Brain-Wide Structural Markers of Familial and Clinical Risk for Bipolar Disorder in Youth

BACKGROUND: Bipolar Disorder (BD) is a severe mental illness, often emerging during adolescence, that is associated with significant psychosocial impairment. BD risk is elevated in offspring of affected parents, particularly those with antecedent symptoms (e.g., mood lability, subthreshold manic symptoms). However, robust, replicable brain-based markers of risk in this population are lacking. We assessed the degree to which the Regional Vulnerability Index for BD (RVI-BD), quantified as an individual's brain-wide similarity to BD patterns derived from meta-analytic studies, is elevated in youth at familial risk and correlates with symptom predictors of BD. METHODS: We recruited n=82 adolescents (10-15 years old), 41 with a first-degree relative with BD ("at-risk") and 41 healthy controls (HC). RVI-BD was calculated separately based on cortical thickness (CT) and subcortical volume (SV) patterns, by computing the average of RVI-BD metrics derived using case-control (alignment with BD patterns) and dimensional (alignment and deviation toward BD patterns) approaches. RESULTS: Compared to HC, at-risk youth showed higher CT-RVI-BD (d=0.66, p=.006). Group differences were driven largely by at-risk individuals with ADHD; however, ADHD was not associated with RVI-BD in a separate population-based sample, suggesting that the combination of familial risk and ADHD most strongly predicts CT-RVI-BD. CT-RVI-BD (and to a lesser degree SV-RVI-BD) were also associated with parent-reported symptom scales, including subthreshold manic symptoms and mood lability. CONCLUSIONS: Findings suggest RVI-BD as a potential marker of familial and clinical risk for BD. Future work should assess the degree to which CT-RVI-BD predicts longitudinal mood trajectories in at-risk youth.