Transcranial Magnetic Stimulation-Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding-Preliminary Findings.

Background: Neurocardiac-guided transcranial magnetic stimulation (TMS) uses repetitive TMS (rTMS)-induced heart rate deceleration to confirm activation of the frontal-vagal pathway. Here, we test a novel neurocardiac-guided TMS method that utilizes heart-brain coupling (HBC) to quantify rTMS-induced entrainment of the interbeat interval as a function of TMS cycle time. Because prior neurocardiac-guided TMS studies indicated no association between motor and frontal excitability threshold, we also introduce the approach of using HBC to establish individualized frontal excitability thresholds for optimally dosing frontal TMS. Methods: In studies 1A and 1B, we validated intermittent theta burst stimulation (iTBS)-induced HBC (2 seconds iTBS on; 8 seconds off: HBC = 0.1 Hz) in 15 (1A) and 22 (1B) patients with major depressive disorder from 2 double-blind placebo-controlled studies. In study 2, HBC was measured in 10 healthy subjects during the 10-Hz "Dash" protocol (5 seconds 10-Hz on; 11 seconds off: HBC = 0.0625 Hz) applied with 15 increasing intensities to 4 evidence-based TMS locations. Results: Using blinded electrocardiogram-based HBC analysis, we successfully identified sham from real iTBS sessions (accuracy: study 1A = 83%, study 1B = 89.5%) and found a significantly stronger HBC at 0.1 Hz in active compared with sham iTBS ( Conclusions: We demonstrated rTMS-induced HBC as a function of TMS cycle time for 2 commonly used clinical protocols (iTBS and 10-Hz Dash). These preliminary results supported individual site specificity and dose-response effects, indicating that this is a potentially valuable method for clinical rTMS site stratification and frontal thresholding. Further research should control for TMS side effects, such as pain of stimulation, to confirm these findings.