Neurophysiological Responses to Stress: A Biomarker of Risk for Suicide in Bipolar Disorder

Suicide is amongst the leading causes of death amongst adolescent/young adults. Despite the importance of understanding the development of suicide risk, little data exists on neural circuitry predictors of suicide, especially during adolescence/young adulthood when suicide behavior often emerges. Bipolar disorder is associated with increased risk for suicide, with estimates that up to 50% of individuals with bipolar disorder will attempt suicide in their lifetime. Research on development of suicide behavior in bipolar disorder is critically needed to prevent suicide and identify biomarkers of risk for targeted intervention(s). We recently identified structural differences within anterior-paralimbic systems associated with risk for future suicide attempts in bipolar disorder. How these structural differences functionally translate into risk for suicide is unknown but might relate to their role(s) in stress response. While stress system hyperactivity is supported in bipolar disorder, there are limited data investigating if variation neural responses to stress may contribute to suicide thoughts and behavior in youth with bipolar disorder. The planned research will investigate the relations between neurophysiological responses to stress and suicide thoughts and behavior in euthymic adolescents and young adults with bipolar disorder type I to test the hypothesis that altered neurophysiological response to stress assessed through functional MRI and physiological monitoring is an early trait marker of risk for suicide thoughts and behavior. Ninety adolescents/young adults (30 with bipolar disorder and history of suicide attempt; 30 with bipolar disorder and no history of attempt, and 30 typically developing controls with no history of mood disorders or attempt) will complete comprehensive clinical and behavioral assessments and functional imaging to investigate neurophysiological responses to an acute psychosocial stress task. Over half of the proposed sample has already completed study assessments with the proposed research increasing power to focus directly on suicide attempt history. Relations with suicide ideation, hopelessness, impulsivity, attempt lethality and executive functioning will be investigated. The relations between responses to stress, childhood maltreatment, and substance use (alcohol, marijuana, and tobacco) will be explored. We hypothesize individuals with bipolar disorder and history of suicide attempt(s), compared to those without, will show increases in paralimbic system activation, decreases in activation of prefrontal cortex, and a loss of functional coupling among regions in response to acute stress. Variation in neural responses to stress will be associated with physiological response to stress, with abnormalities in anterior-paralimbic circuitry related to emotional vulnerability and increasing risk for suicide behavior. Childhood maltreatment and substance use will be associated with ventral and dorsal anterior-paralimbic responses to stress, respectively. Results could greatly contribute to understanding the role(s) of variation in response to acute stress in suicide risk, and potentially neural predictors of suicide, in bipolar disorder, during adolescence/young adulthood when suicidal behaviors often emerge, and more generally, the relations with childhood maltreatment and substance use. This work will provide the basis for a future program of research on suicide, specifically understanding modifiable factors that increase risk for suicide to promote targeted early interventions when early treatment may have the most impact on lifelong outcome.