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

Eva Dijkstra; Hanneke van Dijk; Fidel Vila-Rodriguez; Lauren Zwienenberg; Renée Rouwhorst; John P. Coetzee; Daniel M. Blumberger; Jonathan Downar; Nolan Williams; Alexander T. Sack; Martijn Arns

doi:10.1016/j.bpsgos.2023.01.003

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

Eva Dijkstra^*, Hanneke van Dijk, Fidel Vila-Rodriguez, Lauren Zwienenberg, Renée Rouwhorst, John P. Coetzee, Daniel M. Blumberger, Jonathan Downar, Nolan Williams, Alexander T. Sack, Martijn Arns

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. 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.

Original language	English
Pages (from-to)	939-947
Number of pages	9
Journal	Biological Psychiatry: Global Open Science
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.bpsgos.2023.01.003
Publication status	Published - Oct 2023

Keywords

Dash rTMS
Frontal-vagal network
Heart rate
Heart-brain coupling
iTBS, NCG-TMS

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10.1016/j.bpsgos.2023.01.003Licence: CC BY

Cite this

Dijkstra, E., van Dijk, H., Vila-Rodriguez, F., Zwienenberg, L., Rouwhorst, R., Coetzee, J. P., Blumberger, D. M., Downar, J., Williams, N., Sack, A. T., & Arns, M. (2023). Transcranial Magnetic Stimulation–Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding—Preliminary Findings. Biological Psychiatry: Global Open Science, 3(4), 939-947. https://doi.org/10.1016/j.bpsgos.2023.01.003

@article{4736621384f74a3986145658b62ee142,

title = "Transcranial Magnetic Stimulation–Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding—Preliminary Findings",

abstract = "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 (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. 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.",

keywords = "Dash rTMS, Frontal-vagal network, Heart rate, Heart-brain coupling, iTBS, NCG-TMS",

author = "Eva Dijkstra and {van Dijk}, Hanneke and Fidel Vila-Rodriguez and Lauren Zwienenberg and Ren{\'e}e Rouwhorst and Coetzee, {John P.} and Blumberger, {Daniel M.} and Jonathan Downar and Nolan Williams and Sack, {Alexander T.} and Martijn Arns",

note = "Funding Information: ED is director and owner of Neurowave. FV-R receives research support from Canadian Institutes of Health Research (CIHR), Brain, Canada, Michael Smith Foundation for Health Research , Vancouver Coastal Health Research Institute , and Weston Brain Institute for investigator-initiated research; philanthropic support from Seedlings Foundation; and in-kind equipment support for an investigator-initiated trial from MagVenture. He has received an honorarium for participation in an advisory board for Allergan. DMB receives research support from the CIHR, National Institutes of Health—United States , Brain Canada Foundation and the Temerty Family through the Centre for Addiction and Mental Health Foundation and the Campbell Family Research Institute . He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd . and he was the site principal investigator for 3 sponsor-initiated studies for Brainsway Ltd . He received in-kind equipment support from MagVenture for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated on the advisory board for Janssen and Welcony Inc. JD reports research grants from CIHR, the National Institute for Mental Health, Brain, Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute , the Klarman Family Foundation , the Arrell Family Foundation, and the Edgestone Foundation; travel stipends from Lundbeck and ANT Neuro; in-kind equipment support for investigator-initiated trials from MagVenture; and is an advisor for BrainCheck, NeuroStim TMS, and Salience Neuro Health. NW is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Nooma, and Halo Neuroscience; and has equity/stock options in Magnus Medical, NeuraWell, and Nooma. ATS is the Chief Scientific Advisor of PlatoScience and Alphasys; the Chief Executive Officer of Neurowear Medical BV; received equipment support from MagVenture, Deymed, and MagStim Company; and is the Scientific Director of the International Clinical TMS Certification Course ( http://www.tmscourse.eu ). MA is unpaid chairman of the Brainclinics Foundation, holds equity/stock in neurocare, serves as consultant to neurocare, and is a named inventor on neurocare owned patent and intellectual property related to neurocardiac-guided TMS, but receives no royalties. Research Institute Brainclinics received research and consultancy support from neurocare, Brainify, UrgoTech and equipment support from neuroConn and Deymed. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

doi = "10.1016/j.bpsgos.2023.01.003",

language = "English",

volume = "3",

pages = "939--947",

journal = "Biological Psychiatry: Global Open Science",

issn = "2667-1743",

publisher = "Elsevier Inc.",

number = "4",

}

Dijkstra, E, van Dijk, H, Vila-Rodriguez, F, Zwienenberg, L, Rouwhorst, R, Coetzee, JP, Blumberger, DM, Downar, J, Williams, N, Sack, AT & Arns, M 2023, 'Transcranial Magnetic Stimulation–Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding—Preliminary Findings', Biological Psychiatry: Global Open Science, vol. 3, no. 4, pp. 939-947. https://doi.org/10.1016/j.bpsgos.2023.01.003

Transcranial Magnetic Stimulation–Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding—Preliminary Findings. / Dijkstra, Eva; van Dijk, Hanneke; Vila-Rodriguez, Fidel et al.
In: Biological Psychiatry: Global Open Science, Vol. 3, No. 4, 10.2023, p. 939-947.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Transcranial Magnetic Stimulation–Induced Heart-Brain Coupling

T2 - Implications for Site Selection and Frontal Thresholding—Preliminary Findings

AU - Dijkstra, Eva

AU - van Dijk, Hanneke

AU - Vila-Rodriguez, Fidel

AU - Zwienenberg, Lauren

AU - Rouwhorst, Renée

AU - Coetzee, John P.

AU - Blumberger, Daniel M.

AU - Downar, Jonathan

AU - Williams, Nolan

AU - Sack, Alexander T.

AU - Arns, Martijn

N1 - Funding Information: ED is director and owner of Neurowave. FV-R receives research support from Canadian Institutes of Health Research (CIHR), Brain, Canada, Michael Smith Foundation for Health Research , Vancouver Coastal Health Research Institute , and Weston Brain Institute for investigator-initiated research; philanthropic support from Seedlings Foundation; and in-kind equipment support for an investigator-initiated trial from MagVenture. He has received an honorarium for participation in an advisory board for Allergan. DMB receives research support from the CIHR, National Institutes of Health—United States , Brain Canada Foundation and the Temerty Family through the Centre for Addiction and Mental Health Foundation and the Campbell Family Research Institute . He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd . and he was the site principal investigator for 3 sponsor-initiated studies for Brainsway Ltd . He received in-kind equipment support from MagVenture for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated on the advisory board for Janssen and Welcony Inc. JD reports research grants from CIHR, the National Institute for Mental Health, Brain, Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute , the Klarman Family Foundation , the Arrell Family Foundation, and the Edgestone Foundation; travel stipends from Lundbeck and ANT Neuro; in-kind equipment support for investigator-initiated trials from MagVenture; and is an advisor for BrainCheck, NeuroStim TMS, and Salience Neuro Health. NW is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Nooma, and Halo Neuroscience; and has equity/stock options in Magnus Medical, NeuraWell, and Nooma. ATS is the Chief Scientific Advisor of PlatoScience and Alphasys; the Chief Executive Officer of Neurowear Medical BV; received equipment support from MagVenture, Deymed, and MagStim Company; and is the Scientific Director of the International Clinical TMS Certification Course ( http://www.tmscourse.eu ). MA is unpaid chairman of the Brainclinics Foundation, holds equity/stock in neurocare, serves as consultant to neurocare, and is a named inventor on neurocare owned patent and intellectual property related to neurocardiac-guided TMS, but receives no royalties. Research Institute Brainclinics received research and consultancy support from neurocare, Brainify, UrgoTech and equipment support from neuroConn and Deymed. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2023 The Authors

PY - 2023/10

Y1 - 2023/10

N2 - 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 (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. 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.

AB - 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 (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. 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.

KW - Dash rTMS

KW - Frontal-vagal network

KW - Heart rate

KW - Heart-brain coupling

KW - iTBS, NCG-TMS

U2 - 10.1016/j.bpsgos.2023.01.003

DO - 10.1016/j.bpsgos.2023.01.003

M3 - Article

SN - 2667-1743

VL - 3

SP - 939

EP - 947

JO - Biological Psychiatry: Global Open Science

JF - Biological Psychiatry: Global Open Science

IS - 4

ER -