Neurobiological correlates of susceptibility, resilience, and recovery to substance abuse in participants with childhood maltreatment

The National Institute on Drug Abuse awarded The McLean Hospital Corporation $981,978 on September 15, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to validate and extend neurobiological models of resilience and susceptibility to substance use disorders in adolescents exposed to childhood adversity.

The project investigates whether specific brain network adaptations distinguish adolescents resilient to substance use despite high adversity burden from those susceptible to escalating use, using diffusion tensor imaging and structural connectome analysis within the Adolescent Brain Cognitive Development (ABCD) Study cohort. The research employs an exposome-wide association study approach to identify high-risk youth based on comprehensive multi-domain adversity burden and growth mixture modeling to classify substance use trajectories. Three specific aims will validate a resilience network model using modern tractography and higher-resolution brain parcellations; distinguish constitutional resilience (protective features at baseline ages 9–10) from acquired resilience (progressive network changes across adolescence); and identify modifiable protective factors including family support, school engagement, and peer relationships. The work operates as a Project Grant, a form of assistance funding supporting peer-reviewed basic and translational research to advance prevention, diagnosis, and treatment approaches for substance use disorders.

Performance occurs in Belmont, Massachusetts. The period of performance runs from September 15, 2026, through July 31, 2031. The obligated amount is $981,978.

Abstract

Childhood adversity is a critical risk factor for substance use disorders (suds), yet substantial numbers of exposed individuals remain resilient. Understanding neurobiological mechanisms underlying resilience may provide insights for prevention and intervention. Using diffusion tensor imaging and structural connectome analysis, we identified nine brain network nodes where reduced nodal efficiency distinguished resilient from susceptible young adults with comparable childhood maltreatment, achieving ~80% cross-validated classification accuracy. These findings suggest resilient individuals are not unaffected but effectively compensated through specific network adaptations. This proposal validates and extends these findings in the adolescent brain cognitive development (abcd) study, the largest longitudinal neuroimaging study of adolescent development (n~11,000). We employ an exposome-wide association study (exwas) approach to identify high-risk youth based on comprehensive multi-domain adversity burden. Growth mixture modeling will identify substance use trajectories, classifying participants as resilient (high adversity, low substance use), susceptible (high adversity, escalating use), or low-risk controls. Three aims will: (1) validate our resilience network model using modern tractography and higher-resolution parcellations, testing whether network features distinguish resilient from susceptible adolescents despite equivalent exposome burden and examining disorder-specific versus transdiagnostic mechanisms; (2) distinguish constitutional resilience (protective features present at baseline, ages 9-10) from acquired resilience (progressive node recruitment across adolescence), revealing whether resilience is fixed or modifiable; (3) identify modifiable protective factors (family support, school engagement, peer relationships, activities) associating with resilient architecture and preceding node recruitment, using machine learning to determine which factors at which ages most strongly promote resilience. Exploratory analyses test whether sleep disruption mediates network effects on substance use, building on our finding that sleep efficiency mediated 39-46% of maltreatment effects on brain structure. We hypothesize that sleep degradation emerges 12-18 months before substance use escalation, providing an intervention window. This research establishes whether network architecture represents a robust biomarker of SUD resilience; reveals modifiable environmental targets and critical developmental windows; and distinguishes constitutional from acquired resilience to inform precision prevention. Identifying naturally-occurring protective brain adaptations and fostering experiences transforms resilience from abstract construct into actionable prevention targets for high-risk youth.