Akinesia in Parkinsons Disease 1 Shortening of Simple Reaction Time w Focal Single Pulse TMS

1994;44;884 NeurologyA. Pascual-Leone, J. Valls-Solé, J. P. Brasil-Neto, L. G. Cohen and M. Hallett

focal, single-pulse transcranial magnetic stimulationAkinesia in Parkinson's disease. I. Shortening of simple reaction time with

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Akinesia in Parkinson’s disease. I. Shortening of simple reaction time with

focal, single-pulse transcranial magnetic stimulation

A. Pascual-Leone, MD, PhD; J. Valls-Sol& MD, PhD; J.P. Brasil-Neto, MD; L.G. Cohen, MD; and M. Hallett, MD

Article a b s t r a c G W e studied the effects of transcranial magnetic stimulation (TMS) of the motor cortex on simple reaction time (RT) in 10 patients with Parkinson’s disease compared with 10 age-matched normal controls. The subjects flexed their right elbow rapidly in response to a visual go-signal. In random trials, TMS was applied to the left motor cortex at varying delays after the go-signal. In trials without TMS, RT was longer in the patients. However, in the trials with subthreshold TMS, RT in the patients became as fast as RT in trials without TMS in the controls. This shortening was associated with normalization of the voluntary triphasic EMG pattern and the pre-movement cortical excitability increase.

NEUROLOGY 1994;44:884-891

Delayed motor initiation (akinesia) and slowness of ongoing movements (bradykinesia) are probably the most debilitating manifestations of Parkinson’s disease (PD).1,2 Akinesia is marked by a prolonged reaction time (RT), while bradykinesia leads to prolonged movement time. The pathophysiologic mechanisms responsible for these disturbances re- main unclear. Content, selection, and assembly of motor programs are essentially n ~ r m a l , l , ~ - ~ while there is marked impairment in their execution. 1,2,9-13

This may be related to the fact that in PD it takes abnormally long to activate the motor cortex suff- ciently to initiate the execution of the motor program.2 If so, externally increasing the excitability of the motor cortex may help improve RT.

In normal volunteers, transcranial magnetic stimulation (TMS) delivered over the motor cortex at intensities below motor threshold speeds up simple RT to acoustic, visual, and somatosensory go- ~igna1s.l~ The effects of TMS on RT are thought to be due to modulation of intracortical connection^.^^-^^ In the present study, we investigated the effects of TMS on simple RT in patients with PD.

Methods. Subjects. We studied six men and four women with PD, aged 48 to 73 years (mean, 62 years), whose characteristics are summarized in the table. All patients were evaluated by the Cognitive Neuroscience Section at NINDS with a battery of neuropsychologic tests, and none of the patients entered in this study showed any evi- dence of cognitive impairment. All patients were taking carbidopailevodopa and deprenyl; patients 2, 4, 5, and 7 were also on anticholinergic medications. The medication

regimen had been stable in all patients for a t least 4 months prior to the study. The experiments were con- ducted at the time of peak levodopa effect in all patients. The peak levodopa effect was defined based on the patients’ subjective reports of their motor capabilities in relation to the time of the last levodopa dose and on serial neurologic examinations between doses. In addition, patients l, 3, and 6 were also studied after withholding their medications for 3 days in order to evaluate the effects of levodopa on the results.

We also studied 10 normal volunteers, six men and four women, aged 52 to 71 years (mean, 60 years). All these control subjects were naive to the RT task used in the study, but all had participated in previous studies in our laboratory and had experienced TMS. All subjects gave written informed consent for participation in the study, which had been approved by the institutional re- view board.

Experimental design. The subject was seated comfort- ably on a chair with the right arm slightly abducted a t the shoulder and flexed 90“ at the elbow so that the pronated arm rested on a horizontal platform. An audi- tory warning signal was followed at a random interval (1 to 5 seconds) by a visual go-signal. In response to the go- signal, the subject flexed the right elbow as rapidly as possible to touch the right shoulder with the hand. The visual go-signal was a flash generated by a Grass PS22 photic stimulator and delivered at 100% of the stimulator’s output intensity by a lamp positioned at eye level 30 cm in front of the subject.

The subjects were allowed some time to practice before the experiments began in order to familiarize them with the task. During 30 practice trials, the subjects were given feedback about their RTs and encouraged to move as fast as possible in order to minimize RT variability.

From the Human Cortical Physiology Unit, Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. Received December 27, 1991. Accepted for publication in final form October 26, 1993.

Address correspondence and reprint requests to Dr. Mark Hallett, Building 10, Room 5N226, NINDS, NIH, Bethesda, MD 20892.

884 NEUROLOGY 44 May 1994 by NIZAR YAMANIE on July 20, 2008 www.neurology.orgDownloaded from


Table. Clinical characteristics of the patients with Parkinson’s disease I

URSPO Age* Sex H & Yt S & ES Freezing Tremor¶ Rigidity Bradykinesia# Duration*

1 56 2 62 3 59 4 67 5 73 6 70 7 65 8 48 9 54

10 69

M M F M F F M M F M

I1 11 111 I1 I V 111 111 111 I11 I11

80% 70% 80% 70% 60% 60% 70% 70% 70% 80%

0 1 0 1 3 2 2 1 3 2

0 0 1 1 1 2 1 0 0 2

1 2 2 2 3 3 3 1 2 2

2 3 3 2 4 3 4 4 3 3

9 12 9 7

14 6 9 2 3 4

* Expressed in years. t Hoehn and Yahr classification. $ Schwab and England Activities of Daily Living Scale. 0 Unified Rating Scale for Parkinsonism.

# Mean score for the following URSP categories: finger taps, hand movements, rapid alternating movements of hands, leg agility, and body Mean score for the following URSP categories: tremor, tremor at rest, and action or postural tremor.

bradykinesia.

Experiment 1: reaction time. The experiment was performed in sets of 10 trials presented in random order. In each set, five of the trials were control trials (go-signal only), three were test trials (go-signal plus TMS), and two were catch trials (TMS only) (figure 1A). In the test trials, TMS was delivered before (negative) or after (positive) the go-signal; delay ranged from -50 msec to +60 msec and was randomly varied in the different trials. We also studied the effects of varying intensities of TMS delivered concurrently with the go-signal (delay = 0). The catch trials served to ensure that the subjects were re- sponding to the go-signal and not to the magnetic stimulus.l4JS Twenty sets of trials (200 trials) were completed by each subject. If the subject responded to any of the catch trials in a given set, the entire set of 10 trials was discarded from further analysis. We found no difference in the frequency of responses to catch trials between PD patients and controls. The main reason for omitting an entire set of trials when the subject responded to a single catch trial was to allow comparison of the results with those obtained in our previous studies on normal volun- t e e r ~ . ~ ~ J ~ In addition, errors in catch trials indicate a lapse of attention, and we wanted to make sure that the attention level and the performance of each subject across sets of trials was as constant as possible.

Experiment 2: pre-movement excitability buildup. We recorded 100 to 200 trials per subject. In one-half of the trials we used the visual go-signal (control trials). In the other half, the go-signal was the same visual stimulus coupled with a subthreshold transcranial magnetic stimulus delivered to the ideal position for inducing motor evoked potentials in the contralateral biceps (test trials) (figure 1B). In both control and test trials, a subthreshold transcranial magnetic stimulus (probing stimulus) was delivered at varying times after the go-signal to assess the probability of inducing motor evoked potentials in the biceps as a function of the proximity of voluntary EMG onset.14J9 In test trials, the probing stimulus was identical in intensity and localization to the magnetic stimulus coupled with the visual stimulus as part of the go-signal. The amplitude of the motor evoked potential was expressed as a percentage of the maximal M-response following peripheral electrical nerve stimulation.

Electromyographic recording. Pairs of surface elec-

trodes (DISA 13K60) were placed 4 cm apart on the skin overlying the belly of the right biceps and triceps brachii, and a Grass accelerometer was taped to the subject’s forearm. EMG and accelerometer signals were amplified and filtered (100 to 2,000 Hz) by Grass amplifiers, digi- tized with a sampling rate of 5,000 Hz per channel, rectified, and collected using an AST personal computer. Al- ternatively, EMG activity was recorded by a Dantec Counterpoint electromyograph with a bandpass of 30 Hz to 2 kHz and sensitivity ranging from 50 to 1,000 pV per division.

Transcranial magnetic stimulation. We used a Cad- well MES 10 magnetic stimulator (experiment 1) or a Cadwell Rapid-Rate magnetic stimulator (experiment 2) and an 8-shaped coil in which each wing measured 4.5 cm in diameter. The Cadwell Rapid-Rate magnetic stimulator is capable of delivering twin pulses at intervals as short as 30 msec without changes in the amplitude of the p u l ~ e . ~ ~ , ~ ~ The coil was held flat on the scalp with the in- tersection of the two wings centered over the position at which TMS induced motor evoked potentials of maximal amplitude in the contralateral biceps. This position was determined, with the patient a t rest, by stimulating sev- eral times at the stimulator’s maximal output intensity (approximately 2.5 T) over different scalp positions.21 The handle of the coil was held parallel to the sagittal axis of the subject’s head, pointing occipitally. This tech- nique allows relatively focal stimulation, mostly limited to cortical layers of the brain.22,23 Stimulation intensity was expressed in relationship to the stimulator’s lowest output intensity capable of inducing five motor evoked potentials in the contralateral biceps of at least 50 pV in a series of 10 stimuli (threshold intensity).

Data analysis. RT was measured from the go-signal to the onset of biceps EMG activity. Movement onset was measured to the first deflection of the accelerometer’s trace. In experiment 1, mean f SD RT was calculated for all control trials and for each delay tested in the test trials. Results across subjects were compared with one-way analysis of variance (ANOVA). Comparison of RTs in control and test trials and between normal volunteers and patients was performed using one-way ANOVAs, col- lapsing across subjects. Significance level, tested with Scheffgs test, was set at p < 0.05. To analyze the proba-

May 1094 NEUROLOGY 44 885 by NIZAR YAMANIE on July 20, 2008 www.neurology.orgDownloaded from


A CONTROL TRIALS

B CONTROL TRIALS

Warning Reaction signal Go-Signal (Arm flexion)

TEST TRIALS Magnetic Stimulus

Reaction t h e + l v v I

CATCH TRIALS

Warning Go-Signal Probing React ion Signal (Flash) Stimulus (Arm flexion)

TEST TRIALS

Go-S ignal (Flash t Magnetic Stimulus )

Reaction time '

Figure 1. Experimental designs for experiments 1 (A) and 2 (BI. See text for details.

bility of the probing stimulus inducing a motor evoked potential in experiment 2, we aligned the trials a t EMG onset (response) and expressed the probability as a function of the interval between probing stimulus and EMG onset. We compared the probability curves in the control trials with those in the test trials to assess the effect of TMS in the go-signal (test trials) on the buildup of motor cortex excitability during the RT. We compared the probability curves in normal volunteers and patients to assess the effect of PD on the results.

Results. Exper imen t 1: reaction t ime . In control trials, RT in the patients with PD was slower than in the normal volunteers (173.6 f 22.8 msec versus 151.6 * 17.9 msec, p < 0.001). In test trials, RT was shortened in patients and normal subjects. The amount of RT shortening by TMS depended on stimulation intensity and delay between go-signal and TMS (figure 2). At delay of 0 msec and 90% motor threshold intensity, the mean shortening of RT by TMS was significantly larger in the patients than in the normal volunteers (41.9 msec versus 28 msec,p < 0.001).

In normal volunteers, the shortening of RT by subthreshold TMS was significant ( p < 0.01 to

886 NEUKOI,O(:Y 44 May 1994

40

-xi -40.30-20 -10 o 10 20 M 40 so 60 so 70 N 110 no tso Delay (ms) TMS intensity

(% of motor threshold) I

Figure 2. Difference in RT in trials with and without TMS according to delay and TMS intensity in normal volunteers (open circles) and patients with PD (filled circles). Negative RT difference implies shortening of RT by TMS; positive values imply prolongation of RT b.y TMS. Asterrsks mark significant differences between normal Subjects arid patients (p < 0.0011.



Figure 3. RT (mean SD) i n the parkinsonian patients i n trials without T M S (control, open circle) and in trials with T M S at various intensities. The gray band marks the range of RTs i n trials without T M S in the normal volunteers.

0.005) at delays of -10 msec to +20 msec. At 2 +50 msec delay, RT was significantly prolonged ( p < 0.05) by subthreshold TMS in normal volunteers. In the patients, RT was significantly shortened ( p < 0.01 to 0.005) by subthreshold TMS at delays of -10 msec to +50 msec. Prolongation of RT by subthreshold TMS in the patients was never ob- served a t the delays tested. Comparison of the effects of subthreshold TMS on RT according to the delay in normal volunteers and patients revealed significant differences (figure 2).

The effects of TMS on RT according to TMS intensity were also significantly different between normal volunteers and patients (figure 2). In the normal subjects, TMS significantly shortened RT ( p < 0.01 to 0.005) at 70% to 90% motor threshold intensity, whereas it significantly prolonged RT ( p c 0.01 to 0.005) at 120% to 150% motor threshold intensity. In the patients, TMS significantly shortened RT ( p < 0.01 to 0.005) at 70% to 130% motor threshold intensity. Prolongation of RT by TMS in patients was seen only in occasional trials at 150% motor threshold intensity.

In the patients, RT in trials with TMS at 70% to 130%) motor threshold intensity and 0 msec delay became as short as RT in the normal volunteers in trials without TMS (figure 3). This “normalization” of RT by TMS was associated with a change in the agonist-antagonist EMG pattern (figure 4). In trials without TMS, patients frequently displayed an EMG pattern characterized by multiple agonist and antagonist bursts. In trials with TMS, the first agonist burst was frequently of larger amplitude, and was part of a triphasic (agonist-antagonist-agonist) pattern characteristic of ballistic movements in normal subject^.^^^'" The duration of the agonist and antagonist bursts did not change in trials with or without TMS.

The possibility that the effects of TMS on RT were a function of RT itself was evaluated with a correlation analysis between t h e RT and the

BICEPS WITHOUT

I MAGNETIC I

TRICEPS , STIMULATION

I

BICEPS WITH MAGNETIC STIMULATION

TRICEPS I

1. WITH MAGNETIC

BICEPS

STIMULATION

I

200 p v

100 rns t

Go-Signal

Figure 4. Representative examples of rectified EMG traces in a patient with PD in trials without and with TMS. I n the trial with TMS, the shortened RT is associated with higher amplitude bursts and the absence of both a second antagonist and a third agonist burst.

amount of RT shortening by TMS. We found no correlation between RT and TMS effects on RT among the normal volunteers, among the PD patients, or among all subjects studied. Therefore, the difference in RT reduction by TMS between PD patients and normal volunteers has to be considered a function of PD itself.

In the three subjects studied off medications, the RT in the control trials was significantly longer than on medications (191.4 f 27.4 msec versus 166.2 k 18.6 msec, p < 0.01). However, the effects of TMS on RT were essentially unchanged, with significant shortening of RT by subthreshold TMS at delays of -10 msec to +50 msec ( p < 0.01 to 0.005) and a t TMS intensities of 70% t o 130% motor threshold intensity ( p < 0.01).

Patients 5 to 10 occasionally reported that the movement in response to trials with high TMS intensity was triggered entirely by TMS rather than being voluntary. The analysis of the EMG pattern in such trials revealed that the motor evoked potentials in agonist and antagonist were followed by a n antagonist burst and then a n agonist burst, with absence of an initial agonist burst (figure 5). We do not feel that in such trials a first agonist burs t could have been obscured by the motor evoked potential since the configuration of the motor evoked potential, its latency, and its duration always matched those of trials with a clearly present first agonist burst. In addition, if the motor evoked potential in such trials had coincided with a first agonist burst, it should have been greatly fa- cilitated by the ongoing contraction of the target



ME? ” - 1.0

- 0,s h

-0.6 -= s -0.4 2

L - 0.2

* .I

d

-nn

GO-SIGNAL+ 11 / I

K TRICEPS

I I

I I

Figure 5. Representative examples of trials with high- intensity T M S i n a patient with PD. I n quotations are the patient’s perception of the movement. I n the top example, the motor evoked potentials (MEPs) in agonist and antagonist are followed after a pause by a n initial agonist burst. I n this case the patient felt he had executed the movement voluntarily. I n the bottom example, the MEPs are followed by a burst i n the triceps (antagonist) i n the absence of an initial agonist burst. The patient felt that the movement had been “normal” but that TMS, rather than he, had generated it entirely.

muscle, and this was never the case. Analysis of the movement pattern clinically and on forearm accelerometer recordings in such trials did not reveal any substantial differences. Such trials were not included in the analysis of RT described above.

Experiment 2: pre-movement excitability buildup. The pre-movement motor cortex excitability increase in control trials was slower in patients than in normal subjects (figure 6). In relationship to EMG onset, it began approximately 40 msec earlier in the patients. Considering a mean difference of approximately 35 msec in RT in tr ials without TMS, the pre-movement facilitation began a t approximately the same time in relation to the go-signal in patients and normal volunteers. Eventually, 20 msec before voluntary EMG onset, the probability of evoking a motor potential with the probing stimulus was 1.0 in both patients and normal volunteers. Concurrently with the probability of inducing motor evoked potentials with the probing stimulus, the amplitude of the evoked potentials increased with shorter times to EMG onset and reached approximately 40%’ of the maximal M-response in both patients and normal subjects.

Comparing control and tes t tr ials, t h e t ime course of pre-movement facilitation did not change in the normal volunteers. However, in the patients,

888 NEUROLOGY 44 May 1994

-150-140-130-120-110-100 -90 -80 -70 -60 -50 -40 -30 -20

Time to EMG onset (ms)

Figure 6. Probahility of inducing a motor evoked potential with the probing stimulus according to the interval between probing stimulus and EMG onset in normal volunteers (circles) and parkinsonian patients (squares). Open symhols indicate trials without T M S i n the go-signal; filled symbols indicate trials with TMS.

the excitability increased faster and started closer to EMG onset in the test trials, resembling the course of the pre-movement facilitation in normal subjects (figure 6).

The duration of the pre-movement excitability buildup might have been related to the RT. How- ever, we found no correlation between RT and duration of the excitability buildup in either normal subjects or PD patients. In addition, comparison of results of the two PD patients with the fastest RTs in control trials (155.7 * 13.9 msec and 159.8 14.9 msec) with those of the two normal subjects with the slowest RTs in control trials (155.1 * 17.2 msec and 162.6 * 16.1 msec) still showed a mean difference in duration of the excitability buildup of 22 msec. Therefore, the differences in the duration of the excitability buildup must be interpreted as a function of PD.

Discussion. Theoretical model of response preparation and execution. We divide the processes required for response preparation and execution into a stimulus evaluation system, a task-specific circuitry, and a response ~ h a n n e 1 . l ~ The stimulus evaluation system has to detect, process, and inter- pret the go-signal. The task-specific circuitry pre- pares the motor program for the required response. The response channel includes all the necessary structures to execute the response as rapidly as possible. In a warned, simple RT paradigm, such as the one used in this study, activation of the task- specific circuitry may begin even before the warning signal, since the subject is given all the necessary information to plan the appropriate response in advance. During the foreperiod, the task-specific circuitry and the stimulus evaluation system are active in parallel since the prepared motor program has to be held in memory and the stimulus evaluation system is preparing to detect the go-signal (at- tentional aspects of set). Identification of a stimulus as the go-signal is completed in the “time for



recognition.” The transfer of the motor program from the task-specific circuitry t o the response channel occurs during the “time for initiation.” Fi- nally, the response channel needs a period of time (“time of development”) to execute the response. Therefore, during the RT we can identify a time €or recognition, a time for initiation, and a time of de- ve10pment.l~ The identification of these three times before response initiation does not imply that such times have to occur in a fixed sequence and cannot occur partly in parallel. In fact, there is some evi- dence to suggest that parallel processing does occur during response preparati~n.~~+’~

Simple RT and PD. In agreement with multiple previous studies,s,11,13,2e-31 we found RT in patients with PD to be longer than in normal subjects. A warning stimulus before the go-signal reduces RT by the same amount in patients with PD and in normal subjects, and the variation of RT according to the go-signal modality (time for recognition) is the same in patients as in normal s ~ b j e c t s . ~ ~ , ~ ~ In addition, parkinsonian patients are able to use advance information normally to plan a move- ment3,‘jJ1 and can hold a motor program in store normally during a delay RT task.33 Therefore, the differences in simple RT between parkinsonian patients and normal subjects cannot be due to differences in the stimulus evaluation system or in the task-specific circuitry.

Differences in the pre-movement facilitation in patients and normal subjects (experiment 2) have been preliminarily reported.34 They suggest that the main abnormality in the slow simple RT in PD lies in the time of development. We think of time of development as a n “energizing” phenomenon marked by an increase in firing rate of movement onset-related neurons in the primary motor cor- t e ~ ~ ~ - ~ ~ by which the motor system excitability is increased and response execution occurs when a par- ticular threshold level is reached.41 Therefore, the time of development will depend on the baseline level of cortical activation. In parkinsonism, pri- mate42 and, more recently, human have shown that the motor cortex excitability is lower and inversely correlated with the degree of bradykinesia. In PD, the inhibitory input of the substantia nigra pars compacta on the putamen is r e d ~ c e d . ~ ~ - ~ ~ Therefore, there is an increased inhibition of the external segment of the globus pallidus and subsequently a disinhibition of the subthalamic nucleus. The internal segment of the globus pallidus and the substantia nigra pars reticulata exert excessive inhibition on thalamocortical neurons be- cause of the increased excitatory input from the subthalamic nucleus. This results in decreased cortical f a ~ i l i t a t i o n , ~ ~ - ~ ~ thereby prolonging the time (time of development) required to build up pre- movement cortical excitability past the threshold required for movement execution.

Effects of TMS on simple RT, Our present results on normal volunteers confirm our previous studies.14Js TMS shortens RT primarily by influ-

encing the time for initiation without affecting the time for recognition or the time of development. TMS could induce an earlier transfer of the motor program from the task-specific circuitry to the response channel or it could speed up the transfer process itself, thus shortening the time for initiation.14 We think of this transfer process as a switch of activity from set-related neurons to movement onset-related neuron~.~~-~O Subthreshold TMS to the motor cortex may activate corticocortical connec- tions, enhancing the information transfer between set-related neurons in the premotor and supple- mentary motor cortices and movement onset-related neurons (corticospinal neurons) in the primary motor cortex.

Contrary to the findings in normal subjects, shortening of RT by TMS in patients with PD was associated with a change in the pre-movement cortical excitability increase. We hypothesize that TMS shortens RT in patients with PD by shortening both the time for initiation and the time of development. The additional effect on the time of development may account for the fact tha t TMS shortened RT more in patients than in normal subjects. As mentioned above, akinesia may be due to decreased responsiveness of corticospinal neurons to the inputs involved in movement initiation due to the increased inhibition of thalamocortical neu- r o n ~ . ~ ~ In macaque monkeys with MPTP-induced parkinsonism, movement-related neurons in the primary motor cortex demonstrate abnormally low peak discharge frequencies and prolonged latencies from onset of discharge to motion onset51 (time of development). Subthreshold TMS may raise the level of corticospinal neurons’ activation either di- rectly or through activation of excitatory intracortical interneuron~,~~-~‘j thus temporarily reversing the abnormality underlying akinesia.

Normalization of ballistic EMG pattern by TMS. In normal individuals, ballistic limb movements a re characterized electromyographically by a triphasic (agonist-antagonist-agonist) pattern in which the amplitude of the initial agonist burst correlates with the movement v e l o ~ i t y . ~ ~ , ~ ~ Patients with PD display an inability to generate an ade- quate initial agonist burstgJO so that the exerted force is insufficient to reach the desired target.57 The movement is completed by a series of small amplitude movements characterized by repeated agonist and antagonist burstsgJO or by a prolonged continuous discharge.57 D e L ~ n g ~ ~ has suggested that in PD, due to the high-level tonic discharge of neurons in the internal segment of the globus pallidus, phasic modulation of their activity during movement execution may not be faithfully trans- mitted to the cortex. Therefore, parkinsonian patients are able to scale the first agonist burst according to movement velocity but do so over a re- stricted range.12 In trials with TMS, the first agonist burst was consistently of higher amplitude (figure 4). We suggest that subthreshold TMS acti- vates corticospinal neurons, thus transiently nor-



malizing the scaling of the amplitude of the initial agonist burst. In any case, the speeding up of RT and the normalization of the EMG pattern do not have to be considered to originate from influences of TMS on different structures. EMG patterns depend on response duration,58 and PD patients who move as rapidly as normal subjects tend to have normal EMG p a t t e r n ~ . ~ J ~ J ~

Effect of TMS on the perception o f voluntary movements. Occasionally, some of our patients per- ceived the response movements in trials with high TMS intensity as triggered entirely by TMS rather than being voluntary. In such instances, the motor evoked potentials were followed by an antagonist burst with absence of an initial agonist burst sepa- rable from the motor evoked potential (figure 5 ) . An abnormal modulation of the motor cortical output by the basal ganglia46 may lead to misinterpre- tation of the motor evoked potential as the initial agonist burst, a phenomenon never encountered in normal subjects. Such an abnormality may also ex- plain why, in parkinsonian patients, slight increases of TMS intensity lead to abnormally large increases in the amplitude of the induced motor evoked potential^^^,^^ while facilitation of motor evoked potentials by isometric contraction of the target muscle is d e ~ r e a s e d . ~ ~

Acknowledgment

The authors thank Nguyet Dang for technical assistance during the experiments.

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focal, single-pulse transcranial magnetic stimulationAkinesia in Parkinson's disease. I. Shortening of simple reaction time with

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