Gray and White matter microstructural alterations in major depressive disorder: a multi-center diffusion imaging study.

Diffusion imaging techniques have been widely used to investigate alterations in brain microstructure associated with major depressive disorder (MDD). Due to its technical limitations, diffusion tensor imaging (DTI)-based studies have often been restricted to evaluating white matter (WM), and analyses of gray matter (GM) microstructural changes using advanced diffusion models remain insufficient. 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 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 microstructural tissue disorganization may underlie the pathophysiology of MDD, emphasizing the need for future research to link neuroimaging findings with underlying biological mechanisms.