Brain glucose metabolic changes associated

with neuropsychological improvements after

4 months of treatment in patients with
obsessivecompulsive disorder
Introduction
Obsessivecompulsive disorder (OCD) is charac-
terized by intrusive thought and stereotyped beha-
viour that are severe enough to interfere with daily
function and cause signicant distress (1). Although
the pathophysiology of OCD remains controver-
sial, there is substantial evidence that OCD is
associated with distinct patterns of brain dysfunc-
tion and cognitive impairment. In particular,
previous positron emission tomography (PET)
studies of OCD have found increased glucose
metabolic rates in the orbitofrontal cortex, the
anterior cingulate, the caudate nuclei, and the
thalamus (2, 3), and the stimulations that provoke
OCD symptoms have been found to increase blood
ow to similar brain regions (4, 5). Furthermore,
this hypermetabolism was reduced by successful
pharmacotherapy (6, 7) and even by behavioural
therapy (8, 9). These functional neuroimaging
ndings have led to a theoretical model that
obsessivecompulsive symptoms are mediated
by the hyperactivity in frontalsubcortical circuit
(10, 11). In accordance with functional neuroimag-
ing studies, previous neuropsychological studies of
OCD have found that patients with OCD perform
poorly on tests associated with executive function
and visuospatial memory, which are related with
functional integrity of frontalsubcortical circuitry
(1214), although, it should be added, there have
been some inconsistencies among the ndings of
neuropsychological studies upon OCD. Thus, a
consistent picture is emerging, which points to the
central importance of the frontalsubcortical
Kang D-H, Kwon JS, Kim J-J, Youn T, Park H-J, Kim MS, Lee DS,
Lee MC. Brain glucose metabolic changes associated with
neuropsychological improvements after 4 months of treatment in
patients with obsessivecompulsive disorder.
Acta Psychiatr Scand 2003: 107: 291297. Blackwell Munksgaard 2003.
Objective: The study was designed to elucidate regional brain
metabolic changes according to a treatment and their relationship with
neuropsychological performance changes in obsessivecompulsive
disorder (OCD).
Method: Cerebral glucose metabolic rates were repeatedly measured
before and after treatment in 10 patients with OCD using [
18
F]-2-
uoro-deoxyglucose positron emission tomography (PET). They were
compared on a voxel-basis, and the correlations were counted between
the regional metabolic changes and the degree to improvement on the
neuropsychological assessments.
Results: After treatment, the patients showed signicant (P < 0.005,
two-tailed) regional metabolic changes in multiple brain areas
involving frontalsubcortical circuits and parietalcerebellar networks.
Especially, the metabolic changes of the putamen, the cerebellum, and
the hippocampus were signicantly correlated with the improvement of
the immediate- and delayed-recall scores of the Rey-Osterrieth
Complex Figure Test (RCFT).
Conclusion: These results suggest a possibility that metabolic changes
of frontalsubcortical and parietalcerebellar circuit changes may
underlie cognitive improvements in patients with OCD.
D.-H. Kang
1
, J. S. Kwon
1,2,3,4
,
J.-J. Kim
5
, T. Youn
1,2
, H.-J. Park
3
,
M. S. Kim
1
, D. S. Lee
2
, M. C. Lee
2
1
Department of Psychiatry,
2
Department of Nuclear
Medicine,
3
BK 21 Human Life Science,
4
Clinical
Research Institute, Seoul National University Hospital,
Seoul, Korea and
5
Department of Psychiatry, Yonsei
University College of Medicine, Seoul, Korea
Key words: obsessivecompulsive disorder;
neuropsychology; positron emission tomography
Jun Soo Kwon MD, PhD, Department of Psychiatry and
Nuclear Medicine, Seoul National University College of
Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, Korea
110-744
E-mail: kwonjs@plaza.snu.ac.kr
Accepted for publication November 29, 2002
Acta Psychiatr Scand 2003: 107: 291297
Printed in UK. All rights reserved
Copyright Blackwell Munksgaard 2003
ACTA PSYCHIATRICA
SCANDINAVICA
ISSN 0001-690X
291
system on symptomatic expression as well as the
specic cognitive decits of OCD.
However, relatively few studies have tried to link
the defective cognitive function found in neuro-
psychological studies with a functional neuroimag-
ing approach. Considering that neuropsychological
test, when compared with clinical symptom, is
known to be more appropriate for assessing the
specic cognitive and behavioural consequences of
regional brain abnormalities (15), it is vital that the
relationship between the defective cognitive func-
tions observed in OCD and functional brain
activity be investigated simultaneously to more
accurately understand the pathophysiology of
OCD. Recently, we compared the cerebral glucose
metabolic rates and their relationships with neu-
ropsychological performances in 14 patients with
OCD who were not taking medication with age-
and sex-matched normal controls (16). In this
study, employing a voxel-by-voxel approach, we
demonstrated the cognitive decits observed in
OCD from a functional neuroanatomical perspec-
tive and extended earlier ndings, namely, that the
parietalsubcortical circuits as well as the frontal
subcortical circuits might be involved in the
cognitive decits found in patients with OCD.
Reasonably, the next step involves the investiga-
tion of the changes of neuropsychological per-
formances and their relationships with the changes
in functional brain activities after treatment to
replicate our earlier ndings.
Aims of the study
The aims of the current study were to examine the
relationship between the regional brain metabolic
change and the degree to the improvement on the
neuropsychological performances in patients with
OCD after 4 months of pharmacotherapy with
selective serotonin reuptake inhibitors (SSRI). To
elucidate this, we have investigated the changes in
cognitive function that are defective in patients
with OCD, and then applied a voxel-based region
of interest (ROI) approach to analyze the correla-
tions between these changed cognitive function and
regional brain metabolic changes as determined by
[
18
F]-2-uoro-deoxyglucose (FDG) PET.
Material and methods
Subjects
Fourteen drug-free patients with OCD who were
recruited from an out-patient OCD clinic at Seoul
National University Hospital were previously
scanned as a part of a PET study of OCD (16).
Of this group, 10 patients (seven men and three
women: mean age 29.7 years, SD 8.49; the
mean years of education 15 years, SD 1.94;
the mean duration of illness 10.6 years,
SD 8.31) repeated follow-up examination after
4 months of antiobsessional treatment. Nine
patients were right-handed and one was left-
handed (17). They fullled DSM-IV criteria for
OCD as diagnosed using the Structured Clinical
Interview for DSM-IV (SCID-IV) (18). Exclusion
criteria were the presence of a signicant medical
condition, or any neurological disorder, or any
history of other major psychiatric disorders such as
substance abuse, schizophrenia, and bipolar disor-
der. Only one patient with OCD had past history
of a single episode of transient tic disorder, which
spontaneously resolved. This study was carried out
under guidelines for the use of human subjects
established by the institutional review board. After
complete description of the study to the subjects,
written informed consent was obtained. Patients
were mainly treated with SSRIs (four sertraline,
three paroxetine, three uoxetine), which are pref-
erable than tricyclic antidepressants in case of
OCD (19), with dosages adjusted to their symptom
severity over 12 weeks (mean dosage: sertr-
aline 111.5 mg day, paroxetine 36.9 mg day,
day, uoxetine 47.5 mg day) and three patients
also received antipsychotic treatment because of
their partial response to SSRI (two risperidone: up
to 0.5 mg, one olanzapine up to 2.5 mg).
Clinical and cognitive assessments
Clinical assessments included the Yale-Brown
ObsessiveCompulsive Scale (Y-BOCS) (20) for
measuring OCD symptom severity before and after
treatments. The Beck Depression Inventory (BDI)
(21) and the Beck Anxiety Inventory (BAI) (22)
were also administered.
To provide an IQ estimate, the Vocabulary,
Arithmetic, Block Design, Picture Arrangements,
and Digit Span, which are subsets of the Korean
version of Wechsler Adult Intelligence Scale
(K-WAIS) (23), were administered to all subjects.
Based on previous ndings, we chose four cognitive
tests to assess the cognitive function of OCD, which
included the Controlled Oral Word Association
(COWA) test for evaluating frontal lobe function
such as controlled attention (24), Trail Making B
(TMB) for the visual search and the motor function
speed (15) or the set-shifting ability and the
controlled attention (25), the Wisconsin Card
Sorting Test (WCST) for assessments of the frontal
cortical function (26, 27) and the Rey-Osterrieth
Complex Figure Test (RCFT) for the visuospatial
Kang et al.
292
constructional ability and the visuospatial memory
(25). And, then, total numbers of letter and
category uency test, spending time of the TMB,
perseverative errors of the WCST, and scores of
copy, an immediate-recall (3 min after copy condi-
tion) and a 30-min delayed-recall condition of the
RCFT were used to examine the change of cogni-
tive function after treatments. All tests were applied
for all subjects on the day of PET scanning.
PET method and imaging data analysis
All subjects underwent repeated FDG PET scans
at rest before and after 4 months of SSRI treat-
ment without ear plugs or eye pads, using an
ECAT EXACT 47 scanner (Siemens-CTI, Knox-
ville, TN, USA), and gathered data were recon-
structed in a 128 128 47 matrix with a pixel
size of 2.1 2.1 3.4 mm by means of a ltered
back-projection algorithm employing a Shepp-
Logan (Siemens CT1, Knoxville, TN, USA)
lter with cut-o frequency of 0.3 cycles pixel.
Spatial preprocessing and statistical analysis were
performed using Statistical Parametric Mapping
(SPM) 99 (Institute of Neurology, University Col-
lege of London, London, UK) (28). All recon-
structed images were spatially normalized into the
MNI (Montreal Neurological Institute, McGill
University, CA, USA) standard template to
remove the intersubject anatomical variability
(29, 30). Ane transformation was performed,
and subtle transformed image and the template
were removed by the non-linear registration
method using the weighted sum of the predened
smooth basis functions used in discrete cosine
transformation. Spatially normalized images
were smoothed by convolution with an isotropic
Gaussian kernel with 16 mm full width at half
maximum to increase the signal-to-noise ratio and
accommodate the variations in subtle anatomical
structures.
Statistical analysis
The eects of global metabolism were removed by
normalizing the count of each voxel to the total
count of the brain (proportional scaling in SPM).
Then, signicant changes of regional cerebral meta-
bolismafter treatment in 10 patients with OCDwere
estimated using a paired t-test at every voxel. For
easy interpretation, T-values were transformed to
Z-scores in the standard Gaussian distribution.
Threshold of signicance was dened as a P-value
below 0.005 (uncorrected, two-tailed) and conti-
guous voxels above 50. In order to evaluate corre-
lations between brain metabolic changes and
neuropsychological changes, adjustedmeanregional
activities were counted in both images before and
after the treatment on the basis of the ROI made
fromthe clusters consisting of signicant contiguous
voxels in the voxel-based analysis. Percent changes
of the regional activities after treatment were calcu-
lated, and then Spearman correlation coecients
were computed between regional changes and per-
centage changes in the neuropsychological perform-
ances. The signicance of the correlations was
dened as a level of P < 0.05.
Results
Changes of clinical symptoms and neuropsychological
performance
As shown in Table 1, for the group as a whole,
there was a substantial improvement in symptom
dimensions after SSRI-treatment. In terms of
neuropsychological performance, only immediate-
recall scores (t )2.808, df 9, P < 0.05) and
the delayed-recall scores (t )2.383, df 9, P <
0.05) of the RCFT were signicantly changed after
treatment.
Cerebral glucose metabolic changes after treatment
Areas of signicant dierences found in comparing
glucose metabolic rates at baseline and at follow-
up and their mean voxel activities before and after
treatment are presented in Table 2. As shown in
Fig. 1a, signicant metabolic decreases were iden-
tied in the lateral and medial portion of the
orbitofrontal cortex, the right hippocampus, the
lateral and medial portion of the cerebellum, and
Table 1. Subjects' clinical characteristics, and neuropsychological performances
before and after treatment*
Baseline Follow-up P-value
Clinical characteristics
Yale-Brown ObsessiveCompulsive
Scale score
26.7 (7.3) 13.5 (5.6) 0.001
Beck Anxiety Inventory score 24.3 (26.7) 16.3 (16.8) 0.039
Beck Depression Inventory score 20.0 (13.4) 12.0 (9.0) 0.054
Neuropsychological performances
Word fluency test
Total numbers (letter) 33.6 (9.4) 36.1 (10.6) NS
Total numbers (category) 30.0 (5.3) 32.9 (5.02) NS
Trail Making B (spending time) 74.4 (32.2) 63.5 (24.8) NS
Wisconsin Card Sorting Test
(perseverative errors)
10.9 (9.0) 6.3 (3.7) NS
Rey-Osterrieth Complex Figure Test
Copy scores 33.1 (2.0) 30.9 (6.1) NS
Immediate-recall score 14.3 (6.8) 20.1 (6.1) 0.020
Delayed-recall score 15.4 (5.5) 19.0 (5.5) 0.041
* Data are given as mean (standard deviation), unless otherwise indicated.
Neural correlates of cognitive dysfunction of OCD
293
the right putamen after treatment. In comparison,
metabolic rates of the lateral portion of the right
postcentral gyrus, the posterior portion of the
superior parietal lobe, and the medial portion of
the superior occipital gyrus were signicantly
increased after treatment (shown Fig. 1b).
Correlation with the changes of glucose metabolism
and the neuropsychological performance
As summarized in Table 3, the percentage changes
in regional cerebral glucose metabolism at baseline
and follow-up were compared with percentage
changes in immediate- and delayed-recall scores of
the RCFT. Changes of immediate-recall scores of
the RCFT revealed a signicant negative correla-
tion with glucose metabolic change of the right
lateral cerebellum (r )0.685, P < 0.05), the
right hippocampus (r )0.818, P < 0.05), and
the right putamen (r )0.648, P < 0.05), while
no signicant positive correlations were seen.
Furthermore, changes of delayed-recall scores of
the RCFT also had a signicant negative correla-
tion with metabolic changes of the right hippo-
campus (r )0.636, P < 0.05), and the right
putamen (r )0.721, P < 0.05), while again no
signicant positive correlations were seen.
Discussion
Consistent with the previous ndings obtained by
the ROI method, the glucose metabolic rates of the
orbitofrontal cortex and the right putamen were
signicantly reduced after the SSRI treatment. The
orbitofrontal cortex has been shown to have
increased activity compared with normal control
subjects in resting states (3, 31), and to be
decreased after successful treatment (6, 7, 32),
suggesting that this area may be involved in
mediating the expression of obsessivecompulsive
symptom. Furthermore, there has been much
experimental and clinical evidence that the orbito-
frontal cortex is involved in the mediation of
emotional response to biologically signicant stim-
uli, as well as in the inhibition of behavioural
response (33). The putamen is the major compo-
nent of the basal ganglia, which, along with the
cortical brain regions, is suggested to be implicated
in the symptomatic expression of OCD (34). The
hypermetabolism of the putamen in patients with
OCD (32, 35) and its reduced activity after
treatment (32) were also reported. In particular,
defective activity of the putamen is reported in
patients with Tourette syndrome (36, 37), which
have been shown to display impaired cognitive and
motor inhibition (38) that is closely related with the
phenomenology of various type of compulsion. We
also found metabolic changes of the hippocampus,
the parieto-occipital junction, and the cerebellum
after treatments. Defective activities in the hippo-
campus (39), the parieto-occipital junction (40),
and the cerebellum (4, 41) have been reported in
patients with OCD in previous studies, although it
has not been of importance in their consideration.
Considered together the ndings in the current
study, parieto-cerebellar dysfunction as well as
frontalsubcortical abnormalities may underlie
symptomatic expression of obsessivecompulsive
phenomena. Moreover, these metabolic abnormal-
ities may be state-dependent and change with
improvement of obsessivecompulsive symptoms
after treatment.
Region
Coordinates
Highest Z-value Voxel number
Mean voxel activity*
x y z Before treatment After treatment
Decreased activity
Right lateral orbitofrontal 32 40 20 3.50 2827 7.66 (0.20) 7.34 (0.17)
Right medial orbitofrontal 6 34 )8 3.50 81 7.82 (0.45) 7.53 (0.35)
Left lateral orbitofrontal )32 38 )26 3.89 143 6.34 (0.27) 6.06 (0.26)
Left medial orbitofrontal )6 40 )20 3.17 143 4.19 (0.21) 4.08 (0.22)
Right hippocampus 22 )12 )20 3.46 647 6.56 (0.15) 6.26 (0.18)
Right putamen 12 )42 )5 2.99 308 7.03 (0.33) 6.51 (0.38)
Right lateral cerebellum 46 )64 )50 3.34 443 7.45 (0.56) 6.84 (0.33)
Right medial cerebellum 12 )52 )50 3.39 253 7.11 (0.54) 6.62 (0.28)
Left lateral cerebellum )40 )56 )50 3.64 521 7.52 (0.46) 6.96 (0.30)
Increased activity
Right superior parietal 28 )62 44 3.20 70 7.59 (0.36) 7.84 (0.40)
Right postcentral gyrus 42 )30 38 3.69 438 6.33 (0.26) 6.61 (0.24)
Right superior occipital 18 )82 48 3.12 94 6.78 (0.31) 7.05 (0.27)
Left superior parietal )32 )66 62 3.06 66 5.66 (0.43) 6.07 (0.40)
* Mean voxel activities are given as milligrams of glucose per 100 g brain per minute. All values are the mean
(standard deviation).
Table 2. Comparison of regional glucose meta-
bolic rates before and after treatment and their
mean voxel activities
Kang et al.
294
In neuropsychological performances, scores in
the immediate-recall condition and the delayed-
recall test of the RCFT were signicantly
improved. The RCFT has been widely employed
as a measure of visuospatial constructional and
visuospatial memory (25). Chiulli et al. (42) sug-
gested that conditions of copy, immediate-, and
delayed-recall provide dierent information. They
suggested that while the copy condition reects
perceptual, visuospatial and organizational skill,
immediate recall reects the amount of informa-
tion that is encoded. In addition, the delayed-recall
condition reects the amounts of information that
is stored and retrieved from memory. Savage et al.
(14) reported upon the impairment of immediate
recall in patients with OCD, and used a new
perspective that could evaluate the mediating eect
of organizational strategies on non-verbal memory.
Specically, they suggested that memory problems
observed in OCD occur secondary to impaired
organizational strategies. Taken together, signi-
cant improvements of scores in the immediate-
recall condition and the delayed-recall test of the
RCFT in the present study may be the result of the
improved visuospatial information organization,
which is related with executive function, and not
to improvement in the non-verbal memory func-
tion itself. Furthermore, the signicant positive
correlation (r 0.867) between the immediate-
recall and the delayed-recall score changes supports
this hypothesis. Most interestingly, signicant
correlations were found between the metabolic
rate changes of the right cerebellum, the right
putamen, and the right hippocampus, and change
in the scores in the immediate-recall condition of
the RCFT. It is noteworthy that all of these areas
are parts of abundant prefrontalsubcortical
cerebellar connection, which have been suggested
to play a role in coordinating the complex mental
and non-motor higher cognitive functions (4345).
Recently, impairments in this circuitry has been
postulated to be an underlying factor of a variety
of clinical symptom and cognitive decits in schi-
zophrenia (44, 46), and Kim et al. (47) reported
gray matter abnormalities in these structures in
OCD patients. Furthermore, in our earlier study
of OCD in the resting state (16), dierent from
the normal subjects, the glucose metabolic rates
of these areas were signicantly correlated with
various neuropsychological performance evalua-
tion of executive function, which is impaired in
patients with OCD. Considered together, it is
apparent that non-specic but characteristic pat-
terns of distributed brain circuits involved in
the expression of cognitive dysfunction observed
in patients with OCD. Moreover, cognitive
Table 3. Summary of the correlation analysis between regional glucose metabolic
rate changes and the changes of neuropsychological performances
Region Spearman correlation coefficient Significance (P)
Correlation with the change of the immediate-recall scores of Rey-Osterrieth
Complex Figure Test
Right lateral cerebellum )0.685 0.029
Right hippocampus )0.818 0.004
Right putamen )0.648 0.043
Correlation with the change of the delayed-recall scores of Rey-Osterrieth Complex
Figure Test
Right hippocampus )0.636 0.048
Right putamen )0.721 0.019
Fig. 1. Statistical parametric mapping displaying differences of
glucose metabolic rates between before and after treatment.
Signicant within-group differences before and after treatment
(P < 0.005, k > 50) are shown on three orthogonal telescoped
views and a three-dimensional rendered image. Note that sig-
nicant metabolic decreases were identied in lateral and medial
portion of the orbitofrontal cortex, the right hippocampus, the
lateral and medial portion cerebellum and the right putamen
observed after treatment (a), whereas metabolic rates of lateral
portion of the right postcentral gyrus, posterior portion of the
superior parietal lobe, and medial portion of the superior
occipital gyrus were signicantly increased after treatment (b).
Neural correlates of cognitive dysfunction of OCD
295
dysfunction mediated by these brain circuits
appears somewhat reversible.
In the current study, we investigated regional
brain metabolic changes according to a treatment
and their relationship with neuropsychological
performance changes in OCD. Employment of
the within-subject design has allowed us to use
each subject as or her control, assessing brain
glucose metabolic changes associated with neuro-
psychological improvements, regardless of what
produced the improvements. Our overall ndings
seem to indicate that multiple brain areas are
involved in the improvements of the cognitive
decits observed in OCD. These involvements are
particularly apparent in the frontalsubcortical
circuit and also possible in the parietalcerebellar
circuits. Well-designed cognitive activation para-
digms to probe the functional integrity of the
various cortico-striatal system, as well as of the key
limbic and paralimbic structure, remains to be
investigated to nd out the neural correlates of
cognitive dysfunction of OCD.
Acknowledgement
This study was supported from Seoul National University
Hospital by a research grant (04-2000-046).
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