PROJECT SUMMARY/ABSTRACT Anxiety disorders are the most common psychiatric illnesses and are often resistant to treatment. Adolescence is a core risk period for the development and exacerbation of anxiety, which often has a chronic course, negatively affecting academic, social, and adaptive functioning, and increasing the risk for mental illness through adulthood. Research has highlighted a number of risk factors that likely contribute to the development and maintenance of anxiety. However, there is limited understanding of the earliest precursors of anxiety or how multiple risk factors interact within and across development to influence anxiety risk. Prospective studies beginning in infancy are needed to explicate the origins of anxiety so that (a) biomarkers can be discovered that identify at-risk youth prior to the emergence of symptoms and (b) preventive strategies can be developed and implemented with those at risk. The overall goal of the current project is to test the combined effects of neural, physiological, behavioral, and environmental risk factors on anxiety from infancy through adolescence. The study aims will be accomplished by following our established longitudinal cohort (R01 MH078829; N=807), who have provided a rich dataset, including repeated assessments of neurophysiology (EEG, ERP), physiological stress reactivity, behavioral indicators of threat reactivity, and environmental risk (e.g., maternal psychopathology, negative life events, COVID-19 related stressors) between infancy and age 7 years. In the current proposal, we seek funds to support a follow-up study to age 13 years. We will phenotype our cohort for anxiety symptomatology and diagnoses, across multiple phenotypes, and implement a battery of brain-based measures, physiological and behavioral protocols, and assessments of environmental exposures, including exposures of particular relevance in adolescence and exposures related to the COVID-19 pandemic. We will apply a combination of established and novel analysis approaches to develop diagnostic neural biomarkers of anxiety in adolescence; identify positive and negative environmental characteristics that influence anxiety- relevant neural signatures in adolescence, that affect anxiety-related neural trajectories from infancy to adolescence, and that moderate the effects of neural reactivity on anxiety risk; determine how COVID-19 related stressors interact with childhood pre-pandemic characteristics (neural and behavioral threat reactivity, physiological stress reactivity) to influence adolescent anxiety risk; and to develop assay profiles comprising neural, physiological, behavioral, and/or environmental characteristics from infancy through adolescence that robustly predict anxiety trajectories across development. We expect that the findings will (a) improve our understanding of the neural circuitry underlying anxiety risk in youth, (b) contribute to the discovery of robust developmentally-informed multi-modal profil...