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Published 2000 Wiley-Liss, Inc. †This article is a US Governmentwork, and, as such, is in the public domain in the United States of America.

DEPRESSION AND ANXIETY 12:124–129 (2000)

SIDE EFFECTS OF REPETITIVE TRANSCRANIALMAGNETIC STIMULATION

Eric M. Wassermann*

The side effects of repetitive transcranial magnetic stimulation are largely un-explored and the limits of safe exposure have not been determined except asregards the acute production of seizures. Although tissue damage is unlikely,however, cognitive and other adverse effects have been observed and the possi-bility of unintended long-term changes in brain function are theoretically pos-sible. Depression and Anxiety 12:124–129, 2000. Published 2000 Wiley-Liss, Inc.†

Key words: safety; risk; seizure; stimulation parameters

Brain Stimulation Unit, National Institute of Neurological Dis-orders and Stroke, National Institutes of Health, Bethesda,Maryland

Abbreviations used: rTMS, repetitive transcranial magneticstimulation; TMS, transcranial magnetic stimulation; MEP, motorevoked potential; EEG, electroencephalogram.

*Correspondence to: E.M. Wassermann, Brain Stimulation Unit,10 Center Dr. MSC 1428, Bethesda, MD 20892-1428. E-mail:wassermann@nih.gov

Received for publication 21 August 2000; Accepted 21 August 2000

INTRODUCTIONIf rTMS has the lasting effects on brain function nec-essary for the amelioration of depression, then side ef-fects must also exist, as with any other treatment.What these may be and how significant they are, how-ever, is almost completely unknown. For various rea-sons, rTMS treatments have not been subjected to thekind of study that would precede the release of anynew drug. No large clinical trials have been run andthere have been very few systematic safety studies.The few studies specifically aimed at safety have beenextremely small, somewhat limited in their scope, andhave not examined the effects of treatment over mul-tiple days. Although numerous small trials of rTMS asa treatment for various disorders are proceeding,many are not collecting safety data. Therefore, it isdifficult to provide recommendations for its safe use.To date, one conference has been devoted to the sub-ject that resulted in a published review of the availabledata and guidelines for the use of rTMS [Wasser-mann, 1998]. This document, however, raises manymore questions than it answers and contains a chal-lenge to clinical investigators to perform checks onsafety, particularly in the realm of cognitive function.

KNOWN SIDE EFFECTS OF TMSSEIZURES WITH TMS

Among the known risks of TMS the most obviousand acute is the provocation of epileptic seizures. It is acommon misconception that these have only occurredin subjects exposed to stimulation at frequencies ofgreater than 1 Hz. Seizures have been produced bywidely-spaced single TMS pulses in many patients withlarge cerebral infarcts or other structural brain lesionsincluding contusions. Some of these cases were reportedearly in the history of TMS [Hömberg and Netz, 1989;Kandler, 1990; Fauth et al., 1992], but several othershave occurred. The anatomical extent of these lesions

has not been reported in all cases. There do not seem,however, to be reports of seizures in patients with le-sions that were completely subcortical. Epilepsy subse-quently developed in at least one of these patients,presumably as a result of the underlying abnormality.

Epilepsy patients without gross lesions may also beat a minor degree of risk from single-pulse TMS. Sev-eral studies have evaluated single-pulse TMS as a pro-cedure to provoke seizures in epilepsy patients withmixed results. Hufnagel et al. [1990a–c] in variousstudies on a diversity of patients [Düzel et al., 1996],found that repeated single-pulse TMS was occasion-ally able to induce seizures or activate epileptic EEGfoci. Tassinari et al. [1990], however, were completelyunable to provoke seizures in 58 medicated patients.Only one case has been reported in which single-pulseTMS could produce seizures repeatably in a single in-dividual [Classen et al., 1995]. Dhuna et al. [1991]produced a secondarily generalized seizure in a patientwith temporal lobe epilepsy by stimulating the unin-volved hemisphere, an event that may or may not havebeen related to the underlying disorder.

Accidental seizures have occurred in at least 6 normalvolunteers and at least two patients with depression (seebelow). At the National Institute of Neurological Dis-orders and Stroke, four seizures were produced in ap-

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proximately 250 subjects studied from 1992 through1995, many of whom were stimulated on multiple oc-casions. All seizures were secondarily generalized andoccurred in women between the ages of 20 and 39,despite a predominance of men in the subject group.Three were produced with stimulation of the primarymotor area and the other with posterior prefrontalstimulation. The first seizure occurred during a studyon the safety of rTMS [Pascual-Leone et al., 1993].The first safety limits on stimulation parameters in-cluding train length, frequency, and intensity camefrom that study. Two of the subsequent seizures oc-curred in studies using trains of rTMS that shouldhave been safe according to earlier data [Wassermann,1998], but where the trains were delivered at intervalsof less than 1 sec [Wassermann et al., 1996a]. Theshort intertrain interval apparently permitted a cumu-lative buildup of excitability in the cortex resulting ina lowered seizure threshold [Chen et al., 1998]. Thefourth seizure occurred when investigators interpo-lated between the tested values in the table of recom-mended combinations of stimulation parameter values[Wassermann, 1998] and chose a combination that wason the edge of the safe envelope. Additional informa-tion on these events has been published elsewhere[Wassermann, 1998; Wassermann et al., 1996a]. Sincethe adoption of more stringent internal limits onstimulation parameters, no seizures have occurred inour laboratories.

Three other accidental seizures caused by rTMS inindividuals without anatomical lesions have been anec-dotally reported by investigators. One was caused in anormal man by 7 sec of rTMS, at a frequency of 3 Hzand an intensity of 1.3 times the MEP threshold, de-livered to the primary motor area. It should be notedthat these parameter values are well within the areathat is considered to be safe [Wassermann, 1998] andthere are no other reports consistent with significantlyincreased cortical excitability at similar settings in nor-mal subjects. Nevertheless, this event illustrates thefact that there is a very wide range of susceptibility toepileptogenesis in the normal population. The otherpartial seizure occurred after at least 10 sec of 10 Hzstimulation above the MEP threshold delivered to theprimary motor area. The third seizure occurred in awoman with depression who was participating in atrial of rTMS treatment for depression [Pascual-Leone et al., 1996b]. This occurred when rTMS wasdelivered to the prefrontal area. The subject had ap-parently received the same treatment before withoutmishap. The explanation offered was that the subjecthad begun taking amitriptyline and haloperidol with-out the investigators’ knowledge [Wassermann, 1998].A complex-partial seizure was reported as being trig-gered during rTMS in a depressed patient with a his-tory of a previous seizure [Conca and Koenig, 1999].

None of the subjects who have experienced rTMS-induced seizures has suffered lasting physical sequelae.In most of them, EEGs obtained immediately after the

seizure showed the expected slowing, but were normalwithin 1 or 2 days. Two subjects had neuropsychologi-cal testing before and after the seizures [Pascual-Leoneet al., 1993; Wassermann et al., 1996a]. Both individualshad mild recall deficits that disappeared within 24 hr.The subject reported by Pascual-Leone et al. [1993] ex-perienced a significant degree of anxiety about the pos-sibility of a recurrent seizure.

NEUROPSYCHOLOGICAL SIDE EFFECTSOF RTMS

Although several studies have examined the transienteffects of focal rTMS on various cognitive, perceptual,and motor functions, very few have considered longer-lasting, unintended effects of extended exposure.Pascual-Leone et al. [1993] screened for various typesof deficits in 9 normal subjects before and after stimu-lation of several scalp positions at maximum stimulusintensity and in a range of frequencies. Neuropsycho-logical tests included the immediate and delayed storyrecall tests from the Wechsler Memory Scale-Revised(WMS-R), selective reminding, a verbal fluency test,the Boston naming test, the serial reaction-time test,and a letter identification task. Neurological examina-tions were performed before and after stimulation.There was no significant effect of rTMS on any ofthese measures except in the one subject who had aseizure. There was a trend, however, toward shortenedmotor reaction time and improved verbal memory inthe subjects who received the greatest amount ofstimulation at the highest frequencies.

Wassermann et al. [1996b] examined the delayed(1–2 hr) effects of exposure to two different frequen-cies and intensities of rTMS (1 Hz at 1.25 times theMEP threshold; 20 Hz at 1.0 times the MEP thresh-old) delivered to multiple scalp positions on differentdays in the same subjects. A neuropsychological testbattery including the immediate and delayed tests ofstory recall from the WMS-R and a verbal fluencytask were also administered. The only clear findingwas increased finger tapping frequency that was mostpronounced after 1 Hz stimulation contralateral to thetapping finger. As in the earlier study [Pascual-Leoneet al., 1993], there was a trend toward enhanced de-layed story recall with 20 Hz stimulation and therewas a small but significant increase in verbal fluency.These studies suggest that rTMS treatments may ac-tually enhance some behavioral functions via lastingstimulatory effects or by inactivation of inhibitorymechanisms.

In a study of cognitive side-effects in a trial ofrTMS treatment for depression [Little et al., 2000],we administered a comprehensive neuropsychologicalbattery before, during and after 10 days of either 1(800 pulses) or 20 Hz rTMS (800 pulses in 20 trains)at 80% of MEP threshold to the dorsolateral prefron-tal area in patients in a crossover study and found noadverse effects. Loo et al. [1999] assessed neuropsycho-logical function and clinical EEG in 18 depressed pa-

126 Wassermann

tients before and after a single session and two weeks ofdaily active or sham 10 Hz rTMS delivered at 110% ofMEP threshold to the dorsolateral prefrontal area in 305 s trains. There were no significant-appearing effectson these measures or on mood. In the only investiga-tion to date of the effects of chronic exposure to TMS,we assessed 8 normal subjects who had participated alarge number of TMS and rTMS studies over a periodof years. Tests included EEG, a cognitive self-assess-ment, the Wechsler Adult Intelligence Scale III, theProfile of Mood States, and the California Computer-ized Assessment Package that includes tests of motorand cognitive speed. No abnormalities were found.Several subjects performed at very superior levels, butwe did not attribute this to exposure to TMS.

In other studies, potential and actual lasting adverseeffects of cognitive functions have been observed. In arecent study of 14 depressed patients, we found that per-formance in a task switching paradigm was slightly, butsignificantly poorer approximately 1 hr after 20 HzrTMS delivered to the right dorsolateral prefrontal areathan after rTMS of the same area on the left or of theoccipital area. Subjects received 40 trains, 2s long, of 20Hz rTMS at 80% of MEP threshold over 20 min. Here,because there was no unstimulated condition, the direc-tion of change was not clear and it is hard to estimate itsclinical significance, if any. In another study [Flitman etal., 1998], however, 7 healthy individuals were tested forfinger tapping frequency, completion time for theGrooved Pegboard Test, and WMS-R logical memorysubtest scores before and after exposure to 150 trains ofrTMS (train duration, 750 msec; frequency, 15 Hz; in-tensity, 1.2 times MEP threshold) at each of four scalppositions (study time, approximately 3 hr). There was asignificant decrease in the scores on the WMS-R logicalmemory subtest when subjects were tested within 1 hrafter rTMS. This effect, detected with a standard clini-cal tests, is ominous and shows that significant adverseeffects on brain function may be encountered withrTMS at subconvulsive doses. The threshold for pro-ducing such effects is unknown. The stimulation param-eter settings used in this study, however, exceededsubsequent recommendations for intertrain interval[Chen et al., 1998]. Moreover, a subject participating inthis study had a seizure during posterior prefrontalstimulation. This individual did not contribute to theWMS-R test results. This raises the possibility that thecognitive effects were due to subconvulsive epileptic ac-tivity or that the threshold for adverse effects onmemory may be near that for seizure. No specific guide-lines for avoiding adverse cognitive effects can be of-fered at this point. Nevertheless, protocols wherehigh-intensity trains are delivered at short intervals forlong periods should certainly be avoided when there isno potential clinical benefit for the subject.

EFFECTS ON MOOD AND HORMONESCrying has been observed in some subjects receiving

intense left prefrontal rTMS in studies of speech ar-

rest [Pascual-Leone et al., 1991; Michelucci et al.,1994] and in a subject receiving stimulation of the motorspeech area who also had a seizure shortly afterward[Wassermann et al., 1996a; Flitman et al., 1998]. Thecrying episodes are consistent with reports of dysphoriawith milder left-sided stimulation in normal subjects[George et al., 1996; Pascual-Leone et al., 1996a].

Pascual-Leone et al. [1993] tested serum levels ofhormones, including prolactin, adrenocorticotropichormone, thyroid-stimulating hormone, luteinizinghormone, and follicle-stimulating hormone. No hor-monal changes were found, except in the subject whohad a seizure. Wassermann et al. [1996b] found nochanges in prolactin levels with rTMS at a frequencyof either 1 Hz or 20 Hz. George et al. [1996] foundfairly consistent increases in thyroid-stimulating hor-mone that paralleled subjective decreases in sadnessafter 5 Hz rTMS of the right prefrontal area. In anearlier study on mood [George and Wassermann, un-published observations], one of the subjects had an in-crease in the serum prolactin level accompanied byacute dysphoria after midfrontal rTMS.

EFFECTS ON HEARINGAfter exposure to single-pulse TMS, animals have

had permanent increases of the auditory threshold[Counter et al., 1990] and humans have shown tran-sient increases [Pascual-Leone et al., 1992]. The riskfrom rTMS may be more significant. Foam earplugswere effective in avoiding changes in the auditorythreshold of volunteers participating in the first safetystudy of rTMS [Pascual-Leone et al., 1993] and havebeen used frequently since then.

IMMUNE SYSTEM EFFECTSAmassian et al. [1994] reported lateralized effects of

single-pulse stimulation on T lymphocyte subsets. Forinstance, the number of CD8+ cells increased as muchas 100% with left-sided stimulation, but decreasedwith stimulation on the right. The increases, thatseemed to be consistent across individuals, resolvedwithin 48 hr. Comparable changes in lymphocyte sub-populations can occur with mild stress [Dhabhar et al.,1994, 1995], the normal circadian cycle [Fukuda et al.,1994], and the menstrual cycle [Northern et al., 1994].

POTENTIAL SIDE EFFECTSKINDLING AND OTHER LONG-TERMCHANGES

Kindling is a process whereby the repeated adminis-tration of an initially subconvulsive stimulus results inprogressive intensification of induced neuroelectricalactivity, culminating in a seizure. Classic kindling oc-curs with repeated stimulation at regular intervals withstimuli of specific combinations of intensity, fre-quency, and pulse duration [Goddard et al., 1969]. Al-though kindling can be produced with frequencies inthe single-Hz range [Cain and Corcoran, 1981; Min-

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abe et al., 1986], the most effective frequency for kin-dling is in the range around 60 Hz, that is outside theperformance envelope of the commercially availablerepetitive magnetic stimulators. Kindling has gener-ally been produced with a pulse duration of 1 msecthat is longer than the current pulse produced bythese stimulators. Kindling is easiest to produced inthe amygdala and hippocampus in rodents, whereasthe neocortex is relatively resistant to kindling [Engel,1989; Racine et al., 1989]. Secondary epileptogenesisis an allied process in which ongoing epileptogenic ac-tivity at a single site seems to induce the emergence ofa mirror-image focus in the opposite hemisphere[Morrell, 1989]. Conceivably, repeated rTMS could actas an inducer of epileptogenesis at distant sites. Kin-dling may be a factor in the genesis of human epilepsyand there is a report of a phenomenon resembling kin-dling occurring in a single subject undergoing chronicthalamic stimulation for phantom pain [Sramka et al.,1977]. It has not been observed, however, in humanswho have received even prolonged cortical stimulation[Goldensohn, 1984] or frequent ECT over many years[Devinsky and Duchowny, 1983]. Although kindlingand secondary epileptogenesis are unlikely to occurwith the rTMS protocols currently in use, they mustremain safety considerations, especially with repeatedhigh-intensity stimulation and in long-term treatmentregimens.

A related concern is long-term potentiation (LTP),where repetitive electrical brain stimulation at high fre-quencies results in long-lasting physiological potentia-tion [Sastry et al., 1986; Gustafsson and Wigstrom,1988; Iriki et al., 1991; Sil’kis et al., 1994] and ultra-structural changes [Geinisman et al., 1993] in centralsynapses. The mechanisms underlying LTP and thekindling processes may be related [Matsuura et al.,1993]. It is conceivable that LTP, believed to underliesome types of behavioral conditioning and learning,could be induced by rTMS, with resulting behavioralchanges, some of which might be desirable. Brain stimu-lation seems to be more effective in inducing synapticchanges in younger animals [Geinisman et al., 1994],suggesting that children might be more vulnerable tosuch changes if they can be induced with rTMS.

HISTOTOXICITY AND OTHER POTENTIALPATHOLOGICAL EFFECTS

Theoretically, noxious effects on tissue are possiblewhenever the brain is stimulated with electrical cur-rents. Based on the extensive literature on the effect ofelectrical brain stimulation in animals [see e.g., Mc-Creery et al., 1990], however, the consensus amongexperts, is that the danger of tissue damage from cur-rent TMS devices is negligible [Wassermann, 1998].In the one comparable study performed on humans[Gordon et al., 1990], two patients with epilepsy re-ceived 50 Hz subdural stimulation of the anteriortemporal lobe for fairly brief periods with a maximumcharge per phase of 4.5 µC and a charge density of 57

µC/cm2 before resection of the temporal lobe. Lightmicroscopy showed no evidence of histological dam-age to the stimulated tissue. It should be noted thatthis combination of parameters yields a combinationof charge density and charge per phase that wouldhave been unsafe according to the McCreery et al.[1990]. Manufacturers’ estimates of the maximalcharge density of currently available TMS devices areon the order of 2–3 µC/cm2, and continuous 50 Hzstimulation is beyond the effective operating range ofmost magnetic stimulators. Therefore, the chance ofproducing excitotoxicity with rTMS seems to be veryremote. The only other known potential source of tis-sue injury from rTMS is ohmic heating of tissue byinduced currents. Although theoretically such heatingis possible in poorly perfused volumes, such as infarc-tions and cysts, it is not considered to be a significanthazard of rTMS [Wassermann, 1998].

HISTOLOGICAL AND BIOCHEMICALSTUDIES AFTER TMS

Several studies looking for pathological changes in-duced by prolonged exposure to repeated TMS pulsesgenerated by single-pulse TMS devices have been per-formed in rodents. One [Matsumiya et al., 1992]found microvacuolar changes in the cerebral corticesof rats exposed to over 100 pulses at 2.8 T that wasapproximately 3 times the reported MEP threshold.This stimulation intensity, although high, is not farbeyond the range to which humans have been rou-tinely exposed. Reassuringly, this finding has not beenreproduced. Rabbits exposed to 100–200 pulses/dayover 30–42 days for a total of 5,000 pulses at 2.4 Tshowed no such changes [Nishikiori, 1996] nor didrabbits exposed to 1,000 pulses at 2.0 T over a periodof months [Counter, 1993]. In a rat study [Ravnborget al., 1990] designed to detect changes in blood-brainbarrier permeability, 50–60 pulses at 1.9 T, deliveredover 15 min, failed to produce detectable changes.

Pathological studies after rTMS exposure are few todate, and have not found histological evidence of tox-icity. Examination of a resected human temporal lobethat had been exposed to rTMS revealed no histo-pathological changes [Gates et al., 1992]. Histologicalstudies of animal brains exposed to rTMS have failedto show any histological changes after rTMS at a fre-quency of 7 Hz [Sgro et al., 1991]. When mice wereexposed to rTMS at intensities and frequencies thatusually did not cause seizures, the expression of glialfibrillary acid protein was increased in the hippocam-pus and dentate gyrus, a phenomenon similar to thatwhich occurs after the induction of seizures with elec-trical stimulation [Fujiki and Steward, 1997]. This re-sponse may have been mediated by a transient increasein extracellular potassium released by activated neu-rons that has no intrinsic pathological significance[McCreery and Agnew, 1990].

One fairly consistent finding in rodents after TMSis evidence of increased catecholaminergic activity

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[Mano et al., 1988; Fleischmann et al., 1996]. Al-though interesting from the point of view of potentialtherapeutic applications in humans, this phenomenonis likely to be due to direct stimulation of diencephalicor brainstem structures that is probably unavoidable inrodents due to their small head size, but extremely un-likely to be feasible in humans unless very large stimu-lating coils are developed.

CONCLUSIONSThe most obvious and dangerous side effect of

rTMS is the provocation of epileptic seizures and ex-perience shows that currently available equipment ispowerful enough to produce them with ease. Presentknowledge suggests that if seizure is avoided, short-term exposure to rTMS at moderate intensities has noclear lasting adverse effects. In the one known casewhere adverse effects were observed below the seizurethreshold, the subjects were exposed to prolongedstimulation at high-frequency and intensity and a sei-zure was caused in one subject. Therefore, the thresh-olds for cognitive deficits and overt seizure may besimilar. Animal studies suggest that even at dangerousintensities and durations of exposure, there is verylittle likelihood of structural brain damage. In theclinical setting where potentially therapeutic effectsmay involve neural reorganization and chronic expo-sure is required, there is the possibility of lasting sideeffects at subconvulsive doses. Unfortunately whatthese may be is not known, nor will reliable informa-tion be available until large and systematic studies areundertaken.

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