The possible effect of inflammation on non-suicidal self-injury in adolescents with depression: a mediator of connectivity within corticostriatal reward circuitry

Non-suicidal self-injury (NSSI) in adolescent depression is a prevalent and clinically significant behavior linked to dysregulated peripheral inflammation and corticostriatal circuitry dysfunction. However, the neuroimmune mechanisms bridging these systems remain poorly understood. Here, we combined peripheral cytokine profiling with static/dynamic functional connectivity (sFC/dFC) analysis to investigate the potential influence of inflammaton on corticostriatal circuit related to NSSI. A set of peripheral blood inflammatory markers and resting-state functional magnetic resonance imaging (rs-fMRI) were collected in depression with NSSI (NSSI+), depression without NSSI (NSSI-), and healthy controls (HC). We first ascertain group differences in level of pro- and anti-inflammatory cytokines. And using ventral/dorsal striatal seeds, we compared whole-brain, voxel-wise sFC and dFC differences across three groups. Further, we tested the mediation effects of connectivity in the association between inflammatory markers and NSSI frequency. NSSI+ group exhibited elevated pro-inflammatory cytokines (C-reactive protein (CRP), interleukin (IL)-1, and IL-6) whereas reduced anti-inflammatory cytokines (IL-10), compared to NSSI- and HC. Neuroimaging analysis revealed corticostriatal dysconnectivity mainly characterized by static hyperconnectivity between dorsal striatum and thalamus, dynamic instability in dorsal striatum-lingual pathways, and dynamic rigidity in ventral striatum-prefrontal/temporal/occipital gyrus circuits. Critically, sFC of dorsal striatum-thalamus and dFC of dorsal striatum-lingual gyrus mediated the prospective association between altered CRP and NSSI frequency, establishing corticostriatal circuits as conduits for inflammatory effects on NSSI. By bridging molecular psychiatry with circuit neuroscience, this work advances precision management of NSSI in adolescent depression, prioritizing biomarker-driven strategies to disrupt neuroimmune maladaptation.