White matter free water and depressive symptoms in medication-free depressed adolescents: moderation by peripheral inflammation

Major Depressive Disorder (MDD) often emerges during adolescence and significantly impacts psychological and social functioning. Increasing evidence links both peripheral inflammation and white matter abnormalities to the pathophysiology of MDD. Free-water (FW) imaging, sensitive to neuroinflammatory and microstructural changes, enables investigation of their interplay in depression. However, the role of FW imaging in adolescents with MDD, along with its clinical and inflammatory associations, remains underexplored. Here, we conducted a cross-sectional analysis and exploratory analysis of the relationship between white matter FW, peripheral inflammation, and depressive symptoms in adolescents. 3-T multi-shell diffusion-weighted magnetic resonance imaging data and peripheral cytokine were collected from 147 participants aged 12-18 years, including 63 medication-free adolescents with MDD and 84 healthy controls (HC). FW maps were generated using the DIPY toolbox, followed by voxel-wise analyses conducted with Tract-Based Spatial Statistics in FSL. Our findings reveal that adolescents with MDD exhibited lower levels of inflammatory cytokines, including IFN-γ, IL-2, TNF-α, and IL-4 (all p < 0.05), along with significantly reduced white matter FW (family-wise error-corrected p < 0.05). Importantly, IFN-γ levels significantly moderated the relationship between altered white matter FW and depressive symptoms (β = 0.46, p = 0.003). Specifically, in adolescents with MDD and higher IFN-γ levels, greater white matter FW was associated with more severe depressive symptoms, while in those with lower IFN-γ levels, higher FW was linked to less severe symptoms. These results suggest that peripheral inflammation, particularly IFN-γ, may be associated with the relationship between white matter FW and the severity of depressive symptoms. This highlights the importance of considering an individual's inflammatory status when interpreting the biological and psychological functioning of adolescents with MDD.