Project Summary/Abstract Major Depressive Disorder (MDD) is a devastating clinical disorder and the leading cause of disability worldwide. Adolescence is a key developmental period during which risk for the development of depression is greatest. Behavioral Activation (BA) psychotherapy has emerged as a first-line treatment for adolescent depression, yet the underlying neurobiological mechanisms that mediate treatment efficacy remain unclear. Understanding these target mechanisms is fundamental to developing novel adaptations of BA, augmenting other treatments with BA, and designing new interventions informed by greater comprehension of neural target mechanisms. In the current application, we seek to identify the neural mechanisms that mediate treatment response during BA therapy for adolescent depression. Critically, reductions in avoidance behavior and successful BA treatment may occur through manipulation of multiple neural targets operating on different timescales between and/or within individuals. In cross-sectional neuroimaging studies of adolescent depression, the most common markers are hypo-responding to reward cues in the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) and hyper-responding to negative information in the amygdala and the salience network–comprising the anterior insula (aI) and dorsal anterior cingulate (dACC). These patterns of hypo- and hyper-responding regions may independently or jointly contribute to behavioral avoidance by the RDoC concepts of reduced motivation for rewards and threat avoidance, respectively. Consequently, a fuller understanding of target engagement for BA requires multiple assessments linking trajectories of behavioral and symptom change with trajectories of change in these neural circuits over the course of therapy as opposed to just pre/post comparisons. To address these concerns, we propose to acquire ecological momentary assessment (EMA) and longitudinal neuroimaging data in a sample of 96 depressed adolescents while they complete a 16-week course of BA therapy. Three task-based fMRI scans will occur at baseline and after sessions 7 and 16, and will include a set of paradigms focused on assessing behavioral avoidance for monetary and social rewards. In addition, two brief “behavioral-scheduling-in-scanner” sessions will occur at sessions 3 and 9 during which the patient and therapist will engage in a component of BA therapy while the patient undergoes an fMRI scan. This “behavioral-secheduling-in-scanner” protocol will allow us to better determine the ecological validity of task-based measures of target engagement during psychotherapy. Taken together, these data will enable understanding of the neural mechanisms through which BA reduces avoidance behavior and thereby treats depression, Further, these data will establish a platform for developing future modifications of BA techniques and/or novel treatments based on identifiable neural targets.