Inflammation and reward-related neural circuitry dysfunction: Testing an integrative model of suicidal ideation in adolescents

About This Grant

Suicide is the leading cause of non-accidental death in adolescents in the US, and rates of suicide continue to rise in adolescent populations. Yet, the biological mechanisms leading to adolescent suicide that could inform effective preventive treatments for suicide remain unclear. To understand adolescent suicide, scientists often study suicidal ideation (SI), given that SI is strongly associated with suicidal behavior (SB) and is methodologically more feasible to study in adolescents. This K23 proposal will test a novel and integrative neurobiological model in adolescents with the hypothesis that circulating and stimulated peripheral inflammatory markers (PIMs; e.g. IL-6, TNFα, CRP) contribute to dysfunction in reward-related corticostriatal (CS) circuitry, and that this dysfunction in CS circuitry (and related behavioral correlates) contributes to adolescent SI. Prior research has linked PIM activation to SI/SB, but the biological mechanisms by which PIMs might contribute to SI remain unclear. Existing literature suggests that PIMs might affect CS functional connectivity, and that dysfunction in CS functional connectivity predicts SI and SB, though this integrative model has not been previously tested. Based on conceptual models and early clinical studies, one specific feature of reward processing - effort expenditure for reward (i.e., the amount of effort an individual is willing to expend for a reward) - may specifically be linked to SI/SB. In addition, the described integrative model is particularly relevant in adolescents, who are at a vulnerable developmental epoch for both reward circuitry and immune system maturation. This K23 will test the proposed model in 90 adolescents with unipolar depressive disorders, enriched with adolescents with a history of SI or SB. Adolescents will be followed over four timepoints over twelve months, with measurements of PIMs, CS functional connectivity during a reward task, and SI. This proposal will address key gaps in the field of adolescent suicide research, including understanding (1) the association between PIMs and CS connectivity in predicting future SI, (2) the relationships between PIMs and CS circuitry, and (3) the role of CS circuitry in explaining relationships between PIMs and SI. Understanding these gaps in the literature could elucidate clinically meaningful mechanisms of adolescent suicide, identify biobehavioral markers that could predict future SI, and potentially guide future interventions for adolescent SI/SB. The candidate will receive advanced training from an expert mentorship team, including knowledgeable co-mentors (Drs. Price, Brent, Forbes, and Marsland) and consultants (Drs. Brundin, Treadway, Thoma, and Wallace). The research environment at the University of Pittsburgh provides excellent resources. Consistent with the candidate’s career goals of better understanding biobehavioral mechanisms involved in adolescent suicidality, research findings from this K23 would inform future R01 proposals that could examine mechanisms by which PIMs contribute to SB in large samples, and aid development of interventions targeting PIMs or CS circuitry to reduce SI/SB.