Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996

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Abstract

Single-pulse transcranial magnetic stimulation (TMS) is a safe and useful tool for investigating various aspects of human neurophysiology, particularly corticospinal function, in health and disease. Repetitive TMS (rTMS), however, is a more powerful and potentially dangerous modality, capable of regionally blocking or facilitating cortical processes. Although there is evidence that rTMS is useful for treating clinical depression, and possibly other brain disorders, it had caused 7 known seizures by 1996 and could have other undesirable effects. In June 1996 a workshop was organized to review the available data on the safety of rTMS and to develop guidelines for its safe use. This article summarizes the workshop's deliberations. In addition to issues of risk and safety, it also addresses the principles and applications of rTMS, nomenclature, and potential therapeutic effects of rTMS. The guidelines for the use of rTMS, which are summarized in an appendix, cover the ethical issues, recommended limits on stimulation parameters, monitoring of subjects (both physiologically and neuropsychologically), expertise and function of the rTMS team, medical and psychosocial management of induced seizures, and contraindications to rTMS.

Introduction

From its introduction in 1989 until recently, repetitive transcranial magnetic stimulation (rTMS) was a little known experimental means of stimulating the human brain non-invasively. Its inherent riskiness and the need for expertise in clinical neurophysiology for its use kept it in a few specialized laboratories and out of general scientific and medical awareness. In 1995, with the demonstration of possible therapeutic effects of rTMS on depression, there was a marked increase in interest among psychiatrists, neurologists, basic scientists, and the public. Coincidently, rTMS induced seizures in several subjects who were participating in research studies at the National Institute of Neurological Disorders and Stroke (NINDS) and elsewhere. Although the safety of rTMS had been explored (Hufnagel et al., 1993; Pascual-Leone et al., 1993; Wassermann et al., 1996c) and guidelines for its safe use were promulgated (Pascual-Leone et al., 1993), it became clear that additional information was needed. To this end, an international workshop on the risk and safety of rTMS was held in June 1996 in Bethesda, Maryland. The workshop brought together some of the leading researchers in the fields of neurophysiology and psychiatry who are currently using the technique, along with several basic and applied scientists and clinicians whose work has bearing on decisions regarding the safe and ethical use of rTMS. Other scientists and clinicians who are involved in projects using rTMS were also in attendance. The workshop participants catalogued the known and potential risks of rTMS, and reached consensus on guidelines for its safe and ethical use. They also agreed on a nomenclature for TMS. This paper summarizes the workshop's deliberations.

Section snippets

Nomenclature

In a universal system of referring to the different types of TMS, the term `repetitive TMS' should replace the terms `rapid TMS' and `rapid-rate TMS' and should be used to refer to regularly repeated TMS delivered to a single scalp site. The term `fast' or `high-frequency' rTMS should be used to refer to stimulus rates of more than 1 Hz, and the term `slow' or `low-frequency' rTMS should be used to refer to stimulus rates of 1 Hz or less. This division is based on the different physiological

Principles of TMS

TMS uses the principle of inductance to get electrical energy across the scalp and skull without the pain of direct percutaneous electrical stimulation. It involves placing a small coil of wire on the scalp and passing a powerful and rapidly changing current through it. This produces a magnetic field that passes unimpeded and relatively painlessly through the tissues of the head. The peak strength of the magnetic field is related to the magnitude of the current and the number of turns of wire

TMS of the corticospinal system

In classic TMS experiments, stimulation is delivered to the primary motor cortex (M1), and motor evoked potentials (MEPs) from a muscle or set of muscles are recorded with surface EMG electrodes. The intensity of TMS is typically given as a multiple or percentage of the threshold intensity for evoking MEPs of a certain amplitude in a specified fraction of a series of consecutive trials in a hand muscle. Because thresholds to TMS vary greatly in the population, measures of intensity that take

Language localization and other cognitive studies

Aside from the attempted activation of epileptogenic foci, the earliest application of rTMS was as a non-invasive means of producing speech arrest with stimulation of the motor speech area of the dominant frontal lobe (Pascual-Leone et al., 1991). This important work demonstrated that unlike single-pulse TMS, rTMS could produce sustained and spatially selective interruptions of organized neural activity, which allowed the non-invasive mapping of cognitive and perceptual processes on the human

Adverse effects of rTMS

Aside from its potentially beneficial clinical and research applications, rTMS is not only known to produce certain adverse cerebral and extracerebral effects, but also theoretically may be capable of eliciting other unintended or undesirable effects (Table 1).

Relevance of animal models in TMS

Although animal models have been used to great advantage in studies of the safety of direct electrical stimulation of the brain, the implications of animal work for the safety of TMS in humans must be interpreted with great caution. Differences in the size of the head and brain, as well as in the cortical topology, between animals and humans could have pronounced influences on the efficacy of TMS. For instance, despite intensive efforts, no investigator has succeeded in producing seizures in

Guidelines for the use of rTMS

Guidelines for the use of rTMS bear on ethical and legal considerations, selection of safe and appropriate stimulation parameters, physiological monitoring of data, neuropsychological analysis of subjects, composition and expertise of the rTMS team, management of the medical and psychosocial consequences of rTMS-induced seizures, and contraindications to rTMS. The guidelines are also summarized in the appendix.

Workshop attendees

Australia: Saxby Pridmore, University of Tasmania. Denmark: Stig W. Andersen, Tonic Elektronik A/G, Farum; Finn K. Hansen1, Dantec Medical A/G, Skovlunde; Poul Jennum1, KAS Glostrup, Glostrup. Germany: Hans Martin Kolbinger, Universität Bonn, Bonn; Bernd-Ulrich Meyer1, Virchow Klinikum, Berlin; Walter Paulus, Universität-Göttingen, Göttingen. Israel: Jacob M. Abarbanel, Kaplan Hospital, Rehovot; Robert H. Belmaker1 and Nimrod Grisaru, Ben Gurion University, Beer Sheva; Leon Grunhaus, Sheba

Acknowledgements

Dr. Mark Hallett's leadership in the organization of the workshop is gratefully acknowledged. Thanks are also given to Carol Smith and Deborah Dease for invaluable help in organizing the workshop, and to B.J. Hessie for expert editing. The workshop was supported in part by the National Institute of Neurological Disorders and Stroke, Dantec Medical A/G, and the US Food and Drug Administration.

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