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

Abstract 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. Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT05260086 Funding Statement This work was supported by the German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung, BMBF: 01 ZX 1507, PreNeSt - e:Med). JW was also supported by the Goettingen Promotionskolleg fuer Medizinstudierende, funded by the Jacob-Henle-Programm/Else-Kroener-Fresenius-Stiftung. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University Medical Center Goettingen, Goettingen, Germany; Ethics Committee of the University Medical Center Goettingen; accepted I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes