Network-based functional connectivity predicts response to exposure therapy in unmedicated adults with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is associated with alterations in cortico-striato-thalamo-cortical brain networks, but some resting-state functional magnetic resonance imaging studies report more diffuse alterations in brain connectivity. Few studies have assessed functional connectivity within or between networks across the whole brain in unmedicated OCD patients or how patterns of connectivity predict response to exposure and ritual prevention (EX/RP) therapy, a first-line treatment for OCD. Herein, multiband resting-state functional MRI scans were collected from unmedicated, adult patients with OCD (n = 41) and healthy participants (n = 36); OCD patients were then offered twice weekly EX/RP (17 sessions). A whole-brain-network-based statistic approach was used to identify group differences in resting-state connectivity. We detected altered pre-treatment functional connectivity between task-positive regions in the temporal gyri (middle and superior) and regions of the cingulo-opercular and default networks in individuals with OCD. Signal extraction was performed using a reconstruction independent components analysis and isolated two independent subcomponents (IC1 and IC2) within this altered connectivity. In the OCD group, linear mixed-effects models tested whether IC1 or IC2 values predicted the slope of change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores across EX/RP treatment. Lower (more different from controls) IC2 score significantly predicted greater symptom reduction with EX/RP (Bonferroni-corrected p = 0.002). Collectively, these findings suggest that an altered balance between task-positive and task-negative regions centered around temporal gyri may contribute to difficulty controlling intrusive thoughts or urges to perform ritualistic behaviors.

Association between real-world experiential diversity and positive affect relates to hippocampal-striatal functional connectivity.

Experiential diversity promotes well-being in animal models. Here, using geolocation tracking, experience sampling and neuroimaging, we found that daily variability in physical location was associated with increased positive affect in humans. This effect was stronger for individuals who exhibited greater functional coupling of the hippocampus and striatum. These results link diversity in real-world daily experiences to fluctuations in positive affect and identify a hippocampal-striatal circuit associated with this bidirectional relationship.

Aversive learning strengthens episodic memory in both adolescents and adults.

Adolescence is often filled with positive and negative emotional experiences that may change how individuals remember and respond to stimuli in their environment. In adults, aversive events can both enhance memory for associated stimuli as well as generalize to enhance memory for unreinforced but conceptually related stimuli. The present study tested whether learned aversive associations similarly lead to better memory and generalization across a category of stimuli in adolescents. Participants completed an olfactory Pavlovian category conditioning task in which trial-unique exemplars from one of two categories were partially reinforced with an aversive odor. Participants then returned 24 h later to complete a recognition memory test. We found better corrected recognition memory for the reinforced versus the unreinforced category of stimuli in both adults and adolescents. Further analysis revealed that enhanced recognition memory was driven specifically by better memory for the reinforced exemplars. Autonomic arousal during learning was also related to subsequent memory. These findings build on previous work in adolescent and adult humans and rodents showing comparable acquisition of aversive Pavlovian conditioned responses across age groups and demonstrate that memory for stimuli with an acquired aversive association is enhanced in both adults and adolescents.

Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression.

BACKGROUND: Previously, we identified four depression subtypes defined by distinct functional connectivity alterations in depression-related brain networks, which in turn predicted clinical symptoms and treatment response. Optogenetic functional magnetic resonance imaging offers a promising approach for testing how dysfunction in specific circuits gives rise to subtype-specific, depression-related behaviors. However, this approach assumes that there are robust, reproducible correlations between functional connectivity and depressive symptoms-an assumption that was not extensively tested in previous work. METHODS: First, we comprehensively reevaluated the stability of canonical correlations between functional connectivity and symptoms (N = 220 subjects) using optimized approaches for large-scale statistical hypothesis testing, and we validated methods for improving estimation of latent variables driving brain-behavior correlations. Having confirmed this necessary condition, we reviewed recent advances in optogenetic functional magnetic resonance imaging and illustrated one approach to formulating hypotheses regarding latent subtype-specific circuit mechanisms and testing them in animal models. RESULTS: Correlations between connectivity features and clinical symptoms were robustly significant, and canonical correlation analysis solutions tested repeatedly on held-out data generalized. However, they were sensitive to data quality, preprocessing, and clinical heterogeneity, which can reduce effect sizes. Generalization could be markedly improved by adding L2 regularization, which decreased estimator variance, increased canonical correlations in left-out data, and stabilized feature selection. These improvements were useful for identifying candidate circuits for optogenetic interrogation in animal models. CONCLUSIONS: Multiview, latent-variable approaches such as canonical correlation analysis offer a conceptually useful framework for discovering stable patient subtypes by synthesizing multiple clinical and functional measures. Optogenetic functional magnetic resonance imaging holds promise for testing hypotheses regarding latent, subtype-specific mechanisms driving depressive symptoms and behaviors.