Distinct neural substrates of obsessions and compulsions in adolescent obsessive compulsive disorder

Adolescent obsessive-compulsive disorder (OCD) is characterized by notable clinical heterogeneity, which may limit treatment precision. Although traditional content-based models have improved symptom characterization, they may overlook key pathophysiological features. A complementary process-based framework that distinguishes between obsessions and compulsions offers a promising alternative, but the neurobiological correlates of these dimensions remain poorly understood. To address this gap, we recruited 40 adolescents with OCD and 40 matched healthy controls and conducted connectome-wide association studies (CWAS) using multivariate distance matrix regression (MDMR) to identify brain regions whose whole-brain connectivity patterns were associated with obsessive or compulsive symptom severity. Follow-up seed-based analyses were then performed to delineate the relevant circuits, and cross-modal comparisons were further used to examine the alignment of symptom-connectivity association maps with neurotransmitter receptor distributions and gene expression profiles. We found that obsessive symptoms were associated with altered connectivity patterns centered on the Dorsolateral Prefrontal Cortex and Cerebellum Posterior Lobe, whereas compulsive symptoms were linked to the Ventrolateral Prefrontal Cortex. In both cases, connectivity between each symptom-specific target and the default mode network (DMN) was negatively correlated with the severity of its corresponding symptom dimension. Moreover, the symptom-connectivity association maps for obsessions and compulsions showed distinct associations with neurotransmitter systems and transcriptomic signatures. Together, these findings provide novel evidence for distinct neurobiological substrates underlying obsession and compulsion dimensions in adolescent OCD, support the utility of process-based symptom modeling, and suggest potential targets for dimension-specific intervention.