time course of corticospinal excitability in reaction time and self-paced movements

9
Time Course of Corticospinal Excitability in Reaction Time and Self-Paced Movements Robert Chen, MBBChir, MSc, FRCPC, Zaneb Yaseen, Leonard0 G. Cohen, MD, and Mark Hallett, MD ~~ We used transcranial magnetic stimulation (TMS) to study the time course of corticospinal excitability before and after brisk thumb abduction movements, either in a simple reaction time (RT) paradigm or self-paced. Premovement increase in corticospinal excitability began about 20 msec earlier for self-paced compared with simple RT movements. For both simple RT and self-paced movements after electromyographic (EMG) offset, there was a first period of increased excit- ability from 0 to 100 msec, followed by a second period from 100 to 160 msec. Corticospinal excitability was decreased from about 500 to 1,000 msec after EMG offset for both types of movements. Our results show that motor preparation that begins 1.5 to 2 seconds before self-paced movement is not associated with increased corticospinal excitability. The first phase of increased corticospinal excitability after EMG offset may be due to activity of motor cortex neuron sub- threshold for activating spinal motor neurons, and the second phase may reflect a subthreshold second agonist burst. The period of decreased corticospinal excitability after movement corresponds to the onset of event-related synchronization (ERS) of electroencephalographic signals in the 20-Hz band, and supports the hypothesis that ERS may be related to an inactive, idling state of the motor cortex. Chen R, Yaseen Z, Cohen LG, Hallett M. Time course of corticospinal excitability in reaction time and self-paced movements. Ann Neurol 1998;44:317-325 Premovement increase in corticospinal excitability be- gins about 80 msec before electromyographic (EMG) onset in simple reaction time (RT) This likely represents a period of gradual increase in neuronal activity in the motor cortex (MI), eventually rising above the threshold for discharging of spinal mo- tor neurons. However, the time course of corticospinal excitability before self-paced movements has not been investigated. Electroencephalographic (EEG) studies have shown that changes in movement-related cortical potentials (MRCPs)' and desynchronization of EEG (event-related desynchronization, ERD),7as which likely represent motor preparation and cortical activation, be- gin about 1.5 seconds before self-paced movements. Subdural recordings demonstrated that the contralat- eral precentral gyrus contributes to the different com- ponents of the MRCPS~,"'~; ERD is also maximal over the contralateral precentral It is not known whether corticospinal excitability is increased during the period of motor preparation. Although changes in corticospinal excitability before simple RT movements have been well documented, changes in corticospinal excitability after voluntary movements have not been studied. Event-related syn- chronization (ERS) of EEG' '," and magnetoencepha- lography (MEG)l3?'* signals in the 10-Hz and 20-Hz bands occur after both self-paced and externally paced movements. It has been suggested that ERS represents an inactive, idling state of the c o r t e ~ ' ~ , ' ~ or a period of active immobilization. '* Whether ERS is accompanied by changes in corticospinal excitability is not known. In the present study, we used transcranial magnetic stimulation (TMS) to examine the time course of cor- ticospinal excitability before and after simple RT and self-paced movements. Our first hypothesis is that in- crease in M1 excitability before movement begins ear- lier in self-paced compared with RT movements. Our second hypothesis is that after voluntary movement there is a period of decreased M I excitability corre- sponding to the ERS of EEG signals. Subjects and Methods We studied 13 healthy volunteers (7 men and 6 women; mean age, 40.1 years; range, 17-65 years). All subjects gave written informed consent and the protocol was approved by the institutional review board. Transcranial Magnetic Stimulation TMS was performed with a figure-eight coil (external diam- eter, 5.5 cm for each wing) powered by a Cadwell high-speed From the Human Cortical Physiology Unit, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. Received Dec 23, 1997, and in revised form Mar 3, 1998. Accepted for publication Mar 3, 1998. Address correspondence to Dr Hallett, Building 10, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428. Chen et al: Time Course of Corticospinal Excitability 317

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Page 1: Time course of corticospinal excitability in reaction time and self-paced movements

Time Course of Corticospinal Excitability in Reaction Time and Self-Paced Movements Robert Chen, MBBChir, MSc, FRCPC, Zaneb Yaseen, Leonard0 G. Cohen, MD, and Mark Hallett, MD

~~

We used transcranial magnetic stimulation (TMS) to study the time course of corticospinal excitability before and after brisk thumb abduction movements, either in a simple reaction time (RT) paradigm or self-paced. Premovement increase in corticospinal excitability began about 20 msec earlier for self-paced compared with simple RT movements. For both simple RT and self-paced movements after electromyographic (EMG) offset, there was a first period of increased excit- ability from 0 to 100 msec, followed by a second period from 100 to 160 msec. Corticospinal excitability was decreased from about 500 to 1,000 msec after EMG offset for both types of movements. Our results show that motor preparation that begins 1.5 to 2 seconds before self-paced movement is not associated with increased corticospinal excitability. The first phase of increased corticospinal excitability after EMG offset may be due to activity of motor cortex neuron sub- threshold for activating spinal motor neurons, and the second phase may reflect a subthreshold second agonist burst. The period of decreased corticospinal excitability after movement corresponds to the onset of event-related synchronization (ERS) of electroencephalographic signals in the 20-Hz band, and supports the hypothesis that ERS may be related to an inactive, idling state of the motor cortex.

Chen R, Yaseen Z, Cohen LG, Hallett M. Time course of corticospinal excitability in reaction time and self-paced movements. Ann Neurol 1998;44:3 17-325

Premovement increase in corticospinal excitability be- gins about 80 msec before electromyographic (EMG) onset in simple reaction time (RT) This likely represents a period of gradual increase in neuronal activity in the motor cortex (MI), eventually rising above the threshold for discharging of spinal mo- tor neurons. However, the time course of corticospinal excitability before self-paced movements has not been investigated. Electroencephalographic (EEG) studies have shown that changes in movement-related cortical potentials (MRCPs)' and desynchronization of EEG (event-related desynchronization, ERD),7as which likely represent motor preparation and cortical activation, be- gin about 1.5 seconds before self-paced movements. Subdural recordings demonstrated that the contralat- eral precentral gyrus contributes to the different com- ponents of the MRCPS~," '~; ERD is also maximal over the contralateral precentral It is not known whether corticospinal excitability is increased during the period of motor preparation.

Although changes in corticospinal excitability before simple RT movements have been well documented, changes in corticospinal excitability after voluntary movements have not been studied. Event-related syn- chronization (ERS) of EEG' '," and magnetoencepha-

lography (MEG)l3?'* signals in the 10-Hz and 20-Hz bands occur after both self-paced and externally paced movements. It has been suggested that ERS represents an inactive, idling state of the c o r t e ~ ' ~ , ' ~ or a period of active immobilization. '* Whether ERS is accompanied by changes in corticospinal excitability is not known.

In the present study, we used transcranial magnetic stimulation (TMS) to examine the time course of cor- ticospinal excitability before and after simple RT and self-paced movements. Our first hypothesis is that in- crease in M1 excitability before movement begins ear- lier in self-paced compared with RT movements. Our second hypothesis is that after voluntary movement there is a period of decreased M I excitability corre- sponding to the ERS of EEG signals.

Subjects and Methods We studied 13 healthy volunteers (7 men and 6 women; mean age, 40.1 years; range, 17-65 years). All subjects gave written informed consent and the protocol was approved by the institutional review board.

Transcranial Magnetic Stimulation TMS was performed with a figure-eight coil (external diam- eter, 5.5 cm for each wing) powered by a Cadwell high-speed

From the Human Cortical Physiology Unit, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Received Dec 23, 1997, and in revised form Mar 3, 1998. Accepted for publication Mar 3, 1998.

Address correspondence to Dr Hallett, Building 10, Room 5N226, 10 Center Drive, MSC 1428, Bethesda, MD 20892-1428.

Chen et al: Time Course of Corticospinal Excitability 317

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magnetic stimulator (Cadwell Laboratories, Kennewick, WA). The coil was placed over the optimal position of the head for evoking motor-evoked potentials (MEPs) from the right abductor pollicis brevis (APB) muscle, with the handle of the coil pointing backward. The optimal position was marked on the scalp to ensure identical placement of the coil throughout the experiment. Motor threshold (MT) was de- termined at rest to the nearest 1% of the stimulator output and was the minimum intensity required to evoke MEPs of more than 50 p.V in at least five of 10 trials.

EMG Recordings Surface EMG was recorded from the right APB muscle with surface electrodes (AglAgCI) over the muscle belly in the the- nar eminence and the proximal phalanx of the thumb. The activity of the antagonist muscle, the right adductor pollicis, was recorded in 2 subjects with electrodes over the muscle belly in the first web space and at the base of the proximal phalanx of the thumb. The signal was filtered (bandpass, 50 Hz to 2 kHz), amplified, displayed (Dantec Counterpoint Electromyograph, Slovunde, Denmark) and stored in a lab- oratory computer for off-line analysis. The maximum M wave (MmJ for the APB muscle was determined by supra- maximal electrical stimulation of the median nerve at the wrist.

Study Design and Technical Considerations We used subthreshold and suprathreshold TMS in different experiments. The subthreshold TMS was adjusted such that it did not normally produce MEPs in the baseline resting condition, but a minimal increase in M1 excitability would lead to recordable MEPs. Subthreshold TMS produces a low and stable baseline, and is most suited to detect a small in- crease in corticospinal excitability. In contrast, the baseline for suprathreshold TMS is much more variable because of the considerable variation in MEP amplitudes from trial to trial, and is therefore less sensitive than subthreshold TMS to derecr increased corricospinal excitability. However, sub- threshold TMS can only detect increases in corticospinal ex- citability, whereas suprathreshold TMS can detect both in- creases and decreases. Another technical consideration is the time before and after the EMG burst to be studied. Exam- ining a shorter time allows using a narrower bin width, re- sulting in higher temporal resolution of the time course. Based on the timing of ERS of EEG signals, reduced corti- cospinal excitability was not expected until 750 msec to 2 seconds after movement onset. Therefore, we used subthresh- old TMS to examine a relatively short time before and after the EMG burst to obtain a high temporal resolution of the time course for increased corticospinal excitability for simple RT (Experiment 1) and self-paced movements (Experiment 3). For the suprathreshold TMS studies (Experiments 2 and 4), we studied a longer time after the EMG offset, to detect decreases in corticospinal excitability that may occur up to several seconds after voluntary movement.

Experiment 1: Simple RT and Subthreshold TMS Six subjects (2 men and 4 women; age, 28-65 years) par- ticipated in the study. The experimental design is shown in Figure 1A. The subjects sat comfortably in front of a com-

A Reaction Time Movement

Subthreshold TMS delivered 30 - 600 rns after go-signal - 1 Warning signal Go signal d

EMG offset to TMS TMS to + 4 EMGonsetA I\ - 1 -- v v

1 . 2 - 2 s RT

B Self-paced Movement

TMS delivered at random intervals

. . TMS to EMG onset ~ E T offset to TM;

self-paced movements

Fig 1. Experimental design for simple reaction time (Rr) (Ex- periments 1 and 2) (A) and self-paced (Experiments 3 and 4) movements (B). For trials in which transcranial magnetic stimulation (TMS) was delivered before voluntary electromyo- graphy (EMG), the time from TMS to EMG onset was mea- sured and the trial was used to determine corticospinal excit- ability before EMG onset. For triaE in which TMS was delivered after voluntary EMG, the time from EMG ofiet to TMS was measured and was used to determine corticospinal excitability after EMG ofiet. In the self-paced experiments, the timing of the voluntary EMG and TMS was randomly intermixed.

puter monitor that displayed the instructions for movements. Each RT trial began with a warning signal (a black circle), followed after a variable delay of 1.2 to 2 seconds by a “go signal” (an arrow). The subjects were instructed to abduct the right thumb as fast as possible after the go signal to gen- erate a single burst of EMG in the right APB muscle and to maintain muscle relaxation between trials. Before recordings, each subject had practice trials to ensure familiarity with the task. Initially, some subjects did not maintain complete EMG silence after the EMG burst, but all subjects were able to perform the task after several minutes of training. TMS at 90% of the resting MT was delivered between 30 to 600 msec after the go signal. Control trials consisted of the warn- ing signal followed by TMS but without the go signal. The order of the RT and control trials, and the delay between go signal and TMS for the RT trials were pseudorandomized and controlled by a laboratory computer. The trials were re- peated every 5.5 to 6.2 seconds. Each subject completed eight blocks of trials; each block consisted of 40 RT and four control trials.

Experiment 2: Simple RT and Suprathreshold TMS Six subjects (2 men and 4 women; age, 23-63 years) were studied. Three of the subjects also participated in Experi- ment 1. The paradigm used was identical to that for Exper-

318 Annals of Neurology Vol 44 No 3 September 1998

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iment 1 except that the intensity of TMS was 110% of the resting MT, TMS was delivered between 50 to 2,000 msec after the go signal, and the intertrial interval was 7.5 to 9.5 seconds. Each subject completed eight blocks; each block consisted of 80 RT trials and 10 control trials.

Experiment 3: Self-paced Movement and Subthreshold TMS The 6 subjects who participated in Experiment 1 were stud- ied. The experimental design is shown in Figure 1B. The subjects were instructed to make brisk, self-paced thumb ab- duction movements to produce a single burst of EMG in the right APB muscle and to maintain muscle relaxation (EMG silence) between movements. Frequency of movements was approximately once every 4 to 5 seconds, and the subjects were instructed to vary the time between movements. Each subject had practice sessions before the recordings and all performed the movements without difficulty. TMS at 90% of resting MT was delivered at random intervals between 2.3 and 3 seconds apart. The timing of the self-paced move- ments and TMS was therefore randomly intermixed. EMG was recorded for 500 msec before and for 500 msec after the TMS pulse. Each subject completed 10 blocks, with 110 TMS pulses in each block.

Experiment 4: Self-paced Movement and Suprathreshold TMS Five subjects (4 men and 1 woman; age, 17-23 years) were studied, 1 of whom also participated in Experiment 2. The experimental procedure was similar to that for Experiment 3. The subject made self-paced right thumb abduction move- ments approximately once every 10 seconds; TMS at 110% of resting M T was delivered at random intervals every 7.5 to 10.5 seconds. EMG was recorded for 4,000 msec before and 400 msec after TMS was delivered. Each subject completed eight blocks of trials; each block consisted of 108 TMS pulses.

Relationship Between Thumb Movement and EMG Burst The relationship between the timing of the thumb move- ment and EMG burst was investigated in 1 subject during the simple RT task (Experiment 1) and in another subject during the self-paced task (Experiment 3). An accelerometer (Picotrax, Endevco, San Juan Capistrano, CA) was attached to the proximal phalanx of the right thumb and was posi- tioned to be sensitive to movement in the abduction-adduc- tion direction. The signal from the accelerometer was ampli- fied (device built by the Research Services Branch, NINDS, Bethesda, MD), displayed (Dantec Counterpoint Electro- myograph) and stored in a laboratory computer for further analysis.

Data Analysis Each trial was analyzed individually off-line. The MEP am- plitude, the time between TMS pulse and EMG onset or offset (see Fig l), and the beginning and end of movement, as recorded by the accelerometer, were measured. Trials in which TMS was delivered during the EMG burst were re- jected. The time between TMS and EMG onset or offset

were analyzed in bins of 20 msec for Experiments 1 and 3. Because the range of time between TMS and EMG onset or offset was larger, for Experiments 2 and 4 the time intervals were analyzed in bins of 50 msec to allow a sufficient num- ber of trials for each bin. In the RT studies (Experiments 1 and 2), baseline MEP amplitudes were determined from the control trials (warning signal without go signal). Baseline MEP amplitudes for the self-paced, subthreshold study (Ex- periment 3) were determined from trials in which TMS was delivered more than 500 msec before and 500 msec after the EMG burst. In a similar manner, baseline MEP amplitudes for the self-paced, suprathreshold study (Experiment 4) were determined from trials in which TMS was delivered more than 500 msec before and 4,000 msec after the EMG burst. MEP amplitudes were expressed as percentages of M,, for the subthreshold TMS studies (Experiments 1 and 3), and as percentages of the baseline MEP amplitude for the supra- threshold TMS studies (Experiments 2 and 4).

For each experiment, trials in which TMS was delivered before EMG onset were used to examine corticospinal excit- ability before movement; MEP amplitudes were plotted against the time from TMS to EMG onset. Trials in which TMS was delivered after EMG offset were used to examine corticospinal excitability after movement; MEP amplitudes were plotted against the time from EMG offset to TMS. The effects of time on MEP amplitude were analyzed by analysis of variance (ANOVA) with repeated measures, with MEP amplitude as the dependent variable and time as the repeated measure. If ANOVA showed a significant effect of time, sig- nificant difference from the baseline for each time interval was tested with the unpaired t test. Bonferroni correction was applied to account for multiple comparisons. Differences at each time interval were considered significant if the un- corrected p value was less than 0.05 divided by the number of comparisons. Unless otherwise indicated, values are shown as mean ? SEM.

Results Experiment 1: Simple RT and Subthreshold TMS The time course of corticospinal excitability before EMG onset is shown in Figure 2A; the time course of corticospinal excitability after EMG offset is shown in Figure 2B (mean of 6 subjects). ANOVA showed a sig- nificant effect of time on MEP amplitude before EMG onset ( p = 0.0001) and after EMG offset ( p = 0.007). Bonferroni corrected unpaired t test showed significant increase in corticospinal excitability begin- ning a t 80 msec before EMG onset. Corticospinal ex- citability remained increased for about 160 msec after EMG offset and then returned to baseline. The period of increased corticospinal excitability appears to consist of two phases, a first phase of decreasing excitability from 0 to 100 msec, followed by a second phase with increasing excitability from 100 to 120 msec, returning to baseline around 160 msec after EMG offset.

Experiment 2: Simple R T and Suprathreshold TMS Examples of single trials from 1 subject are shown in Figure 3. The time course of corticospinal excitability

Chen et al: Time Course of Corticospinal Excitability 319

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A

*OI 1 0

i

0 1 % -300 -200 -1 00 0

Time before EMG onset (ms) B

1 0 1

5; 0 u 0 100 200 300 I U

Time after EMG offset (ms)

Fig 2. Results of Experiment 1 (simple reaction time and sub- threshold transcranial magnetic stimulation). Motor-evoked potential (MEP) amplitudes before electromyography (EMG) onset (A) and aft.. EMG ofiet (B) are expressed as percent- ages of M M a . Each point is located at the center of a bin with bin width of 20 msec, and represents the average * SEM for 6 subjects. The horizontal lines represent mean ? 1 SEM of the baseline MEP amplitudes (warning signal but without go signal). * = Signzj%ant difference fiom baseline (unpaired t test, p < 0.05, after Bonferroni correction).

before EMG onset is shown in Figure 4A; the time course of corticospinal excitability after EMG offset is shown in Figure 4B. ANOVA showed that the effect of time on MEP amplitude was significant before EMG onset ( p = 0.03) and after EMG offset ( p = 0.03).

Post hoc unpaired t test showed significant increase in corticospinal excitability beginning at 50 msec be- fore EMG onset. There is a trend for increased corti- cospinal excitability in the first 150 msec after EMG offset, which also consists of two phases, similar to the findings in Experiment 1. However, these time points were not significantly different from the baseline when corrected for multiple comparisons (uncorrected p = 0.007 at 100 msec). In addition, there was a period of reduced MEP amplitude compared with baseline from 700 msec to 1,000 msec after EMG offset. MEP am-

100 ms

D

Y

0.4 mv 100 ms

Fig 3. Representative single trials fiom I subject in Experi- ment 2 (simple reaction time and suprathreshold transcranial magnetic stimulation [TMS]). The motor-evoked potentials (MEPs) are indicated by arrows and the voluntaly electromyo- graphic (EMG) bursts by horizontal lines. (A) Control MEP (amplitude = 0.70 mV). (B) TMS delivered 74 msec before the onset o f EMG burst, with increased MEP amplitude (1.58 mV). (c) TMS delivered 56 msec after EMG ofiet. MEP amplitude (0.36 ml.3 was also increased. (0) TMS delivered 76G msec after EMG oflet, with decreased MEP amplitude (0.11 mV).

plitudes at 750 msec ( p = 0.0006) and 850 msec ( p = 0.00008) were significantly less than the baseline.

Experiment 3: Self-paced Movement and Subthreshold TMS The time course of corticospinal excitability before EMG onset is shown in Figure 5A. The effect of time on MEP amplitude was significant ( p = 0.001, ANOVA). Post hoc unpaired t test showed that signif- icant increase in corticospinal excitability began at 100 msec before EMG onset, which was 20 msec before the onset of increased corticospinal excitability for simple RT movements. The MEP amplitude at 100 msec be- fore EMG onset was also significantly higher for self- paced compared with the simple RT movements (Ex- periment 1) ( p = 0.03, unpaired t test).

The time course of corticospinal excitability after EMG offset is shown in Figure 5B. The effect of time on MEP amplitude was significant ( p = 0.001, ANOVA). Similar to the findings for simple RT move- ments, post hoc unpaired t test showed two phases of increased corticospinal excitability after EMG offset. The first phase consisted of decreasing excitability from 0 to 100 msec and the second phase showed increasing excitability from 100 to 120 msec with a return to baseline around 160 msec after EMG offset.

320 Annals of Neurology Vol 44 No 3 September 1998

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A -9

A

250 h Q

a, u)

.E - 200

150 0

1 i

-I /

t L

s - 100

5 0

Q U 3

P

ffj n o

-300

1 -200 -1 00 0

Time before EMG onset (ms)

* *

0 500 1000 1500 Time after EMG offset (ms)

Fig 4. Results o f Experiment 2 (simple reaction time and su- prathreshold transcranial magnetic stimulation [TMS]). Motor-evoked potential (MEP) amplitudes before electromyo- graphic (EMG) onset (A) and after EMG ofiet (B) are ex- pressed as percentages of baseline. Each point is located at the center of a bin with bin width of 50 msec, and represents the average i SEM f . r 6 subjects. The horizontal lines represent mean ? 1 SEM of the baseline MEP amplitudes (warning signal but without go signao. ' = S&n;fcant dz$&ence fiom baseline (unpaired t test, p < 0.05, afer Bonferroni correction).

Experiment 4: Self-paced Movement and Suprathreshold TMS The time course of corticospinal excitability before EMG onset is shown in Figure 6A; the rime course of corticospinal excitability after EMG offset is shown in Figure 6B. ANOVA indicated a significant effect of time on MEP amplitude both before EMG onset ( p = 0.0002) and after EMG offset ( p = 0.001).

Post hoc unpaired t test showed significant increase

- X 30

I -I- 0 $? 2 0

a 5 1 0

n w o I -500 -400 -300 -200 -100 0

v

a,

= m E LJ, Time before EMG onset (ms)

I, 0 100 200 300 400 5 0 0

Time after EMG offset (ms)

Fig 5. Results of Experiment 3 (self-paced movements and subthreshold transcranial magnetic stimulation). Motor-evoked potential (MEP) amplitudes before electromyographic (EMG) onset (A) and after EMG offjet (B) are expressed as percent- ages of M,, Each point is located at the center of a bin with bin width of 20 msec, and represents the average ? SEM f i r 6 subjects. The horizontal lines represent mean 2 1 SEM of the baseline MEP amplituah. * = SigniJcant differ- ence from the baseline (unpaired t test, p < 0.05, after Bon- ferroni correction).

in corticospinal excitability beginning at 50 msec be- fore EMG onset; there was increased corticospinal ex- citability from 0 to 150 msec after EMG offset. There was also a trend for decreased corticospinal excitability from 400 to 1,000 msec, although the difference from the baseline was not significant with correction for multiple comparisons (uncorrected p = 0.004, at 950 msec).

EMG Burst Durations The EMG burst durations were 85.1 2 8.3 msec for Experiment 1 (simple RT and subthreshold TMS), 141.2 2 8.7 msec for Experiment 2 (simple RT and

Chen et al: Time Course of Corticospinal Excitability 321

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A

- 4 0 0 - Q c Q .- - 0 300 - n

,$ 200 - c 0

Y

0 ‘0

P .- a 100 -

5 n 0 -

-

21.3 L 0.7 msec and EMG offset preceded cessation of movement offset by 241.8 t 4.5 msec.

I i’

-400 -300 -200 -100 0 Time before EMG onset (ms)

B

h

t 200 f 1;

m W a 0 - l I

0 5 0 0 1000 1500 2000 2500 3000 3500 4000

Time after EMG offset (ms)

Fig 6 Results of Experiment 4 fielf-aced movements and suprathreshold transcranial magnetic stimulation). Motor- evoked potential (MEP) amplitudes before electromyographic (EMG) onset (A) and ajer EMG offjet (B) are expressed LZJ

percentages of baseline. Each point is located at the center of a bin with bin width ofso msec, and represents the average 5 SEM for 5 subjects. The horizontal lines represent mean 5 1 SEM of the baseline MEP amplitudes. * = SipiJicant dzfser- ence fiom the baseline (unpaired t test, p < 0.05, after Bon- ferroni correction).

suprathreshold TMS), 93.9 ? 8.3 msec for Experi- ment 3 (self-paced movement and subthreshold TMS), and 141.7 ? 9.8 msec for Experiment 4 (self-paced movement and suprathreshold TMS). There was no significant difference between simple RT and self- paced movements, but the EMG burst durations were significantly longer for suprathreshold TMS than sub- threshold TMS studies ( p = 0.0009 for simple RT, and p = 0.005 for self-paced movements).

Relationship Between Thumb Movement and EMG Burst For simple RT movements, the EMG onset in the APB muscle preceded movement onset by 22.7 2 2.0 msec and EMG offset preceded cessation of thumb movement by 359.7 t 9.3 msec. For self-paced move- ments, EMG onset preceded thumb movement by

Activity of the Antagonist Muscle Surface EMG showed that the adductor pollicis muscle was active during thumb adduction movements. In both subjects, the adductor pollicis muscle during RT and self-paced thumb abduction movements showed activity synchronous with the APB activity, but the amplitudes were about one-tenth of that for the APB muscle. Some of this activity might have been cross- talk from the APB muscle. No antagonist burst was observed after the APB activity in any of the trials.

Discussion This is the first report of the time course of corticospi- nal excitability before self-paced movements and after RT and self-paced movements. We found that the rise in corticospinal excitability occurs slightly earlier for self-paced than simple RT movements, and there are periods of increased and decreased corticospinal excit- ability after both simple RT and self-paced movements.

Premovement-Increased Corticospinal Excitability Before RT and Self-paced Movements The study of simple RT with subthreshold TMS (Ex- periment 1) showed that the premovement-increased corticospinal excitability occurred about 80 msec be- fore EMG onset. This is similar to the results of pre- vious studies using transcranial electrical stimulation’32 and TMS.3-5 Recording from the monkey MI showed increased neuronal activity beginning at 70 to 100 msec before movement onset and that the firing rate increases as the time to movement onset shortens. 17-20

Spinal reflexes are also facilitated from 50 to 100 msec before EMG onset in simple and choice RT paradigms, and are likely due to reduction of presynaptic inhibi- t i ~ n . ~ l - ’ ~ Therefore, during the period of premove- ment-increased corticospinal excitability, M 1 activity is also increased but remains subthreshold for motor unit activation.

With self-paced movements, premovement-increased corticospinal excitability began at 100 msec before EMG onset. Therefore, the duration of the pre- movement-increased corticospinal excitability for sim- ple RT movements is about 20 msec shorter than that for self-paced movements. One difference between sim- ple RT and self-paced movements is that the subjects were required to move as fast as possible in the simple RT paradigm. Our results suggest that the rate of rise in corticospinal excitability before movement onset can be increased in the simple RT paradigm but only to a limited extent.

The premovement-increased corticospinal excitabil- ity for self-paced movemehts occurs much later than the movement preparation, as demonstrated by ERD

322 Annals of Neurology Vol 44 No 3 September 1998

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and MRCP. ERD begins about 2 seconds before mo~ernent .~” Subdural recordings showed that it is maximal over the contralateral precentral gyrus and is likely mediated by mechanisms different from those for MRCP.7 MRCP before self-paced movements may be divided into three components-the Bereitschaftspo- tential (BP), starting 1 to 2 seconds before EMG onset; a steeper rise of the negativity called the negative slope (NS’), occurring 300 to 500 msec before EMG onset; and the initial slope of the movement potential (MP), occurring 50 to 100 msec before EMG Subdural recordings showed that the BP and NS’ can be recorded from a relatively wide area of the contralat- era1 precentral g y r ~ s ~ , ~ , ’ o,26 and bilateral supplemen- tary motor area (SMA).10,27 The MP appears to be generated focally from the involved motor representa- tion in the contralateral precentral g y r ~ s ~ , ~ , ~ ~ ~ ~ ~ and the SMA.27 In contrast to self-paced movements, be- fore simple RT movements only the initial slope of the MP can be recorded.25 The timing of premovement- increased corticospinal excitability for both simple RT and self-paced movements corresponds best with that of the MP. Because TMS stimulates the corticospinal neurons in the M1 both directly and indirectly via cor- tical inter neuron^,^'-^^ our results support the hypoth- esis that the initial slope of the MP arises from the M1,7,9,25 and suggest that the MP is associated with increased excitability of corticospinal neurons or inter- neurons closely connected to corticospinal neurons. Our results also indicate that the NS’ is not associated with increased M1 excitability, as there was no in- creased MEP amplitude from 500 msec to 100 msec before EMG onset. Although the time intervals we studied did not include the onset of BP or Em, it is unlikely that either BP or ERD is associated with in- creased M I excitability, as there was no change with NS’. Because TMS stimulates the corticospinal neu- rons, these results suggest that M1 involvement in movement preparation, as demonstrated by BP, NS’, and ERD, is related to M1 circuitries that are active before the activation of the corticospinal system. Inputs into the motor cortex from the SMA or premotor cor- tex, or the activity of intrinsic cortical circuitries, may underlie the components of BP, NS‘, and ERD gener- ated from the M1.

With suprathreshold TMS, there was no significant change in MEP amplitude at 100 msec before EMG onset for self-paced movements (Experiment 4). This is likely because of the wider bin width of 50 msec, in- stead of 20 msec used in the subthreshold TMS study, resulting in reduced temporal resolution of the time course of corticospinal excitability. The interval at - 100 msec included trials with TMS delivered from 125 to 75 msec before EMG onset, and therefore in- cluded many trials before the premovement-increased corticospinal excitability. In addition, because the base-

line is more variable with suprathreshold than subthresh- old TMS, small changes in corticospinal excitability are therefore easier to detect with subthreshold TMS.

Postmovement Increase in Corticospinal Excitability We found two phases of increased corticospinal excit- ability after movement. The first phase ranges from O to 100 msec and the second phase from 100 to 160 msec after EMG offset. The first phase, immediately after EMG offset, may represent a period in which M1 excitability remained above the baseline but became subthreshold for discharging spinal motor neurons. Al- though the relationship between the activity of cortico- spinal neurons in the monkey M1 and cessation of vol- untary EMG has not been investigated in detail, many corticospinal neurons continue to discharge above base- line levels after EMG ~ f f s e t . ’ ~ , ~ ~ , ~ ~ The EMG offset probably represents the time when decreasing excita- tory input from the M1 falls below that required to activate the spinal motor neurons. However, the activ- ity of M1 neurons remains above baseline levels, ac- counting for the first phase of increased corticospinal excitability after EMG offset.

The second phase of increased corticospinal excit- ability may be related to a subthreshold, second agonist burst. In the present study, we found only a single ag- onist burst, similar to several previous studies of thumb

A triphasic agonist-antagonist-agonist pattern of muscle activity is usually observed when a target position is ~pec i f i ed ,~~-~’ with the antagonist burst serving a braking The absence of the antagonist and the second agonist burst in the present study is likely due to the low inertia load for the thumb, and the antagonist burst was not necessary because the target position was not ~ p e c i f i e d . ~ ~ ’ ~ ~ Al- though our subjects produced only a single EMG burst in the present experiments, the second phase of in- creased corticospinal excitability may be due to in- creased activity of corticospinal neurons related to the second agonist burst but remained subthreshold for ac- tivation of spinal motor neurons. The timing of the second phase of increased corticospinal excitability is similar to the interval between the first and second ag- onist bursts, which was 64 to 104 msec for thumb flex- ion37 and 40 to 150 m ~ e c ~ ~ for elbow flexion. Our findings are consistent with the suggestion that the triphasic pattern is centrally

Increased corticospinal excitability after EMG offset may also be explained by passive movement of the thumb. Accelerometer recordings and EMG of the an- tagonist muscle showed that thumb movement contin- ued for 200 to 400 msec after cessation of EMG; most of this time is due to passive movement of the ab- ducted thumb back to the resting position. Recordings from M1 in monkeys showed that many M1 neurons are reliably activated by passive movement of the con-

Chen et al: Time Course of Corticospinal Excitability 323

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tralateral arm but not by cutaneous stimulation,20341 suggesting that proprioceptive inputs can increase the activity of M1 neurons.

MEG studies have shown that after self-paced finger movements, a movement-related magnetic field known as the movement-evoked magnetic field I (MEFI) can be recorded over the contralateral sensorimotor cortex about 100 to 150 msec after EMG onset. This is fol- lowed by MEFII occurring 200 to 250 msec after movement ~ n s e t . ~ ~ ' ~ ~ As the EMG burst durations in the present experiments were around 100 to 150 msec, the timing of MEFI (-0-50 msec after EMG offset) roughly corresponds to the first phase of postmove- ment-increased excitability and MEFII (- 100-1 50 msec after EMG offset) approximates the second phase of postmovement-increased excitability. However, be- cause there are differences between our paradigms and those used in the MEG experiments,42T43 further stud- ies are necessary to clarify the relationship between in- creased corticospinal excitability and MEFI and 11.

Postmovement Decrease in Corticospinal Excitability We found that corticospinal excitability is reduced from 550 to 1,000 msec after EMG offset in simple RT movements. There is also a trend toward reduced corticospinal excitability at similar times after self- paced movements. Postmovement-decreased corticospi- nal excitability may be related to ERS of EEG signals after voluntary m~vements . '~ The timing of ERS de- pends on the frequency band. ERS of 20-Hz EEG (beta band) begins about 750 msec after EMG onset12 and 900 msec to 1.1 seconds after movement on-

for self-paced movements. Postmovement 20-Hz ERS also occurs after externally triggered move- ments similar to the simple RT movements in our study.lG ERS of 10-Hz EEG (mu band) occurs later at about 2 seconds after EMG MEG record- ings showed similar enhancement of 10- and 20-Hz rhythms after self-paced movements, with the 20-Hz activity preceding the 10-Hz activity by about 300 msec. 13,14 Source localization of MEG suggested that the 10-Hz rhythm occurred in the somatosensory hand

The sources of the 20-Hz rhythm are located more anteriorly, and follow the somatotopic organiza- tion of the body parts along the precentral gyrus, shift- ing from the most medial location for foot movements to the most lateral location for mouth movements.'* EEG studies also showed that the location of the post- movement ERS in the 20-Hz band is anterior to that of the 10-Hz ERS.16 Thus, the 10-Hz rhythm appears to arise from the somatosensory cortex, whereas the 20-Hz rhythm arises predominately from the M 1. 13,44

Because the average EMG burst duration in our studies is about 100 to 150 msec, the period of decreased cor- ticospinal excitability we observed begins about 700 msec after EMG onset, which corresponds well with

Setl 1,16

ERS onset in the beta band. However, the duration of the beta ERS is around 2 seconds,"*'2216 and is con- siderably longer than the postmovement-decreased corti- cospinal excitability. Our findings of decreased cortico- spinal excitability at the time of onset of 20-Hz ERS are consistent with the hypothesis that 20-Hz ERS is related to an idling, resting state of the motor cortex.11316

We thank Professor G. Pfurtscheller for helpful discussions, which led to some of the experiments, and Devera Schoenberg, MS, for skillful editing.

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