Summary' Childhood maltreatment is the most important risk factor for substance use, with maltreatment and household dysfunction accounting for about two thirds of the population attributable risk for drug dependence and iv drug use. Hence, there is a substantial subset of individuals with substance use disorders who experienced maltreatment and a substantial subset who did not. Those with maltreatment tend to have an earlier age of onset, more severe course, more comorbid symptoms, higher rates of relapse following treatments, and are more likely to have abnormalities in brain morphology. A critical question is whether the maltreated ecophenotypic variant is a distinctly different disorder or simply a more severe manifestation of the same underlying disorder. Our previous efforts during the first ten years of this award resulted in important new discoveries regarding type and timing of maltreatment, gender differences, predisposing symptoms and specific brain changes that were prospectively predictive of risk for developing substance use problems in maltreated youths. Our goal during this phase of the award is to compare maltreated and non-maltreated individuals with histories of “hard drug” substance use disorders, with opioids as primary drug of abuse, as well as unexposed non-substance using controls, to provide the first comprehensive test of the ecophenotype hypothesis that there are unique maltreated and non-maltreated substance use disorder subtypes with distinctly different molecular and neurobiological signatures. We further propose that neurobiological alterations associated with attention deficit hyperactivity disorder serve as the primary risk factor in the non-maltreated subtype rather than brain changes associated with early life stress and maltreatment. Verifying that there are two distinctly different pathways to substance use disorders would have critically important implications for prevention, treatment and design of future research studies, as each pathway may require distinctly different strategies for prevention, treatment and discovery. The second aim of the award will be to determine how exposure to maltreatment during sensitive periods becomes biologically embedded and to specifically determine how much inflammation and sleep stage disruption mediate the effects of maltreatment on brain morphometry, brain network architecture and symptoms predisposing to substance use. The purpose of this aim is to identify the most important mediators as potential therapeutic targets to prevent the emergence of substance use disorders in high-risk maltreated youth. Further, ongoing effects of inflammation and sleep disruption on neurobiology and behavior may serve as a barrier to recovery and targeting these mediators in maltreated individuals with opioid and other substance use disorders may facilitate recovery. Hence, one aim of this award is to markedly advance our understanding of substance use by testing the hypothesis that maltrea...