Splitting the reward: Differences in inflammatory marker associations with neural connectivity between reward anticipation and reward outcome in adolescents at high risk for depression

Adolescent depression is associated with both dysfunction in neural reward processing and peripheral inflammatory markers (PIMs), such as interleukin-6 (IL-6), C-reactive-protein (CRP), and tumor-necrosis factor alpha (TNFα). Few adolescent studies have examined neural-inflammatory marker associations and associated behavioral correlates, which would contribute to a better understanding of developmental processes linked to depression. 36 adolescents at high risk of depression completed an fMRI reward task (during anticipation and outcome), blood draw for PIMs (IL-6, CRP, and TNFα), and a behavioral task assessing motivation to expend effort. Analyses examined associations of task-dependent functional connectivity (FC; ventral striatum to frontal and default mode network brain regions), and if the interaction of PIMs and task-dependent FC predicted motivation to expend effort. For anticipation contrast, TNFα was associated with increased task-dependent FC between the LVS and PCC/vmPFC. In moderation analyses, for anticipation contrasts, the combination of higher IL-6 and stronger FC (LVS-precuneus/PCC) was associated with lower motivation to expend effort, while for outcome contrasts, the combination of higher IL-6 and stronger FC (VS-precuneus/PCC) was associated with greater motivation to expend effort. Our findings in adolescents during an important developmental time period suggest that PIMs are directly linked to greater FC between the VS and DMN brain regions during win anticipation, consistent with prior studies. Effects of PIMs on motivation to expend effort may vary the strength/type of neural reward processing (anticipation or outcome), which could guide better understanding how inflammatory markers and neural reward substrates contribute to development of depression in high-risk adolescents.