Abstract
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.
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Data availability
The data are not publicly available due to the fact that they contain information that could compromise the privacy of research participants, but they may be shared upon reasonable request with an institutional data use agreement. Contact person: S.H.S., email address: shsiddiqi@bwh.harvard.edu.
Code availability
The custom-made code used in the current study is publicly available for download via GitHub at https://github.com/brainclinics/HBC (ref. 40).
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Acknowledgements
J.J.T. receives funding from the Brain and Behavior Research Foundation Young Investigator Grant (31081) and NIH (K23MH129829, R01MH113929, R21MH12671 and R21AA030372). S.H.S. was supported by the Brain & Behavior Research Foundation, the Baszucki Family Foundation and the National Institute of Mental Health (PI: K23MH121657, Co-I: R01MH113929). The funders were not directly involved in the conceptualization, design, analysis, decision to publish or preparation of the manuscript. The authors thank W. Drew and E. Ye for supporting administrative and practical tasks during data collection.
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Conceptualization, E.S.A.D., M.A. and S.H.S.; investigation, E.S.A.D., S.B.F. and S.H.S.; formal analysis, E.S.A.D.; project administration, E.S.A.D., S.B.F. and S.H.S.; software, H.v.D.; supervision, M.A. and S.H.S.; writing—original draft, E.S.A.D., M.A. and S.H.S.; writing—review and editing, H.v.D., J.J.T., F.D. and A.T.S. All authors contributed to the article and approved the submitted version.
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E.S.A.D. is director and owner of Neurowave. A.T.S. is Chief Scientific Advisor of PlatoScience and Alphasys, CEO of Neurowear Medical B.V., received equipment support from MagVenture, Deymed and MagStim Company, and is Scientific Director of the International Clinical TMS Certification Course (www.tmscourse.eu). M.A. holds equity/stock in neurocare and Sama Therapeutics, served as consultant to Synaeda, Sama Therapeutics and Roche and is named inventor on patents and intellectual property but receives no royalties. Brainclinics Foundation received equipment support from MagVenture and Deymed. S.H.S. is a scientific consultant for Magnus Medical, is a clinical consultant for Acacia Mental Health, Kaizen Brain Center and Boston Precision Neurotherapeutics, and has received investigator-initiated research funding from Neuronetics and Brainsway. S.H.S. has served as a speaker for Brainsway and PsychU.org (unbranded, sponsored by Otsuka). S.H.S. owns intellectual property involving the use of functional connectivity to target TMS. The other authors declare no competing interests.
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Dijkstra, E.S.A., Frandsen, S.B., van Dijk, H. et al. Probing prefrontal-sgACC connectivity using TMS-induced heart–brain coupling. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00248-8
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DOI: https://doi.org/10.1038/s44220-024-00248-8