Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 657 – 665 www.elsevier.com/locate/pnpbp

Neuropsychological performance and regional cerebral blood flow in obsessive–compulsive disorder Acioly L.T. Lacerdaa,b,*, Paulo Dalgalarrondob, Dorgival Caetanob, Gretchen L. Haasa,c, Edwaldo E. Camargod, Matcheri S. Keshavana a

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Room 984, 3811 O’Hara Street, Pittsburgh, PA 15213, USA b Department of Medical Psychology and Psychiatry, School of Medical Sciences, State University of Campinas, Campinas, Brazil c Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Pittsburgh Healthcare System, Pittsburgh, PA, USA d Medical Sciences Faculty, Department of Radiology, Division of Nuclear Medicine, State University of Campinas, Campinas, Brazil Accepted 14 February 2003

Abstract Convergent findings from neuropsychological and neuroimaging studies have suggested that neural dysfunction in frontal – subcortical circuits may play a central role in the pathophysiology of obsessive – compulsive disorder (OCD). To further examine the relationship between these two sets of findings we investigated both neuropsychological functions and regional cerebral blood flow (rCBF) in a combined study. Fourteen unmedicated patients fulfilling DSM-IV criteria for OCD and 14 healthy controls matched for age, gender, handedness, and education were assessed on neuropsychological tests that included Trail Making Test (TMT), Rey Complex Figure Test (RCF) (copy and 5-min recall), Verbal Fluency Test (VFT), and Wisconsin Card Sorting Test (WCST). rCBF was studied with 99 mTc-hexamethyl-propyleneamine-oxime (HMPAO) single photon emission computed tomography (SPECT). Patients performed more poorly than controls ( P < .05) on RCF (copy), VFT, and WCST (perseverative errors). Spearman’s correlations indicated that severity of OCD correlated inversely with performance on the RCF (copy and recall scores) and positively with rCBF in the right thalamus. Positive correlations were observed between nonperseverative errors (WCST) and rCBF in frontal areas and anterior cingulate. Perseverative errors (WCST) correlated negatively with rCBF in the right thalamus. These findings are consistent with most previously published studies and suggest neural dysfunctions in the frontal – subcortical circuits probably more pronounced in the right hemisphere. They also extend the existing research, showing associations between deficits in cortical – subcortical circuitry and performance on neuropsychological tests of controlled attention and visuospatial functions. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Frontal – subcortical circuits; Neuropsychology; Rey – Osterrieth Complex Figure Test; SPECT; Trail Making Test; Verbal Fluency Test; Wisconsin Card Sorting Test

1. Introduction Obsessive– compulsive disorder (OCD) is a chronic, disabling anxiety disorder that affects about 2% of the popuAbbreviations: DLPFC, dorsolateral prefrontal cortex; OCD, obsessive – compulsive disorder; ROI, region of interest; rCBF, regional cerebral blood flow; RCFT, Rey – Osterrieth Complex Figure Test; SPECT, single photon emission computed tomography; SPSS, Statistical Package for the Social Sciences; TMT, Trail Making Test; VFT, Verbal Fluency Test; WCST, Wisconsin Card Sorting Test. * Corresponding author. c/o Matcheri S. Keshavan, MD, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Room 984, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel.: +1-412-624-0814; fax: +1-412-624-1459. E-mail address: [email protected] (A.L.T. Lacerda).

lation. Clinically, OCD is characterized by the presence of recurrent and persistent thoughts that cause marked anxiety or distress (obsessions) and/or repetitive behaviors or mental acts that are performed to prevent or reduce distress (compulsions). Both obsessions and compulsions are recognized as excessive or unreasonable by the patients, who frequently attempt to ignore or suppress them (American Psychiatric Association, 1994). This clinical presentation resembles some features of organic mental disorders, specifically those related to the so-called ‘‘frontal syndrome,’’ which is characterized by deficits in executive abilities, including the ability to flexibly shift cognitive sets, along with cognitive rigidity in problem solving, anxiety, depression, and poor impulse control as important features (Dolan et al., 1993; Grafman et al., 1996; Robinson et al., 1984).

0278-5846/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(03)00076-9

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As early as 1838, Esquirol anticipated that some neurological dysfunctions would be found to underlie OCD symptomatology; as to its pathophysiology, Ball in 1892, emphasized possible cerebral blood flow abnormalities (from Berrios, 1989). Recently, various lines of evidence supporting the neurobiological basis of OCD have been reported (Insel, 1992): a high prevalence of OCD in some neurological diseases such as Tourette syndrome, postencephalitic Parkinson, Sydenham chorea, and temporal lobe epilepsy (Bihari et al., 1991; Hollander et al., 1990; Jenike, 1984; Malloy et al., 1989; Rapoport, 1990); favorable response to biological treatments such as selective serotonin reuptake inhibitors and psychosurgery (Baer et al., 1995; Humble et al., 2001; Insel et al., 1985; Jenike et al., 1991; Mindus and Jenike, 1992); a high prevalence of neurological soft signs and abnormal evoked potential (Bihari et al., 1991; Hollander et al., 1990; Lieberman, 1984); structural and functional abnormalities detectable by neuroimaging techniques (Robinson et al., 1995; Rosenberg et al., 2000; Saxena et al., 1998); specific neuropsychological deficits (Okasha et al., 2000; Schmidtke et al., 1998); and evidence of genetic transmission in at least some patterns of OCD (Pauls and Alsobrook, 1999). Performance of different cognitive tasks has been assessed in OCD patients. Previous neuropsychological studies, albeit with some contradictory findings, have pointed to impairment in at least four domains: ‘‘frontal lobe’’ and visuospatial functions, memory, and lateralization of assumed cognitive dysfunction (Schmidtke et al., 1998). According to these authors, the apparent contradictions may be due, in part, to methodological differences in the selection, matching, and testing of the subjects studied. Hence, such factors as evaluation of patients on medication, inclusion of subjects with mild forms of OCD or with subtle central nervous system insults, as well as failure to adequately match healthy controls to OCD subjects could be important sources of variance in the findings across studies (Schmidtke et al., 1998). Neuroimaging studies examining OCD patients have consistently described abnormalities in frontal lobes, cingulate, basal ganglia, and thalami (Saxena et al., 1998). Taken together, neuroimaging and neuropsychological findings have provided considerable evidence pointing to dysfunction of prefrontal –subcortical circuits in OCD (Abbruzzese et al., 1995a; Baxter, 1990; Baxter et al., 1987; Martinot et al., 1990; Okasha et al., 2000; Saxena et al., 1998; Schmidtke et al., 1998). In the present study, the authors examined the neuropsychological performance of 14 unmedicated OCD patients and 14 comparison subjects matched for age, gender, handedness, and level of education. Four tests, addressing different cognitive functions such as verbal fluency, visuospatial orientation, set shifting, and memory, were applied. Patients were also investigated with single photon emission computed tomography (SPECT). Bearing in mind the findings of previous studies, we hypothesized that OCD patients would

have an impaired performance on neuropsychological tests evaluating frontal and visuospatial functions and that scores on the same tests as well as severity of symptoms would be associated to regional cerebral blood flow (rCBF) measurements in structures involved in prefrontal –subcortical circuits.

2. Methods 2.1. Subjects All subjects provided written informed consent to participate in the study after the procedures were explained and all recommendations of the ethical committee were met. Fourteen patients were consecutively recruited from both psychiatric outpatient clinics and advertisements in local newspapers. They met DSM-IV (American Psychiatric Association, 1994) criteria for OCD and had been drug-free for at least 30 days before the study. Patients completed the Yale – Brown Obsessive Compulsive Scale (Y-BOCS) (Goodman et al., 1989), and all subjects completed the Annett Inventory, a self-report assessment of functional laterality (Annett, 1970). Level of education corresponded to the number of years successfully completed in formal school. Patients were excluded if they had current medical problems, lifetime history of alcohol or substance abuse or dependence, history of head injury, epilepsy or any other neurological disease affecting the central nervous system (CNS), or exposure to any medication known to have a significant effect upon the CNS in the last 30 days preceding the study. Fourteen healthy control subjects matched for age, gender, handedness, and level of education were selected from advertisements in local newspapers according to sociodemographic data of previously recruited patients. Exclusion criteria for control subjects were lifetime history of head injury or any DSM-IVAxis I diagnosis, current medical problems, and current or past neurological disease. 2.2. Neuropsychological testing Neuropsychological testing was carried out within 24 h of the scan. The Wisconsin Card Sorting Test (WCST) was administered using the standard procedures provided by Heaton (1981). For each subject, the number of categories completed, total trials, total correct responses, total errors, perseverative and nonperseverative errors, and perseverative responses were calculated as described in the manual. For the Verbal Fluency Test (VFT), subjects were asked to speak as many alternating names of colors and animals as possible during 1 min. Alternating categories on the verbal fluency task has been found to be a valuable ‘‘augmentation strategy’’ in the assessment of frontal functioning (Newcombe, 1982). Following the scoring system described by Meyers and Meyers (1995), the Rey – Osterrieth Complex

A.L.T. Lacerda et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 657–665 Table 1 Demographic and clinical data of OCD patients and healthy controls Variables

Patients (n = 14) Controls (n = 14) F mean (± S.D.) mean (± S.D.)

Age

33.07 (± 12.89) (range: 18 – 72) Gender (M/F) 10/4 Handedness (R/L) 12/2 Years of education 11.07 (± 4.05) Y-BOCS 23.71 (± 8.18) (range: 11 – 40) Length of illness 15.64 (± 9.53) (years) (range: 1 – 30) Age at onset 17.43 (± 9.14) (years) (range: 7 – 42)

33.79 (± 11.42) (range: 22 – 66) 10/4 13/1 10.50 (± 4.01) –

P .155

.878

.000 1.000 .373 .541 .375 .711 – –

–

–

–

–

–

–

Figure Test (RCFT) (Osterrieth, 1944; Rey, 1941) was administered using the copy and 5-min recall test procedures. The Trail Making Test (TMT, Parts A and B) (Army Individual Test Battery, 1944) included the assessment of the time for completing the motor sequence and the total number of errors in each part of the test. 2.3. Imaging acquisition and analysis In this study, the SPECT procedures were conducted only with the OCD patients. A venous cannula was inserted into the patients’ right arm 10– 20 min before the injection of 99 m Tc-hexamethyl-propyleneamine-oxime (HMPAO) over approximately 30 s. During the injection and for 10 min afterwards, subjects laid on the imaging table comfortably resting with their eyes closed, when environmental noises were kept to a minimum. All SPECT subjects were imaged using a scintillation camera (Elscint SP-6), equipped with a fan beam collimator. Sixty images were obtained, at 6
intervals for a total of 360
. The intrinsic resolution of the camera was rated as 11 mm full width half maximum (FWHM). The SPECT image acquisition lasted approximately 30 min, starting 30 min after intravenous injection of the tracer. Images were reconstructed following the same procedure in transversal, coronal, sagittal, temporal, and supraorbitomeatal planes on a 64  64 matrix. The reconstruction method used was filtered back projection and a Metz filter. Attenuation correction

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was performed and the coefficient varied from 0.115 to 0.111. Uptakes of the tracer by the regions of interest (ROIs) were calculated and expressed as within-subject ratios to the cerebellar blood flow, which has not been demonstrated to be involved in the OCD pathophysiology (Micallef and Blin, 2001). Activity thresholds for ROIs were not preestablished since these areas were manually drawn in reference to standard anatomical atlases. ROIs included frontal lobes (inferior and superior portions), parietal lobes, temporal lobes (lateral aspect), basal ganglia, thalami, anterior cingulate, primary visual cortex, and vermis. Semiquantitative image analysis was performed blindly by a trained researcher. Independent (right and left hemisphere) unilateral measures were taken for all regions, except for cingulate, primary visual cortex, and vermis that were considered as single bilateral regions. 2.4. Statistical analyses All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) for Windows software, version 10.0 (SPSS, Chicago, 1999) and a twotailed statistical significance level was set at P < .05. Analysis of variance (ANOVA), with diagnostic groupings as the class variable, was performed to examine differences in neuropsychological performance between patients and controls. In view of the nonnormal distribution of some variables such as neuropsychological measures, age at onset, length of illness, and severity of symptoms, we chose to use Spearman’s rho correlation coefficients to investigate significant relationships between neuropsychological performance and SPECT as well as clinical measures. To protect against Type I error with the use of multiple comparisons, the authors limited the exploratory statistical analyses in some ways. First, time measures and their correlations with SPECT data were not taken into account because timed scores are of questionable value in assessing OCD patients, who may present obsessional slowness as a core symptom. Second, we restricted our analyses on the WCST to measures of perseverative and nonperseverative errors, which are most likely to tap cognitive rigidity, difficulties shifting cognitive set, and visuospatial learning

Table 2 Neuropsychological performances of OCD patients (n = 14) and healthy controls (n = 14) Cognitive domain

Test

Patients (mean ± S.D.)

Controls (mean ± S.D.)

F(1,26)

P

Executive functioning

WCST (perseverative errors) WCST (nonperseverative errors) TMT-B (errors) RCFT copy (score) RCFT recall (score) VFT

33.07 ± 21.07 18.14 ± 15.71 3.0 ± 4.28 32.96 ± 3.07 19.89 ± 7.83 14.93 ± 5.25

18.64 ± 13.87 12.21 ± 11.98 0.79 ± 1.12 35.21 ± 1.05 23.67 ± 6.11 18.86 ± 3.35

4.580 1.261 3.508 6.746 2.029 5.566

.042 .272 .072 .015 .166 .026

Visuospatial ability Verbal fluency

TMT-B, Trail Making Test (Part B); RCFT, Rey – Osterrieth Complex Figure Test; WCST, Wisconsin Card Sorting Test; VFT, number of words on the Verbal Fluency Test.

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and have been reported to be significantly increased in patients with prefrontal lesions as well (Drewe, 1974; Klorman et al., 1999; Milner, 1963; Robinson et al., 1980). Third, we selected only Part B of the TMT, which appears to be more sensitive to dorsolateral frontal dysfunction as well as have greater working memory demands as compared to Part A (Crowe, 1998). This strategy made it possible to reduce the number of indices to six from the four neuropsychological tests administered: copy and delayed recall scores from the RCFT; number of errors on the TMT (Part B); number of words generated on the VFT; and number of perserverative and nonperseverative errors on the WCST. Finally, in view of the absence of SPECT data for the control group, correlations between neuropsychological and SPECT measures were limited to those ROIs that compose the frontal –subcortical circuits (frontal, cingulate, basal ganglia, and thalamus) thought to have putative involvement in OCD pathophysiology, on the one hand, and to the neuropsychological tests for which a difference was demonstrated between OCD and control groups, on the other.

3. Results 3.1. Clinical and sociodemographic variables At the time of the examination, no patient met DSM-IV criteria for current depressive episode. There were no significant differences between patients and controls in terms of age, gender, handedness, or years of education (t test, c2, P>.05) (Table 1). Patients (10 males and 4 females) had a mean age of 33.07 ± 12.89 years and controls (10 males and 4 females) had a mean age of 33.79 ± 11.42 years. Nine of the 14 patients (64.3%) had never been previously exposed to psychotropic drugs. 3.2. Neuropsychological measures Table 2 summarizes the neuropsychological test performance of patients and control subjects. Patients performed significantly worse on the RCF copy [32.96 ± 3.07 vs. 35.21 ± 1.05; ANOVA, F(1,26) = 6.746; P=.015]; they made more perseverative errors [33.07 ± 21.07 vs. 18.64 ± 13.87; ANOVA, F(1,26) = 4.580; P=.042] on the WCST and generated fewer words on the VFT [14.93 ± 5.25 vs. 18.86 ± 3.35; ANOVA, F(1,26) = 5.566; P=.026].

Fig. 1. Correlations between OCD severity and performance on RCFT copy (A) and 5-min recall scores (B).

3.3. OCD severity and chronicity Y-BOCS scores correlated negatively with scores on the RCF copy (Spearman, r = .752, P=.002) and 5-min recall (Spearman, r = .642, P=.013) (Fig. 1). Correlations between neuropsychological test measures and chronicity (length of illness) and developmental (age at onset) indices were nonsignificant ( P>.05).

3.4. Relationship between rCBF and neuropsychological performance Correlations involving SPECT and neuropsychological measures are summarized in Table 3. Spearman’s correlations showed that the number of WCST perseverative errors

A.L.T. Lacerda et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 657–665 Table 3 Correlation coefficients between SPECT and neuropsychological measures in OCD patients (n = 14) RCFT (copy) RIF LIF RSF LSF RThal LThal RBG LBG AC

.011 .022 .149 .211 .393 .082 .008 .065 .021

WCST (perseverative errors) .196 .051 .020 .033 .574* .337 .419 .422 .194

VFT .370 .159 .175 .051 .044 .134 .030 .035 .170

TMT-B, Trail Making Test (Part B); RCFT, Rey – Osterrieth Complex Figure Test; VFT, number of words on the Verbal Fluency Test; RIF, right inferior frontal; LIF, left inferior frontal; RSF, right superior frontal; RThal, right thalamus; LThal, left thalamus; RBG, right basal ganglia; LBG, left basal ganglia; AC, anterior cingulate. * Correlation is significant at the .05 level (two-tailed).

correlated negatively with rCBF in the right thalamus (r = .574; P=.032). Correlations involving other regions as well as other neuropsychological tests were nonsignificant. When drug-naive (n = 9) and previously treated patients’ (n = 5) subgroups were analyzed separately, no significant correlations between SPECT measures and neuropsychological performance were observed (Spearman’s, P>.05).

4. Discussion OCD patients performed significantly worse on copying the RCF, they generated fewer words on the VFT, and made more perseverative errors on the WCST. In addition, there was a negative correlation between perseverative errors on the WCST and rCBF in the right thalamus. OCD severity, as measured by the Y-BOCS, was inversely correlated with copy and 5-min recall RCFT scores and positively with right thalamus rCBF. Impaired performance on WCST as well as on VFT has been associated with frontal lobe lesions in different brain diseases (Janowsky et al., 1989; Lombardi et al., 1999; Parks et al., 1988; Segalowitz et al., 1992). Moreover, impaired performance on visuospatial tasks, including copy of the RCF, is consistently associated with malfunctioning of the right cerebral hemisphere (Garcia-Sanchez et al., 1997). In a recent study, Lombardi et al. (1999) demonstrated a negative relationship between the functional integrity of the frontal – subcortical circuits and the number of perseverations on the WCST. Furthermore, these authors reported an inverse correlation between perseverations and metabolism in the right dorsolateral prefrontal cortex (DLPFC), but not in the left. Results of the current study are in close agreement with previous studies that examined both brain activity and neurocognition of OCD patients (Lucey et al., 1997;

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Martinot et al., 1990). To our knowledge, there is only one other study (Lucey et al., 1997) that examined OCD patients by means of both SPECT and neuropsychological tests. These investigators found an impaired and perseverative performance on the WCST that negatively correlated with rCBF in the left inferior frontal cortex and left caudate. Martinot et al. (1990) examined the brain metabolism and cognitive performance of OCD patients and found significant impairment on neuropsychological tasks related to mental control, memory, visuospatial function, executive functions, and attention. The absolute metabolic values for the DLPFC correlated negatively with performance on the Stroop Test, a test that reflects the ability to direct attention and response behavior away from a prepotent response—a task that has been demonstrated to involve prefrontal function. Neuropsychological studies, however, are not homogeneous in their findings. Different studies have described an impaired performance of OCD patients on ‘‘executive’’ functions (Harvey, 1987; Head et al., 1989; Savage et al., 1999, 2000), whereas others have found no impairment on these functions as compared to healthy subjects (Abbruzzese et al., 1995b; Beers et al., 1999; Christensen et al., 1992; Zielinski et al., 1991). This discrepancy might be explained by two main factors: (1) inclusion of patients on medication and/or not meeting strict operational diagnostic criteria, which could have hindered detection of deficits and (2) various components of ‘‘executive functioning,’’ as differently assessed by distinct neuropsychological tests may be neither globally nor homogeneously impaired in OCD (Savage et al., 1999). Although neuropsychological studies have provided important evidence in support of the involvement of frontal – subcortical circuits in the pathophysiology of OCD, the most robust evidence comes from brain imaging studies, which have consistently shown abnormalities in frontal areas (Baxter et al., 1987, 1988; Benkelfat et al., 1990; Breiter et al., 1996; Hoehn-Saric et al., 1991; Machlin et al., 1991; McGuire et al., 1994; Nordahl et al., 1989; Rauch et al., 1994; Rubin et al., 1992; Sawle et al., 1991; Saxena et al., 1999; Swedo et al., 1989, 1992), anterior cingulate (Breiter et al., 1996; Busatto et al., 2000; Ebert et al., 1997), and thalami (Baxter et al., 1992; Gilbert et al., 2000; McGuire et al., 1994; Perani et al., 1995; Schwartz et al., 1996). Considering the correlations involving rCBF and the neuropsychological tests that yielded differences between OCD and control groups, only the number of perseverative errors on the WCST had a significant relationship with SPECT data. Interestingly, this correlation was with rCBF in the right thalamus, the region that also correlated positively with OCD severity. The thalamus acts as the final subcortical input to frontal cortex, stimulates corticofrontal output, playing a crucial role in the processing of sensory inputs and almost all interactions among cortical, subcortical, and brainstem nuclei. That enables the thalamus to mediate both

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behavior and cognition. Thalamic lesions have been associated with deficits in executive function, solely or in combination with memory loss, similar to abnormalities following damage to the prefrontal cortex. Those deficits have been consistently described in OCD patients (Abbruzzese et al., 1997; Cavedini et al., 1998; Gilbert et al., 2000; Van der Werf et al., 2000). In addition, serotonin, probably the most important neurotransmitter implicated in OCD pathophysiology, is densely present in thalamic areas, acting as a complex modulator of thalamocortical development and activity (Gilbert et al., 2000; Lebrand et al., 1996). Furthermore, partial thalamotomy has been reported as a successful neurosurgical intervention in treating refractory OCD patients (Modell et al., 1989). That lends further support to the involvement of the thalamus in the pathophysiology of OCD (Gilbert et al., 2000). When drug-naive and previously treated patients’ subgroups were analyzed separately, no significant correlations between SPECT and neuropsychological measures were observed. However, given the small sample sizes (nine and five subjects, respectively), these findings should be interpreted with caution. In the current study, OCD patients showed poorer performance on visuospatial abilities as compared with healthy controls assessed on the RCFT, which might be related to deficits in right cortical function. Based only on the present findings, this conclusion cannot be drawn because a comparison between verbal and visuospatial processing and memory was not provided. However, the assumption that right hemisphere function may be important in OCD pathophysiology is also supported by the findings of significant negative correlations between Y-BOCS scores and performance on both measures (copy and recall) of the RCFT and between Y-BOCS scores and rCBF in the right but not the left thalamus. This hypothesis is further supported by functional neuroimaging studies that have reported abnormalities predominantly in the right-sided cerebral structures in OCD (Baxter et al., 1992; Lucey et al., 1997; Saxena et al., 1999). Moreover, previous neuropsychological studies have also demonstrated significant impairment on visuospatial tasks (Boone et al., 1991; Galderisi et al., 1995; Okasha et al., 2000), as well as deficits more pronounced in nonverbal as compared to verbal tasks, in OCD patients (Boone et al., 1991; Christensen et al., 1992; Galderisi et al., 1995; Otto, 1992). Finally, studies examining performance of OCD patients on lateralized neuropsychological tasks also point to dysfunction in the right prefrontal – subcortical circuits (Behar et al., 1984; Cox et al., 1989; Galderisi et al., 1995; Insel et al., 1983; Nelson et al., 1993), and at least one study described significant correlations between chronicity and deterioration of visuospatial abilities and delayed visual memory as measured by object assembly test (Okasha et al., 2000). Taking into account those findings as well as our own, one could speculate about the existence of impairment in the right cerebral hemisphere functioning in OCD, which might be more pronounced in chronic patients.

In this respect, the proposed neural dysfunction in the prefrontal – subcortical circuits underlying OCD pathophysiology would be more pronounced in the right cerebral hemisphere. Strengths of the present study included the use of a matching procedure that ensured that age, gender, handedness, and years of education were equivalent for patients and controls. Moreover, all subjects were off any medication for at least 30 days before neuropsychological testing. Finally, more restrictive inclusion and exclusion criteria made possible more homogeneous groups of subjects to be recruited. The present study should, however, be interpreted with caution because of several methodological limitations: (1) the relatively small sample size comprising only 14 patients and 14 healthy control subjects may have limited sensitivity to actual group differences and associations between neuropsychological functions and neural activation; (2) the low spatial resolution of the SPECT scans may limit detection of alterations in small regions thus increasing the risk of false negatives and interference from surrounding regions as well; (3) as the FVT is an inherently timed neuropsychological test, the deficits observed in patients could have been related to eventual obsessional slowness; and, finally, (4) as the tests used to assess executive functions and memory have a strong visuospatial component and adequate control tests with taskmatched verbal components were not conducted, this makes it difficult to evaluate how important was the interference of visuospatial impairment on the executive deficits.

5. Conclusions OCD patients had an impaired performance on the RCFT, WCST, and VFT as compared to healthy controls. Furthermore, OCD severity correlated negatively with performance on the RCFT copy and positively with rCBF in the right thalamus, and perseverative errors on the WCST correlated negatively with rCBF in the right thalamus. Notwithstanding the limitations mentioned above, these findings lend further support to the hypothesis that dysfunction in the prefrontal – subcortical circuits, especially in thalamic areas, is likely to underlie the pathophysiology of OCD. However, the roles of these neuropsychological impairments in the expression of obsessive – compulsive symptomatology, as well as the role of rehabilitative therapies on these impairments, still remain largely unexplored. Future studies addressing these issues are deserved for a further understanding of the pathophysiology of this defiant disorder.

Acknowledgements Dr. Lacerda is funded by the Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Brazil. We are also grateful to Dr. Gerald Goldstein for his valuable

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suggestions regarding the analyses of the neuropsychological data.

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