Inhibitory Mechanisms of Negative Urgency in Adolescent Suicidal Behavior

PROJECT SUMMARY / ABSTRACT This K23 career development project will study the neural underpinnings of impulsivity in adolescent suicidal behavior (SB). The candidate will obtain critical skills and experience in adolescent suicidology and impulsivity research, advanced neurophysiologic and longitudinal methods, and translation of neurophysiologic research to interventional studies needed for a career focused on elucidating brain-behavior mechanisms of adolescent SB. Suicide is the second leading cause of death in adolescence, and rates of adolescent SB are increasing. However, its neurobiology remains poorly understood, and treatments specifically targeting SB are lacking. SB in adolescents is a critical public health problem that demands urgent attention, particularly with research that will rapidly translate knowledge to clinical applications. Negative urgency, a component of impulsivity, is the tendency to act rashly in the context of negative emotion. It has been found to be increased among youth with SB and attempts, and has been linked to impaired inhibition of limbic circuitry by the dorsolateral prefrontal cortex (DLPFC), yet precise mechanisms are unclear. Transcranial magnetic stimulation (TMS) permits noninvasive quantification of DLPFC functions such as cortical inhibition (CI), the process by which cortical interneurons regulate the activity of other circuits. Previous research indicates that adolescents with lifetime SB have reduced CI in the motor cortex that distinguishes them from non-suicidal youth. However, DLPFC CI has not been measured in adolescents with SB, nor is it clear how CI relates to cognitive and emotional systems implicated in SB, such as negative urgency. In order to study CI-related mechanisms of negative urgency in the DLPFC, simultaneous TMS and electroencephalography (TMS-EEG) is required. The candidate proposes a longitudinal study of inhibitory physiology and negative urgency in 40 depressed adolescents with suicidal ideation (but no SB) and 40 depressed adolescents with SB. The study will utilize TMS-EEG and self-report measures of negative urgency to test hypotheses that dysregulated CI is associated with negative urgency, that DLPFC CI is deficient in adolescents with SB, and that CI deficits correlate longitudinally with changes in negative urgency and newly emergent SB. The candidate has prior experience with more basic TMS methods; however, to attain long-term career goals, additional training in EEG analysis, assessment of impulsivity in suicidal adolescents, and longitudinal/neurodevelopmental research methods is necessary. A robust career development plan, with multidisciplinary mentorship and collaboration, will involve intramural and extramural coursework, methodology-specific seminars and training, and a well-defined plan for grant and publication benchmarks. This will ensure the candidate’s successful transition to an independent clinical research career. The long-term goal is to utilize data gathered in this project to design a large-scale longitudinal study assessing neural and behavioral risk factors for developing SB, as well as trials of neuromodulatory treatments that will reduce the transition from suicidal thoughts to behaviors by targeting alterations in CI and negative urgency.