Cerebral activation in children and adolescents with obsessive–compulsive disorder before and after treatment: A functional MRI study

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JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 42 (2008) 1051–1059

www.elsevier.com/locate/jpsychires

Cerebral activation in children and adolescents with obsessive–compulsive disorder before and after treatment: A functional MRI study q Luisa La´zaro a,b,c,*, Xavier Caldu´ b,c, Carme Junque´ b,c, Nu´ria Bargallo´ b,d, Susana Andre´s a, Astrid Morer a, Josefina Castro-Fornieles a,b,c a

Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clı´nic Universitari of Barcelona, Spain b IDIBAPS (Institut d’Investigacions Biome`diques August Pi I Sunyer), Spain c Department of Psychiatry and Clinical Psychobiology, Health Sciences Division, University of Barcelona, Spain d Image Diagnostic Center, Hospital Clı´nic Universitari of Barcelona, Spain Received 24 May 2007; received in revised form 30 November 2007; accepted 14 December 2007

Abstract Background: Structural and functional fronto-striatal abnormalities are involved in the pathophysiology of obsessive–compulsive disorder (OCD). The aims of the present study were: (a) to investigate possible regional brain dysfunction in premotor cortico-striatal activity in drug-naı¨ve children and adolescents with OCD; (b) to correlate brain activation with severity of obsessive–compulsive symptomatology; and (c) to detect possible changes in brain activity after pharmacological treatment. Method: Twelve children and adolescents (age range 7–18 years; seven male, five female) with DSM-IV obsessive–compulsive disorder and twelve healthy subjects matched for age, sex and intellectual level were studied. Functional magnetic resonance imaging data were obtained during the performance of simple and complex sequences. Results: Comparing the complex motor condition with the simple control condition, both patients and controls showed a pattern of cerebral activation involving the fronto-parietal cortex and basal ganglia. Compared with controls, OCD patients presented significantly higher brain activation bilaterally in the middle frontal gyrus. After 6 months of pharmacological treatment and with clear clinical improvement, activation in the left insula and left putamen decreased significantly. Conclusion: In a paediatric OCD sample that was treatment naı¨ve and without another psychiatric disorder we showed hyperactivation of the circuits that mediate symptomatic expression of OCD. The cerebral activation decreases after treatment and clinical improvement. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Obsessive–compulsive disorder; Child and adolescents; Functional MRI; Serial reaction time task; Pharmacological therapy; Fluoxetine

1. Introduction q

Luisa La´zaro designed the study, assessed clinically the patients and wrote the article. Susana Andre´s and Astrid Morer recluted patients and controls. Xavier Caldu´, Carme Junque´ and Nu´ria Bargallo´ realized the fMRI adquisition and their analysis. Josefina Castro-Fornieles colaborated in writing the article. All authors contributed to and have approved the final manuscript. * Corresponding author. Address: Department of Child and Adolescent Psychiatry and Psychology, Hospital Clı´nic Universitari of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain. Tel.: +34 93 2279971; fax: +34 93 2279171. E-mail address: [email protected] (L. La´zaro). 0022-3956/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2007.12.007

Obsessive–compulsive disorder (OCD) is a common psychiatric disorder characterized by the presence of recurrent, intrusive and distressing thoughts (obsessions), repetitive behaviours (compulsions) or both, and up to 80% of all OCD cases emerge during childhood and adolescence (Rasmussen and Eisen, 1990; Pauls et al., 1995; Stein et al., 1997). Neuroimaging studies have shown the involvement of several brain regions in OCD symptomatology. Functional neuroimaging studies in adult patients have provided strong

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evidence about the pathophysiology of OCD. Most of the studies using positron emission tomography (PET) (Baxter et al., 1987; Swedo et al., 1989; Saxena et al., 2004), singlephoton emission computed tomography (SPECT) (Rubin et al., 1992; Lucey et al., 1997; Crespo-Facorro et al., 1999; Busatto et al., 2000; Alptekin et al., 2001; Lacerda et al., 2003) or functional magnetic resonance imaging (fMRI) (Pujol et al., 1999; Ursu et al., 2003; Viard et al., 2005; Rauch et al., 2007) have observed a relationship between OCD and overactivity in the orbitofrontal cortex, anterior cingulate cortex, caudate nucleus and thalamus. Moreover, some studies have found a positive correlation between frontal cortex hyperactivity during task performance (work generation) and severity of obsessive–compulsive symptomatology (Pujol et al., 1999). Interestingly, some functional neuroimaging studies have reported increased activation of these brain areas during the provocation of obsessive–compulsive symptoms (Rauch et al., 1994; Breiter et al., 1996; Adler et al., 2000; Hendler et al., 2003; Shapira et al., 2003; Mataix-Cols et al., 2004) or during cognitive tasks (Rauch et al., 1997a,b; Pujol et al., 1999; Maltby et al., 2005). Treatment effect on brain activation has mainly been investigated in adult OCD patients. The most replicated finding is the presence of hyperactivity in the orbitofrontal cortex in non-treated patients, which then decreases after pharmacological treatment (Rubin et al., 1995; Saxena et al., 1999, 2002; Kang et al., 2003a). Some authors have reported an inverse relationship between brain activity in these areas and the response to selective serotonin reuptake inhibitors (SSRIs) (Swedo et al., 1992; Brody et al., 1998; Saxena et al., 1999; Rauch et al., 2002). The large majority of functional neuroimaging studies in OCD have been carried-out in adult patients (Friedlander and Desrocher, 2006). Nevertheless, there are two studies using SPECT in paediatric OCD samples. The first attempted to determine the effects of pharmacological treatment on regional cerebral blood flow (rCBF) in children and adolescents. Bilateral caudate, dorsolateral prefrontal and cingulate regions showed significantly higher rCBF in children with OCD than in the control group before treatment. These areas, in addition to the right anteromedial temporal region, showed a significant reduction in rCBF after treatment with paroxetine (Diler et al., 2004). In contrast, Castillo et al. (2005) failed to find a significant difference in rCBF ratios after treatment with clomipramine in 14 OCD patients. There are no studies using fMRI techniques with children and adolescents. Neuroimaging studies have enabled researchers to develop models of the relationship between brain abnormalities and behaviour in order to explain the clinical symptomatology of OCD patients. Saxena et al. (1998, 2001) claimed that obsessive–compulsive symptoms result from a dysfunction of the complex frontal, thalamic and striatal circuitry. Rauch (2003) and Rauch et al. (2007) hypothesize that at a neural circuitry level, primary striatal dysfunction in OCD leads to deficits in thalamic filtering, which in turn leads to exaggerated orbitofrontal cortex

(OFC) activity. At a cognitive neuroscience level, striatal dysfunction underlies implicit information processing deficits, whereas hyperactivity in OFC, without forgetting the limbic–paralimbic regions, mediates the obsessions and anxiety symptoms of OCD. One way of testing cortico-striatal dysfunction in OCD would be to assess patients by means of functional imaging during motor tasks involving the striatal region. The serial reaction time (SRT) task is a paradigm used to assess implicit serial learning (Nissen and Bullemer, 1987) and can be used with fMRI to assess regional brain activation during implicit information processing. The most consistent neuroimaging data from PET and fMRI techniques were reported by Rauch et al. (1997a,b), who observed significant cortico-striatal activation during implicit learning. The aims of the present study were as follows: (1) to investigate possible regional brain dysfunction in premotor cortico-striatal activity in drug-naı¨ve children and adolescents with OCD; (2) to correlate the severity of obsessive–compulsive symptomatology with brain activation; and (3) to detect possible changes in brain activity after pharmacological treatment. 2. Methods 2.1. Subjects Twelve children and adolescents with OCD were consecutively recruited at the Child and Adolescent Psychiatry and Psychology Department of the Hospital Clı´nic of Barcelona. Inclusion criteria for admission to the study were a diagnosis of OCD according to DSM-IV (American Psychiatric Association, 1994), being drug-naı¨ve (without previous psychopharmacological treatment), age between 7 and 18 years (mean = 13.1, SD = 2.7), no current general medical illnesses requiring medication, and normal intelligence. Exclusion criteria were a concurrent diagnosis of known neurological disorder, diagnosis of schizophrenia or affective disorder, attention deficit hyperactivity disorder, learning and writing disabilities, and concurrent eating disorder. For the magnetic resonance imaging (MRI) study patients with claustrophobia or anxiety levels that would have required sedation were excluded (N = 2). Twelve healthy controls were matched to patients by age (mean = 13.7, SD = 2.8, U = 57; p = .410), sex and intelligence quotient. This was estimated from the Vocabulary subtest of the Wechsler Intelligence Scale (11.5 ± 2.5 for OCD patients and 12.0 ± 2.9 for controls; U = 63.5, p = .621): the Vocabulary subtest of the Wechsler Intelligence Scale for Children-Revised (WISC-R) (Wechsler, 1974) for subjects younger than 16.11 years, and the WAIS-III for subjects older than 17 years (Wechsler, 2001). Exclusion criteria for the control group included personal history of neurological and psychiatric disorders. Two controls were excluded from the study for the same reason as the OCD patients. The OCD group comprised five girls and seven boys. All subjects were right-handed.

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The study was approved by the Research Ethics Committee of our institution. All patients, controls and their parents were informed of the study objectives and procedures, and signed, written informed consent agreements were obtained in all cases. Clinical and fMRI examinations were carried out twice, at the time of diagnosis and after 6 months of treatment. At the initial assessment, all the patients were in an acute phase of the disorder. They each received a naturalistic pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) and behavioural counselling. SSRIs were administered in a flexible dosage to achieve treatment response (fluoxetine 20– 60 mg/day). No other pharmacological treatment was used. Control subjects were also assessed twice, at the moment of entering the study and 6 months after the initial evaluation. 2.2. Clinical assessment and data analysis Obsessive–compulsive patients were assessed by an experienced child and adolescent psychiatrist (LL). The semi-structured interview used in our clinical service and the OCD section of the Children’s Interview for Psychiatric Syndromes (ChIPS) (Weller et al., 2000) were administered. Past and current comorbidity were assessed by using the clinical semi-structured interview administered to all patients and their parents. OCD symptom severity was assessed by means of the Children’s Yale-Brown Obsessive–Compulsive Scale (CYBOCS) (Scahill et al., 1997). The Children’s Depression Inventory (CDI) (Kovacs and Beck, 1977) was chosen to measure the severity of depression, and the State-Trait Anxiety Inventory for Children (STAI-C) was used to measure severity of anxiety (Spielberger, 1973). In controls, psychiatric diagnosis was ruled out by means of the same semi-structured interview. Possible obsessive–compulsive symptomatology was assessed by means of the Leyton Obsessive Inventory-Child Version (LOI-CV) (Berg et al., 1986). Depressive and anxiety symptoms were also assessed using the CDI and the STAI-C. For clinical data, statistical analysis was performed using SPSS version 10.0. As the sample was distributed across several variables, non-parametric tests were used. Differences between groups in the means obtained for clinical variables were examined using the Mann–Whitney U test. The Wilcoxon signed rank test was used to compare the means obtained for clinical variables between baseline and follow-up assessment. 2.3. Task Subjects performed a serial reaction time task during fMRI acquisition. Although we selected a task that potentially involves cortico-striatal regions according to the model of OCD developed by Rauch et al. (1997a), we did not use implicit motor learning because of a floor effect detected in a pilot study in young subjects. We applied a

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block design with two conditions: simple and complex sequences. For the activation condition (complex motor sequence), the task consisted of a ball appearing each time in one of four horizontally-arranged boxes. Subjects had to press one of four buttons that spatially corresponded to the box where the ball appeared. For the control condition (simple motor task) the ball appeared following an easy and repetitive sequence. It appeared for the first time in the first square on the left of the screen and progressed to the last square on the right. For the first task the sequence was more difficult since the ball appeared in an unpredictable order. There were four blocks for each condition, each one lasting 32 s. 2.4. fMRI acquisition and analysis Functional magnetic resonance imaging data were obtained on a GE Signa 1.5 T (General Electric, Milwaukee, WI) using a T2 weighted gradient-echo planar imaging sequence (TR = 2000 ms; TE = 40 ms; FOV = 24  24 cm; 64  64 matrix; flip angle of 90°), yielding 20 slices of 5 mm width with an interslice gap of 1.5 mm. Preprocessing and statistical analysis of the fMRI data was carried out using SPM2 software (Statistical Parametric Mapping, The Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College London, UK) running on MATLAB 6.5 (MathWorks, Natick, MA). Images were first realigned in order to correct for motion effects. They were then normalized to MNI (Montreal Neurological Institute) stereotactic space. We used the adult-derived template of the SPM2 because there is evidence that, in the case of functional analyses and for ages similar to those of our sample, functional differences are not significant when comparing adult and child brains, so that it is feasible to use a common space for normalization at these ages (Kang et al., 2003b). Finally, an 8 mm full-width at half-maximum (FWHM) Gaussian kernel was used to smooth the images. For each subject, t-test comparisons were performed in order to identify the cerebral areas showing higher activation during the complex motor sequence than during the simple motor task. These images were used to carry out second-level analyses. One-sample t-tests were used to obtain the brain areas of activation during the complex motor condition in the group of patients and controls separately. These analyses were thresholded at p = 0.05, false discovery rate (FDR) corrected. A twosample t-test was used to determine the differences in activation between patients and controls. A paired t-test was used to compare treatment effects in OCD patients. Simple correlation analyses were used to assess the relationship between brain activation and scores on the CYBOCS. The voxelwise significance threshold for these analyses was set at p = 0.001, uncorrected, for multiple comparisons, with a minimum cluster size of 10 contiguous voxels.

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3. Results 3.1. General characteristics The age of onset of OCD was 11.1 ± 2.7 years and the mean duration of the disease 23.2 ± 16.6 months (3–48). The onset was prepubertal in eight patients and sudden onset was observed in seven patients. No patient had comorbidity at the time of initial assessment (nor ADHD, nor tics disorders, or others) but three patients previously had tics, one had anxiety disorder and another a eating disorder not otherwise specified. Psychopathological variables of OCD patients are shown in Table 1. The OCD categories present in the OCD patients were aggressive, sexual, somatic and religious (n = 2), symmetry, ordering and counting (n = 7), and contamination and cleaning (n = 3), according to the factor analysis of Leckman et al. (1997). All patients improved after 6 months of treatment. Significant differences in obsessive–compulsive and depressive symptomatology and state anxiety were found between initial and follow-up assessment but not in trait anxiety (Table 1). Eight patients achieved remission of disorder (CYBOCS < 10), three of them showed a great improvement (CY-BOCS: 10–19) and one of them improved but with persistence of OCD (CY-BOCS = 20). No psychiatric disorder was detected in the control group at baseline assessment or 6 months later. Mean scores of the self-administered questionnaires were lower than clinical cut-off and are shown in Table 1. Significant differences were found between OCD and control subjects for depressive symptomatology and state and trait anxiety symptoms. 3.2. fRMI results Comparing the complex motor condition with the control condition, both patients and controls showed a bilat-

eral pattern of activation involving the anterior and posterior cortex, as well as basal ganglia, thalamus, and cerebellum; thus, the task activates the basal ganglia (Table 2). As can be seen in the figure, patients showed more bilateral activation in the head of the caudate nucleus than did controls. The statistical comparison between patients and controls before treatment showed a significantly higher brain activation bilaterally in the middle frontal gyrus (Brodmann’s area [BA] 9) (MNI coordinates 26 2 40/ 38 2 34; t = 5.93/0.48; cluster size [k] = 72/52; p < 0.001) in the OCD group compared with controls (Fig. 1). After treatment, patients shower higher activation in a region of the right inferior parietal lobe (BA 40; MNI coordinates 64 36 48; t = 4.67; k = 83; p < 0.001, uncorrected) than controls during the performance of the complex motor task compared to the simple motor task (Fig. 2). No brain areas were more activated in controls than in patients during the complex relative to the simple motor task. Before treatment, the correlation analysis between neuroimaging data and obsessive–compulsive symptomatology showed significant correlations between the level of activation and CY-BOCS score. The CY-BOCS total score was positively correlated with the left nucleus accumbens (MNI coordinates 4 0 2; t = 6.58; k = 15; p < 0.001) and with a region in the superior right parietal lobe (BA 7; MNI coordinates 26 64 64; t = 7.04; k = 14; p < 0.001). The CY-BOCS obsessions subscale was positively correlated with a region in the superior right parietal lobe (BA 7; MNI 28 62 64; t = 10.87, k = 21; p < 0.001) and a region in the left cingulate gyrus (BA 23; MNI coordinates 6 56 24; t = 6.61; k = 69; p < 0.001). The comparison between baseline state and post pharmacological treatment in OCD patients showed significant differences in left insula (MNI coordinates 40 12 14; t = 5.24; k = 35; p < 0.001) and left putamen (MNI coordinates 32 2 16; t = 6.11; k = 52; p < 0.001). Both regions

Table 1 Clinical characteristics of the sample pa

Basal assessment

CY-BOCS Obsessive CY-BOCS Compulsive CY-BOCS Total CDI STAIC-S (PC) STAIC-T (Pc) LOI-CV: severity Interference

pb

Follow-up assessment

OCD group

Control subjects

OCD group

Control subjects

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

11.2 13.2 24.5 12.5 63.0 64.5 – –

– – – 7.8 34.4 26.0 5.6 1.6

3.6 3.7 7.4 8.4 40.7 48.0

– – – 4.5 (2.6) 28.2 (23.7) 12.8 (13.7)

(4.1) (2.5) (4.5) (7.3) (32.8) (25.9)

(2.1) (31.7) (25.3) (1.4) (2.9)

0.009 0.006 0.002

(3.8) (3.5) (7.2) (5.0) (30.0) (24.0)

0.001 0.001 0.001 0.003 0.035 0.293

CY-BOCS: Children’s Yale-Brown Obsessive–compulsive disorder; CDI: Child Depression Inventory; STAIC-S: State-Trait Anxiety Inventory for Children (State); STAIC-T: State-Trait Anxiety Inventory for Children (Trait); LOI-CV: Leyton Obsessive Inventory-Child Version. a Mann–Witney U (OCD group and control subjects). b Wilcoxon test (OCD group, basal and follow-up assessment).

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Table 2 Brain areas showing more activation during the complex motor condition compared to the simple motor condition in patients and controls Region

R middle frontal gyrus L middle frontal gyrus R middle frontal gyrus R medial frontal gyrus L middle frontal gyrus L medial frontal gyrus R superior frontal gyrus L superior frontal gyrus R inferior frontal gyrus R superior temporal gyrus L precentral gyrus L precentral gyrus R superior parietal lobe L superior parietal lobe L inferior parietal lobe R inferior parietal lobe R postcentral gyrus R inferior temporal gyrus R middle temporal gyrus R cingulate gyrus R insula R fusiform gyrus R lingual gyrus L lingual gyrus R precentral gyrus L postcentral gyrus L postcentral gyrus R lingual gyrus R middle occipital gyrus L middle occipital gyrus R inferior occipital gyrus L inferior occipital gyrus L precuneus R cuneus R caudate L caudate R thalamus L thalamus L cerebelum R cerebelum

Patients

Controls

BA

t

p FDR-corrected

6 6 8/9 6

17.46 12.21 11.99 9.72

<0.001 0.008 <0.001 <0.001

8 6 44 22 4 6 7 7 40 40 2 37

37 19 18

19 7

3.11 8.46 3.26 2.76 11.95 9.67 10.12 11.22 11.86 9.42 11.76 9.34

8.98 7.89 7.96

MNI coordinates 36 6 62 28 12 62 28 4 42 8 4 54

0.023 <0.001 0.019 0.034 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

<0.001 0.001 0.001

9.02 7.89

<0.001 0.001

2.68 2.80 4.45 10.74

<0.047 <0.034 <0.019 <0.001

20 48 20 8 50 8 64 36 32 10 40 4 18 74 32 48 30 42 42 34 54 32 60 66

28 20 12

68 80 90

42 8

42 50 12 16 58 38 60 64 60 52 44 8

BA

t

p FDR-corrected

MNI coordinates

6

9.59

0.001

34

4 58

6 6 6 6

7.53 9.02 8.03 6.54

0.002 0.001 0.002 0.003

30 2 8 12 20 2 14 4

7

10.66

0.001

26

62 62

40

14.87

0.001

36

40 46

39 24/32

6.23 6.20 4.59

0.003 0.003 0.008

54 70 2 12 2 50 32 20 14

4/6 40 7 18 39/19 18 18

7.26 3.50 6.66 6.17 10.50 6.46 6.75

0.002 0.022 0.003 0.003 0.001 0.003 0.002

24 12 48 64 22 20 26 48 62 22 72 22 38 70 4 48 70 2 40 86 16

18

7.14

0.002

3.20 4.57 8.59 2.68

<0.04 <0.012 0.002 0.028

42 54 50 64

18 18 26

66 14 76 56

12 2 16 4 12 14 20 30

18 18 12 12

24

90 0

16 22 4 20 4 70 10 48

16 10 30 38

BA, Brodmann area; FDR, false discovery rate; MNI, Montreal Neurological Institute; R, right; L, left.

decreased their activation (Fig. 3). No regions showed more activation related to the complex motor task after treatment than before treatment. No differences were found between the first and second fMRI measurements in the group of controls. 4. Discussion To our knowledge, this is the first functional magnetic resonance imaging study in children and adolescents with OCD. We found that patients showed increased activity in bilateral middle frontal gyrus compared to controls during the performance of a complex motor task before treatment. In both groups, the complex serial reaction time task versus the control task activated a similar network involving anterior and posterior cortex, basal ganglia, thalamus

and cerebellum, but indicated more basal ganglia activation in patients. In general, our findings in children and adolescents agree with studies in adult OCD patients which found increased cerebral activation when compared with healthy subjects. PET studies have reported increased glucose metabolite rates in the left orbital gyrus and bilateral caudate (Baxter et al., 1987), in the left orbital frontal and prefrontal and anterior cingulate regions (Swedo et al., 1989), and bilateral thalamus and caudate nuclei (Saxena et al., 2004). SPECT data also point to increased regional blood flow in the right thalamus, left frontotemporal cortex and bilateral orbitofrontal cortex (Alptekin et al., 2001), as well as in the inferofrontal cortex and thalamus (Lacerda et al., 2003). With fMRI, hyperactivation was found in anterior cingulate cortex (Ursu et al., 2003) and left parietal lobe

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Fig. 1. Increased frontal activation in OCD patients respect to control subjects in serial reaction time task before treatment.

in a study carried-out with young adults with paediatric OCD onset (Viard et al., 2005). Nevertheless, a meta-analysis of resting-state studies found that the only consistent findings were increased metabolism in the orbitofrontal cortex and head of the caudate nucleus in patients compared with controls (Whiteside et al., 2004). During the early phases of motor skill acquisition, increased activity has been reported in the anterior caudate nucleus. This activation may reflect a reinforcement of sensorimotor associations in the prefrontal cortex, which is closely interconnected with the basal ganglia. During the late phase of motor learning, the basal ganglia are likely to be involved in the storage of learned sequences (Halsband and Lange, 2006). Although we used a different paradigm due to the age of subjects, our results agree with the findings of Rauch et al. (1997a) in adults, in that they show dysfunction of cortico-striatal systems in OCD. Rauch et al. hypothesized that OCD patients fail to recruit adequately the striatum, which is normally activated during completion of the SRT task. Instead, OCD patients activated medial temporal regions which are associated with conscious information processing and involved in explicit memory in healthy subjects. OCD patients may use medial temporal networks to compensate for striatal dysfunction (Deckersback et al., 2006). Moreover, our results support their model but with a sample of drug-naı¨ve subjects, thus avoiding the treatment effect. Basal ganglia are known to be highly sensitive to psychopharmacological effects in other psychiatric disorders such as schizophrenia (Dazzan

Fig. 2. Increased brain activation in OCD patients compared to controls in serial reaction time task after treatment.

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Fig. 3. Comparison between pre- and post-treatment in OCD patients. We observed a significant decrease in the activation of the insular cortex and left putamen.

et al., 2005; Massana et al., 2005). Thus, the findings about orbitofrontal-subcortical hyperactivity in children and adolescent OCD patients may be the result of abnormal neuroanatomical development of these structures, or due to a failure of pruning of neuronal connections between them, as would be the case in normal development (Saxena and Rauch, 2000). In the present study, the nucleus accumbens activation in the left hemisphere correlated with severity of the symptoms assessed by the CY-BOCS, and activation in left cingulate gyrus was especially associated with the obsession scale in OCD patients. Both cerebral areas are known to be involved in emotional processes and, therefore, in anxiety, a main symptom of OCD. Structural MRI studies in children and adolescents have reported that striatal volumes are inversely correlated with OCD symptom severity but not with illness duration (Rosenberg et al., 1997). In previous studies with adult samples, metabolism in the right hippocampus, left putamen and right parietal region was associated with severity of obsessive–compulsive symptoms (Kwon et al., 2003). In our study, the hyperactivity of superior right parietal lobe also correlated with severity of disorder. There would thus seem to be a clear relationship between severity of symptomatology and overactivation in different cerebral areas, even if the mechanism underlying this relationship remains unclear. In the present study we also found cerebral activation differences between initial assessment and assessment after

treatment and clinical improvement. OCD patients showed decreased activation in the left insula and left putamen in response to the serial reaction task in comparison with the pretreatment pattern of brain activation. The insula is a region of the paralimbic system that plays a role in mediating emotional states, including anxiety. It is possible that clinical improvement after treatment, and therefore less anxiety, leads to decreased activation in this area. Several functional brain imaging studies in adult OCD patients have provided evidence for symptom-related hyperactivity in the orbitofrontal cortex in OCD that normalizes after treatment (Rubin et al., 1995; Saxena et al., 1999, 2002; Kang et al., 2003a,b). Also, it has reported, after improvement of OCD symptomatology following fluvoxamine or behavioural therapy, a decrease in the previous hyperactivation of the frontal lobe related to a symptom-provocative state (Nakao et al., 2005). Nevertheless, we have not found decreased activity in the frontal cortex after treatment as it has been found in adults OCD studies. The strengths of the present study are, firstly, the young age of subjects, which implies less influence of duration of disorder; secondly, restrictive inclusion and exclusion criteria that made it possible to obtain a more homogeneous group of patients without other psychiatric disorders; and thirdly, none of the patients had ever been exposed to psychotropic drugs prior to imaging. Moreover, we used a voxel-based approach in Statistical Parametric Mapping analysis, in contrast to previous functional imaging studies

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for OCD that have used region-of-interest (ROI) approaches. The main limitation of our study is the small sample size. A larger number of subjects would be required in order to create two groups of patients: prepubertal and adolescents. Another possible limitation concerns the paradigm used, which is not sensitive to the orbitofrontal region; according to structural MRI studies this region is clearly involved in OCD. In conclusion, the present data show hyperactivation of the circuits that mediate symptomatic expression of OCD in a paediatric OCD sample who were treatment naı¨ve and without another psychiatric disorder. This hyperactivation decreases after treatment and symptom improvement. These findings are similar to the results with adult samples. The present study focusing on child and adolescent patients may reduce potential confounds due to long evolution, comorbidity and pharmacological treatments. Conflict of interest All authors declare that they have no conflicts of interest. Funding source Funding for this study was provided by grants from the Marato´ TV3 Foundation (Ref. 2010) and the Spanish Ministry of Health, Instituto de Salud Carlos III, REM-TAP Network (Red de Enfermedades Mentales) (Ref. RD06/ 0011/0006). Acknowledgement The participating patients and control subjects are thanked for valuable help. References American Psychiatric Association. Diagnostic and statistical manual of mental disorders. fourth ed. (DSM-IV). Washington, DC: American Psychiatric Association; 1994. Adler CM, McDonough-Ryan P, Sax KW, Holland SK, Arndt S, Strakowski SM. fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive–compulsive disorder. Journal of Psychiatry Research 2000;34:317–24. Alptekin K, Degirmenci B, Kivircik B, Durak H, Yemez B, Derebek E, et al. Tc-99m HMPAO brain perfusion SPECT in drug-free obsessive– compulsive patients without depression. Psychiatry Research 2001;107:51–6. Baxter LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local cerebral glucose metabolic rates in obsessive–compulsive disorder: a comparison with rates in unipolar depression and in normal controls. Archives of General Psychiatry 1987;44:211–8. Berg CJ, Rapoport JL, Flament M. The Leyton obsessional inventory— child version. Journal of American Academy of Child and Adolescent Psychiatry 1986;25:84–91. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN, et al. Functional magnetic resonance imaging of symptom provocation in obsessive–compulsive disorder. Archives of General Psychiatry 1996;53:595–606.

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