Local Cerebral Glucose Metabolic Rates
in Obsessive-Compulsive Disorder
A Comparison With Rates in Unipolar Depression and in Normal Controls
Lewis R. Baxter, Jr, MD; Michael E. Phelps, PhD; John C. Mazziotta, MD, PhD;
Barry H. Guze, MD; Jeffrey M. Schwartz, MD; Carl E. Selin, MS
studied 14 patients with obsessive-compulsive disor-
\s=b\ We
der (OCD) by positron emission tomography and the fluo-
rodeoxyglucose method, looking for abnormalities in local
cerebral metabolic rates for glucose in brain structures that
have been hypothesized to function abnormally in OCD.These
patients were compared with 14 normal controls and 14 pa-
tients with unipolar depression. The patients with unipolar
depression and OCD did not differ in levels of anxiety, tension,
or depression. In OCD, metabolic rates were significantly
increased in the left orbital gyrus and bilaterally in the caudate
nuclei. This was apparent on all statistical comparisons with
both controls and unipolar depression. The right orbital gyrus
showed at least a trend to an increased metabolic rate in all
comparisons. The metabolic rate in the left orbital gyrus,
relative to that in the ipsilateral hemisphere (orbital gyrus/
hemisphere ratio), was significantly elevated compared to
controls and subjects with unipolar depression, and stayed
high even with successful drug treatment. Though it was in the
normal range in the morbid state, with improvement in OCD
symptoms after drug treatment, the caudate/hemisphere meta-
bolic ratio increased uniformly and significantly bilaterally.
This ratio did not increase in patients who did not respond to
treatment. Thus, OCD showed cerebral glucose metabolic
patterns that differed from controls in both the symptomatic
and recovered states.
(Arch Gen Psychiatry 1987;44:211-218)
disorder
(OCD)1"4 characterizedis
Obsessi
by vpersistent,
e-compulsirecurrent,
ve against
that invade conscious awareness
and
repugnant thoughts
an individual's will
("obsessions"). These are usually accompanied by ego-
dystonic, ritualistic behaviors ("compulsions") that the indi¬
vidual feels he must perform to prevent overwhelming
anxiety. Insight into the perverse and senseless nature of
these frequently bizarre rituals is usually preserved. A
serious disorder, the psychosocial morbidity from OCD is
thought to be among the highest seen in any major psychi¬
atric disorder." Though formerly thought to be rare, the
recent National Institute of Mental Health (NIMH) catch¬
ment area epidemiologie study indicated a six-month point
prevalence of 1% to 2% and a lifetime prevalence of 2% to 3%
for OCD.5
Obsessive-compulsive disorder has been the subject of
both diagnostic and etiologic controversy. Its relationship
Accepted for publication Oct 14, 1986.
From the Division of Biophysics and Nuclear Medicine, Department of
Radiological Sciences (Drs Baxter, Phelps, Mazziotta, and Guze and Mr
Selin), Department of Psychiatry and Biobehavioral Sciences (Drs Baxter,
Guze, and Schwartz), and Department of Neurology (Dr Mazziotta), UCLA
School of Medicine.
Presented in part at the Annual Meeting of the American College of
Neuropsychopharmacology, Kaanapali, Maui, Hawaii, Dec 12, 1985.
Reprint requests to UCLA Neuropsychiatric Institute, 760 Westwood
Plaza, Los Angeles, CA 90024 (Dr Baxter).
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to the anxiety disorders, psychoses, Gilles de la Tourette's
disorder ("Tourette's disorder") and particularly depres¬
sion, has been questioned.14,6"12 The inability of the patient's
"will" to control this unwanted mental activity suggested a
deficit in mental energy ("psychasthenia") to Janet,1"3,13·14
while the apparently symbolic nature of obsessions and
compulsions led Freud to view the problem as being related
to complex defenses invoked to deal with potent psychosex-
ual conflicts.1"4 Some have viewed both obsessions and
compulsions as the product of conditioning.1"4 To others, the
association of OCD with Tourette's disorder15"17 and with
cases of von Enconomo's encephalitis13,18"20 have suggested
neurologic dysfunction.21 Studies of cerebrospinal fluid
amines,22 neuropsychological tests,2325 electroen-
cephalographic measures,26,26 sleep studies,9 and response
to pharmacologie treatments3,27"29 have likewise suggested
biologic abnormalities in this disorder.30,31
We studied global and local cerebral metabolic rates for
glucose (LCMRGlc) in patients with OCD using positron
emission tomography and fluoro-2-deoxyglucose labeled
with fluorine 18.32,33 The results were compared with those
obtained from normal controls and patients with major
depressive disorder, unipolar type, who were studied under
similar conditions. A subgroup of the patients with OCD
was also examined after treatment with medication and the
results were compared with pretreatment data and the data
from the normal group.
SUBJECTS AND METHODS
Subjects
This study was carried out under guidelines established by the
UCLA Human Subjects' Protection Committee. Characteristics of
subjects and their scores on various behavior rating scales are
shown in Table 1. Values are given as the mean ± SD.
Patients With OCD.—All 14 patients met both DSM-IIP* and
Research Diagnostic Criteria35 for OCD, as diagnosed using the
Schedule for Affective Disorders and Schizophrenia, Lifetime
Version.36 All patients had compulsive rituals as well as obsessions.
Rituals were further categorized into washing or checking types1
(Table 1). Nine of these individuals also met DSM-III criteria for
major depression (Research Diagnostic Criteria secondary depres¬
sion subtype) at the time of scanning, but had histories of OCD
when not depressed and showed residual OCD symptoms after
their index depressive episode resolved with treatment. Nine of
the patients with OCD were studied when they had been free of
psychotropic drugs for at least two weeks (mean, 6.2 ±3.7; range,
two to 12 weeks). Five patients were not able or willing to stop
taking medications for clinical reasons and they were studied while
they received the following medications (one patient each):
alprazolam, 3 mg/d; alprazolam, 3 mg/d, and desipramine hydro¬
chloride, 150 mg/d; diazepam, 5 mg/d, phenelzine sulfate, 60 mg/d,
and perphenazine, 8 mg/d; haloperidol, 5 mg/d; and trazodone
hydrochloride, 50 mg/d. Ten of the patients were restudied after
treatment with trazodone, with or without a monoamine oxidase
inhibitor.37 Female subjects with OCD underwent scanning with¬
out regard for time in the menstrual cycle. Thirteen subjects were
 Table 1.—Demographic and Symptom Characteristics, and Rating Scale Scores for Normal Controls
and Unipolar Depressed and Obsessive-Compulsive Patients*
Obsessive-
Normal Unipolar Compulsive
Controls Depressed Disorder Pt
No. of subjects 14 14 14
Age, y (range) 31.6 ±4.5 (25-39)t 35.3 ±12.3 (23-64)t 35.1 ±12.1 (22-62)t >.50
Sex, M:F 7:7 5:9 9:5 >.30
HAM-D score (range) 1.14 + 1.92(0-6) 21.57 ±3.34 (17-29)t 19.00 ±7.23 (11-36)t >.25
BPRS tension (range) 1.29 ±0.47 (1-2) 3.57 ±0.94 (2-6)t 3.71 ± 1.20 (2-6)t >.70
BPRS anxiety (range) 1.29 ±0.47 (1-2) 3.14 ±0.95 (2-5)t 3.50 ±1.16 (2-6)t >30
No. of subjects with major depression 0/14 14/14 9/14
No. of subjects with checking rituals only 10
No. of subjects with cleaning rituals only
No. of subjects with mixed cleaning and checking rituals
Score on NIMH-OCD scale (range) 32.00 ±6.58 (23-43)
*HAM-D indicates Hamilton Depression Scale; BPRS, Brief Psychiatric Rating Scale; and NIMH-OCD, National Institute of Mental Health Obsessive-
Compulsive Rating Scale. Age and rating scale scores are the mean ± SD.
fP between (r test) or among (analysis of variance or 2) values indicated.

right-handed and one (woman) was ambidextrous with right-

handed preference on a handedness questionnaire.38
Unipolar Depressed Patients.—All patients met criteria for
both DSM-III and Research Diagnostic Criteria major depressive
disorder, unipolar type, on the Schedule for Affective Disorders,
Lifetime Version. Six patients also had ego-dystonic obsessions
consisting of doubting and accompanied by minor checking rituals. a
These patients had these symptoms when depressed but had no
%
history of such behavior when not depressed, and none showed co ¡
ti.
*~
obsessional symptoms after treatment of the depressive episode. _*·»-
5
Thus, these patients did not meet present DSM-III criteria for "OB"
OCD. All had been free of drugs with known psychotropic effects 'S
for a minimum of one week (mean, 3.7±2.7 weeks; range, one to 4
i
nine weeks). Female subjects with unipolar depression were "

scanned without regard for time in the menstrual cycle. Thirteen 3 Mean 4.66±0.76 4.47 ±0.58 5.26 ±0.80
subjects were right-handed and one (woman) was ambidextrous, ±SD (N 14) =
(N 14)
=
(N 14)
=

O
-

with right-handed preference on the handedness questionnaire.

Normal Controls.—Psychiatric histories obtained by one of us
(L.R.B.) showed no DSM-III axis I psychopathology in the
subjects and their first-degree relatives. All subjects had been
known to the psychiatrist for a minimum of two years before and a
minimum of six months after scanning and were without observed,
diagnosable psychopathology during that time. No subjects admit¬
ted to using prescription or nonprescription drugs, including birth
control pills, for at least one month. Women were scanned between
days 5 and 15 (first day of menstruation, day 1) of the menstrual
cycle. All patients were without abnormalities on general physical
and neurologic examination. Twelve patients were right-handed
and two considered themselves ambidextrous, with right-handed
preference (one man and one woman) on the handedness question¬
naire.39
Methods
Ratings.—All subjects were evaluated by the same rater
(L.R.B.) just before the injection of fluoro-2-deoxyglucose "F.
Ratings included the 24-item version of the Brief Psychiatric
Rating Scale™ (minimum score per item, 1; maximum score, 8)
(scores on the "tension" and "anxiety" items are summarized in
Table 1) and the 21-item Hamilton Depression Scale.41 Patients
with OCD were also rated with the National Institute of Mental
Health Obsessive-Compulsive Rating Scale (NIMH-OCD), which
correlates with the Comprehensive Psychiatric Rating Scale—
Obsessive-Compulsive27,42 subscale (r=.9; T. R. Insel, MD, per¬
sonal communication, 1984).
Scanning Procedure.—All subjects were injected with flu-
oro-2-deoxyglucose 18F while in the supine position in a room with
no conversation and low ambient light and environmental noise
(mostly from the scanner gantry), as previously described.43 The
subjects' ears and eyes were open and the subjects looked at the
Unipolar Obsessive-
Normal
Depressed Compulsive
Fig 1.—Right hemisphere glucose metabolic rates. Metabolic rates
were significantly higher in patients with obsessive compulsive
disorder than in subjects from either comparison group. Subjects
with obsessive-compulsive disorder showed higher rates than
unipolar depressives on all statistical comparisons, but not on all
comparisons with normal controls. (See text.) Left hemisphere
values were essentially same. Circles indicate drug-free subjects;
squares, drug-taking subjects. P<.02.
diffuse white ceiling light above the tomograph. Each subject
received 5 to 10 mCi of fluoro-2-deoxyglucose 18F, prepared as
previously described.44 Blood sampling, scanning methods, and
determinations of plasma glucose and fluoro-2-deoxyglucose ^F
concentrations also have been detailed previously.45,46
Scanning commenced 40 minutes after injection of the drug and
was performed with a Neuro ECAT scanner.47 The in-plane resolu¬
tion used in these studies was 11 mm and the axial resolution was
12.5 mm. Scans were taken at an angle parallel to the canthomeatal
line at 8-mm intervals. The subjects' heads were held in a special
head holder48 during scanning to allow accurate positioning using
the low-power neon laser of the tomograph. A rectilinear prescan
was used to obtain comparable planes for intersubject comparisons
and to allow accurate repositioning for follow-up scans done after
treatment.48 The imaging time ranged from 40 minutes to one hour.
Twelve scan planes were obtained for each subject. Injection of
fluoro-2-deoxyglucose ^F took place between 10 am and 2 pm.
Subjects from the three groups were intermixed for scanning,
which was not in separate time blocks.

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Cl co
=
¬
c
S "5CD
o
Unipolar Obsessive-
Normal
Depressed Compulsive
Fig 2.—Glucose metabolic rates for head of right caudate nucleus.
Rates for all subjects combined were significantly higher in patients
with obsessive-compulsive disorder than in subjects from either
comparison group. (Subjects with obsessive-compulsive disorder
were significantly higher on this measure on all statistical compari¬
sons with normal controls, but only trended higher [P<.10] than
unipolar depressives for right hemisphere. See text.) Left hemi¬
sphere values were essentially same and higher on all statistical
comparisons with normal controls and unipolar depressives. Cir¬
cles indicate drug-free subjects; squares, drug-taking subjects.
P<.005.
Calculation of Glucose Metabolic Rates.—Neuroanatomic
structures were delineated using a set of templates derived from a
positron emission neuroanatomic atlas.49 These were done with
those persons delineating the structures blind to the study from
which the scans came. The accuracy of neuroanatomic localization
was confirmed by the same neuroanatomist (J.C.M.). The local
cerebral (supratentorial) LCMRGlc was calculated using previ¬
ously described methods.45,46 Rates for individual cerebral neu¬
roanatomic structures were calculated in this study by taking the
average of values calculated for all planes in which a given structure
was present.
Statistics.—A statistical strategy was chosen that would tend
to reduce the possibility of false-positive (type I) statistical error.
The first seven patients with OCD were examined for differences
from the two control groups using a one-way analysis of variance
(ANOVA) with post hoc t tests between pairings of subject groups,
with Bonferroni's correction for multiple tests.50,51 This was done
for the following neuroanatomic regions that had been postulated
to show pathology in OCD, based on the literature cited in the
introduction: (1) whole cerebral hemispheres, (2) prefrontal cortex
(precentrai gyrus, rectal gyrus, orbital gyrus, lateral superior
frontal gyrus, medial superior frontal gyrus, middle frontal gyrus,
inferior frontal gyrus, and medial prefrontal cortex—all examined
individually), (3) temporal cortex (lateral superior temporal gyrus,
transverse superior temporal gyrus, middle temporal gyrus, and
inferior temporal gyrus—all examined individually), (4) hippocam-
pal-parahippocampal complex, (5) anterior cingulate gyrus, (6)
heads of the caudate nuclei, (7) putamen, and (8) thalamus. These
structures were examined (1) in terms of absolute LCMRGlc, (2)
relative to the rate of the ipsilateral hemisphere by means of a ratio
of the two (LCMRGlc-structure/LCMRGlc-hemisphere), and (3)
for left-right asymmetries ([LCMRGlc-left-LCMRGlc-right]/
[LCMRGlc-left + LCMRGlc-right]/2).
Structures showing significant (P<.05, two-tailed) differences
from both control groups were then examined in the second group
of seven patients with OCD (against the same controls) employing
planned orthagonal comparisons of group means using a t statistic,
with one-tailed probability limits.52 In addition, a third analysis
was undertaken that examined only those patients with OCD who
were drug free (ANOVA and post hoc t tests with Bonferroni's
correction). Student's t test, with two-tailed values, was used for
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8
2 7'
DC
Í8
Ir 6
S c
119>
t
CD ';=
o
w
o
a
g
E 5
4
f 5
O
Mean 5.09±0.92 5.23±0.75 6.12±1.17
.. ±SD ( 13)
=
( =
14) ( =
13)
Normal Unipolar Obsessive-
Depressed Compulsive
Fig 3.—Glucose metabolic rates for right orbital gyrus. Metabolic
rates were significantly higher in patients with obsessive-com¬
pulsive disorder than in subjects from either comparison group. Left
hemisphere values were essentially same. Circles indicate drug-
free subjects; squares, drug-taking subjects. P<.02.
other comparisons between two groups and the paired t test (two-
tailed) was used when comparing values from the same patients
with OCD who were studied before and after treatment.
Scores on the symptom-rating scales were correlated with pos¬
itron emission findings using the Spearman rank correlation (r,).52
RESULTS
All normal subjects scored the minimal obtainable score on the
Brief Psychiatric Rating Scale, except on the "tension" and
"anxiety" items (see below), with the exception of one male subject
who scored 2 on the "Depressed Mood" item. Prescan scores on
other rating scales are summarized in Table 1.
Comparison of the first seven patients with OCD with the control
groups showed the absolute LCMRGlc for the OCD group to be sig¬
nificantly (P<.05) higher in the cerebral hemispheres, the heads of
the caudate nuclei, and the orbital gyri (all bilaterally), compared
with both control groups. The LCMRGlc-orbital gyrus/LCMRGlc-
hemisphere ratio was also significantly higher in patients with
OCD for the left hemisphere only. No other neuroanatomic struc¬
tures that we examined showed significant (P<.05) intergroup
differences on the ANOVA. Therefore, these structures were
examined for differences from the other control groups in the sec¬
ond set (n 7) and the drug-free set (n 9) of subjects with OCD.
= =
Absolute Glucose Metabolic Rates
Cerebral Hemispheres.—Both left and right hemispheres had
significantly (P<.05) higher LCMRGlc values in OCD than in
unipolar depression. This was seen on all statistical comparisons.
Though patients with OCD had a significantly higher LCMRGlc on
the total-subject group and the drug-free comparisons, rates were
not significantly greater than normals on the analysis of the second
seven patients with OCD. Figure 1 depicts these results in the
right hemisphere for the total group of subjects.
Heads of the Caudate Nuclei.—All comparisons performed for
both left and right caudate nuclei showed the LCMRGlc for OCD to
be significantly (P<.05) higher than that for both normal controls
and patients with unipolar depression. Figure 2 shows these
results for the total group of subjects for the right head of the
caudate nucleus.
Orbital Gyri.—Both orbital gyri showed a significantly (P<.05)
higher LCMRGlc in patients with OCD than in normal subjects in
all comparisons. The left orbital gyrus had a significantly higher
LCMRGlc in patients with OCD compared with patients with
unipolar depression on all statistical comparisons. The right or¬
bital gyrus, however, showed only a trend (P<.10) to be higher in
patients with OCD than in those with unipolar depression in the
second group of seven subjects with OCD and in the drug-free
group. Figure 3 shows these results in the right orbital gyrus for
the total group of subjects. (Technical difficulties made it impossi-
 Table 2.—Cerebral Glucose Metabolic Rates*

Obsessive-Compulsive
Normal Controls (N) Unipolar Depressed ( ) Disorder ( ) Significant
-'-' '-*-' -*-· Differences
L Hemisphere Hemisphere L Hemisphere R Hemisphere L Hemisphere R Hemisphere (P .05)t
Cerebral hemispheres
All subjects 4.73 + 0.76(14) 4.66±0.76 (14) 4.54±0.58 (14) 4.47±0.58 (14) 5.29±0.88 (14) 5.26±0.80 (14) OCD>UD,NI;
_Land R
Drug-free subjects 5.30 ±0.65 (9) 5.25 ±0.61 (9) OCD>UD,NI;
... ... ... ...
Land R
Head of caudate
All subjects 5.70±0.90 (14) 5.81 ±0.89 (14) 5.34±0.62 (14) 5.52±0.69 (14) 6.55±1.31 (14) 6.79±1.32 (14) OCD>UD,NI;
Land R
Drug-free subjects 6.52 ±0.96 (9) 6.73±1.00(9) OCD>UD,NI;
... ... ... ...
Land R
Orbital gyrit
All subjects 5.08±0.91 (13) 5.09±0.92 (13) 5.16±0.71 (14) 5.23±0.75 (14) 6.20±1.32 (13) 6.12 + 1.18 (13) OCD>UD,NI;
L and R
Drug-free subjects 6.02 ±0.90 (8) 5.92 ±0.84 (8) L:OCD>UD,NI;
... ... ... ... R:OCD>NI
*Glucose metabolic rates are given as milligrams of glucose per 100 g of brain per minute. All values are the mean ± SD.
tOCD indicates obsessive-compulsive disorder; UD, unipolar depressed; and NI, normal.
¿Structurenot visible on scans of all subjects.

Table 3.—Glucose Metabolic Rates in Orbital Gyri, Relative to Hemispheric Mean (Orbit-Hemisphere Ratio)*
Obsessive-Compulsive Significant
Normal Controls (N) Unipolar Depressed (N) Disorder (N) Differences
-'-
-'- -'-
(P<.05)
_L_R_L_R_L_R_(See Text)
All subjects 1.09±0.06 (13) 1.11 ±0.08 (13) 1.14±0.05 (14) 1.17±0.06 (14) 1.17±0.08 (13) 1.17±0.08 (13) OCD>NI;
L only
Drug-free subjects ... ... 1.15±0.06 (8) 1.14 ±0.07 (8) OCD>NI;
... ...
L only
*OCD indicates obsessive-compulsive disorder; NI, normal.

ble to calculate the LCMRGlc for the orbital gyri of one normal
subject and one patient with OCD.)
Table 2 gives the LCMRGlc for the cerebral hemisphere, heads
of the caudate nuclei, and orbital gyri, both for the total group of
subjects and for those who were drug free.
Relative Glucose Metabolic Rates
Statistical analysis of metabolic ratio values from the first seven
subjects with OCD, compared with the control groups, showed
significant results only for the left LCMRGlc-orbital gyrus/
LCMRGlc-hemisphere ratio (Table 3). In this structure, ratio
values in subjects with OCD were significantly higher than in
normal controls, but were not higher than those seen in subjects
with unipolar depression on all statistical comparisons. (Even
when the six patients with unipolar depression who had obsessions
were excluded from the analysis, the value of this ratio was not
significantly higher in subjects with OCD compared with subjects
with unipolar depression.) Figure 4 depicts results in the left
orbital gyrus for the total group of subjects with OCD and normal
controls.
Glucose Metabolic Changes After Drug Treatment
Ten subjects with OCD were treated with trazodone hydro¬
chloride, with or without the addition of a monoamine oxidase
inhibitor, in an open-study design.37 (Full details of treatment
strategy and results are reported elsewhere.53) The pretreatment
mean NIMH-OCD scale score was 32.9 ±7.0 and the HAM-D score
was 18.1±6.3. Eight subjects had a clear response and,
in these
patients, the NIMH-OCD scale score went from 34.4±6.7 to
12.6±8.3 and the HAM-D score went from 20.0±5.5 to 6.5±2.7.
The scores of two patients who did not respond (one treated with
trazodone and a monoamine oxidase inhibitor and the other treated
with trazodone alone) went from 30 and 23 to 31 and 27, respec¬
tively, on the NIMH-OCD scale, and went from 12 and 6 to 12 and
15, respectively, on the HAM-D scale. All ten patients underwent
scanning before and after drug treatment, with scans performed
two to four months apart.
The LCMRGlc for both hemispheres, caudate nuclei, and orbital
gyri did not show statistically significant changes after treatment
in the group of eight patients who responded to treatment (P>.25
for all groups), although in all six structures the group means for
these values were lower after treatment than before. These same
values also dropped in the two patients whose conditions did not
improve.
Figure 5 shows that there were significant changes in the
LCMRGlc-caudate/LCMRGlc-hemisphere ratio in the group that
responded to drug treatment, but not in the patients who did not
respond. In the right hemisphere of responders the ratio changed
+ 6.7%, while in nonresponders it changed -5.3%. These were
significant differences (P<.005). Values in responders and nonre¬
sponders changed + 5.9% and -11.4%, respectively (P<.03), in the
left hemisphere. Mean pretreatment values for this ratio in sub¬
jects with OCD were not significantly different from normal
values, either in the total patient group (right: normals, 1.25 ± 0.09;
OCD, 1.29 + 0.06; left: normals, 1.21 + 0.07; OCD, 1.23 + 0.05) or in
the group of eight patients with OCD who responded to drug
treatment (OCD, right, 1.26 + 0.06; left, 1.22 + 0.04) (P>.20). With
successful treatment, however, this ratio increased (right,
1.34 + 0.07; left, 1.29 + 0.08). These posttreatment values were
significantly higher than both the pretreatment values for these
patients with OCD (right, P<.025; left, P<.05) and those values
obtained from the normal controls (right and left, P<.02). In
contrast, the LCMRGlc-orbital gyrus/LCMRGlc-hemisphere ratio
did not change after treatment in either the patients who were
treated successfully (1.17 + 0.06 before treatment vs 1.17 + 0.09
after treatment) or unsuccessfully (the mean value went from 1.20
to 1.17).
Pretreatment and posttreatment percentage changes in the
LCMRGlc-caudate/LCMRGlc-hemisphere ratio ([pretreatment -

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 1.30

1.20
•
___

Œ
1.10t d»

" "
1.00
Mean 1.09±0.06 1.17±0.08
±SD
(N 13)
=
(N 13)
=

Normal Obsessive-
Compulsive

Fig 4.—Glucose metabolic rates for left orbital gyrus divided by rate
for ipsilateral hemisphere as whole. Ratio was significantly higher in
subjects with obsessive-compulsive disorder than in normals.
Values for the right hemisphere did not show significant differences.
Circles indicate drug-free subjects; squares, obsessive-compulsive
disorder.
posttreatmentMpretreatment + posttreatment]/2) were corre¬
lated with both pretreatment HAM-D and NIMH-OCD scores and
pretreatment to posttreatment percentage changes in these
two scales (percent change in HAM-D score; percent change in
NIMH-OCD score). Correlations were stronger with the HAM-D
than the NIMH-OCD score (right hemisphere: pretreatment
score
HAM-D score, r, .85, P<.01; pretreatment NIMH-OCD score,
=
Fig 5.—Glucose metabolic rate of right head of caudate nucleus
divided by that of ipsilateral hemisphere for patients with obsessive-
compulsive disorder studied before and after drug treatment. A
indicates posttreatment values for two patients who did not respond
to drug treatment. B, values on pretreatment scans; C, values for
one subject scanned after partial response to treatment with
trazodone hydrochloride, after which tranylcypromine was added,
with additional response and another scan performed, as indicated
at point D; and D, values for subjects scanned after optimal
response. All subjects who responded to drug showed increase in
ratio (P-C.025, paired t test), while the two who did not respond did
not increase ratio. Percentage change In ratio was significantly
different between group of patients who responded to drug treat¬
ment vs those who did not (P<.005). Values for left hemisphere
were essentially same.

rs .50, P<.20; percent change in HAM-D score, rs=.74,

=

P<.02; percent change in NIMH-OCD score, rs .53, P<.20; left

=

hemisphere: pretreatment HAM-D score, rs .64, P<.05; pre¬

=
treatment NIMH-OCD score, r,= .40, P>.20; percent change in
HAM-D score, rs .56, P-c.10; NIMH-OCD score, r, .38, P>.20).
= =
Pretreatment NIMH-OCD and HAM-D scores did not correlate
significantly with each other (rs=.52, P-c.20), but there was a
strong correlation between the percent change on each scale
(r, .96, P<.0001).
=
Figure 6 shows examples of these findings in selected patients.
The absolute LCMRGlc in OCD vs that in normals is illustrated in
Fig 6, center, while the LCMRGlc-structure/LCMRGlc-hemi-
sphere ratio, before and after successful treatment, is shown in Fig
6, right.
COMMENT
Two technical comments concerning the statistical analy¬
ses are in order. (1) The methods chosen were ones designed
to reduce the chance of type I (false-positive) error. This
increased the possibility of other significant differences
between the subjects with OCD and the control groups not
being reported (type II error). (2) Though otherwise well
matched, our OCD groups included a higher percentage of
male subjects than either control group. Thus, if male
subjects had an intrinsically higher LCMRGlc in the neu¬
roanatomic structures of interest, the differences observed
here between patients with OCD and the other groups
might be trivial. This seems highly unlikely, however, in
that female patients in the normal control group have been
found to have a significantly higher LCMRGlc than normal
male subjects in all neuroanatomic structures examined
herein.39 Furthermore, existing evidence indicates that the
part of the menstrual cycle in which normal women were
studied may be the time at which LCMRGlc values are
highest.39 Thus,the differences in male-female ratios that
were obtained between patients with OCD and both groups
of controls may have made the differences in LCMRGlc
values observed herein seem less significant than they
actually were.
As stated in the introduction, there has been interest in
the relationship of OCD to other DSM-III axis I psychopa¬
thology—especially depression and Tourette's disorder.
Despite close similarities between our patients with OCD
and those with unipolar depression in regard to HAM-D-
measured levels of depression, Brief Psychiatric Rating
Scale-measured tension and anxiety, and even the presence
of obsessional thoughts, the two disorders showed signifi¬
cantly different patterns of LCMRGlc in the caudate nuclei
and orbital gyri. Thus, the two disorders, despite similar
symptoms, and even physiologic manifestations,3,7"9 are
distinct and may be mediated by different cerebral proc¬
esses. In regard to Tourette's disorder, it is interesting to
note that one small study that involved only five patients
and seven control subjects showed a higher LCMRGlc in the
basal ganglia (not further defined) of patients and sug¬
gested hypermetabolism in frontal and temporal regions,
when compared with normal controls.54
Recent advances in behavioral neuroanatomy provide
potential explanations for abnormal metabolic activity in
the orbital gyri and caudate nuclei of patients with OCD.
The frontal lobes have intimate connections to the phyloge-
netically older striatal and limbic systems, and are involved
in the regulation of directed attention, sequencing of motor
and cognitive responses, control and averting of interfering
stimuli, socialized concern for others, and self-conscious-

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 Caudate Orbital Gyri
Left Right Left Right

Fig 6.—Positron emission tomographic scans of patients with obsessive-compulsive disorder. Top, Location of heads
of caudate nuclei and orbital gyri in scans shown below. Center, Scan of patient vs that of age- and sex-matched normal
control. Colors of scans correspond to glucose metabolic rates, which are indicated in color bar to right (in micromoles
of glucose per minute per 100 g of brain tissue; 1 mg of glucose equals 5.56 µ ). Glucose metabolic rates in
obsessive-compulsive disorder are especially high in caudate nuclei and orbital gyri (particularly on left) compared
with normal controls. Bottom, Scan of patient with obsessive-compulsive disorder before and after successful drug
treatment. Scan has been coded to reflect metabolic rate of each area of brain, divided by that of brain as whole. As in
center illustration, red indicates highest values and blue, lowest. Note how value of ratio for head of caudate nuclei
Increased with successful treatment. Patients who did not respond did not show increase in ratio. (See Fig 5.) Notice
how ratio value does not change in left orbital gyrus; despite symptomatic Improvement, it remains high when
compared with normal controls.

ness and awareness.55,56 The orbital gyri in particular, aside
from their probable involvement in the regulation of mood
states, seem important in maintaining the integrated per¬
ception of complex temporal relationships through the
inhibition of external interfering stimuli.55"57 The difficulty
patients with OCD have in diverting their attention from
obsessions might be due to the overactivity of such a
system. Furthermore, certain destructive lesions of the
orbital cortex result in disinhibition characterized by face-
tiousness, sexual and personal hedonism, irritability, and a
lack of socially appropriate concern for others.55 Such
syndromes are the behavioral opposite of the symptoms and
typical personality manifestations seen in individuals with
OCD.lJ< Though consisting mostly of anecdotal reports,
there is a large body of literature that suggests that
neurosurgical procedures that obliterate or isolate the
orbital gyri from the rest of the brain may alleviate some of
the symptoms of OCD, while having a relatively small effect
on other aspects of personality.58"65 However, procedures
that isolate the anterior cingulate gyrus may produce
equally good results.21,66 We are not aware of any attempts to
remove only the left orbital gyrus as a treatment for OCD.
Abnormal metabolic activity in the caudate nuclei can
also be understood in light of available literature. It has
been suggested that the basal ganglia system acts as a
sensory-information gating station or processor and, when
it is dysfunctional, unmodified afferent information leads to
inappropriate behavioral responses.61 Impairment of the
basal ganglia may even produce perseverative behaviors.68
Dysfunction in this region might relate to the perseverative
nature of obsessions and compulsions.
It has been postulated that the orbital cortex and the
ventral caudate nucleus determine if a behavioral response
will occur when an animal must redirect its behavior in re¬
sponse to the environment.69 Lesions in either the orbital
area or areas of the caudate nuclei to which the orbital area

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 projects result in a perseverative interference with an ani¬
mal's capacity to make appropriate switches in behavior.70
We observed that, in the symptomatic OCD state the ac¬
tivity in the caudate nuclei did show a high LCMRGlc. How¬
ever, the LCMRGlc of the caudate relative to that of the
ipsilateral hemisphere (LCMRGlc-caudate/LCMRGlc-
hemisphere) for these patients with OCD was not more
hypermetabolic in our normal subjects, yet on improvement
in OCD symptoms, this ratio increased to values that were
significantly higher than those seen in normal controls. We
have previously reported that this same ratio is low in the
symptomatic state of unipolar depression and increases to
values in the normal range on resolution of the depression.71
Since our treated patients with OCD showed improvements
in both OCD behavior and depression, increases in this ratio
may have been related to improvement in either or both of
these symptom complexes. We make this statement despite
the fact that changes in LCMRGlc-caudate/LCMRGlc-
hemisphere values correlated much more strongly with
pretreatment scores and changes in the HAM-D than in the
NIMH-OCD. The validity of the HAM-D in reflecting
changing levels of depression is well documented over many
years; the NIMH-OCD awaits such testing. Another com¬
plicating factor is the fact that both scales contain items that
rate anxiety and even obsessions and compulsions. In any
event, as previously mentioned, depression is a common
feature of OCD.M Segregating the symptoms that are
pathognomonic for "pure OCD" from those pathognomonic
for depression proved to be very difficult in previous OCD
studies.3,7,72
We now come to a hypothesis. In acutely symptomatic
OCD (with or without depression), activity in the cortex,
and especially in the orbital gyri, is high in terms of absolute
LCMRGlc. Perhaps this indicates that functional activity
has increased beyond the capacity of the caudate nucleus to
maintain its integrative capacities for these cortical re¬
gions. With successful treatment the caudate reestablishes
its processing capacity through an increase in its metabolic
rate relative to the structures with which it interacts. Such
increases in relative metabolic activity may be necessary
for the reestablishment of the caudate nucleus' integrative
capacity. The fact that left LCMRGlc-orbital gyrus/
LCMRGlc-hemisphere value remains abnormally high even
after successful treatment (and is thus a possible trait
marker for OCD) may be related to a need for the
LCMRGlc-caudate/LCMRGlc-hemisphere ratio to become
abnormally high to exert the neuronal modulation needed
for the successful control of OCD symptoms. Furthermore,
given the profound complexity of corticocortical interac¬
tions,66 it is conceivable that the increased glucose utiliza¬
tion in cerebral areas other than the orbital gyri in OCD are
related to the work involved in generating the intricate
defenses and other psychopathologic phenomena in symp¬
tomatic OCD that may be secondary to a mismatch in
orbital-caudate activity. It is also of interest that dopamine
and serotonin, the two neurotransmitters most commonly
implicated in both OCD and the related Tourette's disor¬
der,3,13,21,22,30,73 are present in significant quantities in both
the caudate nucleus and the orbital area of the prefrontal
cortex.74,75
The caudate nucleus and other structures of the basal
ganglia have a well-known topographic organization with
respect to their afferent cortical connections.50,70,76 Positron
emission scanners with improved resolution may allow one
to monitor activity shifts in areas of the basal ganglia that
are specifically associated with various cortical areas, in¬
cluding the orbital prefrontal cortex. We would predict that
other drugs that are helpful in treating OCD,3,2729 other
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treatment modalities such as behavior modification,3,77·78
and spontaneous recovery1"4 would all be accompanied by
positron emission tomography-LCMRGlc-measured func¬
tional changes in these neuroanatomic regions.
Obsessive-compulsive disorder is a classic psychiatric
illness that played a central role in the development of
Freud's theories of the psychoneuroses. Freud79 himself
emphasized that all mental phenomena must be mediated
by neuroanatomically localized neurochemical mechanisms.
Thus he wrote half a century ago: "we may look forward to a
day when paths of knowledge and, let us hope, of influence
will be opened up, leading from organic biology and chemis¬
try to the field of neurotic phenomena," but added "That day
still seems a distant one."80 Present positron emission
tomography-fluoro-2-deoxyglucose 18F methods can dem¬
onstrate glucose metabolic abnormalities in biologic dis¬
eases, and also show metabolic changes that are the result
of acute environmental and behavioral manipulations.32,83
We would like to emphasize that our findings do not address
the cause of OCD, but rather the neuroanatomic localization
of the cerebral glucose metabolic processes that may medi¬
ate its expression.
This work was supported in part by contract AM03-76 SF00012 from the
Department of Energy; grant MH 37916-02 from the National Institute of
Mental Health; grant 1K07-00588-04-NSPA from the National Institute of
Neurological and Communicative Disorders and Stroke (teacher-investiga¬
tor award, Dr Mazziotta); donations from the Jennifer Jones Simon Founda¬
tion; and the Judson Braun Chair in Psychiatry.
Jorge Barrio, PhD, and his chemistry staff and Norman MacDonald, PhD,
and his cyclotron staff prepared the fluoro-2-deoxyglucose "F. We would
also like to thank Joaquín M. Fuster, MD, Jeffrey L. Cummings, MD, and
D. Frank Benson, MD, for critical comments. J. Mark Thompson, MD,
helped with patient treatment and also provided critical comments.
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