Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters

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Abstract

Induction of a seizure in a normal subject with trains of repetitive transcranial magnetic stimulation (rTMS) applied in close succession suggested that short inter-train intervals, a parameter not considered in our previous safety studies, may not be safe. Here, we evaluate the safety of different inter-train intervals for rTMS in 10 healthy volunteers. Ten rTMS trains at 20 Hz for 1.6 s and a stimulus intensity of 110% of motor threshold (MT) were found to be safe at the inter-train interval of 5 s. However, inter-train intervals of 1 s or less were unsafe for trains of 20 Hz for 1.6 s and stimulus intensities higher than 100% of MT. Based on these results, we propose safety guidelines for inter-train intervals at different stimulus intensities. We also analyzed the stimulus parameters, used in 3 studies, that led to seizures in normal subjects. One seizure was due to short inter-train intervals, one was likely related to intense individual rTMS trains close to the limit of our previous safety recommendations, and one was likely due to a combination of these two factors. To provide an additional safety margin, we suggest reducing the duration for individual rTMS trains by 25% from our previous recommendations. Updated safety tables currently in use at our institution are provided.

Introduction

High-frequency repetitive transcranial magnetic stimulation (rTMS) refers to regularly repeated TMS delivered to a single scalp site at frequencies of more than 1 Hz. It provides a noninvasive means of transiently blocking cortical neuronal networks and is a useful technique for studying human cortical physiology (Pascual-Leone et al., 1991; Grafman et al., 1994; Chen et al., 1997b). It may also have applications in treating neurological and psychiatric disorders. For example, rTMS can improve akinesia in Parkinson's disease (Pascual-Leone et al., 1994a), alter the mood in normal subjects (George et al., 1996; Pascual-Leone et al., 1996a) and improve the mood in depressed patients (George et al., 1995; Pascual-Leone et al., 1996b).

The most serious documented side effect of rTMS is the induction of epileptic seizures, caused by rTMS trains of high stimulus intensities and frequencies (Pascual-Leone et al., 1993, Pascual-Leone et al., 1994b). Our previously reported seizure was preceded by spread of excitation to muscles not targeted for stimulation, which can be regarded as a warning sign for seizures and may be due to breakdown of cortical inhibition (Pascual-Leone et al., 1993, Pascual-Leone et al., 1994b). The stimulus parameters that may be important in determining the likelihood of adverse effects of rTMS include stimulus intensity, frequency, train duration and number of pulses for individual trains, inter-train interval and total number of trains delivered (Fig. 1). For single trains of rTMS, we previously reported the different combinations of stimulus intensities, frequencies and durations necessary to induce spread of excitation (Pascual-Leone et al., 1993, Pascual-Leone et al., 1994b). Based on these results, we suggested sets of stimulation parameters that are unlikely to cause spread of excitation and are, therefore, considered safe (Pascual-Leone et al., 1993).

We followed the reported guidelines for rTMS studies in our laboratory for more than 3 years without inducing further seizures. However, in September 1995, a normal volunteer had a seizure during a rTMS study, even when the parameters for individual trains of stimuli were well within these guidelines (Wassermann et al., 1996a). It is likely that the seizure was due to short inter-train intervals. a factor not included in our previous safety study (Pascual-Leone et al., 1993).

It seemed obvious that new safety guidelines for rTMS were necessary and should include limitations on inter-train intervals, since almost all rTMS studies require multiple trains. Here, we report a study of the safety of different inter-train intervals. One subject had a seizure during this study (Wassermann et al., 1996a), and shortly afterwards a different rTMS study in our laboratory led to another seizure (Chen et al., 1997b). Therefore, we also analyzed the stimulus parameters used at the time these 3 seizures occurred in an attempt to understand why they occurred, and to devise possible ways to prevent future occurrence. Based on these findings, we report new safety guidelines for rTMS that are presently used in our laboratory.

Section snippets

Safety of different inter-train intervals

We studied 10 right-handed healthy volunteers (4 men and 6 women, mean age 45.5 years, range 28–64 years). All subjects gave their written informed consent; the study was approved by the Institutional Review Board.

We used a Cadwell rapid-rate magnetic stimulator (Cadwell Laboratories Inc., Kennewick, WA) and water-cooled 8-shaped coil, each loop of which measures 7.5 cm at its inner diameter. The coil was flat, and the position of closest contact with the scalp was the intersection of the two

Safety of different inter-train intervals

The results of the inter-train intervals study are shown in Table 1. Spread of excitation or post-TMS EMG activity was observed in 13 studies. MEP amplitudes in the target muscle (APB) increased with successive trains in 11 of these studies and were unchanged in the other two studies. Examples of spread of excitation and post-TMS EMG activity are shown in Fig. 2Fig. 3.

rTMS at 120% MT and 1 s train duration with an inter-train interval of 1 s was unsafe since spread of excitation or post-TMS EMG

Parameters for single trains of rTMS

The occurrence of seizures in subjects 2 and 3 (Table 2) showed that rTMS parameters at the edge of our previous recommendations (Pascual-Leone et al., 1993) are not safe under some circumstances. However, the risk appears to be small as we have studied over 130 subjects following these guidelines during a 4 year period without complications. Moreover, 10 other subjects were studied with the same parameters as used in subject 3 without adverse effects (Chen et al., 1997b). A likely explanation

Acknowledgements

We thank Devera Schoenberg for skillful editing.

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