Psychiatry Research: Neuroimaging 123 (2003) 125–134

Elevated thalamic and prefrontal regional cerebral blood flow in obsessive–compulsive disorder: a SPECT study Acioly L.T. Lacerdaa,b,*, Paulo Dalgalarrondob, Dorgival Caetanob, Edwaldo E. Camargoc, Elba C.S.C. Etchebeherec, Jair C. Soaresd a

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA b Department of Medical Psychology and Psychiatry, School of Medical Sciences, State University of Campinas, ´ ˜ Geraldo, Campinas, SP 13081-970, Brazil Cidade Universitaria ‘Zeferino Vaz’ – Barao c Division of Nuclear Medicine, Department of Radiology, School of Medical Sciences, State University of Campinas, Campinas, Brazil d Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center in San Antonio, San Antonio, TX, USA Received 26 March 2002; received in revised form 25 November 2002; accepted 22 December 2002

Abstract Functional neuroimaging studies have pointed to a possible role of cerebral circuits involving the prefrontal and anterior cingulate cortices, the striatum, and thalamus in the pathophysiology of obsessive–compulsive disorder (OCD). Regional cerebral blood flow (rCBF) of 16 drug-free Brazilian patients with OCD and 17 healthy subjects matched for age, gender, handedness and level of education was measured with w99m-Tcx HMPAO single photon emission computed tomography. Analysis of covariance identified four regions of interest with significantly higher rCBF: the right superior and inferior frontal cortex and the right and left thalamus. Positive correlations between symptom severity measured by Clinical Global Impression scores and rCBF were found in the right and left inferior frontal lobes and in the right basal ganglia. Compulsive behavior was inversely correlated with rCBF in the right thalamus, and duration of illness correlated positively with rCBF in the right and left superior frontal lobes and with the right thalamus. The findings of this SPECT study conducted in Brazil are in agreement with prior studies and provide additional support for the involvement of prefrontal–subcortical circuits in the pathophysiology of OCD. Furthermore, the study suggests that similar brain mechanisms appear to be involved cross-culturally. 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Single photon emission computed tomography; Functional neuroimaging; Obsessive–compulsive disorder; Prefrontal– subcortical circuits; Thalamus; Frontal cortex

*Corresponding author. Department of Medical Psychology and Psychiatry, School of Medical Sciences, State University of ´ ˜ Geraldo, Campinas, SP 13081-970, Brazil. Tel.: q55-19-3241-4866; fax: Campinas, Cidade Universitaria ‘Zeferino Vaz’ – Barao q55-19-3241-4866. E-mail address: [email protected] (A.L. Lacerda). 0925-4927/03/$ - see front matter 䊚 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0925-4927Ž03.00061-1

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1. Introduction Obsessive–compulsive disorder (OCD) is a common psychiatric disorder, with a lifetime prevalence between 1.9 and 3.1% (Bebbington, 1998). The old belief that OCD is caused by unconscious psychological conflicts or that it cannot be treated effectively with medications has been called into question (Stein et al., 1999). Over the past 15 years, several studies have increasingly demonstrated the importance of neurobiological factors in the pathophysiology of OCD (Insel and Winslow, 1992; Rapoport, 1988). A frontal–subcortical circuit that directly participates in the brain–behavior interactions has been consistently implicated in the pathophysiology of OCD symptoms. The structures involved in the prefrontal–striatal–thalamo-cortical circuits have often been reported as hyperactive in resting brain-imaging studies in OCD patients (Baxter et al., 1988; Machlin et al., 1991; Perani et al., 1995; Rubin et al., 1992; Swedo et al., 1989). Additionally, studies performed before and after treatment (Hoehn-Saric et al., 1991; Rubin et al., 1995; Saxena et al., 1999), as well as symptom provocation studies (Hollander et al., 1995; Rauch et al., 1994), have suggested a possible role of other neuroanatomic circuits involving orbitofrontal and anterior cingulate cortices, striatum, and thalami. Compared with PET and fMRI, brain SPECT imaging displays both lower sensitivity and spatial resolution. However, its lower cost and wide availability permit comparison with a larger pool of prior studies (Busatto et al., 2000), and provide an important potential for clinical application if any of the available or future findings becomes a diagnostic tool. Unfortunately, previous functional neuroimaging studies have frequently included patients on medication, which might hinder the identification of significant abnormalities. A SPECT study was carried out in a sample of Brazilian drug-free OCD patients and matched healthy subjects in order to confirm results of prior studies and examine whether similar brain mechanisms might be involved in this disorder cross-culturally. Additionally, we examined the influence of clinical and

demographic variables on regional cerebral blood flow (rCBF). 2. Methods 2.1. Subjects The sample comprised 16 consecutively recruited patients meeting DSM-IV criteria for OCD (American Psychiatric Association, 1994) who had been drug-free for at least 30 days before the study; 10 (62.5%) of these patients were drugnaive. Fourteen were outpatients and two inpatients. Obsessive–compulsive symptom severity and level of functioning in the patient group were assessed by means of the Yale–Brown ObsessiveCompulsive Scale (Y-BOCS) (Goodman et al., 1989), translated and validated in Brazil by Asbahr (1997), and the Global Assessment Scale (GAS) (Endicott et al., 1976), respectively. The Clinical Global Impression (CGI) scale (Guy, 1976) was used to assess global illness severity, and the Cerebral Laterality Inventory (Annett, 1970) to assess handedness. Exclusion criteria consisted of current medical problems, history of substance or alcohol abuse or dependence at any time, epilepsy, other neurological diseases that affect the central nervous system, and use of any psychotropic medication in the last 30 days. The control group (Ns17) was selected from the healthy control database of the Division of Nuclear Medicine, Department of Radiology, State University of Campinas. Exclusion criteria consisted of any current or past DSM-IV axis I diagnosis, current medical problems, and history of neurological disease. All subjects provided written informed consent after detailed explanation of the study procedures. 2.2. Brain SPECT image acquisition and analysis After placement of a venous access in the arm, the subject was kept in a quiet room with dim light for 20 min, and 1.110 MBq (30 mCi) of wTc-99mx HMPAO was injected. Subjects were asked to relax and did not have their eyes closed

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Fig. 1. Illustration of ROI placement on one subject. The areas delimited are, from left to right and from top to bottom: right cerebellar hemisphere; lateral portion of the right temporal lobe and vermis; inferior portion of the right frontal lobe; anterior aspect of the cingulate and left basal ganglia; superior portion of the right frontal lobe and thalami; primary visual area; left parietal lobe.

nor their ears covered during the brain-imaging procedures. All subjects were imaged with a tomographic scintillation camera (Elscint SP-6), equipped with a fan beam collimator. Sixty images were obtained at 68 intervals for a total of 3608. The intrinsic resolution of the camera was 11 mm at full width half maximum. The SPECT image acquisition lasted approximately 30 min, starting 30 min after the intravenous injection of the tracer. Images were reconstructed in the transaxial, coronal, sagittal, temporal and supra-orbito-meatal planes on a 64=64 matrix using filtered back-projection and a Metz filter. Attenuation correction was performed, and the attenuation coefficient ranged from 0.115 to 0.111. Tracer activity in the regions of interest (ROIs) was calculated and expressed as within-subject ratios to the cerebellar blood flow, since this region has not been demonstrated to be involved in OCD pathophysiology.

A standard template with previously defined ROIs was applied to all scans (Fig. 1). Cortical and sub-cortical structures were delineated. ROIs included frontal lobes (inferior and superior portions), parietal lobes, temporal lobes (lateral aspect), basal ganglia, thalami, anterior cingulate gyrus, visual cortex and vermis. Semi-quantitative analysis was performed blindly by a trained researcher (ECSCE). Counts per pixel of each ROI were acquired, divided by counts per pixel of the cerebellum, and compared with healthy control subjects. All regions were represented in both hemispheres, except for the cingulate gyrus, visual cortex and vermis. Intraclass correlation coefficients for placement of individual ROIs were above 0.90 for all ROIs. 2.3. Statistical analysis Statistical analyses were performed by means of the Statistical Package for the Social Sciences

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Table 1 Demographic and clinical characteristics (mean"S.D.)

Age (years) Gender (MyF) Education (years) Handedness (rightyleft) Age at onset (years) Length of illness (years) Y-BOCS (total) Obsessive sub-scale Compulsive sub-scale CGI GAS

Patients (ns16)

Controls (ns17)

P

29.5"16.4 (range: 18–37) 8y8 9.6"5.8 14y2 15.8"10.7 13.7"9.6 23.71"8.18 11.71"4.45 12.0"3.94 4.79"0.97 54.47"10.78

28.0"7.5 (range: 19–46) 10y7 11.2"7.4 16y1 – –

n.s. n.s n.s. n.s. – –

–

–

– –

– –

n.s., non-significant (P)0.05).

(SPSS for WINDOWS software), version 10.0 (SPSS Inc., Chicago, 1999). A two-tailed statistical significance level was set at P-0.05. The values for tracer uptake in each ROI were found to be normally distributed, according to the Shapiro– Wilks test. In order to assess the possible differences in rCBF between patients and controls, the general linear model analysis of covariance (ANCOVA) was performed, utilizing diagnostic group as class variable, and age and gender as covariates. Comparisons between patients’ subgroups (the ones off medications for at least 30 days and those never medicated) were performed by means of the non-parametric Mann–Whitney U-test, as they constituted small sub-samples. Pearson’s correlation coefficients were calculated to examine the relationship between age and specific clinical and demographic variables. Square root transformation was applied to those variables that did not display a normal distribution (length of illness and age of onset). Spearman’s rho correlation coefficients were used to examine correlations between tracer uptake in ROIs and scores obtained on the Y-BOCS. Finally, a stepwise discriminant analysis was performed to determine if the groups (patients and controls) could be distinguished on the basis of rCBF measurements in the ROIs composing prefrontal–subcortical circuits, e.g. frontal regions, thalami, basal ganglia and anterior cingulate.

3. Results 3.1. Comparison between groups Demographic and clinical variables are presented in Table 1. As the two groups were matched for age, level of education, handedness and gender, no significant differences for these variables emerged. A comparison between OCD patients previously exposed to psychotropic drugs (Ns6) and those never exposed (Ns10) showed that the latter were significantly younger (ages24.4"39.5 vs. 39.5"16.8 years; Ps0.02), had lower CGI scores (4.33"0.7 vs. 5.6"0.89; Ps0.01), better social functioning according to the GAS (60.0"7.5 vs. 46.1"9.8; P-0.01), and a shorter illness duration (10.1"7.3 years vs. 19.1"11.2 years; Ps0.05). 3.2. Brain SPECT imaging results Compared with healthy controls (Ns17), the patients (Ns16) presented significant increases in tracer uptake (ANCOVA, age and gender as covariates, d.f.s1.29, P-0.05) in four ROIs (Table 2, Fig. 2): superior portion of the right frontal lobe, inferior portion of the right frontal lobe, and right and left thalamus. When the P value was Bonferroni-corrected, so that a P value of 0.0055 (0.05y9, number of ROIs) was considered significant, only the differences involving the thalami

A.L. Lacerda et al. / Psychiatry Research: Neuroimaging 123 (2003) 125–134 Table 2 ROIycerebellar rCBF ratios ROI

Healthy controls (Ns17)

OCD patients (Ns16)

Mean

Mean

S.D.

F1,29

S.D.

Superior frontal Right 0.8764 0.1031 0.9549 0.1042 Left 0.8729 0.1183 0.9401 0.1088

6.054* 3.157

Inferior frontal Right Left

0.795 0.085 0.8859 0.115 0.8041 0.0915 0.8631 0.1038

6.949* 3.876

Ant. cingulate

0.9405 0.1320 0.9908 0.1137

2.084

Basal ganglia Right Left

1.009 1.012

0.125 0.211

Thalamus Right Left

0.8400 0.1121 0.9862 0.1134 18.018** 0.8429 0.1056 1.0013 0.1139 22.983**

Parietal lobe Right Left

0.8552 0.1056 0.8584 0.1173 0.8582 0.1071 0.8664 0.1098

0.044 0.119

Temporal lobe Right Left

0.8482 0.1004 0.865 0.0927 0.8315 0.0662 0.8422 0.0573

0.211 0.430

Visual cortex

0.8762 0.0845 0.8911 0.0959

0.322

Vermis

0.9421 0.0892 0.9892 0.0779

3.708

0.1401 0.982 0.1345 0.982

0.1181 0.1181

OCD, obsessive compulsive disorder. * Difference is significant at the 0.05 level (2-tailed). ** Difference is significant after Bonferroni’s correction, at the 0.005 level (2-tailed).

remained statistically significant. Patients previously treated with psychotropic drugs (Ns6) presented lower rCBF (Mann–Whitney U-test) in left (Zs2.18; Ps0.029) and right (Zs2.30; Ps 0.021) inferior portions of the frontal lobes; right (Zs2.06; Ps0.039) and left (Zs2.00; Ps0.045) thalami; cingulate (Zs2.24; Ps0.025); and right basal ganglia (Zs2.30; Ps0.021) in comparison with drug-naive patients (Ns10). We examined rCBF asymmetry in five ROIs (superior and inferior portions of the frontal lobes, parietal lobes, basal ganglia and thalami) that compose the frontal–subcortical circuits. Patients showed asymmetric perfusion in the inferior portions of the frontal lobes, as the right area presented significantly higher rCBF (t-test, d.f.s15,

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ts2.233, Ps0.041) when compared with the corresponding left area. There was no significant right-to-left asymmetry in the other ROIs in the patient group or in the control group. A stepwise discriminant analysis revealed that tracer uptake in the left thalamus (F1,23s20.46; P-0.001), anterior cingulate (F1,23s7.32; Ps 0.013), and right inferior frontal (F1,23s5.25; Ps 0.031) regions were reliable predictors of diagnostic assignment. On the basis of rCBF measurements of the ROIs that compose the prefrontal– subcortical circuits, the equation correctly classified 94% of the patients and 100% of the controls, with an overall correct prediction of 97% (F9,23s7.91; P-0.0001). The discriminant equations were not statistically significant in the other six ROIs (P range, 0.16–0.97). 3.3. Clinical variables CGI scores were directly correlated with rCBF in the inferior portion of the right frontal lobe (rs 0.661; Ps0.027), inferior portion of the left frontal lobe (rs0.641; Ps0.033) and right basal ganglia (rs0.618; Ps0.043). Scores on the compulsive sub-scale of the Y-BOCS inversely correlated with rCBF in the right thalamus (rsy0.631; Ps0.037). Illness duration was directly correlated with rCBF in the superior portion of the right frontal lobe (rs0.501; Ps0.048), superior portion of the left frontal lobe (rs0.542; Ps0.03) and right thalamus (rs0.633; Ps0.009). Correlations between perfusion data and other clinical variables were nonsignificant (P)0.05). 4. Discussion Our findings are in agreement with previous reports of increased resting rCBF in brain regions that compose the frontal–subcortical circuits in OCD patients (Machlin et al., 1991; Rubin et al., 1995, 1992). Most functional brain-imaging studies consistently report increased rCBF or metabolic activity in frontal areas in OCD patients (Alptekin et al., 2002; Baxter et al., 1988; Hoehn-Saric et al., 1991; McGuire et al., 1994; Rauch et al., 1994; Rubin et al., 1992; Swedo et al., 1989). Although less consistently, abnormalities in thalamic areas

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Fig. 2. (Top) 99m-Tc-HMPAO SPECT brain scan in a 24-year-old drug-naive male with OCD, showing elevated rCBF in anterior cingulate and prefrontal regions, bilaterally. (Bottom) 99m-Tc-HMPAO SPECT brain scan in a 30-year-old healthy control, showing a normal distribution of rCBF in the brain.

have also been reported across different cultures (Alptekin et al., 2002; Baxter et al., 1992; Busatto et al., 2001; McGuire et al., 1994; Perani et al., 1995; Saxena et al., 1999). Also, a decrease in medial–frontal and global cortical rCBF has been described after successful treatment (Hoehn-Saric et al., 1991; Rubin et al., 1995), and an increase in global cortical perfusion has been observed in symptom-provocation and ‘pharmacological challenge’ studies (Hollander et al., 1995; Zohar et al., 1989). These reports, however, are not uniform. In contrast, Lucey et al. (1997) found right caudate and superior frontal rCBF reduced in OCD patients. Also, Busatto et al. (2000) reported a

reduced rCBF in the lateral orbitofrontal and left dorsal anterior cingulate cortices. Compared with patients previously treated with psychotropic drugs, drug-naive patients had higher rCBF in the left and right inferior portions of the frontal lobes, right and left thalami, and right basal ganglia. This difference might be accounted for either by psychotropic exposure in the previously treated subgroup or a difference in sample characteristics. The first alternative seems unconvincing since those studies that report psychotropic drugs modifying rCBF refer to subjects that were currently on medication. In addition, there are no studies reporting on persistent changes in rCBF 30

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days after drug washout. However, patients previously exposed to psychotropic drugs were older, and they had lower CGI scores, longer duration of illness, and worse social functioning (lower scores in GAS) (P-0.05). This indicates that the second alternative is probably a better explanation, since patients previously treated may have presented more severe OCD manifestations. Functional neuroimaging studies have described abnormalities predominantly in the right-sided cerebral structures in resting conditions (Lucey et al., 1997) and after successful pharmacological treatment (Baxter, 1992; Saxena et al., 1999). Interestingly, increased rCBF in the right but not in the left frontal regions was found in the present study. Moreover, only the inferior portion of the frontal lobes had an asymmetric perfusion, as the right region showed higher rCBF when compared with the correspondent left region. The right anterolateral–orbitofrontal cortex mediates alternation tasks and modulates behavior in situations that involve choice among two or more possible responses. These tasks are substantially impaired in OCD patients. Also, this region may play a prominent role in mediating OCD symptoms and their response to pharmacotherapy (Saxena et al., 1998, 1999). Although functional neuroimaging studies have pointed to a more prominent role of the right cerebral hemisphere structures in OCD pathophysiology, more robust evidence comes from neuro-psychological studies. Performance deficits have been reported for visual–spatial tasks (Boone et al., 1991; Galderisi et al., 1995; Okasha et al., 2000) and neuropsychological deficits were more pronounced in nonverbal as compared to verbal tasks in OCD patients (Boone et al., 1991; Christensen et al., 1992; Galderisi et al., 1995). Moreover, studies addressing performance in lateralized neuropsychological tasks also suggested dysregulation in right frontal–subcortical circuits (Behar et al., 1984; Cox et al., 1989; Galderisi et al., 1995; Insel et al., 1983; Nelson et al., 1993). Okasha et al. (2000) found a significant correlation between chronicity and deterioration of visual– spatial performance as tested by the object assembly test and delayed visual memory. These tests assess neuropsychological functions of the right

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hemisphere. According to these authors, this could indicate a process of progressive deterioration in right cerebral hemisphere function. Altogether, these findings point to a possible neural dysfunction in OCD that is more pronounced in the right cerebral hemisphere. The thalamus acts as the final subcortical input to frontal cortex, stimulates cortico-frontal output and plays a crucial role in the processing of sensory inputs and almost all interactions between cortical, subcortical and brainstem nuclei. This permits the thalamus to mediate behavior and cognition. Neuropsychological studies have reported deficits in executive function solely or in combination with memory loss following damage to the thalamus. These symptoms are repeatedly found 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 involved in OCD pathophysiology, is densely present in the thalamus, behaving as a complex modulator of thalamo-cortical 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). This lends further support to the involvement of the thalamus in the pathophysiology of OCD (Gilbert et al., 2000). Strengths of the present study include a rigorous match between patients and controls for age, gender, handedness and level of education. All subjects were off any medication for at least 30 days before enrolling in the study. The majority of the patients (62.5%) had never been exposed to psychotropic drugs before imaging. This is a valuable strategy to prevent bias as these drugs may significantly influence cerebral blood flow (Devous et al., 2001; Miller et al., 2001; Reinsel et al., 2000). More restrictive inclusion and exclusion criteria made it possible to recruit a more homogeneous group of patients, thus minimizing the occurrence of variables that potentially could interfere with rCBF measures. The low spatial resolution of brain SPECT imaging scintillation cameras (11 mm) limits the detection of abnormalities in small brain areas or

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the identification of discrete brain abnormalities. In addition, as the brain has massive interconnections among different areas, our findings could reflect processes originating in remote cerebral structures. After Bonferroni correction, only differences involving thalamic regions remained significant. However, we have limited our analyses to brain regions where a clear hypothesis was available. Finally, our sample comprised only 16 patients and 17 healthy controls, which is a relatively modest sample size, and could have limited our ability to detect small differences between patients and controls for other brain regions. In conclusion, this 99mTc HMPAO brain SPECT imaging study showed that OCD patients have higher resting rCBF in the right frontal lobe and the thalami. Additionally, illness duration positively correlated with rCBF in the right thalamus and the superior portion of the frontal lobes, bilaterally. The findings of this study, which was conducted in a sample of Brazilian subjects, are in close agreement with most previous functional neuroimaging studies, suggesting that the potential involvement of prefrontal–subcortical circuits in OCD pathophysiology occurs in different cultures. Acknowledgments Dr Lacerda is funded by the Conselho Nacional ´ ´ de Desenvolvimento Cientıfico e Tecnologico (CNPq), Brazil. References Abbruzzese, M., Ferri, S., Scarone, S., 1997. The selective breakdown of frontal functions in patients with obsessive– compulsive disorder and in patients with schizophrenia: a double dissociation experimental finding. Neuropsychologia 35, 907–912. Alptekin, K., Degirmenci, B., Kivircik, B., Durak, H., Yemez, B., Derebek, E., Tunca, Z., 2002. Tc-99m HMPAO brain perfusion SPECT in drug-free obsessive–compulsive patients without depression. Psychiatry Research: Neuroimaging 107, 51–56. American Psychiatric Association, 1994. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Press, Washington, DC. Annett, M., 1970. A classification of hand preference by association analysis. British Journal of Psychology 61, 303–321.

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