Brain controllability mediates the effects of early life adversity on adolescent behavior and cognition moderated by...

Early life adversity (ELA) is a robust transdiagnostic risk factor for mental health disorders, yet the neurobiological mechanisms mediating its long-term impact remain poorly understood. Network control theory offers a novel framework for capturing how structural brain networks constrain and support brain dynamics. Controllability increases over development, associates with executive function and mental health, and appears sensitive to environmental insults. Thus, it may reflect a neurobiological mediator between ELA and behavioral outcomes. We tested whether alterations in modal controllability mediate the impact of multidimensional ELA on cognitive and behavioral outcomes in youth, and whether these pathways are shaped by genetic risk for neurodevelopmental conditions. Using data from 7,970 children aged 9-11 years in the Adolescent Brain Cognitive Development (ABCD) Study, we derived five latent ELA dimensions from 67 indicators, and computed polygenic risk scores (PRS) for attention-deficit/hyperactivity disorder (ADHD_PRS) and autism spectrum disorder (ASD_PRS). Distinct ELA dimensions were associated with increased controllability in medial frontal, frontoparietal, default mode, and motor networks, as well as with externalizing symptoms and impaired crystallized cognition. Controllability partially mediated these associations, and indirect effects were significantly moderated ADHD_PRS and ASD_PRS. Longitudinal analyses further demonstrated that baseline controllability predicted cognitive performance two years later. These findings delineate a neurodevelopmental cascade linking early adversity and genetic vulnerability to transdiagnostic mental health risk, positioning brain controllability as a promising mechanistic marker and potential target for early intervention.