Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging.

Obsessive-compulsive disorder (OCD) is an impairing psychiatric condition, which often onsets in childhood. Growing research highlights dopaminergic alterations in adult OCD, yet pediatric studies are limited by methodological constraints. This is the first study to utilize neuromelanin-sensitive MRI as a proxy for dopaminergic function among children with OCD. N = 135 youth (6-14-year-olds) completed high-resolution neuromelanin-sensitive MRI across two sites; n = 64 had an OCD diagnosis. N = 47 children with OCD completed a second scan after cognitive-behavioral therapy. Voxel-wise analyses identified that neuromelanin-MRI signal was higher among children with OCD compared to those without (483 voxels, permutation-corrected p = 0.018). Effects were significant within both the substania nigra pars compacta (p = 0.004, Cohen's d = 0.51) and ventral tegmental area (p = 0.006, d = 0.50). Follow-up analyses indicated that more severe lifetime symptoms (t = -2.72, p = 0.009) and longer illness duration (t = -2.22, p = 0.03) related to lower neuromelanin-MRI signal. Despite significant symptom reduction with therapy (p < 0.001, d = 1.44), neither baseline nor change in neuromelanin-MRI signal associated with symptom improvement. Current results provide the first demonstration of the utility of neuromelanin-MRI in pediatric psychiatry, specifically highlighting in vivo evidence for midbrain dopamine alterations in treatment-seeking youth with OCD. Neuromelanin-MRI likely indexes accumulating alterations over time, herein, implicating dopamine hyperactivity in OCD. Given evidence of increased neuromelanin signal in pediatric OCD but negative association with symptom severity, additional work is needed to parse potential longitudinal or compensatory mechanisms. Future studies should explore the utility of neuromelanin-MRI biomarkers to identify early risk prior to onset, parse OCD subtypes or symptom heterogeneity, and explore prediction of pharmacotherapy response.

Obsessive-Compulsive Symptoms: Baseline Prevalence, Comorbidity, and Implications in a Clinically Anxious Pediatric Sample.

Subclinical symptoms of obsessive-compulsive disorder (i.e., obsessive compulsive symptoms, or "OCS") cause functional impairment, including for youth without full-syndrome OCD. Further, despite high rates of OCS in youth with anxiety disorders, knowledge of OCS in the context of specific anxiety disorders is limited. The present study seeks to: (1) compare OCS in pediatric patients with anxiety disorders and healthy youth, (2) determine which categorical anxiety disorder(s) associate most with OCS, and (3) determine relationships between OCS with anxiety severity and impairment. Data on OCS, anxiety, and functional impairment were collected from 153 youth with anxiety disorders and 45 healthy controls, ages 7-17 years (M = 11.84, SD = 3.17). Findings indicated that patients had significantly more OCS than healthy controls. Among patients, GAD was a significant predictor of OCS as well as OCD risk. These results suggest that OCS should be a primary diagnostic and treatment consideration for youth who present in clinical settings with GAD.

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior 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. METHODS: In 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. RESULTS: Functional 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. CONCLUSIONS: Our 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.

Situating the left-lateralized language network in the broader organization of multiple specialized large-scale distributed networks.

Using procedures optimized to explore network organization within the individual, the topography of a candidate language network was characterized and situated within the broader context of adjacent networks. The candidate network was first identified using functional connectivity and replicated across individuals, acquisition tasks, and analytical methods. In addition to classical language regions near the perisylvian cortex and temporal pole, regions were also observed in dorsal posterior cingulate, midcingulate, and anterior superior frontal and inferior temporal cortex. The candidate network was selectively activated when processing meaningful (as contrasted with nonword) sentences, whereas spatially adjacent networks showed minimal or even decreased activity. Results were replicated and triplicated across two prospectively acquired cohorts. Examined in relation to adjacent networks, the topography of the language network was found to parallel the motif of other association networks, including the transmodal association networks linked to theory of mind and episodic remembering (often collectively called the default network). The several networks contained juxtaposed regions in multiple association zones. Outside of these juxtaposed higher-order networks, we further noted a distinct frontotemporal network situated between language regions and a frontal orofacial motor region and a temporal auditory region. A possibility is that these functionally related sensorimotor regions might anchor specialization of neighboring association regions that develop into a language network. What is most striking is that the canonical language network appears to be just one of multiple similarly organized, differentially specialized distributed networks that populate the evolutionarily expanded zones of human association cortex.NEW & NOTEWORTHY This research shows that a language network can be identified within individuals using functional connectivity. Organizational details reveal that the language network shares a common spatial motif with other association networks, including default and frontoparietal control networks. The language network is activated by language task demands, whereas closely juxtaposed networks are not, suggesting that similarly organized but differentially specialized distributed networks populate association cortex.

Changes in Brain Network Connections After Exposure and Response Prevention Therapy for Obsessive-Compulsive Disorder in Adolescents and Adults.

BACKGROUND: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control. METHODS: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks. RESULTS: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group. CONCLUSIONS: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP.

Exposure and response prevention versus stress management training for adults and adolescents with obsessive compulsive disorder: A randomized clinical trial.

OBJECTIVE: Though exposure and response prevention (ERP) is a well-proven treatment for OCD across the lifespan, prior RCTs have not studied adolescent and adult patients with the same ERP protocol relative to an active comparator that controls for non-specific effects of treatment. This approach assesses differences in the effect of OCD-specific exposures in affected adolescents and adults and in response to ERP compared to a stress-management control therapy (SMT). METHODS: This assessor-blinded, parallel, 2-arm, randomized, ambulatory clinical superiority trial randomized adolescents (aged 12-18) and adults (24-46) with OCD (N = 126) to 12 weekly sessions of ERP or SMT. OCD severity was measured before, during and after treatment using the child or adult version of the Yale-Brown Obsessive Compulsive Scale (C/Y-BOCS), depending on participant age. We predicted that ERP would produce greater improvement in OCD symptoms than SMT and that there would be no significant post-treatment differences across age groups. RESULTS: ERP (n = 63) produced significantly greater improvements on C/Y-BOCS scores at post-treatment than SMT (n = 63) (Effect size = -0.72, CI = -0.52 to -0.91, p < .001). ERP also produced more treatment responders (ERP = 86%, SMT = 32%; χ2 = 46.37, p < .001) and remitters than SMT (ERP = 39%, SMT = 7%; χ2 = 16.14, p < .001). Finally, there were no statistically significant post-treatment differences in C/Y-BOCS scores between adolescents and adults assigned to ERP. CONCLUSION: A single ERP protocol is superior to SMT in treating both adolescents and adults with OCD. OCD-specific therapy is necessary across the lifespan for optimal outcomes in this highly disabling disorder, though non-specific treatments like SMT are still all-too-commonly provided.

Error-related brain activity associated with obsessive-compulsive symptoms in youth.

BACKGROUND: Subclinical obsessive-compulsive symptoms (OCS) are common in children, and increase risk for later onset of obsessive-compulsive disorder (OCD). In pediatric patients with OCD, neuroimaging research implicates altered neural mechanisms for error-processing, but whether abnormal brain response occurs with subclinical OCS remains poorly understood. METHODS: Using functional magnetic resonance imaging (fMRI), 113 youth (8-18 years; 45 female) from a community sample were scanned during an error-eliciting Go/No-Go task. OCS were assessed dimensionally using the obsessive-compulsive subscale of the Child Behavior Checklist. The association between OCS scores and error-related brain activity was examined at the whole-brain level. RESULTS: Lower OCS scores associated with stronger response to errors in dorsal anterior cingulate cortex (dACC), caudate, putamen, thalamus, and occipital cortex. Additionally, lower OCS related to higher capacity for inhibitory control, as indexed by greater accuracy on No-Go trials during fMRI scanning. The relationship between lower OCS and better accuracy on No-Go trials was mediated by greater error-related dACC activity. CONCLUSIONS: The inverse relationship between OCS and error-related activity in the dACC and extended cortical-striatal-thalamic circuitry may index an adaptive process by which subclinical OCS are minimized in youth. Further, these results identify an observable pattern of brain activity that tracks with subclinical OCS severity. Understanding the link between neural networks for error processing and the normal to abnormal range of OCS may pave the way for brain-based strategies to identify children who are more likely to develop OCD and enable the targeting of preventive strategies to reduce risk.

Mediating effect of pubertal stages on the family environment and neurodevelopment: An open-data replication and multiverse analysis of an ABCD Study®.

Increasing evidence demonstrates that environmental factors meaningfully impact the development of the brain (Hyde et al., 2020; McEwen and Akil, 2020). Recent work from the Adolescent Brain Cognitive Development (ABCD) Study® suggests that puberty may indirectly account for some association between the family environment and brain structure and function (Thijssen et al., 2020). However, a limited number of large studies have evaluated what, how, and why environmental factors impact neurodevelopment. When these topics are investigated, there is typically inconsistent operationalization of variables between studies which may be measuring different aspects of the environment and thus different associations in the analytic models. Multiverse analyses (Steegen et al., 2016) are an efficacious technique for investigating the effect of different operationalizations of the same construct on underlying interpretations. While one of the assets of Thijssen et al. (2020) was its large sample from the ABCD data, the authors used an early release that contained 38% of the full ABCD sample. Then, the analyses used several 'researcher degrees of freedom' (Gelman and Loken, 2014) to operationalize key independent, mediating and dependent variables, including but not limited to, the use of a latent factor of preadolescents' environment comprised of different subfactors, such as parental monitoring and child-reported family conflict. While latent factors can improve reliability of constructs, the nuances of each subfactor and measure that comprise the environment may be lost, making the latent factors difficult to interpret in the context of individual differences. This study extends the work of Thijssen et al. (2020) by evaluating the extent to which the analytic choices in their study affected their conclusions. In Aim 1, using the same variables and models, we replicate findings from the original study using the full sample in Release 3.0. Then, in Aim 2, using a multiverse analysis we extend findings by considering nine alternative operationalizations of family environment, three of puberty, and five of brain measures (total of 135 models) to evaluate the impact on conclusions from Aim 1. In these results, 90% of the directions of effects and 60% of the p-values (e.g. p > .05 and p < .05) across effects were comparable between the two studies. However, raters agreed that only 60% of the effects had replicated. Across the multiverse analyses, there was a degree of variability in beta estimates across the environmental variables, and lack of consensus between parent reported and child reported pubertal development for the indirect effects. This study demonstrates the challenge in defining which effects replicate, the nuance across environmental variables in the ABCD data, and the lack of consensus across parent and child reported puberty scales in youth.