PROJECT SUMMARY/ABSTRACT Irritability, an increased propensity to experience anger and frustration, is among the most common presenting complaints in child psychiatry. Severe irritability affects up to 10% of youth in the U.S. and causes significant impairment and high rates of service use and school suspensions. Normative irritability follows a low, declining trajectory from childhood to adolescence. However, some youth remain persistently, highly irritable over development, putting them at the greatest risk for later psychopathology and adverse outcomes, including depression, anxiety, and suicidality. Currently, there are no evidence-based treatments for chronic irritability. This is because of the limited understanding of the etiology and mechanisms of chronic irritability. This New Innovator application addresses this significant gap by identifying predictors and mechanisms of chronic irritability trajectory across multiple levels of analysis including the brain, physiology, behavior, social experience, and family/environment. Specific goals of this project are to (1) identify neural markers (i.e., brain function and connectivity) that predict which child will follow a chronic, persistently high irritability trajectory over time and the developmental changes in these neural markers that underlie chronic irritability; (2) identify social and environmental determinants of chronic irritability and their mediating effects on the link between neural alterations and chronic irritability; (3) enhance prediction of chronic irritability using data from multiple levels of analysis including the brain, physiology, behaviors, social experiences, and familial/environmental factors. We will accomplish these goals in a 3-wave longitudinal functional magnetic resonance imaging (fMRI) study, with a sample of 180 children with (n=120) and without elevated irritability (n=60) at ages 8–13 years. Multi-method, multi-informant assessments will occur annually at three timepoints over two years. Parent-, youth-, and clinician- reports will assess youth irritability. An innovative smartphone-based, naturalistic ecological momentary assessment will measure irritability as well as parent-child and peer relationships/interactions in real time. fMRI will be collected during a novel social vs. non-social FNR task, addressing a significant gap in the field by probing the role of contexts in frustration-related neural alterations. Parent and youth will engage in two interactive tasks in the laboratory (conflict discussion and solving difficult puzzles) while their behaviors and heart rates are being measured. We will first chart within-person irritability trajectories over time using data-driven, person-centered latent class growth mixture modeling, and then apply machine learning with the multi-level data to predict chronic irritability trajectory at the single-subject level. This project, a significant leap forward from the current field, will provide novel, important in...