Brain glucose metabolic changes associatedwith neuropsychological improvements after4 months of treatment in patients withobsessive–compulsive disorder

Introduction

Obsessive–compulsive disorder (OCD) is charac-terized by intrusive thought and stereotyped beha-viour that are severe enough to interfere with dailyfunction and cause significant distress (1). Althoughthe pathophysiology of OCD remains controver-sial, there is substantial evidence that OCD isassociated with distinct patterns of brain dysfunc-tion and cognitive impairment. In particular,previous positron emission tomography (PET)studies of OCD have found increased glucosemetabolic rates in the orbitofrontal cortex, theanterior cingulate, the caudate nuclei, and thethalamus (2, 3), and the stimulations that provokeOCD symptoms have been found to increase bloodflow to similar brain regions (4, 5). Furthermore,

this hypermetabolism was reduced by successfulpharmacotherapy (6, 7) and even by behaviouraltherapy (8, 9). These functional neuroimagingfindings have led to a theoretical model thatobsessive–compulsive symptoms are mediatedby the hyperactivity in frontal–subcortical circuit(10, 11). In accordance with functional neuroimag-ing studies, previous neuropsychological studies ofOCD have found that patients with OCD performpoorly on tests associated with executive functionand visuospatial memory, which are related withfunctional integrity of frontal–subcortical circuitry(12–14), although, it should be added, there havebeen some inconsistencies among the findings ofneuropsychological studies upon OCD. Thus, aconsistent picture is emerging, which points to thecentral importance of the frontal–subcortical

Kang D-H, Kwon JS, Kim J-J, Youn T, Park H-J, Kim MS, Lee DS,Lee MC. Brain glucose metabolic changes associated withneuropsychological improvements after 4 months of treatment inpatients with obsessive–compulsive disorder.Acta Psychiatr Scand 2003: 107: 291–297.ªBlackwellMunksgaard 2003.

Objective: The study was designed to elucidate regional brainmetabolic changes according to a treatment and their relationship withneuropsychological performance changes in obsessive–compulsivedisorder (OCD).Method: Cerebral glucose metabolic rates were repeatedly measuredbefore and after treatment in 10 patients with OCD using [18F]-2-fluoro-deoxyglucose positron emission tomography (PET). They werecompared on a voxel-basis, and the correlations were counted betweenthe regional metabolic changes and the degree to improvement on theneuropsychological assessments.Results: After treatment, the patients showed significant (P < 0.005,two-tailed) regional metabolic changes in multiple brain areasinvolving frontal–subcortical circuits and parietal–cerebellar networks.Especially, the metabolic changes of the putamen, the cerebellum, andthe hippocampus were significantly correlated with the improvement ofthe immediate- and delayed-recall scores of the Rey-OsterriethComplex Figure Test (RCFT).Conclusion: These results suggest a possibility that metabolic changesof frontal–subcortical and parietal–cerebellar circuit changes mayunderlie cognitive improvements in patients with OCD.

D.-H. Kang1, J. S. Kwon1,2,3,4,J.-J. Kim5, T. Youn1,2, H.-J. Park3,M. S. Kim1, D. S. Lee2, M. C. Lee21Department of Psychiatry, 2Department of NuclearMedicine, 3BK 21 Human Life Science, 4ClinicalResearch Institute, Seoul National University Hospital,Seoul, Korea and 5Department of Psychiatry, YonseiUniversity College of Medicine, Seoul, Korea

Key words: obsessive–compulsive disorder;neuropsychology; positron emission tomography

Jun Soo Kwon MD, PhD, Department of Psychiatry andNuclear Medicine, Seoul National University College ofMedicine, 28 Yeongon-dong, Chongno-gu, Seoul, Korea110-744E-mail: kwonjs@plaza.snu.ac.kr

Accepted for publication November 29, 2002

Acta Psychiatr Scand 2003: 107: 291–297Printed in UK. All rights reserved

Copyright ª Blackwell Munksgaard 2003

ACTA PSYCHIATRICASCANDINAVICAISSN 0001-690X

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system on symptomatic expression as well as thespecific cognitive deficits 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 neuropsychologicaltest, when compared with clinical symptom, isknown to be more appropriate for assessing thespecific cognitive and behavioural consequences ofregional brain abnormalities (15), it is vital that therelationship between the defective cognitive func-tions observed in OCD and functional brainactivity be investigated simultaneously to moreaccurately understand the pathophysiology ofOCD. Recently, we compared the cerebral glucosemetabolic rates and their relationships with neu-ropsychological performances in 14 patients withOCD who were not taking medication with age-and sex-matched normal controls (16). In thisstudy, employing a voxel-by-voxel approach, wedemonstrated the cognitive deficits observed inOCD from a functional neuroanatomical perspec-tive and extended earlier findings, namely, that theparietal–subcortical circuits as well as the frontal–subcortical circuits might be involved in thecognitive deficits 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 changesin functional brain activities after treatment toreplicate our earlier findings.

Aims of the study

The aims of the current study were to examine therelationship between the regional brain metabolicchange and the degree to the improvement on theneuropsychological performances in patients withOCD after 4 months of pharmacotherapy withselective serotonin reuptake inhibitors (SSRI). Toelucidate this, we have investigated the changes incognitive function that are defective in patientswith OCD, and then applied a voxel-based regionof interest (ROI) approach to analyze the correla-tions between these changed cognitive function andregional brain metabolic changes as determined by[18F]-2-fluoro-deoxyglucose (FDG) PET.

Material and methods

Subjects

Fourteen drug-free patients with OCD who wererecruited from an out-patient OCD clinic at SeoulNational University Hospital were previouslyscanned as a part of a PET study of OCD (16).

Of this group, 10 patients (seven men and threewomen: mean age ¼ 29.7 years, SD ¼ 8.49; themean years of education ¼ 15 years, SD ¼ 1.94;the mean duration of illness ¼ 10.6 years,SD ¼ 8.31) repeated follow-up examination after4 months of antiobsessional treatment. Ninepatients were right-handed and one was left-handed (17). They fulfilled DSM-IV criteria forOCD as diagnosed using the Structured ClinicalInterview for DSM-IV (SCID-IV) (18). Exclusioncriteria were the presence of a significant medicalcondition, or any neurological disorder, or anyhistory of other major psychiatric disorders such assubstance abuse, schizophrenia, and bipolar disor-der. Only one patient with OCD had past historyof a single episode of transient tic disorder, whichspontaneously resolved. This study was carried outunder guidelines for the use of human subjectsestablished by the institutional review board. Aftercomplete description of the study to the subjects,written informed consent was obtained. Patientswere mainly treated with SSRIs (four sertraline,three paroxetine, three fluoxetine), which are pref-erable than tricyclic antidepressants in case ofOCD (19), with dosages adjusted to their symptomseverity over 1–2 weeks (mean dosage: sertr-aline ¼ 111.5 mg ⁄day, paroxetine ¼ 36.9 mg ⁄day,day, fluoxetine ¼ 47.5 mg ⁄day) and three patientsalso received antipsychotic treatment because oftheir partial response to SSRI (two risperidone: upto 0.5 mg, one olanzapine up to 2.5 mg).

Clinical and cognitive assessments

Clinical assessments included the Yale-BrownObsessive–Compulsive Scale (Y-BOCS) (20) formeasuring OCD symptom severity before and aftertreatments. 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 Koreanversion of Wechsler Adult Intelligence Scale(K-WAIS) (23), were administered to all subjects.Based on previous findings, we chose four cognitivetests to assess the cognitive function of OCD, whichincluded the Controlled Oral Word Association(COWA) test for evaluating frontal lobe functionsuch as controlled attention (24), Trail Making B(TMB) for the visual search and the motor functionspeed (15) or the set-shifting ability and thecontrolled attention (25), the Wisconsin CardSorting Test (WCST) for assessments of the frontalcortical function (26, 27) and the Rey-OsterriethComplex Figure Test (RCFT) for the visuospatial

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constructional ability and the visuospatial memory(25). And, then, total numbers of letter andcategory fluency test, spending time of the TMB,perseverative errors of the WCST, and scores ofcopy, an immediate-recall (3 min after copy condi-tion) and a 30-min delayed-recall condition of theRCFT were used to examine the change of cogni-tive function after treatments. All tests were appliedfor all subjects on the day of PET scanning.

PET method and imaging data analysis

All subjects underwent repeated FDG PET scansat rest before and after 4 months of SSRI treat-ment without ear plugs or eye pads, using anECAT EXACT 47 scanner (Siemens-CTI, Knox-ville, TN, USA), and gathered data were recon-structed in a 128 · 128 · 47 matrix with a pixelsize of 2.1 · 2.1 · 3.4 mm by means of a filteredback-projection algorithm employing a Shepp-Logan (Siemens – CT1, Knoxville, TN, USA)filter with cut-off frequency of 0.3 cycles ⁄pixel.Spatial preprocessing and statistical analysis wereperformed 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 theMNI (Montreal Neurological Institute, McGillUniversity, CA, USA) standard template toremove the intersubject anatomical variability(29, 30). Affine transformation was performed,and subtle transformed image and the templatewere removed by the non-linear registrationmethod using the weighted sum of the predefinedsmooth basis functions used in discrete cosinetransformation. Spatially normalized imageswere smoothed by convolution with an isotropicGaussian kernel with 16 mm full width at halfmaximum to increase the signal-to-noise ratio andaccommodate the variations in subtle anatomicalstructures.

Statistical analysis

The effects of global metabolism were removed bynormalizing the count of each voxel to the totalcount of the brain (proportional scaling in SPM).Then, significant changes of regional cerebral meta-bolism after treatment in 10 patients withOCDwereestimated using a paired t-test at every voxel. Foreasy interpretation, T-values were transformed toZ-scores in the standard Gaussian distribution.Threshold of significance was defined as a P-valuebelow 0.005 (uncorrected, two-tailed) and conti-guous voxels above 50. In order to evaluate corre-lations between brain metabolic changes and

neuropsychologicalchanges,adjustedmeanregionalactivities were counted in both images before andafter the treatment on the basis of the ROI madefrom the clusters consisting of significant contiguousvoxels in the voxel-based analysis. Percent changesof the regional activities after treatment were calcu-lated, and then Spearman correlation coefficientswere computed between regional changes and per-centage changes in the neuropsychological perform-ances. The significance of the correlations wasdefined as a level of P < 0.05.

Results

Changes of clinical symptoms and neuropsychologicalperformance

As shown in Table 1, for the group as a whole,there was a substantial improvement in symptomdimensions after SSRI-treatment. In terms ofneuropsychological performance, only immediate-recall scores (t ¼ )2.808, df ¼ 9, P < 0.05) andthe delayed-recall scores (t ¼ )2.383, df ¼ 9, P <0.05) of the RCFT were significantly changed aftertreatment.

Cerebral glucose metabolic changes after treatment

Areas of significant differences found in comparingglucose metabolic rates at baseline and at follow-up and their mean voxel activities before and aftertreatment are presented in Table 2. As shown inFig. 1a, significant metabolic decreases were iden-tified in the lateral and medial portion of theorbitofrontal cortex, the right hippocampus, thelateral and medial portion of the cerebellum, and

Table 1. Subjects' clinical characteristics, and neuropsychological performancesbefore and after treatment*

Baseline Follow-up P-value

Clinical characteristicsYale-Brown Obsessive–Compulsive

Scale score26.7 (7.3) 13.5 (5.6) 0.001

Beck Anxiety Inventory score 24.3 (26.7) 16.3 (16.8) 0.039Beck Depression Inventory score 20.0 (13.4) 12.0 (9.0) 0.054

Neuropsychological performancesWord fluency test

Total numbers (letter) 33.6 (9.4) 36.1 (10.6) NSTotal numbers (category) 30.0 (5.3) 32.9 (5.02) NS

Trail Making B (spending time) 74.4 (32.2) 63.5 (24.8) NSWisconsin Card Sorting Test

(perseverative errors)10.9 (9.0) 6.3 (3.7) NS

Rey-Osterrieth Complex Figure TestCopy scores 33.1 (2.0) 30.9 (6.1) NSImmediate-recall score 14.3 (6.8) 20.1 (6.1) 0.020Delayed-recall score 15.4 (5.5) 19.0 (5.5) 0.041

* Data are given as mean (standard deviation), unless otherwise indicated.

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the right putamen after treatment. In comparison,metabolic rates of the lateral portion of the rightpostcentral gyrus, the posterior portion of thesuperior parietal lobe, and the medial portion ofthe superior occipital gyrus were significantlyincreased after treatment (shown Fig. 1b).

Correlation with the changes of glucose metabolismand the neuropsychological performance

As summarized in Table 3, the percentage changesin regional cerebral glucose metabolism at baselineand follow-up were compared with percentagechanges in immediate- and delayed-recall scores ofthe RCFT. Changes of immediate-recall scores ofthe RCFT revealed a significant negative correla-tion with glucose metabolic change of the rightlateral cerebellum (r ¼ )0.685, P < 0.05), theright hippocampus (r ¼ )0.818, P < 0.05), andthe right putamen (r ¼ )0.648, P < 0.05), whileno significant positive correlations were seen.Furthermore, changes of delayed-recall scores ofthe RCFT also had a significant negative correla-tion with metabolic changes of the right hippo-campus (r ¼ )0.636, P < 0.05), and the rightputamen (r ¼ )0.721, P < 0.05), while again nosignificant positive correlations were seen.

Discussion

Consistent with the previous findings obtained bythe ROI method, the glucose metabolic rates of theorbitofrontal cortex and the right putamen weresignificantly reduced after the SSRI treatment. Theorbitofrontal cortex has been shown to haveincreased activity compared with normal control

subjects in resting states (3, 31), and to bedecreased after successful treatment (6, 7, 32),suggesting that this area may be involved inmediating the expression of obsessive–compulsivesymptom. Furthermore, there has been muchexperimental and clinical evidence that the orbito-frontal cortex is involved in the mediation ofemotional response to biologically significant stim-uli, as well as in the inhibition of behaviouralresponse (33). The putamen is the major compo-nent of the basal ganglia, which, along with thecortical brain regions, is suggested to be implicatedin the symptomatic expression of OCD (34). Thehypermetabolism of the putamen in patients withOCD (32, 35) and its reduced activity aftertreatment (32) were also reported. In particular,defective activity of the putamen is reported inpatients with Tourette syndrome (36, 37), whichhave been shown to display impaired cognitive andmotor inhibition (38) that is closely related with thephenomenology of various type of compulsion. Wealso found metabolic changes of the hippocampus,the parieto-occipital junction, and the cerebellumafter treatments. Defective activities in the hippo-campus (39), the parieto-occipital junction (40),and the cerebellum (4, 41) have been reported inpatients with OCD in previous studies, although ithas not been of importance in their consideration.Considered together the findings in the currentstudy, parieto-cerebellar dysfunction as well asfrontal–subcortical abnormalities may underliesymptomatic expression of obsessive–compulsivephenomena. Moreover, these metabolic abnormal-ities may be state-dependent and change withimprovement of obsessive–compulsive symptomsafter treatment.

Region

Coordinates

Highest Z-value Voxel number

Mean voxel activity*

x y z Before treatment After treatment

Decreased activityRight 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 activityRight 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 theirmean voxel activities

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In neuropsychological performances, scores inthe immediate-recall condition and the delayed-recall test of the RCFT were significantlyimproved. The RCFT has been widely employedas a measure of visuospatial constructional andvisuospatial memory (25). Chiulli et al. (42) sug-gested that conditions of copy, immediate-, anddelayed-recall provide different information. Theysuggested that while the copy condition reflectsperceptual, visuospatial and organizational skill,immediate recall reflects the amount of informa-tion that is encoded. In addition, the delayed-recallcondition reflects the amounts of information thatis stored and retrieved from memory. Savage et al.(14) reported upon the impairment of immediaterecall in patients with OCD, and used a newperspective that could evaluate the mediating effectof organizational strategies on non-verbal memory.Specifically, they suggested that memory problemsobserved in OCD occur secondary to impairedorganizational strategies. Taken together, signifi-cant improvements of scores in the immediate-recall condition and the delayed-recall test of theRCFT in the present study may be the result of theimproved visuospatial information organization,which is related with executive function, and notto improvement in the non-verbal memory func-tion itself. Furthermore, the significant positivecorrelation (r ¼ 0.867) between the immediate-recall and the delayed-recall score changes supportsthis hypothesis. Most interestingly, significantcorrelations were found between the metabolicrate changes of the right cerebellum, the rightputamen, and the right hippocampus, and changein the scores in the immediate-recall condition ofthe RCFT. It is noteworthy that all of these areasare parts of abundant prefrontal–subcortical–cerebellar connection, which have been suggestedto play a role in coordinating the complex mentaland non-motor higher cognitive functions (43–45).Recently, impairments in this circuitry has beenpostulated to be an underlying factor of a varietyof clinical symptom and cognitive deficits in schi-zophrenia (44, 46), and Kim et al. (47) reportedgray matter abnormalities in these structures inOCD patients. Furthermore, in our earlier studyof OCD in the resting state (16), different fromthe normal subjects, the glucose metabolic ratesof these areas were significantly correlated withvarious neuropsychological performance evalua-tion of executive function, which is impaired inpatients with OCD. Considered together, it isapparent that non-specific but characteristic pat-terns of distributed brain circuits involved inthe expression of cognitive dysfunction observedin patients with OCD. Moreover, cognitive

Table 3. Summary of the correlation analysis between regional glucose metabolicrate changes and the changes of neuropsychological performances

Region Spearman correlation coefficient Significance (P )

Correlation with the change of the immediate-recall scores of Rey-OsterriethComplex Figure Test

Right lateral cerebellum )0.685 0.029Right hippocampus )0.818 0.004Right putamen )0.648 0.043

Correlation with the change of the delayed-recall scores of Rey-Osterrieth ComplexFigure Test

Right hippocampus )0.636 0.048Right putamen )0.721 0.019

Fig. 1. Statistical parametric mapping displaying differences ofglucose metabolic rates between before and after treatment.Significant within-group differences before and after treatment(P < 0.005, k > 50) are shown on three orthogonal telescopedviews and a three-dimensional rendered image. Note that sig-nificant metabolic decreases were identified in lateral andmedialportion of the orbitofrontal cortex, the right hippocampus, thelateral and medial portion cerebellum and the right putamenobserved after treatment (a), whereas metabolic rates of lateralportion of the right postcentral gyrus, posterior portion of thesuperior parietal lobe, and medial portion of the superioroccipital gyrus were significantly increased after treatment (b).

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dysfunction mediated by these brain circuitsappears somewhat reversible.In the current study, we investigated regional

brain metabolic changes according to a treatmentand their relationship with neuropsychologicalperformance changes in OCD. Employment ofthe within-subject design has allowed us to useeach subject as or her control, assessing brainglucose metabolic changes associated with neuro-psychological improvements, regardless of whatproduced the improvements. Our overall findingsseem to indicate that multiple brain areas areinvolved in the improvements of the cognitivedeficits observed in OCD. These involvements areparticularly apparent in the frontal–subcorticalcircuit and also possible in the parietal–cerebellarcircuits. Well-designed cognitive activation para-digms to probe the functional integrity of thevarious cortico-striatal system, as well as of the keylimbic and paralimbic structure, remains to beinvestigated to find out the neural correlates ofcognitive dysfunction of OCD.

Acknowledgement

This study was supported from Seoul National UniversityHospital by a research grant (04-2000-046).

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