Lifespan investigation of brain volumetric changes associated with substance use disorders.

Substance use disorder (SUD) stands as a critical public health concern, contributing to substantial morbidity, mortality and societal costs. The effects of SUD on structural brain changes have been well documented. However, the neural mechanisms underlying SUD and the spatial-temporal volumetric changes associated with SUD remained underexplored. In this investigation, neuroimaging, behavioral and genomic data across four large population cohorts jointly covering the full lifespan were harmonized, and whole-brain volumetric trajectories between substance use disorders (SUDs) and healthy controls (HCs) were compared, revealing the potential neurobiological mechanisms and the genomic basis underlying SUD. Results highlighted three distinct life stages critical for the development of SUD: 1) adolescence to early adulthood (before 25y), where SUD is suspected to be the consequence of prefrontal-subcortical imbalance during neurodevelopment; 2) early-to-mid adulthood (25y - 45y), where SUD was strongly associated with compulsivity-related brain volumetric changes; 3) mid-to-late adulthood (after 45y), where SUD-related brain structural changes could be explained by neurotoxicity. Results were externally validated both via longitudinal analysis of these population cohorts and in independent cross-sectional samples. In summary, our study demonstrated the lifespan whole-brain volumetric changes associated with SUD, revealed potential neurobehavioral mechanisms for the development of SUD, and suggested critical time window for effective prevention and treatment of SUD.