Probing prefrontal-sgACC connectivity using TMS-induced heart-brain coupling

Transcranial magnetic stimulation (TMS)-induced heart-brain coupling (HBC) has been proposed as a technique capable of validating target engagement of the frontal-vagal pathways, without the need of fMRI-guided neuronavigation. In parallel, recent fMRI-guided, personalized TMS protocols aim to target prefrontal regions that are negatively connected to the subgenual anterior cingulate cortex (sgACC), as these targets may have better antidepressant efficacy. It has never been tested to what extent the HBC-based target selection and these fMRI-guided targets are overlapping. Here we used fMRI-guided TMS to determine whether TMS-induced HBC is specifically affected when targeting regions negatively connected to the sgACC. In this crossover pilot study, we applied neuronavigated TMS in 14 healthy participants to five frontal and five parietal areas positively connected (bilateral), negatively connected (bilateral) or neutrally connected (midline) to the sgACC. The targets were prospectively determined using individual resting-state fMRI. We compared TMS-induced effects on HBC between different TMS targets, for frontal and parietal areas separately. With prefrontal targets, 12 out of 14 participants (86%) showed maximal HBC at TMS sites negatively connected to sgACC. HBC power was significantly higher in left frontal (d = 0.68) and left parietal (d = 0.75) targets negatively connected to sgACC versus respective targets with neutral connections to sgACC. This effect was unrelated to magnitude of negative connectivity strength. By contrast, HBC power was correlated with sgACC connectivity strength at right frontal (r = 0.56) and right parietal (r = 0.72) targets negatively connected to sgACC. We used fMRI-guided TMS to predictably and selectively modulate heart rate measured using HBC. HBC may be used as an agile readout to identify individualized TMS targets that specifically target prefrontal-sgACC connectivity.