Elsevier

Clinical Neurophysiology

Volume 120, Issue 12, December 2009, Pages 2008-2039
Clinical Neurophysiology

Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research

https://doi.org/10.1016/j.clinph.2009.08.016Get rights and content

Abstract

This article is based on a consensus conference, which took place in Certosa di Pontignano, Siena (Italy) on March 7–9, 2008, intended to update the previous safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings.

Over the past decade the scientific and medical community has had the opportunity to evaluate the safety record of research studies and clinical applications of TMS and repetitive TMS (rTMS). In these years the number of applications of conventional TMS has grown impressively, new paradigms of stimulation have been developed (e.g., patterned repetitive TMS) and technical advances have led to new device designs and to the real-time integration of TMS with electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Thousands of healthy subjects and patients with various neurological and psychiatric diseases have undergone TMS allowing a better assessment of relative risks. The occurrence of seizures (i.e., the most serious TMS-related acute adverse effect) has been extremely rare, with most of the few new cases receiving rTMS exceeding previous guidelines, often in patients under treatment with drugs which potentially lower the seizure threshold.

The present updated guidelines review issues of risk and safety of conventional TMS protocols, address the undesired effects and risks of emerging TMS interventions, the applications of TMS in patients with implanted electrodes in the central nervous system, and safety aspects of TMS in neuroimaging environments. We cover recommended limits of stimulation parameters and other important precautions, monitoring of subjects, expertise of the rTMS team, and ethical issues. While all the recommendations here are expert based, they utilize published data to the extent possible.

Introduction

Transcranial magnetic stimulation (TMS) is a neurostimulation and neuromodulation technique, based on the principle of electromagnetic induction of an electric field in the brain. This field can be of sufficient magnitude and density to depolarize neurons, and when TMS pulses are applied repetitively they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation, even beyond the duration of the train of stimulation. This has behavioral consequences and therapeutic potential.

The last decade has seen a rapid increase in the applications of TMS to study cognition, brain-behavior relations and the pathophysiology of various neurologic and psychiatric disorders (Wassermannn and Lisanby, 2001, Kobayashi and Pascual-Leone, 2003, Gershon et al., 2003, Tassinari et al., 2003, Rossi and Rossini, 2004, Leafaucheur, 2004, Hoffman et al., 2005, Couturier, 2005, Fregni et al., 2005a, Fregni et al., 2005b, Hallett, 2007, George et al., 2007, Málly and Stone, 2007, Rossini and Rossi, 2007, Devlin and Watkins, 2007, Ridding and Rothwell, 2007). In addition, evidence has accumulated that demonstrates that TMS provides a valuable tool for interventional neurophysiology applications, modulating brain activity in a specific, distributed, cortico-subcortical network so as to induce controlled and controllable manipulations in behavior.

Repetitive transcranial magnetic stimulation (rTMS) has been found to be a promising noninvasive treatment for a variety of neuropsychiatric conditions (Devlin and Watkins, 2007, George et al., 2007, Aleman et al., 2007, Fregni and Pascual-Leone, 2007), and the number of applications continues to increase with a large number of ongoing clinical trials in a variety of diseases. Therapeutic utility of TMS has been claimed in the literature for psychiatric disorders, such as depression, acute mania, bipolar disorders, panic, hallucinations, obsessions/compulsions, schizophrenia, catatonia, post-traumatic stress disorder, or drug craving; neurologic diseases such as Parkinson’s disease, dystonia, tics, stuttering, tinnitus, spasticity, or epilepsy; rehabilitation of aphasia or of hand function after stroke; and pain syndromes, such as neuropathic pain, visceral pain or migraine. A large industry-sponsored trial (O’Reardon et al., 2007) and a multi-center trial in Germany (Herwig et al., 2007) of rTMS in medication of refractory depression have been completed, and other appropriately controlled and sufficiently powered clinical trials of TMS are ongoing.

Most claims of therapeutic utility of TMS across conditions need further support and evidence-based clinical trial data, but the potential clinical significance is huge, affecting a large number of patients with debilitating conditions. A number of clinics have been set up worldwide offering TMS for treatment of various diseases, and rTMS is already approved by some countries for treatment of medication-refractory depression (i.e., Canada and Israel). In October 2008, a specific rTMS device was approved by the Food and Drug Administration in the United States for the treatment of patients with medication-refractory unipolar depression who have failed one good (but not more than one) pharmacological trial. It is reasonable to expect that the use of rTMS and its penetrance in the medical community will continue to increase across different medical specialties.

The number of laboratories using TMS for therapeutic or neuroscientific purposes, and consequently the number of healthy individuals and patients with various neurological or psychiatric diseases studied worldwide, has been increasing yearly for the past 20 years (Fig. 1). A further increase in the wide-spread use of TMS in medical therapeutic applications and research is expected. This makes the need for clear and updated safety guidelines and recommendations of proper practice of application critical.

Current safety precautions and practice recommendations remain guided by the consensus conference held at the National Institutes of Health in June 1996 and summarized in Clinical Neurophysiology (Wassermannn, 1998). These recommendations were adopted with minor modifications by the International Federation for Clinical Neurophysiology (Hallett et al., 1999). Ethical considerations on the application of TMS to health and disease were initially dealt with by Green et al. (1997) during the early stages of rTMS testing, and more recently have been addressed by several publications (Wolpe, 2002, Mashour et al., 2005, Illes et al., 2006, Steven and Pascual-Leone, 2006). However, as previously mentioned, the use of TMS has grown dramatically in the past decade, new protocols of TMS have been developed, changes in the devices have been implemented, TMS is being increasingly combined with other brain imaging and neurophysiologic techniques including fMRI and EEG, and a growing number of subjects and patients are being studied with expanding numbers of longer stimulation sessions.

The safety of TMS continues to be supported by recent meta-analyses of the published literature (see Machii et al., 2006, Loo et al., 2008, Janicak et al., 2008), yet there is a clear need to revisit the safety guidelines, update the recommendations of practice, and improve the discussion of ethical aspect to be reflective of the expanding uses of these powerful and promising techniques. Towards this end, a consensus conference took place in Certosa di Pontignano, Siena (Italy) on March 7–9, 2008. As in the 1996 NIH Consensus Conference, the 2008 meeting brought together some of the leading researchers in the fields of neurophysiology, neurology, cognitive neuroscience and psychiatry who are currently using TMS for research and clinical applications. In addition, representatives of all TMS equipment manufacturers were invited and those of Magstim, Nexstim, and Neuronetics were present, along with representatives from various regulatory agencies and several basic and applied scientists, including physicists, and clinicians whose work has bearing on decisions regarding the safe and ethical use of rTMS. The present article represents a summary of the issues discussed and the consensus reached. It follows the outline of the 1998 consensus statement, addressing all issues raised previously to provide corrections or updates where necessary, and including various new topics needed given technological advances.

Section snippets

Nomenclature

TMS can be applied one stimulus at a time, single-pulse TMS, in pairs of stimuli separated by a variable interval, paired-pulse TMS, or in trains, repetitive TMS. Single-pulse TMS can be used, for example, for mapping motor cortical outputs, studying central motor conduction time, and studying causal chronometry in brain-behavior relations. In paired pulse techniques TMS stimulation can be delivered to a single cortical target using the same coil or to two different brain regions using two

Heating

Tissue heating of the brain by a single-pulse TMS itself is very small and is estimated to be definitely less than 0.1 °C (Ruohonen and Ilmoniemi, 2002). It appears to be even smaller in areas with low perfusion such as cysts or strokes (R. Ilmoniemi, personal communication). However, high brain blood perfusion ensures a safety range (Brix et al., 2002). For comparison, heating in the immediate surround of deep brain stimulation electrodes is estimated to be at maximum 0.8 °C (Elwassif et al.,

Side effects

All the known side effects linked with TMS use are summarized in Table 1. It is apparent that data on theta burst stimulation (TBS) are still not sufficient to claim or deny safety hazards. This implies that future therapeutic and research studies employing TBS and other forms of patterned repetitive TMS should explicitly address this issue, which has been neglected up to now. Below, the most significant, potential side effects of conventional TMS are commented on in further detail, including

Considerations on patient selection

The following paragraphs include several issues that should be taken into account (and should be developed in terms of future specific research) before planning a therapeutic course with rTMS, as well as pathophysiological group studies in patients.

To understand the special safety and ethical issues presented by therapeutic applications of TMS, it is important to consider the potential impact of the neurological or psychiatric illness under treatment, the impact of concomitant treatments, and

Considerations on dosing TMS

In addition to the 4 key parameters that define rTMS trains (intensity, frequency, train duration, and inter-train interval), the repeated application of rTMS introduces additional dosing parameters that describe the cumulative exposure to rTMS. These include total pulses per session, sessions per day, days per week, weeks per acute course, and maintenance frequency. Many other emerging variables, besides coil type (see paragraph 1.3), which are addressed in the following paragraphs, should be

Update of the safety guidelines

The above considerations lead to the development of a new set of guidelines for the safe administration of TMS. The new guidelines, whenever possible, use the 1998 guidelines as a basis. Considerations include ethical and regulatory aspects, stimulation parameters, physiological and neuropsychological monitoring of subjects, settings in which TMS can be done, composition and expertise of the rTMS team, management of potential adverse effects, and contraindications to TMS.

Acknowledgements

The workshop was supported by the International Federation of Clinical Neurophysiology (IFCN), the European Chapter of the IFCN, the National Institute of Neurological Disorders and Stroke, the University of Siena, as well as unrestricted gifts from Magstim, Nexstim, and Neuronetics. APL was also supported by the Berenson-Allen Family Foundation.

Authors thank Matteo Feurra, Psy. D. for providing Fig. 2.

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    A Consensus Statement from the International Workshop on “Present and Future of TMS: Safety and Ethical Guidelines”, Siena, March 7–9, 2008.

    1

    Giuliano Avanzini, Neurocienze Cliniche, Istituto Nazionale Neurologico “C. Besta, Milano, Italy.

    Sven Bestmann, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.

    Alfredo Berardelli, Department of Neurological Sciences and Neuromed Institute, University of Rome “La Sapienza”, Roma, Italy.

    Carmen Brewer, National Institute on Deafness and other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.

    Turhan Canli, Department of Psychology, Stony Brook University, New York, USA.

    Roberto Cantello, Dipartimento di Medicina Clinica e Sperimentale, Sezione Neurologia, Università del Piemonte Orientale “A. Avogadro”, Novara, Italy.

    Robert Chen, Toronto Western Research Institute and Division of Neurology, Department of Medicine, University of Toronto, Canada.

    Joseph Classen, Department of Neurology, University of Leipzig, Germany.

    Mark Demitrack, Neuronetics, Inc., Malvern, PA, USA.

    Vincenzo Di Lazzaro, Institute of Neurology, Univesità Cattolica, Roma, Italy.

    Charles M. Epstein, Department of Neurology, Emory University School of Medicine, Atlanta, USA.

    Mark S. George, Medical University of South Carolina, Charleston, SC, USA.

    Felipe Fregni, Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel.

    Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

    Risto Ilmoniemi, Department Biomed. Eng. and Computational Science (BECS), Helsinki, Finland.

    Reza Jalinous, Magstim Company, Boston, MA, USA.

    Barbara Karp, Combined NeuroScience IRB, National Institutes of Health, Bethesda, MD, USA.

    Jean-Pascal Lefaucheur, Service Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil, France.

    Sarah Lisanby, Division of Brain Stimulation & Therapeutic Modulation, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY, USA.

    Sabine Meunier, Service de Réadaptation Fonctionnelle, Hôpital de la Salpêtrière, Paris, France.

    Carlo Miniussi, Cognitive Neuroscience Section, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

    Pedro Miranda, Institute of Biophysics and Biomedical Engineering, Faculty of Science, University of Lisbon, Portugal.

    Frank Padberg, Klinik für Psychiatrie und Psychotherapie, Ludwig-Maximilians-Universität München, Germany.

    Walter Paulus, Department of Clinical Neurophysiology, University of Goettingen, Germany.

    Angel Peterchev, Division of Brain Stimulation and Therapeutic Modulation, Department of Psychiatry and Department of Electrical Engineering, Columbia University, New York, NY, USA.

    Corinna Porteri, Bioethics Unit, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

    Miriam Provost, Medical Devices Biologics Consulting Group, Inc., Athens, GA, USA.

    Angelo Quartarone, Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, Università di Messina, Italy.

    Alexander Rotenberg, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Children’s Hospital, Harvard Medical School, Boston, MA, USA.

    John Rothwell, Sobell Department, Institute of Neurology, Queen Square, London, UK.

    Jarmo Ruohonen, Nexstim Ltd., Helsinki, Finland.

    Hartwig Siebner, Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark.

    Gregor Thut, Centre for Cognitive Neuroimaging, Department of Psychology, University of Glasgow, UK.

    Josep Valls-Solè, Neurology Department, Hospital Clínic, University of Barcelona, Spain

    Vincent Walsh, Institute of Cognitive Neuroscience and Department of Psychology University College London, London, UK.

    Yoshikatzu Ugawa, Department of Neurology, School of Medicine, Fukushima Medical University, Japan.

    Abraham Zangen, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.

    Ulf Ziemann, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Germany.

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