Target-Specificity and repeatability in neuro-cardiac-guided TMS for heart-brain coupling

The dorsolateral prefrontal cortex (DLPFC) is a principal target for transcranial magnetic stimulation (TMS) in treating major depressive disorder, with therapeutic effects thought to be mediated by its connectivity with the subgenual anterior cingulate cortex. As both regions are involved in autonomic regulation, short-term heart rate changes following DLPFC stimulation may serve as physiological markers to identify stimulation targets. We employed neuro-cardiac guided TMS in a cohort of healthy participants to examine the effects of stimulation intensity and DLPFC target specificity on heart-brain coupling (HBC). We used generalized additive models to assess nonlinear effects of stimulation intensity and target location on HBC, while accounting for pain ratings and other side effects. Intra-subject repeatability across three sessions was evaluated using intraclass correlation coefficients. We observed a non-linear modulation of HBC depending on stimulation intensity and target location, with greater effects at the F3 lateral and F3 posterior targets compared to sham. By evaluating these effects across sessions within participants, we demonstrate the robustness of our results beyond the influence of pain and other side effects on HBC modulation. Exploratory analyses of the directionality show a consistent decrease in HR only at the F3 lateral target with suprathreshold stimulation. These results demonstrate that HBC is modulated in a target- and intensity-specific manner, with particularly consistent effects at F3 lateral sites within the DLPFC. The findings enhance the understanding of TMS-modulated heart-brain interactions, offering a potential framework for optimizing individualized rTMS treatment protocols for depression.