Severity-dependent fronto-cingulate network compensation of immune-dependent caudate-insula dysconnectivity in bipolar II depression

Depressive symptoms in bipolar II depression (BDII-D) arise from brain dysconnectivity within medial prefrontal cortex (mPFC)-centered networks, in interaction with peripheral inflammatory alterations. This study aimed to characterize structure-derived functional connectivity (FC) changes in BDII-D and to determine how dysconnectivity relates to depression severity and inflammatory markers, particularly interleukin (IL)-1β. A total of 147 individuals with BDII-D and 150 healthy controls underwent fMRI, peripheral inflammation, and clinical symptom assessments. Based on prior structural alterations in BDII-D, seed-based FC changes were examined. Partial correlation analyses with multiple comparisons correction evaluated associations among altered FC, inflammatory cytokines, psychiatric symptoms, and clinical profiles. A moderation analysis tested whether IL-1β moderated the relationship between altered FC and depressive symptoms in BDII-D. Greater depressive symptoms in BDII-D were associated with higher caudate-insula and right triangular inferior frontal gyrus-bilateral superior frontal gyrus (SFG) connectivity, as well as lower medial SFG-posterior cingulate cortex (PCC) connectivity. IL-1β moderated the relationship between caudate-insula connectivity and depressive symptoms. The association between lower medial SFG-PCC connectivity and greater depressive severity was absent in BDII-D with HAMD < 17 (mild depressive symptoms) but significant in those with HAMD ≥ 17(moderate-to-severe depressive symptoms). Lower left middle frontal gyrus-right lateral superior lateral occipital gyrus connectivity was significantly associated with higher psychotic positive symptoms. Depressive symptoms in BDII-D reflect inflammation-related dysconnectivity across emotion and sensory networks. mPFC alterations may indicate adaptive processes and a potential neuromodulation target, while frontal-visual dysconnectivity is related to psychotic symptoms, suggesting a role of visual processing in the pathophysiology of BDII-D.