Vasovagal syncope as a specific side effect of DLPFC-rTMS: A frontal-vagal dose-finding study

In the treatment of depression using repetitive Transcranial Magnetic Stimulation (rTMS), the intensity of stimulation is based on the motor threshold (MT). However, prior work demonstrated that frontal excitability thresholds are not related to MT but to percentage machine output (%MSO), suggestive of relevant differences between MT and frontal excitability thresholds [[1]Iseger T.A. Padberg F. Kenemans J.L. van Dijk H. Arns M. Neuro-Cardiac-Guided TMS (NCG TMS): a replication and extension study.Biol Psychol. 2021; 108097https://doi.org/10.1016/j.biopsycho.2021.108097Crossref PubMed Scopus (9) Google Scholar]. Neuro-cardiac-guided TMS (NCG-TMS) employs rTMS-induced heart rate deceleration to confirm activation of the frontal-vagal pathway [[2]Iseger T.A. van Bueren N.E.R. Kenemans J.L. Gevirtz R. Arns M. A frontal-vagal network theory for Major Depressive Disorder: implications for optimizing neuromodulation techniques.Brain Stimul. 2020; 13: 1-9https://doi.org/10.1016/j.brs.2019.10.006Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar], and thereby represents a first immediate output of frontal stimulation. NCG-TMS 2.0 is a major update of the NCG-TMS method which we are currently validating, at 4 prefrontal sites (right and left Beam and 5-cm sites) per subject [[3]Dijkstra E, van Dijk H, Vila-Rodriguez F, Zwienenberg L, Rouwhorst R, Blumberger DM, et al. Transcranial Magnetic Stimulation-induced heart-braincoupling: implications for site selection and frontal thresholding; [under review)].Google Scholar]. In the pre-pilot phase, aimed at optimizing the methodology, one subject experienced a near-syncopal event during stimulation. This was a healthy 43-year-old woman with no personal or family history of cardiovascular disease or depression. We want to describe the case-vignette here, which suggests vasovagal syncope could be a specific side-effect of pre-frontal TMS. In this case rTMS was applied with a DuoMag XT-100 system (Deymed Diagnostic, Czech Republic) equipped with a focal figure-of-eight coil. Stimulation was applied in 4 trains of 10 Hz for 5 seconds duration with an ITI of 11 seconds (Dash protocol [[4]Carpenter LindaL. ScottT Aaronson Hutton T.M. Mina M. Pages K. Verdoliva S. et al.Comparison of clinical outcomes with two Transcranial Magnetic Stimulation treatment protocols for major depressive disorder.Brain Stimul. 2021; 14: 173-180https://doi.org/10.1016/j.brs.2020.12.003Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]). This 64 seconds pattern was repeated seven times with an intensity-sweep from low to high intensities defined in 5% MSO, with the fifth intensity matching the individuals 100% MT. This stimulation train was preceded by 60 seconds of rest. The starting intensity of MSO was defined as 20% MSO below 100% of the individual MT (see Fig. 1 for further visualization). The starting site for this subject was Beam-F3, and due to the syncope occurring after stimulation of this site, we did not apply it to the other planned sites. ECG was measured simultaneously using a Brainquiry PET-EEG device and BioExplorer software. ECG data were analyzed offline using a custom python analysis package using several existing packages [[5]Gramfort A. Luessi M. Larson E. Engemann D.A. Strohmeier D. Brodbeck C. et al.MEG and EEG data analysis with MNE-Python.Front Neurosci-Switz. 2013; 7: 267https://doi.org/10.3389/fnins.2013.00267Crossref PubMed Scopus (969) Google Scholar]. As visualized in Fig. 1A, this stimulation pattern induces a specific 1/16 seconds, or 0.0625Hz, rhythmicity superimposed over the cardiac R-R intervals. This rhythm suggests a TMS induced heart-brain-coupling. As visualized in Fig. 1B (Subject A), the mean heart rate (HR) shows a 6–7/min. rhythmicity in the rest and low-intensity stimulations, and only at stimulation intensity 6 and 7 a 4/min rhythmicity becomes apparent as visualized by the heart-brain coupling at 0.0625Hz in the time-frequency representation (TFR). This implies a suprathreshold activation of the frontal-vagal pathway. However, in Fig. 1C (Subject B), the 4/min. rhythmicity already becomes apparent at stimulation intensity 2 (45% MSO, representing 75% MT in this subject). Furthermore, linear regression shows that HR decreased with an average of 2.22 beats per minute (BPM) in Subject B vs. an average of 0.19 BPM in Subject A (β1 = −0.0222 vs. β1 = −0.0023). During 6 minutes of stimulation the resting HR of Subject B dropped from 80 BPM to below 60 BPM, whereas in Subject A the resting HR dropped only from 72 BPM to 64 BPM during 7 minutes of stimulation. The HR-data measured by Subject B's smartwatch collected over the prior month demonstrated an average HR of 67.6 BPM, and a lowest HR value of 65 BPM. This suggests that the DLPFC-rTMS specifically induced a HR deceleration resulting in a HR below Subject B's lowest HR of that month. The subject experienced feelings of dizziness and lightheadedness during the stimulation. Her Calgary Syncope Symptom Score [[6]Romme J.J.C.M. van Dijk N. Boer K.R. Bossuyt P.M.M. Wieling W. Reitsma J.B. Diagnosing vasovagal syncope based on quantitative history-taking: validation of the Calgary Syncope Symptom Score.Eur Heart J. 2009; 30: 2888-2896https://doi.org/10.1093/eurheartj/ehp314Crossref PubMed Scopus (51) Google Scholar] was +1. Additional analyses demonstrated that the heart rate variability (HRV) increased over the stimulation period, further suggesting that the syncope was not simply caused by tension or anxiety since a reduced HRV would be expected in that case. This case report illustrates, in line with an earlier NCG study [[1]Iseger T.A. Padberg F. Kenemans J.L. van Dijk H. Arns M. Neuro-Cardiac-Guided TMS (NCG TMS): a replication and extension study.Biol Psychol. 2021; 108097https://doi.org/10.1016/j.biopsycho.2021.108097Crossref PubMed Scopus (9) Google Scholar], that the frontal threshold can deviate substantially from the MT. The 20 BPM drop in HR combined with an increased HRV, eventually resulting in a near vasovagal syncope, suggests a TMS-induced parasympathetic overdrive in a dose-dependent manner. Syncope has been linked to the mechanism of vasodilation in young adults and to a fall in cardiac output in adults [[7]Jardine D.L. Wieling W. Brignole M. Lenders J.W.M. Sutton R. Stewart J. The pathophysiology of the vasovagal response.Heart Rhythm. 2018; 15: 921-929https://doi.org/10.1016/j.hrthm.2017.12.013Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. It has been suggested that the vasovagal reflex is a protective mechanism against sympathetic overactivity, protecting the heart during emotional and orthostatic stress [[8]Alboni P. Alboni M. Typical vasovagal syncope as a "defense mechanism" for the heart by contrasting sympathetic overactivity.Clin Auton Res. 2017; 27: 253-261https://doi.org/10.1007/s10286-017-0446-2Crossref PubMed Scopus (21) Google Scholar]. Several case studies have reported the occurrence of syncope during single pulse TMS, for example Vallence [[9]Vallence A.M. Fujiyama H. Rurak B.K. Wansbrough K. Haigh Y. Suspected vasovagal syncope during single-pulse TMS in healthy adults: three case reports.Clin Neurophysiol. 2020; 131: 2540-2541https://doi.org/10.1016/j.clinph.2020.08.007Crossref PubMed Scopus (1) Google Scholar] and Van Dam [[10]Dam J.V. Goldsworthy M. Case report of a vasovagal pre-syncope event during single-pulse transcranial magnetic stimulation in a healthy adult participant.Clin Neurophysiol. 2020; 131: 981-982https://doi.org/10.1016/j.clinph.2019.12.401Crossref PubMed Scopus (3) Google Scholar], amongst others. The case presented here shows that future studies into this topic could be of great importance to increase safety and treatment efficacy in major depressive disorder (MDD) as well as our understanding of the working mechanism of rTMS. In case of high-frequency DLPFC stimulation, vasovagal syncope may represent a specific side effect of rTMS. Furthermore, the relatively low threshold at which heart-brain coupling already became apparent in this subject (75% MT), relative to the control subject (>100% MT), is suggestive of possibly relevant inter-individual variability in frontal excitability thresholds, requiring further research. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MA is unpaid chairman of the non-profit Brainclinics Foundation, holds equity/stock in neurocare, serves as consultant to neurocare, and is named inventor on neurocare owned patent and intellectual property related to neuro-cardiac-guided TMS, but receives no royalties; Research Institute Brainclinics received research funding from neurocare group (Munich, Germany) and equipment support from Deymed and neuroConn. All other authors declare no interests.