Inflammation is associated with altered functional connectivity of the cingulate cortex in individuals with subthreshold depression

Subthreshold depression (StD) represents a critical prodromal phase that often precedes clinical depression. Identifying biological indicators during this stage is essential for the prophylaxis of major depressive disorder. The present study investigated the interplay between serum pro-inflammatory cytokines, functional connectivity (FC) within subregions of the cingulate cortex (CC), and psychometric profiles in an StD cohort. The study included 126 participants with StD and 104 healthy controls. Resting-state functional magnetic resonance imaging data, psychological assessments [Center for Epidemiologic Studies Depression Scale (CES-D), 24-item Hamilton Depression Rating Scale (HAMD-24), Hamilton Anxiety Scale (HAMA), Ruminative Responses Scale (RRS)], and serum pro-inflammatory cytokine levels [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and IL-17] were collected. The StD group exhibited increased FC in three specific circuits: The left middle CC (MCC) to the bilateral caudate nucleus (CN); the left supracallosal anterior CC (supACC) to the bilateral anterior cerebellar lobe; the right supACC to the right superior frontal gyrus (SFG). Furthermore, serum concentrations of TNF-α, IL-1β, and IL-17 were significantly increased. FC between the left MCC and bilateral CN was associated with CES-D and RRS scores, whereas FC between the right supACC and right SFG was associated with HAMA scores. Interaction between IL-1β and FC in the right supACC-SFG circuit was independently associated with HAMA scores, whereas interaction between IL-17 and FC in the same circuit independently predicted RRS scores. The statistical interaction between IL-1β and IL-17 levels and right supACC-SFG FC is associated with anxiety and rumination symptoms in StD, which may indicate an increased risk of progression to major depression. These findings underscore the significance of neuroimmune associations in subthreshold depression.