brain activation of patients with ocd during neuropsychological and symptom provocation task before...

8/11/2019 Brain Activation of Patients With OCD During Neuropsychological and Symptom Provocation Task Before and After

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Brain Activation of Patients with Obsessive-Compulsive Disorder During Neuropsychological andSymptom Provocation Tasks Before and After

Symptom Improvement: A Functional MagneticResonance Imaging Study Tomohiro Nakao, Akiko Nakagawa, Takashi Yoshiura, Eriko Nakatani, Maiko Nabeyama,Chika Yoshizato, Akiko Kudoh, Kyoko Tada, Kazuko Yoshioka, Midori Kawamoto, Osamu Togao, andShigenobu Kanba Background: Functional neuroimaging studies have implicated hyperactivity of the frontal cortex in obsessive-compulsive disorder (OCD); however, relationships between abnormal brain activity, clinical improvement, and neuropsychological function have not been clarified in OCD. To clarify the pathophysiology of this disorder, regional changes in brain function were examined during administration of cognitive and symptom provocation tasks in patients with OCD before and after treatment. Methods: Ten outpatients with OCD participated in the study. Functional magnetic resonance imaging (fMRI) was performed before and after treatment. Stroop and symptom provocation tasks were administered during fMRI. Each patient was randomly allocated to receive either pharmacotherapy with fluvoxamine 200 mg/day ( n 4) or behavior therapy ( n 6) for 12 weeks. Results: After 12-week treatment, mean ( SD) total score on the Yale-Brown Obsessive-Compulsive Scale decreased from 29.00 3.59 to 14.60 9.22, representing symptomatic improvement from moderate to mild. After symptom improvement, symptom provocationrelated activation in the orbitofrontal, dorsolateralprefrontal, and anterior cingulate cortices decreased. Conversely,Stroop taskrelated activation in the parietal cortex and cerebellum increased. Conclusions: After improvement of OCD with either fluvoxamine or behavioral therapy, hyperactivation of the frontal lobe related to a symptom-provocative state decreases, and posterior brain activity related to action-monitoring function increases.

KeyWords: Obsessive-compulsivedisorder,functionalMRI, Strooptest, symptom provocation, behavior therapy, uvoxamine

In functional neuroimaging studies of obsessive-compulsive

disorder (OCD), researchers have found abnormalities of cerebral blood flow or glucose uptake throughout the frontalcortex and subcortical structures of patients with OCD. Severalstudies using positron emission tomography, single photonemission computed tomography, or functional magnetic reso-nance imaging (fMRI) have identified abnormally high activationat rest in the orbitofrontal cortex (OFC) and caudate nucleus inpatients with OCD compared with various control subjects, suchas healthy volunteers and patients with depression ( Baxter et al1987; Busatto et al 2000; Hoehn-Saric et al 1991; Machlin et al1991; Nordahl et al 1989, 2001; Swedo et al 1989 ). Otherneuroimaging studies have reported activation in areas such asthe OFC, caudate nucleus, thalamus, and anterior cingulatecortex (ACC) during provocation of obsessive-compulsive symp-

toms ( Rauch et al 1994; Zohar et al 1989 ). Furthermore, severalfunctional imaging studies of patients with OCDboth beforeand after treatment with either selective serotonin reuptakeinhibitors or behavioral therapyhave suggested that decreased

activity in the OFC, thalamus, and caudate nucleus is achieved by successful treatment ( Baxter et al 1992; Benkelfat et al 1990;Swedo et al 1992 ). Our group ( Nakatani et al 2003 ) has alsoreported decreased regional cerebral blood flow on xenon com-puted tomography in the right caudate nucleus after successfulbehavioral therapy.

Conversely, many previous neuropsychological studies havereported cognitive dysfunction in OCD in areas such as executiveand selective function, nonverbal memory, and visuospatial skills(Christensen et al 1992; Flor-Henry et al 1979; Head et al 1989;Savage et al 1999 ). In contrast, Galderisi et al (1995) showed thatOCD patients exhibit unimpaired performance in many cognitivetasks but display neuropsychological slowness in tasks involvingfrontosubcortical systems. Probably because of limitations of neuropsychological testing, such as detection sensitivity andreliability, consensus regarding the neuropsychological deficitsin OCD has not been achieved. Examining the neuropsycholog-ical properties of OCD with a combination of functional neuro-imaging and neuropsychological methods will be useful.

A few studies ( Lucey et al 1997; Martinot et al 1990; Pujol et al1999; Ursu et al 2003 ) have examined relationships betweenbrain and neuropsychological dysfunctions with functional neu-roimaging. These neuropsychological studies have shown thatthe ACC might play a substantial role in action-monitoringfunctions for processing competing sources of information.

Anterior cingulate cortexrelated dysfunction of action monitor-ing was hypothesized as explaining the characteristic of OCD asthe constant feelings of erroneous, incomplete performance andthe need for correction.

Substantial interaction might exist between clinical symptoms,cognitive function, and brain function in OCD ( Saxena et al1998), although few studies have investigated relationships be-

From the Graduate School of Medical Sciences (TN, AN, TY, EN, MN, CY, AK,KT, OT, SK), Graduate School of Human-Environment Studies (KY, MK),Kyushu University; and Kawasaki Medical School (AN), Okayama, Japan.

Address reprint requests to Dr. Akiko Nakagawa, Kawasaki Medical School,Department of Psychiatry, 577, Matushima, Kurashiki City, Okayama,Japan; E-mail: [email protected].

Received July 19,2004;revised December 13,2004;accepted December 18,2004.

BIOL PSYCHIATRY 2005;57:9019100006-3223/05/$30.00doi:10.1016/j.biopsych.2004.12.039 2005 Society of Biological Psychiatry


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tween these dimensions. To precisely identify the roles andabnormalities of regions such as the OFC, ACC, caudate nucleus,and thalamus in OCD, studies must not only examine regionalchanges in OCD with functional neuroimaging during symptomprovocation and neuropsychological tasks but also compare pre-and posttreatment conditions.

In the present study, we hypothesized that patients with OCDmight show abnormal activation of the frontal areas, especially in

ACC, that might influence cognitive work. We thought that it would be a reasonable hypothesis that obsessive-compulsivesymptoms might influence action-monitoring function of the

ACC. We also hypothesized that this change could recover withtreatment. To test these hypotheses, an appropriate neuropsy-chological test for cognitive tasks needed to be selected inaddition to a symptom provocation task, and powerful neuroim-aging procedures had to be used to examine functional brainchanges before and after symptom improvement in OCD. For thecognitive task, we used the Stroop task, a standardized neuro-psychological test; associated functional neuroanatomic proper-ties for this test as a measure of action-monitoring function are

well known. For neuroimaging, fMRI was selected because it isone of the most effective methods for following changes in local

brain regions throughout various activations. To the best of ourknowledge, this is the first study to use both neuropsychologicaltesting and a symptom provocation task in a pre- and posttreat-ment fMRI design.

Methods and Materials

PatientsPatients with OCD were recruited from among outpatients of

the Department of Neuropsychiatry, Kyushu University Hospital, Japan. Subjects had also participated in a randomized controlledtrial for OCD at the institute ( Nakatani et al, in press ) and hadundergone both pre- and posttreatment fMRI. Mean ( SD) age

was 32.4 9.9 years (range, 1860 years). Obsessive-compul-sive disorder and psychosis subsections of a structured clinicalinterview with DSM-III-R-Patient Version (SCID-P, Japanese lan-guage edition; Spitzer et al 1990 ) were administered by a trainedinterviewer to confirm the inclusion criteria of OCD. Patients

who displayed a comorbid Axis I diagnosis, neurological disor-der, head injury, serious medical condition, or history of drug oralcohol addiction were excluded. Intelligence was assessed withthe Wechsler Adult Intelligence Scale-Revised (WAIS-R) ( Wech-sler 1981), and patients with a total intelligence quotient of lessthan 80 were excluded. Each patient also completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS: 0 40) ( Goodmanet al 1989a, 1989b) to assess severity of obsessions and compul-sions. Patients with a total Y-BOCS score of 16 were excluded.Scans from two patients were excluded from the study becauseof imaging artifacts caused by dental bridges. A final total of 10patients with OCD were examined. Patients did not take any medication with central nervous system effects for at least 2

weeks before entering the study. Handedness was determinedaccording to the Edinburgh Handedness Inventory ( Oldfield1971), and all patients were right-handed. Mean duration of illness was 10.5 9.2 years (range, 5 months27 years).

Obsessive-compulsive symptoms were assessed with Y-BOCSand the Maudsley Obsessive-Compulsive Inventory (MOCI)(Hodgson et al 1977 ), with all patients displaying total scores of

18 points on Y-BOCS. Depressive symptoms were assessed with the Hamilton Depression Rating Scale (HDRS: maximumscore, 68) ( Hamilton 1960 ), with all HDRS scores of 18 points

(normal to mildly depressive state). Clinical global severity wasalso assessed with the Clinical Global Impressions-Severity scaleand Global Assessment of Functioning ( Endicott 1976 ). Theseclinical ratings were administered by an experienced psychiatrist

who was blind to treatment assignment. In addition, the 40-itemState-Trait Anxiety Inventory (STAI) ( Spielberger et al 1970 ) wasadministered to all subjects before fMRI to assess how they feltgenerally and at the time of testing.

The institutional research and ethics committee of KyushuUniversity approved all study protocols (No. 138, 2001). Written,informed consent for the study was obtained from all patients inadvance.

Demographic characteristics of patients are presented inTable 1 . Mean Y-BOCS score was 29.0 3.59, indicating that allpatients showed moderate to severe obsessive-compulsivesymptoms. Symptom manifestations and severity for each patientscreened by Y-BOCS are shown in Table 2 . Patients also dis-played depressive (HDRS score: 11.4 4.30) and moderately anxious (STAI state anxiety: 49.2 9.37; trait anxiety: 60.5 8.00) states.

Neuropsychological Assessment

Before fMRI, neuropsychological function was examined. Forassessment of action-monitoring function, the Stroop Test (Chi-nese letter version; Kato 2001) was administered to each subject.For assessment of other neuropsychological functions, the

WAIS-R (intelligence), Wisconsin Card Sorting Test (WCST, ex-ecutive function) ( Kashima et al 1985 ), and Wechsler Memory Scale-Revised (memory) ( Wechsler 1987 ) were used. Concerningneurological abilities, the patients were compared with 13healthy control subjects matched for age, gender, educationlevel, and handedness. The control subjects were screened by SCID-P. All of the control subjects did not present any Axis Idiagnosis and did not have a neurological disorder, a head injury,a serious medical condition, or a history of drug or alcoholaddiction. All of them took no medication. No significant differ-ences were identified between patients and control groups withregard to intellectual level as assessed with the WAIS-R. Obses-sive-compulsive symptoms of control subjects were screened

with the MOCI, and depressive symptoms were assessed with theHDRS. These screening tests indicated that no control subjectsdisplayed significant obsessive-compulsive or depressive symp-toms.

fMRI ScanningBefore and after treatment, fMRI was used to investigate local

brain changes. The Stroop task and a symptom provocation task were administered during fMRI. Each patient was scanned with a1.5-T MRI scanner (Magnetom Symphony; Siemens, Erlangen,Germany) and a standard head coil. A high-resolution T1-

weighted scan was then acquired for anatomic referencing.Functional images were obtained with a gradient echo-planersequence (repetition time, 4000 msec; echo time, 50 msec; flipangle, 90; field of view, 230 mm; matrix, 64 64; slice thickness,3 mm; gap, 1 mm; 32 axial slices). Foam padding was used tominimize motion of the patients head during imaging.

During scanning, patients performed the Stroop task ( Figure 1 )and a symptom provocation task ( Figure 2 ) b y using a block designparadigm in which task trial and control trial were given by turns.Each trial comprised ten 40-sec periods (total, 400 sec) in whichcontrol and task conditions were alternated.

Stroop Task. In the task condition for the Chinese character version of the Stroop task, patients were asked to name the color

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of a character printed in a color different from the semanticmeaning ( Figure 1 ). In the task condition, subjects can experi-ence difficulty reading words because of the mismatch betweensemantic and color values of the printed character. Under thistask (Stroop) condition, one set of information must receiveattention (color value), whereas the other must be ignored(semantic value). During fMRI, the naming activity was per-formed silently. Letters were displayed one by one on a videoscreen at the foot of a subject, with subjects viewing lettersthrough a pair of prismatic glasses. Letters were changed every 2 sec.

Symptom Provocation Task. Principal manifestations andstimulants related to obsessive-compulsive symptoms were iden-tified for each patient, such as contamination, pathologicaldoubt, and violence. Approximately 2030 words related tothese factors were selected through discussion with each patient.

In the task condition, patients were required to generate those words one by one in their minds every 4 sec, at the sound of abell. Under control conditions, patients were asked to generatenames of vegetables, flowers, and fruits in their minds at thesame interval ( Figure 2 ). Symptom manifestations and individu-alized provocative tasks for each patient are shown in Table 2 .

In both control and task conditions, patients were asked toshow the subjective level of anxiety caused by each word by raising one or two fingers (one: no anxiety; two: anxious).

Treatment Session and Assessment After Treatment As treatment, each patient was randomly allocated to receive

either pharmacotherapy with fluvoxamine ( n 4) or behaviortherapy ( n 6) for 12 weeks. Patients allocated to receivepharmacotherapy started taking 25 mg/day of fluvoxamine for

week 1. Dose was increased to 50 mg/day for week 2. Dose was

Table 1. Subject Characteristics and Neuropsychological Performance

Patients with OCD Controls Statistic ( df 21) p

Gender Ratio (Male/Female) 4/6 6/7 2 .09 .77Age (y) 32.4 9.9 30.0 6.4 t .70 .49Handedness (Right/Left) 10/0 13/0 Fishers exact 1.00MOCI Total Score 16.2 4.24 3.85 1.99 t 9.30 .001Y-BOCS Total Score 28.4 4.81

HDRS Total Score 11.3 4.50 1.69 2.21 t 6.74 .001STAI State Anxiety 49.2 9.37STAI Trait Anxiety 60.5 8.00WAIS-R Estimated IQ 98.2 7.57 103 5.55 t 1.90 .07Stroop Test

Total time (sec) 62.2 7.97 63.1 10.9 t .23 .82Difference of time (sec) 12.8 5.05 12.6 6.24 t .09 .93

WCSTNo. of categories 4.2 1.5 4.7 1.4 t .81 .43 Total errors 14.4 5.97 15.2 4.60 t .34 .74

WMS-RVerbal memory 110 10.1 117 16.2 t 1.23 .23Visual memory 106 13.3 110 9.95 t .89 .38 Total memory 111 13.6 118 14.5 t 1.08 .29Attention 116 8.44 110 10.5 t 1.35 .19Delayed recall 107 6.74 117 12.7 t 2.06 .054

Data are presented as mean SD or n. MOCI; Maudsley Obsessive-Compulsive Inventory; Y-BOCS, Yale-BrownObsessive-Compulsive Scale; HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory; WAIS-R,Wechsler Adult Intelligence Scale-Revised; IQ, intelligence quotient; WCST, Wisconsin Card-Sorting Test; WMS-R,Wechsler Memory Scale-Revised.

Table 2. Symptom Manifestations, Severity, and Individualized Provocation Task for Each Subject

PatientNo. Gender

Age(y)

Y-BOCSScore

Symptom Manifestation a :Obsession/Compulsion Individualized Provocation Task b Treatment

Reduction of Y-BOCSAfter Treatment (%)

1 F 30 25 6/2, 5 Shoes, dishes, chairs . . . FLV 44.02 F 29 29 1, 2, 6/1, 2, 3, 4 Door, key, switch . . . BT 44.83 M 21 33 1, 2, 6, 7, 8/1, 2, 5, 7 Cigarette, gas cock, e-mail . . . BT 57.64 M 25 25 2, 7/2, 3, 7 Cleanser, bleach, poison . . . FLV 92.05 M 22 24 1, 7/2, 7 Hitting (someone by car), kicking (somebody) . . . BT 87.56 F 38 27 1, 2/1, 2 Door, key, main tap . . . BT 55.67 M 37 34 2, 3, 5/1, 3 Urine, rubbish, shrines, images of god . . . FLV 2.98 F 29 31 1, 6/3, 4, 5 Shoes, books, clothes . . . BT 64.59 F 54 30 2/1 Sweat, urine, feces . . . BT 46.7

10 F 39 32 2/1 Public telephone, money, public lavatory . . . FLV 21.9

Y-BOCS, Yale-Brown Obsessive-Compulsive Scale; F, female; M, male; FLV, uvoxamine; BT, behavior therapy.a Obsession: 1 aggression; 2 contamination; 3 sexual; 4 hoarding;5 religious; 6 symmetry;7 miscellaneous;8 somatic.Compulsion:1

cleaning; 2 checking; 3 repeating; 4 counting; 5 ordering; 6 hoarding; 7 miscellaneous.b Words related to individual symptoms.

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subsequently increased every week by 50 mg/day up to the finaldose of 200 mg/day, which was maintained for 8 weeks. In thegroup receiving behavior therapy, each weekly session lastedapproximately 45 min. In the first session, the main problems

were identified, and behavioral techniques were explained. Eachpatient then performed individually tailored home practice toexpose themselves gradually to feared situations throughout the12 sessions. Therapy was guided by experienced behaviortherapists.

All clinical symptoms were assessed with Y-BOCS, MOCI,HDRS, and STAI before and after the 12-week treatment. Thesescales were administered by an experienced psychiatrist blindedto treatment assignment.

Statistical Analysis of Imaging ResultsIndividual Maps. The Statistical Parametric Mapping 99 pro-

gram (Wellcome Department of Cognitive Neurology, London,United Kingdom) was used for image processing and statisticalanalyses. To correct for motion of the subjects head, functionalimages from each individual were realigned to the first image inthe series with six-parameter spatial transformation. After realign-ment, functional images were spatially normalized with theMontreal Neurological Institute T1 template, then convolved inspace with a three-dimensional isotropic Gaussian kernel (full

width at half maximum, 12 mm) for smoothing. The effect of theStroop task and the symptom provocation task at each and every

voxel was estimated with a general linear model. A typicaldelayed boxcar model convolved with a hemodynamic responsefunction was used. Confounding effects of fluctuations in globalmean were removed by proportional scaling. Low-frequency noise was eliminated by applying a high-pass filter (.375 cyclesper min). Voxel values for task-versus-control contrast yielded astatistical parametric map of the t statistic and were then normal-ized to z scores. A corresponding contrast image for each patient

was also created for group analysis.Group Maps. Common activation maps of each of four

groupsthe pre- and posttreatment Stroop task and the pre- andposttreatment symptom provocation taskwere obtained with afixed-effects model. After generating all subjects images for eachof the four groups, we used a one-sample t test for comparing

task versus control condition for each group. The coordinates of the most significantly active voxels in these group results werethen used to create activation maps of all brain regions. Voxel-

wise significance thresholds of p .05 (corrected) were used.Only clusters with more than 10 voxels were included.

Between-Group Analysis. Finally, for investigating thechange of brain activation before and after treatment in both theStroop task and the symptom provocation task, between-group

analysis was performed with a random-effects model. For thisanalysis, task versus control contrast images of all patients wereobtained for each task, before and after treatment. Then, pre-treatment contrast images were compared with the posttreatmentcontrast images with a paired t test to determine the effect of treatment on the basis of brain activation. Voxelwise significancethresholds of p .01 (uncorrected) were used. Only clusters withmore than 10 voxels were included.

Results

Results of neuropsychological tests are presented in Table 1 .On every neuropsychological test, including WAIS-R, Stroop test,

WCST, and Wechsler Memory Scale-Revised, no significant dif-

ferences were noted between patient and control groups, al-though patients showed slightly lower delayed recall ability inthe Wechsler Memory Scale-Revised.

Pre- and posttreatment scores for clinical symptoms arecompared in Table 3 . After 12 weekly treatment sessions, mean( SD) Y-BOCS (obsessive-compulsive symptom scale) scoresignificantly decreased, from 29.00 3.59 to 14.60 9.22.Concerning each patients response to the treatment, eightpatients showed significant reduction of Y-BOCS ( 35%, range:44%92%), and two patients did not improve (Y-BOCS reduction2.9% and 21.9%; both patients took pharmacotherapy) (see Table 2 ).Mean scores for Clinical Global Impressions-Severity and Global

Assessment of Functioning also improved significantly. In addi-tion, mean MOCI score decreased significantly, from 16.0 4.03to 8.90 3.98, which was lower than the cutoff point (12/13) forobsessive-compulsive screening. On the basis of these changes,patients showed significant improvement in obsessive-compul-sive symptoms. Mean HDRS score and mean STAI trait anxiety score were also significantly decreased. During the symptomprovocation task in fMRI, under both control and task conditions,patients reported almost no anxiety as self-indicated by raisingtheir fingers.

Figure 2. Provocation task duringfMRI.In the task condition, patients wererequiredtogeneratethosewordsonebyoneintheirmindevery4sec,atthesound of a bell. Under control conditions, patients were asked to generatenames of vegetables, owers, and fruits in their minds at the same interval.Symptom manifestations and individualized provocative tasks for each pa-tient are shown in Table 2 . In both control and task conditions, patients wereaskedto show thesubjectivelevel of anxietycaused byeachword byraisingone or two ngers (one: no anxiety; two: anxious).

Figure 1. Stroop taskduringfMRI.In thetask condition, patientswere askedto name the color of a characterprinted ina differentcolor fromthe seman-ticmeaning.In thetask condition, subjectscan experience difcultyreadingwords because of the mismatch between semantic and color values of theprinted character. Letters were displayed one by one on a video screen atthe foot of the subject, with subjects viewing letters through a pair of

prismatic glasses. Letters were changed every 2 sec.




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Tables 4 and 5 and Figure 3 show pre- and posttreatmentareas of activation under task conditions during the Stroop task.These areas were identified with fixed-effects model analysis.Before treatment, patients showed brain activation in the leftprefrontal and parietal cortices and right cerebellum during theStroop task. After treatment, patients generally showed increasedactivation in bilateral prefrontal cortices, bilateral ACC, parietalcortices, and cerebellum.

Tables 6 and 7 and Figure 4 show pre- and post-treatmentareas of activation under task conditions during the symptomprovocation task. Before treatment, patients showed activation inthe left OFC, temporal cortex, and parietal cortex during theprovocation task. After treatment, contrasting with the results of the Stroop task, patients showed decreased activation in theOFC.

Areas in which activation increased or decreased after treat-ment were also identified with random-effects model analysis.

Areas of increase or decrease during the Stroop task aftertreatment are presented in Tables 8 and 9 and Figure 5 . Areas of decrease during the symptom provocation task after treatmentare presented in Table 10 and Figure 6 . We were unable toidentify any areas showing increased activation after treatment

during the symptom provocation task. Areas identified withrandom-effects model analysis basically corresponded with thosefound with the fixed-effects model. We identified increased activa-tion in the dorsolateral prefrontal cortex (DLPFC) and posteriorregions and decreased activation in frontal regions after treatmentduring the Stroop task. We also found generally decreasedactivation in frontal regions and basal ganglia after treatmentduring the symptom provocation task.

Discussion

Imaging before treatment showed activation in the leftDLPFC, left parietal cortex, and right cerebellum during theStroop task ( Table 4 ). We have already reported that patients

with OCD show activation similar to that in normal controlsubjects in such broad brain areas during the Stroop task ( Nakaoet al, in press ). Along with results showing no differencebetween patients and control subjects with regard to neuropsy-chological performance, including the Stroop test, patients in thisstudy might exhibit similar brain activation to the general popu-

Table 4. Activated Regions During Stroop Task Before Treatment

Region BA x y z Voxels

R Frontal Cortex; DLPFC 44 48 26 26 27

L Frontal Cortex; DLPFC 44 40 26 18 85544 36 2 44 1446 40 38 6 2247 40 12 8 78

R Parietal Cortex 39 22 60 42 3040 40 50 46 36

L Parietal Cortex 7 20 64 52 20940 48 36 40 14

R Cerebellum 10 76 20 6138 60 22 9222 74 18 32

Fixed-effects model, p .05, corrected. These brain regions were esti-mated using standard Talairach space. BA, Brodmanns area; R, right; L, left;DLPFC, dorsolateral prefrontal cortex.

Table 5. Activated Regions During Stroop Task After Treatment


R Frontal Cortex; OFC 10 30 66 8 279 54 12 34 14

L Frontal Cortex; DLPFC 46 50 4 36 1,877

R Anterior Cingulate Cortex (ACC) 32 6 24 42 39L ACC 32 6 16 46 159R Insula 47 34 18 2 234R Parietal Cortex 40 58 36 44 141

7 24 58 58 230L Parietal Cortex 7 28 58 52 1,266

40 60 28 34 10540 48 40 46 35

L Occipital Cortex 18 34 86 14 11R Cerebellum - 26 68 24 2,150

Fixed-effects model, p .05, corrected. Patients showed generally in-creased activation in DLPFC and posterior regions compared withpretreat-ment activation. BA, Brodmanns area; R, right; L, left; OFC, orbitofrontalcortex.

Table 3. Comparison of Clinical Symptoms Before and After Treatment

Before Treatment(Mean SD)

After Treatment(Mean SD) t (df 9) p

MOCI Total Score 16.0 4.03 8.90 3.98 3.74 .01Checking 6.20 2.44 2.20 1.48 4.41 .01Washing 4.10 2.51 2.70 2.16 2.04 .07Slowness 2.70 1.25 2.10 1.45 1.41 .19

Doubting 4.30 1.89 3.20 1.87 1.34 .21Y-BOCS Total Score 29.0 3.59 14.6 9.22 6.68 .001

Obsession 14.4 2.17 7.30 4.90 5.80 .001Compulsion 14.6 1.90 7.30 4.47 6.85 .001

HDRS Total Score 11.4 4.30 6.60 4.99 2.41 .05STAI State Anxiety 49.2 9.37 45.1 7.17 1.61 .14STAI Trait Anxiety 60.5 8.00 48.9 12.9 2.27 .05CGI-S 4.50 0.53 3.00 1.05 4.88 .001GAF 45.0 5.77 56.0 9.37 5.28 .001

Y-BOCS score (obsessive-compulsive symptom scale) signicantly decreased, from 29.00 3.59 to 14.60 9.22.Patients showed signicant improvement of obsessive-compulsive symptoms. HDRS score, STAI trait anxiety score,CGI-S score, and GAF score were also improved. MOCI, Maudsley Obsessive-Compulsive Inventory; Y-BOCS, Yale-BrownObsessive-Compulsive Scale; HDRS, HamiltonDepressionRating Scale; STAI, State-Trait Anxiety Inventory; CGI,Clinical Global Impressions-Severity; GAF, Global Assessment of Functioning.




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lation during the Stroop task. Many previous neuropsychologicalstudies have reported executive and attentional dysfunction inOCD ( Flor-Henry et al 1979; Head et al 1989; Savage et al 1999 ).Conversely, Abbruzzese et al (1995) found no functional impair-ment of the prefrontal cortex in OCD with WCST. Consensus onthe relationship between brain dysfunction and neuropsycholog-ical findings in OCD is therefore lacking, owing to the complex-ity of neuropsychological functions. Regarding the cognitivefunction of attention, Mesulam (1990) postulated a network of attention spanning the parietal, prefrontal, and cingulate cortices.Posner and DeHaene (1994) suggested that these structuresmight form two distinct attentional systems, anterior and poste-rior. The anterior system includes the DLPFC, which is consid-ered responsible for executive aspects of selective attention, andthe ACC, which is involved in action monitoring and plays a rolein tuning attention to competing information. In contrast, theposterior system includes the parietal cortex and cerebellum andis thought to be involved in the selection of information based onperceptual characteristics and spatial location ( Corbetta et al1991). Our results also indicate that performance of the Strooptest involves multiple brain regions, including both frontal andposterior cortices.

Several studies have examined relationships between brainand neuropsychological dysfunctions with functional neuroim-aging. One positron emission tomography study ( Martinot et al1990) reported that glucose metabolic rates in the frontal corticesof patients with OCD were negatively correlated with subscoresin the Stroop test. Another study using single photon emission

computed tomography ( Lucey et al 1997 ) reported that bloodflow in the left caudate and left inferior frontal cortex of patients

with OCD was positively correlated with number of errors on the WCST. An fMRI study ( Pujol et al 1999 ) reported significantly stronger activation of the left frontal cortex in patients with OCDcompared with normal control subjects during administration of the word generation test. Another fMRI study ( Ursu et al 2003 )reported increased ACC activation in OCD during high-conflicttrials of the continuous performance task with region-of-interestmethods. Gehring et al (2000) also indicated that the ACC mightbe involved in action-monitoring dysfunction in OCD by usingevent-related potential. Several researchers, such as Ursu et al(2003) and Gehring et al (2000) , have reported that action-monitoring dysfunction in OCD is related to ACC hyperactivity.In contrast to previous studies, however, we were unable toidentify ACC activation during the Stroop task in patients beforetreatment. As in our previous research, we found that ACCactivation in response to the Stroop task was weaker in patientsthan in normal control subjects ( Nakao et al, in press) . Further-more, the present study found increased activation of the ACCafter treatment ( Tables 4 and 5, Figure 3 ). Paradoxical activationin the present study, however, is not necessarily incompatible

with the studies mentioned above. Baseline conditions in pa-tients might have been activated already, which could be sup-ported by the finding that abnormal activation of the ACC in OCD

Table 7. Activated Regions During Symptom-Provocation Task After Treatment


L Frontal Cortex; DLPFC; OFC 44 42 16 48 8210 34 58 8 3211 44 28 14 19

R Parietal Cortex 39 48 66 40 166L Parietal Cortex 19 42 72 36 1,518L Occipital Cortex 31 10 60 26 1,447R Cerebellum 22 84 34 263

8 86 26 33

Fixed-effects model, p .05, corrected. Patients showed decreasedactivation in OFC compared with pretreatment activation. BA, Brodmannsarea;L, left; R, right; DLPFC, dorsolateral prefrontal cortex; OFC,orbitofrontalcortex.

Figure 3. Regions activated during Stroop task be-fore and after treatment. Before treatment, patientsrevealed brain activation in the left prefrontal andparietal cortices and right cerebellum during theStroop task. After treatment, patients showed gen-erally increased activation of bilateral dorsolateralfrontal cortices, right anterior cingulated cortex, bi-lateral insulae, bilateral temporal and parietal corti-ces, and bilateral cerebella; p .05, corrected.

Table 6. Activated Regions During Symptom-Provocation Task Before Treatment


L Frontal Cortex; OFC; DLPFC 10 32 58 4 34511 50 22 4 25044 44 16 46 106

L Temporal Cortex 19 54 62 22 1,17821 66 28 8 20

L Parietal Cortex 19 10 70 52 1,624R Cerebellum 28 82 30 508

Fixed-effects model, p .05, corrected. Activated regions in left frontalcortex includeOFC regions.BA, Brodmanns area;L, left;R, right; OFC,orbito-frontal cortex; DLPFC, dorsolateral prefrontal cortex.




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patients under resting conditions decreased after successful

treatment ( Schwartz et al 1996 ). Our results might indicate thatthe ACC of the patients was already activated at baseline orcontrol conditions for the Stroop task and that we just observedlower difference between activation under task and controlconditions in the patients than in the control subjects. Aftersymptom improvement, baseline activity might have decreased,resulting in an apparent increase in difference between task andcontrol conditions. We were unable, however, to identify

whether baseline conditions of patients were activated, becauseno baseline period was defined for fMRI. This represents a majorlimitation to the present study.

On the other hand, imaging during symptom provocationbefore treatment showed activation in the left OFC, parietalcortex, and cerebellum ( Table 6 ). Dysfunction of the ventrome-

dial system, which includes the OFC, has been suggested asbeing strongly associated with OCD symptomatology ( Baxter1999). One experimental study suggested that the OFC might beinvolved in mediation of emotional response to biologically

significant stimuli ( Zald and Kim 1996 ). Our results also support

this hypothesis. Other previous reports have implied that theparietal cortex and cerebellum play substantial roles in visuospa-tial processing and mental coordination ( Purcell et al 1998;Zielinski et al 1991 ). Activation of the parietal cortex andcerebellum therefore indicates that visual imagery related toobsessive-compulsive symptoms was activated during the symp-tom provocation task.

After clinical improvement, patients with OCD showed in-creased activation of broad regions such as the DLPFC, ACC,insula, temporal cortex, parietal cortex, and cerebellum in re-sponse to the Stroop test compared with pretreatment findings(Tables 4, 5, and 8, Figures 3 and 5). These areas are among theprefrontalsubcorticalcerebellar connections that have beensupposed to play roles in coordinating complex mental and

nonmotor higher cognitive functions ( Andreasen et al 1998;Schmahmann and Pandya 1997 ). Increased activation of theseareas after treatment thus indicates that obsessive-compulsivesymptoms might suppress these areas and could adversely impact cognitive performance in OCD. The neural mechanismsby which obsessive-compulsive symptoms suppress these cog-nitive-related activities warrant closer attention.

In relation to the symptom provocation task, however, pa-tients generally showed decreased activation in the OFC, ACC,

Table 8. Regions Showing Increased Activation After Treatment:Stroop Task


R Frontal Cortex; DLPFC 46 44 46 2 738 54 10 40 21

R Putamen 24 10 8 332L Putamen 28 10 6 184L Temporal Cortex 20 30 4 36 52

19 58 60 2 4140 64 28 10 37

R Parietal Cortex 40 62 44 30 136L Parietal Cortex 40 64 32 34 336

7 34 60 48 1197 4 70 50 29

L Occipital Cortex 19 26 86 32 36R Cerebellum 22 60 56 53L Cerebellum 44 66 38 75

20 70 34 87

Random-effectsmodel, p .01,uncorrected. Patients showed generallyincreased activation in DLPFC and posterior regions compared with pre-treatment activation. BA, Brodmanns area; R, right; L, left; DLPFC, dorsolat-eral prefrontal cortex.

Table 9. Regions Showing Decreased Activation After Treatment:Stroop Task


R Frontal Cortex 9 32 12 42 20510 18 56 20 2510 18 46 0 21

R Cingulate Cortex 24 14 42 34 50L Cingulate Cortex 24 26 40 36 24

24 18 6 40 21R Hippocampus 36 24 28 18 91R Temporal Cortex 21 64 16 14 60R Parietal Cortex 39 26 34 38 21L cerebellum 18 28 16 91

Random-effects model, p .01, uncorrected. Patients showed de-creased activationmainly in frontal regions.BA, Brodmanns area;R, right; L,left.

Figure4. Regionsactivated during provocation task before and after treatment. Patients showed activa-tion in the left orbitofrontal, temporal, and parietalcortices before treatment. Patients showed gener-allydecreased activation in the orbitofrontal cortex,bilateral anterior cingulate gyri, right putamen, leftinsula, bilateral temporal and occipital cortices, andbilateral cerebella after treatment; p .05,corrected.




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putamen, insula, temporal cortex, occipital cortex, and cerebel-lum after treatment compared with pretreatment conditions(Tables 6, 7, and 10, Figures 5 and 7 ). Several previous studies

have suggested that dysfunctions in areas such as the OFC, ACC,and basal ganglia play a substantial role in OCD symptomatology (Baxter et al 1987; Busatto et al 2000; Machlin et al 1991; Swedoet al 1989 ). A circuit involving the cortico/limbic basal gangli-onicthalamic systems has been postulated as mediating symp-tomatic expression of OCD ( Saxena et al 1998 ). Interestingly, wefound decreased activation in these regions during the symptomprovocation task after patient symptoms improved.

In conclusion, our results show that hyperactivation of thecircuit that mediates symptomatic expression of OCD, whichincludes the OFC, ACC, and basal ganglia, might decrease aftersymptom improvements. Furthermore, comparing activation pat-terns between provocation and Stroop tasks in untreated OCDpatients, our results imply that not only the DLPFC but also

posterior brain regions, such as the parietal cortex and cerebel-lum, play roles in cognitive performance improvement aftertreatment. Using the Stroop task, Banich et al (2001) reportedincreased activities in posterior regions, and Kerns et al (2004)reported ACC hyperactivity. Milham et al (2001) indicated the

involvement of ACC and right prefrontal cortex in attentionalcontrol at response level and of left prefrontal cortex at nonre-sponse level. Researchers have tried to explain the role of theseregions. Paus (2001) proposed that functional overlap of variousbrain regions in the ACC provide the ACC with the potential totranslate intentions to actions. Carter et al (1999) proposed thatthe ACC might detect conflicting processes during task perfor-mance that might be associated with errors. Mesulam (1990) hassupposed a network of attention among the parietal cortex,prefrontal cortex, and cingulate cortex. Posner et al (1997)suggested that the orienting network for visual attention involvesposterior structures, such as the parietal lobe, pulvinar, andsuperior colliculus, and that the executive network is locatedmore anteriorly and includes midline frontal areas and the basalganglia. These results support our hypothesis that abnormalactivation in the frontal areas in OCD might influence posteriorregionrelated cognitive work and could recover with treatment.

To the best of our knowledge, this is the first study to use botha neuropsychological test and a symptom provocation task inpre- and posttreatment fMRI. In addition, we used a voxel-basedapproach in Statistical Parametric Mapping analysis. Most previ-ous functional imaging studies for OCD have used region-of-interest approaches and suffered from technical limitations inrevealing relationships between brain and cognitive functions.

The present study, however, does display several majorlimitations. We were not able to identify whether these obtainedabnormal activations in OCD reflect abnormalities in OCD orefforts to compensate dysfunction. Especially with regard to theStroop task, our results are not conclusive, because we had only task and control trials of the Stroop test without a neutral trial asa baseline period in the fMRI scanning. We therefore were notable to identify whether the brain activation of those areas of thepatients started from the baseline or from the control condition.

Next, the kinds of changes in the brain, if any, due to fluvoxam-ine or behavior therapy could not be statistically identified becauseof the small number of subjects. Obsessive-compulsive disorder isheterogeneous and might display different neural systems, depend-ing on symptom dimensions. Mataix-Cols et al (2003) reporteddifferential patterns of neural activation in normal volunteersassociated with different obsessive-compulsive symptom dimen-sions. Despite the small subject population, however, our resultsare reliable for the following reasons: patients were interviewed

with the SCID and confirmed to display genuine OCD withoutcomorbid major depression; and the drug condition was appro-

Figure 5. Regions showing increased activation after treatment duringStroop task (random-effects model analysis); p .01, uncorrected.

Figure 6. Regions showing decreased activation after treatment duringprovocation task (random-effects model analysis); p .01, uncorrected.

Table 10. Regions Showing Decreased Activation After Treatment:Symptom-Provocation Task


R Frontal Cortex 6 54 10 34 154L Frontal Cortex 10 36 48 18 180L Anterior Cingulate Cortex 24 2 24 22 224R Putamen 20 0 12 1138

R Thalamus 18 30 2 79L Thalamus 12 26 2 214L Temporal Cortex 21 40 10 14 1,636

21 64 30 2 4121 58 42 0 20

R Occipital Cortex 18 32 82 32 16118 42 82 4 17218 16 90 18 22

L Occipital Cortex 19 16 66 2 184R Cerebellum 16 58 20 251L Cerebellum 42 48 24 56

Random-effectsmodel, p .01,uncorrected. Patientsshowed generallydecreased activation including frontal regions and basal ganglia. BA, Brod-manns area; R, right; L, left.




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priately controlled with a sufficient washout period and no use of other drugs. Furthermore, the direct influence of fluvoxamine oncerebral blood flow should be considered. Several studies ( Ben-kelfat et al 1990; Swedo et al 1992 ) have reported that seroto-nergic antidepressant medication decreases cerebral blood flow and metabolism in the medial frontal cortex of patients withOCD.

Additionally, we were not able to identify activation in the

caudate nucleus during the symptom provocation task. Thisresult might be related to the insufficient symptom provocationactivation during task condition, judging from the fact that thepatients reported almost no anxiety as self-indicated by raisingtheir fingers. Many previous neuroimaging studies reportedhyperactivation of these areas in OCD ( Baxter et al 1987; Busattoet al 2000; Machlin et al 1991; Rauch et al 1994; Swedo et al 1989) .The caudate nucleus has several kinds of projections to the OFC,the ACC, and the thalamus. It has been supposed to play asubstantial role in the cortico/limbicbasal ganglionicthalamicsystems that mediate the symptomatic expression of OCD ( Sax-ena et al 1998 ). It might be necessary to use more adequatestimulus that can evoke symptom-related anxiety sufficiently.

To elucidate relationships between OCD symptomatology and brain function more clearly, a larger number of patients withOCD must be examined before and after treatment with eitherfluvoxamine or behavior therapy. Differences in brain changesresulting from fluvoxamine treatment versus behavior therapy also warrant investigation.

This study was presented at the European Association for Behavioral and Cognitive Therapies, Prague, Czech Republic,September 1013, 2003. It was supported by a Grant-in-Aid for Scientific Research (C) (14570931) from the Japanese Ministry of Education, Culture, Sports, Science and Technology and The Research Grant (14A-1) for Nervous and Mental Disorders from

the Japanese Ministry of Health, Labor and Welfare.We thank T. Kuroki, M.D., Ph.D., for his academic and

financial support and N. Tashiro, M.D., Ph.D., whose efforts in launching this research were invaluable.

Abbruzzese M, Ferri S, Scarone S (1995): WisconsinCard Sorting Test perfor-mance in obsessive-compulsive disorder: No evidence for involvementof dorsolateral prefrontal cortex. Psychiatry Res 58:3743.

Andreasen NC, Paradiso S, OLeary DS (1998): Cognitive dysmetria as anintegrative theory of schizophrenia: A dysfunction in cortical-subcorti-cal-cerebellar circuitry? Schizophr Bull 24:203218.

Banich MT, Milham MP, Jacobson BL, Webb A, Wszalek T, Cohen NJ, et al(2001): Attentional selectionand the processing of task-irrelevant infor-mation: Insights from fMRI examinations of the Stroop task. Prog BrainRes 134:459470.

Baxter LR (1999): Functional imaging of brain systems mediatingobsessive-compulsive disorder. In:Charney DS,Nestler EJ,Burney BS,editors. Neu-robiology of Mental Illness . New York: Oxford University Press 534547.

Baxter LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE (1987):Local cerebral glucose metabolic rates in obsessive-compulsive disor-der: A comparison with rates in unipolar depression and in normalcontrols. Arch Gen Psychiatry 44:211218.

BaxterLR, Schwartz JM,Bergman KS,SzubaMP, Guze BH,Mazziotta JC,et al(1992): Caudate glucose metabolic rate changes with both drug andbehavior therapyfor obsessive-compulsivedisorder. Arch Gen Psychiatry 49:681689.

BenkelfatC, Nordahl TE,Semple WE,KingAC, Murphy DL,Cohen RM (1990):Local cerebral glucose metabolic rates in obsessive-compulsive disor-der. Patients treated with clomipramine. Arch Gen Psychiatry 47:840848.

Busatto GF, Zamignani DR,Buchpiguel CA,Garrido GE,Glabus MF,Rocha ET,et al (2000): A voxel-based investigation of regional cerebral blood owabnormalities in obsessive-compulsive disorder using single photonemission computed tomography (SPECT). Psychiatry Res 99:1527.

Carter CS, Botvinick MM, Cohen JD (1999): The contribution of the anteriorcingulate cortex to executive processes in cognition. Rev Neurosci 10:4957.

ChristensenKJ,Kim SW,DyskenMW, Hoover KM(1992): Neuropsychologicalperformance in obsessive-compulsive disorder. Biol Psychiatry 31:418.

Corbetta M, Miezin FM,Dobmeyer S, Shulman GL,PetersenSE (1991): Selec-tive and divided attention during visual discrimination of shape, color,and speed: Functional anatomy by positron emission tomography. J Neurosci 11:23832402.

EndicottJ, Spitzer RL,Fleiss JL,CohenJ (1976):TheGlobal Assessment Scale:A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33:766771.

Flor-Henry P, Yeudall LT, Koles ZJ, Howarth BG (1979): Neuropsychologicalandpower spectralEEGinvestigations of theobsessive-compulsivesyn-drome. Biol Psychiatry 14:119130.

Galderisi S, Mucci A, Catapano F, DAmato AC, Maj M (1995): Neuropsycho-logical slowness in obsessive-compulsive patients. Is it conned to testsinvolving the fronto-subcortical systems? Br J Psychiatry 167:394398.

Gehring WJ, Himle J, Nisenson LG (2000): Action-monitoring dysfunction inobsessive-compulsive disorder. Psychol Sci 11:16.

Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR,

et al (1989a): The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 46:10121016.Goodman WK,Price LH, RasmussenSA, MazureC, FleischmannRL,HillCL, et

al (1989b):The Yale-Brown Obsessive Compulsive Scale. I. Development,use, and reliability. Arch Gen Psychiatry 46:10061011.

Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychi-atry 23:5662.

Head D, Bolton D, Hymas N (1989): Decit in cognitive shifting ability inpatients with obsessive-compulsive disorder. Biol Psychiatry 25:929937.

Hodgson RJ, Rachman S (1977): Obsessive-compulsive complaints. Behav Res Ther 15:389395.

Hoehn-Saric R, Pearlson GD, Harris GJ, Machlin SR, Camargo EE (1991): Ef-fects of uoxetineon regional cerebral blood ow in obsessive-compul-sivepatients. Am J Psychiatry 148:12431245.

Kashima H, Kato M, Handa T, Yokoyama N, Yanai K, ShigemoriK, et al (1985):

A modied Wisconsin Card Sorting Testa comparison of the chronicschizophrenics to the patients with frontal lesions. Folia Psychiat Neurol Jpn 39:97.

Kato M (2001): Prefrontal lobes and attentional control: A neuropsycholog-icalstudy using modied Stroop test. Rinsho Shinkeigaku 41:11341136.

KernsJG, CohenJD, MacDonaldAW III, ChoRY, Stenger VA,Carter CS (2004):Anterior cingulate conict monitoring and adjustments in control. Sci-ence 303:10231026.

Lucey JV, Burness CE, Costa DC, Gacinovic S, Pilowsky LS, Ell PJ, et al (1997):Wisconsin Card Sorting Task (WCST): Errors and cerebral blood ow inobsessive-compulsive disorder (OCD). Br J Med Psychol 70:403411.

Machlin SR, Harris GJ, Pearlson GD, Hoehn-Saric R, Jeffery P, Camargo EE(1991): Elevated medial-frontal cerebral blood ow in obsessive-com-pulsive patients: A SPECTstudy. Am J Psychiatry 148:12401242.

Martinot JL,Allilaire JF,Mazoyer BM,HantoucheE, HuretJD, Legaut-DemareF, et al (1990): Obsessive-compulsive disorder: A clinical, neuropsycho-logical and positron emission tomography study. Acta Psychiatr Scand 82:233242.

Mataix-Cols D, Cullen S, Lange K, Zelaya F, Andrew C, Amaro E, et al (2003):Neural correlates of anxiety associated with obsessive-compulsivesymptom dimensions in normal volunteers. Biol Psychiatry 53:482493.

Mesulam M-M (1990): Large-scale neurocognitive networks and distributedprocessing for attention, language, andmemory. Ann Neurol 28:597613.

Milham MP,BanichMT, Webb A,BaradV,CohenNJ,WszalekT, etal (2001): Therelative involvement of anterior cingulate and prefrontal cortex in atten-tional controldependson nature of conict. Cogn Brain Res 12:467473.

Nakao T, Yoshiura T, Nakagawa A, Nakatani E, Yoshizato C, Kudoh A, et al (inpress): Action-monitoring function of obsessive-compulsive disorder(OCD): A functionalMRIstudycomparingpatientswithOCD withnormalcontrols during Chinese character Stroop task. Psychiatry Res Neuroim-aging .




10/10

NakataniE, NakagawaA, NakaoT, Yoshizato C,NabeyamaM, Kudo A,et al(inpress): A Randomized controlled trial of Japanese patients with obses-sive-compulsive disorder: Effectiveness of behavior therapy and uvox-amine. Psychother Psychosom.

Nakatani E, Nakagawa A, Ohara Y, Goto S, Uozumi N, Iwakiri M, et al (2003):Effectsof behaviortherapyon regionalcerebralblood owinobsessive-compulsive disorder. Psychiatry Res Neuroimaging 124:113120.

Nordahl TE, Benkelfat C, Semple WE, Gross M, King AC, Cohen RM (1989):Cerebralglucosemetabolic ratesin obsessive-compulsivedisorder. Neu-ropsychopharmacology 2:2328.

Oldeld RC (1971): The assessment and analysis of handedness: The Edin-burgh Inventory. Neuropsychologia 9:97113.

PausT (2001): Primate anterior cingulatecortex: Where motorcontrol,driveand cognition interface. Nat Rev Neurosci 2:417424.

Posner MI,DeHaeneS (1994):Attentionalnetworks. TrendsNeurosci 17:7579.Posner MI, DiGirolamo GJ, Fernandez-Duque D (1997): Brain mechanisms of

cognitive skills. Conscious Cogn 6:267290.Pujol J, Torres L, Deus J, Cardoner N, Pifarre J, Capdevila A, et al (1999):

Functional magneticresonance imagingstudyof frontal lobeactivationduring word generation in obsessive-compulsive disorder. Biol Psychia-try 45:891897.

Purcell R, Maruff P, Kyrios M, Pantelis C (1998): Cognitive decits in obses-sive-compulsive disorder in tests of frontal-striatal function. Biol Psychi-atry 43:348357.

Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HC, Savage CR, et al (1994):Regionalcerebralblood owmeasuredduring symptomprovocation inobsessive-compulsivedisorder usingoxygen15-labeled carbon dioxideand positron emission tomography. Arch Gen Psychiatry 51:6270.

Savage CR, Baer L, Keuthen NJ, Brown HD, Rauch SL, Jenike MA (1999):Organizational strategies mediate nonverbal memory impairment inobsessive-compulsive disorder. Biol Psychiatry 45:905916.

SaxenaS, Brody AL,SchwartzJM, BaxterLR (1998): Neuroimagingand fron-tal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry 173:2637.

Schmahmann JD, Pandya DN (1997): The cerebrocerebellar system. Int Rev Neurobiol 41:3160.

Schwartz JM, Stoessel PW, Baxter LR Jr, Martin KM, Phelps ME (1996): Sys-tematic changes in cerebral glucose metabolic rate after successful be-havior modication treatment of obsessive-compulsive disorder. ArchGen Psychiatry 53:109113.

Spielberger CD,GourshR, Lushene R (1970): Manual for the State-Trait Anxi-ety Inventory . Palo Alto, California: Consulting Psychologist Press.

Spitzer RL, Williams JB, Gibbson M, First MB (1990). Structured Clinical Inter-view for DSMIII-R (SCID), Patient Version (SCID-P).Washington, DC: Amer-ican Psychiatric Association Press.

Swedo SE,Pietrini P, Leonard HL, Schapiro MB,Rettew DC, Goldberger EL,etal (1992): Cerebral glucose metabolism in childhood-onset obsessive-compulsivedisorder. Revisualization duringpharmacotherapy. Arch GenPsychiatry 49:690694.

Swedo SE, Schapiro MG, Grady CL, Cheslow DL, Leonard HL, Kumar A, et al(1989):Cerebralglucosemetabolisminchildhoodonsetobsessive-com-pulsive disorder. Arch Gen Psychiatry 46:518523.

Ursu S, Stenger VA, Shear MK,JonesMR, CarterCS (2003): Overactive actionmonitoring in obsessive-compulsive disorder: Evidence from functionalmagnetic resonance imaging. Psychol Sci 14:347353.

Wechsler D (1981): WAIS-R Manual . New York: Psychological Corporation.Wechsler D (1987): Wechsler Memory Scale-Revised . SanAntonio,Texas: Psy-

chological Corporation.Zald DH, KimSW (1996): Anatomy andfunctionof theorbital frontal cortex,

II:Functionandrelevanceto obsessive-compulsivedisorder. J Neuropsy-chiatry Clin Neurosci 8:249261.

Zielinsli CM, Taylor MA, Juzwin KR (1991): Neuropsychological decits inobsessive-compulsive disorder. Neuropsychiatry Neuropsychol Behav Neurol 4:110126.

Zohar J, Insel TR, Berman KF, Foa EB, Hill JL, Weinberger DR (1989): Anxietyand cerebral blood ow during behavioral challenge: Dissociation of central from peripheral and subjective measures. Arch Gen Psychiatry 46:505510.



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