BACKGROUND:Although subtle differences in cortico-striato-thalamo-cortical circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. METHODS:We conducted a mega-analysis of individual-participant data on cerebellar subregional volumes, comparing individuals with OCD and healthy controls (HCs) from the ENIGMA-OCD Working Group. Three-dimensional T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1954 individuals with OCD and 2091 HCs across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-17 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume. RESULTS:In adults with OCD (vs. HCs), we found significantly smaller volumes of the corpus medullare (d = -0.093, false discovery rate (FDR)-corrected p = .036), left VIIb (d = -0.085, pFDR = .039) and right VIIb (d = -0.091, pFDR = .036). None of the comparisons between children or adolescents with OCD versus HCs remained statistically significant after FDR correction. In all 3 age groups, cerebellar (subregional) volumes were significantly moderated by medication status. CONCLUSIONS:We report novel findings implicating specific cerebellar subregions across developmental stages of OCD and the key impact of medication status. Additional research on the functional significance of these findings may offer new translational leads.

Objective:Alterations in autonomic nervous system activity - measured by heart rate variability (HRV) and heart rate (HR) - have been proposed as a relevant biopsychological mechanism in several psychiatric disorders. However, only few studies have examined these parameters in OCD, and evidence from pediatric samples is particularly limited. The aim of this study was to investigate autonomic activity in pediatric OCD. Methods:A five minute resting state electrocardiogram was recorded in adolescents with OCD (n = 64) and age- and IQ-matched healthy controls (HC, n = 52). Autonomic activity was compared using the logarithmized root mean square of differences between successive R-R intervals (logRMSSD), the logarithmized high-frequency HRV (logHF-HRV), the percentage of adjacent NN intervals differing from each other by more than 50 ms (pNN50) and HR. Associations with psychotropic medication status and symptom severity were assessed. Results:Adolescents with OCD showed lower logRMSSD and higher HR than HC, whereas logHF-HRV and pNN50 did not differ between groups. No associations were found between cardiac measures and OCD symptom severity. Exploratory subgroup analyses suggested lower logHF-HRV and logRMSSD in medicated adolescents with OCD. Conclusions:Our findings add to evidence for altered autonomic activity in pediatric OCD, reflected by elevated HR and lower RMSSD. The observed reduction in HRV did not increase with greater symptom severity and appeared most pronounced among medicated adolescents with OCD. Significance:The autonomic imbalance observable in adolescents with OCD is common across anxiety disorders and has been linked to cardiovascular risk.

BACKGROUND:Obsessive-compulsive disorder (OCD) is characterized by persistent, unwanted thoughts and repetitive actions. Such repetitive thoughts and/or behaviors may be reinforced either by reducing anxiety or by avoiding a potential threat or harm, and thus may be rewarding to the individual. The possible involvement of the reward system in the symptomatology of OCD is supported by studies showing altered reward processing in reward-related regions, such as the ventral striatum (VS) and the orbitofrontal cortex (OFC), in adults with OCD. However, it is not clear whether this also applies to adolescents with OCD. METHODS:Using functional magnetic resonance imaging, two sessions were conducted focusing on the anticipation and receipt of monetary reward (1) or loss (2), each contrasted to a verbal (control) condition. In each session, adolescents with OCD (n1=31/n2=26) were compared with typically developing (TD) controls (n1=33/ n2=31), all aged 10-19 years, during the anticipation and feedback phase of an adapted Monetary Incentive Delay task. RESULTS:Data revealed a hyperactivation of the VS, but not the OFC, when anticipating both monetary reward and loss in the OCD compared to the TD group. CONCLUSIONS:These findings suggest that aberrant neural reward and loss processing in OCD is associated with greater motivation to gain or maintain a reward but not with the actual receipt. The greater degree of reward 'wanting' may contribute to adolescents with OCD repeating certain actions more and more frequently, which then become habits (i.e., OCD symptomatology).

Adolescent subcortical structural brain development might underlie psychopathological symptoms, which often emerge in adolescence. At the same time, sex differences exist in psychopathology, which might be mirrored in underlying sex differences in structural development. However, previous studies showed inconsistencies in subcortical trajectories and potential sex differences. Therefore, we aimed to investigate the subcortical structural trajectories and their sex differences across adolescence using for the first time a single cohort design, the same quality control procedure, software and a general additive mixed modeling approach. We investigated two large European sites from ages 14 to 24 with 503 participants and 1408 total scans from France and Germany as part of the IMAGEN project including four waves of data acquisition. We found significantly larger volumes in males versus females in both sites and across all seven subcortical regions. Sex differences in age-related trajectories were observed across all regions in both sites. Our findings provide further evidence of sex differences in longitudinal adolescent brain development of subcortical regions and thus might eventually support the relationship of underlying brain development and different adolescent psychopathology in boys and girls.

OBJECTIVE:Obsessive-compulsive disorder (OCD) is associated with altered brain function related to processing of negative emotions. To investigate neural correlates of negative valence in OCD, we pooled functional magnetic resonance imaging data of 633 individuals with OCD and 453 healthy control participants from 16 studies using different negatively valenced tasks across the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium's OCD Working Group. METHODS:Participant data were processed uniformly using HALFpipe, to extract voxelwise participant-level statistical images of one common first-level contrast: negative versus neutral stimuli. In preregistered analyses, parameter estimates were entered into Bayesian multilevel models to examine whole-brain and regional effects of OCD and its clinically relevant features-symptom severity, age of onset, and medication status. RESULTS:We provided a proof of concept that participant-level data can be combined across several task paradigms and observed one common task activation pattern across individuals with OCD and control participants that encompasses frontolimbic and visual areas implicated in negative valence. Compared with control participants, individuals with OCD showed very strong evidence of weaker activation of the bilateral occipital cortex (P+ < 0.001) and adjacent visual processing regions during negative valence processing that was related to greater OCD severity, late onset of the disorder, and an unmedicated status. Individuals with OCD also showed stronger activation in the orbitofrontal, subgenual anterior cingulate, and ventromedial prefrontal cortex (all P+ < 0.1) that was related to greater OCD severity and late onset. CONCLUSIONS:In the first mega-analysis of this kind, we replicated previous findings of stronger ventral prefrontal activation in OCD during negative valence processing and highlight the lateral occipital cortex as an important region implicated in altered negative valence processing.

(1) Background: 1–2% of children and adolescents are affected by Obsessive-Compulsive Disorder (OCD). The rigid, repetitive features of OCD and an assumed disability to inhibit recent mental representations are assumed to have led to a paradoxical advantage in that the Backward Inhibition (BI) effect was recently found to be lower in adolescents with OCD as compared to healthy controls. It was hypothesized that app-based mindfulness meditation training could reduce the disability to inhibit recent mental representations and thus increase the BI-effect by adapting cognitive flexibility and inhibition abilities according to healthy controls. (2) Methods: 58 adolescents (10–19 years) with OCD were included in the final sample of this interviewer-blind, randomized controlled study. Participants were allocated to an intervention group (app-based mindfulness meditation training) or an (active) control group (app-based audiobook) for eight weeks. Symptom (CY-BOCS), behavioral (reaction times and mean accuracy), and neurophysiological changes (in EEG) of the BI-effect were analyzed in a pre-post design. (3) Results: The intervention and the control group showed an intervention effect (Reliable Change Index: 67%) with a significant symptom reduction. Contrary to the hypothesis, the BI-effect did not differ between pre vs. post app-based mindfulness meditation training. In addition, as expected the audiobook application showed no effects. Thus, we observed no intervention-specific differences with respect to behavioral (reaction times and mean accuracy) or with respect to neurophysiological (perceptual [P1], attentional [N1], conflict monitoring [N2] or updating and response selection [P3]) processes. However, in an exploratory approach, we revealed that the BI-effect decreased in participants who did not benefit from using an app, regardless of group. (4) Conclusions: Both listening to an app-based mindfulness meditation training and to an audiobook reduce symptom severity in adolescent OCD as measured by the CY-BOCS; however, they have no specific effect on BI. The extent of the baseline BI-effect might be considered as an intra-individual component to predict the benefit of both mindfulness meditation training and listening to an audiobook.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Abstract Background Early negative life events (NLE) have long‐lasting influences on neurodevelopment and psychopathology. Reduced orbitofrontal cortex (OFC) thickness was frequently associated with NLE and depressive symptoms. OFC thinning might mediate the effect of NLE on depressive symptoms, although few longitudinal studies exist. Using a complete longitudinal design with four time points, we examined whether NLE during childhood and early adolescence predict depressive symptoms in young adulthood through accelerated OFC thinning across adolescence. Methods We acquired structural MRI from 321 participants at two sites across four time points from ages 14 to 22. We measured NLE with the Life Events Questionnaire at the first time point and depressive symptoms with the Center for Epidemiologic Studies Depression Scale at the fourth time point. Modeling latent growth curves, we tested whether OFC thinning mediates the effect of NLE on depressive symptoms. Results A higher burden of NLE, a thicker OFC at the age of 14, and an accelerated OFC thinning across adolescence predicted young adults' depressive symptoms. We did not identify an effect of NLE on OFC thickness nor OFC thickness mediating effects of NLE on depressive symptoms. Conclusions Using a complete longitudinal design with four waves, we show that NLE in childhood and early adolescence predict depressive symptoms in the long term. Results indicate that an accelerated OFC thinning may precede depressive symptoms. Assessment of early additionally to acute NLEs and neurodevelopment may be warranted in clinical settings to identify risk factors for depression.

We investigated development from adolescence to young adulthood of neural bottom-up and top-down processes using a functional magnetic resonance imaging task on emotional attention. We followed 249 participants from age 14-22 in up to four waves resulting in 687 total scans of a matching task in which participants decided whether two pictures were the same including distracting emotional or neutral scenes. We applied generalized additive mixed models and a reliability approach for longitudinal analysis. Reaction times and error rates decreased longitudinally. For top-down processing, we found a longitudinal increase for the bilateral inferior frontal gyrus (IFG) for negative stimuli and in the left IFG also for positive and neutral stimuli. For bottom-up activation in the bilateral amygdala, we found a relative stability for negative and neutral stimuli. For positive stimuli, there was an increase starting in the twenties. Results show ongoing behavioral and top-down prefrontal development relatively independent from emotional valence. Amygdala bottom-up activation remained stable except for positive stimuli. Current findings add to the sparse literature on longitudinal top-down and bottom-up development into young adulthood and emphasize the role of reliability. These findings might help to characterize healthy in contrast to dysfunctional development of emotional attention.

Structural magnetic resonance imaging (sMRI) offers immense potential for increasing our understanding of how anatomical brain development relates to clinical symptoms and functioning in neurodevelopmental disorders. Clinical developmental sMRI may help identify neurobiological risk factors or markers that may ultimately assist in diagnosis and treatment. However, researchers and clinicians aiming to conduct sMRI studies of neurodevelopmental disorders face several methodological challenges. This review offers hands-on guidelines for clinical developmental sMRI. First, we present brain morphometry metrics and review evidence on typical developmental trajectories throughout adolescence, together with atypical trajectories in selected neurodevelopmental disorders. Next, we discuss challenges and good scientific practices in study design, image acquisition and analysis, and recent options to implement quality control. Finally, we discuss choices related to statistical analysis and interpretation of results. We call for greater completeness and transparency in the reporting of methods to advance understanding of structural brain alterations in neurodevelopmental disorders.

Structural magnetic resonance imaging (sMRI) offers immense potential for increasing our understanding of how anatomical brain development relates to clinical symptoms of neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD). Clinical developmental sMRI may help identify neurobiological risk factors or markers that may ultimately assist in diagnosis and treatment. However, researchers and clinicians aiming to conduct clinical developmental sMRI studies face several methodological challenges. This review offers hands-on guidelines for clinical developmental sMRI. First, we present brain morphometry metrics and review evidence on typical developmental trajectories throughout adolescence, together with atypical trajectories in ADHD, CD, and ODD. Next, we discuss challenges and good scientific practices in study design, image acquisition and analysis, and recent options to implement quality control. Finally, we discuss the impact of choices on statistical analysis and interpretation of results. We call for greater completeness and transparency in methods reports to advance understanding of brain structural alterations in neurodevelopmental disorders.

About 50% of ADHD patients suffer from comorbidity with oppositional defiant disorder/conduct disorder (ODD/CD). Most previous studies on structural morphology did not differentiate between pure ADHD (ADHD-only) and ADHD with comorbid ODD/CD (ADHD+ODD/CD) and only focused on specific measures (e.g. volumetric differences), leading to inconsistent results. Therefore, we aimed to investigate the structural profile of ADHD-only versus ADHD+ODD/CD spanning different indices, i.e. subcortical and cortical volume, cortical thickness, and surface area. We aimed to disentangle disorder-specific etiological contributions regarding structural brain alterations and expected similar and differential alterations between the patient groups. We acquired structural images from an adolescent sample range (11 to 17 years) matched with regard to age, pubertal status, and IQ - including 36 boys with ADHD-only, 26 boys with ADHD+ODD/CD, and 30 typically developing boys (TD). We analyzed subcortical and cortical volume, cortical thickness, and surface area with FreeSurfer. We found reductions in total gray matter and right cerebellar volume as well as total surface area for both patient groups. For the left cerebellar volume ADHD+ODD/CD, but not ADHD only differed from TD. Boys with ADHD+ODD/CD had a thicker cortex than the other groups in a right rostral middle frontal cluster, which was related to stronger ODD/CD symptoms, even when controlling for ADHD symptoms. No group differences in local cortical volume or surface area emerged. Overall, we found similarities but also differences in brain morphology between the two related disorders. Patients with a “double burden” seem to be even more affected than patients with pure ADHD.

Patients with attention deficit hyperactivity disorder (ADHD) suffer from poor emotion regulation that might arise from problems in the distribution of attentional resources when confronted with emotional distractors. Previous studies investigating the neurocognitive basis of these problems remain inconclusive. Moreover, most of these studies did not exclude participants with comorbidity, particularly of conduct or oppositional defiant disorder. The aim of this study was to assess alterations in fronto-limbic activation in ADHD adolescents specifically during negative distractors in an emotional attention task. For this purpose, we used functional magnetic resonance imaging to assess 25 boys with noncomorbid ADHD and 25 typically developing (TD) boys while they performed an emotional attention task with positive, negative, and neutral emotional distractors. Boys with ADHD had increased activation relative to TD boys specifically during the negative valenced stimuli in an emotional processing network comprising left anterior insula reaching into the inferior frontal gyrus. The findings suggest altered salience processing in ADHD of negative valenced emotional stimuli that may lead to higher distractibility in ADHD specifically when faced with negative emotional distractors.

In structural magnetic resonance imaging motion artifacts are common, especially when not scanning healthy young adults. It has been shown that motion affects the analysis with automated image-processing techniques (e.g. FreeSurfer). This can bias results. Several developmental and adult studies have found reduced volume and thickness of gray matter due to motion artifacts. Thus, quality control is necessary in order to ensure an acceptable level of quality and to define exclusion criteria of images (i.e. determine participants with most severe artifacts). However, information about the quality control workflow and image exclusion procedure is largely lacking in the current literature and the existing rating systems differ. Here we propose a stringent workflow of quality control steps during and after acquisition of T1-weighted images, which enables researchers dealing with populations that are typically affected by motion artifacts to enhance data quality and maximize sample sizes. As an underlying aim we established a thorough quality control rating system for T1-weighted images and applied it to the analysis of developmental clinical data using the automated processing pipeline FreeSurfer. This hands-on workflow and quality control rating system will aid researchers in minimizing motion artifacts in the final data set, and therefore enhance the quality of structural magnetic resonance imaging studies.