Toward personalized deep brain stimulation via white matter stimulation and microstructure in depression

Treatment-resistant depression (TRD) affects a substantial proportion of individuals with major depressive disorder, posing a significant clinical and societal burden. Among emerging interventions, tractography-guided Subcallosal Cingulate Deep Brain Stimulation (SCC-DBS) shows promise as a treatment for TRD. However, despite the use of connectome-based targeting methods, clinical outcomes remain variable across individuals. Here, we examined individual white matter (WM) properties underlying the variability of SCC-DBS response for depression by analyzing a patient-specific diffusion MRI dataset of SCC-DBS patients (n = 51), incorporating individualized stimulation modeling and weekly clinical assessments over the first 24 weeks of DBS. We evaluated two distinct WM measures: the volumetric proportion of stimulated WM tracts (STP: stimulated-tract proportion) and the microstructural integrity of these tracts estimated by fractional anisotropy (FA). The STP in the bilateral mid-cingulum bundles and forceps minor reaching the left ventral frontal pole was positively associated with clinical improvement. Although FA alone did not show association with clinical improvement, it moderated the relationship between STP and clinical improvement, suggesting differential contributions of the two pathways in mediating antidepressant effects of SCC-DBS. These findings underscore that future refinements in stimulation delivery may be guided by greater attention to patient-specific WM metrics within the targeted network. A study of 51 patients receiving deep brain stimulation for treatment-resistant depression shows that individual white matter stimulation and integrity jointly influence antidepressant response, supporting more personalized neuromodulation strategies.