7. PROJECT SUMMARY: Cannabis use (CU) initiated in adolescence is associated with substantial consequences, from cognitive decline to addiction. While CU may disrupt normal processes of adolescent brain development, relatively little is known about how adolescent CU disrupts circuits mediating cognitive flexibility (adaptation to changing rewards and punishments) and intrinsic resting state functional connectivity (RSFC), and impacts reward motivation (the amount of goal-directed behavior to earn reinforcement). These domains are all understudied areas relative to adult CU yet advancing knowledge of these processes may explain why adolescent-onset CU is linked to functional impairments and higher rates of problematic substance use. Dr. Thomas’s long-term career goal is to become an independent researcher identifying bio-behavioral mechanisms of risks and effects of adolescent drug use in order to improve identification methods for targeted prevention and treatment. The central hypothesis to be tested in this 4-year patient-oriented mentored career award is that CU in the context of adolescent brain development is linked to frontostriatal alterations and impaired cognitive flexibility, reward motivation, and intrinsic RSFC that will vary as a function of CU exposure. The central methodology is to use symptom, circuit, and behavioral data in 14-17 year old adolescents who are engaged in CU and also typically- developing control adolescents (n=40 of each). The career development objectives of this NIDA K23 application are to gain hands-on mentorship in (a) phenomenology and assessment of adolescent CU, (b) the use of fMRI to measure brain/behavior alterations underlying adolescent CU, and (c) advanced statistical methods for greater level of inference from these data, by learning a computational psychiatry model. The research objectives of this K23 are to: (1) to identify the brain/behavior mechanisms of cognitive flexibility and RSFC associated with CU using fMRI; (2) to define behavioral alterations in reward motivation; (3) to use advanced statistical methods, including a specific computational model, to integrate the neural and behavioral contributions to decision-making during a cognitive flexibility task and determine how decision-making components vary for CU adolescents and control adolescents. Brown University is a rich scientific environment to conduct this research due to the expertise of mentors in adolescent substance use, neuroscience, and advanced statistical methods with ample resources to carry out Dr. Thomas’s training plan consisting of hands- on mentorship, workshops, coursework (e.g., neuroanatomy), and professional development (conference presentations, publications). This project is significant because addressing the dearth of knowledge about cognitive flexibility, reward motivation, and RSFC is the first step towards facilitating mechanism-based (a) predictors of progression from regular CU to addiction, and (b) treatments fo...