Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression

Depressive disorders are linked to dysfunction in reward-related behaviors and corticostriatal reward circuitry. Low-grade dysregulation of the immune system, e.g., elevations in plasma interleukin 6 (IL-6) and tumor necrosis factor α, have been thought to affect corticostriatal reward circuitry. Little is presently known about the degree to which these relationships generalize to patients with treatment-resistant depression (TRD) and/or childhood trauma history.

Resting-state functional connectivity between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) regions and plasma inflammatory marker levels (IL-6, tumor necrosis factor α) were measured in 74 adults with TRD. Regression analyses examined associations of inflammatory markers with VS-vmPFC connectivity and the moderating effects of self-reported childhood trauma on these associations, with exploratory analyses examining trauma subtypes.

IL-6 was negatively associated with VS-vmPFC connectivity (specifically for the left VS). Childhood trauma moderated the relationships between tumor necrosis factor α and VS-vmPFC connectivity (specifically for the right VS) such that greater childhood trauma severity (particularly emotional neglect) was associated with stronger cytokine-connectivity associations.

This study independently extends previously reported associations between IL-6 and reductions in corticostriatal connectivity to a high-priority clinical population of treatment-seeking patients with TRD and further suggests that childhood trauma moderates specific associations between cytokines and corticostriatal connectivity. These findings suggest that associations between elevated plasma cytokine levels and reduced corticostriatal connectivity are a potential pathophysiological mechanism generalizable to patients with TRD and that such associations may be affected by trauma severity.