日本鬼屋医院Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters
Robert Chen,Christian Gerloff,Joph Clasn,Eric M.Wasrmann,
Mark Hallett,Leonardo G.Cohen*
Human Cortical Physiology Unit,National Institute of Neurological Disorders and Stroke,
National Institutes of Health,Bldg.10,Room SN226,10Center Drive,MSC 1428,Bethesda,MD 20892–1428,USA
Accepted for publication:23May 1997
Abstract
Induction of a izure in a normal subject with trains of repetitive transcranial magnetic stimulation (rTMS)applied in clo 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 10healthy volunteers.Ten rTMS trains at 20Hz for 1.6s and a stimulus
intensity of 110%of motor threshold (MT)were found to be safe at the inter-train interval of 5s.However,inter-train intervals of 1s or less were unsafe for trains of 20Hz for 1.6s and stimulus intensities higher than 100%of MT.Bad on the results,we propo safety guidelines for inter-train intervals at different stimulus intensities.We also analyzed the stimulus parameters,ud in 3studies,that led to izures in normal subjects.One izure was due to short inter-train intervals,one was likely related to inten individual rTMS trains clo to the limit of our previous safety recommendations,and one was likely due to a combination of the 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 u at our institution are provided.Published by Elvier Science Ireland Ltd.Keywords:Transcranial magnetic stimulation;Safety;Seizure
1.Introduction
High-frequency repetitive transcranial magnetic stimula-tion (rTMS)refers to regularly repeated TMS delivered to a single scalp site at frequencies of more than 1Hz.It pro-vides a noninvasive means of transiently blocking cortical neuronal networks and is a uful technique for studying human cortical physiology (Pascual-Leone et al.,1991;Grafman et al.,1994;Chen et al.,1997b).It may also have appli
cations in treating neurological and psychiatric disorders.For example,rTMS can improve akinesia in Par-kinson’s dia (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 depresd patients (George et al.,1995;Pascual-Leone et al.,1996b).
The most rious documented side effect of rTMS is the induction of epileptic izures,caud by rTMS trains of high stimulus intensities and frequencies (Pascual-Leone et al.,1993,1994b).Our previously reported izure was pre-ceded by spread of excitation to muscles not targeted for stimulation,which can be regarded as a warning sign for izures and may be due to breakdown of cortical inhibition (Pascual-Leone et al.,1993,1994b).The stimulus para-meters that may be important in determining the likelihood of adver effects of rTMS include stimulus intensity,fre-quency,train duration and number of puls for individual trains,inter-train interval and total number of trains deliv-ered (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.,1993,1994b).Bad on the results,we suggested ts of stimulation parameters that are unlikely to cau spread of excitation and are,there-fore,considered safe (Pascual-Leone et al.,
1993).
Electroencephalography and clinical Neurophysiology 105(1997)415–421
0924-980X/97/$17.00Published by Elvier Science Ireland Ltd.PII S0924-980X(97)00036-2
EEM 97004
*Corresponding author.Tel.:+13014969782;fax:+13014021007;e-mail:lcohen@v
We followed the reported guidelines for rTMS studies in our laboratory for more than3years without inducing further izures.However,in September1995,a normal volunteer had a izure during a rTMS study,even when the parameters for individual trains of stimuli were well within the guidelines(Wasrmann et al.,1996a).It is likely that the izure was due to short inter-train intervals.
中级口译成绩查询a factor not included in our previous safety study(Pascual-Leone et al.,1993).
It emed 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 izure during this study(Wasrmann et al.,1996a),and shortly afterwards a different rTMS study in our laboratory led to another izure (Chen et al.,1997b).Therefore,we also analyzed the stimu-lus parameters ud at the time the3izures occurred in an attempt to understand why they occurred,and to devi possible ways to prevent future occurrence.Bad on the findings,we report new safety guidelines for rTMS that are prently ud in our laboratory.
2.Methods
2.1.Safety of different inter-train intervals
We studied10right-handed healthy volunteers(4men and6women,mean age45.5years,range28–64years). All subjects gave their written informed connt;the study was approved by the Institutional Review Board.
We ud a Cadwell rapid-rate magnetic stimulator(Cad-well Laboratories Inc.,Kennewick,WA)and water-cooled 8-shaped coil,each loop of which measures7.5cm at its inner diameter.The coil wasflat,and the position of clost contact with the scalp was the interction of the two loops where the induced magneticfield was strongest(Cohen et al.,1990).The technical details of the magnetic stimulator and thefigure-of-8-shaped water-cooled coil were described previously(Pascual-Leone et al.,1993).A specially designed coil holder kept the coil in a constant position with reference to the subject’s head.The coil holder con-sisted of an aluminium frame with adjustable plastic joints. The coil was attached by metal screws to a ball and socket joint with adjustable clamps.The position of the coil can be freely adjusted and then cured.After the subject was ated in a comfortable position,a head restraint was applied to prevent movements.The coil was placed at the optimal position over the left motor cortex for eliciting motor-evoked potentials(MEPs)in the right abductor pol-licis brevis(APB)muscle and wasfixed for the remainder of the experiment.The positions of the he
ad restraint and the stimulating coil were also marked on the scalp and moni-tored throughout the experiment.
The motor threshold(MT)was defined as the minimum percentage of the stimulator output that evoked an MEP of 50m V in at least5out of10trials.Surface EMG was recorded from the right APB,biceps and deltoid muscles. Subjects were instructed to maintain relaxation throughout the study.The signals werefiltered(bandpass50Hz to2 kHz),amplified,displayed(Dantec Counterpoint Electro-myograph;Dantec Electronics,Skovlunde,Denmark),and stored in a laboratory computer for off-line analysis. EMG was continuously monitored for spread of excita-tion to proximal muscles and post-TMS EMG activity, which may be warning signs for izures.Spread of excita-tion occurred if there was no MEP in the biceps or deltoid muscles with thefirst train of stimulation but MEP appeared with later trains.In some subjects,it was not possible to evoke MEPs from the APB muscle at the desired stimulus intensity without inducing small MEPs in the biceps or deltoid muscles.In the situations,spread of excitation was regarded as an increa in the deltoid MEP amplitude by more than100%of the baline.Post-TMS EMG activity referred to continuation of EMG activity after cessation of rTMS and may be the EMG correlate of EEG after-dis-charges.As a safety precaution,we considered any EMG activity following rTMS that was not clearly due to poor muscle r
elaxation as post-TMS EMG activity.The stimula-tion was terminated if either spread of excitation or post-TMS EMG activity occurred.A neurologist trained to recognize the warning signs and to manage izures was always prent during the experiments.
All subjects had rTMS trains at20Hz and110%MT for 1.6s(32puls).The train duration was the maximum duration of a single train at this frequency and intensity that did not lead to spread of excitation in our previous study(Pascual-Leone et al.,1993).The inter-train intervals of5s,1s or0.25s were tested and10trains were adminis-tered at each interval.Spread of excitation,post-TMS EMG activities or izures were considered as adver events.The inter-train interval for a particular t of stimulus parameters is considered unsafe if any adver event occurred in any subject.In thefirst4subjects,the inter-train interval of5s was testedfirst,followed by1s and then0.25s.Since the inter-train interval of5s was safe in thefirst4subjects,the next6subjects werefirst tested with an inter-train interval of1s.The longer inter-train interval of5s was tested only if spread of excitation or after-discharges occurred at an inter-train intervals of1s.
In addition to the stimulus intensity of110%MT,we studied some subjects at stimulus intensities of100%(3 subjects),105%(4subjects)or120%(8subjects)of MT at20Hz with inter-train intervals of5s,1s or0.25s.The train duration for100%and105%MT stimulation was1.6s. It was reduced to1s(20
empty的反义词
puls)for120%MT stimulation, which was the maximum recommended duration(Pascual-Leone et al.,1993).We also tested3subjects at the higher rTMS frequency of25Hz,120%of MT and0.4s duration (maximum recommended duration at this intensity)(Pasc-ual-Leone et al.,1993)with inter-train intervals of1s or
416R.Chen et al./Electroencephalography and clinical Neurophysiology105(1997)415–421
0.25s,and one subject at 25Hz,110%of MT and 0.8s duration with an inter-train interval of 1s.One subject was tested with 10Hz,110%of MT and 1s duration with an inter-train interval of 1s.3.Resultscock
hyatt
3.1.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 obrved in 13studies.MEP amplitudes in the target muscle (APB)incread with successive trains in 11of the studies and were unchanged in the other two studies.Exam-ples of spread of excitation and post-TMS EMG activity are shown in Figs.2and 3.
rTMS at 120%MT and 1s train duration with an inter-train interval of 1s was unsafe since spread of excitation or post-TMS EMG activity occurred in 3of 8subjects tested.With rTMS at 110%MT and 1.6
s duration,spread of exci-tation or post-TMS EMG activity occurred in two of 10subjects at an inter-train interval of 1s and in 3of 10sub-jects at an inter-train interval of 0.25s.We consider the inter-train intervals unsafe.Inter-train intervals of 5s can be considered safe becau none of the 10subjects had adver events either at this inter-train interval (5subjects,two of whom had spread of excitation at an inter-train interval of 1s)or at the shorter inter-train interval of 1s (5subjects)(Table 1).
At stimulus intensities of 105%and 100%of MT (20Hz,1.6s),inter-train intervals of less than 1s are unsafe since spread of excitation occurred in one subject (Table 1).With a frequency of 25Hz,stimulation at 120%MT with inter-train intervals of 1or 0.25s were unsafe (Table 1).Since a izure occurred at 25Hz,110%MT with an inter-train interval of 1s (Table 1;subject 2,Table 2),we also consider this t of parameters unsafe.
3.2.Stimulus parameters of rTMS studies that induced izures
The rTMS parameters ud at the time the izures occurred in the 3normal subjects are shown in Table 2.All izures were of focal ont,began on the side being stimu-lated and then condarily generalized.All subjects fully recovered.The clinical descriptions of the izures have been reporte速度与激情7音乐
d (Wasrmann et al.,1996a;Chen et al.,1997b).In subject 1,the train duration of 0.75s was only 47%of the duration required for induction of spread of excitation for single rTMS trains at that intensity and frequency (Table 2).Therefore,the izure was unlikely to be due to the excessive stimulation for individual trains and was probably related to the short inter-train interval of 0.25s.In subject 2,the train duration of 0.8s was clo to the duration that may induce spread of excitation (0.84s)(Table 2).This izure was probably due to a combination of the strong individual trains and the short inter-train interval (1s).EMG monitor-ing was performed and spread of excitation occurred at the end of the third train.Becau of the short inter-train inter-
Table 1
Results of inter-train interval safety study Frequency (Hz)
Stimulus intensity (%of MT)Train duration (s)
Inter-train interval (s)No.of subjects No.of subjects without adver events No.of subjects with spread of excitation,PTEA or izure 1011011111201201511a 020********spread and PTEA;1PTEA
2012010.2511020110 1.6555b 020110 1.611082spread
20110 1.60.251072spread;1PTEA
20105 1.6544020105 1.6144020105 1.60.2544020100 1.6511020100 1.61101spread
equ20100 1.60.25110251200.41202spread and PTEA 251200.40.25321PTEA 25
110
0.8
1
1
1
izure c
Up to 10trains were applied in each study.PTEA,post-TMS EMG activity;MT,motor threshold;spread,spread of excitation;adver events are spread of excitation,post-TMS EMG discharges or izure.a
Four other subjects had no adver event at inter-train interval of 1s;the inter-train interval of 5s was not tested.b
Five other subjects had no adver event at inter-train interval of l s;the inter-train interval of 5s was not tested.c
Subject 2in Table 2.
417
R.Chen et al./Electroencephalography and clinical Neurophysiology 105(1997)415–421
val (1s),we were unable to stop the stimulation before the fourth train was delivered which caud the izure.The inter-train interval in subject 3was long (Ͼ1min)and unli-kely to have contributed to the izure.However,the stimu-lus parameters for individual trains were at the edge of the original safety guidelines and likely caud the izure.4.Discussion
4.1.Parameters for single trains of rTMS
The occurrence of izures in subjects 2and 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 130subjects following the guidelines during a 4year period without complications.Moreover,10other subjects were studied with the same parameters as ud in subject 3without adver effects (Chen et al.,1997b).A likely explanation for the occurrence
of the two izures is that our previous safety guidelines were bad on the minimum number of puls necessary to cau spread of excitation in 10subjects (Pascual-Leone et al.,1993).When more subjects are tested,it is likely that spread of excitation may be more easily induced in some subjects than in any of the subjects previously studied.How-ever,the individual variability in number of puls required to cau spread of excitation among the 10subjects pre-viously studied was small,and was never more than 5puls (Pascual-Leone et al.,1993).In addition,there is some variability in determining MT,and the finding of a higher threshold would lead to using a higher stimulus intensity.In 6subjects,we found that the coefficient of variation for MT determined at two different days was 5.8%,with a maxi-mum difference of 12%between the two MT measurements (unpublished obrvations).To account for the variables,extra safety margins from our original safety recommenda-tions are necessary.We suggest reducing the safe train dura-tion for each combi
nation of stimulus frequency and intensity by 25%of the original recommendation,which should be adequate to account for individual variability in susceptibility to izures in normal volunteers and the mar-gin of error in the determination of MT.
Our recommendations for stimulation parameters for sin-gle trains are shown in Table 3.Our suggestions for 1Hz and intensities of 100and 110%of MT were bad on our recent study of 0.9Hz stimulation for 15min at 115%of MT in 9subjects (Chen et al.,1997a).Eight subjects completed the study without complications,but one subject had spread of excitation after 360stimuli.The safe train duration and number of puls for 1Hz stimulation at 100and 110%of MT is therefore more than 270(75%of 360).It is likely that 1800puls are safe for 1Hz stimulation at 100and
110%
Fig.1.Parameters that may influence the occurrence of adver effects in rTMS studies.Each line reprents one TMS
pul.
Fig.2.Example of spread of excitation.The subject (a 39year old woman)received rTMS at 20Hz,110%of motor threshold,train duration of 1.6s and inter-train interval of 1s.MEPs in the deltoid became evident towards the end of train 1.By train 4,the deltoid MEPs occurred near the ont of the train and amplitudes were much higher (incread by more than 100%of the baline).The MEP amplitude of the APB muscle was also higher in train 4compared to train 1.Although spread of excitation occurred in train 1,it was not recognized until train 4.The stimulation was then immediately terminated.This underscores the risk of short inter-train intervals.
418R.Chen et al./Electroencephalography and clinical Neurophysiology 105(1997)415–421
of MT,since veral subjects (Wasrmann et al.,1997)had stimulation between 100and 110%of MT for 30min (1800puls)with no change in MEP amplitude although moni-toring for spread of excitation was not performed.The recommendation for 1Hz and 120%of MT was bad on our previous study (Wasrmann et al.,1996b)which found no spread of excitation or post-TMS EMG activity in 6subjects with stimulation at 1Hz and 125%of MT for 180s.
4.2.Safe inter-train intervals for rTMS
Since rTMS may be associated with potential adver effects,it is imperative that the potential benefit in advance-ment of knowledge or therapeutic benefit outweighs the inherent risk.For the reasons,we only tested a limited range of rTMS parameters out of a large number of possible combinations in normal volunteers.We cho stimulus parameters that we believe are adequate for most rTMS
studies.Although we stimulated only the dominant (left)motor cortex,the results should be applicable to the non-dominant motor cortex since we found no significant diff-erence between the stimuli that induced spread of exci-tation on the dominant and non-dominant motor cortices.(Pascual-Leone et al.,1993)Our main safety concern was incread cortical excitability and potential for induction of izures.We did not systemically test for other potential side effects of rTMS,such as headaches,changes in cogni-tion or hormone levels.
The izures in subjects 1and 2suggested that individual rTMS trains that are safe when delivered with long inter-train intervals may cau izures if the inter-train intervals are short.We found that at an inter-train interval of 1s or less,facilitation of subquent trains may lead to incread MEP amplitudes,spread of excitation,post-TMS EMG activities or izures.However,we found no evidence of facilitation at the inter-train interval of 5s.Stimulation at high intensities is more likely to cau facili
tation of later trains than stimulation at lower intensities (Table 1).The findings are consistent with the much earlier obrvations of Graham Brown that the respon to a cond train of uni-polar electrical stimulation of the monkey cortex was incread if the first and cond trains were clo together (Graham Brown,1915a,b).Pascual-Leone et al.(1994b)also found an incread probability of producing MEPs and incread MEP amplitudes immediately following rTMS trains.However,there was no cumulative effect when the rTMS trains were delivered 1min apart.
Post-tetanic potentiation may be a mechanism for facil-itation at short inter-train intervals.It is of presynaptic ori-gin and likely due to elevated calcium in the presynaptic terminals (Zucker,1989).Post-tetanic potentiation may last up to 1min.and its decay is slower following tetani of long durations or high frequencies (Schlapfer et al.,1975;Mal-enka,1991).Another potential mechanism is short-term potentiation (STP),which originates postsynaptically and requires activation of N -methyl-D-aspartate (NMDA)receptors.However,STP declines over 5–40min
(Malenka,
Fig.3.Example of possible post-TMS EMG activity.EMG recordings from the biceps muscle are shown.The subject (a 58year old man)received rTMS at 20Hz,120%of motor threshold,train duration of 1s and inter-train interval of 1s.With train 1,most puls elicited an MEP but there was no further EMG activity following the last stimulus.Follow-ing train 2,there was EMG activity of declining amplitude for about 0.3s.
Table 2
Stimulus parameters in rTMS studies that induced izures Subject
Age (years)
Sex
Site of stimulation
Stimulus intensity (%of MT)
Frequency (Hz)
Train duration (s)
No.of puls
Previously recom-mended maximum train duration (s)a Train duration that induced izure expresd as a per-centage of previously recommended maxi-mum train duration a Inter-train interval (s)
127F Left prefrontal cortex 105150.7511 1.6470.25239F Left motor cortex 110250.8200.849513
26
F
Left motor cortex
12015
2.7
41
2.7
100
>60
MT,motor threshold.
vitala
bloodstone
The minimum duration required for spread of excitation at the stimulus intensity and frequency ud (bad on Pascual-Leone et al.,1993).
alice in wonderland419
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