White matter functional connectome gradient dysfunction in major depressive disorder

Background: Major depressive disorder (MDD) is a prevalent psychiatric disorder with disruptions in brain white matter (WM). While much research has focused on WM structure, the dysfunctional organization of WM in MDD remains poorly understood. Methods: Using resting-state functional magnetic resonance imaging data from 48 MDD patients and 68 healthy controls (HC), we characterized the WM functional connectome gradients across participants and identified both global and regional alterations in MDD. Furthermore, we examined the relationship between gradient properties and depressive symptom severity. External validation and sensitivity analyses were finally conducted to ensure the reliability of results. Results: The principal WM connectome gradient extended from the forceps major and superior longitudinal fasciculus to the uncinate fasciculus (UF) and anterior thalamic radiation (ATR), exhibiting a superficial-to-deep pattern in both groups. Compared to HC, MDD patients displayed a narrower gradient range and lower spatial variation, indicating a contracted WM hierarchy. At the tract-specific level, MDD patients exhibited lower gradient scores in the forceps minor, left ATR and UF, and bilateral cingulate gyrus and cingulum hippocampus, but higher gradient scores in the forceps major, bilateral inferior longitudinal fasciculus and superior longitudinal fasciculus. WM tract gradient patterns explained 37.2% of the variance in clinical severity, with the strongest contributions from the inferior fronto-occipital fasciculus, cingulum hippocampus, ATR, UF, and corticospinal tract. Conclusions: These findings highlight altered WM functional connectome gradient in MDD and their association with clinical severity, offering novel insights into the neurobiological mechanisms of the disorder and potential biomarkers for symptom evaluation.