Search

Introduction: Repetitive negative thinking (RNT) is a cognitive process focusing on self-relevant and negative experiences, leading to a poor prognosis of major depressive disorder (MDD). We previously identified that connectivity between the precuneus/posterior cingulate cortex (PCC) and right temporoparietal junction (rTPJ) was positively correlated with levels of RNT. Objective: In this double-blind, randomized, sham-controlled, proof-of-concept trial, we employed real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) to delineate the neural processes that may be causally linked to RNT and could potentially become treatment targets for MDD. Methods: MDD-affected individuals were assigned to either active (n = 20) or sham feedback group (n = 19). RNT was measured by the Ruminative Response Scale-brooding subscale (RRS-B) before and 1 week after the intervention. Results: Individuals in the active but not in the sham group showed a significant reduction in the RRS-B; however, a greater reduction in the PCC-rTPJ connectivity was unrelated to a greater reduction in the RRS-B. Exploratory analyses revealed that a greater reduction in the retrosplenial cortex (RSC)-rTPJ connectivity yielded a more pronounced reduction in the RRS-B in the active but not in the sham group. Conclusions: RtfMRI-nf was effective in reducing RNT. Considering the underlying mechanism of rtfMIR-nf, the RSC and rTPJ could be part of a network (i.e., default mode network) that might collectively affect the intensity of RNT. Understanding the relationship between the functional organization of targeted neural changes and clinical metrics, such as RNT, has the potential to guide the development of mechanism-based treatment of MDD.

Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6–65) was divided into six successive 6–10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6–13 and adults aged 50–65 with OCD taking SRIs (Cohen's d = −0.24 to −0.74). Volumes of putamen, pallidum (d = 0.18–0.40), and ventricles (d = 0.31–0.66) were greater in patients aged 20–29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = −0.27 to −1.31). Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20–29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Objective: Cognitive-behavioral therapy (CBT) is considered a first-line treatment for obsessive-compulsive disorder (OCD) in pediatric and adult populations. Nevertheless, some patients show partial or null response. The identification of predictors of CBT response may improve clinical management of patients with OCD. Here, we aimed to identify structural magnetic resonance imaging (MRI) predictors of CBT response in 2 large series of children and adults with OCD from the worldwide ENIGMA-OCD consortium. Method: Data from 16 datasets from 13 international sites were included in the study. We assessed which variations in baseline cortical thickness, cortical surface area, and subcortical volume predicted response to CBT (percentage of baseline to post-treatment symptom reduction) in 2 samples totaling 168 children and adolescents (age range 5-17.5 years) and 318 adult patients (age range 18-63 years) with OCD. Mixed linear models with random intercept were used to account for potential cross-site differences in imaging values. Results: Significant results were observed exclusively in the pediatric sample. Right prefrontal cortex thickness was positively associated with the percentage of CBT response. In a post hoc analysis, we observed that the specific changes accounting for this relationship were a higher thickness of the frontal pole and the rostral middle frontal gyrus. We observed no significant effects of age, sex, or medication on our findings. Conclusion: Higher cortical thickness in specific right prefrontal cortex regions may be important for CBT response in children with OCD. Our findings suggest that the right prefrontal cortex plays a relevant role in the mechanisms of action of CBT in children.

While much research has highlighted phenotypic heterogeneity in obsessive compulsive disorder (OCD), less work has focused on heterogeneity in neural activity. Conventional neuroimaging approaches rely on group averages that assume homogenous patient populations. If subgroups are present, these approaches can increase variability and can lead to discrepancies in the literature. They can also obscure differences between various subgroups. To address this issue, we used unsupervised machine learning to identify subgroup clusters of patients with OCD who were assessed by task-based fMRI. We predominantly focused on activation of cognitive control and performance monitoring neurocircuits, including three large-scale brain networks that have been implicated in OCD (the frontoparietal network, cingulo-opercular network, and default mode network). Participants were patients with OCD (n = 128) that included both adults (ages 24-45) and adolescents (ages 12-17), as well as unaffected controls (n = 64). Neural assessments included tests of cognitive interference and error processing. We found three patient clusters, reflecting a "normative" cluster that shared a brain activation pattern with unaffected controls (65.9% of clinical participants), as well as an "interference hyperactivity" cluster (15.2% of clinical participants) and an "error hyperactivity" cluster (18.9% of clinical participants). We also related these clusters to demographic and clinical correlates. After post-hoc correction for false discovery rates, the interference hyperactivity cluster showed significantly longer reaction times than the other patient clusters, but no other between-cluster differences in covariates were detected. These findings increase precision in patient characterization, reframe prior neurobehavioral research in OCD, and provide a starting point for neuroimaging-guided treatment selection.

OBJECTIVE To assess the degree to which heavy menstrual bleeding is associated with depression, independent of hormonal contraception. STUDY DESIGN We performed a retrospective cohort study of 1168 female adolescents 9-18 years old presenting to general pediatricians for heavy menstrual bleeding or well visits. Depression was the primary outcome and defined as a diagnosis in the health record. Univariable and multivariable regression models were fit to the data to identify factors associated with depression diagnosis. RESULTS In total, 581 adolescents with heavy menstrual bleeding and 587 without heavy menstrual bleeding were included. Depression diagnoses occurred with greater frequency in youth with heavy menstrual bleeding compared with those without heavy menstrual bleeding (50.9% vs 24.2% P

Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response.Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated).ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group.The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.

BackgroundPrior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal–striatal–thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset.MethodsIn this study, unmedicated female patients with OCD (ages 8–21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN.ResultsFunctional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other.ConclusionsOur findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Childhood internalizing disorders, like anxiety and depression, are common, impairing, and difficult to detect. Universal childhood mental health screening has been recommended, but new technologies are needed to provide objective detection. Instrumented mood induction tasks, designed to press children for specific behavioral responses, have emerged as means for detecting childhood internalizing psychopathology. In our previous work, we leveraged machine learning to identify digital phenotypes of childhood internalizing psychopathology from movement and voice data collected during negative valence tasks (pressing for anxiety and fear). In this work, we develop a digital phenotype for childhood internalizing disorders based on wearable inertial sensor data recorded from a Positive Valence task during which a child plays with bubbles. We find that a phenotype derived from features that capture reward responsiveness is able to accurately detect children with underlying internalizing psychopathology (AUC = 0.81). In so doing, we explore the impact of a variety of feature sets computed from wearable sensors deployed to two body locations on phenotype performance across two phases of the task. We further consider this novel digital phenotype in the context of our previous Negative Valence digital phenotypes and find that each task brings unique information to the problem of detecting childhood internalizing psychopathology, capturing different problems and disorder subtypes. Collectively, these results provide preliminary evidence for a mood induction task battery to develop a novel diagnostic for childhood internalizing disorders.

Maternal depression is a robust risk factor for heightened internalizing symptoms in offspring. Studies also suggest that maternal depression is associated with greater maternal emotion regulation (ER) difficulties. However, emotion regulation has been conceptualized as a multidimensional construct, and few studies have identified specific components of ER related to maternal depression and the role these components may play in the relationship between maternal depression and child internalizing symptoms. Mothers (n = 73) of young children (ages 4–9; 42 females), recruited from both clinical and community settings, reported their depression symptoms and emotion regulation difficulties. Children’s internalizing symptoms were assessed using both parental report and a semi-structured clinical interview. Regression analyses revealed that maternal depression symptoms were positively related to maternal ER, specifically, limited access to emotion regulation strategies and non-acceptance of emotional responses. Structural equation models revealed that the relation between maternal depression and child internalizing problems was mediated only through mother’s limited access to emotion regulation strategies. Our findings offer new insight for targeting mothers’ limited access to emotion strategies as a novel early intervention method to help break the intergenerational transmission of internalizing symptoms from mother to child.

OBJECTIVE: The relative contribution of individual cognitive behavioral therapy (CBT) components to treatment outcomes for child anxiety disorders (CADs) is unclear. Recent meta-analyses suggest that exposure may be the primary active ingredient in CBT for CADs, and that relaxation may be relatively less effective. This brief report tests the hypothesis that exposure-focused CBT (EF-CBT) would outperform a relaxation-based active therapy control (Relaxation Mentorship Training; RMT) for the treatment of CADs. METHOD: Participants were 102 youth with CADs (mean age=11.91, 26 males; 76.4% White, 14.7% Multiracial, 3.9% Black, 3.9% Asian, 0.9% other/do not wish to identify) as part of an ongoing neuroimaging randomized controlled trial. Participants were randomly assigned (ratio 2:1) to receive 12 sessions of EF-CBT (n=70) or RMT (n=32). Clinical improvement was measured at Week 12 (Clinical Global Impression – Improvement scale; CGI-I); treatment response was defined as receiving a rating of ‘very much’ or ‘much improved’ on the CGI-I. Anxiety severity was measured at Weeks 1, 6, 9, 12 (Pediatric Anxiety Rating Scale; PARS). Outcome measures were completed by an independent evaluator unaware of condition. RESULTS: EF-CBT exhibited 2.98 times higher odds of treatment completion than RMT; 13 treatment non-completers were included in analyses. Estimated treatment response rates were higher for EF-CBT (57.3%) than for RMT (19.2%). Longitudinal analyses indicated that EF-CBT was associated with faster and more pronounced anxiety reductions than RMT on the PARS (Hedges’ g=.77). CONCLUSIONS: Results suggest that EF-CBT without relaxation is effective for CADs, and more effective than a relaxation-based intervention.

BACKGROUND. Childhood obsessive-compulsive symptoms (OCS) are common and can be an early risk marker for Obsessive-Compulsive Disorder (OCD). The Adolescent Brain and Cognitive Development (ABCD) Study provides a unique opportunity to characterize OCS in a large, normative sample of school-age children and to explore cortico-striatal and task-control circuits implicated in pediatric OCD. METHOD. The ABCD Study acquired data from 9–10-year-olds (N=11,876). Linear mixed-effects models probed associations between OCS (Child Behavior Checklist) and cognition (NIH Toolbox), brain structure (subcortical volume, cortical thickness), white matter (diffusion tensor imaging), and resting-state functional connectivity. RESULTS. OCS scores showed good psychometric properties, high prevalence, and related to familial/parental factors, including family conflict. Higher OCS related to better cognitive performance (b=0.06, t(9966.60)=6.28, p

A putative biomarker of anxiety risk, the startle response is typically enhanced by negative compared to neutral emotion modulation in adults, but remains understudied in children. To determine the extent to which neutral, negative, and positively valenced emotional conditions modulate startle response in early life, a child-friendly film paradigm was used to vary emotion across these conditions during startle induction in sixty-four 4- to 7-year-old children. Association of emotion-modulated startle with parent-reported anxiety symptom severity and child behavioral inhibition, a risk factor for anxiety problems, were assessed. Analyses revealed no difference in startle magnitude during negative compared to neutral film clips. By contrast, startle during both negative and neutral conditions was greater than startle during the positive condition. Larger startle magnitude during the neutral condition associated with higher levels of child behavioral inhibition (BI). These results are consistent with possible immaturity of startle response in young children, and suggest that startle amplitude in more emotionally ambiguous, neutral conditions could serve as an early biomarker for anxiety risk.

Underdeveloped cognitive control (CC)-the capacity to flexibly adjust to changing environments-may predispose some children to early onset anxiety disorders and represents a promising intervention target. The current study established and pilot-tested "Camp Kidpower"-a novel group-based, interactive CC training intervention-and assessed its impacts on behavioral and neurophysiological indices of CC among preschool children with elevated anxiety symptoms.Forty-four anxious children (4-6 years) were enrolled in Camp Kidpower, delivered in four sessions over 10 days. Before and after camp, children's capacity for CC was measured using well-validated, non-trained behavioral tasks and error-related negativity (ERN). Child anxiety symptoms were measured by parent report on the Spence Preschool Anxiety Scale.Thirty-two children completed the study, as defined by completion of pre- and follow-up assessments and at least three camp sessions. From baseline to after camp, performance on behavioral tests of CC improved, ERN amplitude increased, and anxiety symptoms decreased.Results provide initial evidence that play-based cognitive training targeted to behavioral and brain markers of CC reduces anxiety in preschoolers.

The current study examined concurrent relationships between children's self-regulation, measured behaviorally and by parent-report, and children's internalizing and externalizing symptoms. The aim was to distinguish which components of self-regulation (attention vs. inhibitory control, "hot" vs. "cool" regulation) best predict dimensional symptomatology and clinical disorders in young children. The participants were 120 children, ages 4-8 years old. Results showed that greater parent-reported attention was associated with fewer internalizing and externalizing symptoms. Behaviorally-measured hot inhibitory control related to fewer internalizing symptoms, whereas parent-reported inhibitory control related to fewer externalizing symptoms. Similar patterns emerged for clinical diagnoses, with parent-rated attention most strongly predicting disorders across domains. Results support prior evidence implicating self-regulatory deficits in externalizing problems, while also demonstrating that components of self-regulation are impaired with internalizing symptoms. Further, different sub-components of self-regulation relate to different dimensions of psychopathology in children. Interventions should target these areas in children at-risk for disorders.

Background Schools increasingly provide mental health services to students, but often lack access to implementation strategies to support school-based (and school professional [SP]) delivery of evidence-based practices. Given substantial heterogeneity in implementation barriers across schools, development of adaptive implementation strategies that guide which implementation strategies to provide to which schools and when may be necessary to support scale-up. Methods A clustered, sequential, multiple-assignment randomized trial (SMART) of high schools across Michigan was used to inform the development of a school-level adaptive implementation strategy for supporting SP-delivered cognitive behavioral therapy (CBT). All schools were first provided with implementation support informed by Replicating Effective Programs (REP) and then were randomized to add in-person Coaching or not (phase 1). After 8 weeks, schools were assessed for response based on SP-reported frequency of CBT delivered to students and/or barriers reported. Responder schools continued with phase 1 implementation strategies. Slower-responder schools (not providing ≥ 3 CBT components to ≥10 students or >2 organizational barriers identified) were re-randomized to add Facilitation to current support or not (phase 2). The primary aim hypothesis was that SPs at schools receiving the REP + Coaching + Facilitation adaptive implementation strategy would deliver more CBT sessions than SPs at schools receiving REP alone. Secondary aims compared four implementation strategies (Coaching vs no Coaching × Facilitation vs no Facilitation) on CBT sessions delivered, including by type (group, brief and full individual). Analyses used a marginal, weighted least squares approach developed for clustered SMARTs. Results SPs (n = 169) at 94 high schools entered the study. N = 83 schools (88%) were slower-responders after phase 1. Contrary to the primary aim hypothesis, there was no evidence of a significant difference in CBT sessions delivered between REP + Coaching + Facilitation and REP alone (111.4 vs. 121.1 average total CBT sessions; p = 0.63). In secondary analyses, the adaptive strategy that offered REP + Facilitation resulted in the highest average CBT delivery (154.1 sessions) and the non-adaptive strategy offering REP + Coaching the lowest (94.5 sessions). Conclusions The most effective strategy in terms of average SP-reported CBT delivery is the adaptive implementation strategy that (i) begins with REP, (ii) augments with Facilitation for slower-responder schools (schools where SPs identified organizational barriers or struggled to deliver CBT), and (iii) stays the course with REP for responder schools. Trial registration ClinicalTrials.gov, NCT03541317, May 30, 2018.

Electroencephalography (EEG) data collection can be challenging in preschoolers with anxiety who are often debilitated by fear of the unknown. Thus, we iteratively refined techniques for EEG collection in three cohorts of children with anxiety enrolled in our study of a novel intervention. Techniques involved directing child attention away from the EEG setup (Cohort 1, N = 18), open discussion of equipment and processes during setup (Cohort 2, N = 21), and a preparatory EEG-exposure session prior to data collection (Cohort 3, N = 6). Children (N = 45, 4-7 years) attempted a Time 1 EEG before intervention, and those who completed intervention (N = 28) were invited to a Time 2 EEG. The percentages who provided analyzable EEGs were assessed by cohort. Cohort 3 provided more Time 1 EEGs (83.3%) than Cohorts 1 or 2 (66.7% each), suggesting that the preparatory session supported first-time EEG collection. More children provided Time 2 EEG data across successive cohorts (Cohort 1: 66.7%, Cohort 2: 82%, Cohort 3: 100%), suggesting that more open communication facilitated repeat EEG collection. Ultimately, increased EEG exposure and child-friendly communication about procedures improved data acquisition in this sample of clinically anxious preschoolers. Detailed study procedures are shared to support future EEG research in young children with anxiety.

Structural variations of neural regions implicated in fear responses have been well documented in the pathophysiology of anxiety and may play an important role in treatment response. We examined whether gray matter volume of three neural regions supporting fear and avoidance responses [bilateral amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (PFC)] predicted cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) treatment outcome in two independent samples of patients with anxiety disorders. Study 1 consisted of 81 adults with anxiety disorders and Study 2 included 55 children and adolescents with anxiety disorders. In both studies, patients completed baseline structural MRI scans and received either CBT or SSRI treatment. Clinician-rated interviews of anxiety symptoms were assessed at baseline and posttreatment. Among the adult sample, greater pre-treatment bilateral NAcc volume was associated with a greater reduction in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment. Greater left NAcc volume also predicted greater decreases in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment among youth with current anxiety. Across studies, results were similar across treatments, and findings were maintained when adjusting for patient’s age, sex, and total intracranial brain volume. We found no evidence for baseline amygdala or ventromedial PFC volume serving as treatment predictors across the two samples. Together, these findings provide promising support for the role of NAcc volume as an objective marker of anxiety treatment improvement that spans across development. Future studies should clarify the specific mechanisms through which NAcc volume exerts its therapeutic effects.

Introduction The error‐related negativity (ERN) is a neural response that reflects error monitoring. Contradictorily, an enlarged (more negative) ERN has been cited as both a risk factor and a protective factor, which hinders its utility as a predictive indicator. The aim of the current study was to examine the associations between ERN measured in early childhood with the development of cognitive control (CC), emotion regulation, and internalizing/externalizing symptoms over 1–2 years. Methods When children were ages 5–7, EEG was collected during a Go/No‐Go task. A subset of the original participants (n = 30) were selected based on their baseline ERN in an extreme‐case design: half with high‐amplitude ERN, matched by age and sex with another group with low‐amplitude ERN. Results At follow‐up, children in the High‐Amplitude group showed better executive function, less self‐reported anxiety and depression, less affect dysregulation, more parent‐rated CC, less lability/negativity, and fewer parent‐reported externalizing problems. Many results held even when accounting for baseline levels. Further, emotion dysregulation mediated the relationship between the ERN and both anxiety and externalizing problems, while CC mediated the ERN's relationship with externalizing problems only. Conclusions These results can inform identification and intervention efforts for children at risk for psychopathology., High‐amplitude error‐related negativity (ERN), measured in early childhood, predicts better self‐control, including executive function and cognitive control and less affect dysregulation in middle childhood, and predicts fewer anxiety, depression, and externalizing symptoms over time. Emotion dysregulation mediated the relationship between the ERN and both anxiety and externalizing problems, while cognitive control mediated the ERN's relationship with externalizing problems only.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

Social dysfunction is an intractable problem in a wide spectrum of psychiatric illnesses, undermining patients’ capacities for employment, independent living, and maintaining meaningful relationships. Identifying common markers of social impairment across disorders and understanding their mechanisms are prerequisites to developing targeted neurobiological treatments that can be applied productively across diagnoses and illness stages to improve functional outcome. This project focuses on eye gaze perception, the ability to accurately and efficiently discriminate others’ gaze direction, as a potential biomarker of social functioning that cuts across psychiatric diagnoses. This premise builds on both the monkey and human literatures showing gaze perception as a basic building block supporting higher-level social communication and social development, and reports of abnormal gaze perception in multiple psychiatric conditions accompanied by prominent social dysfunction (e.g., psychosis-spectrum disorders, autism-spectrum disorders, social phobia). A large sample (n = 225) of adolescent and young adult (age 14–30) psychiatric patients (regardless of diagnosis) with various degrees of impaired social functioning, and demographically-matched healthy controls (n = 75) will be recruited for this study. Participant’s psychiatric phenotypes, cognition, social cognition, and community functioning will be dimensionally characterized. Eye gaze perception will be assessed using a psychophysical task, and two metrics (precision, self-referential bias) that respectively tap into gaze perception disturbances at the visual perceptual and interpretation levels, independent of general deficits, will be derived using hierarchical Bayesian modeling. A subset of the participants (150 psychiatric patients, 75 controls) will additionally undergo multimodal fMRI to determine the functional and structural brain network features of altered gaze perception. The specific aims of this project are three-fold: (1) Determine the generality of gaze perception disturbances in psychiatric patients with prominent social dysfunction; (2) Map behavioral indices of gaze perception disturbances to dimensions of psychiatric phenotypes and core functional domains; and (3) Identify the neural correlates of altered gaze perception in psychiatric patients with social dysfunction. Successfully completing these specific aims will identify the specific basic deficits, clinical profile, and underlying neural circuits associated with social dysfunction that can be used to guide targeted, personalized treatments, thus advancing NIMH’s Strategic Objective 1 (describe neural circuits associated with mental illnesses and map the connectomes for mental illnesses) and Objective 3 (develop new treatments based on discoveries in neuroscience and behavioral science).

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

The authors sought to examine whether brain activity is associated with treatment response to cognitive-behavioral therapy (CBT) in adolescents and adults with obsessive-compulsive disorder (OCD), and whether any associations are treatment specific relative to an active control psychotherapy (stress management therapy; SMT).Eighty-seven patients with OCD (age range 12-45 years; 57 female, 39 medicated) were randomly assigned to receive 12 weeks of CBT or SMT. Prior to treatment, functional MRI scans were conducted in patients performing an incentive flanker task, which probes brain activation to both cognitive control and reward processing. Voxelwise linear mixed-effects models examined whether baseline brain activation was differentially associated with change in scores on the Yale-Brown Obsessive Compulsive Scale (standard or Children's version) over the course of CBT or SMT treatment.Within the CBT group, a better treatment response was significantly associated with greater pretreatment activation within the right temporal lobe and rostral anterior cingulate cortex during cognitive control and within the ventromedial prefrontal, orbitofrontal, lateral prefrontal, and amygdala regions during reward processing. In contrast, reduced pretreatment activation within a largely overlapping set of regions was significantly associated with a better treatment response to SMT.The study findings demonstrate that associations between brain activation and treatment response were treatment specific to CBT relative to a control psychotherapy and that these associations were stable from adolescence to mature adulthood. Such treatment-specific associations are important for the development of biomarkers to personalize treatment in OCD.

The error-related negativity (ERN) is an event-related potential that reflects error monitoring. Enhanced ERN indicates sensitivity to performance errors and is a correlate of anxiety disorders. In contrast, youth with externalizing problems exhibit a reduced ERN, suggesting decreased error monitoring. Anxiety and externalizing problems commonly co-occur in youth, but no studies have tested how comorbidity might modulate the ERN. In a sample of youth (N = 46, ages 7-19) with and without anxiety disorders, this preliminary study examined the interactive effect of anxiety and externalizing problems on ERN. Results suggest that externalizing problems moderate the relation between anxiety symptoms and ERN in youth. Anxious youth with less externalizing problems exhibited enhanced ERN response to errors. Conversely, anxious youth with greater externalizing problems demonstrated diminished ERN in response to errors. The regions of significance and proportion affected tests indicated that the moderating the effect of externalizing problems was only significant for youth with anxiety disorders. Findings suggest that enhanced neural error sensitivity could be a specific neurophysiological marker for anxiety disorders, whereas anxious individuals with comorbid externalizing problems demonstrate reduced error monitoring, similar to those with primary externalizing pathology. Results underscore the utility of examining neural correlates of pediatric anxiety comorbidity subtypes.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

The DSM provides distinct criteria for obsessive compulsive and various types of anxiety disorders, but phenomenological overlap, high rates of comorbidity, and early onset suggest common underlying mechanisms. This notion is further supported by use of the same treatments – cognitive behavioral therapy (CBT) and serotonin reuptake inhibitor medication – for managing both obsessive compulsive disorder (OCD) and non-OCD anxiety disorders in clinical settings. While early intervention with these gold standard treatments is recommended for pediatric OCD and anxiety disorders, young patients often remain symptomatic even after treatment. To guide the development of novel, mechanistically targeted treatments to better resolve OCD and anxiety symptoms, the identification of neural circuits underlying psychological constructs with relevance across disorders has been recommended. One construct that may be relevant for understanding pediatric OCD and anxiety disorders is cognitive control, given the difficulty that young patients experience in dismissing obsessions, compulsions and worry despite recognition that these symptoms are excessive and unreasonable. In this review, we examine findings from a growing body of literature implicating brain-behavioral markers of cognitive control in pediatric OCD and anxiety disorders, including before and after treatment. We conclude by suggesting that interventions designed to enhance the functioning of the task control circuits underlying cognitive control may facilitate brain maturation to help affected youth overcome symptoms.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Background Cognitive-behavioral therapy (CBT) is the gold-standard psychotherapeutic treatment for pediatric negative valence disorders. However, some youths do not respond optimally to treatment, which may be due to variations in neural functioning. Methods We systematically reviewed functional magnetic resonance imaging studies in youths with negative valence disorders to identify pre- and post-treatment neural correlates of CBT response. Results A total of 21 studies were identified, of overall weak to moderate quality. The most consistent findings across negative valence disorders consisted of associations of treatment response with pre- and post-treatment task-based activation and/or functional connectivity within and between the prefrontal cortex, the medial temporal lobe, and other limbic regions. Associations of CBT response with baseline and/or post-treatment activity in the striatum, precentral and postcentral gyri, medial and posterior cingulate cortices, and parietal cortex, connectivity within and between the default-mode, cognitive control, salience, and frontoparietal networks, and metrics of large-scale brain network organization, were also reported, although less consistently. Limitations The poor quality and limited number of studies and the important heterogeneity of study designs and results considerably limit the conclusions that can be drawn from this literature. Conclusions Despite these limitations, these findings provide preliminary evidence suggesting youths presenting certain patterns of brain function may respond better to CBT, whereas others may benefit from alternative or augmented forms of treatment.

In the following grant report, we describe initial and planned work supported by our National Institute of Mental Health R01-funded, Research Domain Criteria (RDoc) informed project, "Dimensional Brain Behavior Predictors of CBT Outcomes in Pediatric Anxiety". This project examines response to cognitive behavioral therapy (CBT) in a large sample of anxiety-affected and low-anxious youth ages 7 to 18 years using multiple levels of analysis, including brain imaging, behavioral performance, and clinical measures. The primary goal of the project is to understand how brain-behavioral markers of anxiety-relevant constructs, namely acute threat, cognitive control, and their interaction, associate with CBT response in youth with clinically significant anxiety. A secondary goal is to determine whether child age influences how these markers predict, and/or change, across varying degrees of CBT response. Now in its fourth year, data from this project has informed the examination of (1) baseline (i.e., pre-CBT) anxiety severity as a function of brain-behavioral measures of cognitive control, and (2) clinical characteristics of youth and parents that associate with anxiety severity and/or predict response to CBT. Analysis of brain-behavioral markers before and after CBT will assess mechanisms of CBT effect, and will be conducted once the data collection in the full sample has been completed. This knowledge will help guide the treatment of clinically anxious youth by informing for whom and how does CBT work.

Background Depressive and anxiety disorders affect 20–30% of school-age youth, most of whom do not receive adequate services, contributing to poor developmental and academic outcomes. Evidence-based practices (EBPs) such as cognitive behavioral therapy (CBT) can improve outcomes, but numerous barriers limit access among affected youth. Many youth try to access mental health services in schools, but school professionals (SPs: counselors, psychologists, social workers) are rarely trained adequately in CBT methods. Further, SPs face organizational barriers to providing CBT, such as lack of administrative support. Three promising implementation strategies to address barriers to school-based CBT delivery include (1) Replicating Effective Programs (REP), which deploys customized CBT packaging, didactic training in CBT, and technical assistance; (2) coaching, which extends training via live supervision to improve SP competence in CBT delivery; and (3) facilitation, which employs an organizational expert who mentors SPs in strategic thinking to promote self-efficacy in garnering administrative support. REP is a relatively low-intensity/low-cost strategy, whereas coaching and facilitation require additional resources. However, not all schools will require all three strategies. The primary aim of this study is to compare the effectiveness of a school-level adaptive implementation intervention involving REP, coaching, and facilitation versus REP alone on the frequency of CBT delivered to students by SPs and student mental health outcomes. Secondary and exploratory aims examine cost-effectiveness, moderators, and mechanisms of implementation strategies. Methods Using a clustered, sequential multiple-assignment, randomized trial (SMART) design, ≥ 200 SPs from 100 schools across Michigan will be randomized initially to receive REP vs. REP+coaching. After 8 weeks, schools that do not meet a pre-specified implementation benchmark are re-randomized to continue with the initial strategy or to augment with facilitation. Discussion EBPs need to be implemented successfully and efficiently in settings where individuals are most likely to seek care in order to gain large-scale impact on public health. Adaptive implementation interventions hold the promise of providing cost-effective implementation support. This is the first study to test an adaptive implementation of CBT for school-age youth, at a statewide level, delivered by school staff, taking an EBP to large populations with limited mental health care access. Trial registration NCT03541317—Registered on 29 May 2018 on ClinicalTrials.gov PRS Electronic supplementary material The online version of this article (10.1186/s13012-018-0808-8) contains supplementary material, which is available to authorized users.

Background Research suggests that individuals with anxiety have difficulty ignoring threat distractors when completing tasks with competing stimuli. Studies examining the neural correlates of these emotional processing difficulties in youth anxiety highlight reduced recruitment of regions associated with goal-directed attention, such as the anterior cingulate cortex (ACC). In the current study, we examined neural activation during an emotional conflict task in youth with anxiety disorders before and after treatment. Methods Twenty-five youth (ages 9–19 years) with generalized, separation, and/or social anxiety disorder and 25 healthy controls underwent 2 functional magnetic resonance imaging scans approximately 13 weeks apart. At each scan, participants completed a task in which they matched shapes in the context of emotional distractors (happy and threatening faces). Between scans, anxious youth were treated with the selective serotonin reuptake inhibitor (SSRI) sertraline or cognitive behavior therapy (CBT). Results Prior to treatment, anxious youth exhibited reduced activation of the medial prefrontal cortex, encompassing the rostral ACC, when matching shapes in the context of threat distractors relative to healthy controls. Activation in this region increased in anxious youth after treatment, but remained unchanged in the healthy control group. Increases in rostral ACC activation were related to greater reductions in social anxiety and avoidance symptoms following treatment. Conclusions Effective treatments for pediatric anxiety may enhance rostral ACC response during attempts to filter out threat-relevant stimuli. Enhanced recruitment of this region may constitute one manner in which CBT and SSRI treatment reduce youth anxiety symptoms, particularly social anxiety and avoidance.

Obsessive-compulsive disorder (OCD) and generalized anxiety disorder (GAD) are early-onset disorders with significant overlapping phenomenology, especially in young patients who, due to developmental stage, may have difficulty recognizing obsessions and worries as unrealistic or excessive. Shared phenomenology and high rates of comorbidity between OCD and GAD raise the possibility of common underlying processes, and recent work has focused on intolerance of uncertainty (IU) as a reasonable candidate. With an emphasis on the youth literature, we review the phenomenological overlap between OCD and GAD, how symptoms may relate to IU, and how IU may be measured. We review existing psychotherapeutic treatments and discuss how understanding the role of IU may assist in the development of novel psychotherapeutic strategies to improve treatment outcomes. Neuroimaging studies of IU in OCD and GAD are also discussed and suggestions for further research are offered. We conclude that, consistent with Research Domain Criteria (RDoC), IU represents a transdiagnostic construct with a demonstrable neural basis that could be targeted to improve existing treatments for these disorders.

Temporal phases of threat response, including potential threat (anxiety), acute threat (startle, fear), and post-threat response modulation, have been identified as the underlying markers of anxiety disorders. Objective measures of response during these phases may help identify children at risk for anxiety; however, the complexity of current assessment techniques prevent their adoption in many research and clinical contexts. We propose an alternative technology, an inertial measurement unit (IMU), that enables noninvasive measurement of the movements associated with threat response, and test its ability to detect threat response phases in young children at a heightened risk for developing anxiety. We quantified the motion of 18 children (3-7 years old) during an anxiety-/fear-provoking behavioral task using an IMU. Specifically, measurements from a single IMU secured to the child's waist were used to extract root-mean-square acceleration and angular velocity in the horizontal and vertical directions, and tilt and yaw range of motion during each threat response phase. IMU measurements detected expected differences in child motion by threat phase. Additionally, potential threat motion was positively correlated to familial anxiety risk, startle range of motion was positively correlated with child internalizing symptoms, and response modulation motion was negatively correlated to familial anxiety risk. Results suggest differential theory-driven threat response phases and support previous literature connecting maternal child risk to anxiety with behavioral measures using more feasible objective methods. This is the first study demonstrating the utility of an IMU for characterizing the motion of young children to mark the phases of threat response modulation. The technique provides a novel and objective measure of threat response for mental health researchers.

Offspring of depressed parents are at significantly elevated risk for depressive disorders themselves; however, the specific mechanisms associated with this risk are not well known. Given the well-established link between parental depression and biased attention for negative stimuli in children, this preliminary study sought to examine the neural correlates of directing attention toward and away from emotional faces in children and adolescents in association with parent's current depressive symptoms. Forty-two youth (age 7-18 years) completed a task with conditions that manipulated whether participants were instructed to match emotional faces (explicit emotion processing) or match shapes in the context of emotional face distractors (implicit emotion processing) during functional magnetic resonance imaging. Results revealed a positive correlation between parent depressive symptoms and youths' recruitment of the dorsal anterior cingulate cortex (ACC) during attempts to direct attention away (implicit processing) from negative faces. These findings were maintained after accounting for current anxiety and depressive symptoms among youth suggesting that the findings were not fully attributable to offspring's psychopathology. These preliminary findings suggest that altered dorsal ACC function may contribute to the biased attention for negative information typically demonstrated in youth at high risk for depression by disrupting efficient inhibition of negative stimuli.

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: T-1 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 (Cohen's 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 sub cortical abnormalities in pediatric and adult OCD patients. The patlidum 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.

We write with great concern in response to the recent systematic review and meta-analysis of cognitive-behavioral therapy (CBT) in pediatric obsessive-compulsive disorder (OCD) by Uhre et al.1 Although the authors’ results consistently support the clinical efficacy of CBT for pediatric OCD, we expect that, much like ourselves, readers will be confused by the discordant and inappropriate conclusions that they put forward. These conclusions stem from the authors’ application and interpretation of their particular qualitative methods, which could lead important stakeholders (eg, parents, patients, clinicians, and payers) to wrongly discount clear evidence for what is known to be the best evidence-based therapy for pediatric OCD.

ObjectiveTo identify genetic variants associated with obsessive-compulsive (OC) traits and test for sharing of genetic risks between OC traits and obsessive-compulsive disorder (OCD).MethodsWe conducted a genome-wide association analysis of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of three OCD case-controls samples (cases=3384, controls=8363). Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses.ResultsA locus tagged by rs7856850 in an intron ofPTPRD(protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p=2.48×10−8). The rs7856850 locus was also associated with OCD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069). Polygenic risk scores derived from OC traits were significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p’srg=0.83,p=0.07).ConclusionsWe report the first validated genome-wide significant variant for OC traits. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the importance of the type of measure used to measure traits as well as the feasibility and power of using trait-based approaches in community samples for genetic discovery.