White matter tracts associated with iTBS-induced heart rate deceleration and treatment response in major depressive disorder

Intermittent theta burst stimulation (iTBS) is a well-established treatment for major depressive disorder (MDD), but predicting clinical outcomes remains challenging. Heart rate modulation induced by iTBS has emerged as a potential biomarker for treatment response, yet the role of white matter (WM) properties in mediating these effects is largely unexplored. In this quadruple-blind, crossover study, we investigated the relationship between WM microstructure, iTBS-driven heart rate deceleration, and antidepressant effects. Using correlational tractography, we analyzed four major WM tracts--the cingulum, fornix, superior longitudinal fasciculus, and uncinate fasciculus--and examined short-term WM microstructural changes to assess their predictive value for therapeutic outcomes. Baseline WM findings revealed that in the fornix and right dorsal cingulum fractional anisotropy (FA) negatively correlated with heart rate deceleration. Radial and mean diffusivity (MD, RD) in the fornix positively correlated with heart rate deceleration. FA in the right ventral cingulum positively correlated while MD and RD negatively correlated with symptom improvement. Longitudinally, FA increases in the left cingulum were significantly associated with greater symptom alleviation after treatment. Notably, iTBS-induced heart rate modulations correlated with clinical improvement after six weeks, while WM microstructural properties in the fornix and cingulum demonstrated predictive value for both heart rate modulation and treatment response. WM changes in the cingulum, evident as early as four weeks, highlight its unique neuroplasticity potential along iTBS intervention. Together, these findings provide novel insights into the structural connectivity patterns influencing iTBS outcomes, offering a novel foundation for more personalized therapeutic strategies in MDD.