Chaim Huyser

Paediatric obsessive-compulsive disorder, a neurodevelopmental disorder? Evidence from neuroimaging.

OBJECTIVE To present an overview of neuroimaging data on paediatric obsessive-compulsive disorder (OCD) and discuss implications for further research. METHOD Medline PsycINFO databases and reference lists were searched for relevant articles. All neuroimaging studies up to October 1, 2008 involving children and adolescents with obsessive-compulsive disorder were included. RESULTS Twenty-eight neuroimaging studies using various neuroimaging techniques (CT (2) MRI (15) MRS (8) and SPECT (2) fMRI (2) but no PET or DTI) including a total of 462 paediatric patients were identified. A number of findings indicate a dysfunction of the prefrontal-striatal-thalamic circuit with the involvement of other basal ganglia structures (putamen globus pallidus) and the thalamus in contrast to adult studies which report mainly involvement of the caudate nucleus and orbitofrontal cortex. Several findings point at an aberrant development of the brain in paediatric OCD, patients when compared with healthy controls. CONCLUSION Neuroimaging studies have contributed to our understanding of the neurobiological basis of paediatric OCD. This review provides an agenda for further theory driven research in particular aimed at identifying a critical window of abnormal maturation of prefrontal-striatal-thalamic and limbic circuitry in paediatric OCD patients.

Developmental aspects of error and high-conflict-related brain activity in pediatric obsessive-compulsive disorder: a fMRI study with a Flanker task before and after CBT

BACKGROUND Heightened error and conflict monitoring are considered central mechanisms in obsessive-compulsive disorder (OCD) and are associated with anterior cingulate cortex (ACC) function. Pediatric obsessive-compulsive patients provide an opportunity to investigate the development of this area and its associations with psychopathology. METHODS Repeated measures were carried out using functional magnetic resonance imaging (fMRI) during the performance of an interference task, the arrow version of the Flanker paradigm, before and after cognitive-behavioral treatment of 25 medication-free pediatric obsessive-compulsive patients compared with age- and gender-matched healthy controls. RESULTS During error trials compared to correct trials, pediatric OCD patients and controls showed an interaction effect of Group × Time × Age in the ACC and insula. This effect was mainly driven by an increased activation in older OCD subjects, which was also present after treatment. During high-conflict trials compared with low-conflict trials, a Group × Time × Age interaction effect was found in bilateral insula. This effect was driven by an increase of BOLD (blood oxygen level dependent) signal in older OCD patients before but not after treatment. In addition, a Group × Time interaction effect in dorsomedial prefrontal cortex, premotor region and ACC was found. This effect was driven by an increase of BOLD signal in OCD subjects relative to controls over time. CONCLUSIONS Compared to healthy controls, children and adolescents with OCD show increased activation of the ACC during error responses and in bilateral insular cortex during high-conflict tasks, which is age dependent and which is only partially affected by cognitive-behavioral therapy (CBT). Therefore, we suggest that ACC functioning is a vulnerability marker in pediatric OCD, whereas insular dysfunction may be state dependent.

Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis.

OBJECTIVE Structural brain imaging studies in obsessive-compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta- and mega-analyses of data from OCD sites worldwide. METHOD T1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta-analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. RESULTS The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohens d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. CONCLUSIONS The results indicate different patterns of subcortical abnormalities in pediatric and adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Increased orbital frontal gray matter volume after cognitive behavioural therapy in paediatric obsessive compulsive disorder.

Abstract Objectives. Identify differences in regional brain volume between medication-free pediatric OCD patients and controls and examine changes after cognitive behavioural therapy. Methods. We assessed 29 medication-free paediatric OCD patients (Age: M = 13.78 years; SD = 2.58; range 8.2–19.0) and 29 controls, matched on age and gender, with T1-weighted MR scans in a repeated measures, pre-post treatment design. Voxel based morphometry (VBM) following diffeomorphic anatomical registration through exponential lie algebra (DARTEL) was used to test voxel-wise for the effects of diagnosis and treatment on regional gray matter (GM) and white matter (WM) volumes. Results. After cognitive behavioural therapy, orbitofrontal GM and capsula externa WM increased in paediatric OCD relative to controls. In patients, changes in symptom severity (delta CY-BOCS) correlated positively with GM volume in the orbitofrontal cortex after treatment. Furthermore, before treatment, paediatric OCD patients, compared to the controls, showed larger GM volume in left frontal pole and left parietal cortex and larger WM volume in cingulum and corpus callosum. Conclusions. Our findings underscore the involvement of the ventral frontal-striatal circuit in paediatric OCD and the plasticity of this circuit in response to the modulatory effects of CBT. The possible relation to brain development is discussed.

Mandometer treatment not superior to treatment as usual for anorexia nervosa

OBJECTIVE A comparison of the efficacy of a novel treatment method for anorexia nervosa (AN), the Mandometer treatment (MT), with treatment as usual (TAU). METHOD During treatment data were collected to determine weight recovery and outcome as assessed by the Morgan Russell Outcome Assessment Schedule (MROAS). RESULTS After treatment 63% of the MT group and 85% of the TAU group had reached a normal weight level and both MT and TAU showed a good outcome on the MROAS (75 and 71%, respectively). After two years more MT than TAU patients were still in treatment and more MT patients had relapsed. DISCUSSION The outcome for both treatments in our study were similar and comparable with, if not better than outcome data of other AN studies. MT is not superior to TAU in outcome results and in relapse rate during the first two years following admission for AN treatment.

A longitudinal VBM study in paediatric obsessive-compulsive disorder at 2-year follow-up after cognitive behavioural therapy

Abstract Objectives. To identify neurodevelopmental differences in regional brain volume between medication-free paediatric obsessive–compulsive disorder (OCD) patients and controls at 2-year follow-up after cognitive behavioural therapy. Methods. We assessed 17 medication-free paediatric OCD patients (mean age 13.8 years; SD = 2.8; range 8.2–19.0) and 20 controls, matched on age and gender, with T1-weighted MR scans in a repeated measures design at three time points with intervals of 6 months and 2 years. Voxel based morphometry (VBM) was used to test whole brain voxel-wise for the effects of diagnosis and time on regional grey matter (GM) and white matter volumes. Results. GM volume of the orbitofrontal cortex showed a group × time interaction effect, driven by an increase of GM volume over the whole time period in OCD patients and a decrease in controls. When splitting the groups in two age groups (8–12 and 13–19 years) this interaction effect was only seen in the youngest age group. Conclusions. Neuroimaging findings in paediatric OCD after 6 months of CBT in the GM volume of the orbital frontal cortex are still present at 2-year follow-up.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent–child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case–control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive–compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Cortical Abnormalities Associated with Pediatric and Adult Obsessive-Compulsive Disorder: Findings from the Enigma Obsessive-Compulsive Disorder Working Group

OBJECTIVE Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. METHOD T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. RESULTS In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortex and a thinner inferior parietal cortex. Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showed significant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohens d effect sizes varied from -0.10 to -0.33. CONCLUSIONS The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

Long-term effects of cognitive behavioural therapy on planning and prefrontal cortex function in pediatric obsessive-compulsive disorder

Introduction Half of all patients with obsessive compulsive disorder (OCD) have their disease onset in childhood and adolescence of which up to 40 percent shows persistence of symptoms into adulthood [1]. In addition to their clinical symptoms, patients also show an underperformance in neurocognitive functioning that may hamper the efficacy of cognitive behavioral therapy (CBT) [2]. Previous studies showed changes after CBT in prefrontal cortex function and cognitive performance in pediatric OCD [3]. It remains unknown whether these changes are short lasting or persistent during a period of brain maturation. Here, we investigated the long-term effects of CBT on planning performance and brain function in pediatric OCD using a longitudinal design. Methods Fifteen pediatric OCD patients and sixteen matched healthy controls ranging from the ages of 8-18 years performed the Tower of London planning paradigm during functional magnetic resonance imaging (fMRI) at three time points; before treatment, after 16 sessions of CBT and after two years of naturalistic follow up. The task consisted of six conditions: a baseline condition and five planning conditions with increasing difficulty. Weighted contrasts for each subject for the effect of all planning moves versus baseline and for the linear effect of the increasing task load were computed. Voxel-wise statistical tests were family wise error (FWE) rate corrected (P Results Pediatric OCD patients performed the planning task significantly slower than healthy controls at baseline (pre-treatment), but with the same accuracy. After two years of follow up, reaction times were at the level of healthy controls. Imaging results at baseline showed that increasing task difficulty was associated with stronger recruitment of the left inferior frontal gyrus, middle frontal gyrus and anterior insula in patients than controls. With increasing age, activity in the left insula and right cingulum decreases, opposed to increasing activity in the parietal lobe. Normalization of the anterior insula and inferior frontal gyrus that occurred shortly after CBT continued during the two-year follow-up. Conclusion Pediatric OCD patients showed longer reaction times and additional recruitment of frontal brain regions during planning complexity compared with healthy controls. These differences tended to normalize after CBT and the process continued during two years of follow-up. This longitudinal study shows long-lasting changes in cognitive performance and prefrontal cortex function after CBT during a period of ongoing brain maturation. In addition, the temporary effects of this longitudinal study suggest that modest planning dysfunction in pediatric OCD is a state rather than a trait characteristic of the disorder.

NEUROIMAGING OF SUBCORTICAL BRAIN VOLUME ALTERATIONS IN PEADIATRIC AND ADULT OBSESSIVE-COMPULSIVE DISORDER: Preliminary findings from the ENIGMA Obsessive-Compulsive Disorder working group

Objective Structural MRI studies investigating the neural correlates of OCD have been numerous. Nevertheless, results of these studies have not always been consistent. Variability in study results may partially be explained by small sample sizes resulting in limited statistical power, clinical heterogeneity between patient samples, and methodological differences between studies. In this context, we initiated the ENIGMA-OCD working group. Our aim is to identify robust imaging markers of OCD using coordinated standardized image processing and statistical analysis protocols. Here, we perform the largest study to date of subcortical brain volumes in OCD patients and healthy controls using an individual participant data (IPD) based meta-analysis approach. Methods Structural T1-weightred MRI scans from 3722 subjects (361 paediatric OCD patients, 1574 adult OCD patients, 314 paediatric controls and 1473 adult controls) from 25 research sites worldwide were analysed using FreeSurfer 5.3. Segmentations of subcortical regions, lateral ventricles and total intracranial volumes (ICV) were visually inspected for accuracy and compared between patients and controls using regression models controlling for age, sex, and ICV. Each site followed standardized protocols designed to facilitate harmonized image analysis across multiple sites. Separate stratified analyses assessing effects of age of onset, disease duration, symptom dimensions, and symptom severity were performed. Results were combined in random-effects meta-analysis models. Meta-regression analyses were used to test whether mean age of each sample and field strength of MR images explained a significant proportion of the variance in effect seizes across sites in the meta-analysis. Results were considered significant if they exceeded a Bonferroni corrected P-value threshold (p=0.05/9 regions = 5.6x10-3). Results Adult patients, compared to adult controls, had significantly smaller hippocampal volumes (Cohen’s d= -0.15, p= 7.4x10-4) and bigger pallidum volumes (d= 0.16, p=1.8x10-3). This effect was notably stronger in medicated patients versus controls (d= -0.29, p=2.8x10-6 and d= 0.24, p=2.5x10-4, respectively). The hippocampus effect seemed to be driven by patients with comorbid depression d= 0.29, p=4.8x10-5). Also, symptom severity was associated with a smaller hippocampus (R= -0.08, p=4.9x10-3). Sample characteristics such as mean age and field strength did not moderate brain volume alterations. None of the subcortical structures, neither ICV nor lateral ventricles were significantly different between paediatric OCD cases and controls after Bonferroni correction. However, unmedicated paediatric patients show bigger thalamus volumes (d= 0.40, p=9.0x10-4) relative to control children. Additionally, longer disease duration and ad trend-significant level, younger age of onset was associated with bigger thalamus volume in paediatric OCD (d= 0.18, p=5.1x10-3 and d= -0.17, p=5.7x10-3, respectively). Conclusion Results of this subcortical meta-analysis indicate a key role of the pallidum in the pathophysiology of OCD. Different ENIGMA disease working groups, such as MDD, schizophrenia, and bipolar disorder also observed hippocampal abnormalities, which suggests that our findings regarding hippocampal abnormalities are aspecific for OCD. In addition, we showed that unmedicated paediatric OCD patients have significantly enlarged thalamus volumes. Moreover, our findings suggest a different pattern of subcortical abnormalities in paediatric OCD patients and adult OCD patients in line with the developmental nature of the disease.