Leveraging Distributed Brain Signal at Rest to Predict Internalizing Symptoms in Youth: Deriving a Polyneuro Risk Score From the ABCD Study Cohort

Background: The prevalence of internalizing psychopathology rises precipitously from early to mid-adolescence, yet the underlying neural phenotypes that give rise to depression and anxiety during this developmental period remain unclear. Methods: Youths from the Adolescent Brain Cognitive Development (ABCD) Study (ages 9–10 years at baseline) with a resting-state functional magnetic resonance imaging scan and mental health data were eligible for inclusion. Internalizing subscale scores from the Brief Problem Monitor-Youth Form were combined across 2 years of follow-up to generate a cumulative measure of internalizing symptoms. The total sample (N = 6521) was split into a large discovery dataset and a smaller validation dataset. Brain-behavior associations of resting-state functional connectivity with internalizing symptoms were estimated in the discovery dataset. The weighted contributions of each functional connection were aggregated using multivariate statistics to generate a polyneuro risk score (PNRS). The predictive power of the PNRS was evaluated in the validation dataset. Results: The PNRS explained 10.73% of the observed variance in internalizing symptom scores in the validation dataset. Model performance peaked when the top 2% functional connections identified in the discovery dataset (ranked by absolute β weight) were retained. The resting-state functional connectivity networks that were implicated most prominently were the default mode, dorsal attention, and cingulo-parietal networks. These findings were significant (p < 1 × 10⁻⁶) as accounted for by permutation testing (n = 7000). Conclusions: These results suggest that the neural phenotype associated with internalizing symptoms during adolescence is functionally distributed. The PNRS approach is a novel method for capturing relationships between resting-state functional connectivity and behavior.