Electroconvulsive therapy modulates neurite density and free water in discrete white matter compartments in major...

Electroconvulsive therapy (ECT) is the most effective treatment for severe or intractable depression. The disrupt-potentiate-rewire framework proposes that ECT's therapeutic effects include neural remodeling. We used the neurite orientation dispersion and density imaging (NODDI) model to characterize ECT-related longitudinal white matter (WM) microstructural changes. Fifty-two adults with treatment-resistant major depressive episodes (32 female) from two cohorts underwent multi-shell diffusion MRI and clinical assessment before the first ECT session and after completion of the index course. Plasma interleukin-6 (IL-6) was measured in one cohort. Linear mixed-effects models assessed longitudinal changes in neurite density, orientation dispersion, and free water across major WM tracts, with false-discovery-rate correction. Regression analyses examined relationships between WM changes, symptom improvement, and IL-6 change if available. Fractional anisotropy (FA) was also examined for comparison with prior studies. Depressive symptoms improved substantially, and IL-6 levels decreased following treatment. Neurite density, free water, and FA decreased across multiple frontolimbic pathways, including the uncinate fasciculus, external capsule, and internal capsule, whereas orientation dispersion remained unchanged. Free-water reductions were predominantly right-lateralized. In contrast to FA, greater NODDI-derived microstructural change was associated with greater depression symptom improvement across several mood-relevant pathways, while reductions in IL-6 showed trend-level associations with WM change. ECT was associated with coordinated reductions in neurite density and free water, alongside preserved fiber organization, within distributed WM pathways. These findings support microstructural remodeling during the putative rewiring phase of ECT and link WM change to both antidepressant improvement and changes in peripheral inflammation.