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 deceleration 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 modulation, and antidepressant effects. Using correlational tractography, we focused on four major WM tracts-the cingulum, fornix, superior longitudinal fasciculus, and uncinate fasciculus-to examine short-term microstructural changes in relation to therapeutic outcomes. At baseline, findings revealed that fractional anisotropy (FA) in the fornix and right dorsal cingulum was negatively correlated with heart rate deceleration, while radial and mean diffusivity (MD, RD) in the fornix were positively correlated. In the right ventral cingulum, FA showed a positively correlation, while MD and RD were negatively correlated with symptom improvement. Longitudinally, FA increases in the left cingulum were significantly associated with greater symptom alleviation post-treatment. Notably, the correlation between iTBS-induced heart rate modulations and clinical improvement after six weeks, previously demonstrated in this cohort, was identified, 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.