Gray and White Matter Microstructural Alterations in Major Depressive Disorder: A Multi-Center Diffusion Imaging Study

Alterations in gray matter (GM) and white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). While previous neuroimaging studies have primarily focused on WM microstructural changes, limited attention has been given to GM alterations. Additionally, many of these studies concentrate on region-specific associations with symptoms rather than a comprehensive assessment of broader microstructural changes. In this study, we employed neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) to investigate GM and WM microstructural changes at both whole-brain and regional levels. Data were collected from 159 MDD patients and 112 healthy controls across multiple centers. Our findings revealed significantly increased mean free water fraction (FWF) in GM, elevated mean orientation dispersion index (ODI) in WM, and decreased fractional anisotropy (FA) in WM among MDD patients compared to healthy controls. Furthermore, the mean FA of WM exhibited a negative correlation, and the mean ODI of WM showed a positive correlation with illness duration. No significant correlations were observed between diffusion indices and Hamilton Depression Rating Scale (HAMD-17) scores. Gray matter-based spatial statistics demonstrated increased FWF in several GM regions, including the frontal lobes, temporal lobes, and limbic system. Tract-based spatial statistics revealed widespread reductions in FA across WM in MDD patients. These findings suggest that neuroinflammation and myelin abnormalities may underlie the observed microstructural changes, emphasizing the need for future research to link neuroimaging findings with underlying biological mechanisms of MDD.