Published online Mar 18, 2021.
https://doi.org/10.12786/bn.2021.14.e6
Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation
Abstract
Studies using repetitive transcranial magnetic stimulation (rTMS) in healthy individuals and those with neuropsychiatric diseases have rapidly increased since the 1990s, due to the potential of rTMS to modulate the cortical excitability in the brain depending on the stimulation parameters; therefore, the safety considerations for rTMS use are expected to become more important. Wassermann published the first safety guidelines for rTMS from the consensus conference held in 1996, and Rossi and colleague then published the second safety guidelines from the multidisciplinary consensus meeting held in Siena, Italy in 2008, on behalf of the International Federation of Clinical Neurophysiology. More than 10 years after the second guidelines, the updated third safety guidelines were recently published in 2021. The general safety guidelines for conventional rTMS have not substantially changed. Because the most frequently used rTMS protocol is conventional (low- and high-frequency) rTMS in research and clinical settings, we focus on reviewing safety issues when applying conventional rTMS with a focal cortical stimulation coil. The following issues will be covered: 1) possible adverse events induced by rTMS; 2) checklists to screen for any precautions and risks before rTMS; 3) safety considerations for dosing conventional rTMS; and 4) safety considerations for using rTMS in stroke and traumatic brain injury.
Highlights
• Repetitive transcranial magnetic stimulation (rTMS) conforming to the safety guideline is generally safe.
• Any precautions and risks for rTMS should be screened prior to starting rTMS.
• Risk-benefit ratios of rTMS should be carefully discussed in high-risk situations.
INTRODUCTION
Studies using repetitive transcranial magnetic stimulation (rTMS) in healthy individuals and those with neuropsychiatric diseases have rapidly increased since the 1990s [1, 2], due to the potential of rTMS to modulate cortical excitability in the brain depending on the stimulation parameters [3]. Recent evidence-based guidelines have recommended the application of rTMS in various neurological and psychiatric diseases, with higher evidence of efficacy in depression, pain, and motor recovery after stroke [2]. Therefore, rTMS use in research and clinical settings is anticipated to become more common, and the safety considerations for rTMS use are expected to become more important.
Wassermann [4] published the first TMS safety guidelines from the consensus conference held in 1996, and Rossi et al. [1] then published the second safety guidelines from the multidisciplinary consensus meeting held in Siena, Italy in 2008, on behalf of the International Federation of Clinical Neurophysiology. More than 10 years after the second guidelines, the updated third safety guidelines were published in 2021 [5]. The general safety guidelines for conventional rTMS did not substantially change in the new safety guidelines. Because the most used rTMS protocol is conventional (low- and high-frequency) rTMS in research and clinical settings, we focus on reviewing the safety issues when applying conventional rTMS with a focal cortical stimulation coil (e.g., a figure-8 coil). The following issues will be covered: 1) possible adverse events induced by rTMS; 2) checklists to screen for any precautions and risks before rTMS; 3) safety considerations for dosing conventional rTMS; and 4) safety considerations for using rTMS in stroke and traumatic brain injury (TBI). Updated safety issues for new devices (e.g., new pulse generators or new coils), other stimulation paradigms including patterned rTMS and paired associated stimulation, as well as combinations with other devices, are comprehensively reviewed in the 2021 safety guidelines by Rossi et al. [5].
ADVERSE EVENTS
Seizures
Seizures induced by rTMS are the most concerning acute adverse event, and can occur during or immediately after rTMS or during the after-effects of rTMS due to the long-lasting modulation of cortical excitability. In a recent systematic review including 93 placebo-controlled clinical trials (n=1,854 in the placebo-treated group and n=2,290 in the TMS-treated group), the risk of seizures was extremely low (0.1% in the active TMS group and 0.2% in the placebo group) [6]. Lerner et al. [7] conducted a survey to investigate observed seizures between 2012 and 2016 in 714 active laboratories or clinics, which reported an estimated 318,560 TMS sessions. Overall, TMS induced rare cases of seizures (24 seizures, 8/100,000 sessions). Only 4 seizures (<2/100,000 sessions) occurred when TMS was delivered within the dosing parameters according to previously published guidelines in subjects without risk factors (e.g., brain lesions and epilepsy) [1, 4]. The total risk of seizures was comparable between different rTMS protocols (low frequency: 3/1,000,000 sessions, high frequency: 5/1,000,000 sessions, intermittent theta burst: 6/1,000,000 sessions, continuous theta burst: 0/6,924 total sessions). No seizure cases were reported in either low- or high-frequency rTMS delivered within the specifications of the published guidelines to subjects with no risk factors for seizure. Therefore, the risk of seizures induced by rTMS is low if the stimulation parameters are within the previously published safety guidelines and focal coils [5]. However, since seizures can arise in any subject and using any rTMS protocol [8], medical readiness to deal with a seizure during rTMS and immediately after the rTMS session is necessary, especially when treating individuals with risk factors (Table 1).
Syncope
Vasovagal syncope is common during noninvasive or minimally invasive medical procedures due to procedure-related anxiety or psychophysical discomfort, which can lead to fall-related injuries. In the survey by Lerner et al. the most common adverse events were syncope or presyncope (17% among 174 respondents) [7]. Distinguishing syncope from seizure is often difficult, but the following symptoms and signs may favor syncope over seizure: light-headedness, sweating, pallor, slow pulse, and low blood pressure [16].
Hearing
rTMS can evoke a transient repetitive acoustic artifact with a maximum sound pressure level ranging from 96.5 to 110 dB [17, 18], which exceeds the 80 dB safety threshold, for 3 seconds. Moreover, conventional sound measurements cannot quantify the bone conduction through skull during rTMS and can underestimate the acoustic artifact [18, 19]. The effect of the acoustic artifact induced by rTMS on the subject's ear can be influenced by the simulation intensity, frequency, coil type, stimulation site (proximity to the ear) and pre-existing auditory symptoms (e.g., tinnitus). The recent expert guidelines recommended well-fitted hearing protection (e.g., earplugs) for both subjects and rTMS operators, and careful screening for any hearing-related complaints after rTMS [5].
Other minor side effects
Headache or local pain around the stimulation site after TMS was found to be common (16% among respondents from active laboratories or clinics) [7]. In a systematic review on the safety of rTMS for depression including sham-controlled studies, headache (28%) and local pain or discomfort (39%) were also common [20]. The cause of pain during rTMS is not clear, but it is postulated that scalp or upper facial muscle contractions or trigeminal stimulation by rTMS may play a role [1]. The headache and local pain is usually transient and long-term continuation of pain after rTMS is rare. Acute psychiatric changes (e.g., mania, hypomania, anxiety, agitation, or psychotic symptoms) have been reported in several rTMS studies and the survey by Lerner et al., but the occurrence rate is low and these changes were usually transient [1, 5, 7, 21, 22, 23]. Moreover, most studies reporting acute psychiatric changes after rTMS were conducted in patients with psychiatric disorders; therefore, it is unclear whether these psychiatric symptoms are induced by rTMS or occurred during the natural course of the underlying psychiatric disorders [5, 21, 22, 23]. However, the recent safety guidelines by Rossi et al. [5] recommended that “patients with depression undergoing rTMS should be informed about the unlikely possibility of developing acute psychiatric side effects.”
CHECKLISTS FOR rTMS CANDIDATES
To reduce the potential risk of adverse events induced by rTMS, checklists to screen rTMS candidates must be considered (Table 2) [1].
SAFETY CONSIDERATIONS ON DOSING PARAMETERS FOR rTMS
The consensus-based safety table for conventional rTMS (low- or high-frequency) using a figure-8 coil was presented in the previous guidelines by Rossi et al. in 2009 (Tables 3, 4, 5) [1]. These safety tables were considered to be effective to prevent seizure in healthy subjects and patients, and no revisions were made in the 2021 safety guidelines [5]. In high-frequency rTMS, an inter-train interval of more than 5 seconds is usually considered to be safe (Tables 4 and 5). The maximal safe duration of a single rTMS train according to the frequency and stimulation intensity also must be considered. For example, the safe parameters for 10 Hz rTMS with a stimulation intensity of 110% of the resting motor threshold using a figure-8 coil according will be an inter-train interval of >5,000 ms, with up to 5 seconds (50 pulses) in a single rTMS train (Tables 3, 4, 5). A longer duration of the inter-train interval is considered as the number of rTMS trains increases. However, an enormous variety of combinations of rTMS parameters, some of them exceeding the safety limits, have been applied in numerous rTMS papers. The 2021 safety guidelines recommend that “the principal investigator has to balance the overall risk/benefit ratio of the proposed intervention and use neurophysiological monitoring in case the combination of parameters of stimulation exceed the 2009 safety guidelines” [5]. Regarding the safety parameters of patterned rTMS (quadripulse stimulation, theta burst stimulation), supplementary tables S3 and S5 in the 2021 safety guidelines should be consulted [5].
Table 3
Maximum safe duration (seconds) of single trains of conventional rTMS using a figure-8 coil
Table 4
Safety recommendations for inter-train intervals for 10 trains at <20 Hz
Table 5
Safety recommendations for maximal duration of pulses for individual rTMS trains at each stimulus intensity
SAFETY CONSIDERATIONS IN STROKE AND TBI
Stroke
rTMS to improve the recovery of motor and non-motor impairments has been actively investigated [24, 25]. In recent large clinical trials of low-frequency rTMS using a figure-8 coil in subacute or chronic stroke, no seizure was reported and serious adverse device events were not statistically significantly different between real and sham rTMS [26, 27]. In a recent systematic review of rTMS and upper limb motor recovery after stroke [28], only three studies reported adverse events among 28 studies monitoring adverse events, and these events were minor and transient (e.g., mild headache, nausea, neck pain, dizziness, tingling sensation, abnormal sleep) [29, 30, 31]. In addition, no serious adverse events were reported for high-frequency rTMS [28]. In a systematic review of high-frequency rTMS for post-stroke depression, minor adverse events including headache, loss of appetite, local pain, local discomfort, and anxiety were reported in 6 studies [32]. Among those reported adverse events, only headache was more common in the high-frequency rTMS group than in controls. Therefore, rTMS within the parameters of the safety guidelines is generally safe in patients with stroke, but the individual risk-benefit ratio for rTMS should be evaluated, especially for patients with an elevated risk of seizure or requiring precautions for rTMS, and when new devices or protocols are applied.
TBI
In a recent scoping review by Pink et al. [33], 30 empirical rTMS studies including case reports and randomized controlled trials in patients with traumatic brain injuries were fully reviewed. Although most studies reported no adverse events [34, 35, 36] or minor side effects such as headache, dizziness, and fatigue [37, 38, 39], Cavinato et al. [40] reported a partial and secondarily generalized tonic-clonic seizure after the fourth daily session of 20 Hz rTMS within the parameters in the safety guidelines. Pape et al. [41] also reported an electroencephalographic seizure without clinical accompaniment after the 21st excitatory rTMS session in a 32-year-old man with disordered consciousness after TBI. In an open-label study including seven patients with disordered consciousness after traumatic brain injuries, 75 nonserious adverse events and one seizure were reported during total 30 excitatory rTMS sessions (300 pulses/session) over the right or left dorsolateral prefrontal cortex [42]. One patient with a seizure event during the rTMS trial continued planned rTMS sessions with antiepileptic drugs and no seizure recurrence was observed. Therefore, rTMS protocols for TBI patients conforming to the safety guidelines [1] seem generally to be safe, but the potential for seizure induction and any precautions for rTMS should be thoroughly evaluated based on the clinical information before rTMS. Possible seizure events should also be closely monitored during and after rTMS sessions with an appropriate seizure management plan.
SUMMARY
rTMS conforming to the current safety guidelines (Tables 3, 4, 5) can be applied safely to both healthy volunteers and patients with acquired brain diseases such as stroke and TBI. However, the principal investigator and clinician should screen rTMS candidates with a checklist (Table 2) to identify any contraindications and precautions for rTMS, as well as risk factors for rTMS-induced major side effects such as seizures (Table 1). If rTMS candidates have higher risks for serious adverse events or rTMS protocols are not considered to be safe (e.g., parameters exceeding safety guidelines, a new stimulation paradigm, new stimulation devices), the risk-benefit ratio should be carefully evaluated, and an adequate management and monitoring plan should be established prior to rTMS.
Funding:This study was supported by Seoul National University Bundang Hospital Research Fund (14-2015-030).
Conflict of Interest:Nam-Jong Paik is the medical advisor for REMED Co. (Korea) without remuneration.
References
-
Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipović SR, Grefkes C, Hasan A, Hummel FC, Jääskeläinen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorová I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018). Clin Neurophysiol 2020;131:474–528.
-
-
Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Pascal Lefaucheur J, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M. basis of this article began with a Consensus Statement from the IFCN Workshop on “Present, Future of TMS: Safety, Ethical Guidelines”, Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert guidelines. Clin Neurophysiol 2021;132:269–306.
-
-
Zis P, Shafique F, Hadjivassiliou M, Blackburn D, Venneri A, Iliodromiti S, Mitsikostas DD, Sarrigiannis PG. Safety, tolerability, and nocebo phenomena during transcranial magnetic stimulation: a systematic review and meta-analysis of placebo-controlled clinical trials. Neuromodulation 2020;23:291–300.
-
-
Dhamne SC, Kothare RS, Yu C, Hsieh TH, Anastasio EM, Oberman L, Pascual-Leone A, Rotenberg A. A measure of acoustic noise generated from transcranial magnetic stimulation coils. Brain Stimulat 2014;7:432–434.
-
-
Koponen LM, Goetz SM, Tucci DL, Peterchev AV. Sound comparison of seven TMS coils at matched stimulation strength. Brain Stimulat 2020;13:873–880.
-
-
Goetz SM, Lisanby SH, Murphy DL, Price RJ, O'Grady G, Peterchev AV. Impulse noise of transcranial magnetic stimulation: measurement, safety, and auditory neuromodulation. Brain Stimulat 2015;8:161–163.
-
-
Janicak PG, O’Reardon JP, Sampson SM, Husain MM, Lisanby SH, Rado JT, Heart KL, Demitrack MA. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry 2008;69:222–232.
-
-
Sakai K, Yasufuku Y, Kamo T, Ota E, Momosaki R. Repetitive peripheral magnetic stimulation for impairment and disability in people after stroke. Cochrane Database Syst Rev 2019;11:CD011968
-
-
Kim WJ, Rosselin C, Amatya B, Hafezi P, Khan F. Repetitive transcranial magnetic stimulation for management of post-stroke impairments: an overview of systematic reviews. J Rehabil Med 2020;52:jrm00015
-
-
Harvey RL, Edwards D, Dunning K, Fregni F, Stein J, Laine J, Rogers LM, Vox F, Durand-Sanchez A, Bockbrader M, Goldstein LB, Francisco GE, Kinney CL, Liu CY, Ryan S, Morales-Quezada L, Worthen-Chaudhari L, Labar D, Schambra H, Kappy CR, Kissela B, Pratt W. NICHE Trial Investigators. Randomized sham-controlled trial of navigated repetitive transcranial magnetic stimulation for motor recovery in stroke. Stroke 2018;49:2138–2146.
-
-
Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, Wagner T, Fecteau S, Rigonatti SP, Riberto M, Freedman SD, Pascual-Leone A. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006;37:2115–2122.
-
-
Du J, Tian L, Liu W, Hu J, Xu G, Ma M, Fan X, Ye R, Jiang Y, Yin Q, Zhu W, Xiong Y, Yang F, Liu X. Effects of repetitive transcranial magnetic stimulation on motor recovery and motor cortex excitability in patients with stroke: a randomized controlled trial. Eur J Neurol 2016;23:1666–1672.
-
-
Paxman E, Stilling J, Mercier L, Debert CT. Repetitive transcranial magnetic stimulation (rTMS) as a treatment for chronic dizziness following mild traumatic brain injury. BMJ Case Rep 2018;2018:bcr2018226698
-
-
Pape TL, Rosenow JM, Patil V, Steiner M, Harton B, Guernon A, Herrold A, Pacheco M, Crisan E, Ashley WW Jr, Odle C, Park Y, Chawla J, Sarkar K. RTMS safety for two subjects with disordered consciousness after traumatic brain injury. Brain Stimulat 2014;7:620–622.
-
-
Kletzel SL, Aaronson AL, Guernon A, Carbone C, Chaudhry N, Walsh E, Conneely M, Patil V, Roth E, Steiner M, Pacheco M, Rosenow J, Bender Pape TL. Safety considerations for the use of transcranial magnetic stimulation as treatment for coma recovery in people with severe traumatic brain injury. J Head Trauma Rehabil 2020;35:430–438.
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MeSH Terms
Tables
ORCID IDs
Funding Information
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Seoul National University Bundang Hospital
14-2015-030