Neural response to reward as a potential pathway from inflammation to anhedonia in adolescents at risk for depression

Depression in adolescents has been associated with high levels of circulating inflammatory markers, with a putative mechanism including disrupted function in neural reward circuitry leading to anhedonia, a symptom that involves difficulty with motivation or enjoyment of pleasant experiences. Adolescence provides an opportunity to examine these pathways, as it is the time of onset of anhedonia and depression, and developmental changes in the immune system and reward circuitry. This study used a high-risk design to examine whether development of depression and anhedonia in 45 healthy adolescents (age 13-19) is related to higher levels of inflammatory markers via response in neural reward circuitry. Depression and anhedonia were assessed at enrollment and 6 months later, with a subset of participants completing additional assessment approximately 1 year after study entry. At baseline, adolescents completed a functional magnetic resonance imaging monetary reward task and provided blood samples for assessment of serum levels of tumor necrosis factor-alpha (TNF- α), interleukin-6 (IL-6), and C-reactive protein (CRP). Higher levels of TNF-α and CRP were associated with lower depression and anhedonia severity at baseline and 6-month follow-up, respectively. Higher response in rostral anterior cingulate cortex/medial prefrontal cortex partially statistically mediated the association between baseline CRP level and anhedonia severity 6 months later. Adolescents who were assessed 1 year later did not exhibit higher anhedonia severity at that time point, suggesting that findings could reflect a mechanism of resilience. This study provides a step toward understanding the interplay of inflammation and neural reward circuitry in the development of anhedonia.