PROJECT SUMMARY/ABSTRACT: BACKGROUND: Non-suicidal self-injury (NSSI)—defined as deliberate destruction of one's body in the absence of intent to die (most commonly self-cutting)—accounts for 25% of 7-24 year olds seen in emergency departments annually for self-harm and increases the risk for a suicide attempt (SA) by as much as 7-fold. Moreover, suicide is the second leading cause of death of 10-24 year olds in the U.S. Thus, there is a critical need to identify the brain/behavior mechanisms underlying NSSI itself and also the circuit/behavior/symptoms predictors of which youths engaged in NSSI-only will make a first-onset SA (and which will not). THE PRIMARY OBJECTIVES are (1) to identify functional magnetic resonance imaging (fMRI) differences between youths engaged in NSSI vs. controls without psychopathology, (2) to determine the circuit, behavior, and symptom factors associated with first-onset SA, and (3) to test moderators of this relationship including irritability, social function, and impulsive aggression. OUR CENTRAL HYPOTHESIS, based on preliminary data from our American Foundation for Suicide Prevention study of teens engaged in NSSI-only is that (a) youths engaged in NSSI-only without a prior SA have behavior/circuit alterations in a prefrontal cortex (PFC)- amygdala circuit during tasks tapping implicit associations with suicide and response to peer acceptance vs. rejection, and (b) these circuit alterations, moderated by irritability, impulsive aggression, and social dysfunction, put youths at greater risk for future suicidal behavior. RESEARCH METHOD: We will test this hypothesis by comparing 150 youths engaged in NSSI-only (without prior SA) vs. 50 typically-developing control (TDC) youths on circuit, behavior, and symptom measures, and then following the sample for 18 months to delineate what distinguishes those who progress to suicidal behavior. THE RATIONALE FOR THIS PROPOSAL is that greater knowledge of the brain/behavior mechanisms underlying NSSI and the relationship to subsequent first-onset SA will ultimately lead to a more brain-based classification and treatment approach for NSSI and suicide, which in turn would reduce risk, and enhance prevention for, suicidal behavior among children and adolescents. INNOVATION: Our study is innovative because it will uniquely synergize circuit and behavioral methods based on solid preliminary data with innovative ecological momentary assessments of NSSI/suicide and irritability, real-world assessment of social function, longitudinal follow up, and a committed multi-disciplinary team. SIGNIFICANCE: Our study is significant because it addresses gaps in knowledge about bio-behavioral mechanisms of both NSSI and also of a first-onset SA highlighted by the NIMH/National Action Alliance for Suicide Prevention's (NAASP) “Prioritized Research Agenda for Suicide Prevention” and the June 2016 NIMH-sponsored meeting on “Mechanisms of Suicide Risk”—as these mechanisms provide the foundation for...