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 disease profile and developmental stage.Methods-To address these limitations, we conducted a meta-and mega-analysis of data from OCD sites worldwide. T 1 images from 1,830 OCD patients and 1,759 controls were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ in OCD patients and healthy controls. We 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 (Cohen's d=−0.13; p=5.1x10 −3 , % difference −2.80) and larger pallidum volumes (d=0.16; p=1.6x10 −3 , % difference 3.16) compared to adult controls. Both effects were stronger in medicated patients compared to controls (d=−0.29; p=2.4x10 −5 , % difference −4.18 and d=0.29; p=1.2x10 −5 , % difference 4.38, respectively). Unmedicated pediatric patients had larger thalamic volumes (d=0.38, p=2.1x10 −3 ) compared to pediatric controls. None of these findings were mediated by sample characteristics such as mean age or field strength. Overall the mega-analysis yielded similar results. Conclusion-Our study indicates a different pattern of subcortical abnormalities in pediatric versus 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. This highlights the potential importance of neurodevelopmental alterations in OCD, and suggests that further research on neuroplasticity in OCD may be useful. IntroductionObsessive-compulsive disorder (OCD) is a neurodevelopmental disorder that affects 1-3% of the population (1; 2). In more than 50% of all OCD cases, symptoms emerge during Location of work and address for reprints: Premika S.W. Boedhoe, M.Sc.,

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.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s11682-016-9629-z) contains supplementary material, which is available to authorized users.

These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.