ABSTRACT/PROJECT SUMMARY Cannabis initiation during adolescence confers four-fold greater risk for cannabis use disorder (CUD) than initiation in adulthood and is associated with increased risk for negative psychiatric outcomes. No effective pharmacologic treatment exists for adolescent cannabis use or CUD, and most adolescents do not achieve sustained abstinence with psychosocial interventions. Functional MRI (fMRI) holds promise for identifying new intervention targets and/or clarifying mechanisms of existing treatments but has yet to lead to clinical translation. New, large-scale neuroimaging data and complementary patient intervention designs with precision neuroimaging can begin to address remaining questions on the cause vs. effect between neural markers and cannabis use, the extent to which putative neural markers of cannabis use instead reflect psychiatric, familial, and/or social determinants of substance use disorders (SUDs), and whether neural markers normalize with abstinence. Through this 4-year K23 award, I will build upon my existing skillset in developmental neuroscience and big data neuroimaging with new training in addiction phenotyping in population studies (e.g., Adolescent Brain Cognitive Development [ABCD] study) and mentored implementation of complementary precision neuroimaging approaches within patient intervention designs for adolescents with CUD. The proposed research aims will (1) utilize existing ABCD Study data to validate known and identify new functional MRI markers of cannabis use initiation and (2) leverage a precision neuroimaging study within a CUD patient intervention design to test the modifiability of functional MRI markers of cannabis use during the transition from regular use to abstinence. Matched neuroimaging protocols, out-of-sample validation, design approaches to increase reliability, and high frequency scanning in the precision neuroimaging study (3 scans over 6 weeks in adolescents with CUD randomized to cannabis abstinence (n=24) or cannabis monitoring (n=20), and matched controls (n=20)) provide key innovations towards rigor and reproducibility. With these methods, we will test the overarching hypothesis that hyperfunction of fronto-striatal reward circuitry is both a trait-level risk-factor and modifiable consequence of adolescent cannabis use. Recognizing the need for both neural and phenotypic specificity, we will compare hypothesis-driven, fronto-striatal circuit markers to data-driven, whole-brain effects and also examine the potential moderating role of psychiatric, environmental, and social determinants of SUD. Through these scientific aims, associated training goals, and guidance from an exceptional multidisciplinary mentorship team, I will gain the necessary skills to address the current methodological issues facing my field and contribute to improved translational research on the neurodevelopment of SUDs. Complementary skillsets in large-scale neuroimaging and clinically relevant, patien...