. H.A. Brown, Port Moresby; Rev. F. Fischer, Lutheran Mission, Okapa;
Dr. J. Linsley Gressitt, Wau Ecology Institute, Wau; Richard Lloyd, Summer
Institute of Linguistics, Aiyura; Mr. Ivan Mbagintao, J.K. McCarthy Museum,
Goroka; Dr. Stuart Merriam, Highland Christian Mission, Yagusa; Dr. Jack Onno,
Department of Public Health, Port Moresby; Dr. Kerry Pataki-Schweizer,
University of Papua New Guinea, Port Moresby; Euan Scrimeour, University of
Papua New Guinea; Dr. Alan Tarutia, Public Health Headquarters, Konedobu ;
Dr. Jeffrey Tuvi , Poroko.
PERU: Vt. Carlos Monge, Universidad Cayetano Heredia, Lima.
PHILIPPINES: Dr. Benjamin Catubay, Provincial Health Officer, Ilocos Norte;
Dr. Martesio C. Perez, Universtiy of Philippines, Manila;
Dr. Virginia Bas^cci Sevilla, Ministry of Health, Manila;
Dr. Elizabeth Zaraspe-Yoo, University of Philippines, Manila.
MADAGASCAR: Dr. Pierri Coulanges, Institute Pasteur de Madagascar, Antanarivo.
MAURITIUS: Pr. B. Gurburrum, Ministry of Health, Port Louis.
REPUBLIC OF CHINA: Dr. R. Palmer Beasley, University of Washington, Taipei.
REUNION ISLAND: Dr. Charles Bosquet, Hopital de Terre Rouge, St. Pierre;
Dr. Jean-Baptiste Dandelot, Hopital de Terre Rouge, St. Pierre; Dr. Maurice Jay,
Hopital Psychiatrique, St. Paul.
SCOTLAND: Pr. Alan G. Pickinson, A.R.C. Animal Breeding Research Organization,
Edinburgh; Dr. J.D. MacGregor, Shetland Health Board, Shetland.
SINGAPORE: Chong Keat Lim, Architects Team 3; Prof. Dr. Lim Kok Ann,
Dr. Ivan Polunin, University of Singapore; Dr. Foo Keong Tatt, Singapore General
Hospital .
31 - LCNSS/IRP
ZOl NS 01282-18 CNSS
COOPERATING UNITS: continued
SOLOMON' ISLANDS: Or. P. Mackay, Center Hospital, Honiara; Pr. A.M.O. Solomon,
Health Pepartment, Kirakira; Pr. B. Wilkin, Central Hospital, Honiara.
SWnZERLANP: Pr. Liana Polis, World Health Organization, Geneva;
Pr. Stephen Fazekas, Basel Institute for Immunology, Basel.
USSR: Dr. Mikhail Petrovich Chumakov, Institute for Poliomyelitis and Virus
Encephalides, Moscow; Pr. Lydia L. Fadeeva, Ulitsa Valters Ulbrichta, Moscow;
Pr. L.C. Ooldfarb, Institute of Poliomyelitis and Viral Encephal itides , Moscow;
Prof. Vera I. II 'yenko. All -Union Research Institute of Influenza, Leningrad;
Miss Pela Kaplan, Institute of Poliomyelitis and Fncephal itides, Moscow;
Prof. O.K. Lvov, D.I. Ivanovskii Institute of Virology, Moscow;
Pr. Prokopii Andrevich Petrov, lakut Ministry of Public Health, lakutsk;
Pr. Anatoli Alexandrovich Smordintsev, Leningrad; Pr. Victor Zhadanov,
Ivanovskii Institute of Virology, Moscow.
UNITED STATES: Alabama--Dr. James Dutt, University of South Alabama, Mobile;
Pr. Charles Hoff, University of South Alabama, Mobile; Pr. Wladimir Wertelecki,
University of South Alabama, Mobile; Arizona--Dr. Tim Kuberski, National
Institute of Arthritis, Metabolism, and Digestive Diseases, Phoenix;
Califbrnia--Mr. James Boykin, Valencia; Dr. L.L. Cavall i -Sforza, Stanford
University, Palo Alto; Dr. Michael N. Oxman, V.A. Hospital, San Diego;
Delaware--Dr. Roger Rodrique, Wilmington; Hawaii --Dr. Arwin Diwan, University of
Hawaii, Honolulu; Dr. Leon Rosen, Pacific Research Center, Honolulu;
Don Rubinstein, University of Hawaii, Honolulu; Dr. Gordon Wallace, Pacific
Research Station; II 1 inbis--Judith Farquhar, Chicago; Dr. Walter P. Kirschbaum,
Chicago; Ma'rylahd--Dr. Richard T. Johnson, Johns Hopkins Hospital, Baltimore;
Dr. David Lang, University of Maryland, Baltimore; Dr. Guy McKhann, Johns
Hopkins University, Baltimore; Dr. Chris Plato, Gerontology Research Center,
Baltimore; Dr. Constantine Sakles, University Hospital, Baltimore;
Dr. Charles Wisseman, University of Maryland, Baltimore; Dr. K.V. Shah, Johns
Hopkins University, Baltimore; Mr. T.C. Rains, National Bureau of Standards,
Gaithersburg ; Massachusetts--Dr. John Enders, Brookline; Mr. Peter Fetchko,
Peabody Museum, Salem; Michigan--Prof . J.V. Neel , University of Michigan, Ann
Arbor; Dr. Ernst A. Rodin, Lafayette Clinic, Detroit; Mlnnesota--
Dr. Leonard Kurland, Mayo Clinic, Rochester; Dr. G. Albin Matson, Minneapolis;
Nevada--Dr. Warren V. Huber, V.A. Medical Center, Reno; New Jerse^--
Dr. Karl Maramorosch, Rutgers University, New Brunswick; Dr. Richard Masland,
Englewood; New York--Dr. Robert Glasse, Queen's College, Flushing;
Dr. Shirley Lindenbaum, The New School, New York; Dr. Ralph D. Peterson, New
York Hospital -Cornell Medical Center, New York; Dr. Roger D. Traub, IBM Thomas
W. Watson, Yorktown; Ohio--Dr. Richard Feinberg, Kent State University, Kent;
Dr. Frank P. Saul, Medical College, Toledo; Dr. Arthur G. Steinberg, Case
Western Reserve University; Pennsyl vania--Dr. Paul T. Baker, Pennsylvania State
University, University Park; Dr. Napolean Chagnon, Pennsylvania State
University, University Park; Drs. Werner and Gertrude Henle, Children's Hospital
of Philadelphia, Philadelphia; Rhbde lsland--Dr. Terrence E. Hays, Rhode Island
32 - LCNSS/IRP
ZOl NS ni?8?-18 CNSS
COOPERATING UNITS: continued
College, Providence; Dr. John Strom, Rhode Island Hospital, Providence; South
Carolina-- Dr. Paul M. Hoffman, V.A. Hospital, Charleston; Dr. Albert Sabin,
Medical University of South Carolina, Charleston; Texas — Dr. Heather P. Mayor,
Baylor University Medical School, Houston; Dr. Steven Wiesenfeld, Southwest
Allergy Service, Inc., Midland; Washington — Dr. Ronald DiGiacomo, University of
Washington, Seattle; Wisconsin--Dr. G.R. Hartsough, Great Lakes Mink
Association, Pittsville; Dr. Richard F. Marsh, University of Wisconson, Madison;
Dr. Gabriel Zu Rhein, University of Wisconsin, Madison.
YUGOSLAVIA: Prof. J. Vesenjak-Hi rjan, Sveucilistau Zagrebu, Zagreb.
Sub-Project I: Study of the development patterning of the human nervous
system (cybernetics of human development).
Sub-Project II: Human evolutionary studies in isolated primitive groups.
Sub-Project III: Studies of isolated Micronesian populations.
Sub-Project IV: Studies of isolated New Guinea populations.
Sub-Project V: Studies of Australian Aborigines.
Sub-Project VI: Studies of isolated New Hebrides and Solomon Islands
populations.
Sub-Project VII: Studies of Central and South American Indians.
Sub-Project VIII: Developmental, genetic and disease patterns in primitive
populations of Asia, Africa, Indonesia, Melanesia,
Micronesia, Polynesia and the Arctic.
Sub-Project IX: Experimental developmental neuropediatrics in infantile
programming: a empirical approach to the language of
information input into the nervous system.
Sub-Project X: Ciphers and notation for the coding of sensory data for
neurological information processing.
Sub-Project XI: Racial distribution and neuroanatomic variations in the
structure of the human brain.
Sub-Project XII: Studies of high incidence of neurological disease in specific
racial and ethnic groups and in primitive or geographic
population studies.
33 - LCNSS/IRP
Z01 NS 01282-18 CNSS
Project Pescription: Neurobiology of Population Isolates: Study of Child
Growth and Development, Behavior and Learning, and Disease
Patterns in Primitive Cultures (are attached)
Publications: Listed on pages 43- LCNSS/IRP through 54- LCNSS/IRP
34 - LCNSS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00969-18 CNSS
PERIOD COVERED
October 1. 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
Chronic CNS Disease Studies: Slov^, Latent and Temperate Virus Infections
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PRINCIPAL INVESTIGATORS: D. Carleton Gajdusek, M.D., Chief, LCNSS; and
Clarence J. Gibbs, Jr., Ph.D., Deputy Chief, LCNSS
OTHER: Herbert L. Amyx, D.V.M.; David M. Asher, M.D.; Sina Baymanyar, M.D.;
Maria-Teresa Borras, Ph.D.; Paul W. Brown, M«D.; Marie-Claude
Moreau-Dubois, Ph.D.; Ryo Fukatsu, M.D.; Ralph M. Garruto, Ph.D.; Yasuo Kuroda,
Ph.D.; Pyung-Woo Lee, Ph.D.; Maryellen F. Masciangelo, Ph.D.;
Maurizio Pocchiari, M.D.; Robert G. Rohv^er, Ph.D.; Richard T. Yanagihara, M.O.;
Francoise Cathala, M.D.; Dimitry Goldgaber, Ph.D.
COOPERATING UNITS (if any) AUSTRALIA: Dr. Byron A. Kakulas, University of Western
Australia, Nedlands; Dr. Chev Kidson, Queensland Institute of Medical Research.
Brisbane; Dr. Robert L. Kirk, Australian National University, Canberra;
Dr. Ian MacKay, Royal Melbourne Hospital, Melbourne; (continued)
lab/branch ~ '
Laboratory of Central Nervous System Studies, Intramural Research Program
SECTION
INSTITUTE AND LOCATION National Institute of Neurological and Communicative Disorders
and Stroke, National Institutes of Health, Bethesda, Maryland 20205
CHECK APPROPRIATE BOX(ES)
H (a) HUMAN SUBJECTS
Q (al) MINORS [^ (a2) INTERVIEWS
TOTAL MANYEARS:
24
PROFESSIONAL:
14
OTHERi
10
H (b) HUMAN TISSUES
□ (c) NEITHER
Studies elucidate cause and
SUMMARY OF WORK (200 words or less - underline keywords)
pathogenesis of chronic degenerative CNS disorders with emphasis on MS, ALS,
parkinsonism-dementia, Parkinson's, Pick's, and Alzheimer's disease,
Huntington's chorea, supranuclear palsy, other presenile dementias, chronic
encephalitis with focal epilepsy, muscular dystrophies, chronic schizophrenia,
SSPE, PML, dialysis encephalopathy, and intracranial neoplasms. Even familial,
apparently hereditary diseases may be slow virus infections. Subacute
spongiform virus encephalopathies (kuru and Creutzfeldt-Jakob (CJD) disease of
man; scrapie and mink encephalopathy) are caused by unconventional viruses with
unique properties posing important theoretical problems to microbiology and
molecular biology; a major goal is elucidation of their structure and mechanisms
of replication. Transmissible virus dementias are increasingly recognized
worldwide causes of death: high incidence foci, transmission by corneal
transplant or brain surgery, and occupational hazards from exposure to brain
occur. In order to determine the usual mode of infection with the virus, a
worldwide epidemiological study of transmissible virus dementia (CJD) cases is
underway with special attention to familial clusters of cases and with a quest
for possible relationship of scrapie of sheep to the human disease.
PHS-6040 35 - LCNSS/IRP
(Rev. 2-81)
Zni NS 00969-18 CNSS
COOPERATING UNITS: (continued)
AUSTRALIA: Pr. Colin Masters, University of Western Australia, Perth; Pr. Eric
Shaw, Red Cross Blood Transfusion Service, Brisbane; Dr. Vincent Zigas,
Sunnybank.
AUSTRIA: Prof. F. Seitel berger. University of Vienna, Vienna.
BELGIUM: Dr. A. Lowenthal , L'Institut Bunge, Antwerp.
CANADA: Pr. John H. Peck, Toronto Western Hospital, Toronto; Pr. Joseph
Gilbert, University Hospital, London; Pr. Arthur J. Hudson, University
Hospital; London; Pr. Andrew Kertez, St. Joseph's Hospital, London; Pr. Theodore
Rasmussen; McGill University, Montreal; Dr. N.B. Rewcastle, Banting Institute,
Toronto.
CHILE: Dr. Sergio Galvez, Institute de Neuroci rugia, Santiago.
CHINA: Prof. Chi-lu Chen, National Taiwan University, Taipei; Dr. C.H. Yen,
National Health Administration; Taipei; Pr. Chin-Yun Yi i , Kaohsinung Medical
College, Kaohsiung.
CUBA: Dr. Segundo Mesa-Castillo, Hospital Psiquiatrico de la Habana, Havana.
CZECHOSLOVAKIA: Dr. Helena Libokova, Slovak Academy of Sciences, Bratislava;
Dr. Vlastimil Mayer, Slovak Academy of Sciences, Bratislavia; Dr. Eva Mitrova,
Research Institute for Preventative Medicine, Limbova.
EGYPT: Pr. Harry Hoogstraal , Naval Medical Research Unit, Cairo.
ENGLAND: Mrs. Elisabeth Beck, Institute of Psychiatry, London; Dr. M.C. Clark,
Agricultural Research Council, Compton; Prof. P.M. Daniel, Royal College of
Surgeons, London; Prof. George Dick, Regional Dean's Office, London; Prof. L.W.
Duchen, The National Hospital, London; Dr. D.A. Haig, Agriculture Research
Council, Compton; Dr. Gordon D. Hunter, Agricultural Research Council, Compton;
Prof. W.B. Matthews, University of Oxford, Oxford, Dr. R. Kimberlin,
Agricultural Research Council, Compton.
FINLAND: Prof. Nils Oker-Bloom, University of Helsinki, Helsinki.
FRANCE: Dr. Jacques Bert, Centre Hopital et Universite, Marseille; Dr.
Francoise Cathala, Hopital de la Salpetriere, Paris; Dr. Henri-Pierre Cathala,
Hopital de la Salpetriere, Paris; Dr. Louis Court, Centre de Recherches du
Service, Clamart; Dr. Michel Dumas, CHU, Limoges; Prof. A.E. Escourolle, Charles
Foix La Salpetriere, Paris; Dr. Henri Gastaut, University de Marseille,
Marseille; Dr. Patrick Gourmelon, CRSSA, Clamart; Dr. Raymond Latarjet, Institut
du Radium; Paris; Dr. Martin, CHU, Nice; Dr. Francis Rohmer, CHU, Strasbourg;
Dr. Michel Samson, CHU, Roen ; Pr. Schott, CHU, Lyon; Prof. Tamalet, Hopital de
La Timone, Marseille.
36 - LCNSS/IRP
ZOl NS 0P969-18 CNSS
COOPERATING UNITS: (continued)
GERMANY: Pr. Freidrich Peinhardt, Max-van-Pettekoffer Institute, Munich; Pr.
Klaus Mannweiler, Henrich-Pette-Institute fur Virologie und Immunologie,
Hamburg; Pr. W.K. Muller, Country Psychiatric Hospital, Wiesloch; Pr. Volker ter
Meulen, Institute fur Virologie, Wurzburg; Dr. Wolfgang Zeman, Lahstein.
GUAM: Dr. Kwang-Ming Chen, NINCPS Research Center, Tamuning; Dr. Leon
Concepcion, Guam Memorial Hosptial, Agana; Dr. Olivia Cruz, NINCDS Research
Center, Tamuning; Jose Torres, NINCDS Research Center, Tamuning; Dr. Yushiro
Uebayashi, NINCDS Research Center, Tamuning; Dr. Richard T. Yanagihara, NINCDS
Research Center, Tamuning.
ICELAND: Pr. Margret Gudnadottir, University of Iceland, Reykjavik; Dr. P. A.
Palsson, University of Iceland, Reykjavik; Dr. G. Petursson, University of
Iceland, Reykjavik.
INDONESIA: Pr. Budi Subianto, Public Health Department, Jayapura.
JAPAN: Dr. Tomonobu Aoki, Department of Microbiology, Kyushu University,
Fukuoka; Dr. Fushahiro Ikuta, Brain Research Institute, Niigata; Dr. Kiyotaro
Kondo, Brain Research Institute, Niigata; Dr. Reisaku Kono, National Institute
of Health, Tokyo; Pr. Yoshigoro Kuroiwa, Kyushu University, Fukuoka; Pr. Takao
Makifuchi, Brain Research Institute, Niigata; Dr. Ryoichi Mori, Kyushu
University, Fukuoka; Dr. Shigeru Mori, Brain Research Institute, Niigata; Pr.
Nobuyuki Murakami, Nagoya University of School of Medicine, Nagoya; Dr. Seiho
Nagafuchi , Kyushu University, Fukuoka; Pr. Ikuya Nagata, Nagoya University,
Nagoya; Dr. Hiroshi Oda, Kagoshima University, Kagoshima; Dr. Tadao Tsubaki ,
Tokyo Metropolitan Neurological Hospital, Tokyo; Pr. Yoshiro Yase, Wakayama
Medical College, Wakayamashi.
KOREA: Dr. Ho Wang Lee, Korea University Medical College, Seoul.
MEXICO: Dr. Julio Sotelo, Institut Nacional de Neurologia, Mexico City.
NETHERLANDS: Pr. Jan ten Brink, University Hospital of Amsterdam, Amsterdam; Pr.
Jan van der Noordaa, Laboratorium voor GezondheidsLeer, Amsterdam.
NEW ZEALANP: Pr. R. W. Hornabrook, Wadestown.
PAPUA NEW GUINEA: Dr. Michael Alpers, Institute for Medical Research, Goroka.
PERU: Pr. Luis Palomino, Hospital Santo Toribio, Lima.
POLAND: Dr. P.P. Liberski, Department of Neurology, Lodz; Prof. Dr. Ewa
Osetowska, Polish Academy of Sciences, Minsk.
PUERTO RICO: Dr. Victor Mojica, Veterans Administration Center, San Juan.
REPUBLIC OF CHINA: Prof. Chi-lu Chen, National Taiwan University, Taipei; Pr.
C.H. Yen, National Health Administration; Taipei; Dr. Chin-Yun Yii, Kaohsinung
Medical College, Kaohsiung.
37 - LCNSS/IRP
ZOl NS 00969-18 CNSS
COOPERATING UNITS: (continued)
SCOTLAND: Dr. Alan 0. Dickinson, A.R.C. Animal Breeding Research Organization,
Edinburgh; Dr. Hugh Eraser, A.R.C. Animal Breeding Research Organization,
Edinburgh; Dr. J.D. MacGregor, Shetland Health Board, Shetland.
SOUTH AERICA: Dr. J.H.S. Gear, National Institute of Virology, Sandringham.
SPAIN: Dr. J. A. Sanchez-Martin, Institute de Investigaciones, Madrid; Dr.
Alberto Portera-Sanchez, Cuidad Savitaria Primero, Madrid.
SWEDEN: Dr. Erling Norrby, Karolinska Institue, Stockholm; Dr. Arne Svedmyr,
Central Bacteriological Laboratory, Stockholm.
SWITZERLAND: Dr. Christoph Bernoulli, Uni versitsspital , Zurich; Dr. Liana
Bolis, World Health Organization, Geneva; Dr. Breget, University of Geneva,
Geneva; Dr. B. Ney, University of Geneva, Geneva.
USSR: Dr. Mikhasil Petrovcich Chumakov, Institute of Poliomyelitis and Virus
Encephalides, Moscow; Pr. Lydia L. Fadeeva, Ulitsa Valtera Ulbrichta, Moscow;
Dr. Sophia Janovna Gaidamovich, Ivanovskii Institute of Virology, Moscow; Prof.
Vera I. 11 'yenko. All-union Research Institute of Influenza, Leningrad; Dr.
Prokopii Andrevich Petrov, lakut Ministry of Public Health, lakutsk; Dr. Vanda
V. Pogodina, The Institute of Poliomyelitis and Virus Encephal itides, Moscow;
Dr. Peter Rytik, Bilorussioan Institute of Epidemiology, Minsk.
UNITED STATES: Cal ifornia--Dr. J. Richard Baringer, V.A. Hospital, San
Francisco; Dr. Ashley T. Haase, V.A. Hospital, Palo Alto; Dr. R. Nick Hogan,
V.A. Medical Cednter, San Francisco; Dr. Kenneth P. Johnson, San Francisco; Dr.
David E. Kohne, Center for Neurologic Studies, San Diego; Dr. Peter Lampert,
University of California, La Jolla; Dr., Edwin H. Lennette, State Department of
Health, Berkeley; Dr. Michael N. Oxman, V.A. Hospital, San Diego; Dr. Linus
Pauling, Linus Pauling Institute, La Jolla; Dr. Stanley Prusiner, University of
California, San Francisco; Dr. Gunther Stent, University of California,
Berkeley; Dr. W. W. Tourtel lotte, V.A. Hospital, Los Angeles; Dr. Myron Varon,
Amyotrophic Lateral Sclerosis Society, Sherman Oaks; Dr. Steven Waxman, Stanford
University, Stanford; Dr. Leslie P. Weiner, University of Southern California,
Los Angeles. Connecticut--Dr. P. N. Bhatt, Yale University, New Haven; Dr. G.D.
Hsiung, V.A. Medical Center, West Haven; Dr. Elias and Laura Manuelides, Yale
University School of Medicine; New Haven. Hawaii — Dr. Arwin R. Diwan,
University of Hawaii, Honolulu; Dr. Scott B. Halstead, University of Hawaii,
Honolulu; Dr. Hong-Yi Yang, University of Hawaii, Honolulu. II linois--Dr.
Raymond A. Classen, Presbyterian-St. Lukes 's Hospital, Chicago; Dr. Raymond
Roos, University of Chicago, Chicago. Indiana--Dr. Bernadino Ghetti , Indiana
University School of Medicine, Indianapolis; Dr. Morris Pollard, Lobund
Laboratory, Notre Dame; Dr. A.N. Siakotos, Indiana University, Indianapolis.
Kentucky --Dr. Dan Tynan, V.A. Hospital, Lexington. Louisiana--Dr. William
Greer, Gulf South Research Institute, New Iberia. Maryland--Dr. Frederick B.
Bang, Johns Hopkins University, Baltimore; Dr. Theodore 0. Piener, Agricultural
Research Center West, Beltsville; Dr. Richard T. Johnson, Johns Hopkins
38 - LCNSS/IRP
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COOPERATING UNITS: (continued)
University, Baltimore; Dr. David Lang, University of Maryland, Baltimore; Mrs.
Meta Neumann, Bethesda: Dr. Robert Traub, University of Maryland, Baltimore; Dr.
Charles Wisseman, University of Maryland, Baltimore; Pr. K.V. Shah, Johns
Hopkins University, Baltimore; Mr. T.C. Rains, National Bureau of Standards,
Gaithersburg. MassachusettS_--Dr. Amico Bignami, Children's Hospital Medical
Center, Boston; Dr. Bernard Fields, Harvard Medical School, Boston; Dr. E. P.
Richardson, Jr., Massachusetts General Hospital, Boston; Dr. W.C. Schoene, Peter
Bent Brigham Hospital, Boston. Nevada--Dr. Warren V. Huber, V.A. Medical
Center, Reno. New York--Dr. Samuel J. Ayl , The National Foundation March of
Dimes, White Plains; Dr. Jordi Casals, Mt. Sinai School of Medicine, New York;
Dr. Alfred E. Earle, The Public Health Research Institute, Otisville; Pr.
Teresita S. Elizan, Mt. Sinai School of Medicine, New York; Mr. Ernie Green, The
New York Public Health Research Institute, Otisville; Dr. Asao Hirano,
Montefiore Hospital, Bronx; Dr. John Hotchin, Department of Health, Albany; Dr.
J. Moor-Jankowski , New York University Medical Center, New York; Dr. Imaharu
Nakano, Montifiore Hospital and Medical Center, New York; Dr. Michael L.
Shelanski, New York University Medical Center, New York; Dr. Robert A.
Sommerville, New York State Institute for Basic Research in Mental Retardation,
Staten Island; Dr. Robert D. Terry, Albert Einstein Medical Center, Bronx; Dr.
Roger D. Traub, IBM Thomas B. Watson Research Center, Yorktown Heights; Dr.
James D. Watson, Cold Spring Harbor Laboratory, Cold Spring. Ohio--Pr. S.M.
Chou, Cleveland Foundation, Cleveland; Dr. Maurice Victor, Metropolitan General
Hospital, Cleveland. Pennsyl vania--Pr. Milton Alter, Temple University Medical
Center, Philadelphia; Dr. Donald Gilden, Wistar Institute, Philadelphia; Dr.
Neal Nathanson, University of Pennsylvania School of Medicine, Philadelphia.
South Carolina-- Dr. Paul M. Hoffman, V.A. Hospital, Charleston. Texas--Dr.
Samuel Baron, University of Texas, Galveston; Dr. Steven Wiesenfeld, Southwest
Allergy Service, Midland. Vi rginia--Dr. J. L. Hourrigan, Arlington.
Washington--Dr. Ellsworth C. Alvord, Jr., University of Washington, Seattle.
Washihgtbh", D.C.--Dr. Harold Booker, Veterans Administration Central Office,
Washington; Col. Dan C. Cavanaugh, Walter Reed Army Institute, Washington; Pr.
John Kurtzke, V.A. Hospital, Washington; Dr. Frederick C. Robbins, National
Academy of Science, Washington; Pr. Fuller Torrey, St. Elizabeth's Hospital,
Washington. Wisconsih--Dr. Richard F. Marsh, University of Wisconsin, Madison;
Dr. Gabriel Zu Rhein, University of Wisconsin, Madison.
YUGOSLAVIA: Dr. Miha Likar, Mi krobioloski Institut, Ljubljana; Prof. J.
Vesenjak-Hi rjan. University of Zagreb, Zagreb.
Sub-Project I: Attempts to isolate, identify and characterize transmissible
agents from humans and animals with subacute degenerative
diseases of the central nervous system: transmissible
heredofamilial diseases, presenile and senile dementias of
the sporadic and familial types and primary sclerosing and
demyel inating diseases.
Sub-Project II: Characterization and pathogenesis of kuru virus.
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ZOl NS 00969-18 CNSS
Sub-Project III: Characterization and pathogenesis of Creutzfeldt-Jakob
disease (transmissible dementia virus).
Sub-Project IV: Scrapie: studies on the purification, physical and
biological characterization and nature of the virus.
Sub-Project V: In vitro cultivation of the viruses of the subacute
spongiform virus encephalopathies in cell cultures.
Sub-Project VI: Host range of susceptible laboratory animals to the
viruses of the subacute spongiform virus encephalopathies.
Sub-Project VII: Strain variations among the viruses of the subacute
spongiform virus encephalopathies.
Sub-Project VIII: Cell-fusing properties of the viruses of the subacute
spongiform virus encephalopathies.
Sub-Project IX: Resistance to radiation of the viruses of the subacute
spongiform virus encephalopathies.
Sub-Project X: Resistance to disinfectants of the viruses of the subacute
spongiform virus encephalopathies.
Sub-Project XI: Tissue and cell culture techniques used to unmask slow
infection of man and animals using brain and viscera biopsy
and early autopsy, bone marrow and peripheral leucocyte
specimens.
Sub-Project XII: The syncytium-forming viruses (simian and human foamy
viruses).
Sub-Project XIII: Studies on transformed human brain tissue in vitro and
characterization of associated virus.
Sub Project XIV: Electron microscopic membrane studies of subacute
spongiform virus encephalopathies.
Sub-Project XV: Characterization and identification of new herpes viruses
from explant cultures of tissues from subhuman primates.
Sub-Project XVI: Studies on persistent asymptomatic cytomegalovirus
infections of healthy rhesus monkeys.
Sub-Project XVII: Focal movement disorders in rhesus monkeys following
experimental infection with a strain of tick-borne
encephalitis virus.
40 - LCNSS/IRP
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Sub-Project XVIII: Fluorescent antibody studies on the intracellular
localization and identification of virus antigens in vivo
and in vitro in tissues from patients with subacute
diseases of the central nervous system.
Sub-Project XIX: Isolation and characterization of adenovirus from the urine
of chimpanzees.
Sub-Project XX: Development of serological and immunological test system
for use in the study of slow infections of the central
nervous system.
Sub-Project XXI: Immune responsiveness of multiple sclerosis patients to
established viral antigens by detection of specific
antibodies in serum and cerebrospinal fluids collected
serially during remission and exacerbation.
Sub-Project XXII: Animal management and intercurrent diseases in subhumans
primates on long-term studies of slow infections.
Sub-Project XXIII: Studies to determine the possible presence of cryptic viral
genomes in human brain tissues.
Sub-Project XXIV: Sequential development of kuru-induced neuropathological
lesions in spider monkeys.
Sub-Project XXV: Studies on the isolation, characterization, identification
and pathogenicity of type C viruses from human and animal
tissues.
Sub-Project XXVI: Biochemical studies of the etiology of amyotrophic lateral
sclerosis and parkinsonism-dementia.
Sub-Project XXVII: Study of mitochondrial mutants from scrapie-infected mouse
brain cells.
Sub-Project XXVIII: Isolation and characterization of the etiological agent of
Scandinavian nephro-nephritis epidemica.
Sub-Project XXIX: The pathogenesis of Korean hemorrhagic fever virus and the
elucidation of its biological and physical properties.
Sub-Project XXX: Worldwide seroepidemiological evidence of antibodies in
human populations to the virus of Korean hemorrhagic
fever.
Sub-Project XXXI: Development of an enzyme-linked immunoadsorbent (ELISA)
test for the diagnosis and epidemiology of
cysticercosis-induced epi lepsy.
41 - LCNSS/IRP
Sub-Project XXXII
Sub-Project XXXIII
Sub-Project XXXIV:
Sub-Project XXXV:
Sub-Project XXXVI:
Sub-Project XXXVII
ZOl NS 00969-18 CNSS
Studies on the cytochemical and morphological properties of
neurons cultured in vitro.
Development of immunological markers for the detection of
autoantibodies to neurofilaments in the sera of patients
with subacute spongiform encephalopathies.
Studies to determine the neurophysiological changes of
neurons in vitro infected with CJD.
Effects of the subacute spongiform viruses on nerve cells
grown 2_n vitro.
In vivo ard J_n vitro studies to determine the etiology of
myasthenia gravis.
Neurophysiological study of animals experimentally infected
with subacute spongiform virus encephalopathies.
Project Description:
Chronic Central Nervous System Disease Studies (described
fully on pages 1-LCNSS/IRP through 27-LCNSS/IRP).
The projects (I through XXXVII) listed herein, as itemized in the Project
Reports of previous years, have continued throughout this year and have been
expanded, as are reflected in the extensive list of publications and the summary
will follow. Contractural phases of this work are being conducted at: Gulf
South Research Institute, New Iberia, Louisiana; and Public Health Research
Institute of the City of New York, Inc., Otisville, New York.
Publications:
Listed on pages 43 - LCNSS/IRP throuah 54 - LCNSS/IRP
42 - LCNSS/IRP
PUBLISHED: ZOl NS 01282-18 CNSS and ZOl NS 00969-18 CNSS
1. Asher, D.M., Masters, C.L., Gajdusek, D.C., and Gibbs, C.J., Jr. (1982)
Familial spongiform encephalopathies. In "Genetics of Neurological
and Psychiatric Disorders," S.S. Kety, L.P. Rowland, R.L. Sidman, and
S.W. Matthysse. Raven Press, New York, pp. 273-291.
2. Bahmanyar, S., Gajdusek, D.C., and Sotelo, J. (1982) Longitudinal spinal
cord sections as substratum for anti-neurofilament antibody detecton.
Journal of Neurological Sciences, 53:1 (January), 85-90.
3. Beck, E., Daniel, P.M., Davey, A., and Gajdusek, D.C. (1982) The
pathogenesis of spongiform encephalopathies: an uUrastructural study.
Brain, 105:4, 755-786.
4. Board, P.G., Gibbs, C.J., Jr. and Gajdusek, D.C. (1981) Polymorphism
of erythrocyte glyoxalase II in anthropoid primates. Folia
primatologica, 36, 138-143.
5. Borras, M.T., Kingsbury, D.T., Gajdusek, D.C. and Gibbs, C.J., Jr. (1982)
Inability to transmit scrapie by transfection of mouse embryo cells in
vitro. Journal of General Virology, 58: 263-271.
6. Brown, P. (1982) Response to a letter to the editor about the article:
An Epidemiologic Critique of Creutzfeldt-Jakob disease. American
Qiburnal of Epidemiology, 115:1 (January), 145-151.
7. Brown, P., Cathala, F., and Gajdusek, D.C. (1981) Mycobacterial and
fungal skin sensitivity patterns among remote population groups in
Papua New Guinea, and in the New Hebrides, Solomon, and Caroline
Islands. American Journal of Tropical Medicine and Hygiene, 30:5,
1085-1093. '
8. Brown, P., Gibbs, C.J., Jr., Amyx, H.L., Kingsbury, D.T., Rohwer, R.G.,
Sulima, M.P. and Gajdusek, D.C. (1982) Chemical disinfection of s to
Creutzfeldt-Jakob disease virus. New England Journal of Medicine,
306:21 (May 27), 1279-1282.
9. Brown, P., Moreau-Dubois, M.C. and Gajdusek, D.C. (1982) Persistent
asymptomatic infection of the laboratory mouse by simian foamy virus
type 6: a new model of retrovirus latency. Archives of Virology,
7J_, 229-234.
10. Brown, P., Rohwer, R.G., Green, E., and Gajdusek, D.C. (1982) Effect of
chemicals, heat and histopathologic processing on high infectivity
hamster-adapted scrapie virus. Journal of Infectious Diseases, 145:5
(May) 683-687.
11. Cathala, F., Brown, P., Chatelain, J., Raharison, S., Lecanuet, P.,
Castaigne, P., Gibbs, C.J., Jr. and Gajdusek, D.C. (1982) Maladie de
Creutzfeldt-Jakob en France: contribution a une recherche
epidemiologique. Revue Neurologique (Paris), 138:1, 39-51.
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12. Cathala, F., Court, L. , Breton, P., Mestries, J.C, Gourmelon, P.,
Dormont, D., Lemercier, M., Gray, F., Hauw, J.J., Escourolle, R.,
Gibbs, C.J., Jr. and Gajdusek, D.C. (1981) La maladie de
Creutzfeldt-Jakob experimental e du singe ecureuil. Revue Neurologique
(Paris), 237:12, 785-805.
13. Chatelain, J., Cathala, F., Brown, P., Raharison, S., Court, L., and
Gajdusek, D.C. (1981) Epidemiologic comparisions between
Creutzfeldt-Jakob disease and scrapie in France during the 12 year
period 1968-1979. Journal of the Neurological Science^, 51 ;3,
(September), 329-337.
14. Coker-Vann, M., Subianto, B., Brown, P., Diwan, A., Desowitz, R.,
Garruto, R.M., Gibbs, C.J., Jr. and Gajdusek, D.C. (1981) ELISA
antibodies to cysticerci of Taenia solium in human populations in
New Guinea and Southeast Asia. Southeast Asia Journal of
Tropical Medicine and Public Hea]th^ U:A (December), 499-505.
15. Coker-Vann, M., Subianto, B., Brown, P., Diwan, A., Desowitz, R.,
Garruto, R.M., Gibbs, C.J., Jr. and Gajdusek, D.C. (1981) ELISA
antibodies to cysticerci of Taenia solium in human populations in
New Guinea and Southeast Asia. Southeast Asia Journal of
Tropical Medicine and Public Health, 12:4 (December), 499-505.
16. Diwan, A., Coker-Vann, M., Brown, P., Subianto, D.B., Yolken, R.,
Desowitz, R., Escobar, A., Gibbs, C.J., Jr. and Gajdusek, D.C.
(1982) Enzyme-linked immunosorbant assay (ELISA) for the detection
of antibody to cysticerci of Taenia solium. American Journal of
Tropical Medicine and Hygiene, 31 :2 (March) , 364-369.
17. Doi , H. , Tateishi, J., Ohta, M., Kuroiwa, Y., Gajdusek, D.C, Chen,
K.-M., and Gibbs, C.J., Jr. (1982) Neuropathological study of
amyotrophic lateral sclerosis and parkinsonism-dementia on Guam:
an analysis of 24 autopsy cases. Brain and Nerve, 34:1 (January),
63-70.
18. Franko, M.C., Koski, C.L., Gibbs, C.J. , Jr., McFarlin, D.E., and
Gajdusek, (1982) Monoclonal Pq protein-specific antibody:
derivation and characterization. Proceedings of the National
Academy of Science, 79^:11 (June), 3618-3622.
19. Franko, M.C., Masters, C.L., Gibbs, C.J., Jr. and Gajdusek, D.C.
(1981) Monoclonal antibodies to central nervous system antigens.
Journal of Neuroimmunology 1:4 (December), 391-411.
20. Gajdusek, D.C. (1982) Hemorrhagic fever with renal syndrome (Korean
hemorrhagic fever, epidemic hemorrhagic fever, nephropathia
epidemica): A newly recognized zoonotic plague of Eurasian
landmass with the possibility of related infections on other
continents. Abstract number 5E-2 in "Programme and Abstracts of
the International Seminar on Viral Diseases in South-East Asia and
the Western Pacific," Austral ian Academy of Science, Canberra,
February 8-12, p. 21.
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21. Gajdusek, D.C. (1982) Viral infections in childhood in southeast Asia
and the western Pacific. Abstract number 1-5 in"Programme and
Abstracts of the International Seminar on Viral Diseses in
South-East Asia and the Western Pacific" Australian Academy of
Science, Canberra, February 8-12, p. 2.
22. Gajdusek, D.C. (1982) Editorial in the Papua New Guinea Medical
Journal on Huntington's Chorea. Papua New Guinea Medical Journal,
25:1, (March), 1-2.
23. Gajdusek, D.C. (1982) Hemorrhagic fever with renal syndrome (Korean
hemorrhagic fever, epidemic hemorrhagic fever, nephropathia
epidemica): A newly recognized zoonotic plaque of the Eurasian
landmass with the possibility of relative muroid virus
nephorpathies on other continents. In "Viral Diseases in
South-East Asia and the Western Pacific," J.S. Mackenzie, editor.
Academic Press, Sydney, pp. 576-594.
24. Gajdusek, D.C. (1982) Viral infections in childhood in South-East
Asia and the Western Pacific. In "Viral Diseases in South-East
Asia and the Western Pacific," J.S. Mackenzie, editor. Academic
Press, Sydney, pp. 77-78.
25. Gajdusek, D.C. (1982) Foci of neurologic disease in high incidence
in isolated populations of East Asia and the Western Pacific. In
"Human Motor Neuron Diseases," L.P. Rowland, editor. Raven
Press, New York. pp. 365-395.
26. Gajdusek, D.C. and Gibbs, C.J., Jr. (1982) Slow Virus Infections and
Aging. In: "Neuronal Aging and Its Implications in Human
Neurological Pathology", Aging, Vol. 18, R. Terry, C.G. Bolis,
and G. Toffano, editors. Raven Press, New York, p. 1-13.
27. Gajdusek, D.C. and Salazar, A. (1982) Amyotrophic lateral sclerosis
and parkinsonism syndromes in high incidence among the Auyu and
Jakai people of West New Guinea. Neurology, 32^: (February),
107-126. ~
28. Gibbs, C.J., Jr. (1982) Virus-induced slow infections of the central
nervous system. In "Viral Infections in Oral Medicine", J.J.
Hooks and G.W. Jordon, editors. Elsvier/North Holland, Inc. pp.
255-266.
29. Gibbs, C.J., Jr. and Gajdusek, D.C. (1982) An update on long-term jji
vivo and in vitro studies designed to identify a virus as the
cause of amyotrophic lateral sclerosis, parkinsonism-dementia, and
Parkinson's disease. In "Human Motor Neuron Diseases," L.P.
Rowland, editor. Raven Press, New York. pp. 343-353.
30. Garruto, R.M. Polycythemia, altitude, and human adaptation. In:
"Abstracts of the Golden Jubilee Conference on Human Genetics and
Adaptation, Indian Statistical Institute", Calcutta, February 1-5.
p. 10.
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31. Garruto, R.M., Gajdusek, D.C., and Chen, K.W. (1981) Amyotrophic
lateral sclerosis and parkinsom'sm-dementia among Filipino
migrants to Guam. Annals of Neurology, 10:4 (October), 341-350.
32. Haase, A.T., Swoveland, P., Stowring, L., Ventura, P., Johnson, K.P.,
Norrby, E. and Gibbs, C.J., Jr. (1981) Measles virus infections
of the central nervous system. Journal of Infectious Diseases,
144:2 (August), 154-160.
33. Kakulas, B.A., Tan, N. , Masters, C.L., Garruto, R.M., Gajdusek, D.C.,
Gibbs, C.J., Jr. and Chen, K-M. (1982) Neuropathological
observations on the Parkinsonian-dementia (PD) complex and
amyotrophic lateral asclerosis (ALS) of Guam. A report of 102
cases. Abstract number B4-9 in "Abstracts of the Ninth
International Congress on Neuropathology," Vienna, September 5-10,
1982. p. 114.
34. Kingsbury, D.T., Smeltzer, D.A., Amyx, H.L., Gibbs, C.J., Jr., and
Gajdusek, D. C. (1982) Evidence for an unconventional virus in
mouse-adapted Creutzfeldt-Jakob disease. Infection and
Immunity, 37^:3, (September), 1050-1053.
35. Kohne, D.E., Gibbs, C.J., Jr., White, L., Tracy, S.M., Meinke, W.
and Smith, R.A. (1981) Virus detection by nucleic acid
hybridization: Examination of normal and ALS tissues for the
presence of poliovirus. Journal of General Virology, 56,
223-233.
36. Lee, P.W., Svedmyr, A., Amyx, H.L., Gibbs, C.J., Jr., and Gajdusek,
D.C. (1982) Indirect immunofluorescence tests in Korean
hemorrhagic fever and epidemic (endemic) nephropathia: treatment
at low pH for removal of "non-specific" flourescence in tissues
from immunocompetent hosts. Intervirology, 18:1-2 (July),
38-44.
37. Lee, P.W., Yanagihara, R., Masciangelo, M. , Amyx, H.L., Gibbs, C.J.,
Jr., Gajdusek, D.C. and Traub, R.T. (1982) Antibody against
Korean haemorrhagic fever virus in North American rodents. New
England Journal of Medicine, 307:10 (September 2), 623-625.
38. Makifuchi, T. , Ikuta, F. , Takeda, S., Oyanagi, K., Chen, K-M, Gibbs,
C.J., Jr., Gajdusek, D.C, and Chase, T.N. (1982) Neuronal loss
and neurofibrillary tangles in parkinsonism-dementia complex
and amyotrophic lateral sclerosis on Guam. Abstract number
Dl-12 in"Abstracts of the Ninth International Congress of
Neuropathology, "Vienna, September 5-10, 1982. p. 31.
39. Masters, C.L. and Gajdusek, D.C. (1982) The spectrum of
Creutzfeldt-Jakob disease and the virus-induced subacute
spongiform encephalopathies. Chapter 6, in "Recent Advances in
Neuropathology, Volume 2". W.T. Smith and J.B. Cavanagh,
editors. Churchill Livingstone, Edinburgh, pp. 139-163.
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40. Moreau-Dubois, M.C., Brown, P., Rohwer, R.G., Masters, C.L., Franko,
M. and Gajdusek, D.C. (1982) Experimental scrapie in the golden
Syrian hamster: temporal comparison of in vitro cell fusing
activity with brain infectivity and histopathologic changes.
Infection and Immunity, 37:1 (July), 195-199.
41. Nakashima, S., Abe, S., Makifuchi, T. , Gyanagi , K., Ikuta, F., Chen,
K-M, Gibbs, C.J., Jr., Gajdusek, D.C, and Chase, T.N. (1982)
The reduced activities of catecholamine synthesizing enzymes in
parkinsonism-dementia complex on Guam. Abstract number 11-90 in
"Abstracts of the Ninth International Congress of Neuropathology;'
Vienna, September 5-10, 1982. p. 262.
42. Nyberg, P., Almay, B., Carlsson, A., Forsgren, L., Masters, C.L.,
and Winblad, B. (1982) Brain monoaminine in two types of
Creutzfeldt-Jakob disease. Acta Neurol ogica Scandinavica, 66:1 ,
16-24.
43. Perl, D.P., Gajdusek, D.C, Garruto, R.M., Yanagihara, R.T., and
Gibbs, C.J., Jr. (1982) Intraneuronal aluminum accumulation in
amytrophic lateral sclerosis and Parkinsonism-dementia of Guam.
Science, 217_:4564 (September 10), 1053-1055.
44. Perl, D., Gajdusek, D.C, Garruto, R.M., Yanagihara, R.T. and Gibbs, C.J.,
Jr. (1982) Intracellular aluminum (Al) accumulation in
neurofibrillary tangle (NFT)-bearing neurons in Guamanian ALS and
parkinsonism-dementia (PD). Abstract number Dl-13 in"Abstracts of the
Ninth International Congress of Neuropathology^ Vienna, September 5-10,
1982. p. 31.
45. Prusiner, S.B., Gajdusek, D.C. and Alpers, M.P. (1982) Kuru with incubation
periods exceeding two decades. Annals of Neurology, 12:1 (July), 1-9.
46. Salazar, A.M., Masters, C.L., Gajdusek, D.C, and Gibbs, C.J., Jr. (1982)
Syndromes of amyotrophic lateral sclerosis and dementia: relation to
transmissible Creutzfeldt-Jakob disease. Abstracts of the American
Acadeniy Neurology. April 25-May 1, 1982, Washington, D.C. Neurology
32_:4, Part 2, A167.
47. Schoene, W.C, Masters, C.L., Gibbs, C.J., Gajdusek, D.C, Tyler, H.R. and
Dammin, G.J. (1981) Transmissible spongiform encephalopathy (CJD)
with atypical clinical and pathological findings. Archives of
Neurology, 38: (August), 473-477.
48. Takeda, S., Ohama, E., Izumo, S., Makifuchi, T., Ikuta, F., Chen, K-M,
Gibbs, C.J., Jr., Gajdusek, D.C, and Chase, T.N. (1982) Substantia
Nigra and locus ceruleus in Parkinsonism-Dementia Complex on Guam and
Olivopontocerebellar atrophy. Abstract number B4-10 in"Abstracts of
the Ninth International Congress of Neuropathology" Vienna, September
5-10, 1982. p. 115.
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49. Tsuji, S., Muraoka, S., Kuroiwa, Y., Chen, K.-M., and Gajdusek, D.C.
(1981) Auditory brainstem evoked response (ABSR) of parkinsonism-
dementia complex and amyotrophic lateral sclerosis in Guam and Japan.
Rinksho Shinkeigaku. Clinical Neurology. 21: 37-41.
50. White, B.J., Crandall, C. , Goudsmit, J., Morrow, C.H., Ailing, D.W.,
Gajdusek, D.C, and Tijio, J.-H. (1981) Cytogenetic studies of
familial and sporadic Alzheimer disease. American Journal of Medical
Genetics. ^O: 77-89.
51. Yanagihara, R.T. (1982) Heavy metals and essential minerals in motor
neuron disease. In "Pathogenesis of Human Motor Neuron Diseases,"
L.P. Rowland, editor. Raven Press, New York. pp. 235-249.
48 - LCNSS/IRP
IN PRESS: ZOl NS 01282-18 CNSS and ZOl NS 00969-18 CNSS
Amyx, H.L., Salazar, A.M., Newsome, D.A. , Gibbs, C.J., Jr. and Gajdusek,
D.C. (1982) Nasopharyngeal carcinoma with intracranial extension in a
chimpanzee. Journal of the American Veterinary Medical Association.
(December).
Asher, D.M., Gibbs, C.J., Jr. and Gajdusek, D.C. (in press) Slow viruses: Safe
handling of the agents of spongiform encephalopathies. In: "Manual of
Laboratory Safety^' ed. Groschel . American Society for Microbiology,
Washington, 1982
Asher, D.M., Masters, CM., Gajdusek, D.C. and Gibbs, C.J., Jr. (in press)
Genetics and the spongiform encephalopathies. ARNMD.
Benfante, R.J. and Gajdusek, D.C. (in press) Antibody studies in the kuru
region. II. Respiratory Viruses. Papua New Guinea Medical Journal.
Blake, N.M., Hawkins, B.T., Kirk, R.L., Bhatia, K. , Brown, P., Garruto, R.M. and
Gajdusek, D.C. (in press) A population genetic study of the Banks and
Torres Islands (Vanuatu) and of the Santa Cruz Islands and Polynesian
outliers (Solomon Islands). American Journal of Physical Anthropology.
Blake, N.M., Kirk, R.L., Wilson, S.R., Garruto, R.M., Gajdusek, D.C, Gibbs,
C.J., Jr. and Hoffman, P. (in press) Search for a red cell enzyme or serum
protein marker in amyotrophic lateral sclerosis and parkinsonism-dementia of
Guam. American Journal of Medical Genetics.
Brody, J. and Gibbs, C.J., Jr. (in press) Chronic Neurological Diseases.
Subacute sclerosing panencephalitis, progressive multifocal
leucoencephalitis, kuru and Creutzfeldt-Jakob disease. In: "Viral
Infections of Man',' Second Edition , A.S. Evans, editor.
Brown, P., Rohwer, R.G., Amyx, H. and Gajdusek, D.C. (in press) Practical
aspects of the disinfection of spongiform encephalopathy viruses. Presented
at the "Symposium Virus Non-Conventionnels et Affections du Systeme Nerveux
Central". Paris. November 5-7, 1981. In: "Unconventional Viruses and the
Central Nervous System", L. Court, F. Cathala, P. Brown, and C.J. Gibbs,
Jr., editors, Masson, Paris, 1982.
Brown, P., Smallwood, L.A., Gerety, R.J., Breguet, G. , Ney, R. and Gajdusek,
D.C. The seroepidemiology of viral hepatitis in Bali, Indonesia. Southeast
Asian Journal of Tropical Medicine and Public Health, 1982.
Cathala, F., Chatelain, J., Brown, P., and Delasnerie-Laupretre, N. (in press)
La maladie de Creutzfeldt-Jakob dans la region Parisienne: etude de la
mortalite annuelle par rapport a I'age des populations dans les differents
zones de densite. Pathologie Biologie.
Chatelain, J., Delasnerie-Laupretre, N., Cathala, F. and Brown, P. (in press)
Scrapie in France: racial and other possible predisposing factors in the
naturally acquired disease of sheep. Vet. Microbiology.
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Chen, K-M, Murakami, N. , Gibbs, C.J., Jr., and Gajdusek, D.C. (in press) A
study of the natural history of amyotrophic lateral sclerosis and
Parkinsonism-dementia of Guam. Neurology.
Fieschi, C, Orzi, F., Pocchiari, M., Nardini, M., Rocchi, R., Asher, D.M.,
Gibbs, C.J., Jr., and Gajdusek, D.C. (in press) Creutzfeldt-Jakob disease
in the the province of Siena: two cases transmitted to monkeys. Italian
Journal of Neurological Science.
Gajdusek, D.C. (in press) Dementia and the aging nervous system: Causes and
suspected etiologies as a result of natural experiment in isolated human
groups. Abstract presented at the American Association of Physical
Anthropologists,
Gajdusek, D.C. (in press) Muroid virus nephropathies and muroid viruses of the
Hantaan virus group. Closing discussion at the VIII International Congress
of Infectious and Parasitic Diseases, June 7-11, 1982. Stockholm, Sweden.
Gajdusek, D.C. (in press) Environmental factors provoking physiological changes
which induce motor neuron disease and early neuronal aging in high incidence
foci in the Western Pacific: Calcium deficiency induced secondary
hyperparathyroidism and resultant CNS deposition of calcium and other
metallic cations as the cause of ALS and PD in high incidence foci.
Presented at the Motor Neuron Disease Association International Symposium on
Progress in Motor Neuron Disease, July 5-7, 1982, London, pp.
Gajdusek, D.C. (in press) Viral damage to the central nervous system with
special attention to the subacute spongiform encephalopathies. Proceedings
of the World Health Organization/Meniari Foundation Symposium on
Immunopathology of the Central and Peripheral Nervous System, Milan, June
14-16, 1978.
Gajdusek, D.C, Gibbs, C.J., Jr., Lee, P.W., Svedmyr, A., Amyx, H.L., and
Goldgaber, D. (in press) Global epidemiology of Hantaan and related
viruses. Abstract presented at the 4th International Conference on
Comparative Virology October 17-22, 1982. Banff, Alberta, Canada.
Gajdusek, D.C, Goldgaber, D., Millard, E., and Ono, S. (in press) Bibliography
of Hemorrhagic Fever with Renal Syndrome.
Garruto, R.M. (in press) Environmental Challenge — Bi ©cultural Response: The
concept of optimal and critical levels in the adaptation of man to the
natural environment. Abstract presented at Symposium on Human Adaptation to
the Environment: Relative Impacts of Physical Environmental and
Sociocultural Factors. XI International Congress of Anthropological and
Ethnological Sciences. August 20-25, 1983. Vancouver.
Garruto, R.M. (in press) Polycythemia, altitude and human adaptation.
Proceedings of the Conference on Human Genetics and Adaptation, Indian
Statistical Institute, Calcutta, India.
50 - LCNSS/IRP
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Garruto, R.M. (in press) Health consequences of migration in Micronesia. In:
Proceedings of the Conference on Migration and Adaptation to Environmental
Change Among Pacific Populations. East-West Center Press, University of
Hawaii, Honolulu.
Garruto, R.M. and Dutt, J.S. (in press) Lack of prominent polycythemia in
traditional Andeans living at 4200 M. Journal of Applied Physiology.
Garruto, R.M. and Gajdusek, D.C. (in press) Pacific cultures: a paradigm for the
study of late onset neurological disorders. In: "Risk Factors for
Senility", H. Rothschild, editor. Oxford University Press.
Garruto, R.M., Plato, C.C, Myrianthopoulous, N., Schanfield, M.S., and Gajdusek,
D.C. (1983) Blood groups, immunoglobulin allotypes and dermatoglyphic
features of patients with amyotrophic lateral sclerosis and
parkinsonism-dementia of Guam. American Journal of Medical Genetics, 14:2
(10 pp). —
Garruto, R.M., Yanagihara, R.T., Arion, D., Daum, C, and Gajdusek, D.C. (in
press) Bibliography of amyotrophic lateral sclerosis and
Parkinsonism-dementia of Guam. U.S. Department of Health and Human
Services, National Institutes of Health, Bethesda, Maryland.
Gibbs, C.J., Jr. (in press) Perspectives in virus induced slow infections. In
"Unconventional Viruses and the Central Nervous System", L. Court, F.
Cathala, P. Brown, and C.J. Gibbs, Jr., editors, Masson, Paris, 1982.
Gibbs, C.J., Jr. (in press) Scrapie-kuru Group: The subacute spongiform virus
encephalopathies. In "Medical Microbiology: Principles and Concepts." S.
Baron and F. Dianzani, editors.
Gibbs, C.J., Jr., Masters, C.L., and Gajdusek, D.C. (in press) Virus-induced
slow degenerations of the central nervous system and related diseases. In
"Update on the Zoonoses," W.T. Hubbert and P. Schnurrenberger, editors.
Goldgaber, D., Lee, P.W., Fukatsu, R., Amyx, H.L., Gibbs, C.J., Jr., Gajdusek,
D.C. and Lee, H.W. (in press) Reovirus type 2 in strains of Korean
hemmoraghic fever virus. Lancet.
Hoffman, P.M., Robbins, D.S., Gibbs, C.J., Jr., Gajdusek, D.C. (in press)
Decline in immune function with age among normal Guamanians. Journal of
Gerontology.
Hoffman, P.M., Robbins, D.S., Gibbs, C.J., Jr., and Gajdusek, D.C. (in press)
Serum immunoglobulin levels in Guamanian ALS and PD. American Neurological
Association.
51 - LCNSS/IRP
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Kingsbury, D.T., Amyx, H.L., and Gibbs, C.J., Jr. (in press) Biophysical
Properties of the Creutzfeldt-Jakob disease agent. Presented at the
Symposium Virus Non Conventionnel s et Affections du Systeme Nerveux
Central. Paris. November 5-7, 1981. In: "Unconventional Viruses and
the Central Nervous System", L. Court, F. Cathala, P. Brown, and C.J.
Gibbs, Jr., editors, Karger, Basel, 1982.
Kuroda, Y. , Gibbs, C.J., Jr., Amyx, H.L. and Gajdusek, D.C. (in press)
Creutzfeldt-Jakob disease in the mouse: persistent viremia and preferential
replication of virus in low density lymphocytes. Infection and Immunity.
Lee, P.W., Amyx, H.L., and Gajdusek, D.C. (in press) Korean hemorrhagic fever
virus infections in nude mice. Unknown publisher as yet.
Lee, P.W., Amyx, H.L., and Gajdusek, D.C. (in press) The susceptibility of nude
mice to Hantaan virus. Proc. Soc. of Exper. Biol, and Med.
Lee, P.W., Goldgaber, D., Gajdusek, D.C, Gibbs, C.J., Jr. and Amyx, H. (in
press) Differentiation of nephropathia epidemica from East Asian strains
of hemorrhagic fever with renal syndrome by blocking antibody and
neutralizing antibody determinations. New England Journal of Medicine
Lee, P.W., Svedmyr, A., Amyx, H.L., Gajdusek, D.C, Gibbs, CJ., Jr., Lofgren,
0. and Nystrom, K. (1982) HFRS antigen and antibody in two species of
Swedish Voles. Scandanavian Journal of Infectious Diseases, 14:
Makifuchi, T., Ikuta, F., Oyanagi , K. , Chen, K-M, Gibbs, C.J., Jr, , Gajdusek,
D.C. and Chase, T.N. (in press) Parkinsoni sm-dementia complex and ALS on
Guam: A study on Onufrowicz nucleus. Abstract presented at the Annual
Meeting of the Japanese Neuropathological Association, Fukuoka, May 9-11,
1981.
Masters, C.L., Rohwer, R.6., Franko, M., Brown, P., and Gajdusek, D.C. (in
press) The sequential development of spongiform change and gliosis of
experimental scrapie in the golden Syrian hamster. Journal of
Comparative Pathology.
Moreau-Dubois, M.C, Brown, P., and Gajdusek, D.C (in press) La fusion
cellulaire dans 1 'etude des encephalopathies spongiforms. Presented at
Symposium Virus Non Conventionnels et Affections du systeme Nerveux
Central. Paris. November 5-7, 1981. In: "Unconventional Viruses and the
Central Nervous System", L. Court, F. Cathala, P. Brown, and C.J. Gibbs,
Jr., editors, Masson, Paris, 1982.
Nakashima, S., Abe, S., Makifuchi, T., Ikuta, F., Chen, K-M, Gibbs, C.J.,
Jr., Gajdusek, D.C and Chase, T.N. (in press) Parkinsoni sm-Dementia Complex
on Guam: The decreased activities of tyrosine hydroxylase and DOPA
decarboxylase. Abstract presented at the Annual Meeting of the Japanese
Neuropathological Association, Fukuoka, May 9-11, 1981
52 - LCNSS/IRP
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Plato, C.C. and Garruto, R.M. (in press) Collection and recording of
dermatoglyphic data. Abstract presented at the 52nd Annual Meeting of the
American Association of Physical Anthropologists, Indianapolis, April 7-9,
1983. American Journal of Physical Anthropology.
Plato, C.C, Garruto, R.M. and Gajdusek, D.C. (in press) Further studies of
the genetics of the Chamorros of Guam: Dermatoglyphics. Human Heredity.
Plato, C.C, Garruto, R.M., Yanagihara, R.T., Chen, K-M, Wood, J.L., Gajdusek,
D.C. and Morris, A.H. (in press) Cortical bone loss and measurements of the
second metacarpal bone. I. Comparisons between adult Guamanian Chamorros
and Amercian Caucasions. American Journal of Physical Anthropology.
Raverdy, P., Hauw, J.J., Cathala, F., Lecanuet, P., Remy, A., Brown, P., and
Perie, G. (in press) Maladie de Creutzfeldt-Jakob ayant evolve 34 mois chez
une femme de 26 ans. Rev. Neurol .
Rohwer, R.G. (in press) Implications of the kinetics of physical and chemical
inactivation of the viruses of scrapie and Creutzfeldt-Jakob disease.
Presented at the Symposium Virus Non Conventionnels et Affections du System
Nerveux Central. Paris. November 5-7, 1981. In: "Unconventional Viruses and
the Central Nervous System", L. Court, F. Cathala, P. Brown, and C.J.
Gibbs, Jr., editors, Masson, Paris, 1982.
Salazar, A.M., Masters, C.L., Gajdusek, D.C, and Gibbs, C.J., Jr. (in press)
Syndromes of Amyotrophic lateral sclerosis and dementia. Relation to
transmissible Creutzfeldt-Jakob disease. Annals of Neurology.
Salazar, A.M., Brown, P., Gajdusek, D.C, and Gibbs, C.J., Jr. (in press)
Alzheimer's disease. Relation to Creutzfeldt-Jakob disease and other slow
virus infections. In "Alzheimer's Disease and Senile Dementia", B.
Reisberg, editor. Macmillian Publishing Company, New York, 1982.
Salazar, A.M., Gibbs, C.J., Jr. and Gajdusek, D.C. (in press) Viral and immune
mechanisms of demyeli nation. In: "Demyel inating Diseases", A. Lowenthal ,
J.J. Martin and A. Neetens, editors. Belgian Ophthalmo1o§1cal Soctety,
Antwerp.
Salazar, A.M., Gibbs, C.J., Jr., Gajdusek, D.C. and Smith, R. (in press)
Clinical usage of interferons. Central Nervous System. In "Handbook of
Experimental Pharamacology, Vol. , Interferon", P. Came and W. Carter,
editors. Springer-Verlag, Vienna.
Scrimgeour, E.M., Masters, C.L., Alpers, M.P., Kaven, J. and Gajdusek, D.C. (in
press) A cl inico-pathological study of a case of kuru. Journal of the
Neurological Sciences.
Svedmyr, A., Lee, P.W., Gajdusek, D.C, Gibbs, C.J., Jr. and Nystrom, K. (in
press) Antigenic difference between European and East Asian Strains of HFRS
Virus. Presented at the VIII International Congress of Infectious and
Parasitic Diseases, Stockholm, June 7-11. Supplement to Scandinavian
Journal of Infectious Diseases.
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Simmons, R.T., Graydon, J.J., Rodrique, R.B., Zigas, V., and Gajdusek, D.C. (in
press) Blood group genetic data from the Southern and Western highlands
districts and the western district, Papua New Guinea. American Journal of
Physical Anthropology.
Takeda, S., Makifuchi, T., Ghama, E., Ikuta, F., Chen, K-M., Gibbs, C.J., Jr.,
Gajdusek, D.C., and Chase, T.N. (in press) Parkinsoni sm-dementia complex on
Guam: Lesions of the substantia nigra and locus caeruleus. Abstract for
the Annual Meeting of the Japanese Neuropathological Association, Fukuoka,
May 9-11, 1981.
White, L., Laing, C, Wakkle, Siegle, L., and Gibbs, C.J., Jr. (in press)
Inability to transmit scrapie by transfection of mouse embryo cells in
vitro. Journal of General Virology.
Viret, J., Dormont, D. , Court, L., Leterrier, P., Cathala, P., Gibbs, C.J., Jr.,
and Gajdusek, D.C. (in press) Structural modifications of nerve membranes
during experimental scrapie evolution in mouse. Nature.
Yanagihara, R.T., Garruto, R.M., and Gajdusek, D.C. (1983) Epidemiological
surveillance of amyotrophic lateral sclerosis and parkinsonism dementia in
the Commonwealth of the Northern Marianas Islands. Annals of Neurology,
(January).
Yanagihara, R.T., Garruto, R.M., Gajdusek, D.C, Tomita, A., Konagaya, Y.,
Uchikawa, T. , Chen, K-M., Plato, C.C., Gibbs, C.J., Jr., and Sobue, I. (in
press) Calcium and vitamin D metabolism in Guamanian Chamorros with
amyotrophic lateral sclerosis and Parkinsoni sm-dementia. New England
Journal of Medicine.
Zaninovic, V., Barreto, P., Biojo, R., and Gajdusek, D.C. (in press) A high
incidence focus of non inherited Spastic Paraparesis in the South Pacific
coast of Colombia. Annals of Neurology.
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CONTRACTS
Gulf South Research Institute
New Iberia, Louisiana
Contract #N01-NS-8-09931
$ 600,000.00
Public Health Research Institute of the City of New York, Inc.
Otisville, New York
Contract #N01-NS-7-0082
$ 131,000.00
Litton Bionetics, Inc.
(Administration by NCI)
Contract #N01-C0-75380
$ 420,000.00
Mrs. Elisabeth Beck
Institute of Psychiatry
London, England
Contract #263-78-0-0049
$ 24,500.00
55 - LCNSS/IRP
CO
o
5
-<
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Molecular Biology
National Institute of Neurological and Communicative Disorders
and Stroke
Table of Contents
RESEARCH SUMMARY
PROJECT REPORTS
Control Mechanisms and Differentiation
Z01 NS 01244-18 LMB
k
Control of Meiosis and Morphogenesis
Z01 NS 01886-12 LMB 5
Development and Teratology in Rodent Embryo Culture
Z01 NS 02364-04 LMB ^
Intercellular Communications and Transmembrane Signals
Z01 NS 02365-04 LMB 7
The Role of Methylation and Differentiation
Z01 NS 02527-01 LMB ^
i - LMB/IRP TAB 10
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Molecular Biology
National Institutes of Neurological and Communicative
Disorders and Stroke
Ernst Freese, Chief
The Laboratory has unraveled the physiological processes controlling the
initiation of differentiation (sporulation) in bacteria and of meiosis and the
resulting sporulation in yeast. Use of these organisms has the advantage that
their genetic and biochemical properties are most thoroughly known among all
differentiating organisms. The Laboratory has also used this knowledge to
isolate and characterize the gene for a developmental enzyme. Studies in
mammalian cells and mouse embryos have revealed the appearance of
developmental proteins and the role of insulin in the coupling of an
extracellular receptor to the intracellular messenger.
1 . Molecules controlling bacterial differentiation (sporulation).
Differentiation of microbes and embryonic cells is generally initiated by
nutritional deprivation. In Bacillus subtilis, the Laboratory has
demonstrated that massive differentiation (sporulation) is observed only when
the concentration of guanosine triphosphate (GTP) decreases below a critical
value. This can be achieved by partial nutritional deprivation or by the
"stringent response" which results from partial amino acid deprivation and is
accompanied by the increase of ppGpp. More specifically, it can be produced
by inhibitors of guanosine monophosphate (GMP) synthesis, or by the
deprivation of GMP in guanine auxotrophs. In contrast to the normal stringent
strains, relaxed (rel) mutants did not sporulate as a result of partial amino
acid deprivation. Certain antibiotics (e.g. chloramphenicol, fusidate,
kasugamycin, etc.) also prevented the sporulation resulting from the stringent
response when they were used at concentrations at which they did not
significantly inhibit growth. In all these cases, sporulation was restored
when GMP synthesis was directly inhibited, e.g., by the addition of
decoyinine. The effect of GTP deprivation on various cellular processes was
compared with the effect of partial UTP deprivation, which does not initiate
sporulation. Both deprivation conditions caused a drastic decrease in the
synthesis of rRNA and tRNA and an increase (derepression) in the synthesis of
some nucleotide degrading enzymes, but they had only a small effect on the
synthesis of mRNA. Specific effects were observed for changes in membrane
transport, the uptake of uracil being specifically decreased by GTP
deprivation and that of adenine and guanine specifically decreased under
conditions of stringent response (increase of ppGpp) . Although GTP is not
used for the synthesis of a cell wall precursor, its decrease caused a
decrease in wall synthesis. As wall synthesis and cell septation, which is
important for cell division as well as sporulation, seem to depend on the
opening of crosslinks in the cell wall and may in turn be correlated with wall
turnover, the latter, which can be easily quantitated, was studied. Wall
turnover is usually assumed to depend on known autolytic enzymes. But it was
found that different mutants, deficient in known autolytic enzymes, exhibited
the same rate of turnover as the standard strain. Therefore, some unknown
enzyme seems to control wall turnover and may be important for wall synthesis.
1 - LMB/IRP
Interestingly, all conditions reducing the rate of cell expansion, including
those causing sporulation, decreased the rate of turnover, as if turnover
depends on the physical separation of mucopeptides from other molecules that
inhibit their hydrolysis.
In addition to the massive sporulation resulting from GTP deprivation,
certain mutations or amino acid analogs (e.g., ethionine) greatly increased
the frequency at which cells continually switch from cell division to spore
development. In some mutants this continual sporulation resulted from a
slightly reduced activity of pyruvate carboxylase which, by reducing the
concentration of aspartate, caused a slight stringent response throughout
growth. Such results demonstrate that minor alterations in the function of an
enzyme, which cannot be detected by changes in cellular growth properties, can
have major repercussions for differentiation. Introduction of a relaxed (rel)
mutation prevented the increased sporulation. Ethionine addition or secondary
mutations resistant to ethionine produced a high frequency of continual
sporulation even in rel strains. Because the resistant mutants contained only
2% of the normal S-adenosylmethionine synthetase, a partial deficiency of
S-adenosylmethionine apparently causes an increase in the frequency at which
cells continually enter sporulation. It is worth noting that a deficiency of
DNA methylation has been shown to increase the frequency of differentiation in
eukaryotic cells.
2. Cloning of the gene for glucose dehydrogenase. Although many proteins
participate in development, for only a few of them is an enzymatic property
known. Of particular interest is glucose dehydrogenase because this enzyme is
synthesized exclusively in the forespore cell compartment, which is surrounded
by two membranes having opposite polarity. As it is not known how the
synthesis of any developmental enzyme is controlled, the Laboratory has made
specific antibodies against glucose dehydrogenase and used them to isolate
clones of DNA containing the gene for glucose dehydrogenase. Surprisingly,
the gene, which is not expressed in growing B. subtilis cells, produced highly
active glucose dehydrogenase in Escherichia coli. By using a plasmid which
did not contain any promoter in the neighborhood of the single EcoRI
restriction site into which the glucose dehydrogenase fragment was inserted,
it was further shown that the isolated DNA fragment of B. subtilis contained
its own promoter. This will now make it possible to determine whether the
expression of this gene in vegetative B. subtilis cells is prevented by a
specific repressor, whether a unique promoter enables transcription only by a
changed RNA polymerase (e.g., production of a new sigma factor), or whether
some other mechanism, e.g., at the translational level, is involved. Studies
determining the genetic location of the gene and the role of this enzyme in
sporulation or germination are also under way.
3. Mechanisms controlling meiosis and yeast sporulation. The eukaryote
Saccharomyces cerevisiae is known to undergo meiosis before the four haploid
nuclei develop into spores. Because 10 cells per ml enter this
differentiation process almost synchronously, yeast provides an ideal system
to study meiosis and its abnormalities which in humans lead to defects (e.g.,
Down's Syndrome). Whereas it was previously thought that yeast would enter
meiosis and sporulation only under conditions of nitrogen starvation and the
presence of acetate, the Laboratory has shown that partial deprivation of
carbon, nitrogen, phosphate, or sulfur can initiate the process. To narrow
2 - LMB/IRP
down further the suppressor compound, inhibitors and mutants were used.
Although most inhibitors cannot enter the highly protected yeast wall,
hadacidin, an aspartate analog and ribovirin, an inhibitor of GMP synthesis,
inhibited growth and induced sporulation. Also in mutants deficient in the
synthesis of guanine and uracil nucleotides sporulation usually occurred when
either of these nucleotides was partially deficient. Analysis of nucleotide
pools by high pressure chromatography showed that the concentration of GTP or
UTP, respectively, decreased when the corresponding base was missing. A
further analysis of the sulfur-containing S-adenosylmethionine will be
necessary before firm conclusions about the molecule controlling meiosis can
be drawn. Because a detailed analysis of numerous HPLC peaks was needed, a
system was developed to measure the whole spectrum of each eluate every 2.5
seconds, to store the information in a computer, and to determine the
absorption maximum of each compound. This provided a novel way to identify
compounds eluting from a column.
H. Characterization of developmental proteins. During the sequential
development from a growing differentiated cell or from a fertilized egg into a
whole organism, many developmental proteins are sequentially synthesized, and
some of them are later destroyed again. The two-dimensional electrophoresis
of proteins combined with radioautography or silver staining, makes it
possible to follow the appearance and disappearance of all but minor proteins.
To identify specific proteins appearing during development, C-methylated or
P-phosphorylated proteins, enzymes to which iodinated antibodies bind, and
proteins made radioactive by photoactivated covalent linkage of a radioactive
ligand were identified. In addition, proteins with high affinity to GTP were
isolated by affinity chromatography and then separated by two-dimensional
electrophoresis. Numerous differences between normal cells and sporulation
mutants were observed in B_^ subtilis. The same technique was also used for
individual mouse embryos making it possible to identify the time of
development at which certain proteins appear. Individual enzymes and receptor
proteins are now being identified.
5. Control of the synthesis of neuro-receptor proteins. Earlier
experiments performed in this Laboratory using HeLa cell lines had shown that
short-chain fatty acids, in particular butyrate, caused an increase in the
number/cell of beta-adrenergic receptors and of the proteins coupling them to
AMP-cyclase. It has now been shown that these receptor proteins and the
proteins coupling them to the cyclase also increase greatly when cells are
transferred from a serum-containing medium to one containing basal nutrients
and certain hormones. This phenomenon results in part from the absence of
catecholamines and in part from the presence of epidermal growth factor. When
the HeLa (ES-1) cells were grown in the basal medium supplemented only with
epidermal growth factor and hydrocortisone but no insulin, many
beta-adrenergic receptors were produced but they were not coupled to adenylate
cyclase. Thus insulin is essential for this coupling. Further experiments
investigated whether the increase in receptor proteins resulted from an
increase in receptor synthesis or a decrease in degradation. For example,
tunicamycin, an inhibitor of protein glycosylation, caused an increase in the
number of receptor proteins per cell because it prevented their degradation.
LMB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space}
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02365-04 LMB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Intercellular Communications and Transmembrane Signals
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. C. Henneberry
OTHERS: P. Lysko
R. Elliott
Chief, MNS
Senior Staff Fellow
Visiting Fellow
LMB NINCDS
LMB NINCDS
LMB NINCDS
COOPERATING UNITS (if any)
Developmental and Metabolic Neurology Branch, NINCDS
lab/branch
Laboratory of Molecular Biology
SECTION
Molecular Neurobiology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
2.5
1.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The major goal of this project is to understand the biochemical events
involved in the response of individual cells to external signals. We have
previously shown that several types of hormone/neurotransmitter receptors
increase in several cell lines when the cells are grown in the presence of
certain short-chain fatty acids. This ability to modulate receptor expression
has permitted us to analyze the biochemical events in adenylate cyclase
activation by extracellular signals. In FY 82 we have concentrated on
adapting several human cell lines to growth in serum-free media and examined
the effects on receptor number and function. Our aim is to study the
interactions of several hormones acting simultaneously on the same cell under
well-defined conditions not possible with serum present. Elimination of serum
causes a striking increase in beta-adrenergic receptor number partly
explainable by release from down-regulation due to catecholamines in serum;
however, we have also found important roles for other media components in the
regulation of receptor number and function.
k - LMB/IRP
' PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01886-12 LMB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Control of Meiosis and Morphogenesis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. B. Freese
OTHERS: Z. Olempska-Beer
A. Hartig
Biologist
Visiting Associate
Visiting Fellow
LMB NINCDS
LMB NINCDS
LMB NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Molecular Biology
SECTION
Developmental Biology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.5
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Meiosis and sporulation of the yeast Saccharomyces cerevisiae can be initiated
by partial deprivation of carbon, nitrogen, phosphorus, or sulphur sources.
It can also be induced by the deprivation of guanine or, less efficiently,
uracil nucleotides. It can be prevented by the addition of methionine plus
adenine or by S-adenosyl-methionine (SAM) . The results suggest that meiosis
may be controlled by some methylation reaction.
LMB/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02527-01 LMB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Role of Methylation and Differentiation
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. Freese
OTHERS: K. Ochi
H. Nakashita
Chief LMB NINCDS
Visiting Associate LMB NINCDS
Visiting Fellow LMB NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Molecular Biology
SECTION
Developmental Biology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.0
OTHER:
1.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
Q (al) MINORS D (^2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Sporulation of B. subtilis could be induced by the stringent response to
partial amino acid deprivation; relaxed (rel) mutants could not be induced.
The induction was prevented by certain antibiotics when they were added at
concentrations at which they had almost no effect on growth. Mutants (spd)
were isolated which sporulated continually in a medium (with excess glucose)
in which normal B. subtilis strains do not sporulate. Some of them were
partially deficient in amino acid synthesis, and the introduction of a (rel)
mutation prevented this effect. Other spd mutants sporulated continually when
in a rel background; they had 50% less than the normal S-adenosyl-methionine
(SAM) synthetase activity. Addition of partially inhibitory concentrations
of ethionine or seleno-methionine to a rel mutant induced sporulation, and
ethionine resistant mutants deficient in SAM synthetase sporulated during
growth at increased frequency. Apparently, reduced methylation of some cell
component increases the frequency of spontaneous sporulation.
6 - LMB/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01244-18 LMB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Control Mechanisms and Differentiation
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. Freese
OTHERS: H. Cheung
B. Uratani
N. Vasantha
L. Vitkovic
Chief
Visiting Fellow
Visiting Associate
Visiting Associate
Senior Staff Fellow
LMB NINCDS
LMB NINCDS
LMB NINCDS
LMB NINCDS
LMB NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Molecular Biology
SECTION
Developmental Biology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
5.5
PROFESSIONAL:
4.0
OTHER:
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Various parameters related to the onset of bacterial differentiation
(sporulation) were investigated. It was found that guanine nucleotide
deprivation, responsible for the initiation of sporulation, caused a drastic
decrease in the synthesis of rRNA and tRNA but only a small decrease in the
synthesis of mRNA. Cell wall synthesis and cell wall turnover were also
reduced. The latter decreased under any conditions decreasing the expansion
of the cell. The decrease of GTP also caused a decrease in uracil uptake,
whereas the stringent response (increase of ppGpp) to amino acid deprivation
caused a decrease of purine uptake. The gene of glucose dehydrogenase, and
enzjnne made only in the forespore compartment, was isolated by cloning in
lambda charon phage. The insertion piece also contained a promoter that
allowed production of high amounts of glucose dehydrogenase in E. coli. A
bypass of fructose bisphosphatase was discovered and mutants (gene symbol bfd)
deficient in it were isolated. Strains can grow on gluconeogenic carbon
sources if either the fdp or the bfd gene is functional.
7 - LMB/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02364-04 LMB
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development and Teratology in Rodent Embryo Culture
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. C. Henneberry
OTHERS: A. Bruckner
P. Grojec
Chief, MNS
NIH Expert
Visiting Fellow
LMB NINCDS
LMB NINCDS
LMB NINCDS
COOPERATING UNITS (if any)
Office of Biometry and Field Studies, NINCDS
lab/branch
Laboratory of Molecular Biology
SECTION
Developmental Biology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.8
PROFESSIONAL:
2.3
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
1 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The major goals of this project are (1) to adapt newly developed methods of
embryo culture for teratogenicity studies; (2) to determine the teratogenic
potential of certain lipophilic drugs selected on the basis of their strong
growth inhibition of cultured mamanalian cells; and (3) to evaluate the utility
of the embryo culture system for basic studies in developmental biology. In
FY 82 we completed a study showing that the anticonvulsants valproic acid and
diphenylhydantoin cause developmental defects in a dose-dependent manner,
independent of maternal metabolism. We also adapted two-dimensional
electrophoretic techniques and improved silver-staining methods for
computer-assisted analysis of embryo proteins. The proteins from a single
10-day mouse embryo can be analyzed by this approach, permitting studies on
the appearance of certain identifiable proteins during early stages of
development.
8 - LMB/IRP
PHS-6040
(Rev. 2-81)
>
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o
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o
>
ANNUAL REPORT
October I, 1981 through September 30, 1982
Laboratory of Molecular Genetics
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-2
CONTRACT NARRATIVE
Large Scale Preparation of VSV and its DI Particles NOl-NS-12353 3
PROJECT REPORTS
Regulation of Viral Nucleic Acid Synthesis in Animal Cells
ZOl NS 02026-10 LMG ^
Regulation of Myelin Synthesis
ZOl NS 02528-01 LMG 5
LMG/IRP TAB 11
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Molecular Genetics
National Institute of Neurological and Communicative
Disorders and Stroke
Robert A. Lazzarini, Chief
The Laboratory of Molecular Genetics was officially established on January 30,
1981. Thus far, the major efforts of the Laboratory have been administrative, largely
directed toward recruiting personnel, acquiring designated space, and ordering
equipment. During its first year, however, the Laboratory has had a quantum growth
jump: the section on Electron Microscopy, IDB, NINCDS was transferred to the
Laboratory of Molecular Genetics and established as a new section. Consequently, the
Laboratory now has three sections: the Molecular Virology Section, the Recombinant
Genetics Section, and the Neural and Molecular Ultrastructure Section (formerly the
section on Electron Microscopy, IDB).
The research programs of all three sections have been integrated, and a number of
new program initiatives are now under way. Substantial advances have been made in
each of the sections' programs. Summarized below are the advances made in the
Recombinant Genetics Section and the Molecular Virology Section. The activities of the
Neural and Molecular Ultrastructure Section will be reported this year as part of the IDB
Annual Report.
The Recombinant Genetics Section has defined its first major research program:
the study of myelin formation and its regulation. This is an umbrella program that
covers both the molecular and cellular aspects of the developmental program which
culminates in myelin sheath formation. The Recombinant Genetics Section will
contribute principally the molecular studies, while the Neural and Molecular
Ultrastructure Section will contribute studies at the cellular level. Four proteins of a
peripheral and central nervous system have been targeted for initial study— the myelin
basic protein, P2, Po and proteolipid. The first phase of the molecular level studies is
the cloning of the genes coding for these proteins. To this end, we have obtained the
necessary human perinatal brain tissue, prepared cDNA libraries from brain mRNA's, and
we are presently searching among the five hundred library clones to identify those which
contain the genes for myelin basic protein. We have tentatively identified several such
clones and are characterizing them extensively to establish whether they contain the
desired genes.
The Molecular Virology Section has successfully assembled a clone for the vesicular
stomatitis virus gene coding for the nucleocapsid protein. This done has been shown to
be functional when appropriately positioned in expression vectors. Using an SVfO vector,
we have obtained quantities of a protein whose synthesis is directed by the recombinant
gene. This protein appears in every way to be identical to that formed during a virus
infection. We have also obtained expression of the cloned gene in the prokaryotic cell,
E. coll. Currently, this protein produced by the recombinant gene is being employed in
studies of viral assembly— the formation of a viral nucleocapsid structure from purely
recombinant genetic elements. If successful, these studies will open the way to the
production of hybrid viruses which will have numerous clinical, as well as basic
applications.
1-LMG/IRP
The Molecular Virology Section has also employed recombinant DNA techniques to
study the structure of viral chromosomes. By preparing DNA copies of RNA virus
chromosomes, we have been able to study the structure (sequence) of the viral nucleic
acid. During the last year, we have employed these techniques to establish that a
defective interfering particle of VSV is a "Simple Deletion" mutant and to precisely
establish the sequences around the deletion point. These sequences were crucial in ruling
out certain models for the formation of DI particles and for establishing the
reasonableness of a generalized model proposed by us.
2 - LMG/IRP
CONTRACT NARRATIVE
Laboratory of Molecular Genetics
Fiscal Year 1982
UNIVERSITY OF VIRGINIA (NOl-NS-12353)
Title: Large Scale Preparation of VSV DI Particles, and E. coli Plasmid DNA Containing
VSV Sequences.
Contractor's Project Director; Dr. Jay C. Brown
Current Annual Level: $81,900
Objectives: To establish conditions for the growth and purification of VSV defective
particles which will reproducibly yield materials of the requisite purity and activity, to
devise procedures for the purification of plasmid DNA's that contain VSV sequences, and
to supply such materials to the Laboratory of Molecular Genetics, IRP/NINCDS.
Major Findings:
a) Conditions and procedures have been devised for the purification of the virus
particles and plasmids. Materials prepared by this new scheme meet the specifications
set forth in the contract.
b) The contractor has delivered to the Laboratory of Molecular Genetics,
IRP/NINCDS, the amounts of purified VSV DI particles and plasmid DNA stipulated in
the contract.
c) The contractor has established procedures for the preparation of plasmid DNA
from E, coli and has supplied the materials designated on the contract.
Significance to the NINCDS Program and Biomedical Research: The procedures and
materials developed under this contract are immediately used by the Molecular Genetics
Laboratory. This contract, therefore, forms an integral part of the Laboratory's
research program, namely, the regulation of viral nucleic acid synthesis in animal cells.
This contract has supplied the Program with the raw materials for RNA sequencing of
the viral genomes. These studies have characterized sites on the chromosomes that are
important for autointerference, DI particle genesis, and the replication of the viral
genome.
3 - LMG/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02026-10 WG
PERIOD COVERED
October 1, 1981 throijgh September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regulation of Viral Nucleic Acid Synthesis in Animal Cells
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. A. Lazzarini Chief, Lab. of Molecular Genetics IMS NINCDS
OTHER: M. Schubert
J. Condra
Y. Murooka
F. Yang
B. Gitomer
S. Yamaguchi
J. Sprague
H. Arriheiter
G. Harmison
Staff Fellow
Staff Fellow
Visiting Scientist
Visiting Fellow
Visiting Fellow
Psychologist
Chemist
Guest Worker
Chemist
LMG NINCDS
IM; NINCDS
mC NINCDS
IiyC NINCDS
LMG NINCDS
WG NINCDS
IMS NINCDS
IMS NINCDS
IM; NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Molecular Genetics
SECTION
Molecular Virology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
7.5
PROFESSIONAL:
6.0
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The long range objective of this project is the description of the conponent
molecular events involved in the replication of the negative strand viruses
(niyxo, paramjTxo, rhabdo, arena and bunya viruses). The topics that are
currently being investigated are:
1. The origin of DI particles.
2. Nucleocapsid assembly.
4 - IMG/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02528-01 IM;
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regulation of Myelin Synthesis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. A. Lazzarini Chief, Lab. of Molecular Genetics LM3 NINCDS
OTHER:
N. Zeller
H. Amheiter
S. Yamaguchi
J. Sprague
Staff Fellow
Guest Worker
Psychologist
Chemist
WG NINCDS
IM; NINCDS
IMS NINCDS
IMG NINCDS
COOPERATING UNITS (if any)
Department of Biology, University of Maryland
lab/branch
Laboratory of Molecular Genetics
SECTION
Reconibinant Genetics Section
INSTITUTE AND LOCATION
NINCDS, NIH, BethescJa, MD 20205
TOTAL MANYEARS:
3
PROFESSIONAL:
2.5
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS ^ {b) HUMAN TISSUES
n (c) NEITHER
D (al) MINORS D (a2) INTERVI
EWS
SUMMARY OF WORK (200 words or less - underline keywords)
Four proteins of a peripheral and central nervous system have been targeted for
study—the myelin basic" protein, V^, Pq and proteolipid. The first phase of the
ix)lecular level studies is the cloning of the genes coding for these proteins.
To this end, we have obtained the necessary human perinatal brain tissue, pre-
pared cDNA libraries from brain iriRNA's, and we are presently searching among
the five hutidred library clones in order to identi^ those which contain the
genes for rnyelin basic protein. We have tentatively identified several such
clones and are characterizing them extensively to establish v^iether they con-
tain the desired genes.
5 -LMS/IRP
PHS-6040
(Rev. 2-81)
>
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neural Control, Intramural Research Program
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-6
PROJECT REPORTS
Motor Control Systems in the Spinal Cord 7
ZOl NS 01686-14 LNLC
Techniques for Making Connections with the Nervous and 8
Musculoskeletal Systems
ZOl NS 01687-14 LNLC
Cortical Mechanisms of Voluntary Motor Control 9
ZOl NS 01688-14 LNLC
Models of Neural Interactions 10
ZOl NS 02079-09 LNLC
Neuron Activity During Locomotion 11
ZOl NS 02080-09 LNLC
Intrinsic Properties of Motor Units 12
ZOl NS 02160-08 LNLC
i - LNLC/IRP TAB 12
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neural Control, Intramural Research Program
National Institute of Neurological and Communicative Disorders and Stroke
Robert E. Burke, M.D., Chief
Introduction
Research work in the Laboratory of Neural Control (LNLC) is devoted largely
to studies of the central and peripheral neural mechanisms involved in the
control of movement in mammals, emphasizing neural organizations at the level of
the spinal cord and those regions of the brain stem and cerebral cortex that
project directly to the spinal cord.
Present Organization
During FY 1982, the staff of the Laboratory of Neural Control (LNLC) has
consisted of up to 10 investigators (four permanent senior scientists and six
post-doctoral fellows). The permanent staff also includes three senior support
personnel (two engineers and one physiologist), a biological technician, and the
laboratory secretary. Non-permanent, part-time staff includes one Laboratory
Aide and a student computer programmer. Because of the close interaction and
collaboration among the Laboratory staff, LNLC has not been divided into formal
Sections. The research effort can be described under four general headings,
divided roughly by methodological approach:
1. Electrophysiological and morphological analysis of the cellular
physiology and neuronal circuitry operating in the control of movement at the
spinal cord level, largely using acute, reduced preparations (both cats and
monkeys).
2. Projects that utilize novel methods for recording the activity of
individual neural elements, activity patterns in whole muscles, and
kinesiological data in awake, intact animals (both cat and monkey) that are
comfortable and performing normal motor behaviors.
3. Theoretical and computer modeling studies of information processing in
neural networks, or of the properties of complex elements such as muscle
spindles.
4. Activities concerned directly with the development of new instruments
and techniques, and the further refinement of existing methods, for recording
and analyzing neural ly-relevant data from intact, freely moving animals.
Project Summaries:
Systematic study of the output elements of the motor system, the motor
units, is included in a project entitled "Intrinsic Properties of Motor Units".
This continued in FY 1982 primarily with studies of the detailed morphology of
type-identified a-motoneurons, labeled by intracellular injection of horseradish
peroxidase (HRP). This involves reconstruction of entire motoneurons from
serial sections, with measurement of the legnths, diameters, and branching
patterns of their dendrites. Initial evidence provides for the first time
direct evidence that the membrane area of a-motoneurons varies with motor unit
type: FF motoneurons statistically have the largest total areas, type S the
smallest, and type FR are intermediate in size. Preliminary data also suggests
1 - LNLC/IRP
that the specific membrane resistivity of type S motoneurons is likely to be
two- to three-fold greater than that of type FR or FF cells. These findings
have important implications for resolution of controversies about the mechanisms
by which motor unit recruitment is controlled. We are currently comparing
detailed reconstructions of motoneurons with data about their electrophysio-
logical input resistance, membrane time constant, and dendritic electrotonic
length. Using the anatomical data, we can then construct realistic computer
compartmental models to constrain possible ranges of variation in specific
membrane properties in different cell types.
Work on the "Motor Control Systems in the Spinal Cord" is closely related to
the above and includes several aspects. The first has been a continuation of
studies, begun about 5 years ago, of the detailed anatomy of the intraspinal
trajectory of group la muscle stretch receptor (group la) afferents, and of the
contacts they establish on defined types of a-motoneurons. This work depends on
intracellular injection of HRP into functionally identified afferents and,
subsequently, into type-identified motoneurons. Over 20 functionally identified
afferent-motoneuron pairs ("contact systems") have now been fully reconstructed
at the light microscope level. These show synaptic boutons arranged in a
variety of configurations, from quite localized to very dispersed. Measurements
of the postsynaptic motoneuron dendrites have permitted estimation of the
electrotonic distance between individual boutons in a given system and the
motoneuron soma. Depending on the choice of postsynaptic membrane character-
istics, boutons from a single la afferent to a given motoneuron may occur at any
electrotonic distance, up to maximum values (2-4 length constants), and the
contacts can be dispersed over 1 to 1.5 length constants. Such electrotonic
dispersion appears to be the rule rather than the exception. This finding
represents a considerable departure from expectations based on earlier electro-
physiological evidence from this and other laboratories around the world. The
number of boutons in a given contact system is variable, ranging from 4 to 35
for homonymous systems (i.e., afferents that project to motoneurons of the same
muscle), and 3 to 5 for heteronymous (synergist) contact systems.
A related subproject concerns the interaction of post-tetanic potentiation
(PTP) with primary afferent depolarization (PAD) in group la afferents in the
cat spinal cord. PTP is produced by prolonged, high frequency tetanization of
the la afferents in a muscle nerve (e.g., medial gastrocnemius), while PAD is
generated by short volleys delivered to group I afferents in certain other
muscle nerves, such as those from the hamstring muscles. PTP and PAD are the
two main mechanisms by which synaptic transmission can be modulated presyn-
aptically, but there has been surprisingly little study of their interaction.
We have found that tetanization of a group of la afferents markedly increases
PAD, as measured by micropipette recordings within individual group la afferent
axons, and by measures of afferent excitability to direct electrical stimulation
within the ventral spinal gray matter. At the same time, presynaptic inhibition
of group la excitatory postsynaptic potentials (EPSPs) is markedly enhanced in
the wake of a conditioning tetanus to the la afferents. The evidence available
from these experiments is necessarily indirect but it is consistent with the
view that PAD is generated by a postsynaptic conductance change in afferent
terminal arborizations produced by axo-axonic synapses. However, the shape of
phasic PAD potentials recorded intra-axonally, and the time course of changes in
PAD shape after a conditioning tetanus to la fibers, suggest that the
presynaptic transmitter produces complex changes in the membrane conductance of
group la synaptic terminals which cannot be entirely accounted for with
conventional models.
2 - LNLC/IRP
A final aspect of this project has been continued investigation of the
organization of synaptic input systems that project to motoneurons of the flexor
digitorum longus (FDL) and flexor hallucis longus (FHL) muscles. As reported
previously, these anatomical synergists actually exhibit quite disparate
functional activity patterns in intact cats. Intracellular recording and
electrical stimulation of a wide variety of peripheral nerves suggest that some
polysynaptic systems can make quite different patterns of connection with FDL
and FHL motoneurons but the differences in these peripheral inputs seem
insufficient to account for the marked functional disparity. Therefore, we have
examined the behavior of FDL and FHL motor pools during fictive locomotion in
decerebrate cats that are paralyzed and immobile. In this preparation, all
phasic sensory input is abolished but the functional activity patterns of FDL
and FHL are exactly the same as found in the intact cat. Thus, the functional
disparity between these motor pools must result from highly specific synaptic
inputs from the "central locomotor pattern generator" that is known to exist in
the spinal segments, and which can operate to produce locomotor rhythms without
any phasic sensory feedback. This observation opens the way for a continued
exploration for interneuronal systems that must separately drive the two motor
pools, which will continue in FY 1983.
The project entitled "Neuron Activity in Locomotion" is designed to test
ideas about motor control that derive from more conventional, neurological ly
reduced preparations. The work has depended on the development of new methods
and techniques that permit recording the activity of individual neural elements
in freely moving cats, along with the force and length of individual muscles or
muscle groups, and the movements of the entire animal. Chronically implanted
electrodes and transducer devices have been developed to permit recording
temporally correlated, multi-channel data streams. The systems available in
LNLC at present permit relatively reliable chronic recording from individual,
functionally-identified sensory afferent neurons and a-motoneuron axons, as well
as mass activity from peripheral nerves and muscles, in freely-moving, intact
cats during normal motor behaviors.
During FY 1982, considerable progress was made in elucidating the action of
Y-motoneurons in modulating muscle spindle stretch receptor sensitivity during
normal movement. A key development was a new nerve cuff electrode combined with
a microcatheter, through which dilute solutions of local anesthetic can be
injected. The anesthetic, in proper doses, can produce relatively selective
blockade of the fine y-motor axons, leading to functional spindle
de-efferentation during the course of a movement behavior like locomotion and
permitting inferences about fusimotor control in the intact animal. This work
has revealed clear evidence of bursts of y-motoneuron action that are phased
with the step cycle. It is also possible to compare the movement behavior of
individual spindles with their responses to standardized tests in the
anesthetized animal. The results have led to data which will serve as the basis
for a computer model of spindle behavior (see below) that is fully testable in
the intact animal - something that has never before been possible.
Chronic microelectrode implant methods also permit recording the firing
patterns of individual a-motoneuron axons in the spinal ventral roots during
normal motor behaviors. The bursts observed during normal locomotion exhibit
few "doublets", in contrast to observations in decerebrate or fictive stepping.
Moreover, motoneurons show a much wider range of firing frequency modulation
than anticipated on the basis of previous indirect evidence. The frequency
envelope of burst firing by single motoneurons recorded during normal stepping
shows, in many cases, a close similarity to the whole muscle EMG. Such cases
3 - LNLC/IRP
suggest that the EMG signal can be used to represent the excitatory driving
function to the motoneuron pool. This notion has been tested experimentally by
injecting rectified and filtered versions of EMG records into motoneurons via
intracellular pipettes, which produces firing patterns \/ery similar to those
observed for units recorded during the same step cycles.
The representation of motor pool drive by the EMG signal is, however,
tempered by our recent observations that some muscles with complex morphology
may in fact contain more than one functional pool of motor units. The sartorius
muscle of the cat, for example, gives evidence of containing at least two, and
very likely three, distinct populations of motor units, each of which is active
in only one phase of the step cycle. The whole muscle EMG exhibits multiple
bursts but each of these bursts is apparently composed of different sets of
motor units. This surprising finding represents a variation on the theme
already described with the FDL-FHL muscle pair - i.e., groups of motor units
arranged in parallel (in this case, within the same muscle) but performing
different functions. These observations suggest that the CNS must deal with the
control of populations of motor units comprising "task groups" which are not
necessarily organized according to muscle anatomy. Thus, it appears likely that
the notions of "synergists", antagonists", and even of "muscles" as discrete
entities, that have been developed on the basis of gross anatomy may well not
always reflect the actual patterns of functional organization.
Over the past year or two, the above project has become more and more
closely linked with that devoted to "Models of Neural Interactions". Much of
the current work in the latter project is devoted to development of strategies
and methods for handling the multichannel data streams that emerge from chronic
recording experiments. This effort has taken two forms, one primarily concerned
with data reduction techniques, and the other with the development of
computer-based models that emerge from experimental data but which serve as
conceptual frameworks for understanding and describing experimental results,
rather than as data reduction tools. Considerable progress has been made in the
development of computer programs to permit reduction and display of complex data
from locomotion experiments, particularly in applications in which stimulus
timing must be integrated with phase information about step cycles that are
nearly, but not exactly, equal in duration.
With respect to the development of conceptual models, several aspects
deserve mention. First, experimental data about the behavior of muscle spindle
stretch receptors studied in intact cats, with and without y-triotoneuron drive
(described above), have permitted formulation of a computer model of spindle
function that results in predictions that can be tested in intact animals. The
behavior of a given muscle spindle, already recorded during normal movements,
can be tested with controlled limb manipulations with a torque motor device
under deep anesthesia (to eliminate fusimotor effects) to permit quantitative
inferences to be made about fusimotor effects. Second, the wealth of
experimental data already at hand about the length and force trajectories of a
variety of cat hindlimb muscles (reported in previous Annual Reports), plus the
growing evidence for the existence of "task-groups" of motor unit pools (see
above), has stimulated the initial development of a computer model of the cat
hindlimb, which will include a framework based on the static anatomy of the
bones, joints, muscles, and moments of inertia of the hindlimb. Upon this we
can superimpose dynamic conditions of movement, constrained by experimental data
about joint angles, limb trajectories, limb loading, and the activities of
individual muscles as signalled by EMG recordings and implanted tendon force
transducers. Such a model will be of enormous potential utility in defining
4 - LNLC/IRP
members of task-groups, in understanding their patterns of activity during
stereotyped and non-stereotyped movements, and in making sense of the complex
activity patterns observed for stretch and force receptor afferents that emerge
from task-group members. Finally, a collaborative project with the University
of California, San Francisco, on a new model of auditory signal processing and
pitch perception was completed in FY 1982. This model suggests that recognition
of mid-range frequencies may be accomplished by precise timing comparisons made
by neurons in the medial superior olivary nucleus.
Work on "Cortical Mechanisms of Voluntary Motor Control" has, during FY
1982, continued to concentrate on activity patterns, recorded during voluntary
movement in awake monkeys, of neurons in regions of the arm and hand area of the
cerebral cortex that have relatively direct pathways to the spinal cord and
brain stem (the sensorimotor cortex and supplementary motor area). Of
particular interest is the influence of sensory input in modulating cortical
cell activity. Current studies have focussed on the effect of brief passive
shortening of tonically active muscles. Such perturbations most often result in
silencing cortical units that are tonically active during maintained contraction
of the shortened muscle, a result that is consistent with the currently
controversial notion of "long-loop" cortical reflexes. LNLC has recently
received several monkeys with unilateral or bilateral forelimb deafferentation.
These animals are being trained to perform arm and hand tasks similar to those
used with intact monkeys. Although it is more difficult for deafferented
animals to learn the precise movements necessary, preliminary indications
suggest that they will acquire the requisite facility. When the animals are
fully trained, the behavior of cortical units will be tested and compared with
results from comparable samples of units from normal animals, in order to infer
the role of sensory information in the control of cortical cell action.
Definition of "comparable samples" is a difficult problem in such research but
will include criteria such as anatomical location, presence or absence of
pyramidal tract axons, location in regions in which intracortical
microstimulation produces localized muscle activation, and definition of
monosynaptic projection to particular muscles by spike-triggered averaging, all
of which have been used in the normal monkeys.
A subproject of considerable interest is built on evidence reported
previously that the flexor carpi ulnaris (FCU) muscle of the monkey forearm has
a complex internal architecture with very different muscle fiber populations on
either side of the central tendon. Studies are underway of the possibility that
the two halves of FCU represent another example of two motor unit task-groups
that have different functions but reside within a single muscle. Attempts to
determine whether the two halves of FCU are innervated by anatomically distinct
populations of motoneurons (i.e., spinal cord motor nuclei) have led to
investigation of novel double-labeling methods using retrograde transport of
exogeneous substances, primarily combining horseradish peroxidase and wheat germ
agglutinin.
Work done under the project entitled "Techniques for Making Contact with the
Nervous System" largely results from requirements generated by other projects in
LNLC, although some input is received from outside groups in terms of questions
or specific fabrication needs. A number of new observations described above
directly result from these efforts (e.g., the combined catheter - nerve
electrode cuff for chronic implantation). Evaluation of a miniature Ta-TaOs
capacitor stimulating electrode, suitable for chronic implantation in the cortex
or in deeper structures, has continued during FY 1982, in collaboration with
members of the Neural Prosthesis Program of NINCDS. This electrode design,
5 - LNLC/IRP
first developed some years ago in LNLC, has theoretical advantages for neural
prosthesis applications and it has undergone substantial improvement in terms of
miniaturization, due to technical advances in fabrication. During FY 1982,
additional developments have included: 1.) a new treadmill system for the
locomotion experiments, especially designed to minimize electrical and auditory
interference and to improve speed and stability of belt movement; 2.) a
behavioral training apparatus for cats designed to permit isometric force tasks
for hind- or forelimb; 3.) improvements to the percutaneous connector and cable
system that permits leadoff of up to 40 simultaneous data channels from freely
moving cats; 4.) an interface system between the widely used Nicolet signal-
averaging devices and the PDP series of laboratory computers; 5.) devices that
facilitate anatomical reconstruction of neurons from serial microscope sections;
and 6.) a series of modular electronic devices required for signal processing in
several LNLC projects. All of these items are designed within LNLC and most are
also fabricated in-house. The staff members involved also continue to consult
with other laboratories within NIH and in other institutions around the world.
6 - LNLC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01686-14 LNLC
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Motor Control Systems in the Spinal Cord
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Robert E. Burke, M.D.
Other: James W. Fleshman, Ph.D.
Loyd L. Glenn, Ph.D.
Aharon Lev Tov, Ph.D.
Chief
Staff Fellow
Guest Worker
Visiting Fellow
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neural Control
SECTION
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
2.0
PROFESSIONAL:
1.5
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is designed to provide information on the mechanisms operating
within reflex systems in the spinal cord, which include alpha motoneurons as
the output link, as well as on the interconnections and interactions between
reflex pathways and control systems descending to the spinal cord from
supraspinal centers. Particular consideration is also given to correlations
between synaptic organization, intrinsic neuronal properties, and dynamic
behavior of the alpha motoneurons and the motor unit type, defined by the
physiological characteristics of the innervated muscle fibers.
7 - LNLC/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01687-14 LNLC
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Techniques for Making Connections with the Nervous and Musculoskeletal
Systems
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Martin J. Bak
Other: George M. Dold
Joaquin A. Hoffer, Ph.D.
Gerald E. Loeb, M.D.
William B. Marks, Ph.D.
Edvjard M. Schmidt, Ph.D.
Electronics Engineer
Engineering Technician
Senior Staff Fellow
Medical Officer (Res.)
Research Physiologist
Research Physiologist
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
LNLC NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neural Control
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
0.4
OTHER:
1.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is intended to develop techniques for the acquisition and
processing of neuroelectric signals from the central and peripheral nervous
system in acute and chronic neurophysiological preparations. Because of this
laboratory's continuing interest in sensorimotor neural activity during
unrestrained movements, the project also includes development of chronically
implantable mechanical transducers, catheters, and connectors.
8 - LNLC/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZUl NS 01b88-14 LNLC
PERIOD COVERED
October 1, 1981 to September 1982
TITLE OF PROJECT (80 characters or less)
Cortical Mechanisms of Voluntary Motor Control
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Edward M. Schmidt, Ph.D.
Other: Martin J. Bak
George M. Dold
Lloyd Glenn, Ph.D.
Michael E. Gordon
Frederick T. Hambrecht, M.D.
Joan S. Mcintosh
Biological Engineer
LNLC
NINCDS
Electronics Engineer
LNLC
NINCDS
Engineering Technician
LNLC
NINCDS
Guest Worker
LNLC
NINCDS
Engineering Technician
LNLC
NINCDS
Head, Neuroprosthesis
FNP
NINCDS
Program
Physiologist
LNLC
NINCDS
COOPERATING UNITS (if any)
Fundamental Neurosciences Program, NINCDS
lab/branch
Laboratory of Neural Control
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
0.9
1.6
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is designed to investigate the size and spatial distribution
of cortical "colonies" that are associated with individual muscles or closely
related groups of muscles, as well as the activity of neurons in such
colonies in the motor cortex during defined voluntary motor behaviors.
Intracortical microstimulation (ICMS) is used to map regions that produce
excitation or inhibition of particular muscles or muscle groups, and the
resultant cortical maps are compared with these for synergist or antagonist
muscle groups. Cortical cell discharge patterns during normal movements are
evaluated with respect to the excitation or inhibition of muscle activity
that is produced by ICMS. Intracortical capacitor stimulating electrodes are
being evaluated for efficacy, stability and safety for chronic implantation.
9 - LNLC/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZUl NS 02U79-09 LNLC
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Models of Neural Interactions
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: William B. Marks, Ph.D.
Other: Joaquin A. Hoffer, Ph.D.
Gerald E. Loeb, M.D.
Naotoshi Sugano, Ph.D.
Research Physiologist LNLC NINCDS
Senior Staff Fellow LNLC NINCDS
Medical Officer (Research) LNLC NINCDS
Visiting Fellow LNLC NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neural Control
SECTION
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1.9
PROFESSIONAL:
1.
OTHER:
0.1
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is concerned with the detection of patterns of simultaneous
activity among groups of neurons and muscles, with describing these patterns
mathematically, and with the underlying principles of neural organization that
these patterns may exemplify.
10 - LNLC/IRP
PHS-6040
(Rev. 2-81)
ENCE INFORMATION EXCHANGE
PROJECT nUmBER (Do NOT use this space)
PERIOD COVERED
October 1, 1981 to September 30, 1982
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02080-09 LNLC
TITLE OF PROJECT (80 characters or less)
Neuron Activity During Locomotion
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Gerald E. Loeb, M.D.
Medical Officer, Research
LNLC NINCDS
Others:
Martin J. Bak
Electronics Engineer
LNLC NINCDS
Robert E. Burke, M.D.
Chief
LNLC NINCDS
Joaquin A. Hoffer, Ph.D.
Senior Staff Fellov/
LNLC NINCDS
William B. Marks, Ph.D.
Research Physiologist
LNLC NINCDS
Andrew Rindos
Guest Worker
LNLC NINCDS
Naotoshi Sugano, Ph.D.
Visiting Fellow
LNLC NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neural Control
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.6
PROFESSIONAL:
2.0
1.6
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(3 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A variety of new techniques are being used to monitor the afferent and efferent
neural activity in the spinal cord of intact cats during normal and perturbed
locomotion. Flexible wire electrodes in the lumbar dorsal root ganglia (DR6)
and ventral roots record stable, identifiable unit activity which is correlated
with kinesiological data including, of muscle force, length, and EM6 activity
from chronically implanted gauges developed for this project. Neurons are
characterized by conduction velocity, anatomical origin, and modality using
spike-triggered averaging of EMG signals and neurograms obtained from specially
designed nerve cuff electrodes implanted around peripheral nerves. The reflex
effects of various electrical stimuli to motor and cutaneous nerves are
systematically examined as they vary through the step cycle. The normal
functional use of the various hindlimb muscles is being surveyed during a
variety of normal behaviors in an attempt to correlate these patterns with
their anatomical specializations regarding muscle fiber type, orientation, and
proprioceptive feedback.
11- LNLC/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAW SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02160-08 LNLC
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Intrinsic Properties of Motor Units
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. E. Burke, M.D.
Others: James W. Fleshman, Ph.D.
G. F. Gauthier, Ph.D.
Loyd L. Glenn, Ph.D.
Aharon Lev-Tov, Ph.D.
John P. Miller, Ph.D.
W. Rail, Ph.D.
Chief
LNLC
NINCDS
Staff Fellow
LNLC
NINCDS
U. of Massachusetts Med.
Sch.
Guest Worker
LNLC
NINCDS
Visiting Fellow
LNLC
NINCDS
Guest Worker
MRB
NIADDK
Staff Scientist
MRB
NIADDK
COOPERATING UNITS (if any)
University of Massachusetts Medical School
Mathematics Research Branch, NIADDK
Worcester, Massachusetts
lab/branch
Laboratory of Neural Control
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 2020b
TOTAL MANYEARS:
2.7
PROFESSIONAL:
2.2
0.5
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is designed to provide information on the ranges and
distributions of the electrophysiological and morphological characteristics
of alpha motoneurons and of the interrelated mechanical, histochemical and
morphological properties of the muscle fibers innervated by them (i.e., the
muscle unit) in various hindlimb muscles in the cat. In some experiments,
motor unit populations in normal animals are compared with those in animals
after various conditioning treatments.
12 - LNLC/IRP
PHS-6040
(Rev. 2-81)
tt
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ANNUAL REPORT
October 1, 1981 to September 30, 1982
Laboratory of Neurochemistry
National Institute of Neurological and Conimunicative Disorders
and Stroke
Table of Contents
RESEARCH SUMMARIES
Section on Cellular Neurochemistry 1-3
Sec ton on Neurochemical Pharmacology 3-4
Section on Neuronal Development and Regeneration 4-5
Section on Enzyme Chemistry 5-9
PROJECT REPORTS
Enzymological Aspects of Neural Functions 10
ZOl NS 00813-21 LNC
Trophic Function of Neurons 11
ZOl NS 01586-15 LNC
Regulation of Metabolism in Glioma and Neuroblastoma Cell 12
Lines
ZOl NS 02006-10 LNC
Cerebral Metabolism in Altered Metabolic States of the 13
CNS
ZOl NS 02142-08 LNC
The Use of Neurological Grafts to Repair the Injured Peri- 14
pheral or Central Nervous System
ZOl NS 02254-06 LNC
Metabolic Profiles in Normal and Diseased Retina 15
ZOl NS 02256-06 LNC
Metabolic Correlates of Neuronal Transmission in the 16
Hippocampal Slice
ZOl NS 02455-02 LNC
Neuropharmacology of Cerebral Metabolism 17
ZOl NS 02257-06 LNC
Coordinate Effects of Amphetamine on Brain Energy 18
Metabolism and Protein Synthesis
ZOl NS 02429-03 LNC
Aspects of Calcium Metabolism in Electric Tissue 19
ZOl NS 02430-03 LNC
1 - LNC/IRP TAB 13
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neurochemi s tr y , Intramural Research
National Institute of Neurological and Communicative
Disorders and Stroke
Janet V. Passonneau, Chief
The Laboratory of Neur ochemi s t r y is composed of four
sections, the Section on Cellular Neurochemi s try , the Section on
Neurochemical Pharmacology, the Section on Enzymes, and the
Section on Neuronal Development and Regeneration. These
sections are engaged in a variety of projects which are related
to the functions of the central nervous system.
Section on Cellular Neurochemi s try
The Section on Cellular Neur ochemi s try has three projects
currently in progress.
a. Metabolic Profiles in Normal and Diseased Retina.
The study of metabolites linked to the production and
consumption of energy-rich stores in the retina is in progress.
Variable periods of dark-adaptation, and exposure to high
intensity (250 foot candles) or dim light (2.5 foot candles) have
been used to evaluate the effects on metabolism. Of particular
interest are changes in cyclic GMP concentrations in the
individual layers of the retina, since the concentrations of this
compound vary dramatically in light and dark, and among layers of
the retina.
Studies are also in progress to ascertain whether high- or
low- intensity light is required to effect responses of the
cyclic nucleotide system. By using filters, light of selected
wave lengths is being tested in an attempt to determine whether
rod and/or cone pigments are involved in the transduction
phenomenon .
A collaborative effort with the Eye Institute has been a
study of granular dystrophy of the cornea. The disease is a
dominant autosoma 1 -linked lesion which results in opaque granular
aggregates in the stroma and can lead to impairment of vision.
These studies have identified a high molecular weight protein
which is unique to the diseased cornea. Another protein which
resembles normal keratin accumulates in abnormally high amounts
in the pathological state.
b. Coordinate Effects of Amphetamine on Brain Energy
Metabolism and Protein Synthesis.
The effects of amphetamine on the body temperature of mice
has been shown to be dependent on the ambient temperature. At
temperatures greater than 20°C, the body temperature of the test
animal is elevated by the drug, while at ambient temperatures
1 - LNC/IRP
below 15°C, the body temperature is decreased. At intermediate
temperatures the response varies with individual animals.
Amphetamine has been found to inhibit brain protein synthesis and
also to decrease the concentration of brain energy reserves,
including glycogen, and high energy phosphates.
A method of assessing i_n vivo brain protein synthesis by
amino acid incorporation i_n vitro has been developed. Glycogen,
glucose, phos phocr eat ine and adenine and guanine nucleotides are
measured by emzymatic techniques.
It has been possible to evaluate the effecs of
amphetamines on brain protein synthesis and metabolic events.
During drug-induced hyperthermia, brain protein synthesis is
markedly inhibited, and the inhibition is tightly correlated to
the body temperature of the animal. The inhibitory effect is
seen at 40°-41°C. Hyperthermia of a similar magnitude induced
in mice by extreme elevation of ambient temperature has a
comparable effect on brain protein synthesis.
The induction of hyperthermia by either amphetamine or
elevated ambient temperatures, results in decreases in brain
energy reserves. These changes, unlike protein synthesis, have
proven to be not so closely coupled to the individual ody
temperatures .
c. Metabolic Correlates of Neuronal Transmission in the
Hippocampal Slice.
Studies have been made to evaluate the hippocampal slice
preparation from guinea pig brain as a model for
electrophysiological and metabolic occurrences in vivo. The
thickness of the hippocampal slice and the preparative procedures
have been studied in detail. The physiological state of the
slice was evaluated by the analysis of energy metabolites, and of
the evoked orthodromic response in the dentate gyrus.
Energy metabolites decrease from in vivo concentrations
during slice preparation, but recover to a new steady-state level
within an hour of incubation in the perfusion chamber. The
concentration of the compounds studied (adenylates,
phosphocreat ine , cyclic nucleotides, and lactate) remain stable
for at least eight hours. The thickness of the slice had little
or no effect in metabolite profiles from 0.5 to 1 mm. Thicker
slices appeared to be energetically depressed. The method of
preparation in which temperature, oxygen, and glucose were varied
prior to incubation appeared to have little effect on metabolic
recovery. However, the evoked response was compromised if the
preparative medium were devoid of oxygen and glucose.
The relationship of increased energy stores to synaptic
transmission was evaluated. The concentration of phos phocr eat ine
in the slices was increased by incubation with varying
concentrations of creatine in the medium. In such slices,
2 - LNC/IRP
synaptic transmission during anoxia was prolonged, compared to
preparations without creatine.
Cyc loc r ea t ine in the incubation medium presumably
increases cyc locr eat ine phosphate in the slices. After
incubation with cyc locr eaine , synaptic transmission was prolonged
during anoxia but to a lesser degree than with creatine. The
effect was diminished after longer periods of incubation (5
hours). In addition, incubation with cyc locrea t ine elicited
sei zure s -like discharges in the hippocampal slice.
S ection on Neurochemical Pharmacology
a . I schemi a
The search for a biochemical basis for the loss of brain
function following an ischemic episode continues utilizing
several in vivo as well as in vitro models of ischemia. Previous
studies on the neurochemical events that occur during
recirculation have shown that both cyclic nucleotide and energy
metabolism are perturbed. In addition, the degree of abnormality
increases with increasing periods of ischemia.
Of particular interest was the large postischemic rise in
cyclic AMP. Previously, this pathophysiological response was
duplicated in brain slices by the addition of oxygen and glucose
to a medium devoid of the materials. Of the agents tested, only
adenosine, nor ephinephr ine , histamine and certain prostaglandins
stimulated the accumulation of cyclic AMP in the gerbil brain.
Attempts to block the postischemic rise in cyclic AMP with the
appropriate antagonists to these agents were unsuccessful. Even
the deprivation of the divalent cations, magnesium and calcium,
had little effect on the response.
A recent observation that the CA 1 neurons of the
hippocampus died 4 days after 5 min of bilateral ischemia
provides a useful model for the neurochemist to investigate the
selecive vulnerability of certain neurons. Certain metabolites
have been measured in the CA 1 and CA 3 regions of the
hippocampus and in the cerebral cortex from 1.5 to 96 hours after
5 min of bilateral ischemia. There were many delayed changes in
the levels of glucose, glycogen, glutamate and GABA up to 2 days
following 5 min of bilateral ischemia, but the alterations were
uniform in all regions examined. The metabolite profile in the
CA 1 regions at 4 days of recirculation was substantially
different from both control values and those seen in the other
two regions. This undoubtedly reflects the infiltration of glia
into the CA 1 region. The depression of cyclic AMP and elevation
of cyclic GMP at 6 hours of recirculation may indicate a critical
period in the selective loss of the CA 1 neurons.
b. Motor neurons diseases.
3 - LNC/IRP
Mice were infected with ADR virus and various metabolites
were examined in the cerebellum, cerebral cortex and spinal cord
of affected (paralyzed) and unaffected mice. While the changes
were relatively minor in the cerebellum and cerebral cortex,
there were marked differences in the spinal cord. When the
differences in the cyclic nucleotides, glycogen, ATP and
P-creatine were examined in 3 regions of the spinal cord, the
changes were most dramatic in the anterior horn. To determine
if these derangements result from the paralysis, these
metabolites are currently being measured prior to the onset of
paralysis .
c. Experimental seizures.
The relationship of the energy status of the tissue to
neural function is being examined in the hippocampal slice.
Various neurological disorders including seizures and ischemia
deplete the tissue of its energy stores and thereby lead to a
dysfunction of the nervous system. Utilizing compounds such as
creatine and eye locreat ine which should increase the endogenous
energy stores, the failure of synaptic transmission to an anoxic
episode is substantially delayed.
Section on Neuronal Development and Regeneration
The Section on Neuronal Development and Regeneration is
continuing its investigation of the various factors involved in
the use of a nerve graft to aid in the repair of injured nerve
tissue. Another area of research seeks to determine how neurons
exert their trophic influence on end-organs.
A. Nerve Allograft Studies
It has long been recognized that transplantation antigens
on the cells of a nerve allograft evoke an immune reaction from
the host and that this response inhibits host nerve fiber growth
through the graft especially if it is longer than 2 cm. Previous
work in this section has shown that the immunosuppressive agent
cyclosporin A (CyA) prevents allograft rejection with the result
that host axons can now regenerate through 4-6 cm of nerve.
Current studies with CyA indicate that host axons which
regenerate through a long nerve allograft are functional in that
they can reinnervate denervated muscles. It has also been found
that the dose of CyA can be reduced from a potentially toxic dose
of 15 mg/kg to 5 mg/kg. This should permit long-term studies
with CyA since late side effects of the drug are as yet unknown.
CyA also prevents the rejection of nerve allografts in sensitized
recipients, but it is ineffective in preserving nerve xenografts
(grafts between different species like guinea pig to rat).
Muscle as well as neuronal allografts survive during CyA
treatment, but when CyA is abruptly stopped rejection eventually
ensues. It is anticipated that work with CyA will continue
particularly along avenues which might reduce allograft
4 - LNC/IRP
antigenicity and promote the induction of immunological
tolerance .
B.
Th
denervat i
lingual e
do cumen t e
known tha
buds , i t
which is
neur o t oxi
rats, the
with this
many B-ty
taste bud
find ing s
for indue
Neurotrophic Studies
e ob
on a
pith
d ex
t th
is n
r esp
c to
dev
age
pe s
s an
hows
ing
s ervat
nd r ea
e li a 1
amp les
e s ens
o t kno
ons ib 1
the B
e lopme
nt . I
ensor y
d thei
that
and ma
ion that
ppear ( vi
cells) af
of tr oph
ory neuro
wn whethe
e for thi
-type neu
nt of tas
t was obs
neurons
r innerva
the A-typ
intaining
taste
a the
t er r
ic ne
n med
r it
s act
r ons
te bu
erved
d i s ap
t i on
e neu
the
buds disappear after
differentiation of ordinary
einnervation is one of the best
rve function. Although it is
iates the trophic effect on
is the A or B type of neuron
ion. Since capsaicin is
after injection into newborn
ds was followed after treatment
that after capsaicin treatment,
peared from sensory ganglia but
developed normally. This
rons are the ones responsible
buds.
In another study, motor axons were made to reinnervate
denervated tongue tissue in an attempt to find out why these
axons fail to cause taste bud formation. It was observed that
despite their presence in the connective tissue, no motor axons
penetrated into the epithelium where the induction of buds must
occur. Further studies are needed to determine what property of
sensory neurons permit these, but not other types of axons, to
enter and remain in gustatory epithelium.
Section on Enzyme Chemistry
I. General program
The overall objective of the section is to investigate
enzymology of particular relevance to neural function. The
principal area of study is the mechanism of active transport for
sodium and potassium ions. Related projects are directed at
elucidation of possible mechanisms for regulating sodium
transport and studies of analogous systems for calcium ion
transport. Each of these is discussed below.
II. Studies on the mechanism of the sodium transport system
A. Background
Nerve cells function to receive signals, to transmit
signals between points in the nervous system, and to modify these
signals in the process of transmitting them to other cells. All
of these processes require energy derived from cell metabolism.
The basic link between cell metabolism and these various neural
processes is the concentration gradient of sodium ions across the
outer cell membrane (plasma membrane). Both the electrical
activity and the specific neurochemical transmission of signals
5 - LNC/IRP
utilize this store of potential energy. The Na"*" gradient is
generated by a process of Na"*" extrusion that uses metabolic
energy .
The principal
cells is one driven
This process is medi
integral component o
cells. Work from th
that metabolic energ
its direct phosphory
a series of structur
changes constitute t
cell in exchange for
laboratory has inclu
sodium-dependent pho
and Knoval, 1963), d
transformation of th
phosphorylation (Fah
the low-energy natur
ouabain (Albers, Kov
independent existenc
on the Na,K-ATPase (
recently we have eng
pr es t eady-s tat e kine
(Froehlich et al , 19
These studies have b
the earlier evidence
phosphorylation and
elucidations of the
by the potent inhibi
B. Current studies
mode of sodium ion extrusion from animal
by the free energy of hydrolysis of ATP.
ated by a protein, Na,K-ATPase, which is an
f the outer membrane of virtually all animal
is and other laboratories has established
y is transferred to the membrane protein by
lation by ATP. This phosphorylation induces
al changes in the ATPase protein and these
he process that extrudes sodium ions from the
potassium ions. Previous work from this
ded the initial demonstation of the
sphorylation of the Na,K-ATPase (Fahn, Albers
emonstration of the conformational
e Ka,K-ATPase consequent to its
n, Albers and Koval , 1966), demonstration of
e of the enzyme acy Iphospha t e complexed with
al and Siegel, 1972), the simultaneous and
e of sodium and potassium ion binding sites
Albers, Koval and Swann , 1975). More
aged in a series of studies of the
tics of the enzyme phosphorylation reactions
76, 1979, Hobbs et al , 1980 and in press),
een concerned with confirming more directly
for conformation changes accompanying
ligand binding. Recent results have included
mechanisms of inhibition of the Na,K-ATPase
tors, vanadate and oligomycin B.
Recent transient kinetics studies in collaboration with
Froehlich (NIA) have been designed to establish the sequence of
binding of cations to the pump protein in the different phases of
the pump cycle. Current experiments suggest the existence of a
tightly bound Mg"*""*" at one stage of the reaction. Other
experiments indicate a step in which Na"*" and K"*" may
simultaneously bind in confirmation of deductions from earlier
steady-state experiments.
III. Studies on regulatory mechanisms for the sodium pump.
A. Background
Although the primary function of the sodium pump in
neurons is undoubtedly that of generating the ionic gradients
which produce the resting cell membrane potential and drive
various Na"*" dependent transport systems for neurotransmitters and
nutrients, several hypotheses have been advanced for more
specialized functions of the sodium pump. With respect to neural
function, an interesting hypothesis arises from the observation
6 - LNC/IRP
that a membrane hyperpo lar i zat ion resulting from pump activity
can occur. This electrogenic sodium pumping is a natural
consequence of the observed s to ichiome try of 3 Na"*" ions moved
outward to only 2 K"*" moved inward per pump cycle. It remains to
be established whether this hyperpo lar i zat ion is under the sort
of regulatory control that would make it an important factor in
such processes as synaptic excitability. Other hypotheses
suggest that the s t oichiome t ry of Na"*" pumping relative to ATP
hydrolysis may be under some type of regulatory control, thus
producing a pump of varying efficiency.
These various theories postulate the existence of
ancillary regulatory process: endogenous regulatory substances,
modification by protein pho s phokinas es , etc. There are, in fact,
recent reports of the isolation of endogenous factors from brain
with ouabain-like inhibitory activity. Papers continue to be
published claiming significant modification of Na,K-ATPase
activity by neurotransmitters.
It now seems well established that there are two variants
of Na,K-ATPase in brain tissue, one of which appears to be
specific to neurons. A report has recently appeared suggesting
that the relative amounts of these two ATPase "isozymes" might be
influenced by the catecholamine levels in brain.
B. Current studies
We have confirmed the existence of two forms of
Na,K-ATPase in rat brain. We have been unsuccessful in obtaining
evidence of an influence of catecholamine levels on the relative
amounts of these forms. We plan to explore other possible
physiological roles for these two forms in brain.
B
ec aus e the
isozymes are dis
tinguished p
basis of
differential sensitivities
to cardioac
inhibition, we are
engaged in a detailed study
of this
type of in
hibition. This s
tudy has so
important results.
We have develop
ed a rapid k
determining the re
lative amounts of
the two enz
samp le .
Second ly ,
we have observed
condi t ions
binding
kinetics o
f cardioactive steroid inhibi
order wi
th respect
to the inhibitor
concentrati
extend in
g these ob
servations in the
expectation
ins ight s
into the
mechanism of inhi
bit ion . Our
hypothesis is tha
there are two parallel pathwa
cardioactive steroid binding with d
if f er ent bin
We have
evidence f
or the formation
of an ini t i a
complex
that does
not produce inhib
it ion .
r imar i ly on the
t ive steroid
of the mechanism
far produced two
inetic method for
ymes in a given
in which the
tion are not first
on . We are
of ob t aining
current
ys for
ding affinities.
1 drug- en zyme
IV. Structural studies of the purified Na,K-ATPase
A. Background
LNC/IRP
The
Na,K-ATP
as e consis t s o
and be ta ,
that are
thought
to exi
the abs 0 lu
te s toich
iome try
within
Both subunits are o
f high
mo le cu 1
pr e 1 iminar
y efforts
at de t erminin
made in a
few laboratories
, progr
to be s low
Because these
large
lipid matrix, there
are on
ly a f e
ob t aining
crystalline memb
rane pr
ob t aining
detai led
thr ee-d
imens i o
the sodium
pump seems small at pr
reported a
method f
or obtaining t
purified N
a,K-ATPase which
may b e
studies .
f two types of subu
St in 1:1 proportio
cell membranes is
ar weight and, alth
g primary structure
ess in this directi
protein structures
w successful instan
oteins. Thus, the
nal structural info
esent. One laborat
wo-dimens i ona 1 arra
useful for electro
nits, alpha
ns a 1 though
unknown .
ough some
have been
on is likely
exist in a
c es of
1 i ke 1 ihood of
rmation about
ory has
ys of
n diffract ion
Because of the fundamental importance of this system and
the number of basic questions about its function that could be
answered by structural information, some alternative approach
would be valuable. Complex proteins are considered to have
evolved from simpler structures with conservation of structural
domains that have analogous functions in different proteins. For
example, nucleotide binding sites are known to have common
structures in a variety of different dehydrogenases. One might
envision approaching the structure of a complex protein by
delineating each functional domain as a separate entity.
One difficulty with this approach is that much of the
important structure is dependent upon precise folding and
apposition of primary chains so that functionally competent
structures may not be expected to survive procedures that
fragment the protein, although occasional successes have occurred
For example, it has been possible to isolate a functionally
competent ATPase fragment of the myosin molecule.
We have previously attempted to isolate a fragment of the
Na,K-ATPase that might retain ionophoric activity with respect to
sodium ions (Shamoo et al, 1973 and later). The limited success
of this attempt led to analogous experimentation with the
Ca-ATPase of muscle sarcoplasmic reticulum and in this case, a
fragment with divalent cation-specific ionophoric activity could
be isolated.
B. Current studies
From earlier work with antibodies to the individual
subunits of Na,K-ATPase (Jean et al, 1974 and later), we were
able to demonstrate an antibody that blocked binding of the
specific Na,K-ATPase inhibitor, ouabain, to the enzyme. This
observation suggests that antibodies may be useful in defining
structural domains of large enzymes. We are now in the process
of developing monoclonal antibodies to the Na,K-ATPase. This is
presently an informal collaboration among several laboratories.
Upon developing a series of monoclonal antibodies to different
8 - LNC/IRP
sites on the same protein, we expect to use these as reagents to
identify functional domains in the intact enzyme and to identify
corresponding fragments in proteolytic digests. Thus, these
antibodies will be useful both in defining function and in
aligning fragments to associate structure and function.
Definition of small fragments associated with particular
functions should provide a more manageable alternative to the
direct approach of correlating function with primary amino acid
sequence of the whole protein.
So far, our role in this collaboration has been to supply
purified enzyme for use as antigen and to assist in the
development of suitable screening procedures.
Several Na , K-ATPas e -pos i t ive clones have been detected
among a series of hybridomas developed against rat brain synaptic
membranes by A. de Bias (SUNY, Stony Brook).
V. Calcium metabolism in electric tissue.
A. Background
Calcium ions are known to be involved in important neural
functions, in particular in the release of neurotransmitters.
Intracellular levels of calcium are regulated primarily by an
ATP-dependen t pump analogous to the Na,K-ATPase and by a N a ■*■ ' C a '*"'"
exchange mechanism. Most intracellular functions of calcium are
thought to be mediated by a regulatory protein, calmodulin.
E lee tr ophorus electric organ is a cho linergical ly innervated
tissue that provides an opportunity to study the mechanism of
calcium regulation in excitable tissues. It is known to have a
high concentration of calmodulin.
B
Current studies
A Ca'''"*'-dependent ATPase found in E lee tr ophorus electric
organ membranes has been characterized. It is found to share
several characteristics with other plasma membrane Ca''"'"-ATPas es
which are though to be Ca"*""*" pumps. However, this enzyme activity
is not stimulated by exogenous calmodulin.
Calmodulin from electric organ has been purified and its
further characterization is underway.
These two projects will be terminated because of the
departure of the responsible investigators.
9 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00813-21 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Enzymological Aspects of Neural Functions
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: R. Wayne Albers
Other: Ann S. Hobbs
Head, Sec. on Enzyme Chemistry
Staff Fellow, Enzyme Chemistry
LNC, IRP, NINCDS
LNC, IRP, NINCDS
COOPERATING UNITS (if any)
Jeffrey P. Froehlich (NIA), Gerontology Research Center, Baltimore, MD
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Enzyme Chemistry
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.1
PROFESSIONAL:
1.9
OTHER:
1.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
t] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project is an investigation into the mechanism and structure of the enzyme,
Na,K-ATPase, that catalyzes the ATP-dependent extrusion of sodium ions from
neurons and other cells. Studies are proceeding along the following lines:
(a) measurements of the transient [pi^e-steady state) kinetics of the phosphoryl-
ation and dephosphorylation reactions of the Na,K-ATPase; (b) experiments de-
signed to define the relation of structure to function of different domains of
the Na,K-ATPase molecule; (c) steady-state kinetic and ligand-binding studies
directed toward elucidation of the mechanism of energy transfer from ATP
hydrolysis to the ionophoric process.
PHS-6040
(Rev. 2-81)
10 - LNC/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01586-15 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Trophic Function of Neurons
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: A. A. Zalewski, Head, Section on Neuronal Development
and Regeneration
Other: A.K. Gulati, Visiting Fellow
LNC NINCDS
LNC NINCDS
COOPERATING UNITS (if any)
T.H. Oh, Department of Anatomy, University of Maryland
Laboratory of Neurochemi stry
SECTION
Neuronal Development and Regeneration
INSTITUTE AND LOCATION
NINCDS, NIH. Bethesda, Maryland 20205
TOTAL MANYEARS:
0.4
PROFESSIONAL:
0.2
0.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) SenSOry ganglia COntain tWO popula-
tions of neurons which can be identified by their size, organelle content,
degree of myelination, or histochemical profile. Since the chemical capsaicin
(the hot ingredient of red peppers) is neurotoxic to one of the groups of
sensory neurons when injected into newborn rats, we used this drug to determine
which type of neuron is responsible for causing taste bud development. Cap-
saicin treatment destroyed many of the B-type sensory neurons, but this loss did
not interfere with the temporal pattern of development, number, or degree of
innervation of the buds. It can, therefore, be concluded that the A-type
sensory cells are the gustotrophic neurons. In another study, denervated
tongue tissue was reinnervated by hypoglossal motor fibers in order to help re-
solve why these axons cannot induce taste buds. Although regenerated motor
fibers were observed in the connective tissue of the tongue, none of these
axons penetrated the epithelium where the buds are normally found. Since axons
must enter the epithelium to induce buds, this result suggests that certain
sensory, but not motor, axons are endowed with some unique property which
permits them to enter and remain within appropriate epithelium.
PHS-6040
(Rev. 2-81)
11 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02006-10 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regulation of Metabolism in Glioma and Neuroblastoma Cell Lines
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Janet V. Passonneau Chief, LNC LNC NINCDS
Other: Craig J. Cummins Staff Fellow LNC NINCDS
W. David Lust Head, Sec. Neurochem. Pharm. LNC NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neurochemistry
Section on Cellular Neurochemistry
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0
PROFESSIONAL:
0
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
3 (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been terminated.
PHS-6040
(Rev. 2-81)
12 - LNC/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02142-08 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cerebral Metabolism in Altered Metabolic States of the CNS
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: W. David Lust
Other: Janet V. Passonneau
Hajime Arai
Alexander Wheaton
Gretchen K. Feussner Chemist
Yukisama Yasumoto Visiting Fellow
Head, Sec. Neurochem. Pharm.
Chief, LNC
Visiting Fellow
Biol. Lab. Tech. (Micro)
LNC
NINCDS
LNC
NINCDS
LNC
NINCDS
LNC
NINCDS
LNC
NINCDS
LNC
NINCDS
COOPERATING UNITS (if any)
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Neurochemical Pharmacology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.7
PROFESSIONAL:
1.4
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Studies are being performed on the neurochemical aspects of selective
vulnerability induced by short-term ischemia. The CA 1 neurons of the
hippocampus have been shown to disappear by 96 hours after 5 minutes of
bilateral ischemia in the gerbil brain. This observation provides a model
for the examination of the neurochemical events which lead up to the selec-
tive loss of neurons. Metabolites were measured in the CA 1 and CA 3 of
the hippocampus and in the cerebral cortex. Marked changes in the levels
of glycogen, glucose, GABA and glutamate were evident between 1.5 and 48
hours of recirculation. However, these changes were essentially uniform
in the 3 regions examined. By 96 hours of postischemia, the metabolite
concentrations in the CA 1 regions were substantially different than the
other two regions which could be attributed to the infiltration of glia.
The only differences between the CA 1 region and the other 2 regions were
an elevation of cyclic GMP and a depression of cyclic AMP which occurred
at 6 hours of recirculation. The 6 hour period appears to be critical to
the eventual loss of the CA 1 neurons.
PHS-6040
(Rev. 2-81)
13 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space;
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02254-06 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Use of Neurological Grafts to Repair the Injured Peripheral or Central
Nervous System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: Andrev*; A. Zaiewski, Head, Sec. on Neuronal Development LNC NINCDS
and Regeneration
Other: Adarsh K. Gulati, Visiting Fellow
LNC NINCDS
COOPERATING UNITS (if any)
W. K. Silvers, Department of Human Genetics, University of Pennsylvania
lab/branch
Laboratory of Neurochemistry
section
Neuronal Development and Regeneration
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.6
PROFESSIONAL:
1.8
0.8
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Nerve allografts (grafts between genetically different members of the same
species) are rejected by normal rats but not by rats that have been treated
with the immunosuppressive agent cyclosporin A (CyA). Further studies have
shown that host axons can regenerate through allografts in CyA-treated hosts
and that these axons will reinnervate denervated muscles. CyA also prevents
the rejection of ner\/e allografts in allogeneically sensitized recipients, but
the drug is ineffective in preserving xenografts (grafts between different
species; e.g., guinea pig and rat). Immunosuppressive treatment with CyA had
to be continuous because if therapy is stopped, rejection occurs even when only
minor histoincompatibilities exist. Allogeneic muscle and neurons also sur-
vive during CyA treatment; in the case of muscle, it becomes reinnervated by
host axons while transplanted neurons can regenerate their axons and induce
taste buds in tongue tissue.
PHS-6040
(Rev. 2-81)
14 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02256-06 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Metabolic Profiles in Normal and Diseased Retina
P.L
Other:
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Janet V. Passonneau Chief, LNC & Chief,
Cellular Neurochemistry
Elizabeth K. Barbehenn Expert Consultant
W. David Lust Head, Section on Neuro-
chemical Pharmacology
Deirdre Noelker Biologist, Cellular Neuro
chemistry
LNC, IRP, NINCDS
LNC, IRP, NINCDS
LNC, IRP, NINCDS
LNC, IRP, NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neurochemistry
Section on Cellular Neurochemtstry
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.4
PROFESSIONAL:
1.4
1.0
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Studies are continuing on retinal metabolism employing freeze-dned sections of
frog retina. The concentrations of adenyl nucleotides (ATP, ADP, and AMP) and
P-creatine were measured as a function of dark adaptation or light exposure
using 2 sec or 2 min of bright light (approximately 250 ft candles) as well as
2 hrs of dim light (approximately 2.5 ft candles). For AMP, although each area
sampled gave discrete tightly-bunched sets of numbers, levels even within one
layer could vary up to 2.5 fold. This was not true for the other metabolites
measured. A fluormetric assay for calmodulin was developed utilizing its
ability to stimulate calmodul in-dependent phosphodiesterase. Sensitivity of
the assay ranged from 0.5 to 5 mg. Additional work to further increase the
sensitivity is planned. A project will begin to study the adenyl nucleotides,
P-creatine, and cyclic nucleotide levels in retinal layers of Irish setter dogs.
Levels in normal setters will be compared to levels in dogs with an inherited
rod-cone dysplasia in order to gain some insight into the nature and course of
this degeneration.
PHS-6040
(Rev. 2-81)
15 LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02455-02 LNC
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Metabolic Correlates of Neuronal Transmission in the Hippocampal Slice
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Janet V. Passonneau
Other: Tim S. Whittingham
W. David Lust
Alexander B. Wheaton
Yukisama Yasumoto
Chief, LNC LNC NINCDS
Staff Fellow LNC NINCDS
Head, Sec. Neurochem. Pharm. LNC NINCDS
Biol. Lab. Tech. (Micro) LNC NINCDS
Visiting Fellow LNC NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Cellular Neurochemistry
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
1.1
0.2
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
0 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) , , , ^ ^ . .
The relationship between cellular metabolite levels and neuronal transmission
is being investigated in hippocampal preparations in vitro. The concentrations
of the adenylates, phosphocreatine, creatine, lactate, and the cyclic nucleo-
tides are evaluated for slices during in vitro incubations of up to 8 hr, and
during transient periods of anoxia and ischemia. The magnitude of the evoked
field potential is also recorded. The rate and degree of metabolic recovery
following decapitation appear to be dependent on slice thickness, but not on
the presence of glucose and oxygen during the initial preparation period. In
addition, creatine and cyclocreatine are being tested for their dose and time-
dependent effects on high energy phosphates and duration of transmission during
anoxia. Added creatine results in the elevation of phosphocreatine concentra-
tions, while cyclocreatine presumably causes an accumulation of cyclocreatine
phosphate. ATP levels are unaffected by added creatine, and decreased by
cyclocreatine. Both compounds prolong transmission when present in concentra-
tions from 5 to 25 mM, though cyclocreatine also appears to act as a convulsant.
PHS-6040
(Rev. 2-81)
16 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02257-06 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neuropharmacology of Cerebral Metabolism
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.: W. David Lust
Other: Janet V. Passonneau
Alexander B. Wheaton
Yukimasa Yasumoto
Tim Whittingham
Head, Section on Neurochemical LNC,IRP,NINCDS
Pharmacology
Chief, LNC LNC,IRP,NINCDS
Biol. Lab. Tech. (Micro) LNC,IRP,NINCDS
Visiting Fellow LNC,IRP,NINCDS
Staff Fellow LNC,IRP,NINCDS
COOPERATING UNITS (if any)
Pharmacology Laboratory, Epilepsy Branch, NOP, NINCDS (Bldg. 36)
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Neurochemical Pharmacology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
0.9
OTHER:
0.4
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
j^(c)
SUMMARY OF WORK (200 words or less - underline kevwords)
Studies are being performed on the relationship of the energy status of the
hippocampal slice to synaptic transmission in the region of the dentate gyrus.
Creatine and the cyclic analog, cyclocreatine, were added to the incubation
medium for various periods of time and the concentration of creatine phosphate
and cyclocreatine phosphate were determined. The perforant pathway axons were
stimulated and the activity recorded in the region of the dentate gyrus during
an anoxic insult. In the creatine studies, the loss of signal was delayed
during anoxia which was attributed to a significant increase in the levels of
phosphocreatine. At both 5 and 25 mM cyclocreatine, there was evidence of
seizure discharge under normoxic conditions. In spite of this, the cyclo-
creatine still prolonged neuronal function during the anoxic challenge. Thus,
increasing the pool of energy reserves in the brain may prolong brain function
during a variety of insults.
PHS-6040
(Rev. 2-81)
17 - LNC/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02429-03 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Coordinate Effects of Amphetamine on Brain Energy Metabolism and
Protein Synthesis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P. I.: Janet V. Passonneau Chief, LNC LNC NINCDS
Other: Thaddeus S. Nowak, Jr. Staff Fellow LNC NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Cellular Neurochemistry
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.9
PROFESSIONAL:
0.9
OTHER:
.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Effects of amphetamine on brain protein synthesis and energy metabolism are
investigated in mice under conditions which give rise to changes in body
temperature in response to the drug. Protein synthesis is assayed by an
in vitro amino acid incorporation method developed in the laboratory to replace
polyribosome profiles. Glycogen, glucose, phosphocreatine, and adenine and
guanine nucleotides are measured enzymatically. During a period of drug induced
hyperthermia, the inhibition of brain protein synthesis is tightly correlated
with body temperature, inhibition occurring abruptly between 40 and 41 C.
Brain glycogenolysis induced by the drug is more pronounced at elevated ambient
temperatures, but does not correlate well with temperatures of individual mice.
Through these and other observations, the reduction in brain protein synthesis
by amphetamine can largely be dissociated from its effects on energy metabolism.
Further studies will examine the possible activation of a translational inhibi-
tor in extracts of hyperthermic animals.
PHS-6040
(Rev. 2-81)
18 - LNC/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02430-03 LNC
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Aspects of calcium metabolism in electric tissue
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.r.: R. Wayne Albers Head, Section on Enzyme Chemistry LNC, IRP, NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neurochemistry
SECTION
Section on Enzyme Chemistry
UTE AND LOCATION . , , ^^^
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.5
PROFESSIONAL:
0.1
0.4
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
1^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Regulatory roles of calcium in Electrophorus electric organ are under
investigation. The studies consist of two parts: (1) the isolation and
purification of calmodulin from electric tissue; (2) isolation and charac-
terization of a Ca-ATPase from electric tissue.
PHS-6040
(Rev. 2-81)
19 - LNC/IRP
>
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neuro-otolaryngology
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1
PROJECT REPORTS
Inner Ear Neuronal Mechanisms: A Multidisciplinary
Analysis 2
ZOl NS 02216-07 LNO
Synaptic Transmission and Neuronal Connections
of the Mammalian Cochlear Nucleus 3
ZOl NS 02217-07 LNO
i-LNO/iRP TAB 14
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neuro-otolaryngology, IRP
National Institute of Neurological and
Communicative Disorders and Stroke
Jorgen Fex, M.D., Ph.D., Chief
The Laboratory has continued its multidisciplinary approach with the focus
on the inner ear and cochlear nucleus of mammalian species, of normal animals
as well as of genetically deaf animals. The two Projects of the Laboratory have
been advanced, these being Project Number ZOl NS 02216 07 LNO, Inner Ear Neuronal
Mechanisms: A Multidisciplinary Analysis, respectively Project Number ZOl NS
02217 07 LNO, Synaptic Transmission and Neuronal Connections of the Mammalian
Cochlear Nucleus. In particular, during this fiscal year, the Laboratory contri-
buted with the following new knowledge.
We have extended our previous, published, immunocytochemical studies of the
distribution of opioid peptides in the cochlea and have now findings indicating
there are at least two different substances in the organ of Corti with
enkephalin-like immunoreactivity. To complement these studies we have gone to
other neuronal systems and have described in a published paper the first
findings of enkephalin-like immimoreactive cells and fibers in a mammalian
(guinea pig) retina. As a further complement to serve our ongoing studies of
opioids in the cochlea and elsewhere in the nervous system we use high per-
formance liquid chromatography (HPLC) and radio immuno assay (RIA) as techniques;
a manuscript on HPLC identification of met -enkephalin in the inner ear has been
submitted for publication.
Our immunocytochemical studies of the distribution of the two enzymes,
aspartate aminotransferase and glutaminase, are ongoing and have continued
to provide evidence for the hypothesis that these enzymes may serve as markers
for neurons using the excitatory amino acids, glutamate and aspartate, as neuro-
transmitters. Our findings of the localization of aspartate aminotransferase
in the cochlear nucleus, respectively in photoreceptors of the guinea pig, have
been published, respectively have been submitted for publication. A report on
aspartate aminotransferase in the guinea pig cochlea is in press. A manuscript
on glutaminase as a marker for excitatory amino acid neurons in the auditory
nerve and other regions is in preparation.
Immunocytochemical studies are being carried out on the distribution in the
cochlea of the enzyme choline acetyltransf erase; antisera against this enzyme
have been received as gifts. The studies are expected to provide strong
evidence concerning the cholinergic nature of the medial and the lateral efferent
neurons of the organ of Corti.
We have studied how the apparently initially homogenous population of spiral
ganglion cells of the immature cochlea develops into the two subpopulations of
Type 1 and Type II cells of the adult cochlea; a manuscript is under preparation.
A neuropharmacological study is underway, using microiontophoretic
techniques on synapses of cells of the cochlear nucleus in a brain slice.
1~LN0/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02216 07 LNO
PERIOD COVERED
October 1, 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
Inner Ear Neuronal Mechanisms: A Multidisciplinary Analysis
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
J. Fex
R. A. Altschuler
D, W. Hoffman
A. M. Schwartz
J. L. Mosinger
Chief, LNO
Staff Fellow
Staff Fellow
Staff Fellow
Guest Worker
LNO NINCDS
LNO NINCDS
LNO NINCDS
LNO NINCDS
LNO NINCDS
COOPERATING UNITS (if any)
F. Eckenstein, Max-Planck- Institute fiir Psychiatrie, Abteilung Neurochemie Am
Klopfersptiz, D-8033, Martinsried, Germany
lab/branch
Laboratory of Neuro-otolaryngology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
6.0
PROFESSIONAL:
3.9
OTHER:
2.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The long-range purpose of the project is to study the biochemistry, morphology,
pharmacology and physiology of inner ear neurons and other cells and to describe
the mechanisms of their interactions.
1. Immunocytochemical evidence indicates that at least two opioid peptides
are present in the guinea pig cochlea. One of these is met-enkephalin , as in-
dicated by biochemical studies using high performance liquid chromatography
(HPLC) and radio immuno assay (RIA) . 2. Complementing immunocytochemical
studies have demonstrated the presence of enkephalin-like immunoreactivity in
cells and nerve fibers in the guinea pig retina. 3. The study of the differ-
ential distribution of aspartate aminotransferase and glutaminase-like
immunoreactivity at a high level in spiral ganglion cells in the modiolus and
in nerve fibers and endings in the organ of Corti is ongoing. 4. An immuno-
cytochemical study of the distribution of choline acetyltransferase in the
cochlea has been initiated.
PHS-6040
(Rev. 2-81)
2-LNO/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02217 07 LNO
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Synaptic Transmission and Neuronal Connections of the Mammalian Cochlear Nucleus
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J. Fex
R. A. Altschuler
M. R. Martin
OTHER: J. P. Donoghue
Chief, LNO
Staff Fellow
Senior Staff Fellow
Staff Fellow
LNO NINCDS
LNO NINCDS
LNO NINCDS
LNP NIMH
COOPERATING UNITS (if any) C. W. Cotman, Dept. Psychobiol., Univ. Calif, Irvine, CA
92717; T. Hokfelt, Fogarty Scholar, N.I.H., Dept. Histol. , Karolinska Inst.,
Stockholm, Sweden; N. Curthuys, Dept. Biochem. , Univ. Pittsburgh, Pittsburgh, PA;
R. J. Wenthold, Dept. Neurophysiol. , Univ. Wisconsin, Madison, Wisconsin 53706
lab/branch
Laboratory of Neuro-otolaryngology
SECTION
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
3.6
PROFESSIONAL:
1.7
OTHER:
1.9
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of the project is to study the biochemistry, morphology, pharmaco-
logy and physiology of synaptic transmission and neuronal connection of nerve
cells of the mammalian cochlear nucleus: 1. Complementing previously published
findings on the cytochemically localized aspartate aminotransferase-like immuno-
reactivity we have now found highly concentrated such activity in photoreceptors
of the guinea pig. 2. Synapses between the auditory nerve and cells in the
cochlear nucleus are being studied in vitro, using microiontophoretic techniques
applied to a brain slice preparation.
PHS-6040
(Rev. 2-81)
3-LNO/IRP
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neuropathology and Neuroanatomical Sciences
National Institute of Neurological and Communicative disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-6
PROJECT REPORTS
The Regional Selectivity of Blood-Brain Barrier (BBB) Changes
Induced by Various Epileptogenic Agents and Acute Hypertension
ZOl NS 02456-02 LNNS 7
Regional Cerebral Blood Flow (rCBF) Changes in Variously Induced
Epileptiform Seizures
ZOl NS 02457-02 LNNS 8
Changes in Specific Gravity (SG) of Rabbit Brain Tissue During
Drug-Induced Epileptiform Convulsions
ZOl NS 02458-02 LNNS 9
Changes of Spontaneous Neuronal Activity of Cortical and Hippo-
campal CAl Neurons Following 5 Minute Ischemia in Gerbils
ZOl NS 02545-01 LNNS 10
Behavior of the Blood-Brain Barrier (BBB) and the Regional Cere-
bral Blood Flow (rCBF) in Cerebral Ischemia Produced by Middle
Cerebral Artery (MCA) Occlusion in Cats
ZOl NS 02546-01 LNNS 11
Observations on Behavior of the Blood-Brain Barrier (BBB), Region-
al Cerebral Blood Flow (rCBF) and Glucose Utilization in Gerbils
Subjected to 5 Minutes Bilateral Occlusion of the Common Carotid
Arteries
ZOl NS 02547-01 LNNS 12
Evaluation of Electrical Impedance in the Cerebral Ischemia Pro-
duced by Occlusion of the Middle Cerebral Artery (MCA) in Cats
ZOl NS 02548-01 LNNS 13
Cerebral Capillary Endothelial Cultures: Response to Vasoactive
Substances
ZOl NS 02275-06 LNNS 14
Studies on the Blood-Brain Barrier (BBB) to 5-Hydroxytryptamine and
Norepinephrine Metaboli tes: Cerebral Capillary Endothelial Cul-
ture Metabolism and Synthesis of 5-Hydroxytryptamine
ZOl NS 02324-05 LNNS 15
i - LNNS/IRP TAB 15
Table of Contents (cont'd)
The Study of Monoamines' Uptake and Pinocytotic Activity of Pia
Arachnoid Cultures
ZOl NS 02327-05 LNNS 16
The Therapeutic y-Hydroxybutyrate Effect on Experimental Cerebral
Ischemia in Mongolian Gerbils
ZOl NS 02357-04 LNNS 17
Investigations on Blood-Brain Barrier (BBB) Permeability
ZOl NS 02361-05 LNNS 18
Biochemistry of Brain Ischemia and Ischemic Edema in Mongolian
Gerbils: g-Adrenergic Receptor Studies
ZOl NS 02462-02 LNNS 19
The Effect of Central Nervous Tissue on Cerebral Endothelial
Properties
ZOl NS 02463-02 LNNS 20
Investigation of Extraneuronal Catechol Synthesizing Enzymes in
the Central Nervous System
ZOl NS 02552-01 LNNS 21
Morphological Studies of Myelin Formation, Breakdown and Regen-
eration
ZOl NS 01995-10 LNNS 22
Animal Models of Herpesvirus-Induced Demyeli nation and Relation
to Human Disease
ZOl NS 02549-01 LNNS 23
Biochemical and Immunologic Mechanisms in Viral ly-Induced CNS
Demyeli nation
ZOl NS 02550-01 LNNS 24
Pemieability of Cellular Layers in the Vertebrate Nervous System
ZOl NS 01442-16 LNNS 25
Structural Basis of Synaptic Transmission
ZOl NS 01881-12 LNNS 26
Structure of Neuronal Cytoplasm
ZOl NS 02551-01 LNNS 27
Membrane Structure of Astrocytes
ZOl NS 01805-14 LNNS 28
Regeneration in Peripheral and Central Nerves
ZOl NS 02086-09 LNNS 29
TAB 15 ii - LNNS/IRP
Table of Contents (cont'd)
The Blood-Brain Barrier and Ganglion Implants
ZOl NS 02144-08 LNNS 30
Mechanism of Cerebral Hemorrhages
ZOl NS 02286-06 LNNS 31
Effect of Dimethyl Sulfoxide on the Histochemical Demonstra-
tion of Glycogen in the Perfusion Fixed Brain
ZOl NS 02362-04 LNNS 32
LNNS/IRP TAB 15
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neuropathology and Neuroanatomical Sciences, IRP
National Institute of Neurological and Communicative
Disorders and Stroke
Igor Klatzo, Chief
The main accomplishments in the LNNS during the past year v/ere as follows:
The Section on Cerebrovascular Pathology made significant progress in eluci-
dation of the pathophysiology of the blood-brain barrier (BBB) in cerebral isch-
emia. A biphasic character of BBB breakdown following release of ischemic occlu-
sion was demonstrated in two different models. In cats subjected to one hour of
middle cerebral artery (MCA) occlusion, the first opening of the barrier occurred
shortly after recirculation and was related to high elevations of the regional
cerebral blood flow (rCBF), measured by hydrogen clearance method with platinum-
coated electrodes implanted bilaterally into the caudate nucleus and the Sylvian
cortex. Following this, there was a refractive period during which no BBB leak-
age could be demonstrated in spite of extremely low rCBF values during ischemic
occlusion and very pronounced reactive hyperemia following recirculation. The
second opening of the barrier was observed after 5 hours of recirculation at
which time there was a conspicuous ischemic damage of the tissue. Both openings
of the BBB were observed only when the drop of rCBF during ischemia reached below
12 ml/100 g/min threshold values. Similar biphasic breakdown of the BBB was
observed also in gerbils subjected to bilateral 5-minute occlusion of the common
carotid arteries. The first opening was demonstrated with horseradish peroxidase
tracer, immediately following release of occlusion, and it was associated with
patchy foci of hyperemia shown by^application of Sokoloff's C iodoantipyrine
radioautographic method and with H nicotine assays. The second opening of the
barrier was observed 3 days after recirculation and coincided with severe isch-
emic cell damage in the CAl sector of the hippocampus.
Studies on bilateral 5-min carotid occlusion in gerbils provided insight
into several aspects of pathophysiology of cerebral ischemic injury. First of
all, it demonstrated features of selective vulnerability expressed in a different
character of ischemic injury in various sectors of the hippocampus. The most
interesting were changes in CAl neurons which for 2 days appeared structurally
intact and then on the 3rd day the neurons showed rapid disintegration. During
the first two days after recirculation there was evidence of uncoupling between
rCBF and glucose utilization as assessed by the radioautographic methods of
Sokoloff . At the same time spontaneous electrical activity recordings with
microelectrodes from the CAl sector and the cerebral cortex revealed a greatly
increased neuronal activity in the former.
1 - LNNS/IRP
Investigations on the dynamics and pathophysiology of ischemic brain edema
were continued in cats subjected to the MCA occlusion. Correlative evaluation
of the rCBF changes, behavior of the BBB, and water content changes by specific
gravity measurements were supplemented by measurements of electrical impedance
in the ischemic regions by chronic implantation of electrodes. With this approach
it is possible to follow development of the cytotoxic ischemic edema indicated by
progressive increase in impedance. Also possible to determine with impedance
measurement is the event of increased vascular permeability and dilatation of
extracellular spaces. It is expected that forthcoming data on electrical imped-
ance will essentially contribute to better understanding of the pathomechanisms
of ischemic brain edema.
The continuous goals of the Section on Neurocytobiology have been: A) to
develop and utilize new model systems for the investigation of basic mechanisms
operative on the level of normal and pathologically altered blood-brain barrier
(BBB); B) to study the metabolic processes occurring in cerebral ischemia and
ischemic edema especially their prevention and therapy.
In studies related to BBB in cerebral endothelial cultures the establishment
of metabolically active endothelial cells in culture provided a new "living" model
system for the study of cerebroendothelial properties and the regulatory mechanism
of their function and its relationship to BBB. These investigations showed that
the capillary endothelial cells contain a specific g^ and g^-adrenergic sensitive
adenylate cyclase (AC). The presence of a^-type receptors fs of special interest
since they were so far associated with the smooth muscle function only. Their
existence on the endothelial level is compatible with the recent concept of g-
adrenergic receptors' participation in the central regulation of blood pressure.
Among the effects of various tested hormones, PGE-, and PGE^ (prostaglandins)
were found to be the most potent '\C activators, while adenosine, angiotensin I
and II, GABA and VIP inhibited the enzyme activity. However, acetylcholine,
histamine, serotonin, glycine, glutamine, bradykinin, neurotensin and vasopressin
did not influence the AC activity in the disrupted cultured endothelial cells.
The susceptibility of the cerebrovascular endothelial AC system to the vasoactive
substances as well as the presence of Pp and g^-type adrenergic receptors linked
to AC in the cultured endothelium provides supf^ort for the proposed endothelial
involvement in the regulation of cerebrovascular permeability, blood flow and
blood pressure. ~ ~~ ~~ ~ ~
The presence of phenyl ethanol ami ne-N-methyl transferase (PNMT), a catechol-
amine synthesizing enzyme which converts norepinephrine to epinephrine in the
endothelial cell cultures and cerebral microvessels was demonstrated by bio-
chemical and immunocytochemical techniques. Until now, the activity of this
enzyme was associated with the brain regions containing catecholaminergic cell
bodies. Thus, the demonstration of PNMT in the capillary endothelium, an extra-
neuronal compartment, indicates that the microvessels themselves are capable of
synthesizing epinephrine from norepinephrine, although the function of the
formed monoamine is unknown. Since the vascular adrenergic innervation has been
implicated in the regulation of BBB permeability and cerebral blood flow, it
is possible that the synthesized epinephrine in the microvessels might participate
in the regulation of cerebral vascular permeability and/or blood flow as one of
the substrates necessary for autoregulation or for the metabolic integrity of the
LNNS/IRP
In studies in gerbils on cerebral ischemia, its pathophysiology, prevention
and therapy - a continuous evaluation of the effects of naturally occurring cen-
tral nervous system depressant [y-butyrolactone (GBL) and y-hydroxybutyrate (GHB)]
on cerebral ischemia has been focused on the elucidation of the possible mecha-
nisms responsible for the observed beneficial effect of GBL and GHB on ischemic
brain edema. During these studies an accumulation of free tryptophan was found
in the brain along with decreased levels of monoamines (5-HT and NE) and in-
creased concentrations of their metabolites in the first phase of ischemic edema .
GHB treatment prevented the cerebral accumulation of free tryptophan, 5-HIAA and
HVA, Moreover, it diminished the loss of NE and stabilized the 5-HT content of
the brain. The investigation in gerbils concerned with the ischemic effect on
the e-receptors suggested a change in sensitivity of the B-receptors to catechol-
amine and an alteration of GTP regulatory site of the B -receptors in the brain
subjected to ischemia.
In the Section on Cellular Neuropathology, investigators used immunocyto-
chemical methods to study the distribution of viruses, myelin proteins, and
glial constituents in experimental and human demyelinating diseases.
In two projects, distributions of myel in-associated glycoprotein (MAG), an
oligodendroglial constituent, and basic protein (BP), a compact myelin component
were compared. In hexachlorophene intoxication, CNS myelin sheaths become vacu-
olated. Splitting of compact myelin layers occurs as intramyelinic edema pro-
gresses but myelin sheath breakdown is uncommon and if hexachlorophene administra-
tion is stopped, the process is reversible. In these lesions, MAG-stained peri-
axonal processes of oligodendroglia remain normal suggesting that these processes
and this glycoprotein have an important role in the interactions needed for mye-
lin sheath maintenance and repair. Progressive multifocal leukoencephalopathy
( PML ) i s a papova virus infection of oligodendroglia that produces myelin break-
down in patients with defective immune responses. In PML, histologically identi-
fied zones of myelin breakdown correspond closely to areas in adjacent sections
with absent or abnormal BP staining. But zones of decreased MAG staining are
much larger and extend into normal appearing white matter that surrounds demye-
linated areas. Here, the density of viral ly infected oligodendroglia is highest
suggesting that altered MAG staining is a sign of early oligodendroglial abnor-
malities that precede and may cause myelin breakdown. It is of interest that
patterns of MAG and BP staining in multiple sclerosis (MS) resemble that seen
in PML, suggesting that oligodendroglia may be the primary target in MS. A
different pattern is seen in both acute and chronic relapsing EAE.
Another important project has demonstrated that the MS strain of type 2
herpesvirus can produce spinal cord and optic nerve demyelination when injected
intracerebral ly into mice. Types of lesions seen and their distribution are
age and dose-dependent. Typical herpesvirus particles are found in glial cells
located in acute lesions; later, fewer virions are present. This is the first
experimental demyelinating disease that has been produced with a virus known to
cause human disease and will serve as an important model to study how viruses
produce myelin breakdown.
Finally, electron microscopic immunocytochemical methods and tissue prepara-
tive techniques have been modified to study the localization of proteins in
myelin's lamellar structure. In the project, BP has been localized in dense
LNNS/IRP
line regions of both CNS and PNS myelin, a site favored also by indirect evidence
from biochemical experiments. The modifications created for BP localization will
be useful in electron microscopic studies of other myelin constituents.
The goal of the Section on Functional Neuroanatomy is to investigate impor-
tant problems in cellular neurobiology by means of modern structural techniques.
In the course of studying release of transmitter at synapses, an important tech-
nique for freezing tissue directly was developed. These studies of transmitter
release have been completed, and our current program depends on exploring several
new avenues opened by the freezing technique.
The first advantage of the direct freezing technique is that rapid structural
changes can be stopped with a msec time resolution. In the last year, papers
have been published showing the fate of synaptic vesicle membrane following exo-
cytotic transmitter release, and how exocytosis begins as a punctate rearrange-
ment of the plasma membrane in a secretory cell. Differences between the mem-
brane ultrastructure of synapses on tonic (slow) muscle fibers and twitch (fast)
muscle have been found in two different species.
Direct freezing can also be used to visualize intrinsic membrane proteins
in greater detail and closer to their natural state. For this purpose a special
apparatus has been developed to freeze-fracture tissue at temperatures near
absolute zero (10°K). This approach prevents many of the structural changes
which normally occur during fracturing and shadowing. Application of this tech-
nique to open and closed channels ("connexons") at gap junctions shows new struc-
tural details which change depending on their functional state. The substructure
of membrane particles at acetylcholine receptors, SR-T junctions in muscle,
tight junctions, and in astrocyte membranes involved in the blood-brain barrier
are being examined. Lipid polymorphism turns out to make an important contri-
bution to membrane structure at tight junctions, and the contribution of such
nonbi layer lipid organization at gap junctions and at sites of membrane fusion
is being explored. One criterion for recognizing lipid polymorphism in membranes
is to find structures in liposomes similar to the naturally occurring structures.
The new freeze-fracture technique allows the cytoskeleton of axons to be
visualized without any of the chemical pretreatments that have been used up to
now to prepare cytoskeletons. Organelles involved in axoplasmic transport are
situated in special "compartments" of the axoplasm, and each type of organelle
has characteristic relationships with cytoskeletal elements. This approach has
also been applied to show the relationships of the cytoskeleton to the post-
synaptic membrane of auditory brain stem synapses. Fine filaments connect com-
ponents of the postsynaptic membrane, believed to be receptors, with a micro-
filament network lying in the cytoplasm beneath the synapse. This finding
explains the long-term stability of the postsynaptic region of the neuronal
membrane. Recently, monolayers of cultured cells are being frozen after ob-
serving them with light microscopical methods and then examined in a 200 KV
electronmicroscope to determine: how organelles move through axoplasm; the
relationships of membrane turnover to the cytoskeleton in growth cones; and the
relationships between acetylcholine receptor clustering and the cytoskeleton in
cultured myocytes.
LNNS/IRP
Another advantage of the freezing technique is that soluble components
of the cell interior are preserved in their natural positions. Methods have
been developed to use cryopreparation to measure the distributions of elements,
particularly calcium, in rapidly frozen tissue by means of analytical electron
microscopical techniques. The initial aim of developing these methods was to
examine the redistribution of calcium during exocytosis at synapses and secretory
cells. Nov^ that the major technical obstacles to these original goals have been
surmounted, any element can be measured in small regions of cells (20 nm) with
the time resolution afforded by rapid freezing (1-2 msec). Specific aims are to
determine whether presynaptic active zones are sites for calcium entry during
evoked transmitter release, and also to determine the site and role of internal
calcium stores in secretion. The results, so far, have provided evidence that
the endoplasmic reticulum is a major calcium buffering system in nerves and
secretory cells. Also, it becomes apparent that secretory granules in various
cells store calcium and may even release it during exocytosis.
The Section on Neurocytology continued to explore the interactions between
allografts of peripheral and central nervous tissue to brain surfaces, the be-
havior of a glycolytic enzyme in regenerating neurons and the responsiveness of
certain particles within the plasma membrane of astrocytes. The neurotropic
effect exerted by transplants of superior cervical ganglion (SCG) has now been
found to include the interneurons and astrocytes of the olfactory bulb. By
placing an SCG graft on the dorsal surface of the bulb in 6-day-old rat recipi-
ents, the granule cells and, probably, periglomerular and tufted neurons, migrate
anomalously toward the graft. Induction of post-natal, aberrant migration of
neurons is beginning to appear as a. general effect on certain interneurons. The
availability of synaptic targets determined the number of surviving ganglion
cells in the transplant. By removing the host's own SCG ganglia bilaterally
at the time of transplantation, the ganglia's targets: blood vessels of the pia
and choroid plexus, were denervated and thus became available to regenerating
neurites. As a result, the number of surviving neurons was increased about
7-fold in a 6-month-old graft. These results emphasized the importance of pro-
viding available, specific targets for the long-term survival of neuronal grafts.
A consequence of by-passing the blood-brain and blood-CSF barriers to horse-
radish peroxidase (HRP) through SCG grafts was a rapid and pronounced uptake of
the glycoprotein by the astrocytes (Golgi epithelial cells) of the cerebellum.
This uptake appeared to be stimulated by the presence of the graft. The glio-
tropic effect of the SCG may now be taken to include augmented endocytosis.
In regenerating hypoglossal neurons, there was a very modest but consistent
increase in non-neuronal enolase (NNE) and a concomitant marked fall in neuron-
specific enolase (NSE), detected immunocytochemically. There appeared to be,
therefore, a conversion to the fetal ratio of these isoenzymes during regeneration
of a cranial nerve. There was also found a target-dependent recovery of NSE
levels. If, after axotomy, the proximal and distal stumps of the XII nerve are
anastomosed, the NSE level largely recovered by 60 days. If, instead, the proxi-
mal stump was inserted into an inappropriate muscle so that reinnervation does
not take place, the levels of NSE remained low. These results are the first to
show that the levels of a neuronal glycolytic enzyme are not necessarily influ-
enced by regeneration alone, but rather by some signal from the target muscle.
5 - LNNS/IRP
The responses of assemblies, the orthogonal aggregates of particles within
the plasma membranes of astrocytes, have been further elucidated. At the periph-
ery of a cold lesion of the cerebral cortex in young rats, the assemblies with-
in astrocytes began to increase within 30 minutes and, by 4 to 6 hours, were
4 to 5 times higher than control values. Catabolites, such as CO^, also aug-
mented the number of assemblies four-fold within 30 minutes. WeaK acids, such
as lactate caused a rearrangement of assemblies, whereas acetic and proprionic
brought about a marked decrease in number. These results demonstrated rapid
changes in the astrocyte membrane to catabolites such as COp» and lactate, which
accumulate during ischemia. These alterations are part of a rapidly developing
and incipient stage of reactive gliosis, hitherto unknown.
LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02456-02 LNNS
PERIOD COVERED
October 1, 1981 to September 30;
1982
TITLE OF PROJECT (80 characters or less)
The regional selectivity of blood-brain barrier (BBB) changes induced by
various epileptogenic agents and acute hypertension
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
Neuroanat. Sci. LNNS NINCDS
PI:
C.
Nitsch
Visiting Scientist
Other:
K.
Fujiwara
Visiting Fellow
H.
Laursen
Visiting Associate
R.
Suzuki
Visiting Fellow
P.
Ting
Expert
I.
Klatzo
Chief, Lab. Neuropath.
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
g (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been terminated.
7 - LNNS/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02457-02 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regional cerebral blood flow (rCBF) changes in variously induced epileptiform
seizures
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Visiting Scientist LNNS NINCDS
Visiting Fellow LNNS NINCDS
Expert LNNS NINCDS
Chief, Lab. Neuropath. Neuroanat. Sci. LNNS NINCDS
PI:
C.
Nitsch
Other:
R.
Suzuki
P.
Ting
I.
Klatzo
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
section
Section on Cerebrovascular Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D {a2) INTERVIEWS
n (b) HUMAN TISSUES
H (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords
This project has been terminated.
PHS-6040
(Rev. 2-81)
8 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02458-02 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Changes in specific gravity (SG) of rabbit brain tissue during drug-induced
epileptiform convulsions
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Visiting Scientist LNNS NINCDS
Visiting Fellow LNNS NINCDS
Visiting Fellow LNNS NINCDS
Visiting Fellow LNNS NINCDS
Chief, Lab. Neuropath. Neuroanat. Sci. LNNS NINCDS
PI:
C.
Nitsch
Other:
K.
Fujiwara
T.
Kuroiwa
R.
Suzuki
I.
Klatzo
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
NSTITUTE AND LOCATION , , „ ^
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
□ (b) HUMAN TISSUES
[^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been terminated.
PHS-6040
(Rev. 2-81)
9 - LNNS/IRP
SMITHSONIAN SC
PROJECT NUMBER
ENCE INFORMATION EXCHAN
(Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02545-01 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Changes of spontaneous neuronal activity of cortical and hippocampal CAT neurons
following 5 minute ischemia in gerbils
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. Suzuki
Other: T. Yamaguchi
C.-L. Li
I. Klatzo
Visiting Fellovj
Visiting Fellow
Medical Officer
Chief, Lab. Neuropath.
Neuroanat. Sci
LNNS NINCDS
LNNS NINCDS
SN NINCDS
LNNS NINCDS
COOPERATING UNITS (if any)
Surgical Neurology Branch, NINCDS
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.6
PROFESSIONAL:
1.0
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Activity of cortical neurons and hippocampal CAT neurons was recorded during
5 minute forebrain ischemia and following recirculation in gerbils. Spontaneous
activity in both cortical and CAl neurons ceased to appear within 60 sec of the
onset of ischemia and it began to reappear 10-20 min after recirculation. Fur-
thermore, during 24 hrs a considerable number of CAl neurons showed hyperactiv-
ity as shown by an increase in spike discharges. However, on the second day of
ischemia CAl neurons became completely silent, although histological sections
showed a relatively good preservation of their cellular structure.
PHS-6040
(Rev. 2-81)
10 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02546-01 LNNS
PERIOD COVERED
October 1 ,
1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Behavior of the blood-brain barrier (BBB) and the regional cerebral blood flow
(rCBF) in cerebral ischemia produced by middle cerebral artery (MCA) occlusion
in cats
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
INVESTIGATORS AND ALL OTHER
PI: T. Kuroivja
Other: P. Ting
T. Yamaguchi
I. Klatzo
Visiting Fellow LNNS NINCDS
Special Expert LNNS NINCDS
Visiting Fellow LNNS NINCDS
Chief, Lab. Neuropath. Neuroanat. Sci. LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.0
PROFESSIONAL:
1.4
OTHER:
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Two independent openings of the BBB were demonstrated following one hour MCA oc-
clusion in cats. The first opening occurred shortly after release of occlusion
and was associated with high elevations of the rCBF. The second opening of the
barrier was demonstrable after 5 hours following release of occlusion and was
associated with severe ischemic tissue changes. Both openings of the barrier
were dependent on the rCBF falling below threshold values (12 ml/100 g/min)
during the occlusion.
PHS-6040
(Rev. 2-81)
11 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02547-01 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less) ^ /r,r,n\ ■ i u t
Observations on behavior of the blood-brain barrier (BBB), regional cerebral
blood flow (rCBF) and glucose utilization in gerbils subjected to 5 min bi-
lateral occlusion of the common carotid arteries
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. Suzuki
Other: T. Yamaguchi
F. Orzi
I. Klatzo
Visiting Fellow
Visiting Fellow
Visiting Fellow
Chief, Lab. Neuropath. Neuroanat. Sci.
LNNS NINCDS
LNNS NINCDS
LCM NIMH
LNNS NINCDS
COOPERATING UNITS (if any)
Laboratory of Cerebral Metabolism, NIMH
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.6
PROFESSIONAL:
1.0
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
BBB, rCBF and glucose utilization (GU) were compared in gerbils during 5 min
cerebral ischemia and after recirculation. There was an increased permeability
of the BBB shortly after release of the circulation and this was correlated with
patches of hyperemia demonstrated in rCBF radioautography. Ten minutes after
release of occlusion there was a pronounced hypoperfusion expressed in markedly
reduced rCBF values. This was associated with conspicuous increase in glucose
utilization in the hippocampus which lasted for 24 hours and then became greatly
reduced when assayed at 48 hours. Secondary breakdown of the BBB was observed
3 days after release of occlusion in the hippocampus and this coincided with
severe ischemic damage of the CAl neurons.
PHS-6040
(Rev. 2-81)
12 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
1 HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02548-01 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Evaluation of electrical impedance in the cerebral ischemia produced by occlu-
sion of the middle cerebral artery (MCA) in cats
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: P. Ting
Other: H. Wagner
T. Yamaguchi
T. Kuroiwa
R. Cahn
I. Klatzo
Special Expert LNNS NINCDS
Chief, Neuronal Interactions Section LNP NINCDS
Visiting Fellow LNNS NINCDS
Visiting Fellov^ LNNS NINCDS
Visiting Fellow LNNS NINCDS
Chief, Lab. Neuropath. Neuroanat. Sci . LNNS NINCDS
COOPERATING UNITS (if any)
Laboratory of Neurophysiology, NINCDS
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Cerebrovascular Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda. Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
1.9
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
£] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The changes in electrical impedance were studied in cats subjected to left MCA
occlusion, either permanent or followed by the release of occlusion. The main
findings indicate that shortly following MCA occlusion there is a progressive
increase in impedance, reflecting the onset of cytotoxic edema in the ischemic
regions. The breakdown of the BBB is reflected in decrease of impedance. The
correlation of impedance measurements with those of rCBF in the same experiment
should greatly elucidate the dynamics of ischemic brain edema.
PHS-6040
(Rev. 2-81)
13 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02275-06 LNNS
PERIOD COVERED
October 1. 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cerebral capillary endothelial cultures: Response to vasoactive substances.
[Former title: Cerebral capillary endothelial cultures]
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
M. Spatz Head, Section on Neurocytobiology LNNS NINCDS
I. Karniouchina Visiting Fellow LNNS NINCDS
PI:
COOPERATING UNITS (if any)
Dr. Lawrence DeBault, Department of Pathology, Children's Hospital, Oklahoma
City, Oklahoma
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.6
PROFESSIONAL:
0.7
OTHER:
0.9
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
H (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The established cerebral endothelial cell cultures derived from dissociated
cerebral microvessels possess g^ ^"^^ a^-adrenergic sensitive adenylate
cyclase (AC). The endothelial AC system was also found to be stimulated by
prostaglandins E-, and E
■2-
PHS-6040
(Rev. 2-81)
14 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02324-05 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Studies on the blood-brain barrier (BBB) to 5- hydroxy try ptamine and norepi-
nephrine metabolites: Cerebral capillary endothelial culture metabolism and
synthesis of 5-hydroxytryptamine
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: M. Spatz Head, Section on Neurocytobiology LNNS NINCDS
Other: C. Maruki Visiting Fellow LNNS NINCDS
COOPERATING UNITS (if any)
Dr. Ikuko Nagatsu, Department of Anatomy, Fujita-Gakuen University School of
Medicine, Toyoake, Aiche 470-11, Japan
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.0
PROFESSIONAL:
0.3
0.7
check APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
0 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Cerebral endothelial cultures derived from 2-day-old rats and propagated for
7-10 weeks showed the capability not only of taking up and metabolizing 5-HT
but also of synthesizing this amine.
PHS-6040
(Rev. 2-81)
15 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02327-05 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
The study of monoamines' uptake and pinocytotic activity of pia arachnoid cul
tures.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: M. Spatz Head, Section on Neurocytobiology LNNS NINCDS
COOPERATING UNITS (if any)
Dr. H. Hervonen, Department of Biomedical Sciences, University of Tampere,
Tampere, Finland
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
TOTAL MANYEARS:
PROFESSIONAL:
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
y (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been temporarily discontinued.
PHS-6040
(Rev. 2-81)
16 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02357-04 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
The therapeutic y-hydroxybutyrate effect on experimental cerebral ischemia in
Mongolian gerbils
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: M. Spatz Head, Section on Neurocytobiology
Other: C. Maruki Visiting Fellow
LNNS NINCDS
LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.8
PROFESSIONAL:
0.3
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
0 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The y-hydroxybutyrate (GHB) amelioration of ischemic cerebral edema (cytotoxic
type) correlated v/ell with the stabilization of monoamines' synthesis and
metabolism, especially that of 5-HT.
PHS-6040
(Rev. 2-81)
17 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02361-05 LNNS
PERIOD COVERED
October 1, 1981 tto September 30, 1982
TITLE OF PROJECT (80 characters or less)
Investigations on blood-brain barrier (BBB) permeability
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
M. Spatz
Head, Section on Neurocytobiology
LNNS NINCDS
COOPERATING UNITS (if any)
Prof. K. G. Go and Dr. H. J. Hauthof, Departments of Neurosurgery and
Pathology, University of Groningen, The Netherlands
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.6
PROFESSIONAL:
0.2
0.4
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
y] (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The enhancement of serum protein permeability was investigated in bilateral
cerebral ischemia induced by occlusion of both carotid arteries for 15
minutes. The demonstration of extravasated protein depended on the protein
marker used. The most sensitive protein tracer was found to be the ^rum
antibodies (IgG class) to horseradish peroxidase.
PHS-6040
(Rev. 2-81)
18 - LNNS/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02462-02 LNNS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biochemistry of brain ischemia and ischemic edema in Mongolian gerbils;
beta-adrenergic receptor studies
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: I. Karniouchina
Other: C. Maruki
M. Spatz
Visiting Fellow
LNNS NINCDS
Visiting Fellow LNNS NINCDS
Head, Section on Neurocytobiology LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS, NIH Bethesda, Maryland 20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
0.8
0.5
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The pathogenetic investigations of cerebral ischemia have been con-
cerned with determining the effect of this process on the neurotransmitter re-
ceptors, in particular the beta-adrenergic type; these studies have shown that
brain ischemia affects the membrane affinity for ^h dihydroalprenolol (^H-DHA)
binding sites due to a decreased association but not dissociation rate of the
ligand to the beta-receptors.
This study was presented at the 3rd Belgrade Symposium on Develop-
mental and Circulatory Aspects of Brain Metabolism, and the proceedings will be
published by the Plenum Press. This project has been completed.
PHS-6040
(Rev. 2-81)
19 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02463-02 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
The effect of central nervous tissue on cerebral endothelial properties
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
M. Spatz
Head, Section on Neurocytobiology
LNNS NINCDS
COOPERATING UNITS (if any)
Dr. Ronald F. Dodson, Division of Experimental Pathology, East Tyler Chest
Hospital, Tyler, Texas
LAB/BRANCH
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
H (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project has been temporarily discontinued.
PHS-6040
(Rev. 2-81)
2U - LNNS/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02552-01 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Investigation of extraneuronal catechol synthesizing enzymes in the central
nervous system
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: M. Spatz
Other: C. Maruki
Head, Section on Neurocytobiology LNNS NINCDS
Visiting Fellow LNNS NINCDS
COOPERATING UNITS (if any)
Dr. Ikuko Nagatsu, Department of Anatomy, Fujita-Gakuen University School of
Medicine, Toyoake, Aiche 470-11, Japan
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Section on Neurocytobiology
INSTITUTE AND LOCATION
NINCDS. NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.1
PROFESSIONAL:
0.5
0.6
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Immunohistochemical and biochemical studies of cerebral microvessel and
cerebrovascular endothelial cultures showed the presence of phenyl ethanol-
amine-N-methyl transferase (PNMT) activity in both tissues. These findings
indicate that the extraneuronal tissue contains a catecholamine synthesizing
enzyme which is responsible for conversion of norepinephrine to epinephrine.
PHS-6040
(Rev. 2-81)
21 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01995-10 LNNS
PERIOD COVERED October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Morphological studies of myelin formation, breakdown and regeneration
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I.
Other:
H. deF. Webster
H. Shii
F.X. Omiin
J.R. Martin
G.L. Stoner
H. Lassmann
E.P. Richardson Jr.
Associate Chief
Visiting Fellow
Guest Worker
Senior Staff Fel low
Senior Staff Fellow
Associate professor
Professor
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
Univeristy of Vienna
Medical School, Vienna,
Austria
Massachusetts General
Hospital , Boston, MA
COOPERATING UNITS (.f any)Ne,jpo-, Qg, ^a] Institute, University of Vienna Medical School,
Vienna, Austria; Department of Neuropathology and Neurology, Massachusetts
General Hospital, Boston, Massachusetts
LAB/BRANctHaboratory of Neuropathology and Neuroanatomical Sciences
Section on Cellular Neuropathology
INSTITUTE AND LOCAT I ONN I NCOS, NIH, Bethesda , Maryland 20205
TOTAL MANYEARS:
6.2
PROFESSIONAL:
=3.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
B (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The long range goal of this project is to combine immunocytochemical methods
with light and electron microscopy to study cellular mechanisms of myelin
formation, breakdown and regeneration. Nervous tissues from experimental
animals have been studied in the following current projects: 1) Distribution
0^ myel in-associated glycoprotein (MAG) and basic protein (BP) in chronic re-
lapsing experimental allergic encephalomyelitis (EAE), an animal model for
multiple sclerosis (MS); 2) Electron microscopic immunocytochemical local iza-
tion of basic protein in the Lamellar structure of myelin; 3) Electron micro-
scope and immunocytochemical studies of abnormal axon-glial relationships in
jimpy mice (mutants with a severe defect in CNS myelin formation).
PHS-6040
(Rev. 2-81)
22 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02549-01 LNNS
PERIOD COVERED October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Animal Models of Herpesvirus-induced demyeli nation and relation to
human disease
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J.R. Martin
Other: G.L. Stoner
H.deF. Webster
Senior Staff Fel low
Senior Staff Fellow
Associate Chief
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
COOPERATING UNITS (if any)
LAB/BRANCH Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Cellular Neuropathology
MSTiTUTE AND LOCATION NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.1
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
OTHER:
2.1
□((b) HUMAN TISSUES
□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The main objective of this research project is to look for evidence which links
herpesvirus infections, especially herpes simplex virus type 2 (HSV-2), to
human neurological disease, particularly multiple sclerosis^ ^Thus far, these
studies have included: 1) A comparison of the epidemiology of herpes simplex
virus types 1 and 2 and that of multiple sclerosis, and 2T A search for CNS
demyeli nation in experimental HSV-2 infections, and initial studies of the
conditions which favor development of this pathol ogy.
PHS-6040
(Rev. 2-81)
23 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
701 N.s n?s'sn-ni [ ms
PERIOD COVERED
October 1, 1981 to Septpmhpr 30, 198?
TITLE OF PROJECT (80 characters or less)
Biochemical and immunologic mechanisms in vi rally-induced CMS demyeli nation
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: G.L. Stoner
Other: J.R. Martin
H.deF. Webster
Senior Staff Fellow
Senior Staff Pel lov^
Associate Chief
LNNS NINCDS
LNNS NINCDS
LNNS NINCDS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Cellular Neuropathology
INSTITUTE AND LOCATION
NIN(:DS. NIH. Bethesda, M,
PROFESSIONAL:
ryland 20205
THER:
TOTAL MANYEARS:
-4^
-UQ-
-&a-
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
f5 (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The first phase of this work has concentrated on the preparation of antisera
to Herpes simplex virus types 1 and 2 for use in the peroxidase-anti peroxidase
(PAP) immunocytochemical technique^ Antisera have been obtained which can
differentiate the two types of HSV in paraffin sections of infected mouse CNS.
Expression of viral antigens will be studied in the CNS of unimmunized mice
and of mice immunized with the homologous or heterologous HSV type. The long
range goal of this project is the understanding of the mechanisms of
demyeli nation in viral infections of the CNS, the mechanisms of immunity to
these infections, and the relationship between these two phenomena.
PHS-6040
(Rev. 2-81)
24 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 01442-16 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Permeability of Cellular Layers in the Vertebrate Nervous System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: T. S. Reese
Other: B. Kachar
Head, Section on Functional Neuroanatomy LNNS NINCDS
Visiting Fellov^ LNNS NINCDS
COOPERATING UNITS (if any)
R. P. Rand, Brock University, Ontario
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Functional Neuroanatomy
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.9
PROFESSIONAL:
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
{^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The substructure of tight junctions is investigated by direct freezing
techniques that avoid any chemical fixation and serve to increase the resolution
of individual membrane components. The backbone of the tight junction is a
pair of rod-shaped structures embedded in the central lipophilic domain of each
of the paired component membranes. This conclusion replaces the previous view
that tight junctions are comprised of rov^s of intramembrane proteins. Instead,
the rod-shaped structures, v\;hich are comparable to cylindrical micelles in
liposomes, are nov^f interpreted as inverted cylindrical micelles of membrane
lipids. These results lead to an understanding of how tight junctions serve in
the blood-brain barrier system to prevent small charged solutes from entering the
brain. Similar techniques are being applied to understand the substructure
of specific glial membrane structures which are regarded as components of the
blood-brain barrier system.
PHS-6040
(Rev. 2-81)
25 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01881-12 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Structural basis of synaptic transmission.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
T.
S. Reese
Other:
C.
P. Ko
K.
R.
D.
V.
J. Lynch
L. Ornberg
W. Pumplin
Verma
J.
Walrond
Head, Section on Functional
Neuroanatomy
Guest Worker
Guest Worker
Staff Fellow
Guest Worker
Visiting Fellow
Staff Fellow
LNNS
LNNS
LNNS
LNNS
LNNS
LNNS
LNNS
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
COOPERATING UNITS (if any)
T. Sejnowsky, Neurobiology Dept. Harvard Medical School
S. Nakajima, Purdue University, West Lafayette, IN
R. L. Gulley, Lab. Neuro-otolaryngology, NINCDS
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Functional Neuroanatomy
INSTITUTE and LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
7.5
PROFESSIONAL:
5.0
2.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
{% (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project seeks to determine the location and mechanism of neurotransmitter
secretion. Rapid freezing and subsequent freeze-fracture of synapses capture
fleeting structural changes in the cell membrane accompanying discharge of
synaptic vesicles. By these means, the prodromata and aftermath of synaptic
vesicle exocytosis have been determined. This approach has been extended to othe
secretory cells where details surrounding the initiation of secretion are more
readily studied. New methods have been developed to use rapid freezing to deter
mine how the distribution of intracellular calcium changes vr^ different functionejl
states. Organelles which store and release calcium during secretion as well as
sequestering it afterwards have been found. This work is significant in that it
defines the dynamic structure of normal synapses by relating normal variations in
structure to different functional states. The current program also includes
freeze-fracture of developing and degenerating synapses; the results will aid in
understanding of normal development as well as the effects of diseases and de-
velopmental failures on synaptic structure in the brain and peripheral nervous
system.
PHS-6040
(Rev. 2-81)
26 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02551-01 LNNS
PERIOD COVERED Qctober 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Structure of Neuronal Cytoplasm
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: T. S. Reese Head, Section on Functional
Neuroanatomy LNNS NINCDS
Other: Gadi Benshalom Visiting Fellow LNNS NINCDS
Paul Bridgman Guest Worker LNNS NINCDS
COOPERATING UNITS (if any)
Bruce Schnapp, Queen Square, London, England
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Functional Neuroanatomy
INSTITUTE AND LOCATION
, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.5
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This new project seeks to determine the structure of neuronal and glial cyto-
plasm particularly as it pertains to axoplasmic transport, secretion, cell move-
ment, and the organization of the cell surface. Living cells or tissues are
directly rapid-frozen and the structure of their cytoplasm is determined by one of
two methods, freeze-etching or freeze-substitution. Axons in turtle optic nerves
have different axoplasmic domains, each characterized by specific types of fila-
ments and by its content of organelles. In other experiments, cultured myocytes
grown on grids, frozen, and freeze-substituted are examined directly at high
voltages in an electromicroscope. So far, it has been shown that the cytoplasmic
an! age consists of fine filaments instead of a microtubular meshwork. We pi an
to use this direct method of observing the cytoskeleton to observe the relation-
ship to the cytoskeleton of organelles moving by fast axoplasmic transport, and
to observe how the cytoskeleton changes near aggregations of receptors at post
synaptic membranes in developing synapses.
PHS-6040
(Rev. 2-81)
27 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE!
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01805-14 LNNS
PERIOD COVERED Qctober 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Membrane Structure of Astrocytes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J. J. Anders Expert Consultant LNNS NINCDS
M. W. Brightman Head, Section on Neurocytology LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Neurocytology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.6
PROFESSIONAL:
1.5
0.1
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The assemblies or orthogonal aggregates of particles within the cell membrane
of astrocytes increase in number at the periphery of a cold lesion of the
cerebral cortex in 9 day-old rats within 30 minutes. By 4 to 6 hours fol-
lowing the lesion, the number of assemblies is 4 to 5 times greater than that
of resting astrocytes. Hypercapnia also leads to a marked and rapid augment-
ation. Within 30 minutes, there is a four- fold rise in assembly number. Weak
acids^, such as acetic and proprionic, when added to the culture medium, result
in a decrease of about 10 to 3-fold, respectively, in the assembly number in
astrocytes maintained in vitro for 14 days. Lactic acid did not appear to
cause a significant change in the number of assemblies, but did cause them
to aggregate. Etching of the uncleared astrocyte surface exposed to the lectin,
concanavalin A, did no^ result in capping of surface particles, a finding which
implies that the assemblies may not have an extrinsic, carbohydrate component.
PHS-6040
(Rev. 2-81)
28 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02086-09 LNNS
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regeneration in Peripheral and Central Nerves
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Visiting Fellow LNNS NINCDS
Guest Worker LNNS NINCDS
Guest Worker LNNS NINCDS
Head, Section on Neurocytology LNNS NINCDS
PI:
T.
Kirino
Other:
J.
Rosen stein
D.
Pagnanelli
M.
Brightman
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Neurocytology
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.4
PROFESSIONAL:
2.3
OTHER:
0.1
check APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Neuronotropic effect of superior cervical ganglion (SC6) grafts has been
extended to the olfactory bulb, where granule cells and, possibly, other
interneurons migrate anomalously and postnatal ly toward the graft. The column
of migrating cells incudes astrocytes which migrate with microglial cells
and neurons to push aside glomeruli. Within the transplant, the number of
neurons that survive depends on the availability of target tissue: the blood
vessels of the pia and choroid plexus. Bilateral removal of the rat's own
SCG at the time of transplantation increases the number of surviving ganglion
cells about 4-fold during the first month and about 7-fold during the sixth
month after grafting. In regenerating hypoglossal neurons of monkeys, there
is a very modest rise in non-neuronal enolase concurrent with a pronounced
fall in neuron-specific enolase (NSE). If the regenerating nerve, in rats.
is allowed to reinnervate the tongue, the level of NSE approaches near-
normal levels in 60 days. If the nerve is prevented from doing so, the NSE
level remains low.
PHS-6040
(Rev. 2-811
29 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02144-08 LNNS
PERIOD COVERED Qctober 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Blood-Brain Barrier and Ganglion Implants.
Former Title: The Blood-Brain Barrier. Bypassed With Ganglion Implants,
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
M. W. Brightman
J. Rosenstein
Head, Section on Neurocytology LNNS NINCDS
Guest Worker LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
Section on Neurocytology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
.9
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
[J (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
No fenestrated endothelium -induced or invasive- that could exude hematogenous
horseradish peroxidase (HRP), has been found in^ the cerebral tissue adjacent to
grafted superior cervical ganglion. The extracellular route taken by blood-borne
HRP, from permeable vessels of the graft to brain extracellular fluid, has thus
been confirmed. However, the non-fenestrated endothelium of capillaries in the
brain adjacent to the graft has many more pits and vesicles than that of
neighboring regions; most of them become labeled with HRP coming from the blood
itself and the cerebral extracellular clefts. Some of the HRP^ that escapes from
the fenestrated vessels of the graft, enters the subarachnoid space from which it
is endocytosed by the bordering astrocytic end-feet adjacent to the graft. The
HRP is then transported retrogradely to lysosomes within the astrocyte cell body.
The sharply demarcated line of labeled astrocytes stands in sharp contrast to the
unlabeled glial cells on either side. Even without HRP, the lysosomes in the
soma of astrocytes adjacent to the graft, are far more numerous and larger than
those of its neighbors, presumably due to the repeated uptake of cellular debris
from the ganglion cells that have not found targets and that, consequently, have
degenerated.
30 - LNNS/iRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02286-06 LNNS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Mechanism of Cerebral Hemorrhages
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI;
J. Cammermeyer
Guest Worker
LNNS NINCDS
COOPERATING UNITS (if any)
None
LAB/BRANCH
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Office of the Chief, LNNS
INSTITUTE AND LOCATION . „„ ^
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.3
PROFESSIONAL:
0.3
OTHER:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
[^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Petechial cerebral hemorrhages induced by oil embolism in material fixed
by perfusion are compared with those in material fixed by immersion.
This project has been completed and the manuscript is being prepared
for publication.
PHS-6040
(Rev. 2-81)
31 - LNNS/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02362-04 LNNS
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Effect of dimethyl sulfoxide on the histochemical demonstration of glycogen in
the perfusion-fixed brain.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
J. Cammermeyer
Guest Worker
LNNS NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Laboratory of Neuropathology and Neuroanatomical Sciences
SECTION
Office of the Chief, LNNS
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0.7
PROFESSIONAL:
0.7
check APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS 0 (a2) INTERVIEWS
n (b) HUMAN TISSUES
I] (c) NEITHER
SUMMARY OF WORK (200 v,ords or less - underline keywords)
When normal Netherlands dwarf rabbits were perfused with dimethyl
sulfoxide CDMSO)-containing solutions, the brains exhibited pericapillary foci
with acute tissue destruction and perivenous areas in which neurons were filled
with glycogen. Glycogen was also discernible in mi "oglial cells and oligo-
dendrocytes. Because of the irregular distribution of glycogen-filled cells,
this method of fixation is not recommended for systematic studies on the dis-
tribution of glycogen in normal and experimental animals. This project has been
completed and the manuscript is being prepared for publication.
PHS-6040
(Rev. 2-81)
32 - LNNS/IRP
en
-<
m
c:
:o
o
■V
o
ANNUAL REPORT
October 1,1981 through September 30, 1982
Laboratory of Neurophysiology
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
Research Summary 1-2
Project Reports
Electrophysiological Studies on Neuronal Excitability
ZOl NS 02019-10 LNP 3
Cellular Biological Studies of CNS Neurons
ZOl NS 02330-05 LNP 4
Neural Coding and Processing of Information in
the Visual System
ZOl NS 02339-05 LNP 5
Synaptic Contacts of Retinal Neurons
ZOl NS 01559-14 LNP 6
Neural Connections in the Retina
ZOl NS 02152-08 LNP 7
i-LNP/IRP TAB 16
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Laboratory of Neurophysiology
National Institute of Neurological and
Communicative Disorders and Stroke
Chief
Jeffery L. Barker, M. D.
In July, 1981 the Administrators of the Intramural Program of the
NINCDS appointed a permanent Chief to lead the Laboratory of Neurophysi-
ology. He has proposed a multi-disciplinary program designed to study
the biological properties of specific types of ner\ie cells resident in
the mammalian CNS. Several rooms have been renovated, the appropriate
equipment requisitioned, and some of the personnel integral to the pro-
gram appointed. At the same time principal investigators and their
collaborators in the Laboratory have continued research on a variety of
research topics all of which are related to an understanding of the
physiology of the nervous system at the cellular level.
Dr. Lasansky has continued to examine structure-function relation-
ships among elements in the retinas of tiger salamanders and snapping
turtles. His work has revealed that the membrane response of rods and
cones which occurs when light is directed at surrounding areas of retina
is similar for both types of cells. He has hypothesized that the cone
elements may mediate the observed response in rods through a synaptic
form of interneuronal communication.
Dr. Wagner and collaborators have continued to analyze the spatial
distribution of sensitivity in the vertebrate retina and to correlate
this distribution with visual acuity, light adaptation and wavelength
contrast enhancement. Dr. Wagner has also entered into collaboration
with the Laboratory of Neuropathology and Neuroanatomical Sciences in
order to study some of the pathophysiological changes in Drain ischemia
with electrophysiological recording techniques.
Dr. Smith and colleagues have studied certain aspects of electrically
excitable membrane processes in ganglion neurons of Aplysia. They have
found evidence to support their notion that Na"*" ions play a major
charge-carrying role in pacemaker activity. They have also found that
the cell body of ganglion cells in Aplysia is not the primary site of
generation of action potentials, but rather acts in a relatively passive
manner during spike generation. In another project they have developed
and utilized a fluorescence microscope for examining Ca "*■ binding sites
in cultured mammalian neurons. Their initial results indicate that these
binding sites are localized to the cell bodies of sensory neurons.
1-LNP/IRP
Dr. Barker and colleagues have used electrophysiological recording
techniques to study excitable membrane processes in cultured mammalian
neurons and the actions of clinically important drugs. The principal
observations from this year's research include the following: 1) one-half
of the sensory neurons generate Ca"^"''-dependent K"*" conductances, prob-
ably by releasing Ca'*'"'" from intracellular stores; 2) a majority of
spinal and hippocampal neurons possess a K"*" conductance which acts to
regulate excitability; 3) a variable number of spinal and hippocampal
neurons generate Ca"*" conductances and Ca''"^-dependent K"*" conduct-
ances; 4) 4-aminopyridine, a convulsant in vivo, produces paroxysmal
episodes of excitatory activity and enhances transmitter release in cul-
ture by blocking the K"*" conductance described in 2) and promoting the
Ca"^"'"-dependent events described in 3); 5) a majority of spinal and
hippocampal neurons generate a Na"''/K''' conductance at relatively
hyperpolarized levels of membrane potential; 5) all hippocampal neurons
respond to GABA, muscimol and pentobarbital and the membrane response
appears to be comprised of two-state ion channels whose properties are
somewhat different from those found on spinal neurons; 7) neuroblastoma-
glioma hyorid cells, which possess opiate receptors coupled to adenylate
cyclase, respond to opiates and opioids with a novel type of increase in
membrane conductance, possibly to Na"*" ions; 8) benzodiazepines and
sub-anesthetic concentrations pentobarbital, but not phenobarbital,
ethosuximide, or valproate potentiate membrane responses to GABA; 9)
patch clamp recordings of GABA and muscimol-activated channels in cul-
tured spinal neurons have confirmed the two-state nature of the events;
10) cholecystokin causes long-lasting excitatory effects in spinal neu-
rons. The results from this research demonstrate that a variety of exci-
table membrane processes are present in mammalian CNS neurons. A primary
goal will be to characterize how each excitable membrane process func-
tions physiologically. Another related aim will oe to show whicn forms
of excitability are present in what types of mammalian central neurons.
The project. Neural Connections in the rletina: ZOl NS 02152-08 LNP,
has been terminated with the publication of the following paper:
Amacrine Cells, Bipolar Cells, and Ganglion Cells of the Cat Retina. A
Golgi Study, Helga Kolb, Ralph Nelson and Andrew Mariani. Vision
Research 21: (1981) 1081-114.
2-LNP/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02019 - 10 LMP
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Electrophysiology and Neuropharmacology of Simple Cellular Systems
New title: Electrophysiological Studies on Neuronal Excitability
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J.L. Barker Laboratory Chief LNP, NINCDS
r.G. Smith Section Chief LNP, NINCDS
OTHER;
R
Canada
Staff Fellow
LNP,
NINCDS
E.
Gratz
Staff Fellow
EB,
NINCDS
K.
Futamachi
Staff Fellow
LNP,
NINCDS
M
A. Rogawski
PRAT Fellow
LNP,
NINCDS
R.
E. Study
Staff Fellow
LNP,
NINCDS
0
A. Mathers
Visiting Fellow
LNP,
NINCDS
D.
G. Ovjen
Visiting Fel low
LNP,
NINCDS
W,
Vaughn
Computer Specialist
RS3,
NIMH
J.
Mazzetta
Technician
LNP,
NINCDS
Kesearch ^ervic^es Branch, NIMH; R.N. McBurney, University of Newcastle-
upon-Tyne Medical School, England; M. Segal, Weizmann Institute, Rehovot,
Israel.
lab/branch
Laboratory of Neurophysiology
SECTION
Sections on Neurobiology and General Physiology
INSTITUTE AND LOCATION
NINCDS. NIH. Bethesda. Maryland 20205
TOTAL MANYEARS:
5
PROFESSIONAL:
4
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n {a2) INTERVIEWS
D (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Experiments using intracellular and extracellular recording techniques
have been carried out on various in vitro preparations of vertebrate and
invertebrate neurons. The research has focussed primarily on character-
izing the types of excitable membrane processes resident in neurons and
secondarily on studying the effects of various transmitter substances and
clinically important drugs on these processes. The principal conclusions
are that multiple forms of electrically and chemically excitable conduct-
ance mechanisms are present in spinal, hippocampal, and hypothalamic
nerve cells grown in tissue culture and that ooth endogenous transmitters
and exogenous drugs alter these conductances in superficially similar
ways. The results of this research improve our basic understanding of
neuronal excitability and of the physiological roles of transmitters and
the pharmacological actions of drugs.
3 LNP/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCI
PROJECT NUMBER
ENCE INFORMATION EXCHANGE
(Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02330 - 05 LMP
PERIOD COVERED
OctoDer 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biochemical Pharmacology of Cultured Nerve Cells
New Title: Cellular Biological Studies of CNS Neurons
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J.L. Barker Laboratory Chief LNP, NINCDS
OTHER:
M.
Rogawski
PRAT Fellovj
A.
Schaffner
Staff Fellow
R.
Study
Staff Fellow
P.
Sher
Staff Fellow
J.
Mazzetta
Technician
V.
Smal Wood
Technician
LNP, NINCDS
LNP, NINCDS
LNP, NINCDS
LDN, NICHO
LNP, NINCDS
LNP, NINCDS
COOPERATING UNITS (if any)
LDN, NICHD: J. Neale, Department of Biology, Georgetown University; R.
W. Olsen, University of California at Riverside; L. Skirboll, LCS, NIMl
lab/branch
Laboratory of Neurophysiology
SECTION
Section on Neurobiology
INSTITUTE AND LOCATION
NINCDS. NIH. Bethesda. Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL: OTHER:
_CLi.
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Mouse spinal and sensory neurons grown in
been studied with various biochemical and
The research has focussed on revealing the
and cytoplasmic properties resident in cul
Observations from this year's research inc
glutamic acid decarboxylase activity in cu
rons and its localization primarily to bou
cell bodies; 2) the demonstration of immun
leucine-enkephal in throughout the cytoplas
rons; 3) the demonstration of immunoreacti
level of the cell body in 1-5 percent of s
stration by radioimmunoassay and immunohis
and its receptors in sub-populations of ce
binding to benzodiazepines by chronic expo
dissociated cell culture have
immunohistochemical methods,
presence of specific membrane
tured neurons. The principal
lude: 1) the demonstration of
Itures of embryonic spinal neu-
ton-like structures investing
oreactivity to methionine- and
m of 1-5 percent of spinal neu-
vity to dynorphin (1-13) at the
pinal neurons; 4) the demon-
tochemistry of cholecystokinin
lis; and 5) down-regulation of
sure to the drug.
4 LNP/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02339 - 05 LNP
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neural Coding and Processing of Information in the Visual System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
LNP, NINCDS
Duke Univ.
Marine Biological Lab.
University of Montreal
Scripps Institute
LNP, NINCDS
PI:
H.G. Wagner
Section Chief
OTHER:
M.L. Wolbarsht
Professor
E.F. MacNichol, Jr
Director
M.A. Alii
Professor
3. David Lange
Associate Professor
William Beane
Electronic Technician
COOPERATING UNITS (if any)
Ophthalmology Department, Duke University, Durham, N.C.; Marine
Biological Laboratory, Woods Hole, Mass.; Biology Department, University
of Montreal, Canada; Scripps Institute of Oceanography, Calif.
lab/branch
Laboratory of Neurophysiology
section
Section on Neuronal Interactions
institute and location
NINCDS, NIH, Bethesda, Maryland 20205
total MANYEARS:
LJL
PROFESSIONAL:
SLA-
OTHER:
-(Li
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 yvords or less - underline keywords)
We have continued our study of the receptive field of the retinal
ganglion cells by analysing data collected on carp. We have found that
the distribution profile of sensitivity across the field under either
dark adapted or light adapted conditions can be described as gaussian.
The gaussian shape suggests that the dendritic inputs to the ganglion
cell would also show a gaussian distribution. Our examination of the
morphological evidence indicates that this is not so. In addition, short
duration stimuli were found to substantially broaden the quantitatively
definable width for this receptive field.
Microspectrophotometric absorption curves for the outer segments of carp
cones can be grouped into three classes which are identical to those
observed in goldfish. Discrepancies which were present concerning the
olue cone xmax have been resolved. Preliminary efforts to use these
"class" curves as templates for the construction of spectral sensitivity
curves in other fish such as the cichlids have met with some success.
5 LNP/IRP
'PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl MS 01559 - 14 LNP
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Synaptic Contacts of Retinal Neurons
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
A. Lasansky
J. Lohr
Research Biologist
Technician
LNP-NINCDS
LNP-NINCOS
COOPERATING UNITS (if any)
lab/branch
Laboratory of Neurophysiology
SECTION
Section on Cell Biology
INSTITUTE AND LOCATION
NINCDS. N I H. Bethesda. iMaryland 20205
TOTAL MANYEARS:
2
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The responses of retinal rods of the turtle to annular illumination
include a depolarizing component not seen v>/hen the center of the
receptive field is also illuminated. While the latter feature indicates
that the depolarization is of synaptic origin, it seems to exclude
horizontal cell feedback as its source. Since the surround effect on
rods can be seen under illumination Dright enough to completely
desensitize them, it must originate in the cone system and may reflect
direct cone-rod interactions.
6 LNP/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02152-08 LNP
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Neural Connections in the Retina
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
P.I,
OTHER:
Henry G. Wagner Chief
H. Kolb
R. Nelson
A. Mariani
Research Biologist
Research Biologist
Research Biologist
LNP, NINCDS
Univ. of Utah
LVR, NEI
LVR, NEI
COOPERATING UNITS (if any)
Dept. of Physiology, Univ. of Utah, Salt Lake City, Utah;
Laboratory of Vision Research, NEI.
lab/branch
Laboratory of Neurophysiology
Section on Neuronal Interactions
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0
PROFESSIONAL:
0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
XKc) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This research project was terminated in Fiscal Year 1981 with the publication
of the paper cited below. The full citation of the published paper was not
available at the time that the FY '81 report was submitted, and it is for that
reason included in the FY '82 Annual Report.
Publication;
Kolb, H., Nelson, R., and Mariani, A.: Amacrine cells, bipolar cells and
ganglion cells of the cat retina: A Golgi study. Vision Research 21:7,
1081 - 1114, 1981.
PHS-6040
(Rev. 2-81)
LNP/IRP
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>
73
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o
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Clinical Neurosciences Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-5
RESEARCH PROJECTS
Cognitive and Emotional Profile of Neuropsychiatric
Disorders
ZOl NS 00200-28 CN 6
EEC Learning Correlates Using Scalp and Intracranial
Depth Electrodes
ZOl NS 01245-17 CN 7
Response Modulation by the Limbic System in Man:
Neuropsychological and Physiological Changes
ZOl NS 01424-16 CN 8
Hemispheric Development and Specialization of the
Intellectual Functions
ZOl NS 01658-15 CN 9
Visual Evoked Potentials in Clinical Neurology and
Neuro-Ophthalmology
ZOl NS 02269-06 10
Experimental Epilepsy: Seizures Produced by Kindling
in Rat
ZOl NS 02431-03 CN 11
Brainstem Auditory Evoked Potentials in Clinical
Neurology
ZOl NS 02432-03 CN 12
i - CNB/IRP TAB 17
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Clinical Neurosciences Branch
National Institute of Neurological and Communicative
Disorders and Stroke
Paul Fedio, Ph.D., Acting Chief
Summary of Program Activity
The Clinical Neurosciences Branch (CNB) formulates and conducts basic and applied
clinico-investigative research to advance an understanding of brain-behavior
relations, applying electrophysiologic and neuropsychologic procedures to study
altered neurologic conditions and events in man. These activities are supported
by the equivalence of 6 man-years (1 professional, 3.5 technical and 1.5
secretarial staff members) .
I. Clinical Diagnostic Services:
The principal clinical activities provide electroencephalographic (EEC) diagnostic
services, including computer-derived, evoked potential studies of epilepsy, brain
tumors, neuromuscular disorders and developmental metabolic anomalies. These
consultative services are extended to the parent Institute NINCDS, and to other
Institutes within NIH, and the sources of referral are listed as follows:
Diagnostic Services
Referral Sources
EEC
%
Evoked Potential
%
NINCDS
542
58.7
142
68.3
NIMH
117
12.7
2
0.9
NICHD
95
10.3
20
9.6
NHLBI
26
2.8
3
1.4
NCI
30
3.2
6
2.9
NIAID
44
4.8
8
3.9
NIADDK
37
4.0
12
5.8
NEI
8
0.8
1
0.5
MISC
25
2.7
14
6.7
TOTAL (1132) 924 100.0 208 100.0
The acturarial distribution reflects an increase in the total number of standard
EEC referrals since the past year: 59% of patient referrals were submitted
by NINCDS physicians, the remaining 41%, from other NIH sources. Services identi-
fied as miscellaneous represent bedside EEC recording performed in the CCU and
electrocorticography (ECG) administered in the neurosurgical suite. Requests for
the use of evoked potential studies have increased considerably during this period
(visual, brainstem auditory and somatosensory potentials) , a supplementary pro-
cedure which has proved especially useful in the diagnosis and management of
demyelinating neurologic diseases.
1 - CNB/IRP
The Branch also provides varied and suitable clinical opportunities and patient-
study materials for clinicians who intend training in Clinical Electroencephalo-
graphy. Each year, one or two of the Clinical Associate trainees become eligible
for examination for the American Board of Qualification in EEC.
In addition to the EEC service, a team of neuropsychologists provides consultation
to patients in NINCDS and other Institutes. Standard and specialized psycho-
metric examinations are performed to provide diagnostic information, and to guide
habilitative management of patients with neurologic and neuropsychiatric disorders.
Special studies at preoperative and postoperative intervals have been developed
to chart the course of neurosurgical treatments of patients with brain tumors
and epilepsy.
II. Research Activities:
Branch members actively conducted seven (7) research projects during this reporting
period, and in addition, engaged in secondary collaboration with other investi-
gators within NINCDS and other Institutes.
Clinical seizure patterns elicited with different types of epilepsy continue to
be a primary field of interest. Branch members have been using a standard EEC
machine in tandem with Video recording instrumensts. This unique monitoring
system allows the investigators to observe crucial ictal, clinical and EEC
patterns simultaneously, which affords an opportunity to record observations
and events for precise analysis. This system has greatly Increased the reli-
ability to correlate EEC parameters with specific seizure patterns, and to
document rare electrocllnical relations which occurred incidentally, during
routine recordings with epileptic patients.
The branch staff has been heavily involved in a correlative study of "Electro-
encephalography (EEC) , Computerized Axial Tomography (CAT) , and Positron Emission
Tomography (PET) with [^^F]2-Fluoro-2-Deoxyglucose (^^FDG)" in adults with gliomas.
The relationship between EEC and static and dynamic radiographic parameters has
been studied in 23 patients. PET scans showed cortical suppression in 14 of 16
patients and focal EEC slowing in 6 of 7 patients. Electrographic records show
focal delta activity in 9 of 14 patients with tumors situated in both gray
and white substance, and in 5 of 8 with tumors in white matter, verified only on
CT scans. PET scans showed suppression of metabolic rate in areas adjacent to the
tumor in 20 patients, including 6 of the 8 with tumors in white matter only.
Fifteen (15) patients had focal EEC slowing, as did 2 of the 3 patients without
cortical suppression. In 3 patients with rhythmic delta EEC activity, 2 had
tumors which invaded the thalamus as documented by both the PET and CT scans.
Four (4) patients had focal attenuation of the EEC background, and 3 of these also
had thalamic involvement; none of the patients without background attenuation had
thalamic involvement. Preliminary impressions suggest that focal EEG slowing
cannot be directly related to involvement of white matter alone or to suppression
of cortical metabolic activity. Rhythmic delta activity and suppression of EEG
background, however, appear to be related to involvement of thalamic structures.
Parenthetically, several patients with thalamic or subcortical involvement showed
global cortical hypoactivity, inviting a proposal to study possible neuro-
psychological deficits.
2 - CNB/IRP
In the collaboration with the Epilepsy Section, positron emission tomography
with simultaneous EEG monitoring has been performed with 18-f luoro-2-deoxyglucose
(FDG) in 10 patients with complex partial seizures; these patients presented
normal CT profiles and neurological status at examination. Four (4) patients
had unilateral epileptiform discharges, 2 had predominantly unilateral dis-
charges, and 4 had bilateral epileptiform abnormalities. PET images were
consistent with hypometabolic lesions in all patients except for 2 epileptic
subjects with bilateral discharges. The PET scans were unaffected by the seizure
frequency, state of alertness, or number of spike discharges. However, a change
in antiepileptileptic medication between interictal scans has affected the imaged
metabolic rate. Seizures occurring 18 and 90 minutes prior to FDG injection did
not alter the hypometabolic area whereas seizures beginning 3 minutes after FDG
injection in one patient (and occurring throughout FDG uptake in another) pro-
duced hypermetabolic uptake at the original interictal, hypometabolic focus.
Part of the effect at 10 and 20 minutes in the former patient may have been due
to increased cerebral blood flow. These data and impressions suggest that focal
lesions may be detected by PET scan, even if the EEG abnormality is not well
localized. Because PET provides reliable localization of focal abnormalities,
this noninvasive procedure is especially significant in patients with medically
intractable epilepsy, normal neurological and CT examinations, and who may be
suitable surgical candidates.
An integrated effort is also being initiated to investigate the psychosocial and
intellectual problems associated with epilepsy. Patients who have submitted
to a unilateral left or right temporal lobe resection for the relief of intract-
able seizures, will serve as subjects. A series of studies, utilizing standard
and specially designed tests of perception and memory, have been developed to
assess reasoning and analytical defects, memonic disorders and the therapeutic
effect of resection; the long term effects of brain surgery on cognitive and
emotional behavior will be analyzed.
Emotional or affective changes experienced by patients with temporal lobe damage
will also be addressed within the hypothesis that left and right brain mechanisms
contribute differentially to emotional perception and regulation. The relation-
ship between brain damage and ideative versus emotive changes will be examined
with the intent of better understanding the nature of neuropsychiatric disorders
in man and the role of defective neural mechanisms in regulating emotional
behavior.
Apart from human experimentation, animal models will be used to extract data and
information about epilepsy. Altered metabolic conditions and the relation-
ship to seizure disorders will guide studies dealing with the effect of hypoxia
or kindling in rats. Specifically, adult rats are exposed to nitrous oxide in
an airtight chamber for a duration of 15 and 25 seconds, after which, the animals
are allowed to recover for prescribed periods of time. Electrodes will then be
implanted in the amygdala and over the cortical surface of brain. Awaiting their
recovery for one more week, electrical stimulation for kindling will commence.
So far, only a few rats have been prepared and subjected to the experiment, and
a preliminary analysis does not show any significant difference in the rate of
kindling between controls and hypoxic rats. This work will be amplified and
include refinement of the experimental procedures. In order to assess the
impact of hypoxia during early development of the CNS, newly born animals will
be used.
3 - CNB/IRP
CNB investigators have been also actively studying visual evoked potentials
(VEP) in relationship to eye dominance. The results indicate that the amplitude
of pattern-reversal VEPs in 25 healthy volunteers was significantly higher with
stimulation of the dominant eye than the nondominant eye in subjects with pre-
ferred right eye sighting. The differences in VEP tracings were recorded over both
cerebral hemispheres and midline leads; handedness did not appear to influence
the amplitude asymmetry. A similar trend was noted for left eye dominant subjects,
but the differences were significant only at an occipital reference (0 ). The
mean latency of the PlOO peak was significantly shorter with stimulation of the
dominant eye. These amplitude and latency disparities between responses by
dominant and nondominant eyes to stimulation provide additional electrophysiological
evidence of lateralization in the nervous system.
To complement these studies which emphasize altered responsivity for early
components in evoked potentials, new initiatives have been developed to
examine the later waveform components (P300) . This event-related brain
potential has become established as a reliable index of the time and manner
whereby information is processed. The P300 analysis will be utilized with
various neurologic and neuropsychiatric patients, examining defects in memory,
concept formation and the use of feedback to influence behavior, allowing the
examiners to analyze the consequences of neurologic diseases in human behavior.
Apart from the electrophysiological techniques, a comprehensive neuropsychological
study of human aging and alterations by dementia have been completed, describing
and comparing cortical and subcortical dysfunctioning in patients with Alzheimer's
and Huntington's Disorders. Preliminary impressions indicate that Alzheimer
patients are troubled by pervasive or global intellectual decline. In most
instances there appear to be no qualitative differences between demented and
age-matched normal subjects. That is the patients did poorly in managing
visual auditory, verbal and nonverbal memory tasks of a short or long term
nature, and yielded a pattern of performance which was similar to that for normal
individuals, but at a greatly reduced level of efficiency.
The initial analysis also shows that the memory impairment for Alzheimer's
disease may result from 'poor encoding' of material presented to memory stores.
This contrasts sharply with the basic flaw recorded for amnesic disorders where
the deficit involves an inability to store and/or retrieve newly learned
experiences or information.
Relatedly, Alzheimer patients exhibited selective neurolinguistic deficits, and
did poorly with confrontation naming tasks. Their performance was characterized
by a loss of knowledge about specific object attributes, while broad categorical
information was relatively preserved. Coupled with spatial imperception, this
defect disturbs the daily activities of demented patients, and to a lesser degree,
in senesence, especially in novel, unfamiliar or unstructured personal-social
situations, and may be cast as confusion and disorientation.
This pattern of functional flaws was not common to patients demented by Hunting-
ton's Disease. With visuospatial judgmental and constructional tasks, Huntington
patients did poorly with 'egocentric' tasks, that is, manipulation of one's own
body (internal) in space. In contrast, Alzheimer patients were more troubled in
handling 'allocentric' tasks, that is, manipulation of objects in external
space. These findings are interpreted within the framework of frontal versus
parietal lesions respectively, implicating distinct structurofunctional
differences between Alzheimer's and Huntington's disorders.
4 - CNB/IRP
A statistical, discriminant analy&is j;s currently being executed to evaluate the
notion that dementia of the Alzheimer's variety does eyolve in a uniform manner,
that various subgroups- exist, wi;th salient and progressive weaknesses in
language, attention or constructional def j^its-, -reflecting differential bjrain
changes .
Relatedly, parallel neuropsychological efforts were extended to Guam where a high
incidence of Parkinson Dementia prevails among laembers of the indigenous
Chamorros race. The research findings indicate that Parkinson Dementia (Guam)
and Alzheimer's Disorder OP.S.I produced functionally similar deficits in compari-
son with matched normal subjects. Defects were recorded on measures of attention,
memory, visual spatial construction, and language. The resultant differences
however, were noteworthy: with auditory-language dependent tasks, the Guamanian
patients did more poorly than Alzheimer patients, whereas, with visual memory tasks,
the Alzheimer patients were inferior to the Parkinson-demented subjects on Guam.
These data underscore that mental deterioration following diffuse brain changes,
are tempted by native cognitive styles, and that functional organization of brain
mechanisms is shaped by environmental and genetic determinants.
Specialized study of neuropsychiatric disorders involved patients with obsessive-
compulsive ideation and mannerisms, addressing hypothetical impressions about
disturbances to frontal-structural systems. In collaboration with NIMH scientists,
adolescents and adults with obsessive-compulsive features were studied by special-
ized procedures. The findings established selective defects with spatial
procedures involving perception, memory and learning. The patients tended to
ignore prescribed test constraints and shifted prematurely from one learned concept
to another. The data implicate altered functions dependent on frontal lobe inte-
grity and invite conjecture of possible overexcitation of frontal limbic mechanisms
in obsessive-compulsive disorders.
in collaboration with medical specialists and scientists in NINCDS and NIMH,
developmental irregularities of metabolic disorders and the early effects of
radiation of the brain are being examined. In one study, neuropsychological
sequelae were examined in pediatric patients receiving prophylactic CNS treat-
ments for acute Lymphoblastic Leukemia. Radiographic study of these patients
illustrated dilation of the ventricles and subarachnoid spaces, and evidence of
calcification in the basal ganglia. In behavioral terms, these changes were
related to major deficits in attention, memory and learning, and diminished
intellectual competence.
5 - CNB/IEP
SMITHSONIAN SCIENCE -
PROJECT NUMBER (Do NOT use th
NFORMATION EXCHANGE
space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00200-28 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Cognitive and Emotional Profile of Neuropsychiatric Disorders.
Former Title: Involuntary Movements
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
P. Fedio
A. Martin
P. Brouwers
C. Cox
J. Bravo
T. Chase
Psychologist
Psychologist
Psychologist
Psychologist
Psychologist
Neurologist
CN
NINCDS
CN
NINCDS
CN
NINCDS
CN
NINCDS
CN
NINCDS
ET
NINCDS
COOPERATING UNITS (if any)
Experimental Therapeutics Branch, NINCDS
lab/branch
Clinical Neurosciences
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.7
PROFESSIONAL:
1.2
0.5
CHECK APPROPRIATE BOX(ES)
H (a) HUMAN SUBJECTS
D (al) MINORS [l;(a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
X
A neuropsychological profile of dementia was drafted for individuals
with Alzheimer's Disease, Huntington's Disease and 'at risk' for
Huntington's Disease. The evaluations extended into memory, learning
and perceptual areas, utilizing standard and experimental tasks, also
establishing normative references for functional changes encouraged by
the aging processes. These behavioral data will be collated with bio-
chemical and neuroradiometric measures, and independent indicators of
deterioration and dementia will be developed. In collaboration with
NINCDS facilities on Guam, the investigation will attempt to study
Parkinsonian Dementia among the indigenous population and compare data
with results obtained from demented patients in the U.S.
PHS-6040
(Rev. 2-81)
6 - CNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01245-17 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
EEG Learning Correlates Using Scalp and Intracranial Depth Electrodes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: P. Fedio Psychologist CN NINCDS
R. Johnson Psychologist CN NINCDS
OTHER: M. Buchsbaum Research Medical
Officer BPB NIMH
A. Martin Psychologist CN NINCDS
P. Brouwers Psychologist CN NINCDS
COOPERATING UNITS (if any)
Biological Psychiatry Branch, NIMH
lab/branch
Clinical Neurosciences
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, B.ethesda, MD 20.205
TOTAL MANYEARS:
0.4
PROFESSIONAL:
0.2
OTHER:
0.2
CHECK APPROPRIATE BOX(ES)
[3c(a) HUMAN SUBJECTS
n(al) MINORS S(a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Information processing by the human brain was monitored and quantified
by averaged evoked response techniques. The electrographic activity was
recorded from left and right brain regions during memory and perception
in normal subjects, and in patients with neuropsychiatric disorders
(Alzheimer's) . Suspect electroencephalographic disturbances in brain -
behavior relations in psychiatric patients was also evaluated, relating
left brain dysfunction to ideational disorders, and right brain activity
to maladaptive emotional reactions.
PHS-6040
(Rev. 2-81)
7 - CNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHAN
PROJECT NUMBER (Do NOT use this spacej
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01424-16 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Response Modulation by the Limbic System in Man: Neuropsychological
and Physiological Changes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
P. Fedio
A. Martin
P. Brouwers
C. Cox
J. Bravo
Psychologist
Psychologist
Psychologist
Psychologist
Psychologist
CN NINCDS
CN NINCDS
CN NINCDS
CN NINCDS
CN NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Clinical Neurosciences
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MP 20205
TOTAL MANYEARS:
1.1
PROFESSIONAL:
0.6
0.5
check APPROPRIATE BOX(ES)
B (a) HUMAN SUBJECTS
D (al) MINORS [3(a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Emotional and cognitive characteristics are studied in epileptic
patients with unilateral left or right temporal lobe injury.
Temporal epileptic patients are compared with matched normal
subjects and patients with other neurologic disorders. The
epileptic patients judge and learn information conveying different
emotional states, while behavioral and physiological events are
recorded. The research examines the role of the temporal lobe in
establishing specific limbic associations between the left and
right hemispheres in regulating cognitive functions and emotional
experiences in man.
PHS-6040
(Rev. 2-81)
8 - CNB/IR,P
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01658-15 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Hemispheric Development and Specialization of the Intellectual Functions
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Psychologist CN NINCDS
Psychologist CN NINCDS
Psychologist CN NINCDS
Psychologist CN NINCDS
Medical Officer SN NINCDS
PI:
P.
Fedio
OTHER:
A.
Martin
P.
Brouwers
C.
Cox
C.
Kufta
COOPERATING UNITS (if any)
Surgical Neurology Branch, NINCDS
lab/branch
Clinical Neurosciences
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.6
PROFESSIONAL:
0.6
1.0
CHECK APPROPRIATE BOX(ES)
B (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The disabling effects of cerebral insult were evaluated by a broad
range of neuropsychological tests evaluating brain-behavior in man.
Changes in the intellectual behavior of neurologically-impaired
individuals were evaluated before and after surgery, during
electrical stimulation of the brain with specialized CNS procedures.
PHS-6040
(Rev. 2-81)
9 - CNB/IKP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02269-06 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Visual Evoked Potentials in Clinical Neurology and Neuro-Ophthalmology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: S. Sato, M. D.
OTHER: J. Chassy
Medical Officer
EEC Technologist
EB
CN
NINCDS
NINCDS
COOPERATING UNITS (if any)
Clinical Epilepsy Section, ETB, NINCDS
lab/branch
Clinical Neurosciences, IRP
Clinical Neurophysiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MP 20205
TOTAL MANYEARS:
0.5
PROFESSIONAL:
0.2
0.3
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
n (b) HUMAN TISSUES
□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An analysis of the morphology, amplitude and latency of visual evoked
potentials to photic flashes and reversing checkerboard pattern is
being conducted. Normative data have been collected from normal
individuals, predominantly of 20-39 years. Visual evoked responses
also have been examined in patients with various neurological
disorders. Prolonged latencies of the major positive peak have
been noted in patients with multiple sclerosis and neurological
disorders.
PHS-6040
(Rev. 2-81)
10 - CNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02431-03 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Experimental Epilepsy: Seizures Produced by Kindling in Rat
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: S. Sato, M.D.
OTHER: S. Walbridge
Medical Officer EB NINCDS
Laboratory Specialist CN NINCDS
COOPERATING UNITS (if any)
Clinical Epilepsy Section, ETB, NINCDS
LAB/BRANCH
Clinical Neurosciences, IRP
SECTION
Clinical Neurophysiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
0.8
PROFESSIONAL:
0.6
OTHER:
0.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Seizures produced by chronic stimulation (Kindling) are a good model for
human epilepsy. In rat, seizures are produced by daily electrical stimu-
lation of amygdaloid complex and other central nervous system sites. In
this project. Kindling of the various sites of the central nervous system,
interictal epileptiform discharges and their propagation, and effects of
sleep-wake cycles and maturation on the epileptiform discharges are being
investigated .
PHS-6040
(Rev. 2-81)
11 - CNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02432-03 CN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Brainstem Auditory Evoked Potentials in Clinical Neurology
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
S. Sato, M. D.
J. Chassy
Medical Officer
EEC Technologist
ETB
CNB
NINCDS
NINCDS
COOPERATING UNITS (if any)
Clinical Epilepsy Section, ETB, NINCDS
lab/branch
Clinical Neurosciences , IRP
SECTION
Clinical Neurophysiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MP 20205
TOTAL MANYEARS:
0.5
PROFESSIONAL:
0.2
CHECK APPROPRIATE BOX(ES)
0 (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
0.3
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Analysis of the morphology, amplitude and latency of brainstem auditory
evoked responses to clicks is being conducted. Normative data have been
collected from normal subjects, predominantly of 20-29 years. The test
has been carried out in patients with various neurological disorders.
Prolonged latencies and distortion of morphology have been observed in
patients with Multiple Sclerosis and Spinocerebellar Degeneration. The
effect of pharmacological agents on the evoked responses is also being
studied.
PHS-6040
(Rev. 2-81)
12 - CNB/IRP
OO
o
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Developmental and Metabolic Neurology Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-4
CONTRACT NARRATIVES 5.6&7
PROJECT REPORTS
Inborn Errors of Metabolism of Diverse Etiology
ZOl NS 00706-23 DMN 8
Metabolism of Complex Lipids of Nervous Tissue
ZOl NS 00815-22 DMN 9
Biosynthesis and Function of Glycosphingol ipids and
Other Glycoconjugates
ZOl NS 01309-17 DMN 10
The Chemical Synthesis of Radioactive Sphingol ipids
ZOl NS 01457-16 DMN 11
Metabolism of Neurohumoral Substances in Marine Animals
ZOl-NS-01480-15 DMN 12
Studies on the Composition and Metabolism of Cellular Membranes
ZOl NS 01481-15 DMN 13
Glycoproteins of Myelin in Development and Disease
ZOl NS 01808-13 DMN 14
Synthesis of Compounds Analogous to Glycol ipids
ZOl NS 02162-08 DMN 15
Development of Special Analytical Methods and Preparative
Techniques to Investigate the Etiology and Therapy of the
Sphingoli pi doses
ZOl NS 02163-08 DMN 16
Regulation of Hormone-Responsive Adenylate Cyclase
ZOl NS 02366-04 DMN 17
Models of Lysosomal Storage Disease
ZOl NS 02433-03 DMN 18
i - DMN/IRP TAB 18
studies of Lysosomal Function: Receptor-Mediated
Pinocytosis of Lysosomal Enzymes
ZOl NS 02434-03 DMN 19
Studies on the Mechanism of Pathogenesis of the
Mucopolysaccharidoses
ZOl NS 02435-03 DMN 20
Gaucher's Disease: Biochemical and Clinical
Studies.
ZOl NS 02453-02 DMN 21
Development of Enzymes that Inactivate Neurotoxic
Agents
ZOl NS 02529-01 DMN 22
Development of Non-sensitizing Thrombolytic Enzyme
Preparations
ZOl NS 02530-01 DMN 23
TAB 18 ii - DMN/IRP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Developmental and Metabolic Neurology Branch
National Institute of Neurological and Communicative Disorders and Stroke
Roscoe 0. Brady, Chief
The principal activities of the Branch concern the following areas of
investigation: 1. Metabolism of complex lipids and mucopolysaccharides in
normal and pathologic states. 2. Enzyme replacement therapy for the treatment
of patients with hereditary metabolic disorders. 3. Transmembrane signalling
mechanisms and the role of glycolipids and glycoproteins in this process.
4. The involvement of glycoproteins of the myelin sheath in nervous system
development and in demyelinating diseases. 5. The role of cell surface
enzymes in cellular communication and in affective disorders. 6. Development
of non-sensitizing enzymes for the treatment of thromboembolic diseases.
7. Preparation of enzymes that degrade neurotoxic substances.
I. HEREDITARY METABOLIC DISORDERS
A. Molecular genetics of Gaucher' s disease.
We have developed a large-scale high pressure liquid chromatography pro-
cedure for the preparation of homogeneous human placental glucocerebrosidase.
This innovation has permitted us to determine the precise molecular weight
and characteristics of the enzyme, its carbohydrate content, and the ability to
raise polyclonal and monoclonal antibodies to this protein. Using these anti-
bodies, we have demonstrated the nature of the discrete allelic modifications
of glucocerebrosidase in non-neuronal (Type 1) and the neuronal (Types 2 and
3) forms of Gaucher' s disease.
B. Excretion of Sphingolipids Via the Bile.
During the past year we discovered that comparatively large quantities of
sphingolipids, such as glucocerebroside that accumulates in patients with
Gaucher's disease, are excreted in the bile. This observation is consistent
with an earlier finding that only a small percent of the daily turnover of
glucocerebroside actually accumulates in patients with this disorder. This
discovery has important implications for the development of alternative thera-
peutic strategies such as attempting to increase the excretion of accumula-
ting sphingolipids by agents that stimulate the flow of bile.
C. Development of Animal Models of Human Hereditary Disorders.
The cyanohydrin derivative of glucocerebroside was synthesized. It is
expected that this cyanogenic substance will enable us to select mutated cells
that are deficient in glucocerebrosidase in order to develop a true genetic
counterpart of Gaucher's disease in rodents. We have continued studies with
the suramin-induced model of mucopolysaccharide storage disorders discovered
by our Branch. Specific enzyme alterations have been demonstrated that ex-
plain the accumulation of these substances as well as gangliosides that occur
1 - DMN/IRP
in excess in the brain of these animals and in patients with disorders of this
type. Current research deals with attempts to understand the pathogenesis of
the organomegaly in these animals and in patients with mucopolysaccharide
storage diseases. In addition, we are participating in a study with investi-
gators in NIADDK with a recently discovered canine model of Hurler's disease
that should be useful for numerous investigations concerning this metabolic
disorder and for comprehensive examinations of various therapeutic
strategies.
II. ENZYME REPLACEMENT THERAPY FOR LIPID STORAGE DISEASES
A. Enzyme Replacement Trials in Gaucher 's Disease
We have continued our investigation of enzyme replacement therapy in
young patients with Type 1 (non-neuronal ) Gaucher' s disease. We continue to
gratified by their clinical response and we are now in the control (third)
stage of this investigation. We have carried out experiments to secure
specific data concerning platelet sequestration and survival in these patients.
The initial results indicate that platelet recovery and survival is vastly
improved in Gaucher patients after enzyme replacement.
B. Specific Targeting of Exogenous Enzymes
We have demonstrated that the addition of linear pentamannoside chains
to native human placental glucocerebrosidase causes little improvement in the
delivery of the enzyme to the storage (Kupffer) cells in the liver. However,
covalent linkage of triantennary molecules of trimannosyldi lysine to the
enzyme significantly increases the delivery of this enzyme by selective
removel of hexoses provides even greater delivery of the enzyme to cells of
the monocyte-macrophage system and we plan to employ enzyme modified in this
fashion in clinical trials.
C. Delivery of Enzymes to the Central Nervous System
A major development in the past year was the conclusion of an agreement
with investigators at the University of Alabama in Birmingham to collaborate
in enzyme replacement trials in cats with the metabolic disorder known as
generalized (G^,-]) gangliosidosis. We shall provide purified g-galactosidase
for this effort! and we shall measure the effect of this exogenous enzyme on
the quantity of stored ganglioside in the brain of the animals after appropri-
ate temporary alteration of the blood-brain barrier. This is an immensely
important step forward since we should be able to decide with this model whether
enzyme replacement can reduce the quantity of accumulating lipid in the
neurons in the brain of humans. If successful, this demonstration will provide
a sound basis for enzyme replacement trials in human metabolic disorders that
involve the central nervous system.
2 - DMN/IRP
III. MEMBRANE RECEPTORS FOR ENVIRONMENTAL SIGNALS
The ganglioside Gj^-, can function as receptor for both cholera toxin and
for the heat-labile toxin of ^. coli which activate the enzyme adenylate
cyclase to increase intracellular cyclic AMP (the "second messenger system")
through ADP-ribosylation of a component of this enzyme complex. Gangliosides
are synthesized within the cell and then transported to the plasma membrane.
This transport is temperature-dependent but not affected by inhibitors of
protein synthesis, agents that alter the cytoskeleton or energy metabolism.
Glucocerebroside is synthesized in the rough endoplasmic reticulum and other
sugars are added in the Golgi apparatus in cells. Various drugs including
the ionophore monensin, block the conversion of glucocerebroside to higher
sphingolipid homologues such as gangliosides by preventing the transport of
glucocerebroside to the Golgi apparatus.
Critical studies have advanced our knowledge concerning the coupling of
receptors on cell surfaces to the various components of the adenylate cyclase
system. Many cells lose their responsiveness to hormones upon exposure to
these agents (downregulation). This process appears to occur by the following
sequence of events. First, the receptor is uncoupled from adenylate cyclase;
second the receptor and its bound hormone are internalized; and third the
hormone and receptor are degraded intracellularly.
IV. MULTIPLE SCLEROSIS
Information on the processing and metabolism of the specific myel in-
associated glycoprotein (MAG) has accumulated rapidly in FY-82. It has been
found that this myelin component is selectively localized in the periaxonal
region of the myelin sheaths in the central and peripheral nervous system
where it is likely involved in glia-axon interaction. We have demonstrated a
proteolytic enzyme which is maximally active at neutral pH, is present in
myelin and catalyzes the degradation of MAG to a smaller derivative (dMAG).
The activity of this enzyme is considerably greater in peri plaque areas in the
brains of patients with multiple sclerosis than in comparable regions of normal
brain. The dMAG that is produced by this enzyme is much more easily solu-
bilized from myelin than is the parent compound. It is therefore likely that
in multiple sclerosis, MAG is partially degraded and it becomes dislocated
from its natural periaxonal location. These events lead to disruption of
the normal glia-axonal relationship and initiate the breakdown of myelin.
Another important discovery during FY-82 was the demonstration that MAG
is the peripheral nerve antigen that reacts with monoclonal IgM antibodies in
a number of cases with plasma cell dyscrasias that are associated with periph-
eral neuropathy. Elucidation of the pathogenetic mechanism of this phenomenon
should provide cnsiderable insight into the role of MAG in autoimmune diseases
of the nervous system.
V. ECTO- ENZYMES
Important progress was made in FY 82 concerning the role and function of
enzymes on the surfaces of cells (ecto-enzymes) . It was discovered that there
is an important feed-back system that recognizes when there is a requirement
for these enzymes as they are depleted by exfoliation in the form of micro-
3 - DMN/IRP
vesicles (exosomes) from cultured brain cells. The precise role of these
enzymes in intercellular communication remains to be determined.
Studies on calcium-activated ATPase, a similar enzyme on the surface
of erythrocytes, provided the following extraordinarily interesting observa-
tion. In a comparison of the activity of this enzyme in red blood cells from
normal individuals and from manic-depressive patients, it was found that the
activity of this enzyme varied much more in patients with bipolar affective
disorders than in the control population. These wide fluctuations appear to
be caused by alterations in the level and interaction of modulating factors
such as calmodulin that bind to erythrocyte membranes and radically alter
their biological properties including the activity of this ATPase. If this
observation is substantiated in independent studies, it will provide an
important handle for the investigation of the pathogenesis of human
effective disorders.
VI. TREATMENT OF STROKES WITH CL0T-LYSIN6 ENZYMES
The bacterial enzyme streptokinase is being used with increasing
frequency to dissolve fibrin clots in the treatment of strokes and acute
myocardial infarctions. A principal limitation of this approach is that
the bacterial enzyme elicits a strong antibody reaction in recipients which
severely reduces its effectiveness on repeated administration. In an attempt
to circumvent this difficulty, we prepared high molecular weight poly-
ethylene glycol adducts of streptokinase and examined their antigenicity and
thrombolytic effectiveness. The adducts were much less antigenic than the
unmodified enzyme and they retained full activity with chromogenic peptides
commonly used to assay amidolytic activity. However, the adducts demonstrated
marked reduction in fibrin clot lysis. Antigenicity and thrombolytic
capacity will be examined using adducts prepared with lower molecular weight
polyethylene glycol congeners.
VII. ENZYMES THAT DEGRADE NEUROTOXIC SUBSTANCES
In collaboration with investigators in NHLBI, an enzyme that degrades
barbital has been isolated for the first time from a soil microorganism. The
characteristics and requirements of this enzyme are being determined and its
effectiveness in counteracting lethal doses of barbiturates will be examined
in experimental animals. If this approach to the treatment of neurotoxins is
successful, we shall try to develop enzymes that degrade other toxic sub-
stances and we shall attempt to render them non-antigenic with polyethylene
glycol adducts as indicated in Section VI.
4 - DMN/IRP
CONTRACT NARRATIVE
Developmental and Metabolic Neurology Branch
Intramural Research Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: NEW ENGLAND ENZYME CENTER, TUFTS UNIVERSITY {NOl-NS-0-2339)
Title: Preparation of Ceramidetrihexosidase from Human Placental Tissue
Contractor's Project Director: Henry E. Blair
Current Annual Level of Support: $80,933
Objectives: To isolate human placental ceramidetrihexosidase in
sufficient quantity and purity so that it can be used in enzyme
replacement trials in patients with Fabry's disease.
Major Findings: A procedure is being developed for the large-scale
isolation of human placental ceramidetrihexosidase of sufficient purity
and catalytic activity so that it can be safely administered to patients
with Fabry's disease. Previous replacement trials with small quantities
of this enzyme indicated that it catalyzed the clearance of accumulated
lipid but that much larger quantities of the enzyme would be required in
order to expect a beneficial clinical response. The necessary trials
have been delayed by the presence of pyrogenic material (s) in larger
batches of the enzyme. During the past year satisfactory progress has
been made by the contractor in eliminating this this contaminant
and it is anticipated that further clinical trials will soon be
possible.
Significance to Biomedical Research and to the Program of the Institute:
A principal mission of the Institute is to develop effective procedures
for the treatment of human diseases. If the early encouraging results
with small quantities of enzyme can be extended and enlarged, it is
expected that this form of treatment will be useful for Fabry's patients.
Proposed Course of the Contract: We expect that adequate quantities of
pyrogen- free ceramidetrihexosidase will be made available by the
contractor for clinical trials. If the results that are obtained are
sufficiently promising, a sufficient number of patients will be examined
so that a reliable decision can be made concerning the effectiveness of
enzyme replacement therapy in Fabry's disease.
5 - DMN/IRP
CONTRACT NARRATIVE
Developmental and Metabolic Neurology Branch
Intramural Research Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: WEIZMANN INSTITUTE OF SCIENCE (NOl-NS-0-2333)
Title: Production of Three Radiolabeled Glycol ipid Substances
Contractor's Project Director: David Shapiro, Ph.D.
Current Annual Level of Support: $56,000
Objectives: The enzymatic defects in heritable sphingolipid storage
disorders in humans is ultimately best diagnosed through the use of
radioactively labeled natural lipid substrates. The Weizmann Institute of
Science provides the NIH with radioactive carbon-14 labeled glucocerebro-
side, sphingomyelin, and ceramidetrihexoside for the diagnosis of
patients and detection of carriers of Gaucher's disease, Niemann-Pick
disease, and Fabry's disease respectively.
Major Findings: The principal investigator is a world-recognized expert
in the chemical synthesis of sphinqolipids. He has devised procedures for
incorporating radioactive carbon-1^ into critical portions of sphingolipid
molecules. Using these substrates, we incubate human tissue specimens to
determine the activity of glucocerebrosidase, sphingomyelinase, and
ceramidetrihexosidase enzymes. These determinations permit us to diagnose
patients with the disorders listed above, to identify heterozygous
carriers of these metabolic diseases, and to monitor pregnancies at risk
for any of these conditions. These labeled lipids are also required
to monitor the enzymes for therapeutic replacement trials. During
the past year, the project director completed the synthesis of the first
syanohydrin derivative of a sphingolipid. This analogue will be used in
an attempt to develop rodent model of Gaucher's disease.
Significance to Biomedical Research and to the Program of the Institute:
The ability to diagnose patients, identify heterozygotes, and monitor
pregnancies at risk for any of the known lipid storage diseases represents
major contributions to the control of the incidence of the sphingolipidoses
at the present time.
Proposed Course of the Contract: The contractor will provide necessary
radioactive sphingolipids for diagnostic tests and enzyme purification
procedures. He will develop additional sphingolipid analogues for the
production of animal models of human lipid storage diseases and he will
prepare specific ligands for the purification of various sphingolipid
hydrolases by affinity column chromatography.
DMN/IRP
CONTRACT NARRATIVE
Developmental and Metabolic Neurology Branch
Intramural Research Program, NINCDS
October 1, 1981 through September 30, 1982
Contractor: NEW ENGLAND ENZYME CENTER, TUFTS UNIVERSITY (NOl-NS-5-2321 )
Title: Preparation of Glucocerebrosidase from Human Placental Tissue
Contractor's Project Director: Henry E. Blair
Current Annual Level of Support: $300,000
Objectives: To isolate human placental glucocerebrosidase in sufficient
quantity and purity so tht it can be used in enzyme replacement trials
in patients with Gaucher' s disease.
Major Findings: A procedure has been developed for the large-scale
purification of human placental glucocerebrosidase that is of sufficient
purity and catalytic activity that it can safely be administered to
humans with Gaucher' s disease. The intravenous infusion of this enzyme
to 12 patients with this disorder has brought about the following effects:
(1) The progressive enlargement of the spleen and liver of these patients
has been arrested. (2) The blood platelet count has been stabilized.
(3) The general health and vigor of the recipients has dramatically
improved.
Significance to Biomedical Research and to the Program of the Institute:
One of the principal missions of the Institute is to develop effective
therapy for the treatment of human diseases. If the results obtained
in the initial trials of prospective enzyme replacement therapy
discussed in the preceding paragraph can be extended and confirmed, we
will have accomplished an unprecedented feat.
Proposed Course of the Contract: We have entered the control (third
phase) of this investigation. Recipients have been randomized, some
receiving the enzyme and others only the vehicle used to stabilize the
enzyme preparation. We are also seeking to modify the enzyme so that
it is more efficiently delivered to the specific cells that store the
accumulating lipid. Finally, we shall investigate the possibility of
altering the bloodbrain barrier to try to deliver the enzyme to the
central nervous system in patients with the neuronopathic form of this
disease.
7 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00706-23
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characiers or less)
Inborn Errors of Metabolism of Diverse Etiology.
TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: John A. Barranger, M.D., Ph.D. Chief, Clinical
Investigations and Therapeutics Section
Other: George Constantopoulos, Ph.D. Research
Daniel W. Stovjens, M.D. Clinical
Edward I. Ginns, M.D., Ph.D. Clinical
Norman Barton, M.D., Ph.D. Clinical
Shutish C. Patel, M.D. Medical
Roscoe 0. Brady, M.D. Chief
DMN
NINCDS
Biochemist
DMN
NINCDS
Associate
DMN
NINCDS
Associate
DMN
NINCDS
Associate
DMN
NINCDS
Staff Fellov^
DMN
DMN
NINCDS
NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Clinical Investigations and Therapeutics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.8
PROFESSIONAL:
1.7
0.1
CHECK APPROPRIATE BOX(ES)
[^ (a) HUMAN SUBJECTS
(al) MINORS D (a2) INTERVIEWS
E (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) /\ better Understanding of metabolic
disorders which affect the nervous system is the goal of this project. In some
phases, the studies are purely diagnostic and area applied to assist in identi-
fying the less common disorders of metabolism. Other phases deal with biochemical
observations in known disorders that suggest steps in the pathogenesis of the
disease. In some poorly understood groups of neurologic disease, studies are cor
ducted to draw biochemical correlations where none had previously been known or
were poorly developed. Therapeutic trials are conducted in selected disorders.
A new phenotype of glycerol kinase deficiency has been identified. Pyruvate de-
hydrogenase complex has been examined in subjects with spinocerebellar degenera-
tions. Contrary to published reports, no deficiency of this enzyme has been_
established in any case. Work has begun to examine other oxidative enzymes in
these diseases. In addition, hexosaminidase has been measured in these patients
and found to be normal in all cases. Neurotransmitter alterations have been
suggested by the clinical status of this group and study of their neurotrans-
mitter concentrations and metabolites has begun.
PHS-6040
(Rev. 2-81)
8 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00815-22 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Metabolism of Complex Lipids of Nervous Tissue
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. 0. Brady, Chief
OTHER: P. G. Pentchev, Biochemist
A. E. Gal, Organic Chemist
J. A. Barranger, Section Chief
A. D. Soothe, Veterinary Pathologist
H. Weintraub, Visiting Fellow
N. Sakuragawa, Guest Worker
T. Neff, Chemist
INVESTIGATORS AND ALL OTHER
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
COOPERATING UNITS (if any)
Weizmann Institute of Science, Rehovot, Israel
Tufts University Medical School, Boston, Massachusetts
National Center for Nervous, Mental and Muscular Disorders.
Tokyo, Japan
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Enzymology and Genetics
INSTITUTE AND LOCATION
NlNCnS. NTH. Rpthpsda,
Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
7.6
6.6
OTHER:
1.0
CHECK APPROPRIATE BOX(ES)
D (^) HUMAN SUBJECTS
n (al) MINORS D (a2) INTERVIEWS
n ij^) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
1. Significant excretion of glucocereb^roside via the bile in patients v\(ith
Gaucher's disease has been demonstrated. This observation is consistent with
our previous finding that only a small portion of the daily turnover of
glucocerebroside accumulates and contributes to the pathogenesis of Gaucher's
disease. We propose to investigate how this excretory pathway might be
augmented in order to reduce the accumulation of lipid in this hereditary
metabolic disorder. 2. The chemical synthesis of the cyanohydrin derivative
of glucocerebroside has been accomplished. We intend to use this compound to
select for mutant cells deficient in glucocerebrosidase to develop an animal
model of Gaucher's disease. 3. We have demonstrated the catabolism of
accumulated sphingomyelin by exogenous sphingomyelinase in tissue specimens
from our animal model of human Type C Niemann-Pick disease and we have
improved our procedure for the isolation of sphingomyelinase from human
placental tissue in order to pursue enzyme replacement in Niemann-Pick
disease.
PHS-6040
(Rev. 2-81)
DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01 309-1 7-DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biosynthesis and Function of Glycosphingolipids and Other Glycoconjugates
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: P. H. Fishman, Ph.D., Section Chief DMN NINCDS
OTHER: H. Miller-Podraza, Ph.D., Visiting Fellow DMN NINCDS
R. V. Rebois, Ph.D., Staff Fellow DMN NINCDS
R. 0. Brady, M.D. , Branch Chief DMN NINCDS
COOPERATING UNITS (if any)
Laboratory of Cellular Metabolism, NHLBI
lab/branch
Developmental & Metabolic Neurology Branch
SECTION
Membrane Biochemistry
INSTITUTE AND LOCATION
NINCDS, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.6
PROFESSIONAL:
2.0
0.6
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
H (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) 1. The ganglioside QM] , the receptor
for cholera toxin (CT) , can also function as a receptor for E. coli heat-labile
snterotoxin. Thus, these two pathogenic toxins, which activate intestinal mucosa
adenylate cyclase by the same mechanism of ADP-ribosylation, appear to utilize
bhe same receptor. 2. Although gangliosides function as receptors for bacterial
toxins, they are not involved in the binding and action of glycopeptide hormones
such as LH and hCG. Murine Leydig tumor cells contain gangliosides and bind and
respond to hCG and CT. Using various techniques, GM] was shown to be the CT re-
:eptor in these cells whereas the hCG receptor was found to be a glycoprotein. In
addition, gangliosides were not required for hormone action. 3. Gangliosides are
synthesized inside the cell and then transported to the plasma membrane. Transport
istemperature dependent but not blocked by inhibitors of protein synthesis, cyto .
skeletal assembly or energy metabolism. Synthesis appears to occur at two separat^
ites. Glucosylceramide is formed to the rough endoplasmic reticulum whereas
Further glycosylation occurs in the Golqi apparatus. Several drugs including mo
lensin, an ionophore, block the conversion of glucosylceramide to more complex
glycol ipids by preventing its transport to the second glycosylation site in the
Go 1 g 1 . .
PHS-6040
(Rev. 2-81)
10 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01457-16 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Chemical Synthesis of Radioactive Sphingolipids
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. E. Gal, Chief, Neurochemical Methodology Section DMN, NINCDS
OTHER: F. J. Fash, Bio. Lab. Technician DMN, NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Neurochemical Methodology Section
INSTITUTE AND LOCATION
NINCDS. NIH. Bethesda.
2Q2m.
TOTAL MANYEARS:
0.4
PROFESSIONAL:
0.3
OTHER:
0.1
CHECK APPROPRIATE BOX(£S)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
^(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) In the frameWOrk Of thiS prOJeCt.
Spingolipids containing radioactive isotopes v/ere synthesized and used for
metabolic studies and as diagnostic tools in sphingolipidoses. ^4c and H
labels were introduced by synthetic and semi -synthetic techniques, gas
exposure, and a new approach: functional group exchange. These techniques
were used for the syntheses of radioactive enantiomorphic derivatives of
sphingolipids. These products are not metabolizable. Experimentation with
these in animals creates "animal models" for metabolic diseases and opens
new areas for biomedical studies.
PHS-6040
(Rev. 2-81)
11 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01-NS-01480-15
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Metabolism of Neurohumoral Substances in Marine Animals
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. G. Trams, Chief , Physiology and Metabolism Section, DMN, NINCDS
OTHER: N. Salem, Senior Staff Fellow DMN, NINCDS
C. Lauter, Chemist DMN, NINCDS
J. Doherty, Toxicology Branch, EPA
COOPERATING UNITS (if any)
Mote Marine Lab., Sarasota, Florida
Hazard Evaluation Division, Environmental Protection Agency, Washington, D.C.
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Physiology and Metabolism
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD.
20205
TOTAL MANYEARS:
0.4
PROFESSIONAL:
0.4
CHECK APPROPRIATE BOX(ES)
Q (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
Q((c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) The purpOSe Of thiS prOJect iS tO eX-
plore the great variety and abundance of the marine environment for molecular
models of neurobiology. In particular it was designed to investigate species or
phenomena which display an amplification or simplification of human physiologic
or pathologic metabolism. Further studies were conducted on the neurotoxic
effects of several pesticides in tissue preparations derived from lobster axons
and from manmalian brains. Pyrethroid markedly inhibit calcium and dopamine
uptake in rat brain nerve ending preparations and in lobster plasma membranes.
Comparative studies of brain nucleotide and ecto-enzyme levels in elasmobranch,
teleost, reptile, and avian species demonstrated remarkably similar nucleotide
profiles but widely differing phosphoesterhydrolase activities.
PHS-6040
(Rev. 2-81)
12 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01481-15 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Studies on the Composition and Metabolism of Cellular Membranes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: E. G. Trams, Chief, Physiology and Metabolism Section DMN.NINCDS
OTHER: N. Salem, Senior Fellow DMN,NINCDS
C. Lauter, Chemist DMN,NINCDS
E. MacDonald, Visiting Fellow DMN.NINCDS
S. Patton, Professor, University of California
COOPERATING UNITS (if any)
Dept. of Neurosciences, University of California, San Diego, CA.
lab/branch
Developmental & Metabolic Neurology Branch
SECTION
Physiology and Metabolism
INSTITUTE AND LOCATION
JINCDS , NIH, Bethesda, MP.
20205
TOTAL MANYEARS:
3.3
PROFESSIONAL:
3.3
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n {a2) INTERVIEWS
^ (b) HUMAN TISSUES
n (c) NEITHER
I he objective of this project is to
SUMMARY OF WORK (200 words or less - underline keywords)
lecul
elucidate the relationship between molecular composition and topographic arrange
ments of membrane building blocks with reference to plasma membrane function.
Bioelectrogenesis, transport and many metabolic phenomena are based on the propeij'
associations of membrane proteins and lipids. Membrane ecto-enzymes are glycopro
teins and require a lipophilic environment for optimal activity. Ecto-phospho-
esterhydrolases appear to be a part of a regulatory system which modulates mem-
brane permeability and excitability. We have challenged this system by inacti-
vation of ecto-5-nucleotidase with membrane impermeable modifiers such as Conco-
navalin A or trinitrobenzenesulfonic acid. Cultured brain cells respond by
replacing the surface enzyme and decreasing exfoliation of activity in the form
of microvesicles (exosomes). This response appears to be the result of recogniti
of decreased ecto-5' -nucleotidase activity and a selective conservation of the
enzyme in the exfoliative process. Studies of ATPases in human erythrocyte
membranes of normal and manic-depressive populations suggest that the variations
found in patients with bipolar effective disorders is caused by periodic fluctua
tions in levels of factor(s) which bind to erthrocyte membranes and radically
alter their biological properties.
on
PHS-6040
(Rev. 2-81)
13 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01808-13 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Glycoproteins of Myelin in Development and Disease
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. H. Quarles, Chief, Myelin and Brain Development Section,
DMN, NINCDS
OTHER: R. 0. Brady, Chief DMN, NINCDS
D. Johnson, Visiting Fellow DMN, NINCDS
T. Inuzuka, Visiting Fellow DMN, NINCDS
COOPERATING UNITS (if any)
Cellular Neuropathology Section, LNNS,
Electron Microscopy Section, ID, NINCDS
NINCDS
lab/branch
Developmental and Metabolic Neurology Branch.
NINCDS
SECTION
Myelin and Brain Development
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD.
20205
TOTAL MANYEARS:
4.1
PROFESSIONAL:
3.1
1.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) The myel i n-associ ated qlycoprotein
(MAG) is selectively localized in the periaxonal part of CNS and PNS myelin
sheaths where it is likely to be involved in glia-axon interactions. In the PNS,
it is also present in the outer mesaxon, Schmidt-Lanterman incisures, and the
lateral loops. It is hypothesized that the bulky MAG molecule is responsible for
the greater separation of the Schwann cell membranes in these locations than in
the compact myelin. During peripheral nerve myelination, MAG increases slightly
before the major PO glycoprotein increase. MAG has been identified as the myelin
antigen that reacts with monoclonal IgM in a number of patients with peripheral
neuropathy associated with paraproteinemia. Metabolic studies in developing rat
brain have demonstrated membrane fractions that contain MAG of wery high speci-
fic radioactivity and which may be precursors of compact myelin. There is a^neutrAl
protease in myelin purified from human brain which rapidly converts MAG to a
slightly smaller derivative (dMAG) . This proteolytic activity is significantly
greater in myelin isolated from multiple sclerosis brain than in myelin from
control brain.
PHS-6040
(Rev. 2-81)
14 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02162-08
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Synthesis of Compounds Analogous to Glycol ipids
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. E. Gal, Chief, Sect, on Neurochem. Methodol. DMN, NINCDS
OTHER: F. J. Fash, Bio. Lab. Technician DMN, NINCDS
COOPERATING UNITS (if any)
None
lab/branch
nevelnpmental and Metabolic Neurology Branch
SECTION
Neurochemical Methodology Section
INSTITUTE AND LOCATION
tot^MP^arHIH' Bothcoda^^jjl^g^i^^r^d 20205
IU4.
IL2.
JLL
CHECK APPROPRIATE BOx(ES)
D (a) HUMAN SUBJECTS
□ (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
j^ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Conduritol B-epoxide. a saccharide that strongly inhibits e-glucosidases,
was synthesized by a method developed by this section that provides the
product in greater yield than previously available and permits the preparation
of this compound containing a tracer with extraordinarily high specific
radioactivity. Administration of conduritol g-epoxide to animals produces a
syndrome that resembles Gaucher's disease in humans by inhibiting the enzyme
glucocerebrosidase. Radioactive conduritol p-epoxide reacts with the active
site of glucocerebrosidase isolated from normal human tissues and from
patients with Gaucher's disease. This use of the radioactive conduritol
6-epoxide will materially accelerate the identification of the amino acid
substitutions (or deletions) that occur in the glucocerebrosidase molecule in
patients with Gaucher's disease.
PHS-6040
(Rev. 2-81)
15 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02163-08
PERIOD COVERED
October 1, 1981 through September 30 ^
1982
TITLE OF PROJECT (80 characters or less)
Development of Special Analytical Methods and Preparative Techniques to
Investigate the Etiology and Therapy of the Sphingolipidoses
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: A. E. Gal, Chief, Neurochemical Methodology Section DMN NINCDS
OTHER: F. J. Fash, Biol. Lab. Technician DMN NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Developmental and Metabolic Neurology Branch
Neurochemical Methodology Section
INSTITUTE AND LOCATION
TOTAL MANYEARS:
NINCDS. NIH. Bethesda. Maryland 20205
_QJ_
PROFESSIONAL:
JLA.
iLJl.
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS 0 (a2) INTERVIEWS
H<(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
New analytical techniques were developed and used in enzymatic research and
in clinical investigations of lipidoses. The lipid content in human tissues,
the diagnosis of lipid storage diseases by gas, thin- layer chromatography
and other techniques were studied at the microgram level. The techniques we
developed previously were improved, modified and used in connection with
ongoing projects related to lipidoses in our laboratories and also as joint
projects with outside groups. Numerous analytical studies were undertaken by
using these techniques. Complex lipids were determined in pericardium,
in human gl ionic cell lines, erythrocyte lipids and in tissues from patients
with lipofuscinosis.
PHS-6040
(Rev. 2-81)
16 - DMN/IRP
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02366-04
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Regulation of Hormone-Responsive Adenylate Cyclase
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: P. H. Fishman, Ph.D., Section Chief DMN, NINCDS
OTHER: S. Kassis, Ph.D., Visiting Fellow DMN, NINCDS
R. V. Rebois, Staff Fellow
COOPERATING UNITS (if any)
Laboratory of Molecular Biology, NINCDS
lab/branch
Developmental & Metabolic Neurology Branch
SECTION
Membrane Biochemistry
NSTITUTE AND LOCATION
NINCDS. IRP, Bethesda, Maryland 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
2.1
1.4
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
?}C(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) I.Hela CellS COntain g-adrenerqic
receptors (gAR) but respond poorly to 3-agonists. Cells treated with butyrate
(Bu) become highly responsive and acquire more gAR. By using membrane fusion
techniques, pAR from control and Bu-treated cells were shown to be equally
effective in stimulating adenylate cyclase (AC) in membranes that lack BAR. Bu
also induced an increase in GTP-binding components (N) as measured by cholera
toxin-catalyzed ADP-ribosylation and reconstitution into eye" membranes that
lack N. Both N from control and Bu-treated HeLa were able to couple AR and AC
present in eye" membranes. Thus, Bu induces not only AC components in HeLa but
also increased coupling of the components. 2. Incubation of membranes from human
fibroblasts with either g-agonists or PGE-, results in desensitization of AC. The
process is time and temperature dependent and requires GTP. As was observed in
intact cells, PGE, causes a heterologous desensitization whereas 3-agonists
cause a homologous one. 3. When exposed to hCG, murine Leydig tumor cells lose
their responsiveness to hCG (desensitization) , their hCG receptors (downregula-
tion) and degrade bound hCG in that temporal sequence. Preliminary results indi
cate that initially the receptors become uncoupled from AC, then internalized an
degraded along with bound hCG. '-
PHS-6040
(Rev. 2-81
17 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02433-03
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Models of Lysosomal Storage Disease.
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
John A. Barranger, M.D., Ph.D.
Investigations and Therapeutics
Other: George Constantopoulos, Ph.D.
Igal Gery, Ph.D.
F. Scott Furbish, Ph.D.
Peggy Rands
Susan H. Sorrel 1
Gary J. Murray, Ph.D.
Edv^ard I. Ginns, M.D., Ph.D.
Norman Barton, M.D., Ph.D.
Roscoe 0. Brady, M.D.
Chief, Clinical
Section
Research Biochemist
Visiting Scientist
Staff Fellov^
Guest Worker
Chemist
Visiting Associate
Clinical Associate
Clinical Associate
Chief
DMN NINCDS
DMN NINCDS
LVR NEI
DMN NINCDS
DMN NINCDS
DMN NINCDS
DMN NINCDS
DMN NINCDS
DMN NINCDS
DMN NINCDS
COOPERATING UNITS (if any)
Laboratory of Vision Research, NEI
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Clinical Investigations and Therapeutics
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.5
PROFESSIONAL:
2.0
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
H (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) Human storage di sease cel Is in culture
and a mutant GM-) gangliosidosis cat have been used for these studies. Study of
physiologic and biochemical parameters of these models is aimed at defining the
milieu in which enzyme replacement studies are conducted. Macrophages derived
from circulating monocytes will survive in culture for approximately two weeks.
Under special conditions, dividing cultures have been established without the use
of transforming virus. These cells have survived more than six months. Alteratic
of lysosomal enzymatic activities have been recorded in both short and long term
cultures. Estimation of lectin occurrence and function in these cells has been
evaluated. The ability of cells to incorporate added lipids has been measured.
Catabolism of added lipid has been compared in control and disease cells. Studie|s
in the cat mutant have revealed that human placental g-galactosidase can be
delivered to brain following blood-brain barrier opening. The placental enzyme
loses about half its activity in human plasma and thus may not be ideal for
enzyme replacement trials. Preparation of a more stable enzyme from feline or
bovine tissues has begun. Further characterization of the cat mdoel as a model
for enzyme replacement in neurological disorders is progressing.
PHS-6040
(Rev. 2-81)
18 -DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02434-03 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Studies of Lysosomal Function: Receptor-Mediated Pinocytosis of Lysosomal Enzymes
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
John A. Barranger, M.D., Ph.D. Chief, Clinical
Investigations and Therapeutics Section
F. Scott Furbish, Ph.D.
Edward I. Ginns, M.D., Ph.D.
Norman Barton, M.D., Ph.D.
Susan H. Sorrel 1
Gary J. Murray, Ph.D.
Peggy Rands
Roscoe 0. Brady, M.D.
Staff Fellov^
Clinical Associate
Clinical Associate
Chemist
Visiting Associate
Guest Worker
Chief
AND ALL
OTHER
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
DMN
NINCDS
COOPERATING UNITS (if any)
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Clinical Investigations and Therapeutics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.0
PROFESSIONAL:
1.5
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
□((b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) The Uptake Of active glycoprotein
lysosomal enzymes occurs, in part, through the mechanism of adsorptive pino-
cytosis. Receptors for various parts of the enzyme molecule as ligands are
present on the plasma and organelle membranes. It is the purpose of this project
to study these receptors and tuilize them for targeting enzymes to cells. These
binding capacities may also play a role in localizing glycoproteins within the
cell and thus may have a bearing on the survival of enzymes that have been
incorporated into the cell. Studies are directed toward increasing the survival
of exogenous enzymes within certain subcellular organelles. The goal is to
increase the interaction of exogenous enzyme with stored material in the cell and
increase the efficiency of enzyme replacement. Studied will be carried out in
rats and later in human macrophages. Studies of the distribution of glucocerebro
sidase confirm that infused enzyme can reach the lysosome and does not require th
ligand mannose-6-phosphate (M-6-P). Moreover, hepatocytes lack a endocytic
lectin with M-6-P specificity.
PHS-6040
(Rev. 2-81)
19 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02435-03
PERIOD COVERED
October 1, 1981 through September 30. 1982
TITLE OF PROJECT (80 characters or less)
Studies On The Mechanism Of Pathogenesis Of The Mucopolysaccharidoses,
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: George Constantopoulos, Ph.D. Research Biochemist
Other: Roscoe 0. Brady, M.D. Chief
John A. Barranger, M.D., Ph.D. Chief, Clinical
Investigations and Therapeutics Section
DMN NINCDS
DMN NINCDS
DMN NINCDS
COOPERATING UNITS (if any)
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Clinical Investigations and Therapeutics
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
1.5
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
a (al) MINORS n (a2) INTERVIEWS
fl (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) The mUCOpolySaCChari doSeS (MPS) are 3
group of hereditary diseases characterized by defective metabolism of glycosamino
glycans (GAG). The disorders are usually associated with severe dysfunction of
the nervous system as well as of liver, spleen, heart, bone, and other tissues
Objective of this project is the study of mechanism of pathogenesis of these
diseases with emphasis on brain involvement and mental retardation. We are using
a comparative approach. For this purpose we study the changes in GAG, sphingo
lipids, and pertinent lysosomal enzymes in tissues of patients with various types
of MPS and we make correlation in terms of clinical and ultrastructural findings
Our laboratory contributed significantly in understanding the chemical pathology
and in particular the neurochemistry of MPS IH, MPS IS, MPS II, MPS III A and
MPS III B. To complement the studies with human subjects, a drug (suramin) in-
duced animal model of MPS has been developed and a canine model , (natural) , of
MPS I is being studied. Both animal models may prove useful for understanding
the pathogenesis of MPS and in the development and assessment of therapeutic
trials by enzyme replacement.
PHS-6040
?n - nMM/TRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02453-02
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Gaucher' s Disease: Biochemical and Clinical Studies.
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: John A. Barranger, M.D., Ph.D.
Investigations and Therapeutics
Roscoe 0. Brady, M.D.
Other: F. Scott Furbish, Ph.D.
Edward I. Ginns, M.D., Ph.D.
Daniel Stowens, M.D.
Norman Barton, M.D., Ph.D.
Shutish C. Patel, M.D.
Susan H. Sorrel
Gary J. Murray, Ph.D.
Peggy Rands
Carol Moore
S OF PRINCIPAL INVESTIGATORS
AND ALL
OTHER
Chief, Clinical
Section
DMN
NINCDS
Chief
DMN
NINCDS
Staff Fellow
DMN
NINCDS
Clinical Associate
DMN
NINCDS
Clinical Associate
DMN
NINCDS
Clinical Associate
DMN
NINCDS
Medical Staff Fellow
DMN
NINCDS
Chemist
DMN
NINCDS
Visiting Associate
DMN
NINCDS
Guest Worker
DMN
NINCDS
Biologist
DMN
NINCDS
COOPERATING UNITS (if any)
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Clinical Investigations and Therapeutics
NSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOx(ES)
S (a) HUMAN SUBJECTS
D (al) MINORS n {a2) INTERVIEWS
?] (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords) G1 ucocerebros i dase from human placenta
has been purified to homogeneity and characterized kinetically. The carbohydrate
content of the purified protein is 6%; composition and structure of the sugar
moieties have been estimated. The molecular weight of the enzyme is 67,000 daltdns,
Several different isoelectric forms of the enzyme from white cells have been
identified. Further work led to the identification of multiple allelic mutations
in Gaucher's disease which distinguish the clinical sub-types. These isozymes
differ in molecular weight and preliminary evidence suggests they are processed
differently during synthesis. Polyclonal and monoclonal antibodies have been
raised to enzyme and work is in progress to isolate the gene. Clinical studies
in the disease have (1) identified an immune defect ,"T2) further characterized th|e
hepatic complications and (3) described a rational approach to the neurologic
symptoms by an analysis of the neuropathology and responses to a number of neuro
transmitter agonists and antagonists. Serum lipoprotein abnormalities and the
role of the macrophage in manifestations of the disease are being studied. Patho
genesis of the bone lesions are being defined and therapeutic strategies have
been indicated.
PHS-6040
(Rev. 2-81)
21 - DMN/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAHURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02529-01 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development of Enzymes That Inactivate Neurotoxic Agents
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R. 0. Brady, Chief
OTHER: J. M. Poston
A. E. Gal
DMN NINCDS
LB NHLBI
DMN NINCDS
COOPERATING UNITS (if any)
Laboratory of Biochemistry, NHLBI
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Enzymology and Genetics
INSTITUTE AND LOCATION
NTNCnS, NTH, Ret.hps.f1a. Maryland 20205
TOTAL MANYEARS:
0.2
PROFESSIONAL:
0.2
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n {a2) INTERVIEWS
n (b) HUMAN TISSUES
n>(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
An enzyme that degrades barbital has been identified and partially purified
from extracts derived from a soil microorganism. The requirements for maximal
catalytic activity are being determined. The ability of this enzyme to
reverse lethal quantities of barbital will be investigated in toxicological
experiments with appropriate animals. If this approach proves successful,
enzymes that inactivate other neurotoxins wil 1 be developed in this fashion.
PHS-6040
(Rev. 2-81)
22 - \m/lRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02530-01 DMN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Development of Non-sensitizing Thrombolytic Enzyme Preparations
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J. Nev>;mark
OTHER: R. 0. Brady, Chief
A. Abuchov/ski
G. Murano
DMN NINCDS
DMN NINCDS
Rutgers University
Bu. Biologies, FDA
COOPERATING UNITS (if any)
Department of Biochemistry, Rutgers University
New Brunswick, NJ
lab/branch
Developmental and Metabolic Neurology Branch
SECTION
Enzymology and Genetics
INSTITUTE AND LOCATION
NTNrn^, NTH, Rpt.hP^Ha, Maryland 20205
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SUMMARY OF WORK (200 words or less - underline keywords)
Adducts of streptokinase and strep toki nase-pl asmi nogen complex with
polyethylene glycol and the pluronic polyol F38 were prepared with the aim of
developing a non-sensitizing form of streptokinase. The adducts were much
less antigenic than the native protein or protein complex. Full amidolytic
activity was retained when catalysis was measured with a chromogenic
substrate. However, dissolution of fibrin clots by the adducts was greatly
reduced from that obtained with native streptokinase.
PHS-6040
(Rev. 2-81)
23 - DMN/IRP
>
CO
ANNUAL REPORT
October 1 , 1 981 through September 30 , 1 982
Experimental Therapeutics Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-12
PROJECT REPORTS
Biochemical and Pharmacological Studies of 13
Dopamine Receptors
ZOl NS 02263-06 ET
Pharmacology and Physiology of Central 14
Neurotransmitters
ZOl NS 02139-08 ET
Pharmacology, Biochemistry and Physiology of 15
Central Neurotransmitters
ZOl NS 02265-06
Therapeutic Studies in Parkinsonism and 1 6
Other Movement Disorders
ZOl NS 02258-06 ET
Diagnostic and Therapeutic Reevaluation of Patients 17
with Intractable Epilepsy
ZOl NS 02236-07 ET
Clinical Pharmacology of Antiepileptic Drugs 18
ZOl NS 02318-05 ET
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ANNUAL REPORT
October 1, 1981 through September 30, 1982
Experimental Therapeutics Branch, IRP
National Institute of Neurological and Communicative Disorders and Stroke
Thomas N. Chase, M.D., Acting Chief
The past year has witnessed several important changes in Branch organization
and activities. Dr. Donald B. Calne, former Branch Chief left NIH _ f or an
academic post in Vancouver, Canada. His Therapeutics Section, which_ has
continued active under the leadership of Dr. Peter LeWitt, will be discontinued
at the end of this fiscal year. A search for a new ETB Chief has_ now been
initiated. The Branch moved from its Building 36, 5A corridor and Building 10,
6D corridor facilities to contiguous laboratory and office space on the 5th
floor of the ACRE. Despite these changes, the basic thrust of the Branches
scientific activities, directed towards the improved treatment of neurologic
disease, has remained essentially unchanged.
BIOCHEMICAL NEUROPHARMACOLOGY SECTION
1. Direct Identification of the D-2 Dopamine Receptor in the Intermediate
Lobe of the Rat Pituitary Gland
The hypothesis that two categories of dopamine receptors exist
continues to gain support. It was especially gratifying that the paper
putting forward the two dopamine receptor hypothesis was the second most
highly cited Life Science paper in the period 1979 to 1981. In FY '81 the
efforts of the section were directed towards providing experimental
evidence to back up this hypothesis.
In FY '81, experiments were performed to directly identify the D-2
dopamine receptor in the intermediate lobe (IL) of the rat pituitary
gland. The rationale behind these experiments was to use radiolabeled
spiroperidol to identify specific binding sites in the IL and to compare
the properties of the specific binding site to the properties of the
dopamine receptor inhibiting adenylate cyclase activity (which had been
characterized in FY '80). The experimental conditions used in the binding
assays replicated (as closely as possible) the experimental conditions
used to determine adenylate cyclase activity in order to facilitate the
comparison of the data obtained in the two different assays.
The IL of the rat pituitary gland contains 16 fmole of high affinity
specific spiroperidol binding sites. The density of these binding sites
in the IL (8.3 pmole/g tissue) is equivalent to the density of
spiroperidol binding sites in the neostriatum. The properties of the IL
spiroperidol binding sites have been characterized in experiments testing
the ability of various drugs to compete with the radiolabeled ligand for
occupancy of the specific binding site. With the exception of (-)-
sulpiride, the rank order of potency of dopaminergic compounds in the
spiroperidol binding assay and the adenylate cyclase assay were similar.
Furthermore, for each drug tested, the apparent affinity constant derived
from the two assays agrees within an order of magnitude. Therefore we
have adopted the "working hypothesis" that some or all of the specific
spiroperidol binding sites in the IL are the dopamine receptors inhibiting
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adenylate cyclase activity in the homogenates of IL tissue. In contrast
to the good agreement obtained in the two biochemical assays, the intact
IL cells respond to agonists at 100-fold lower concentrations than are
required to elicit either biochemical response in the cell-free assay
systems. A similar discrepancy is encountered for the beta-adrenoceptor
in the IL. An understanding of the basis for these discrepancies may add
to our understanding of the biochemical basis for dopamine receptor
activity.
The binding experiments in the intermediate lobe are of some
theoretical interest. Although binding experiments claiming to identify
dopamine receptors are extremely popular, the value of this approach is
limited because there are few in vitro measurements with which the results
of the binding experiments can be compared. However, in the case of the
experiments performed with the intermediate lobe, the data can be compared
with the results obtained from adenylate cyclase assays which were
performed under identical conditions. It might be anticipated that the
data obtained in the intermediate lobe would provide the standard against
which other dopamine receptor binding studies would be compared.
2. Coordinated Action of Calcium and cAMP on the Release of Alpha-MSH from
the IL
Calcium and cyclic AMP participate in the specific cellular events
leading to secretion from a variety of cells. Previous investigators had
shown that calcium was essential for the stimulated release of alpha-MSH
from the intermediate lobe. During FY '81, calcium was shown to
participate in the release of alpha-MSH elicited by a variety of drugs
affecting cyclic AMP metabolism. Thus, calcium was essential for the L-
isoproternol-, the 3-isobutyl 1-methylxanthine-, or the cholera toxin-
induced release of alpha-MSH. In the case of each drug tested, a fixed
concentration of calcium elicited more release from cells with enhanced
synthesis or content of cAMP.
3. YM-09151-2, a Selective D-2 Antagonist
YM-09151-2, (cis-N-(l-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-
methoxy-4-methyl-aminobenzamide) , a substituted benzamide, was shown to be
a potent antagonist of the dopamine receptor in the intermediate lobe of
the rat pituitary gland. Assuming that YM-09151-2 and dopamine compete
for occupancy of the D-2 receptor, the affinity of the interaction between
the antagonist and the receptor was calculated as 10.5 nM. YM-09151-2 was
approximately equipotent with fluphenazine as a dopamine antagonist, and
was significantly more potent than the other substituted benzamides
tested. YM-09151-2 was found to be an extremely weak antagonist of the D-
1 receptor in the fish retina. Therefore because YM-09151-2 can
discriminate between these two categories of dopamine receptor, it may
prove to be a useful tool for investigating the pharmacology of the
receptors mediating the physiological effects of dopamine.
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4. A D-2 Dopamine Receptor in the Neostriatum
Previously, we had proposed that in the neostriatum both D-1 and D-2
dopamine receptors regulate the efflux (and by inference the formation) of
cyclic AMP. Stimulation of the D-1 receptor increases the formation of
cyclic AMP. Stimulation of the D-2 dopamine receptor reduces the cAMP
formation stimulated by D-1 agonists. Based on experiments performed in
FY '81, we hypothesize that the inhibitory effect of D-2 agonists upon
cyclic AMP formation results from a direct interaction between the D-1 and
the D-2 receptor. This conclusion is based on the observation that the
inhibitory effect of D-2 agonists persists in the absence of calcium ions
in the superfusion medium.
Previously, selective D-2 dopamine receptor agonists had been shown
to cause an accumulation of acetylcholine in the neostriatum of the rat
brain. In the present experiments, selective D-2 receptor agonists were
shown to inhibit the potassium-evoked release of acetylcholine. In
contrast, the selective D-1 agonist, SKF 38393, did not inhibit
acetylcholine release. The inhibitory effect of the D-2 agonists could be
reversed with (-)-sulpiride. These observations suggest that the rn vivo
accumulation of acetylcholine may arise as a consequence of diminished
release of acetylcholine. Such an action of selective D-2 agonists may be
of theoretical interest for the treatment of Parkinson's disease. A
balance between the dopaminergic and the cholinergic system is thought to
participate in the regulation of extrapyramidal function by the
neostriatum. The deficiency of neostriatal dopamine occurring in
Parkinsonism disrupts this balance between dopamine and acetylcholine. It
is conceivable that the D-2 dopaminergic agonists used in the treatment of
Parkinsonism (e.g., bromocriptine, lergotrile or lisuride) may achieve
some of their therapeutic effect by interacting with a D-2 dopamine
receptor on cholinergic interneurons, inhibiting the release of
acetylcholine and restoring the balance between dopaminergic and
cholinergic function in the neostriatum. However, the selective D-2
agonists may have additional effects entirely unrelated to cholinergic
activity in the neostriatum (the inhibition of the efflux of cyclic AMP
stimulated by D-1 agonists is an example of such an effect of D-2
agonists) .
PHYSIOLOGICAL NEUROPHARMACOLOGY SECTION
1 . Physiological effects of dopamine and dopamine agonists in the basal
ganglia.
To gain insight into how dopamine and the dopamine agonists affect
information processing in the basal ganglia, we have been examining the
effects of these agents at sites where information funnels out of the
basal ganglia, the pars reticulata of the substantia nigra and the globus
pallidus. The actions of dopamine agonists at these sites have been
compared with their effects on the activity of dopamine neurons
themselves.
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a. Substantia Nigra Pars Reticulata Studies
We have continued our investigations of the direct and indirect
effects of dopamine and dopamine agonists on the activity of tonically
firing neurons in the substantia nigra pars reticulata, concentrating on
confirming and extending our earlier observation that iontophoretically-
applied dopamine can consistently and markedly diminish the inhibitory
effects of iontophoresed gamma-aminobutyric acid (GABA) on the neurons in
this region. The consistent modulatory interaction of dopamine and GABA
appears, to date, to be specific for these two transmitters,
lontophoretically-applied dopamine has more variable effects upon
responses of reticulata cells to glycine. Similarly, no consistent
modulatory interactions have been detected between dopamine and either of
two transmitters known to stimulate reticulata cell firing, acetylcholine
and glutamic acid. These results demonstrate that the potential exists
for dopamine, released from dendrites within the pars reticulata, to serve
an important local function, downstream from the striatum, adjusting or
"fine-tuning" the relay of striatal commands to premotor nuclei outside
the basal ganglia.
Studies were undertaken to determine whether similar modulatory
interactions between dopamine and GABA could occur as a consequence of
endogenous local release of dopamine from dendrites of neighboring pars
compacta dopamine neurons. d-Amphetamine, a drug reported to induce
release of dopamine from dendrites within the substantia nigra, could also
attenuate responses of reticulata neurons to GABA. This effect was found
to be dependent upon the existence of an intact dopamine system in the
substantia nigra. Moreover, studies in rats with lesions of the dopamine
neurons, indicate that the dopamine receptors involved in the modulatory
interaction may ultimatley become supersensitive in a dopamine deficient
substantia nigra.
The ability of amphetamine to attenuate reticulata cells' responses
to GABA, observed in rats with intact nigral dopamine systems, provides
evidence of a physiological role of dopamine, presumably released from
dendrites, as a modulator of GABA effects on substantia pars reticulata
neurons projecting to pre-motor nuclei outside the basal ganglia.
However, the observation that amphetamine could induce changes in the
baseline firing rates of reticulata cells, even in rats with apparently
effective unilateral lesions of the nigrostriatal dopamine pathway,
suggested that this drug can also alter the activity of these neurons by
other mechanisms.
b. Globus Pallidus Studies
In the globus pallidus, as in the substantia nigra, we have confirmed
and extended our previous finding that dopamine modulates GABA-induced
inhibition of pallidal activity. Since the dopamine neurons of the
substantia nigra pars compacta are known to send a sparse but widespread
projection to the globus pallidus, it seemed possible that endogenous
dopamine might be able to exert a similar modulatory effect on the actions
of GABA in this brain region. It was found that after amphetamine
administration, 45% of the cells recorded showed attenuated responses to
iontophoresed GABA. These results suggest that under normal conditions,
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pallidal dopamine may be able to exert a modulatory effect on the actions
of GABA released from striatopallidal fibers. This ability of endogenous
dopamine to modulate GABA's effects in the globus pallidus may also
contribute to the pharmacological effects of systemically-administered
dopamine agonists in the basal ganglia.
In the past year, we have continued our investigations of the effects
of systemically administered dopamine agonists on the activity of
tonically firing pallidal neurons, since pallidal cells are in a good
position to reflect the net effects of these drugs on dopamine receptors
at several sites in the basal ganglia. Results from studies with
norepinephrine and serotonin agonists suggest that dopamine receptor
stimulation is more effective than serotonin or norepinephrine receptor
stimulation at inducing increases in pallidal activity. The effects of
dopamine agonists with putatively selective actions at specific
subcategories of dopamine receptors were also examined. There is
currently considerable interest in the possibility that there may be
subtypes of the D-2 receptor (such as the presynaptic dopamine receptor)
with specific functions which could be differentially manipulated
pharmacologically. If dopamine agonists selective for some of these
dopamine receptor subtypes can be found, it is hoped they might be useful
in the treatment of disorders such as tardive dyskinesia or
schizophrenia. Pallidal effects of SK&F 38393, a drug which
preferentially stimulates D-1, as opposed to D-2, dopamine receptors in
the striatum, and 3-PPP, a drug thought to preferentially affect
presynaptic dopamine receptors, have been investigated. The results
suggest that drugs thought to be effective at selectively stimulating D-1
or presynaptic dopamine receptors do not significantly alter pallidal
firing rates. The increase in pallidal activity which have been observed
with apomorphine, lisuride and pergolide administration appear to be
related to their postsynaptic D-2 dopamine receptor stimulating
properties. Comparisons of the effects of dopamine agonists on the
activity of dopamine cells and pallidal neurons may provide useful
information about the j^ vivo selectivity of new dopamine agonists and
antagonists and help establish the physiological relevance of the various
binding and biochemical tests currently used to screen for agents with
selective dopamine agonist properties.
We have also continued in the past year to explore a second aspect of
the effects of apomorphine on the activity of tonically firing pallidal
neurons. As reported previously, the administration of small non-
excitatory doses of this drug has an apparent priming effect on the
system; subsequent administration of larger doses which would normally
cause a significant excitation of the cells' activity now causes only a
small change in firing rate. Since it seemed possible that this priming
effect of apomorphine might provide insight into the mechanism behind the
paradoxically useful effects of dopamine agonists in treatment of tardive
dyskinesia and schizophrenia, we have explored it further. Studies have
shown that the phenomena is not unique for apomorphine; similar results
have been observed with a second dopamine agonist, lisuride. In addition,
a priming dose of apomorphine has been shown to alter the response of the
pallidal neurons to amphetamine and haloperidol. Binding studies have
ET/IRP
been undertaken to determine whether small doses of a dopamine agonist can
alter the ability of the striatum and globus pallidus to bind
spiroperidol, i_n vitro, but the results have been inconclusive to date.
2. Physiological effects of GABA and GABA agonists in the basal ganglia.
In our previous investigations of the role of the striatonigral
GABAergic pathway in the substantia nigra, we found that benzodiazepines,
drugs thought to act by potentiating the effects of GABA, have inhibitory
effects on the firing rates of neurons in the substantia nigra pars
reticulata. Recent findings from studies of the interactions between GABA
agonists and antagonists, and the benzodiazepines are consistent with
previous reports which suggest that the benzodiazepines may act through a
GABAergic mechanism. While it has been proposed that the benzodiazepines
may also act by blocking the reuptake of adenosine, thereby potentiating
the depressant action of this endogenous inhibitory substance, results
from our iontophoretic studies suggest that a potentiation of adenosine's
actions cannot account for the inhibitory effects of the benzodiazepine on
pars reticulata neurons. Additional studies with RO 15-1788, an
imidazodiazepine thought to function as a specific benzodiazepine
antagonist suggest that cells of the substantia nigra pars reticulata do
not receive a substantial tonic inhibition mediated by an endogenous
benzodiazepine-like substance. They also indicate that the
methylxanthines increase reticulata cell firing, at least in part, through
mechanisms unrelated to the blockade of benzodiazepine receptors.
PHARMACOLOGY SECTION
1 . Positron Emission Tomography Studies
Regional neuronal activity has now been studied in 12 patients with
clinically diagnosed Alzheimer's disease by means of positron emission
tomography (PET) following intravenous l8-F-2-fluoro-2-deoxyglucose
administration. These investigations seek to correlate various aspects of
cognitive function with regional cortical metabolic activity. Results to
date indicate that performance on standardized tests of general cognitive
function tend to correlate with overall cortical metabolic rates for
glucose. Moreover, patients with aphasia out of proportion to their other
cognitive deficits had substantial reductions in glucose utilization in
the left temporal and parietal regions; those with disproportionately
severe constructional apraxia evidenced a prominent hypometabolic focus
involving the right parietal lobe. Combined results from all patients
studied thus far suggest that the cortical distribution of regions in
which there is a close positive correlation between language performance
and cerebral metabolism, while varying with the specific function tested,
tend to cluster in the left frontal, temporal, and parietal areas. On the
other hand, the cortical localization of regions having a close
association between visuo-constructive test performance and glucose
metabolism tended to aggregate in the posterior right hemisphere. Since
these localizations generally agree with those provided by other means,
attempts to map a broad range of cortical functions have now begun.
Future applications of the f luorodeoxyglucose - positron emission
tomographic technique will be directed towards the validation — by means of
various pharmacologic and physiologic manipulations of cerebral function —
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o£ the localizing hypothesis generated by the present investigations, as
well as the search for regional abnormalities in neuropsychiatric
disorders, such as dystonia and Tourette's syndrome, where no pathologic
changes have been found to account for clinical symptoms.
2. Cerebrospinal Fluid
During the past year it has been found that the administration of the
experimental GABA agonist, TRIP, is associated with a significant
elevation in CSF homovanillic acid, the major metabolite of dopamine.
This observation suggests that TRIP may stimulate dopaminergic function
and could explain the lack of antidyskinetic efficacy of this agent.
3. Dopamine Agonists
The ability of dopamine receptor agonists to ameliorate hyperkinetic
extrapyramidal disorders continues to be evaluated. These investigations
are based on the hypothesis that dopamine agonists which preferentially
stimulate dopamine autoreceptors might inhibit dopaminergic transmission
and thus diminish neurologic and psychiatric symptoms reflecting
hyperfunction of this system. Since data supporting this contention in
part derive from previous experience with apomorphine, current studies
have focused on n-propylnorapomorphine (NPA), a relatively non-toxic
apomorphine derivative, suitable for oral administration. Results from an
acute, rising dose, double-blind, placebo-controlled study revealed
antipsychotic and antianxiety activity in a group of drug-free
schizophrenic patients. In each patient the antipsychotic response to NPA
appeared to correlate with their response to neuroleptic drugs, supporting
the view that NPA may act at the dopamine autoreceptor to mimic the
clinical effects of neuroleptics. An extension of these studies to
patients with tardive dyskinesia is now planned. In addition, a new and
apparently extremely selective dopamine autoreceptor agonist, EMD 23 448,
will now be tested in similar manner for evidence of antipsychotic and
antidyskinetic activity.
4. GABAmimetic Drugs
Based on preclinical biochemical and pharmacologic observations
suggesting that augmentation of GABA-mediated synaptic function may
benefit patients with tardive dyskinesia and related naturally occurring
or drug-induced hyperkinetic extrapyramidal disorders, clinical studies of
two experimental GABAmimetic compounds have been conducted during the past
year. Gamma-vinyl GABA blocks GABA degradation in the brain, by
inhibiting GABA-transaminase. Five patients with tardive dyskinesia, who
were free from other centrally active medication, have now been evaluated
during the oral administration of this compound. All evidenced some
diminution in their dyskinesia. Since no significant side effects
occurred, studies with this compound will continue. In addition, the
therapeutic efficacy of orally administered TRIP, a selective GABA
receptor agonist, has been evaluated in four patients with classical
Huntington's disease and one with the rigid-akinetic form of this
disorder. No consistent improvement in motor or cognitive function was
observed. At maximum dose levels, however, TRIP mimicked another putative
GABA agonist, muscimol, in producing unsteadiness of gait, diminished
7 - ET/IRP
attention to sensory stimuli, and somnolence, thus supporting the view
that central GABA systems participate in the regulation of certain motor
and behavioral functions in man.
5. Cholecystokinin
Laboratory studies with cholecystokinin octapeptide (CCK-8) have
sought to extend previous findings and identify the central mechanism of
CCK-8 interaction with the dopamine system. CCK-8 occurs in some
dopamine-containing neurons and thus might affect dopamine-mediated
synaptic transmission. Our previous observation that systemically
administered CCK-8 possesses some neuroleptic-like activity has now been
confirmed and extended. The neuroleptic-like effects occur at relatively
low dose levels and are not mimicked by tetragastrin, a 4 amino acid
peptide possessing most of the gut actions of CCK-8. This latter finding
supports the view that the behavioral effects of CCK-8 reflect a centrally
mediated response to the peripherally administered neuropeptide. Recent
studies also indicate that tolerance may occur in avoidance paradigms to
the repeated administration of CCK-8; the mechanism of this effect is now
being investigated. In related studies the structure-activity
relationships of sulfated, N-terminal analogues of CCK-8 are being
explored. One such CCK-8 fragment appears to antagonize the effects of
CCK-8 when tested in the pancreatic acinar cell bioassay, suggesting that
products of CCK-8 degradation may inhibit the primary action of the parent
peptide.
6. Substance P
Laboratory investigations of the behavioral effects of systemically
administered substance P and several of its biologically active fragments
have remained active in collaboration with the Department of Psychology,
University of Colorado. Studies during the past year have revealed that
the subcutaneous post-trial administration of the neuropeptide reverses
the amnestic effects of electroconvulsive shock or cycloheximide in both
inbred and genetically heterogeneous mice. Peripheral injection of
substance P was also found to facilitate the retention of a single-trial
passive avoidance habit in animals of both genotypes, provided a weak
foot-shock was used during training. Further studies are now planned to
elucidate the mechanisms by which exogenously administered substance P may
influence memory processing in the mammalian central nervous system.
7. Neuroendocrine
Additional evidence of hypothalamic dysfunction in Huntington's
disease (HD) has been found during the past year. Our results now
indicate that circulating daily growth hormone levels are significantly
elevated in HD women as compared with matched controls, and further that a
higher peak response occurs with either dopamine agonist (apomorphine) or
GABA agonist (muscimol) stimulation in male or female HD patients than in
control subjects. Since no consistent abnormalities in basal or
stimulated prolactin levels were found, it appears unlikely that dopamine
system hyperactivity could account for the growth hormone changes. The
search for alternative explanations led to measurements of somatostatin
(SRIF), the hypothalamic hormone which inhibits growth hormone release, in
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the suprachiasmatic hypothalamus. While SRIF levels tended to be lower in
HD subjects, no statistically significant difference could be documented
in the small number of cases assayed to date.
THERAPEUTICS SECTION
1. Antiparkinson Efficacy of Pergolide
A study of 27 patients has been completed in which bromocriptine and
pergolide therapy was compared in a double-blind, crossover fashion. Each
drug was tested to optimal dose, which varies over a tenfold range.
Efficacy against parkinsonian symptoms, and the spectrum of adverse
reactions, were similar. Thirteen patients previously underwent
comparison of lisuride and bromocriptine in an identical study format,
permitting comparison among the three drugs. One patient developed
hepatotoxicity and pleural reaction to the drugs, while other adverse
symptoms included "benign" hallucinations and other side effects
previously observed with lisuride and bromocriptine. Long-term follow-up
of pergolide treatment has established its continuing efficacy and safety
for over one year.
2. Therapy of Parkinsonism with Tetrahydrobiopterin (THB)
Earlier studies showing decreased levels of THB in the cerebrospinal
fluid of parkinsonian patients suggested that this cofactor might have
therapeutic potential for this condition. THB is a substrate for tyrosine
hydroxylase, the rate-limiting enzyme of dopamine synthesis. In
collaboration with NHLBI scientists, the entry into the central nervous
system and biochemical effects of THB administration have been studied in
animals. With evidence of entry and effect on the dopamine system, THB
was administered parenterally on three successive days to two parkinsonian
volunteers. Neither clinical improvement nor toxicity resulted.
Biochemical studies of cerebrospinal fluid are currently under analysis.
3. Therapeutics of Movement Disorders Related to Parkinsonism
Progressive supranuclear palsy (PSP) and dystonia are disorders
involving the extrapyramidal system and sharing some features with
parkinsonism. Using dopaminergic ergot derivatives previously proven
effective in parkinsonism (bromocriptine and lisuride), therapeutic trials
have been undertaken. In 12 patients with dystonia and poor response to
conventional therapy, bromocriptine has been shown, in a double-blind
study, to offer improvement from clinical symptoms and functional
disability. Initial results indicate that this medication is well
tolerated and compatible with other agents sometimes effective in
dystonia, such as anticholinergic drugs and clonazepam. In some patients,
the clinical impression is of synergy between these agents. No
significant toxicity has been encountered.
PSP therapy with lisuride has been initiated in five patients.
Improvement of rigidity and bradykinesia has been encountered, as well as
improvement of voice and swallowing abilities. Most of the patients have
been quite sensitive to the medication, and a few have exhibited toxicity
such as hallucinations. Nevertheless, the use of this therapy, in
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combination with anticholinergic medication, may offer benefit to
patients, who generally are unresponsive to levodopa.
4. Studies of Therapeutics and Mechanisms of Essential Tremor
Current work has investigated the mechanisms and treatment of
essential tremor. Studies have involved electromyographic recording
techniques, and testing of the role of the adrenergic system in tremor by
infusion of isoproterenol. Four patients with stable essential tremor
have undergone such testing, indicating that peripheral beta-receptor
sensitivity is normal in essential tremor. In one patient with severe
essential tremor, and no response to propranolol, a normal peripheral
action of propranolol was demonstrated. Six essential tremor patients
have undergone studies measuring amine transmitters and metabolites from
plasma, urine, and cerebrospinal fluid. Three patients have been treated
with clonidine, a drug with pre-synaptic adrenergic effects in the brain;
preliminary results are promising.
Electromyographic activity of agonist and antagonist muscles in the
forearm has been studied in 4 essential tremor patients. Contrary to
previous reports in the literature, simultaneous activity in antagonist
muscle groups was not found. Rather, there was alternate activity of
action potential bursts in phase with the tremor frequency. An additional
study has shown that propranolol suppresses fatigue tremor in normal
subjects.
5. Binding Receptors in Human Brain
Ligand binding of striatal neurotransmitter receptors (encephalin,
dopamine, beta-neurotensin, and diazepam) was studied in autopsy brain
specimens from 5 parkinsonian patients, 4 controls, and 2 schizophrenic
patients. Preliminary studies show decreased binding of dopamine,
encephalin, and neurotensin ligands in parkinsonian brains.
6. Studies with Thyrotropin-releasing Hormone in Ataxic Disorders
Following promising results from research in Japan, 13 patients have
been treated with parenteral thyrotropin releasing hormone (TRH). In
responders, further studies were planned with cholinergic medications and
with analogues of TRH. One responder was identified, but subsequent
testing in a double-blind protocol failed to sustain this impression of
improvement.
1 • Decarboxylation of Levodopa in Dyskinetic Parkinsonian Subjects
Using a technique of analyzing radio-labeled carbon dioxide excreted
after administration of labelled levodopa, parkinsonian patients have been
studied in regard to adverse reactions with levodopa, such as "on-off"
phenomenon and dyskinesia. Findings confirm earlier impressions that
fluctuations response to levodopa are independent of the rate of
decarboxylation. These studies, conducted in collaboration with NIMH
scientists, have also suggested that blockade of peripheral
decarboxylation during levodopa therapy is not reduced linearly with
increasing doses of carbidopa.
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CLINICAL EPILEPSY SECTION
1. Diagnostic and Therapeutic Reevaluation of Patients with Intractable
Epilepsy.
The Clinical Epilepsy Section has been developing and testing new
techniques to achieve improved seizure control, reduce drug-induced side
effects, and achieve better rehabilitation in patients with severe
epilepsy. These include simultaneous video and telemetered EEC recording
of seizures, daily determination of antiepileptic ^ drug serum
concentration, and most recently, the concomitant use of positron emission
tomography.
The use of positron emission computer tomography (PECT) may greatly
alter our understanding of localized brain lesions in patients with
partial seizures. Current studies, limited to metabolic evaluations using
F 2-deoxyglucose, demonstrate focal hypometabolic cerebral areas
corresponding to the interictal seizure EEC focus. During a seizure, this
region is converted from a hypometabolic to hypermetabolic focus. Focal
PECT lesions may be identified in some patients even if the EEC
abnormality itself is not well localized. In other cases, an ictal PECT
scan may clarify the results of an equivocal interictal scan. These
studies allow more definitive overall identification of the localization
of the epileptic lesion and permit a more precise surgical approach to
patients with partial seizures, patients who are often refractory to
medical therapy. The PECT scan is noninvasive and lesions are often
documented in patients whose neurological examinations and CT scan are
normal.
Intensive monitoring with simultaneous video and EEC recordings
continue to elucidate new areas of seizure classification and
differentiation. Studies recently concluded are those of the clinical
characteristics of complex partial seizures, and of psychogenic (non-
epileptic) seizures; in both cases the differential diagnosis is very
important to appropriate therapy. Intensive monitoring has been useful in
an on-going study of secondary generalization, and its effectiveness in
intractable epilepsy has been documented.
The study of evoked responses in patients with epilepsy has new
investigations of patients with intractable seizures. Early studies have
shown that the dominant eye may greatly influence the amplitude of the
visual evoked response, an important feature to recognize in all patients.
In addition, patients with complex partial seizures are currently being
evaluated for abnormalities of the visual evoked response, auditory and
brainstem evoked potentials, and the somatosensory evoked potentials.
Evoked potentials are also being utilized in the evaluation of new drugs.
Finally, the video-taped seizures at the Clinical Epilepsy Section
have formed the basis of an unparalleled library of seizures for teaching
and analysis. In collecting these seizures, the Clinical Epilepsy Section
is constantly making technical advances in intensive monitoring.
11 - ET/IRP
Clinical Pharmacology of Antiepileptic Drugs
Pharmacologic studies in epilepsy have concentrated on studies of
drug interactions and of new antiepileptic drugs.
Nine normal volunteers have participated in a pharmacokinetic study
of Progabide, a new drug being evaluated for epilepsy which is already
being tested in eight European countries. The drug is a putative GABA
agonist and its mechanism of action may be through its effect on this
inhibitory transmitter. Preliminary results confirm linear kinetics and
dose proportionality.
A new potential antiepileptic agent, flupirtine, is in the final
stages of testing in Germany as an analgesic. The structure of the
compound is completely different from currently marketed antiepileptic
drugs. The drug is effective in animal models of epilepsy which suggest
that it may be effective in partial seizures or absence seizures. The
Clinical Epilepsy Section is studying both of these seizure types in
different patients in an open pilot study of intensive design.
Preliminary results show a promising decrease in seizure frequency in some
patients. It is likely that the current upper limit of dose is inadequate
to obtain maximal seizure control; planning is underway to arrange for
higher doses.
A number of studies have been performed in drug-drug interactions of
antiepileptic drugs. A study of the interaction between phenytoin and
primidone demonstrated that metabolite levels of primidone are altered by
the phenytoin, with the major effect being a direct inhibition of the
metabolite phenobarbital by phenytoin. In a different study, the
interaction between valproic acid and phenobarbital was studied in which
valproic acid also inhibited phenobarbital metabolism. In order to
evaluate the mechanism of this effect, the influence of valproic acid on
acetaminophen was studied, and this demonstrated that the effect on
phenobarbital is likely to be inhibition of hydroxylation rather than
glucoronidation. A study evaluating the effect of carbamazepine on
phenytoin has been carried out using heavy-labeled phenytoin in which the
pharmacokinetic parameters of phenytoin have been determined before and
after the addition of carbamazepine. This study shows that carbamazepine
interacts and increases the plasma levels of phenytoin when these drugs
are given in combination. Recently completed studies include those on the
effect of food on drug absorption and the effect of total removal of
sedative-hypnotic antiepileptic drugs from patients with severe epilepsy.
12 - ET/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02263-06 ET
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biochemical and Pharmacological Studies of Dopamine Receptors
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: J.W. Kebabian Chief
Biochemical Neuropharmacology Section
Other: T.E. Cote Senior Staff Fellow
M. Beaulieu Visiting Fellow
K. Tsuruta Visiting Fellow
E. Frey Staff Fellow
R. Eskay Senior Staff Fellow
R. Long Biologist
C. Grewe Biologist
M. Goldman Guest Worker
K. Miyazaki Visiting Fellow
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
ET
NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Experimental Therapeutics Branch
SECTION
Biochemical Neuropharmacology Section
INSTITUTE AND LOCATION
NINCDS. NIH. Bethesda. MP 20205
TOTAL MANYEARS:
PROFESSIONAL:
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
S (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
This project investigates the biochemistry of dopamine receptors. Using the
insight gained about the biochemical basis of dopamine receptor function, drugs
selectively interacting with the various sxibcategories of dopamine receptor are
identified and characterized. The availability of drugs selectively stimulating
or blocking the various subcategories of dopamine receptor will be useful in the
treatment of Parkinson' s disease, endocrine disorders, psychiatric disorders,
hypertension and as antiemetics in cancer chemotherapy . Among the topics
studied during the current fiscal year are: binding of spiroperidol to the D-2
dopamine receptor in the intermediate lobe of the rat pituitary gland; charac-
terizing the D-2 dopamine receptor regulating acetylcholine release and cyclic
/u"IP synthesis in the striatum; identifying YM- 09 15 1-2 as a selective D-2
antagonist; identifying the coordinated role of calcium ions and cyclic AMP in
the intermediate lobe of the rat pituitary gland and investigating the hypothesis
that drugs can discriminate between the pre- and postsynaptic dopamine
receptors.
PHS-6040
(Rev. 2-811
13
ET/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02139-08 ET
PERIOD COVERED
October 1, 1981 through September 20, 1982
TITLE OF PROJECT (80 characters or less)
Pharmacology and Physiology of Central Neurotransmitters
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
J.R. Walters Head ET NINCDS
Physiological Neuropharmacology Section
B.L. Waszczak Staff Fellow
D.A. Bergstrom Staff Fellow
ET NINCDS
ET NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Experimental Therapeutics Branch
SECTION
Physiological Neuropharmacology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
4.2
PROFESSIONAL:
2.7
OTHER:
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
E (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this project is to develop an understanding of the role of
specific neurotransmitters in basal ganglia function, with the goal of
developing improved strategies for pharmacological treatment of neurological
disorders. Topics currently under investigation include (1) the ways in which
systemically administered dopamine agonists may affect neuronal activity in the
pars reticulata and pars compacta of the substantia nigra and in the globus
pallidus; (2) the ability of iontophoresed dopamine to modulate the actions of
other neurotransmitters in these brain regions and (3) effects of GABA, GABA
agonists, and drugs, such as the benzodiazepines which modulate GABA's effects
on the activity of identified regions of the basal ganglia and substantia nigra.
PHS-6040
(Rev. 2-81)
14 - ET/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02265-06 ET
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Pharmacology, Biochemistry and Physiology of Central Neurotransmitters
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
T.N. Chase
Other: N. Foster
M. Knight
C. Tamminga
A. Denaro
Chief
Pharmacology Section
Clinical Associate
Staff Fellow
Guest Worker
Visiting Associate
ET NINCDS
ET NINCDS
ET NINCDS
ET NINCDS
ET NINCDS
COOPERATING UNITS (if any)
K. Schlesinger, University of Colorado: G. Sedvall, Karolinska Institute,
Stockholm; D. Samuel, Weizmann Institute, Rehovot; S. Cohen, Bloomsburg State
College, Bloomsburg, Pennsylvania.
lab/branch
Experimental Therapeutics Branch
SECTION
Pharmacology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
4.25
PROFESSIONAL:
2.75
OTHER:
1.5
CHECK APPROPRIATE BOX(ES)
[3(a) HUMAN SUBJECTS
D (al) MINORS 1^ (a2) INTERVIEWS
g (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The goal of this project is to develop improved drug therapies for nervous
system disease. Clinical and preclinical investigations seek to elucidate how
the activity of specific transmitter systems relate to neuropsychiatric function
Based on these relationships, novel pharmaceutical agents are evaluated for
their ability to influence central synaptic processes and thus modify neurologic
symptoms. Major topics now under study include: 1) evaluations of human trans-
mitter system function in the brain generally (through assays of endogenous or
radioactively labelled transmitters or their metabolites in spinal fluid) or
locally (by means of positron emission tomography using the f luorodeoxyglucose
method) , and 2) preclinical and clinical tests of the ability of selected
dopamine agonists, GABAmimetics , and neuropeptide analogs to influence motor
and cognitive behavior.
PHS-6040
(Rev. 2-81)
15 - ET/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02258-06 ET
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Therapeutic Studies in Parkinsonism and Other Movement Disorders
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI;
OTHER:
P. LeWitt
A. Larsen
R . Newman
M. Raphaelson
C. Ward
D. Calne
Clinical Associate ET NINCDS
Visiting Fellow ET NINCDS
Senior Staff Fellow ET NINCDS
Consultant Neurologist ET NINCDS
Visiting Scientist LCS NIMH
Former Chief, Therapeutics ET NINCDS
COOPERATING UNITS (if any)
Laboratory of Clinical Science, NIMH; Adult Psychiatry Branch, Division
of Special Mental Health Research, NIMH; Biochemical Pharmacology
Section, HE, NHLBI.
lab/branch
Experimental Therapeutics Branch
SECTION
Therapeutics Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
3.5
CHECK APPROPRIATE BOX(ES)
X] (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The therapeutics of parkinsonism ana related neurological disorders has been
the goal of projects assessing the efficacy and safety of new drugs in clinical
studies. These investigations have provided insight into biochemical and phy-
siological disturbances underlying movement disorders. Conclusions reached
over the past year include: (1) two new ergot derivatives, lisuride and
pergolide, have comparable clinical profiles against parkinsonism despite their
pharmacological differences. Our pharmacokinetic studies with lisuride offer
explanations for variability in effects of the drug; (2) tyrosine hydroxylase
cof actor, deficient in parkinsonism, produced increased dopamine synthesis in
animals. However, parenteral administration to parkinsonian patients was with-
out benefit; (3) two movement disorders with parkinsonian features but
generally without response to L-DOPA, dystonia and progressive supranuclear
palsy, have responded in some instances with dopaminergic ergot therapy; (4)
clonidine therapy may be effective in essential tremor. Peripheral adrenergic
mechanisms do not differ from normals, as shown by isoproterenol testing; (5)
binding studies show other neurotransmitter substances (in addition to
dopamine) to be decreased in parkinsonian brain.
PHS-6040
(Rev. 2-81)
16 - ET/IRP
SMITHSONIAN SC
PROJECT
IAN SCIENCE INFORMATION EXCHANGE
NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02236-07 ET
PERIOD COVERED
October 1, 1 981 to September ?0, 1982
TITLE OF PROJECT (80 characters or less)
Diagnostic and Therapeutic Reevaluation of Patients with Intractable Epilepsy
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: R.J. Porter Acting Chief, ET NINCDS
Clinical Epilepsy Section
OTHERS: E.S. Gratz
W.H. Theodore
R. Long
H.J. Kupferberg
Medical Staff F'ellow
Neurologist
Video Engineer
Pharmacologist
ET NINCDS
EB NINCDS
EB NINCDS
EB NINCDS
COOPERATING UNITS (if any)
Epilepsy Branch, NDP,
Clinical Center, NIH
NINCDS; Office of Administrative Management,
lab/branch
Experimental Therapeutics Branch
SECTION
Clinical Epilepsy Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.0
PROFESSIONAL:
1 .0
OTHER:
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
a (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Clinical Epilepsy Section has been developing and testing new techniques
to achieve improved seizure control, reduce drug-induced side effects,
and achieve better rehabilitation in patients with severe epilepsy. These
include simultaneous video and telemetered EEC recording of seizures, daily
determinations of antiepileptic drug serum concentrations, and most recently,
the concomitant use of positron emission tomography. Patients with very
long histories of uncontrolled seizures are admitted for a complete evaluation,
including all basic neurologic studies and daily objective toxicity battery.
Intensive monitoring techniques are used to establish a seizure diagnosis,
which is then utilized to design an appropriate therapeutic regimen for
each patient. The study of positron emission computerized tomography (PECT)
in patients with localized brain lesions has demonstrated focal hypometabolic
cerebral areas corresponding to the interictal seizure EEC focus. Such
studies allow more definitive overall identification of the localization
of the epileptic lesion and suggest new avenues of investigation into the
basic mechanisms of the epilepsies.
PHS-6040
(Rev. 2-81)
17 - ET/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01 NS 02318-05 ET
PERIOD COVERED
October 1, 1 981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Clinical Pharmacology of Antiepileptic Drugs
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
R.J. Porter
OTHER: E.S. Gratz
H.J. Kupferberg
W.H. Theodore
Acting Chief ET NINCDS
Clinical Epilepsy Section
Medical Staff Fellow ET NINCDS
Pharmacologist EB NINCDS
Neurologist EB NINCDS
COOPERATING UNITS (if any)
Epilepsy Branch, NDP, NINCDS
lab/branch
Experimental Therapeutics Branch
SECTION
Clinical Epilepsy Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
1.2
PROFESSIONAL:
1.2
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
E (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The Clinical Epilepsy Section continues to study the clinical pharmacology of
old and new antiepileptic drugs. Special emphasis has been placed on studies
of two new antiepileptic compounds, progabide and flupirtine. Progabide has
been studied pharmacokinetically in normal volunteers, whereas flupirtine is
being evaluated both clinically and pharmacologically in patients with either
complex partial or absence seizures. Flupirtine is especially promising in
models of epilepsy and preliminary clinical results are encouraging. Drug
interactions continue to be a major pharmacologic interest of the Section.
Most recently, the interaction between phenytoin and carbamazepine has been
evaluated using mass spectrometry methodology. Other studies recently
completed include the interaction of phenytoin and primidone, as well as
valproate and phenobarbital. The pharmacologic evaluation of these drugs is
coupled with efficacy studies, carried out by intensive monitoring techniques
including videotape analysis of epileptic seizures with simultaneous
telemetered EEC recording, and daily determination of antiepileptic drug
levels.
PHS-6040
(Rev. 2-81)
18 - ET/IRP
CD
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Infectious Diseases Branch
National Institute of Neurological and Conmunicative Diseases and Stroke
Table of Contents
RESEARCH SUMMARY
CONTRACT NARRATIVES
1-7
Provide Special Tissue Culture Cells and Reagents to NINCDS
NOl NS 1 2351
Development and Delivery of Antigen, Antisera and Viral
Diagnostic Reagents
NOl NS 9 2324
Preparation and Delivery of Special Tissue Culture Cells,
Media and Immunological Reagents
NOl NS 1 2386
Isolated Housing and Care of Animals Used in Several
Studies of Infectious Diseases
NOl NS 7 2375
11
12
PROJECT REPORTS
Perinatal Infections Causing Damage to the Child
— Collaborative Perinatal Project
ZOl NS 00402-26 ID 13
Presence of Viral and Nonviral Antigens or Antibodies
in Perinatal and Neurological Diseases
ZOl NS 01985-11 ID 14
Combined Clinical, Viral and Immunological Investigations
of Acute and Chronic Diseases of the Central Nervous
System
ZOl NS 02038-10 ID 13
Isolation, Characterization and Diagnosis of Infectious
Agents From Chronic Diseases
ZOl NS 01731-14 ID 16
Chronic Viral Infections
ZOl NS 01983-11 ID
17
i - IDB/IRP
TAB 20
Table of Contents (cont'd)
Maternal Infection and Pregnancy Outcome
ZOl NS 01984-11 ID 18
Immunological, Histological and Immunocytochemical Studies
in Neuromuscular and Central Nervous System Diseases
and Investigations of their Experimental Models
ZOl-NS-02531-Ol-ID 19
Role of Viruses and Other Microorganisms in the Perinatal
Period of Experimental Animals
ZOl NS 00972-11 ID 20
Inoculation of Animals with Tissue Culture Grown Materials
from Patients with Chronic Neurological Diseases
ZOl NS 01986-11 ID 21
Control of Acute Infectious Diseases in Experimental Animals
Using Biologicals and Chemotherapeutic Agents
ZOl NS NS 02136-08 ID 22
Papovaviruses in Non-human Primates
ZOl NS 02271-06 ID 23
Electron Microscopic Studies of Viruses of the Nervous
System and of Demyelination
ZOl NS 02034-10 ID 24
TAB 20 ±± _ iDB/IRP
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Infectious Diseases Branch, IRP
National Institute of Neurological and
Conimunicative Disorders and Stroke
John Louis Sever, M.D. , Ph.D., Chief
I. RESPONSIBILITY OF THE BRANCH
The responsibility of the Infectious Diseases Branch is to carry out planned,
coordinated research programs concerned with infections which damage the human
nervous system. The Branch is divided into three sections: 1) Immunochemistry
and Clinical Investigations; 2) Experimental Pathology; and 3) Neurovirology .
These sections utilize the techniques of immunology, clinical investigations
including human volunteers and clinical trials, experimental pathology with
nonhuman primates, virology, bacteriology, mycoplasmology , neurovirology, human
tissue culture and electron microscopy.
II. PROGRAM SEGMENTS
The program segments are: a) perinatal; b) acute; and c) chronic. In each
segment we are concerned with: 1) etiology and diagnosis; 2) treatment; and 3)
prevention.
The research areas in the program segments include:
A. Perinatal
Develop and utilize large scale methods to study the relation between viral,
bacterial, mycoplasmal and protozoal infections in the perinatal period and
birth defects, related abnormalities and pediatric neurological diseases.
Investigate approaches to early diagnosis, treatment and prevention using
combined laboratory and clinical studies.
B. Acute
Investigate agents which may be responsible for acute neurological diseases
such as meningitis, encephalitis, Reye ' s syndrome. Bell's palsy, and tic
douloureux as well as possible methods for rapid diagnosis, treatment and
prevention.
C. Chronic
Study chronic neurological diseases such as multiple sclerosis, amyotrophic
lateral sclerosis, progressive multifocal leukoencephalopathy , Parkinson's
disease, peripheral neuropathy, polymyositis, subacute sclerosing
panencephalitis, Alzheimer's and Pick's disease and epilepsy using combined
tissue culture, immunological, serological, genetic, electron microscopic and
clinical approaches for possible infectious etiologies. Whenever possible,
explore methods for early diagnosis, treatment and prevention,
1 - IDB/IRP
III. SECTION ACTIVITIES
A. Section on Immunochemistry and Clinical Investigations (ICI)
1 . Perinatal
The Section is responsible for the research and the analysis of Collaborative
Perinatal Project sera and data for infection in 60,000 pregnancies. The
approaches being used include: 1) clinical infections - correlation with
pregnancy outcomes; 2) serological investigation of 8,000 abnormals and 8,000
controls; and 3) high IgM among 30,000 children as a method to identify infected
children. Highly sensitive ELISA tests are being applied to these studies.
Additional studies include infection in high risk children in relation to
neonatal deaths and abnormal outcomes. A study is being conducted to determine
the rate of herpes infections in pregnant women in several different geographic
locations .
2. Acute
New tests for the detection and diagnosis of genital herpes virus infections are
being perfected and evaluated in patients with this disease. The methods used
employ a new biotin-avidin reaction to provide high sensitivity and
specificity.
The ELISA tests are being used in studies of CSF and serum patients with a
number of different neurological diseases. Group B streptococcal meningitis
infections are being studied in experimental monkeys in our laboratories.
Reye's syndrome patients are being studied for viral antibody levels and aspirin
tolerance .
3. Chronic
Oligoclonal IgG has been found in the CSF of patients with several different
neurological diseases including MS, Epstein-Barr virus infection and myasthenia
gravis. Specific tests for antibody are in progress using the new micro-
oligoclonal method. Special serological investigations of MS and ALS patients
are in progress.
Using a new Flow Cytof luorograph technique, studies are underway to define the
immune responses in MS and other neurological diseases.
Patients with various chronic neurological diseases are being studied for virus
antibodies and antigens. These diseases include: postpolio ALS, ALS,
polymyositis, and peripheral neuropathy.
B. Section on Experimental Pathology (EP)
1. Perinatal
This Section is conducting studies using nonhuman primates as models to
investigate the effects of in utero infection of several common human pathogens-
Current agents include cytomegalovirus (CMV), rubella and toxoplasmosis.
2- IDB/IRP
2. Acute
New methods of treatment and prevention of Group B streptococcal meningitis are
being studied using the monkey model developed in this Section. Acute
encephali tides induced by herpes type I, the "Delta Agent," and toxoplasmosis
are continuing to be investigated.
3. Chronic
Studies of subacute sclerosing panencephalitis in monkeys are in progress.
Mechanisms by which the latent viral infection produced by the varicella-like
"Delta Agent" can be reactivated and rescued are being studied. The neuro-
oncogenic studies continue with the owl and squirrel monkey models inoculated
intracerebrally with JC virus, a human polyomavirus . EAN is being studied in
rhesus monkeys.
C. Section on Neurovirology (NV)
1. Perinatal
Studies are being conducted on the natural history of antibody formation to
herpes infections in pregnant women. The possible role of immune complexes in
influencing the initiation of the immune response in recurrent infections is
being investigated. Infection of newborn rhesus monkeys with cytomegalovirus
was studied to determine the pathogenesis of fetal infection. Maternal and
fetal antibody responses were evaluated.
2. Acute
Studies of acute herpes infections are being conducted jointly with the Section
on Immunochemistry and Clinical Investigations.
3. Chronic
Immunologic studies were continued to determine the role of immune response to
viruses in multiple sclerosis. These investigations included responses to
measles virus, rubella viruses, herpes simplex virus, cytomegalovirus and
Epstein-Barr virus.
Studies of the pathogensis of JC virus infection in sub-human primates and
humans were extended. Molecular probes were prepared and used to demonstrate JC
viral DNA sequences located in tumor tissue but not in normal tissue.
Structural organization, sequence and function of JC viral DNA in these tumors
is under study. Antibody to JC viral and "T" antigen demonstrated a transient
active viral infection preceding tumor initiation.
Differences between acute and persistent infections are being sought via use of
the patas monkey - simian hemorrhagic fever virus model. Virological and
immunological techniques are being used to determine the mechanism of
elimination of persistent SHF virus infection by superinfection. Physical-
chemical differences between acute and persistent strains of SHF virus are being
investigated by monoclonal antibody and molecular biology techniques. Cellular
3 - IDB/IRP
immunology techniques are being used to elucidate the cellular interactions
involved in restricting the immune response and maintaining tolerance of
persistent SHF virus infection. Immune enhancement of death is being studied in
macaque monkeys.
Studies of multiple sclerosis patients are directed at the specificity of
antibody in the oligoclonal bands of IgG in the CSF and to determine the
specificity of antibody produced by "B" cells in the CSF.
IV. FINDINGS
A. Perinatal
1. Management of Genital Herpes During Pregnancy (ICl)
The use of weekly cultures for herpes during the last month of pregnancy was
studied in 60 women with recurrent genital HSV infections. The women with
positive cultures were delivered by cesarean section. All of the children were
free of herpes infection.
2. Diagnostic Tests For Torch Infections (ICI)
Problems with the reliability and reproducibility of diagnostic tests for
perinatal infections makes it difficult for the physician to counsel patients
with these infections. Some tests are quite unreliable and should be confirmed
by reference laboratories.
3. Congenital Toxoplasmosis Causes Abortion In Monkeys (EP)
Oral administration of toxoplasmosis cysts to pregnant patas monkeys resulted
in abortion of the fetuses and the organisms were isolated from the products of
conception.
4. Rubella Infection of Patas Monkeys Results in Infection of Fetus (EP)
Intraamniotic infection of patas monkeys at 40 days gestation resulted in
chronic fetal infection and increased rates of abortion.
B. Acute
1. Herpes Infection In Pregnant Women (ICI)
A study of 210 pregnant women in Bethesda, MD showed that 25 had a history of
prior genital herpes infection and 10 were shedding virus at 37 weeks gestation.
This showed a high risk group for acute infection of the newborn.
2. New Biotin-Avidin Test for Genital Herpes (ICI)
A new 24 hour test for genital herpes was developed which employs tissue culture
followed by a highly sensitive biotin-avidin reaction. This test has direct
clinical value for the diagnosis of genital herpes.
4- IDB/IRP
3. IgM Serological Test for Zoster Infection (ICI)
An IgM ELISA test for IgM antibody to varicella-zoster was developed. This test
is useful for the diagnosis of recent varicella or zoster infections.
4. Immunization with Live Strep B Protects Fetus from Intraamniotic Challenge
TepT
Immunization of adult rhesus monkeys with live strep B organisms resulted in
protection of the fetus from group B infection when challenged
intraamniotically at term.
5. PYR-Sulfa Treatment Effective for Monkeys with Toxoplasmosis (EP)
The drug PYR-Sulfa was effective in treating monkeys infected with
toxoplasmosis .
C. Chronic
1 . Cellular Immune Responses In Sub-Human Primates (ICI)
New markers have been developed for cell populations involved in immune
responses to infections in sub-human primates. These antibodies label the cells
which are then studied in a cytof luorograph. This new method makes it possible
to analyze the immune responses to infection in these animals.
2. Elimination of Persistent Infection with Super Infection (NV)
Expanded studies of persistent SHF infection have shown that natural infection
can be elevated by super infection with a related virus. The process clears the
chronic infection and makes the animals free of infectious virus.
3. Characterization of SHF (NV)
The molecular weight of SHF virus RNA was determined to be 5.5 x 10 Daltons.
The sedimentation coefficient of the RNA was found to be 49 S. The parental
genome was shown to code for structural polypeptides of the virus by i^ vitro
translation.
4. Immune Enhancement of Death with SHF (NV)
Infected macaques, shortly after recovery, are immune to infection and disease.
If these animals are challenged several months later they experience a rapid
death.
5. JC Virus Produces Glioblastomas In Second Monkey Species (EP)
The polyomavirus JC produced CNS glioblastomas in squirrel monkeys in 1*2 to 2%
years. TTriis confirmed the observations we made previously in owl monkeys.
5 - IDB/IRP
6. Patients with Dysgammaglobulinemic Polyneuropathy have Increased
Suppressor Cells (ICI)
These patients were found to have increased numbers of suppressor cells in their
blood. This suggests abnormal immunoregulation. Similar findings are noted
with certain viral and parasitic infections. Two of these patients have
antibody to MAG. Patients with IgA polyneuropathy have an abnormal marker on
the lymphocytes and IgA immune complexes.
7. ALS - PETT Scan Studies (ICI)
Patients with ALS have been studied with PETT scan and show metabolic changes
although they have normal CAT scans.
8. Circulating Factors in Polymyositis Against Sarcoplasma Reticulum (ICI)
Patients with polymyositis were shown to have factors against sarcoplasma
reticulum.
9. Immunocytochemical Localization of Thymosin Beta 4 (ICI)
Thymosin beta 4 was found to localize in microglial cells, certain
oligodendrocytes along the long tracts, certain macrophages, and reticular-
dendritic cells of lymph nodes.
10. DMSO Changes Markers of Lymphocytes (ICI)
Treatment of animals with DMSO results in surface changes of the lymphocyte
markers .
11. JC Viral Genomes Detected in Brain Tumors of Monkeys (NV)
Using cloned recombinant DNA probes, JC virus DNA was found in brain tumors of
monkeys .
12. Antibodies to JC Virus Found During Tumor Development in Monkeys (NV)
Antibody patterns suggest that active viral infection does not persist and after
a long latent phase, viral transformation becomes evident in animals which
develop JC virus induced CNS tumors.
13. Cloned Probe DNA to JC Transfected into Human Fetal Cells (NV)
Cloned JC DNA was transfected and was functionally capable of producing
infectious virus in human fetal cells.
14. MS Patients Have High Levels of Several Antibodies (NV)
An increased frequency of patients with MS were found to have high levels of
antibody to rubella, EB virus as well as measles.
6 - IDB/IRP
15 . Cytomegalovirus Antibody In Autoimmune Deficiency (AID) Patients Found to
be Unusually High (NV)
Patients with AID had uniquely high antibody levels to CMV and not other
viruses.
7- IDB/IRP
CONTRACT NARRATIVE
Infectious Diseases Branch, IRP, NINCDS
Fiscal year 1982
Bio Tech Research Laboratories Inc. (NOl-NS-1-2351)
TITLE; Provide Special Tissue Culture Cells and Reagents to NINCDS
Contractor's Project Director: Dr. Anton F. Stewen
Current Annual Level; $78,333.00
Objective; This is a service contract to produce a variety of cells and
reagents not available under other mechanisms for use in the research programs
of the Branch.
Major Findings; A number of satisfactory lots of special tissue culture cells
have been submitted to the Branch for use in our studies of the JC virus in owl
monkeys and the study of herpes, CMV and rubella virus in neurological disease.
Attempts to develop lymphadenoma to herpes virus have so far produced several
unstable clones.
Significance to the NINCDS Program and Biomedical Research; The cells and
viruses produced by this contract have been utilized in the research programs of
the Branch. The reagents supplied have helped to identify the role of the "T"
and "t" antigens in tumors of owl monkeys.
Proposed Course of the Project; This contract will be continued for another
year.
Publications; None
8 - IDB/IRP
CONTRACT NARRATIVE
Infectious Diseases Branch, IRP, NINCDS
Fiscal Year 1982
Microbiological Associates (NOl-NS-9-2324)
Title; Development and Delivery of Antigen, Antisera and Viral
Diagnostic Reagents.
Contractor's Project Director; Dr. Jeff litis
Current Funding; $482,500.00
Objectives; This is a service contract to provide reagents for the
Collaborative Perinatal Research, the JC papovavirus studies and other
neurological diseases.
Major Findings; A large number of high quality viral diagnostic reagents have
been provided. These include antigens for Herpes viruses types I and II,
Cytomegalovirus, Measles, Rubella, Influenza and Coxsackie A and B. These
antigens are used in an attempt to identify the etiology of perinatal infection.
Enzyme-linked immunosorbent (ELISA) tests have been developed for herpes,
cytomegalovirus and measles. Some of the unexplained differences associated
with plastic plates have been identified as unrecognized manufacturer changes.
It has been shown that for each antigen the parameter of the test must be
individually identified and standardized and that one lot of plates may not be
satisfactory for another antigen. Reagents for ELISA and hemagglutination
tests for the JC virus are being developed. Reagents prepared for determination
of the molecular genetics of the BK and JC virus have been used successfully.
Reagents to study the herpes delta agent in patas monkeys have been prepared and
a new plaque variant has been identified.
Significance to the NINCDS Program and Biomedical Research; This contract
provides to the Collaborative Perinatal Research Projects consistent reagents
which are made under similar protocols with the same cells and strains of
viruses. This allows us to test these sera for antibodies with viruses that
were prevalent in 1964 -1970. Using similar production techniques, data
obtained several years ago can be combined with current data. To date, over 80
publications have resulted from analyses of data from these studies. Many of
the reports help establish the frequency of disease, the disease syndrome that
develops and provides information on which to base rational therapeutic and
preventative measures. We are well on the way to identifying the major segments
of the JC virus genome. This information provides basic information as to the
initiation of viral growth and may help explain the host-related mechanism of
persistent infection. The experimental model for herpes zoster is needed to
permit development of methods to identify people at risk and to test therapies
which will modify the neurological sequelae.
Proposed Course; The contract will be continued for the next year.
9 - IDE /IRP
Publications; Shekarchi, I.C., Sever, J.L. , Tzan, N. , Ley, A., Ward, L.C.,
Madden, D.L. Comparison of hemagglutination inhibition test and enzyme-linked
immunosorbent assay for determining antibody to rubella virus. J. Clin.
Microbiol. l^CS) :850-854, 1981.; litis, J. P., Aarons, M.C., Castellano, G.A, ,
Madden, D.L., Sever, J.L., Curfman, B.L. , London, W.T. Simian varicella virus
(Delta herpesvirus) infection of patas monkeys leading to pneumonia and
encephalitis ' . Proceedings of the Society for Experimental Biology and
Medicine, 169:266-279, 1982.
10 - IDB/IRP
CONTRACT NARRATIVE
Infectious Diseases Branch, IRP, NINCDS
Fiscal Year 1982
Microbiological Associates; (NOl-NS-1-2386)
TITLE ; Preparation and Delivery of Special Tissue Culture Cells, Media
and Immunological Reagents.
Contractor's Project Director; Norma Parker
Current Level of Funding; $99,500.00
Objectives; This is a service contract to provide special tissue culture
cells, media and immunological reagents for use by the Branch.
Major Findings; A large lot of pretested fetal bovine serum was obtained for
use in cellular immunity studies. This lot of sera was non-stimulated to human
lymphocytes. Antigens for use in the various types of cell immunity studies was
grown in cells produced with this lot of fetal calf serum in order to reduce
non-specific cell stimulation. Large lots of pretested microelisa plates have
been obtained. Several large lots of high quality alkaline phosphatase labeled
anti-human IgG or IgM have been produced which are significant to NINCDS
programs and biomedical research.
Production of antigens for cell immunity studies in pretested media and use of
that serum in the test itself reduces the nonspecific reactions. This allows us
to determine more accurately the specific reaction. Use of specialized
equipment and the knowledge of highly qualified individuals on this contract
allows us to be far more flexible in purchase of equipment and hiring of
personnel. Thus this contract permits us to obtain good reagents at a
reasonable price and to maintain a high commitment to research on neurological
disease.
Proposed Course of the Project; The contract will be continued for
another year.
Publications: None
11 - IDB/IRP
CONTRACT NARRATIVE
Infectious Diseases Branch, IRP, NINCDS
Fiscal Year 1982
Meloy Laboratories, Inc.: (NOl-NS-7-2375)
Title: Isolated Housing and Care of Animals Used in Several Studies of
Infectious Diseases.
Contractor's Project Director: Dr. John L. Cicmanec
Current Annual Level; $225,000.00
Objectives: To provide isolated housing and care of a colony of nonhuman
primates consisting of several genera - example: owls Aotus trivirgatus,
squirrels Saimiri sciureuis , rhesus Macaca mulatta, patas Erythrocebus patas,
cynomolgus Macaca fascicularus . To provide housing and care for rodents,
rabbits, guinea pigs and mice as required. The animals on experimental
studies are monitored daily and biological specimens are collected as directed
by written protocols.
Major Findings: This contract involves the housing and care of several
species on non human primates, and several species of rodents. The animals
are on various infectious disease studies. These studies involve prescreening
the animals for the presence of antibody followed by inoculation of the
animals by a variety of routes. The animals must then be held in strict
individual isolation units. Each unit must be serviced as an individually
infected area since a number of different agents are used simultaneously in
the same room. Facilities for decontamination, as well as treatment of all
contaminated waste and cages, must be available for the conduction of these
studies.
In addition to the above, the Contract personnel under the supervision of the
Contractor's Project Director, inoculates animals, monitors their health
during the experiment, collect specimens as required by protocols, and perform
the necropies at the termination of the experiments. Investigators on the
contract must provide clinical care, with strict isolation, as well as
modification of studies as necessary to achieve the overall goals of the
contract.
Significance to the NINCDS Program and Biomedical Research: The goal of the
NINCDS is to carry out planned, directed, research programs concerned with the
diseases which damage the human nervous system. This contract provides the
backup source in housing and monitoring laboratory animal models to study
perinatal and neurological diseases.
Proposed Course of the Project: This Contract will be continued for the
following year to provide the isolated housing and care of a colony of non
human primates and rodents inoculated with various infectious agents.
Publications ; None. All publications from this Contract are listed in each
area of study of the Experimental Pathology Section.
12 - IDB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01-NS-00402-26-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Perinatal Infections Causing Damage to the Child - Collaborative Perinatal
Project
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: John L. Sever
David L. Madden
Other: Jonas Ellenberg
Anita C. Ley
Nancy Tzan
Dorothy M. Edmonds
Chief
Veterinary Director
IDB, IRP, NINCDS
IDB, IRP, NINCDS
Biostatistician
Microbiologist
Microbiologist
Clinical Nurse
OB & FS, OD, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
Johns Hopkins University; Univ. of CA, Los Angeles; Kaiser Hospital George
Washington University Medical School; OB & FS, OD, NINCDS
lab/branch
Infectious Diseases Branch
SECTION
Immunochemistry and Clinical Investigations
INSTITUTE AND LOCATION
NTNCms, NIH, Be the s da. Maryland 20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
0.5
1.0
CHECK APPROPRIATE BOX(ES)
B (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this study is to determine insofar as possible the role of perinatal
infections in the production of fetal damage. To accomplish this, clinical data and a large
number of serial serum specimens have been obtained from the 58,000 women and their
children in the Collaborative Perinatal Project. Now that the project is complete, it is
possible to study perinatal infections with three main approaches: 1) clinical infections;
2) subcEnical infections detected serologically using abnormals and matched controls; and
3) high risk children with elevated IgM levels. Special investigations included the
epidemiology of infections and the frequency of congenital toxoplasmosis. Serum, IgM
volumes, plus clinical findings are being used to identify infected infants at risk for
perinatal damage. Specific tests are then applied for identification of the infection. The
data indicates that congenital toxoplasmosis is rare. These studies should be completed
by December, 1983.
13 - IDB /IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01985-11 ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Presence of Viral and Nonviral Antigens or Antibodies in Perinatal and Neuro-
logical Diseases
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: David L. Madden
Other: John L. Sever
Aurella Krezlewicz
William London
Maneth Gravell
William Wallen
Lilly Jacob
Lata Nerurkar
Veterinary Director
Chief
Microbiologist
Veterinary Director
Research Microbiologist
Senior Staff Fellow
IPA Guest Worker
IPA Guest Worker
IDE, IRP, NINCDS
IDE, IRP,
IDE, IRP,
IDE, IRP,
IDE, IRP,
IDE, IRP,
IDE, IRP,
IDE, IRP,
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
NINCDS
COOPERATING UNITS (if any)
University of California, Los Angeles
Electronucleonics, Inc.
Microbiological Associates, Inc.
lab/branch
Infectious Diseases Eranch
SECTION
Immunochemistry and Clinical Investigations
INSTITUTE AND LOCATION
NINCDS, NIH, Eethesda Maryland
20205
TOTAL MANYEARS:
4.5
PROFESSIONAL:
2.5
OTHER:
2.0
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
(b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less -.underline J<eYwordsJ • ^ j • ^v, n.- i i
Efforts to determine the etiological agents associated with multiple sclerosis
have continued. We have completed the immunological studies using direct migra-
tion inhibition, lymphocyte cytotoxicity and complement mediated cytotoxic test
and have concluded that there is no significant difference in the cellular im-
mune responses of MS patients and carefully matched controls. Flow cytofluoro-
metric techniques to measure the cellular itmnune response of lymphocytes from a
number of non-human primates have been completed. Correlation of T and B lympho
cyte markers as detected by monoclonal antibodies have been initiated in human
and non-human primate systems. Significant alterations in the response of non-
human primate Ijnnphocytes when treated with ammonium chloride to these mono-
clonal antibodies have been observed. Application of the ELISA technique to
measure IgG and IgM against a variety of viruses has been completed. A rapid,
viral antigen diagnostic technique which reduces the time necessary to identify
herpes virus in clinical specimens from 3-7 days to 6 - 24 hours has been de-
veloped using the avidin-biotin system. Routine monitoring of tissue cultures
from experimental viral studies from mycoplasma contamination and efforts to de-
velop new techniques to monitor cultures for contamination have been continued.
PHS-6040 ~ ;
(Rev. 2-81) 14 - IDB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02038-lO-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Combined Clinical, Viral and Immunological Investigations of Neuromuscular
Diseases and Diseases of the Central Nervous System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: John L. Sever Chief IDB, IRP, NINCDS
Marinos C. Dalakas Senior Staff Fellow IDB, IRP, NINCDS
Other: David L. Madden
Maneth Grave 11
Monique Dubois-Dalcq
Giovanni DiChiro
Sidney A. Houff
Anita Chu
J. Woyciechowska
Veterinary Director
Research Microbiologist
Research Microbiologist
Neuroradiologist
Neurologist
Visiting Associate
Medical Staff Fellow
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
SNB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
VA Hospital, Washington, D.C.; George Washington Univ. Medical Center and
Georgetown Univ. Medical School, Washington, D.C.; Children's Hospital,
Washington, D.C.; National Naval Medical Center (NNMC), Bethesda, MD
lab/branch
Infectious Diseases Branch
SECTION
Immunochemistry and Clinical Investigations
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
4.5
PROFESSIONAL:
1.5
OTHER:
3.0
CHECK APPROPRIATE BOX(ES)
[3((a) HUMAN SUBJECTS
n (a1 ) MINORS n (a2) INTERVIEWS
[J(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Clinical and laboratory studies are conducted to determine etiology (infection.
immunity and/or genetics) for chronic diseases of the peripheral and central
nervous system. Current studies include amyotrophic lateral sclerosis , (ALS),
polymyositis/dermatomyositis , demyelinating polyneuropathies and chronic
Guillain-Barre syndrome, Reye ' s syndrome , multiple sclerosis , progressive
multifocal leukoencephalopathy , subacute sclerosing panencephalitis and
myasthenia gravis . Combined clinical data, genetic information, HLA and MLC
typing virus serology and virus isolation studies are obtained for these studies.
The nature of oligoclonal bands found in the CSF of patients with chronic
neurological diseases is under investigation. A new neuromuscular disease that
occurs in patients who have had poliomyelitis at an early age has been clinically
defined; the possiblity that this might be due to a late or slow polio virus
infection or an immune reaction to it is under investigation. Abnormal
immunoregulation has been recognized in patients with paraproteinemic
polyneuropathies . In patients with hereditary neuropathy and elevated IgA,
abnormal phenotypic markers on B lymphocytes and IgA immune complexes have been
identified.
PHS-6040 ■" """"^
(Rev. 2-81) -,^3 _ XDB/IRP
SMITHSONIAN SCI
PROJECT NUMBER
ENCE INFORMATION EXCHANGE
(Do not use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01-NS-01731-14-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less]
Isolation, Characterization and Diagnosis of Infectious Agents from Chronic
Diseases
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Maneth Grave 11
Research Microbiologist IDB, IRP, NINCDS
Other;
William T. London Veterinary Director
Marta Monzon Guest Worker
Jose Luis Sagripanti Visiting Fellow
Rebecca S. Hamilton Biologist
Otto Gutenson Biologist
Blanche Curfman Biologist
Robert Brown Biological Lab Tech
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
Section on Experimental Pathology, IDB, NINCDS
lab/branch
Infectious Diseases Branch
SECTION
Neurovirology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
4.6
PROFESSIONAL:
2.4
2.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Macaque monkeys undergoing primary infection with simian hemorrhagic fever
(SHF) virus develop an acute, febrile hemorrhagic disease and generally die 5 to
14 days after infected. Occasionally, infected macaques completely recover
from infection. Animals infected 6 months or more after recovery with homotypic
or heterotypic strains of SHF virus died more rapidly (<2 days) than primarily
infected animals. At the time of second infection, high serum antibody titers
to viral antigens were detected, but this antibody lacked neutralizing
activity. Antibody did not appear to be the cause of the more rapid death
because macaques receiving passively transferred specific viral antibody did
not die anymore rapidly than primarily infected animals. These results suggest
that vaccination of macaques with SHF virus would afford short lived protection
and, in fact, could exacerbate subsequent SHF virus infections. Many of the
physical-chemical characteristics of SHF virus, a member of the Togaviridae
family, have not been determined. We have found the genome of SHF virus to be a
single linear positive stranded molecule of RNA (Mol. Wt. 5.5 x 10 daltons,
sedimentation coefficient 49S). SHF virions contain 5 polypeptides ranging in
Mol. Wt. from 50K to lOK daltons.
PHS-6040
(Rev. 2-81)
16 - IDB /IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-01983-ll-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Chronic Viral Infections
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: William C. Wallen Senior Staff Fellow IDB, IRP, NINCDS
Other: David L. Madden
John L. Sever
William T. London
Sidney A. Houff
Renee G. Traub
Nancy Miller
Eugene Major
Norma Witzel
Veterinary Director
IDB,
IRP,
NINCDS
Chief
IDB,
IRP,
NINCDS
Veterinary Director
IDB,
IRP,
NINCDS
Clinical Associate
IDB,
IRP,
NINCDS
Microbiologist
IDB,
IRP,
NINCDS
Expert Consultant
IDB,
IRP,
NINCDS
IPA
IDB,
IRP,
NINCDS
Microbiologist
IDB,
IRP,
NINCDS
COOPERATING UNITS (if any)
Microbiological Associates, Bethesda, MD; Loyola Univ., Maywood , IL; George
Washington Univ. Medical School, Washington, DC; Veterans Admin. Hospital,
Washington, DC; Georgetown Univ. Medical Center, Washington, DC
lab/branch
Infectious Diseases Branch
SECTION
Neu ro V i r o 1 o gy
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.8
PROFESSIONAL:
0.8
2.0
CHECK APPROPRIATE BOX(ES)
(5 (a) HUMAN SUBJECTS
n (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
In studies on chronic central nervous system diseases, markers for tumor
involvement in the CNS of patients with Burkitt ' s lymphoma were described.
Elevated antibodies to Epstein-Barr virus, myelin, basic protein and cerebroside
were detected. Oligoclonal IgG was demonstrated and immune complexes
were found in CSF of these patients. Immunoregulatory deficiencies were
potentially described in homosexual males who heavily used amyl nitrite.
In studies of patients with multiple sclerosis, immune complex levels
were found to vary with disease exacerbation in MS patients but antibody
levels to several viruses were shown to remain unchanged.
In studies regarding JC virus pathogenesis, JC virus DNA was demonstrated
in brain tumors and tumor cell lines from owl monkeys inoculated with
JC virus. Cloned JCV DNA was transfected into oligodendroglial cells
and infectious virus was recovered.
17 - IDB /IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-01984-ll-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Maternal Infection and Pregnancy Outcome
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Other:
William C. Wallen Senior Staff Fellow
John L. Sever
David L. Madden
William T. London
John H. Grossman
Frank J. West
Chief
Veterinary Director
Veterinary Director
Guest Worker
Bio Lab Technician
IDB, IRP, NINCDS
IDE, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
George Washington IFniversity Medical School, Washington, D.C.
lab/branch
Infectious Diseases Branch
SECTION
Neurovirology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1.2
PROFESSIONAL:
0.2
OTHER:
1.0
CHECK APPROPRIATE BOX(ES)
Dx(a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The natural history and immune response of women with HSV infections were
studied. Most virus isolates from 50 pregnant women were serotyped as HSV-II
or very similar to HSV-II. None of the isolates typed as HSV-I. Antibody to
HSV-II as measured by neutralization or by indirect hemadsorption tended to
rise early but did not correspond with clinical symptoms while cytotoxic
antibody arose later and tended to correspond better with clinical symptoms.
18 - IDB /IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl-NS-02531-Ol-ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Immunological, Histological and Immunocytochemical Studies in Neuromuscular and
Central Nervous System Diseases and Investigations of their Experimental Models
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: John L. Sever
Marinos C. Dalakas
Other: David L. Madden
Maneth Grave 11
Monique Dubois-Dalcq
William T. London
Bruce Trapp
Richard Quarles
M. Gelfand
Allan Goldstein
H. Costa
Chief
Senior Staff Fellow
Veterinary Director
Research Microbiologist
Research Microbiologist
Veterinary Director
Microbiologist
Biochemist
Associate Professor
Professor and Chairman
Pathologist
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
DMN, IRP, NINCDS
Georgetown Universi
George Washington U
tf
L.eorge wasningco
Clinical Center,
NIH
COOPERATING UNITS (if any)
VA Hospital, Washington, D.C.; George Washington University Medical Center and
Georgetown University Medical School, Washington, D.C.; Children's Hospital,
Washington, D.C.; National Naval Medical Center (NNMC), Bethesda, MD
LAB/BRANCH
Infectious Diseases Branch
SECTION
Immunochemistry and Clinical Investigations
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
4.5
PROFESSIONAL:
1.5
OTHER:
3.0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
(b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Enzyme histochemistry in muscle and nerve biopsies is carried out for diagnostic
purposes in patients with several neuromuscular disorders. Immunocytochemical
studies are conducted using specific antibodies to thymic peptides, to
investigate changes in the distribution of epithelial cells and thymocytes in the
thymus of patients with myasthenia gravis. Using the cytof luorograph, specific
subsets of lymphocytes that carry thymic markers are now being defined. The
immunoglobulin of certain patients with paraprote inemic polyneuropathies has
been identified as a specific antibody to myelin associated glycoprotein; nerve
biopsies from these patients are studied by electron microscopy and
immunocytochemically with specific antimyelin antibodies. Serum from patients
with demyelinating polyneuropathies is tested in cultures of human Schwann cells
for cytotoxicity and specific binding. Because muscle and nerves are involved in
antigen-antibody immune reactions, the presence of Fc receptors for IgG and
complement in fresh muscle and nerve tissues is being examined. Immune cellular
markers during evolution of EAN and EAE induced in monkeys are being investigated
and therapies are planned using some novel immunomodulating agents.
PHS-6040
(Rev. 2-81)
19 - IDB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 00972-11 ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Role of Viruses and Other Microorganisms in the Perinatal Period of Experi-
mental Animals
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: William T. London Veterinary Director IDB, lEP, NINCDS
James S. Harper, III Veterinary Medical Officer IDB, IRP, NINCDS
Other: John L. Sever
William C. Wallen
Blanche L. Cur f man
Robert L. Brown
Frank J. West
Chief
Senior Staff Fellow
Biologist
Biological Lab Technician
Biological Lab Technician
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
University of Pittsburgh Presbyterian Hospital, Department of Neuropathology,
Pittsburgh, Pennsylvania
Meloy Laboratories, Inc., Springfield, Virginia
lab/branch
Infectious Diseases Branch
SECTION
Experimental Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.3
PROFESSIONAL:
0.5
1.8
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
§(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Congenital Toxoplasmosis: Erythrocebus patas is the monkey most suitable for
studies of acquired toxoplasmosis. They are readily infected by oral adminis-
tration of toxoplasma cysts. The infection in this monkey closely resembles
that in humans. The animals become ill for several days, then as antibody
develops they gradually recover. A dosage that will infect the pregnant animal
and not invariably result in abortion is being determined.
Rubella Virus: Rubella virus produces congenital infection in the patas monkey.
The virus was isolated from various fetal tissues 77 to 120 days after intra-
amniotic inoculation into pregnant patas monkeys at 40 days gestation. This
presents an opportunity to study the pathogenesis of this important human
teratogen.
PHS-6040
(Rev. 2-81)
20 - IDB/IRP
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01986-11 ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Inoculation of Animals with Tissue Culture Grown Materials from Patients with
Chronic Neurologic Diseases
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: William T. London
Other: Marinos C. Dalakas
John L. Sever
Blanche L. Curfman
Robert L. Brown
Veterinary Director
Senior Staff Fellow
Chief
Biologist
Biological Lab Technician
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
Meloy Laboratories, Springfield, Virginia
Microbiological Associates, Bethesda, Maryland
lab/branch
Infectious Diseases Branch
SECTION
Experimental Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.0
PROFESSIONAL:
0.5
1.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
XX(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Delta herpesvirus infection in Erythrocebus patas monkeys - A model for human
herpes zoster complications: Experimental studies have indicated that patas
monkeys become persistently infected with Delta herpesvirus (DHV) . We are in-
vestigating how to activate this persistent infection in the monkey model.
Experimental allergic polyneuritis (EAN) in rhesus monkeys: Although cellular
immune mechanisms are thought to be responsible for the development of EAN, the
immunoregulatory mechanisms and participation of specific lymphocyte subsets in
antigen recognition and demyelination during evolution of EAN are now known. We
are serially recording lymphocytes during the development of EAN in rhesus mon-
keys using mouse monoclonal antibodies that recognize membrane markers of dif-
ferent lymphocyte subpopulations.
Subacute sclerosing panencephalitis (SSPE) : Young cynomolgus monkeys Macaca
fasiculorus that were inoculated with "Biken" strain of measles virus (SSPE)
have been monitored for clinical signs of disease. This is a long term project
and signs of disease are not expected until 24 - 30 months post inoculation.
PHS-6040
(Rev. 2-81)
21 - IDB/ IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02136-08 ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Control of Acute Infectious Diseases in Experimental Animals Using Biologicals
and Chemotherapeutic Agents
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI;
William T. London
James S. Harper III
Other: John L. Sever
William C. Wallen
Blanche L. Curfman
Robert L. Brown
Veterinary Director
Veterinary Medical Officer
Medical Director, Chief
Senior Staff Fellow
Biologist
Biological Lab Technician
IDB, IKP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB, IRP, NINCDS
COOPERATING UNITS (if any)
Meloy Laboratories, Inc., Springfield, Virginia
Microbiological Associates, Bethesda, Maryland
lab/branch
Infectious Diseases Branch
SECTION
Experimental Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
2.2
PROFESSIONAL:
0.7
1.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
XX(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
A major question in the prevention of group B Streptococcus type III CGBS)
meningitis in humans is the efficacy of vaccination. Killed vaccines have not
elicited good immune responses in both animal and human test groups. We have
asked the question: "Will maternal immunization with live organisms prevent
disease in offspring following in-utero challenge 24 hours before delivery?".
Preliminary data indicate that vaccination with live organisms is efficacious
in the rhesus monkey model.
Several drug regimens were compared in the squirrel monkey model for the treat-
ment of acute toxoplasmosis. The combination of pyrimethamine/ sulfadiazine
(PYR/SLD) or trimethoprim/sulfamethoxazole (TMP/SMZ) were equally effective in
treating toxoplasmosis in the monkey model. TMP has been associated with fewer
htraian toxic side effects than PYR. TMP has also been used in pregnant women
without demonstrated teratogenic effect. It is available in an intravenous
solution so that therapeutic blood levels can be quickly achieved. Controlled
human studies of the use of TMP/SMZ in acute toxoplasmosis may be indicated.
PHS-6040
(Rev. 2-81)
22 - IDB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
Z01-NS-02271-06-ID
PERIOD COVERED
October 1,1981 through September 30,1982
TITLE OF PROJECT (80 characters or less)
Papovaviruses in Non-human Primates
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: William T. London
Sidney A. Houff
Other: William C. Wallen
John L. Sever
Giovanni Di Chiro
Nicholas J. Petronis
Ronald G. Blasberg
Paul E. McKeever
Blanche L. Cur f man
Robert L. Brown
Veterinary Director
Research Associate
Senior Staff Fellow
Chief
Chief
Medical Officer
Senior Investigator
Medical Officer
Biologist
Biological Lab. Technician
IDB, IRP, NINCDS
IDB, IRP, NINCDS
IDB,
IDB,
NCT,
NCT,
DTP,
SNB,
IDB,
IDB,
IRP, NINCDS
IRP, NINCDS
SNB, NINCDS
SNB, NINCDS
DCT, NCI
NINCDS
IRP, NINCDS
IRP, NINCDS
COOPERATING UNITS (if any)
University of Wisconsin Medical School, Departments of Medical Microbiology
and Pathology, Madison, Wisconsin; SNB, NINCDS
Meloy Laboratories, Inc., Springfield, Virginia
lab/branch
Infectious Diseases Branch
SECTION
Experimental Pathology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
1.3
PROFESSIONAL:
0.3
1.0
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (a1 ) MINORS n (a2) INTERVIEWS
□ (b) HUMAN TISSUES
f3 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)^
Eighteen owl monkeys (Aotus trivirgatus ; and four squirrel monkeys (Saimiri
sciureus) developed intracerebral gliomas that were predominantly astrocytic in
cell type. This is the completion of the studies using 92 owl monkeys and 15
squirrel monkeys that were inoculated in 1978 with JC virus, a human
polyomavirus or control material. The monkeys were monitored for 36 months
(August, 1981) before the studies were terminated.
Additional owl and squirrel monkeys were inoculated with JC virus or control
material. Animals developing intracerebral tumors from this group of monkeys
will be studied using positron emission tomography or autoradiography. Some of
the tumor material from the monkeys will be used to complete hybridization
studies between JC virus DNA and DNA extracted from tumor cells to delineate
portions of JC virus DNA present in the tumor genome.
23 - IDB/IRP
PHS-6040
(Rev. 2-81)
SMITHSONIAN SCIENCE INFORMATION EXCHAN
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02034-10 ID
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Electron Microscopic Studies: Viruses of the Nervous System and Demyelination
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: Dr. Monique Dubois-Dalcq Research Microbiologist
*LMG, IRP, NINCDS
Other;
Dr
B. Trapp
Dr
R. Nick Hogan
Dr
S. Ohno
R.
Rusten
S.
Schmidt
A.
Baron
Senior Staff Fellow *LMG,
Senior Staff Fellow *LMG,
Fogarty Postdoctoral Fellow *LMG,
Biological Lab Technician *LMG,
Microbiologist *LMG,
Ph.D. Student *LMG,
Collaborators: Dr. R. Quarles
Dr. M. Dalakas
Dr. K. Ramohan
Dr. H. Arnheiter
Chief, Section on Myelin
& Brain Development DMN,
Senior Staff Fellow IDB,
Clinical Associate NIB,
Guest Worker LMG,
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
IRP, NINCDS
COOPERATING UNITS (if any)
Dr. J. Griffin, Department of Neurology, Johns Hopkins University School of
Medicine; Dr. J. Ochoa, Department of Neurology, Dartmouth Medical School.
lab/branch Infectious Diseases Branch
[*Transferred to Laboratory of Molecular Genetics (4/1/82)]. *Formerly with IDB.
SECTION
Electron Microscopy Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Md 20205
TOTAL MANYEARS:
5.7
PROFESSIONAL:
2.7
OTHER:
3.0
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or le_ss - underline keywords)
A. Human sensory ganglia and spinal cord of fetal origin are cultured and
characterized using nerve cell specific markers and autoradiography. Neurite
growth of postmitotic sensory neurons is enhanced specifically by mouse nerve
growth factor (NGF) and the adhesion molecules laminin and fibronectin.
Synergism between NGF and laminin results in a three-fold increase of neurite
length. B. Neurotropic viruses: human fetal spinal cord cultures infected with
measles virus develop extensive fusion and virus production in non-neuronal
(NN) cells while neurons do not show infection until much later. Addition of
antiviral antibodies to the cultures results in prolonged infection of NN
cells with sparing of neurons. Viral assembly of a rhabdovirus is studied with
monoclonal antibodies to 3 viral proteins: the glycoprotein G, the membrane
protein M, and the nucleocapsid protein N, and each of them display different
intracellular. C. Immunocytochemical studies of peripheral myelin: P? protein
is located throughout Schwann cell cytoplasm and at the major dense line of
compact myelin and myelin associated glycoprotein plays a role in maintaining
periaxonal space. Sural nerve biopsies from paraproteinemia patients with
neuropathy show axonal and not demyelinating lesions.
PHS-6040
(Rev. 2-81)
24 - IDB /IRP
g
ro
0
70
O
-<
50
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Medical Neurology Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1
i - MNB/IRP TAB 21
ANNUAL REPORT
October 1, 1981 to September 30, 1982
Medical Neurology Branch
National Institute of Neurological and
Connnunicative Disorders and Stroke
The Medical Neurology Branch conducted no research activities during the
past year and has now been discontinued.
1 - MNB/IRP
o
o
G)
-<
CO
>
n
X
td
TO
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Neuroimmunology Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARY 1-3
PROJECT REPORTS
Immunological Studies in Patients with Multiple
Sclerosis and Other CNS Diseases
ZOl NS 02202-07 NI 4
The Immune Response Against Membrane Antigens
ZOl NS 02203-07 NI 5
Immunologic Mechanisms Operative in Experimental
Autoimmune Diseases of the Nervous System
ZOl NS 0220A-07 NI 6
Interaction Between Viruses and the Host
Immune-System
ZOl NS 02205-07 NI 7
i - NIB/IRP TAB 22
Annual Report
October 1, 1981 to September 30, 1982
Neuro immunology Branch
National Institute of Neurological and
Communicative Disorders and Stroke
Dale E. McFarlin, M.D. , Chief
Research in the Neuroimmunology Branch (NIB) is directed at assessment of
immune mechanisms operative in neurological diseases. These investigations
include studies of both experimental diseases in animals and human diseases
which may have an immunological basis. Over the last year emphasis has been
given to three general areas. First, the interactions of immunologically
competent cells have been studied extensively in both experimental models and
man. These investigations have been facilitated by the use of monoclonal
antibodies in conjunction with cell sorting technology. Secondly, attention
has been focused on the characterization of antigens which are the targets of
the immune response. Monoclonal antibodies have also contributed
significantly to the progress of this work. Thirdly, in the design and
execution of our studies, considerable attention is being given to genetic
factors which are linked to regulation of the immune response.
Studies on experimental allergic encephalomyelitis (EAE) have focused on
the production of this disease in mice because many of the fundamental
principles of basic immunology have been established in this species. Our
laboratory has pioneered in the reproducible induction of this autoimmune
disease in mice which should facilitate the analysis of the underlying
mechanisms. Three different types of murine EAE have been produced. Each
has merit in addressing specific immunological questions. Chronic relapsing
EAE has been systematically evaluated pathologically. Over a six month
period as many as six clinical episodes were documented in some mice; these
correlated pathologically with multiple lesions of different ages. The
central nervous system changes included hemorrhages and significant nerve
fiber depletion during the early stages of the disease as well as primary
demyelination. These were followed by remyelination, gliosis and invasion of
the central nervous system by Schwann cells which were active in
myelination. These processes seemed to recur with each acute episode. It is
anticipated that this model will have widespread application in investigation
of pharmacological and immunological manipulations which modify the disease.
Acute EAE produced in response to myelin basic protein can be adoptively
transferred to normal syngeneic recipients. This has permitted
characterization of the immunological cells involved in the transfer
process. It was found that the active cells belonged to a particular set of
thymus -derived lymphocytes which are Lyt l+2~. The biological and
pharmacological properties of these cells are distinct from the other major
subset of murine thymus-derived lymphocytes. These studies have been
extended to initiate characterization of the antigenic determinants
responsible for the murine disease. The long-term goal of the studies is to
understand the pathogenesis and the immunoregulatory processes which, when
modified, result in disease.
1 - NIB/IRP
Subsets of peripheral blood Ijnnphocytes are also being extensively
studied. Most of our studies are being performed with the OKT series of
markers. The 0KT3 antiserum identifies approximately 95°/o of T-cells in
the peripheral blood while the 0KT4 and 0KT8 reagents identify subpopulations
with helper-inducer and suppressor/killer functions respectively. Normal
values for these lymphocyte phenotypes in the peripheral blood have been
established and these are currently being measured in our patients. Although
reduced numbers of Ijnnphocytes bearing the 0KT8 marker have been seen in some
patients with multiple sclerosis, in our experience this occurs in a much
smaller percentage of patients than reported by other laboratories. Further,
the majority of patients with active multiple sclerosis have normal peripheral
blood phenotypes. Because disease activity may be related to abnormalities in
the peripheral blood lymphocyte subsets, a longitudinal study of a few
patients is being conducted. In addition, focus is being placed on the
cellular immune response to specific antigens. The cellular immune response
to both influenza and measles viruses have been studied extensively. Detailed
analysis of the cellular response to measles has been conducted in identical
twins who are discordant for multiple sclerosis and who differ in the response
to this virus as measured by lymphocyte proliferation. The responding cells
are OKT3+4+8~ and require antigen presenting cells. Because most normal
individuals are relatively low responders to measles virus as measured by the
lymphocyte proliferative assay, a defect in suppressor lymphocytes has been
postulated in the individuals with multiple sclerosis who are high
responders. Extensive studies have not identified such cells. A different
subset of human T cells is responsible for mediating a cytotoxic response
against influenza infected cells. These effector cells are OKT3+4~8+. In
order to generate these cytotoxic cells, antigen presenting cells and another
subset of activated T cells, 0KT3+4+8~ are required. These studies of
cellular immunity against viruses indicate that the various T cell
subpopulations react with different types of antigenic targets. The
OKT3+4~8+ cells which are cytotoxic to influenza infected targets require
antigen presented in the presence of HLA-A or -B identical targets. However,
the proliferation of OKT3+4+8~ cells can be obtained with both HLA identical
and HLA nonidentical measles infected fibroblasts. It is likely that these
lymphocytes respond to antigen presented on macrophages in the presence of DR
antigens and produce a variety of soluble substances such as interferon and
inter leukin-2. Such cellular interactions are being analyzed with T-cell
clones directed at viral determinants.
Studies on the antigenic determinants which are the targets of the immune
response have progressed. Because measles virus is highly cell associated and
does not turn off synthesis of host proteins, in the past, it has been
extremely difficult to study the production of antigens encoded for by this
virus. Monoclonal antibodies against individual components of measles virus
have made it possible to overcome these technical problems. These
investigations have focused on the HA protein, a glycoprotein which is
expressed on the surface of the virus. The biosynthesis, transport and
insertion of this important antigen in infected cells has been characterized
in considerable detail. Not only is this work important, per se, but in
addition it provides background and insight for the use of monoclonal
antibodies to study trace substances in normal and infected cells.
2 - NIB/IRP
Variation in the HA antigen among various strains of measles virus has
been documented. This is particularly relevant because the hampster
neurotropic strain (HNT) tends to have different antigenic determinants than
some of the more common strains of the virus. Previously, our laboratory
demonstrated that mice which are infected with the HNT strain of measles virus
become acutely ill and die. However, if the infected mice are given
hyperimmune anti-measles antibody three days after inoculation of virus, the
animals do not develop the acute disease, and a significant proportion of the
survivors develop a chronic neurological condition. It was subsequently shown
that one of the monoclonal antibodies against the HA protein produced similar
effects. Further, it is of considerable interest that this phenomenon was not
obtained with all monoclonal antibodies which react with the HA protein of the
Edmonston strain of measles. Our data indicate that some of the antigenic
determinants present on the Edmonston strain of virus are not expressed in the
neurotropic strain. These observations suggest that changes in viral antigen
are related to neurotropism. This possibility will be the focus of additional
studies.
As part of our effort to understand immunoregulatory mechanisms operative
during infection, the role of idiotypes and anti-idiotypes in the immune
response to the measles HA protein have been studied. Syngeneic anti-
idiotypes against monoclonal antibodies directed at the HA protein were
produced. The anti-idiotypes blocked the biological function of the
monoclonal anti-HA antibodies. Search for a major dominant cross-reacting
idiotype in the sera of hyperimmunized animals was conducted. Although some
limited cross-reactivity was encountered with one of the anti-idiotypes, a
predominant cross-reactive idiotype was not detected. Since auto
anti-idiotypes significantly interfere with the biological effect of the
idiotypic bearing molecules or possibly inmiunologically competent cells, it is
our belief that idiotypic heterogeneity is a beneficial component of an
anti-viral immune response.
As noted above, cytotoxic T cells directed at influenza virus recognize
this infectious agent in conjunction with HLA-A and -B gene products. Thus,
the histocompatibility antigens on the surface of the infected target cell
control the capacity of lymphocytes to recognize the viral antigen. Studies
of this problem have identified individuals who carry variant HLA-A2 and
HLA-A3 molecules. These variants lack one or more of the epitopes necessary
for recognition of virus infected targets by cytotoxic lymphocytes.
Biochemical analysis of these variant HLA molecules is in progress and the
preliminary results indicate that at least two discrete sites on the HLA-A2
molecule control the interaction between lymphocytes and infected targets.
Over the last year, the clinical activities of the Neuroimmunology Branch
have been expanded. In addition to the studies of immune regulation in
multiple sclerosis, a new protocol involving assessment of immune function in
myasthenia gravis and three therapeutic trials of a preliminary nature in
patients with multiple sclerosis have been initiated.
3 - NIB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02202-07 NI
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Immunological Studies in Patients with Multiple Sclerosis and Other CNS
Diseases
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
Chief NI NINCDS
Asst. Chief NI NINCDS
Sr. Staff Fellow NI NINCDS
Sr. Staff Fellow NI NINCDS
Med. Staff Fellow NI NINCDS
Sr. Staff Fellow NI NINCDS
Med. Staff Fellow NI NINCDS
Guest Worker NI NINCDS
PI:
D.E.
McFarlin
H.F.
McFarland
OTHER:
K.W.
Rammohan
J.I.
Greens tein
J.W.
Rose
W.E.
Biddison
C.T.
Bever
X.H.
Xu
COOPERATING UNITS (if any)
ID, NINCDS
NES, ODIR, NINCDS
lab/branch
Neuro immunology
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
5.0
PROFESSIONAL:
3.0
2.0
CHECK APPROPRIATE BOX(ES)
3 (a) HUMAN SUBJECTS
D (al) MINORS Q (a2) INTERVIEWS
n (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The general aim of this project is to obtain a more precise understanding of
multiple immunological and genetic factors possibly related singly or in
combination to the pathogenesis of multiple sclerosis. These include: (1)
Determination of histocompatibility types in a carefully selected population of
MS patients and appropriate controls. (2) Correlation of histocompatibility
data with the humoral and cell-mediated immune response to viruses . (3)
Identification of new lymphocyte antigens which may show greater correlation
with multiple sclerosis than presently identified lymphocyte antigens. (4)
Evaluation of cerebrospinal fluid immunoglobulin content and specificity. (5)
Evaluation of families with a multiple incidence of multiple sclerosis and
examination of affected and nonaffected members of these families with respect
to the above. To minimize some of the variables in the disease, identical and
nonidentical twins who are either discordant or concordant for MS are being
studied. (6) Similar studies are being conducted in patients with SSPE,
myasthenia gravis and other neuromuscular diseases.
PHS-6040
(Rev. 2-81)
4 - NIB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02203-07 NI
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
The Immune Response Against Membrane Antigens
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
D.E.
McFarlin
Chief
NI
NINCDS
OTHER:
W.J.
Bellini
Staff Fellow
NI
NINCDS
W.E.
Biddison
Sr. Staff Fellow
NI
NINCDS
H.F.
McFarland
Asst. Chief
NI
NINCDS
J.W.
Rose
Med. Staff Fellow
NI
NINCDS
J.M.
Gheuens
Visiting Assoc.
NI
NINCDS
C.L,
Koski
Guest Worker
NI
NINCDS
M.C.
Franko
Staff Fellow
CNSS
NINCDS
COOPERATING UNITS (if any
lab/branch
Neuro immunology
SECTION
Neurological Diseases Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.5
0.5
CHECK APPROPRIATE BOX(ES)
n (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
E (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The goal of this project is to characterize the immune response to virus
components and other antigens expressed on the surface of infected
cells. The function of histocompatibility antigens in forming the target
of the immune response is being assessed. Monoclonal antibodies to a
major surface component of measles virus, the hemagglutinin, have been
produced and used to characterize the biosynthesis, glycosylation and
insertion of this protein. Syngeneic anti-idiotypic antibodies directed
at monoclonal anti-hemagglutinin antibodies have been produced and are
being used to seek major cross-reactive idiotypes. The interaction
between anti-idiotypes and the anti-viral immune response is being
investigated as well as the regulation of individual idiotypes.
PHS-6040
(Rev. 2-81)
5 - NIB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02204-07 NI
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Immunologic Mechanisms Operative in Experimental Autoimmune Diseases of the
Nervous System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
D.E. McFarlin
C.B. Pettinelli
A.M. Brown
R. Fritz
J. Richer t
F. Mohktarian
Chief
Sr. Staff Fellow
Guest Worker
IPA
IPA
Sr. Staff Fellow
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
COOPERATING UNITS (if any)
Departments of Pathology (Neuropathology) and Neuroscience, Albert
Einstein College of Medicine, New York, NY
lab/branch
Neuro immunology
SECTION
Neurological Diseases Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MP 20205
TOTAL MANYEARS:
1.5
PROFESSIONAL:
1.0
OTHER:
0.5
CHECK APPROPRIATE BOX(ES)
□ (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
Q (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The aim of this project is to identify the relative role of various
mechanisms operative in the production of experimental allergic
encephalomyelitis , a model of autoimmune disease which is manifested by
demyelination. Focus is being placed on the production of this disease in
mice because this species is ideally suited for the analysis of immunologic
and genetic factors which lead to disease.
PHS-6040
(Rev. 2-81)
6 - NIB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02205-07 NI
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Interaction Between Viruses and the Host Inmune-System
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: H.F. McFarland
OTHER: D.E. McFarlin
J.I. Greenstein
W.J. Bellini
S. Jacobson
K.W. Rannnohan
W.E. Biddison
Asst. Chief
Chief
Clinical Assoc.
Staff Fellow
Staff Fellow
Clinical Assoc.
Sr. Staff Fellow
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
NI NINCDS
COOPERATING UNITS (if any)
LMB, NINCDS
ID, NINCDS
LAB/BRANCH
Neuroimmunology
SECTION
Cellular Immunology Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.0
PROFESSIONAL:
2.5
0.5
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
B (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The purpose of this study is to examine the host immune response to viruses
which can produce either acute or chronic infections of the CNS. These
studies will examine the host immune response and its relationship to
mechanisms of protection as well as disease production. In addition,
attention will be directed at the immune response to viruses in order to
permit identification of disease associated abnormalities .
PHS-6040
(Rev. 2-81)
7 - NIB/IRP
>
o
r-
o
(T>
-<
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>
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3:
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Surgical Neurology Branch
National Institute of Neurological and Communicative Disorders and Stroke
Table of Contents
RESEARCH SUMMARIES
1. Summary of Studies in the Surgical Neurology Branch 1-3
2. Biological, Immunological and Chemotherapeutic
Studies in Human Brain Tumors 4 -14
3. Biological Studies of Human Pituitary Tumors 14
4. Neurodiagnostic Studies Including the PET Scan 14 - 15
5. Neurophysiological Studies 15
PROJECT REPORTS
Biological, Immunological and Chemotherapeutic
Studies of Human Brain Tumors
ZOl NS 02367-04 SN 16
Biological and Immunological Factors in Peripheral
Nerve Regeneration
ZOl NS 02368-04 SN 17
Biological Studies of Human Pituitary Tumors
ZOl NS 02454-02 SN 18
Radionuclide Ventriculography and Cisternography
ZOl NS 01047-20 SN 19
Radiographic and Radioisotopic Angiography of the
Spinal Cord
ZOl NS 01195-18 SN 20
Experimental Spinal Cord Angiography
ZOl NS 01654-15 SN 21
Computed Tomography (Transmission) and Nuclear
Magnetic Resonance (NMR)
ZOl NS 02073-09 SN 22
Positron Emission Computed Tomography
ZOl NS 02315-05 SN 23
Neurophysiological Mechanisms of Pain
ZOl NS 02010-10 SN 24
i - SNB/XRP TAB 23
ANNUAL REPORT
October 1, 1981 through September 30, 1982
Surgical Neurology Branch, IRP
National Institute of Neurological and Communicative
Disorders and Stroke
Paul L. Kornblith, M.D. ,. Chief
Summary of Studies in the Surgical Neurology Branch
This annual report is the fourth of the Surgical Neurology Branch
beginning October 1, 1981 under the leadership of Dr. Paul Kornblith.
The Branch has continued to mature and become increasingly productive in
its mission of the conduct of basic and clinical research on brain tumors.
Reorganization of the Branch including the reequipping and redesign of
of all laboratory facilities is complete and the tissue culture, electron
microscopy and quantitative image analysis, neuropathology, humoral
immunology, cellular immunology, metabolism and neurochemistry, positron
emission tomography, and differentiation/monoclonal antibody modules are
all functioning.
Addition of scientific personnel to work in each of these areas has
included:
Dr. Joseph Bressler - cell differentiation - monoclonal
antibody (1982)
Dr. Craig Cummins - metabolism and neurochemistry (1981)
Dr. Maurice Gately - cellular immunology (1979)
Dr. Paul McKeever - neuropathology and cell biology (1979)
Senior clinical personnel, in addition to Drs. Kornblith and Smith
include:
Dr. Conrad Kufta
Dr. Edward Oldfield
Dr. Raymond Sawaya
Dr. Donald Wright (EOD 7/1/82)
To be added are additional scientific personnel in the areas of cellular
and humoral immunology and electron microscopy/image analysis.
The primary areas of our research activities have included:
1. Biological, immunological and chemo therapeutic studies
in human brain tumors.
2. Biological studies of human pituitary tumors.
3. Neurodiagnostic studies including the PET scan.
4. Neurophysiological studies.
1-SNB/lRP
The Clinical Service now has 14 beds on both 5E and 5W as well
as operating facilities in Building lOA. More than 100 major neurosurgical
cases will be done this year. Clinical admissions are close to 150 per
year with consultations for other Institutes at NIH numbering approximately
80/year. Two clinics are functional with more than 700 clinic visits per
year. The SNB, through Dr. McKeever, now provides a neuropathology service
to the NIH. Ten clinical protocols for brain tumor patients are currently
in effect. These are:
1. Evaluation of Biological, Immunological and Chemotherapeutic
Parameters in Brain Tumor Patients.
Project No. 79-N-89
2. Immunotherapy of Malignant Brain Tumors
Project No. 70-N-133
3. Biological Studies of Human Pituitary Tumors
Project No. 79-N-151
4. Evaluation of Thrombo-embolic Complications in Brain Tumor
Patients Using 125i-Fibrinogen Scanning
Project No. 82-N-23
5. Evaluation of Biological, Immunological and Chemotherapeutic
Parameters in Patients with Non-Astrocytic Central Nervous
System Tumors
Project No. 82-N-25
6. Selective Intra-Arterial Chemotherapy in the Treatment of
Recurrent Malignant Brain Tumors
Project No. 82-N-41
7. -'-°F-2-Fluoro-2-deoxy-D-glucose (FDG) Positron Emission Computed
Tomography (PECT) in Typing of Cerebral Gliomas
Project No. 80-N-36
8. Use of Argon Laser for Surgical Excision of Brain, Spinal Cord,
and Pituitary Tumors
Project No. 81-N-181
A Phase I Study of Bromodeoxyuridine (NSC 38297) Given
by Peripheral Venous Infusion
10. Phase II Trial of AZQ in Patients with Malignant Glioma \ In collab-
and Metastatic Brain Tumors ^ oration
with NCI
11. Phase I Trial of CBDCA
12. Prospective in vitro Selection of Chemotherapy Agents
for Patients with Malignant Brain Tumors
2-SNB/lRP
The clinical neurosurgical service includes formal rounds twice a
week, a yearly sequence of neuroscience, neuro-oncology, and neuro-
chemistry courses for junior and senior clinical staff as well as
a weekly neurosurgical journal review, a weekly neuropathology
conference and a biweekly neuroradiology conference. In addition,
the SNB takes an active part in the weekly NINCDS Grand Rounds.
The sequence of protocols developed over the past three years,
covers each of the major present or potential treatment modalities for
brain tumors. This year, for surgery, the argon laser has been introduced
to attempt to improve surgical resection. Rapid frozen section glial
fibrillary acidic protein and fibronectin staining have been implemented
to provide more accurate intraoperative neuropathological diagnostic
techniques (Dr. McKeever and co-workers). For radiation therapy, we have
added the use of a radiation sensitizer (BUdR) to enhance the benefits of
radiation therapy, in collaboration with Dr. Glatstein of the National
Cancer Institute. With intravenous administration, it is now possible
for patients to administer the drug to themselves outside the hospital
via special pump devices and new externalized catheter systems. To date,
eleven patients have received BUdR as an adjunct to their radiation therapy
and we are in the process of collecting survival data.
For clinical chemotherapy we have been able to add two new drugs to
the antiglioma armamentarium - AZQ (aziridinylbenzoquinone) and "chocolate"
or CBDCA platinum. AZQ is now in Phase II testing with some 20 patients
having received the drug. CBDCA platinum is now in early Phase I testing.
Selective intraarterial BCNU therapy has also been instituted. This
method of drug delivery, most suitable for patients in whom the main
vascular tumor supply is via the anterior or middle cerebral artery,
permits the delivery of up to five times the dose delivered by the intra-
venous route without apparent increase in the bone marrow toxicity of the
BCNU. Such elevated BCNU levels should increase overall tumor response
to the nitrosourea since in vitro microcytotoxicity data indicate that
many cell lines resistant at normally-achieved intravenous levels are
sensitive at the higher concentrations achieved by intraarterial drug
delivery.
Tumors available for in vitro study now number well over 100 each year
and include glial as well as other types of central nervous system tumors.
Cooperating centers include Walter Reed Army Medical Center, George Washing-
ton University, Georgetown University, Childrens' Hospital (Washington, DC)
and a variety of other centers scattered around the country.
Over the period of this report, over one hundred surgical cases have
been done, which have provided new tumor material for study. Major up-
grading of the surgical facilities has been ongoing and has included the
testing of an argon laser and a cavitron. Metabolic studies of patients
with brain tumors have continued. Studies in over 70 patients with the
positron emission tomographic scanner have shown a relationship between
glucose uptake and degree of tumor growth.
3-SNB/lRP
1. BIOLOGICAL, IMMUNOLOGICAL AND CHEMOTHERAPEUTIC STUDIES
IN HUMAN BRAIN TUMORS
A. Biological Characterization and Neuropathological Studies
A major fact emerging from cell biological as well as chemotherapy
studies in the Surgical Neurology Branch has been that of the diversity
of glioma cell populations. This heterogeneity has been found not only for
tumors of the same pathological grade, but also within the cell populations
of a single tumor. While the biological origins of this diversity are not
as yet clear, the therapeutic significance of such facts makes individual-
ized glial tumor study critical to further clinical and basic research
progress. The tissue culture of human brain tumor cells obtained at
surgery offers the opportunity for both improved understanding of the
cell biology of these tumor cells and the individualization and, thereby,
optimization of brain tumor therapy.
A variety of morphological, cell biological and biochemical parameters
are relevant to the characterization of glial tumor cells. For example,
from a morphological point of view, surface membrane, nuclear, and cyto-
plasmic features have long been felt to be useful in the evaluation of
malignancy in tumor cells at both the light and electron microscopic
levels. Evident with experience with any one characterization modality
are the limitations of "static" evaluations. Morphologic features of
extensive surface microvilli, dilated endoplasmic reticulum, and bizarre,
multilobular nuclei are, in themselves, indicators of limited value in
determining the dynamic response characteristics of any given malignant
cell, just as static metabolic measurements of anaerobic or oxidative
metabolism, cytogenetic analyses, or even cell kinetics may tell only a
part of the tumor cell's biology. No one "static" approach to glial
tumor cell characterization is likely to lead to significant advances in
understanding malignant cell behavior. Needed are "dynamic" behavioral
characteristics of tumor cells to which a multimodal analytical, biophysical
and biochemical approach can be applied. Utilizing these approaches it
has been possible to show that certain characteristics of cultured human
brain tumor cells not only parallel those of the cells in a patient but
also provide the opportunity to add therapeutically relevant Information
to the planning of optimal therapy and the prediction of the way in which
a tumor will grow in a given patient. This type of work has two major
areas. First is the area of the prediction of the behavior of tumors
which are known to be malignant. Here the major question is how malignant
a given tumor will be. Secondly, in certain tumors, which by and large
are benign or nonmalignant in their growth, there are occasional instances
in which tumors do grow in a malignant fashion. In the second category,
the question is how to pick out ahead of time those tumors which behave
in a malignant or invasive fashion. These are the two primary goals of
the program in the study of tumor biology. There are, in addition,
several secondary goals. These include: studies of the basic biologic
mechanisms of tumor growth and the similarities and differences of this
tumor growth to the growth of normal cells.
4-SNB/lRP
The observations made in our laboratory that glial and other central
nervous system tumor cells vary in their sensitivity to the nitrosourea
BCNU as well as aziridinylbenzoquinone (AZQ) and cis-platinum have provided
cellular response phenomenology suitable for a dynamic analysis as described
above. In other words, the response of glial tumor cells to given chemo-
therapeutic (cytotoxic) agents as well as biological growth regulatory
agents, provides both a meaningful and easily accessible set of tumor cell
properties on which to base a new dynamic characterization of glial tumor
cells. Thus, the clinical chemotherapy agents become biological probes in
the characterization process as well as objects of sensitivity/resistance
testing.
At the heart of this approach to the glial tumor cell is the aqueous
microcytotoxicity assay. This simple assay has provided a quick, reliable
determination of chemotherapeutic agent sensitivity or resistance applicable
to almost all human glioma lines available from the operating room. In
addition, as shown in a retrospective clinical study in fourteen patients,
it appears to have clinical predictive value, most reliably for resistance.
One limitation of the aqueous assay is the fact that certain agents
one would like to test are of limited or no aqueous solubility. The use
of organic solvents, even in low concentrations, can complicate the
determination of cytotoxicity and thus may be undesirable. Accordingly, we
have continued to develop an assay in which the drug to be tested is
solubilized in a volatile organic solvent. The organic solvent is then
evaporated, leaving the drug as a surface coat on the bottom of the well.
The tumor cells to be evaluated are then plated on top of the drug and
exposed for periods of up to 168 hours. In this case, the tumor cell
membrane acts as the drug solvent and delivers the drug directly into
the cytoplasm. For both BCNU and AZQ, which have limited aqueous solu-
bility but can be tested in both the aqueous and solid-phase assay, the
data indicate the solid-phase assay provides a comparable and equally
reliable measure of glial tumor cell resistance or sensitivity.
Another limitation of the microcytotoxicity assay system, whether
aqueous or solid-phase, is the time-consuming nature of the cell-counting
process required for evaluation of sensitivity and/or resistance. For
an experienced human observer, counting a single plate (48 wells) takes
40-60 minutes with another 30 minutes required for calculations of
cytotoxic indices,
, _ _ # cells test well )
# cells control well )
standard deviations, and t-values. To solve this problem we have developed
an automated, image-analysis based system permitting the processing of each
plate, including statistical output within 15 minutes. The methodology
developed should have a broad utility for both chemotherapeutic and immuno-
logic assays using microtiter or other multiwell plates. It is worth
adding that the automated image analysis system is capable of quantitative
morphometry as well as simple counting so that it is possible to determine
morphological changes resulting from drug or other treatment as well (i.e.
change in area, perimeter, length-to-breadth ratio, maximum chord, etc.).
5-SNB/lRP
Since the image analysis system has also been interfaced to our scanning
and transmission electron microscopes, this analysis can be extended to
ultrastructural analysis of drug action and cellular response.
An adequate glioma cell characterization program is, of course,
much more than the few elements mentioned above. Without going into
further detail about other subcomponents, the following list is a summary
of the elements as they are currently used in the SNB:
1. Aqueous and solid phase microtiter plate assays - Sensitivity -
Resistance,
2. Antigenic expression and tumor cellular immune characteristics
3. DNA alkaline elution assay; Interstrand cross-links; strand breaks,
4. DNA flow cytometry,
5. Bioelectrical properties,
6. Receptor analysis; protein kinase coupling,
7. Metabolic techniques aerobic, anaerobic metabolism,
8. Peptide protein synthesis release characterization,
9. Marker expression GFA, FN S-100 Factor VIII,
10. Scanning and transmission EM preps quantitative autoradiography,
11. Image analysis quantitative morphometry.
The following chemotherapeutic agents and/or other biological probes
have been used thus far in the characterization program outlined above:
Growth-regulatory or
"Differentiation-Active"
Chemotherapy Agents: Biological Agents:
cAMP
cGMP
Dimethylformamide and other
polar solvents
Interferon (glioma)
Interferon (fibroblast)
Epidermal Growth Factor (EGF)
Fibroblast Growth Factor (FGF)
3-adrenergic agonists
Butyrate
Phenytoin
A 23187
5-azacytidine
6-SNB/lRP
1.
Nitrosoureas
BCNU
PCNU
He GNU
CCNU
2.
AZQ
3.
Cis-platinum
4.
Spirohydantoin
5.
Rapamycin
This paradigm involves the individual as well as collaborative work
of Drs. J. Bressler, B. Chronwall, C. Cummins, M. Gately, P. Komblith,
P. McKeever, N. Shitara and B. Smith.
The major findings of these studies over the past year include:
1) The variability of glioma cell lines as defined by their responses
to chemotherapy agents is clear. This has been documented in
approximately 150 human glioma-derived cell lines for BCNU,
60 such lines for AZQ and some thirty lines for cis-platinum in
the microcytotoxicity assays. Thirteen lines have now been eval-
uated with the DNA alkaline elution assay in collaboration with
Drs. Kurt Kohn and Len Erikson of the National Cancer Institute
with good correspondence to the microcytotoxicity assay data.
Not only do glioma-derived cell lines differ from each other
with respect to sensitivity and resistance to any given agent,
but there are relatively sensitive and resistant sub-populations
within a single tumor-derived cell line.
2) Although there are relatively sensitive and resistant cells
within a given glioma cell population, the level of population
sensitivity as measured by the C.I. is a useful indicator of
population properties and appears to correlate with clinical
response. For the DNA alkaline elution assay, the number of
interstrand cross-links and strand breaks appear to be similarly
predictive.
3) The variability of response noted for the chemotherapy agents
is also seen with the biological agents including cyclic AMP,
dimethylformamide (DMF) , glioma or f ibroblast-derived interferon
(GDIF, HFIF) and epidermal growth factor (EGF) and fibroblast
growth factor (FGF) . This variability is seen whether "response"
is defined as quantitative morphological change or receptor coupling
to protein kinase, interferon production, or growth kinetics
and cytotoxic index.
4) It is possible to determine mechanisms of sensitivity and/or
resistance to chemotherapy agents or their biological probes.
Clearly established in the past year have been:
a) The selective mitochondrial toxicity of AZQ;
b) Independence of resistance to BCNU and platinum such that
for a BCNU-resistant glioma cell, platinum provides a
realistic therapeutic alternative ;
c) Sulfhydryls in tumor cells inhibit platinum's action
and may represent part of the mechanism of resistance to
platinum .
Neuropathological characterization has also continued and has been
directed toward improving diagnosis of biopsies at surgery and charac-
terizing the cells which are cultured from gliomas. The first of these
7-SNB/lRP
activities has coincided with the establishment of a diagnostic neuro-
pathology service at the NIH Clinical Center by Dr. McKeever with the full
assistance from and support of Drs. Komblith, Rabson, Costa and Valsamis.
Fluorescence and peroxidase staining of frozen sections for glial
fibrillary acidic protein (GFAP) , fibronectin, carbohydrate containing
stroma and pituitary granules has been successfully employed to improve
diagnosis of gliomas, nonglial neoplasms and pituitary adenomas.
Proteins released from neoplasms outside of the central nervous system
have provided diagnostic information about the neoplasms and biological
information about their cells of origin. Therefore, primary attention was
focused on the question of protein release by cells cultured from gliomas.
Since these cells required serum for growth in vitro, a system was sought
which would test for cellular synthesis and release of proteins in the
presence of serum. Cells from human gliomas were exposed to radiolabeled
amino acids and assays for protein synthesis and release. A number of
previously unknown proteins designated P175, P125 , P60, P47 and P40 for
their particular molecular weights were found to be released. Specific
inhibition of protein synthesis with cycloheximide showed that the released
proteins had been synthesized by the cells. Prototype mammalian gliomas
also released a number of proteins. The possibility that one or more of
the proteins are responsible for the lymphocyte suppression by gliomas
(see Immunology section) is of great interest and being pursued.
In order to locate and identify cells on an individual basis, a marker
for astrocytes was borrowed from Surgical Neuropathology. Immunofluores-
cence for GFAP had been developed and used on biopsy material. Double
immunofluorescence for anti-glial fibrillary acidic protein (anti-GFAP)
and for fibronectin was being used to distinguish glial from non-glial
neoplasms on frozen sections with clear-cut results. Of particular
relevance in astrocytomas, the neoplastic glial cells contained GFAP
and not fibronectin while divergent cells, in particular the paraneo-
plastic cells which contribute to vascular and vessel wall proliferation
contained fibronectin and not GFAP. Sterile astrocytomas from surgery
were followed with markers for GFAP and fibronectin through the process
of frozen sectioning of whole tumor, mincing, explanting and passing into
culture. At initial explantation, cells containing only GFAP grew from
certain fragments of tumor while cells containing only fibronectin grew
from other fragments. This phenomenon would not have been noticed without
examination of initial explants, since the cells become thoroughly mixed
upon initial passage. It was thus possible to separate known glial cells
from divergent cells upon explantation.
Electron microscopic studies have revealed differences between the
two immunologically defined cellular subpopulations cultured from gliomas.
Glial cells seem to have more intermediate filaments, while divergent
cells appear to have more extracellular filaments and more swollen endo-
plasmic reticulum. Scanning electron microscopy demonstrated the known
glial cells to have more and thinner processes than the divergent cells.
These morphologic impressions are being quantitated by computerized
8-SNB/lRP
morphometry. Work on the localization of S-100 and Factor VIII (an
endothelial cell marker) is also in process.
Metabolic characterization studies have also been conducted over the
past year. The major research effort in this area has been to elucidate
the unique features of the energy metabolism of glial tumors. The rates
of glucose consumption in glia-derived tumor cell lines measured in vitro
appear close to the CMRgic of the tumor in situ, measured by PET scanning
techniques. This lends credence to the use of glioma-derived cell lines
as a reasonable model system for gliomas in situ. Also being evaluated in
these studies are the utilization of carbon sources other than glucose (i.e.,
glutamate and glutamine) in malignant glial cells. On the basis of the
rates of uptake, and the number of moles of ATP potentially generated from
each mole of glutamate or glutamine, these amino acids from our studies may
be a more significant energy source than glucose. Finally, tumor cell
hexokinase as a regulator of glycolysis is being studied. We have measured
the affinity (Km) for the constant carbohydrate substrate and the maximal
catalytic activity (V max) from a variety of glioma-derived and fibroblast
(control) cell lines. The kinetic constants are close to those reported
for other mammalian brain enzymes.
Overall, then, the characterization program is moving ahead on several
fronts and the complex matrix of malignant brain tumor properties being
unravelled. Progress is gratifying in this area.
B. Chemotherapy
The basis for the clinical protocol progress in chemotherapy that has
been achieved in the SNB has been the application of in vitro microcyto-
toxicity testing, i.e., the testing of individual patient tumor lines with
a series of chemotherapy agents to determine which may be most effective
for a given tumor. Such studies, together with other characterization
efforts, have indicated the diversity of properties of malignant glial
tumors. Given the same pathological diagnosis for a group of these tumors,
a wide range of biological properties and, consequently, therapeutic
sensitivities are found.
Utilizing the aqueous in vitro chemotherapy sensitivity assay developed
by Dr. Kornblith and the solid-phase assay developed by Dr. Smith, popula-
tions of glial tumor cells either sensitive or resistant to the nitrosourea,
BCNU, and several other anticancer drugs including AZQ, cis-platinum, CBDCA,
Henkel compound, rapamycin and spirohydantoin have been determined. The
basis of resistance to BCNU of glial tumor cells, based on collaborative
studies with Drs. Kurt Kohn and Len Erikson of the National Cancer Insti-
tute, is the ability of the tumor cell to repair DNA damage resulting from
drug-induced interstrand cross-links and strand breaks. In addition, we
have determined that different cell membrane and microsomal protein
properties (i.e., p 450) in sensitive and resistant cell populations also
play a role in BCNU's effectiveness in tumor cell killing. The knowledge
of such differences as they relate to the mechanisms of actions of various
drugs has thus led not only to an appreciation of the importance of
9-SNB/IRP
individualized glioma patient chemotherapy but also directly to the
clinical protocols described above. In addition, the microcytotoxicity
assay-derived sensitivity and mechanism data are suggesting ways to
modify or circumvent tumor cell resistance mechanisms, thereby making it
possible to begin to attempt to convert resistant cells into drug-
sensitive cells.
The in vitro assays utilized have, for example, suggested the useful-
ness of both AZQ and cis-platinum (or derivatives thereof) for malignant
glioma therapy. AZQ has been of particular interest because of:
a) Its demonstrated effectiveness in our in vitro microcytotoxicity
assay,
b) Its high central nervous system penetration,
c) Its apparent 10-fold concentration in glial tumors as
opposed to plasma (as determined in our clinical studies),
d) Its selective mitochondrial destruction as well as nuclear
DNA interstrand cross- linking.
e) Its relatively minimal side effects as seen in our Phase I studies.
Although BCNU, AZQ and cis-platinum all attack DNA, we have determined
that they are not limited by the same mechanisms of resistance. Thus,
AZQ and cis-platinum are rationally-based therapeutic alternatives to
BCNU.
Based on SNB studies of AZQ in 20 patients (with recurrent malignant
gliomas and failure to respond to radiation therapy and other chemotherapy),
we have achieved a 25% response rate as demonstrated by clinical and CT
scan improvement. Mean duration of response is approximately four months
to date. Patients have been carried on this drug (monthly cycles) for up
to 9 months. Our data parallel that of the Mayo Clinic and the M.D.
Anderson Hospital.
Progress in this area has been such that it is now possible to
think in practical terms about an individualized attack on each glioma
patient's tumor. This progress has lead to a new SNB protocol designed
to prospectively plan optimal chemotherapy for each patient based on
three in vitro assay modes - aqueous microcytotoxicity testing, solid
phase microcytotoxicity testing, and an alkaline elution DNA assay.
The in vitro assays are also being utilized to develop promising
new antiglioma agents, both of the traditional chemotherapy agent type
as well as the newer biological growth control or "differentiation"
agents such as dimethylformamide (DMF) and the various subtypes of
interferon. Basic studies underway in these areas should be productive
of new SNB clinical protocols. A major new protocol "The Prospective
In Vitro Selection of Chemotherapy Agents for Patients with Malignant
Brain Tumors" is now being implemented as the natural outgrowth of the
basic studies.
10-SNB/lRP
A significant event in the SNB laboratory relevant to both chemo-
therapy and immunological microcytotoxicity testing has been the design
and development of an automated image analysis system for the quantita-
tion of not only cell number but also morphometric characteristics of
treated glioma cells by Dr. Smith in collaboration with the Biological
Engineering and Instrumentation Branch of the NIH, Division of Research
Service. The time to process the microtiter plates and produce accurate,
statistically analyzed results has been reduced from 90 to 15 minutes
per plate. The availability of this system has significantly increased
our capability for both basic and clinical evaluation of central nervous
system tumor cell biological properties and the responses of such cells
to chemotherapeutic, immunological and biological modifying agents. Its
availability is critical to the type of prospective clinical chemotherapy
agent selection trial described above.
C . Immunology
Work has proceeded in both humoral and cellular immunology. In the
serological response studies the correlation of serological immune response
with malignancy and glioma patient survival has been evaluated. These
studies of glioma patients' circulating antiglioma antibody tested against
their own tumor cells in culture have shown diminishing effectiveness with
increasing malignancy of the tumor. In general, high levels of antibody
are found in younger patients and correlate with increased survival.
Thus, these immune assays have prognostic value — a first for glioma
studies.
In the past year we have determined that it is possible to modify
tumor cell susceptibility to antibody-induced, complement- mediated cytolysis.
Treatment of malignant glial tumor cells in vitro with either dibutryl
cyclic AMP or DMF has resulted in the conversion of antibody-resistant
glioma cells to sensitive cells. Work is currently in progress to
determine the reason for this change. Altered antigenic expression is a
leading possibility.
In studies of tumor defenses against host cellular immunity mechanisms,
we have previously demonstrated three mechanisms by which human gliomas
may escape cellular immune attack: (1) a defect in immunogenic! ty which can
be overcome by "help" from an allogeneic mixed lymphocyte reaction (MLR),
(2) the secretion of mucopolysaccharide cell coats, and (3) the production
of a macromolecular immunosuppressive substance. Work during the past
year has been directed at further understanding how these mechanisms
operate. Major new findings include the following. "Help" provided by
MLR in facilitating cytolytic lymphocyte responses to glioma-associated
antigens is due to the action of soluble factors released by lymphocytes
during the course of the MLR. Likewise, the secretion of large mucopoly-
saccharide cell coats by glioma cells is due to the interaction of
the glioma cells with a soluble macromolecular factor (s) produced by some
component of the blood mononuclear cell population. In the absence of
blood mononuclear cells or supernatants from cultures of blood mononuclear
cells, only thin mucopolysaccharide coats are made by the glioma cells.
11-SNB/lRP
The immunosuppressive substance released by glioma cells was found to
elute from a gel filtration column in the same fractions as marker
proteins of 60,000 - 80,000 molecular weight. The factor recovered from
the column inhibited mitogen responses as well as the generation of
cytolytic lymphocytes in mixed lymphocyte cultures.
A clinical immunological protocol designed to evaluate the effects
of peripherally injected, irradiated autologous tirnior cells on patient
cellular and humoral Immune status has been in progress for two years.
Data in three patients so treated indicate no toxicity but no significant
immune effects of such treatment. Clearly, if immunological therapy of
this and other types (such as tumor-specific, monoclonal antibody) are to
be successful, both tumor and host immune defense mechanisms and weaknesses
will have to be understood. Current progress in the SNB makes practical
advances in this area look likely in the near future.
D. Brain Tumor - Coagulation System Interactions
Alterations of hemostasis in cancer patients have long been
recognized, and continue to be the subject of extensive research.
Thrombolic and/or hemorrhagic complications have been reported with
almost any type of cancer but are thought to be more common in carcinoma
of the pancreas, lung, stomach and ovary. Brain tumors, on the other
hand, have not been evaluated in any systematic way; however, existing
information namely, blood clotting changes, increased platelet stickiness,
and induction of thrombosis in animals with extracts of glial tumors
coupled with our observation of the frequent occurrence of thrombo-
embolic complications, indicate that hemostatic disorders probably occur
with a certain frequency and represent a real threat to the survival of
our patients.
In order to elucidate the frequency, pathogenetic mechanisms and
significance of such complications, this year we have established, under
the direction of Dr. R. Sawaya, a program combining clinical and labora-
tory research. The clinical program includes a complete historical and
physical evaluation of our patients, pre- and postoperatively, in a
combination with detailed nursing assessment and ll25-f ibrinogen scanning
prospectively in our attempts to determine the incidence of thrombotic
phenomena and to identify the risk factors particular to our patient
populations. Basic hematological assessment is also included and corre-
lated with clinical and scanning data.
The laboratory program evaluates the thromboplastic and fibrinolytic
potential of gross tumor explants freshly obtained from the operating
room and of tissue culture explants obtained from our tissue culture
laboratory.
E. PET Scanning
Another area of significant accomplishment for the Branch has been
the development of a positron emission tomographic scan capability by
the section of Neuroradiology and Computed Tomography under Drs. G. Di Chiro
12-SNB/lRP
and R. Brooks. Two major facets of this program have Included: 1) study
of -'-° F-2-deoxyglucose tumor metabolism in some 70 glioma patients over
the past two years; 2) the development, building and operation of a new
SNB-designed high resolution PET Scanner - the NEUROPET - designed for the
central nervous system and offering a resolution three-fold better than
that available in state-of-the-art commercially produced equipment.
PET studies in the 70 glioma patients studied to date have shown
a correlation of malignancy and tumor metabolism — the more malignant
the tumor, the higher its metabolic rate. Parallel in vitro studies of
glxoma cell metabolism carried out by Dr. Craig Cummins have helped to
validate this correlation. Not only improved "non-invasive" tumor
grading but also earlier detection of recurrence and thus improved patient
follow-up have all been achieved thus far. With the new higher resolution
NEUROPET, the availability of glioma-specif ic monoclonal antibody, and an
expanding positron-emitter labelling capability for a variety of metabolic
substrates and other markers, rapid progress in this area seems possible.
More details are given in the section on Neurodiagnostic Studies.
F. Animal Model (RT9) Tumor Studies for Evaluation of Tumor Blood
Flow, Blood-Tumor Transport and Drug Delivery
The RT9 glial tumor has been studied after intracranial implantation
in rats with respect to blood flow, blood-to-brain transport, and drug
delivery in collaboration with Drs. J. Fenstermacher and R. Blasberg
of the NCI. Using radiolabelled iodoantipyrene (lAP) amino-isobutyric
acid (AIB) , and misonidazole, these studies involving both scintillation
counting techniques as well as quantitative autoradiography have
demonstrated:
1) Heterogeneity of blood flow with a given intracranial RT9 tumor
with flow not necessarily correlated with histology;
2) Depression of blood flow to the entire tumor-containing
hemisphere ;
3) Variability within regions of a given tumor of blood-to-brain
transport with no necessary correlation with flow or histology
but an overall increase of such transport in tumor as compared
to normal brain of up to 26-fold;
4) Variability in misonidazole delivery without necessary
correlation to blood flow or histology.
These facts are important for understanding the complexity of
tumor organization, especially as it relates to drug delivery.
13-SNB/IRP
2. BIOLOGICAL STUDIES OF HUMAN PITUITARY TUMORS
The secretion of hormones by normal and neoplastic anterior pituitary
cells has been an ongoing effort of this laboratory for several years.
As noted in the previous report, a surprising finding has been that certain
pituitary tumor cells in tissue culture secrete not only the hormone which
they have classically been known to produce clinically but also a range
of other hormones.
Efforts have continued to include:
1) Improvement in the diagnostic classification of pituitary tumors;
2) Regulation of hormone secretion as phenotypic expression in
neoplastic pituitary cells;
3) Mechanisms and regulation of secretion of pituitary hormones.
A major problem in this area continues to be the fall-off in hormone
production over time in most lines. Continued searching for stable lines
is an important element of this project area. We continue to obtain
secreted hormone profiles over periods of time, ranging from 1 week to
several months. Hormones in the assay have included ACTH, GH, PR2,
L21, and FSH. CRF is also being examined in intact animal models.
3. NEURODIAGNOSTIC STUDIES INCLUDING THE PET SCAN RESEARCH IN THE
NEURORADIOLOGY AND COMPUTED TOMOGRAPHY SECTION
The bulk of the research efforts of this section have concentrated
on Positron Emission Tomography (PET) .
Positron Emission Tomography (PET) using [■'-°F] fluorodeoxyglucose (FDG) ,
represents a totally new approach to the understanding of the pathophysiology
of many neurological diseases. This method provides physiological informa—
tion not available with any other imaging procedure.
During the past year we have:
1) Obtained and analyzed data with the FDG-PET technique in a large
number of patients (over 70 cases at the last count) harboring
cerebral tumors. These data clearly indicate that the FDG-PET
technique is a powerful research tool to obtain information on
some metabolic features of the new diagnostic and basic insights
about these lesions;
2) Completed the construction of the NEURO-PET, a new high resolution-
high sensitivity PET tomograph. This device has already been
tested successfully in patients;
3) Provided the indispensable theoretical and technical expertise
for FDG-PET project by other NINCDS branches. These projects
deal with epilepsy, Alzheimer's disease, dyskinesias, Parkinson's
disease and ALS.
14-SNB/lRP
The Neuroradiology and Computed Tomography Section is also involved
in the following other research projects:
Transmission Computed Tomography (CT) . Our work involves continuing
clinical-animal/experimental research projects. These include studies of
demyelinating, degeneiative and atrophic processes of the brain^ brain
edema, hydrocephalus, postradiation cerebral necrosis, diseases of the spine
and the spinal cord, surgically correctable lesions in young patients
affected by chronic epilepsy, attempts at tissue characterization of normal
and tumoral cerebral tissue, and an experimental glioma model in primates.
Selective Arteriography of the spinal cord is a diagnostic technique
which has been most informative in cases of tumor, arteriovenous malforma-
tion, trauma, obstructive vascular disease, and postradiation damage of
the spinal cord.
Radioisotope angiography of the spinal cord offers distinct advantages
as a method of screening, and may give information not available by any
other diagnostic test in certain kinds of intraspinal pathology.
Our experience with dynamic computed tomography (DCT) of the spine
after injection of contrast medium shows that this methodology is helpful
in the evaluation of certain vascular lesions of the spinal cord.
Our preliminary digital subtraction angiography (PSA) studies of
the spine in cases of arteriovenous malformation and tumors of the spinal
cord have been very successful. DSA is a valuable screening and follow-up
technique for the evaluation of certain vascular conditions of the spinal
cord.
4. NEUROPHYSIOLOGICAL STUDIES
Under the direction of Dr. Choh-Luh Li, investigations of the neuro-
physiological mechanisms of pain have been carried out. Over the course
of the year Dr. Chang Hsiang-Tung of the Peoples Republic of China has
continued to collaborate in the research. Emphasis has continued to be
on pain mechanisms using the cat vagus nerve model. The left vagus nerve
and right sural nerve are utilized and brain stem recordings have been made
in the ganglion nodosum, nucleus tractus solitarius and nucleus parafasci-
cularis. We have determined that there are direct connections of the
A-delta and C-fibers with the ganglion nodosum and that this transmission
is not affected by morphine. In the nucleus tractus solitarius, neuronal
actlviation is also by vagal input (C or A-delta) . Metabolic studies of
this activation as well as of activity patterns in the nucleus parafasci-
cularis and nucleus centralis lateralis continue.
15-SNB/lRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02367-04-SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biological, Immunological and Chemotherapeutic Studies of Human Brain Tumors
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Paul L. Kornblith
OTHER: Barry H. Smith
Maurice K. Gately
Paul E. McKeever
Nobuyuki Shitara
Bibie Chronwall
Craig Cummins
Yoshio Moriya
Joseph Bressler
Raymond Sawaya
Conrad Kufta
Edward Oldfield
Chief
Deputy Chief
Senior Staff Fellow
Medical Officer
Visiting Scientist
Visiting Fellow
Staff Fellow
Visiting Fellow
Senior Staff Fellow
Visiting Scientist
Senior Staff Fellow
Senior Staff Fellow
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
COOPERATING UNITS (if any)
BEIB, DRS, NIH
Radiation Oncology, NCI; Medical Oncology, NCI:
lab/branch
Surgical Neurology Branch
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
5.0
PROFESSIONAL:
4.0
OTHER:
1.0
CHECK APPROPRIATE BOX(ES)
[^ (a) HUMAN SUBJECTS
n (al) MINORS n (a2) INTERVIEWS
g (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Human brain tumors are evaluated in a tissue culture environment as to their
basic biological behavior, their response to chemotherapeutic agents and the
detailed immunological interactions between the host and the tumor. A primary
goal is to improve the therapy of patients by understanding the basic cellular
biology of malignant human brain tumors.
SNB has continued the biological characterization program with the inclusion
of flow cytometry, karyotyping, glial fibrillary acid protein, fibronectin,
S-100 and Factor VIII assays, DNA repair, adrenergic and other receptor assays,
ganglioside and glycoprotien assays, cloning techniques, in-depth neuropatho-
logical studies, and automatic image analysis; utilized both aqueous and surface
chemotherapy assays to test several new potential antiglioma agents and initiatec
a prospective in vitro selection of clinical trials with these agents; carried
out protocols with AZQ and platinum derivatives; defined the basis of cellular
sensitivity or resistance to nitrosoureas; characterized the humoral cellular
immunological response to gliomas; and carried out correlative cellular and
PET scan glucose metabolic studies.
PHS-6040
(Rev. 2-81)
16 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHAI^GE:
PROJECT NUMBER (D
NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02368-04 SN
PERIOD COVERED
October 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biological and Immunological Factors in Peripheral Nerve Regeneration
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Barry H. Smith
Paul L. Komblith
Deputy Chief
Chief
SN
SN
NINCDS
NINCDS
COOPERATING UNITS (if any)
None
lab/branch
Surgical Neurology Branch
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS;
0
PROFESSIONAL:
0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
n (b) HUMAN TISSUES
[5 (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
The studies were designed to determine factors contributing to failure of
peripheral nerve regeneration in animals and humans. A rat model for
study of these factors was developed successfully and several factors defined.
The study has been discontinued for the present due to lack of scientific
personnel to work in this area.
PHS-6040
(Rev. 2-81)
17 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02454-02-SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Biological Studies of Human Pituitary Tumors
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
Edward H. Oldfield
Other: Barry H. Smith
Paul E. McKeever
Paul L. Kornblith
Craig Cummins
Senior Staff Fellow
Deputy Chief
Medical Officer
Chief
Staff Fellow
SN
NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
SN NINCDS
COOPERATING UNITS (if any)
Department of Neurosurgery, Georgetown University
lab/branch
Surgical Neurology Branch
SECTION
Office of the Chief
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
0.2
PROFESSIONAL:
0.2
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS D (a2) INTERVIEWS
Kl (b) HUMAN TISSUES
□ (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Pituitary tumor cells in tissue culture have been determined in this laboratory
to produce not only the hormones which they have been classically known to
produce but also a range of one to several other hormones. The purpose of this
study is to explore the mechanisms which control the production of hormones
by these tumor cells in an effort to improve pathological classification and
diagnosis, accuracy of prognosis, prediction of recurrence, and ultimately
therapeutic approaches. Cushing's disease is of special interest in this
regard.
PHS-6040
(Rev. 2-81)
18 - SNB/IRP
SMITHSONIAN SCIENC INFORMATION EXCHANGE
PROJECT NUMBER (Dr iOl use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01047-20 SN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Radionuclide Ventriculography and Cisternography
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
G. Di Chiro
OTHER: G.S. Johnston
A.E. Jones
R.A. Brooks
Chief, Neuroradiology and
Computed Tomography Section
Chief, Nuclear Medicine Dept.
Assistant Chief
Staff Physicist
SN NINCDS
NM CC
NM CC
SN NINCDS
COOPERATING UNITS (if any)
Nuclear Medicine, Clinical Center, NIH
lab/branch
Surgical Neurology Branch
SECTION
Neuroradiology and Computed Tomography Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0
PROFESSIONAL:
0
CHECK APPROPRIATE BOX(ES)
§ (a) HUMAN SUBJECTS
g] (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Radionuclide ventriculography and cisternography are diagnostic tools
permitting the morphologic and djmamic study of the cerebrospinal fluid
pathways more accurately than has even been possible with any other
diagnostic test.
This project has been discontinued.
PHS-6040
(Rev. 2-81)
19 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01195-18 SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Radiographic and Radioisotopic Angiography of the Spinal Cord
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI;
OTHER:
G
Di Chiro
J
L. Doppman
K
G. Reith
P
L. Kornblil-h
E
.H. Oldfield
A
E. Jones
A
L. Tievsky
D
0. Davis
Chief, Neuroradiology and
Computed Tomography Section
Chief
Staff Radiologist
Chief
Senior Staff Physician
Acting Chief
Staff Fellow
Chairman, Dept. of Radiology
SN NINCDS
DR CC
DR CC
SN NINCDS
SN NINCDS
NM CC
Geo. Wash. Univ.
Geo . Wash . Univ .
COOPERATING UNITS (if any) Diagnostic Radiology and Nuclear Medicine Departments,
Clinical Center, NIH; Department of Radiology, George Washington University
Medical School, Washington, DC; Medical Examiner's Office, Department of
Public Health, Philadelphia, PA
lab/branch
Surgical Neurology Branch
SECTION
Neuroradiology and Computed Tomography Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD
20205
TOTAL MANYEARS;
0.166
PROFESSIONAL:
0.166
CHECK APPROPRIATE BOX(ES)
g (a) HUMAN SUBJECTS
g (al) MINORS D (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
keywords)
lie) of
SUMMARY OF WORK (200 words or less - underline ke.
Selective arteriography (radiographic) of the spinal cord is a diagnostic
technique which has proven to be very informative in cases of arteriovenous
malformation, tumor, obstructive vascular disease, trauma, and postradiation
damage of the spinal cord.
Radioisotope angiography of the spinal cord offers distinct advantages as a
screening method, and in certain types of intraspinal pathology may give
information not available by any other diagnostic test.
Preliminary experience with two new techniques, dynamic computed tomography
(DCT) and digital subtraction angiography (DSA) of the spine indicate that
these methods are useful, and indeed excellent screening and follow-up
procedures in the evaluation of certain vascular lesions of the spinal cord.
PHS-6040
(Rev. 2-81)
20 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 01654-15 SN
PERIOD COVERED
October 1, 1981 through September 30, 1982
TITLE OF PROJECT (80 characters or less)
Experimental Spinal Cord Angiography
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI: G. DiChiro Chief, Neuroradiology and SN NINCDS
Computed Tomography Section
OTHER:
P.L.
B.H.
Kornblith
Smith
Chief
Deputy Chief
SN NINCDS
SN NINCDS
COOPERATING UNITS (if any) J. Fein, Department of Neurological Surgery, Albert
Einstein College of Medicine, Bronx, NY, formerly of Armed Forces Radiobiology
Research Institute, Bethesda, MD; K. Earle, Chairman, American Registry of
Pathologists, Washington DC
LAB/BRANCH
Surgical Neurology Branch
SECTION
Neuroradiology and Computed Tomography Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland 20205
TOTAL MANYEARS:
0
PROFESSIONAL:
0
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
(c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Experimental spinal cord angiography in the rhesus monkey is increasing our
understanding of the blood supply of the spinal cord both in physiological
and pathological conditions.
This project has been discontinued.
PHS-6040
(Rev. 2-81)
21 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02073-09 SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Computed Tomography (Transmission) and Nuclear Magnetic Resonance (NMR)
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
G. Di Chiro
R.A.
Brooks
K.G.
Rieth
V.J.
Sank
P.L.
Kornblith
B.H.
Smith
A.M.
Cormack
J.L.
Sever
W.T.
London
Chief, Neuroradiology and
Computed Tomography Section
Staff Physicist
Staff Radiologist
Expert
Chief
Deputy Chief
Physicist
Chief
Chief, Experimental
Pathology Section
SN NINCDS
SN NINCDS
DR CC
SN NINCDS
SN NINCDS
Tufts University
ID NINCDS
ID NINCDS
COOPERATING UNITS (if any) Diagnostic Radiology, Nuclear Medicine Department, CC, NIH;
Infedtious Diseases Branch, IRP, NINCDS, NIH; Physics Department, Tufts
University, Medford, MA.
lab/branch
Surgical Neurology Branch
SECTION
Neuroradiology and Computed Tomography Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
0.333
PROFESSIONAL:
0.333
CHECK APPROPRIATE BOX(ES)
a (a) HUMAN SUBJECTS
EX(al) MINORS n (a2) INTERVIEWS
D (b) HUMAN TISSUES
D (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
Computed Tomography (CT) in its transmission, emission and soon NMR modali-
ties, represents the main research area of the Neuroradiology & Computed
Tomography Section.
Ongoing clinical - animal/experimental research projects in transmission CT
include studies of degenerative, demyelinating and atrophic processes of the
brain, hydrocephalus, brain edema, postradiation cerebral necrosis, surgically
correctable lesions in young patients affected by chronic epilepsy, diseases
of the spine and the spinal cord, attempts at tissue characterization of
normal and abnormal (e.g. tumoral) cerebral tissue, and an experimental glioma
model in primates.
Physics projects: improved dual-energy CT scanning using both a split-detector
and a dual kVp method; analysis of aliasing effects and development of methods
for their elimination; phantom studies for the evaluation of artifacts and
calibration of CT machines; feasibility tests for a new type of CT device
which will use protons instead of x-rays.
PHS-6040
(Rev. 2-81)
22 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Oo NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02315-05 SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
Positron Emission Tomography
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
G. D
i Chiro
R.A.
Brooks
V.J.
Sank
N.J.
Patronas
P.L.
Kornblith
B.H.
Smith
R.J.
Porter
M. E
. Newmark
T.N.
Chase
A.E.
Jones
R.M.
Kessler
R.G.
Blasberg
A, P.
Wolf
Chief, Neurorad. & Comp. Tomog. Section SN NINCDS
Staff Physicist SN NINCDS
Expert SN NINCDS
Guest Staff Fellow SN NINCDS
Chief SN NINCDS
Deputy Chief SN NINCDS
Act's Chief, CES (Also Chief, EB, NDP) ET NINCDS
Neurologist EB NINCDS
Director IRP NINCDS
Acting Chief NM CC
Staff Physician NM CC
Medical Officer LCP NCI
Senior Chemist (*See below for "OTHER") Brookhaven
COOPERATING UNITS (if any)BEIB, DRS , NIH; Naval Res. Lab., Washington, D. C;
Washington University, St. Louis, MO; Lab. of Cerebral Metabolism, NIMH, NIH;
Brookhaven National Lab., Upton, NY; Div. of Nuclear Medicine, Dept. of Rad. Sci
UCLA, Los Angeles, CA; ODIR/'IRP, EB/NDP, ETB/IRP, NINCDS, NIH; LCP, NCI, NIH.
lab/branch
Surgical Neurology Branch
SECTION
Neuroradiology and Computed Tomography Section
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, MD 20205
TOTAL MANYEARS:
3.5
PROFESSIONAL:
3.5
CHECK APPROPRIATE BOX(ES)
1 (a) HUMAN SUBJECTS
S (al) MINORS n (a2) INTERVIEWS
n (b) HUMAN TISSUES
n (c) NEITHER
SUMMARY OF WORK (200 words or less - -t o
Positron Emission Tomography (PET) with ( F)-f luorodeoxyglucose (FDG) allows
us to obtain anatomical data (e.g., axial transverse or coronal images of the
brain) as well as dynamic functional data (such as regional cerebral glucose
consumption rate; measurements of the storage, degradation and turnover of
tagged metabolites; follow-through of the movement of the CSF in the deep CSF
intracranial cavities) . The unique property of PET is that it provides
physiologic information not available with any other imaging procedure.
During the last year the construction of a high-resolution high-sensitivity
scanner for head and animal studies — the Neuro-PET has been essentially
completed. Patients have been studied using this new tomography. The obtained
scans provide excellent, high resolution images of the brain.
*OTHER: L. Sokoloff
D.E. Kuhl
M.E. Phelps
PHS-6040
(Rev. 2-81)
Chief
LCM NIMH
UCLA
UCLA
23 - SNB/IRP
SMITHSONIAN SCIENCE INFORMATION EXCHANGE
PROJECT NUMBER (Do NOT use this space)
U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NOTICE OF
INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl NS 02010-10 SN
PERIOD COVERED
October 1, 1981 to September 30, 1982
TITLE OF PROJECT (80 characters or less)
NeurophysiolDgical Mechanisms of Pain
NAMES, LABORATORY AND INSTITUTE AFFILIATIONS, AND TITLES OF PRINCIPAL INVESTIGATORS AND ALL OTHER
PROFESSIONAL PERSONNEL ENGAGED ON THE PROJECT
PI:
OTHER:
Choh-Luh Li
Medical Officer
Chang Hsiang-Tung Scholar-in-Residence
(Director, Brain Research Institute, Shanghai, PRC)
Takekane Yamaguchi Visiting Fellow
SN NINCDS
SN NINCDS
SN NINCDS
COOPERATING UNITS (if any) grain Research Institute, Shanghai, PRC;: Academia Sinica
Hormone Research Laboratory, University of California School of Medicine,
San Francisco, California; Laboratory of Cerebral Metabolism, NIMH
lab/branch
Surgical Neurology Branch
SECTION
Laboratory of Neurophysiology
INSTITUTE AND LOCATION
NINCDS, NIH, Bethesda, Maryland
20205
TOTAL MANYEARS:
1
PROFESSIONAL:
1
OTHER:
CHECK APPROPRIATE BOX(ES)
D (a) HUMAN SUBJECTS
D (al) MINORS □ (a2) INTERVIEWS
D (b) HUMAN TISSUES
[f (c) NEITHER
SUMMARY OF WORK (200 words or less - underline keywords)
As generally accepted, the A-delta and C-fibers in the peripheral
nerves are related to pain sensation. It has also been found that about
80% of the fibers in the vagus nerve are C-fibers presumably mediating the pain
sensation from the visceral organs. In the present experiment the vagus
nerve of the cat and of the rats are stimulated and extracellular and intra-
cellular responses are recorded from the ganglion nodosum, nucleus tractus
solitarius, dorsal nucleus of vagus, nucleus centralis lateralis and nucleus
parafascicularis. In the same experiment, as the vagus nerve is stimulated,
the sural nerve or saphenous nerve is also stimulated at different intervals
in order to investigate the interaction of the impulses from somatosensory
and autonomic nerves recorded from the various subcortical nuclei. Further-
more as the vagus nerve is repetitively stimulated, changes in metabolism
of the various nuclear structures were studied. The latter is performed in
collaboration with Dr. Louis Sokoloff of the NIMH.
PHS-6040
(Rev. 2-81)
24 - SNB/IRP
U. S. GOVERNMENT PRINTING OFFICE : 1983 381-132/3037
N
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