1Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1428; 2Department of Clinical Neurophysiology, University of Göttingen, 37075 Gottingen; and 3Department of Neurology, University of Rostock, 18147 Rostock, Germany
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ABSTRACT |
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Sommer, Martin, Joseph Classen, Leonardo G. Cohen, and Mark Hallett. Time Course of Determination of Movement Direction in the Reaction Time Task in Humans. J. Neurophysiol. 86: 1195-1201, 2001. The primary motor cortex produces motor commands that include encoding the direction of movement. Excitability of the motor cortex in the reaction time (RT) task can be assessed using transcranial magnetic stimulation (TMS). To elucidate the timing of the increase in cortical excitability and of the determination of movement direction before movement onset, we asked six right-handed, healthy subjects to either abduct or extend their right thumb after a go-signal indicated the appropriate direction. Between the go-signal and movement onset, single TMS pulses were delivered to the contralateral motor cortex. We recorded the direction of the TMS-induced thumb movement and the amplitude of motor-evoked potentials (MEPs) from the abductor pollicis brevis and extensor pollicis brevis muscles. Facilitation of MEPs from the prime mover, as early as 200 ms before the end of the reaction time, preceded facilitation of MEPs from the nonprime mover, and both preceded measurable directional change. Compared with a control condition in which no voluntary movement was required, the direction of the TMS-induced thumb movement started to change in the direction of the intended movement as early as 90 ms before the end of the RT, and maximum changes were seen shortly before the end of reaction time. Movement acceleration also increased with maxima shortly before the end of the RT. We conclude that in concentric movements a change of the movement direction encoded in the primary motor cortex occurs in the 200 ms prior to movement onset, which is as early as increased excitability itself can be detected.
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INTRODUCTION |
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In monkeys, cell recordings
from the motor cortex have shown increased activity 200-500 ms before
the onset of voluntary movement (Kubota and Hamada
1979), and a specification of movement direction 150-100 ms
before the onset of voluntary movement (Georgopoulos 1995
; Georgopoulos and Pellizer 1995
;
Georgopoulos et al. 1988
, 1989
). The
latter result was based on simultaneous recordings from a sample of
motor cortex cells. The preferred direction of each cell and its firing
rate at different time points during the reaction time were analyzed to
calculate a "population vector" indicating the direction signaled
by all the cells acting together. It was found that the vector
increased in length and rotated toward the target direction during the
reaction time (RT).
In humans, evidence for increased motor cortex excitability during the
RT has been provided by transcranial magnetic stimulation (TMS)
(Pascual-Leone et al. 1994; Tomberg
1995
). TMS can also indicate the directional excitability of a
stimulated region of the motor cortex (Classen et al.
1998
). Development of directional specificity during the
reaction time was shown by Ghez and colleagues from studies in which
subjects were forced to move before completing full movement planning
(Ghez et al. 1997
).
Using TMS, we sought to determine 1) the timing of the premovement specification of movement direction in the human motor cortex and 2) how its time course relates to that of motor cortex facilitation, i.e., whether the specification of movement direction occurs simultaneous with or after increased motor cortex excitability.
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METHODS |
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We investigated six healthy, right-handed subjects using a
choice RT task. All but one subject were investigated twice to assess
the intra-individual variability of the results, and each recording was
analyzed as an independent data set. The protocol was approved by the
institutional review board, and all subjects gave their written
informed consent. None of the subjects had a history of neurological
disease or any signs of visual deficits as could be determined by a
routine neurological examination. The mean age was 45.2 (range 24-62)
years. Handedness was determined by the Oldfield handedness
questionnaire (Oldfield 1971), and subjects had more
than 18 of 23 points of right-handedness. The subjects were seated in
front of the screen of the computer that controlled the experiment
(Macintosh IIci, Apple Inc., Cupertino, CA). The right forearm,
wrist, and fingers 2-5 were supported by a holder. This holder kept
the hand in a slightly extended and pronated position. In this setup,
the axes of abduction/adduction and of flexion/extension were close to
the horizontal and vertical space axes, respectively. During a typical
trial, three successive signals occurred on the screen: a warning
stimulus of 1,000 ms duration, a go-signal of 10 ms duration indicating
the requested direction of movement, and a blank signal of 8,000 ms
duration (Fig. 1). We administered two
types of go-signals in a pseudorandom order: One was an arrow to the
left, thus requesting thumb extension, i.e., when viewed from behind, a
movement in the 9 o'clock direction (9:00 task). The other one was a
downward arrow, indicating thumb abduction, i.e., a movement in the 6 o'clock direction (6:00 task). The subjects were asked to relax
completely before trial onset and to move their right thumb briskly in
the requested direction immediately after the go-signal occurred on the
screen. Acoustic feedback of the electromyographic (EMG) signal was
provided throughout the experiment to ensure complete relaxation during
each trial.
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Trials of five experimental conditions were presented in a randomized order. In condition 1, the 9:00 go-signal was tested without TMS to determine the RT individually as well as the movement direction in the 9:00 task. In condition 2, the 6:00 go-signal was investigated without TMS to find similar baseline data. In condition 3, TMS stimuli were presented with no preceding go-signal. This made it possible to determine the baseline motor-evoked potential (MEP) as well as the direction of the involuntary thumb movement evoked by TMS. To keep the subjects' attention comparable with the other conditions, the usual warning stimulus was presented; it ended 10 ms before the TMS stimulus. In condition 4, the 9:00 go-signal was combined with single TMS at various delays. This allowed determination of the amplitude of the MEP as well as the direction of thumb movement at various intervals before onset of the 9:00 movement. In condition 5, the 6:00 go-signal was combined with single TMS at various delays. This allowed determination of the amplitude of the MEP as well as the direction of thumb movement at various intervals before onset of the 6:00 movement. Each experiment consisted of 20 trials with TMS only, 20 trials without TMS (10 each for the 6:00 and 9:00 movements), and the remaining 120 were equally distributed among the 6:00 and the 9:00 tasks, with 10 trials for each of the selected intervals between go-signal and TMS. These intervals were adjusted so as to cover the time window of 200 ms before the end of the individual RT that had been determined in 40 practice trials undertaken before starting the actual experiment. The different conditions were pseudorandomly administered; inter-trial interval was 8 s.
Magnetic stimulation was delivered from a Cadwell high-speed magnetic stimulator (Cadwell Labs, Kennewick, WA) and administered via a figure eight-shaped coil in which the outer diameter of each wing was 55 mm. The coil was placed over the left motor cortex at the optimal position evoking isolated thumb movements of the right hand. Before starting the actual experiment, we determined the minimal intensity of stimulation capable of inducing slight thumb movements visible to the experimenter's observation in at least 5 of 10 trials. The average movement threshold across subjects was 56% (range 45-62%) of the maximum stimulator output. Intensity of stimulation was 10% above the individual movement threshold. In a typical trial, a single magnetic stimulus was triggered by the computer that controlled the experiment at delays varying from 10 to 280 ms after occurrence of the go-signal.
TMS-evoked movements were recorded at 3,000 Hz sampling frequency by
two EMG channels and two accelerometers. For the EMG, surface
electrodes were fixed with adhesive tape over the abductor pollicis
brevis (APB), which is mainly involved in the 6:00 downward movement,
and over the extensor pollicis brevis (EPB, 9:00 movement). The signals
were amplified by a Counterpoint EMG device (Dantec, Skovlunde,
DK), low-pass filtered at 100 Hz, depicted on the EMG screen for visual
control, and transferred to a data-storing PC (Premium 386/33, AST
Research, Taiwan). The EMG data provided information about the RT
between the go-signal and the onset of voluntary movement as well as
about the amplitude of the MEP. Two accelerometers (Picotrax, Endevco,
San Juan Capistrano, CA) were fixed on the radial side of the proximal
thumb phalanx. One of them was oriented in the axis of abduction and
adduction, the other in the axis of flexion/extension; both were
equally calibrated in units of millivolt/g. Their data were
amplified with a gain of 100 (40 dB, device built by the Research
Services Branch, NIH, Bethesda, MD), filtered between 0.4 and 100 Hz,
displayed on the EMG screen for visual control, and transferred to the
data-storing PC. A control experiment showed that the first peak of
accelerometer data (Classen et al. 1998) provides
sensitive information about the direction of thumb movements (Fig.
2A; for details see legend). We assumed that accelerometers are superior to tracking devices in
detecting minimal displacements of the thumb frequently induced by TMS
at weak intensities.
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Data analysis
In a typical trial, two bursts of EMG activity were observed: one sharp and short potential reflecting the involuntary movement evoked by the transcranial stimulus and a second large and broad potential reflecting the voluntary activity in response to the go-signal. These two bursts of EMG activity were accompanied by two separate shifts in the accelerometer traces. A typical example of the raw data of one trial is shown in Fig. 2B. Trials in which there was background activity with amplitude of more than 25 µV in the first 100 ms of recording were rejected from analysis.
Since TMS may influence the RT (Day et al. 1989), we
determined the RT in trials without TMS and measured the latency of the onset of the broad peak of voluntary EMG activity. The RT of the APB
was used for the task that involved abduction more than extension (6:00); for the 9:00 task we used the RT of the EPB.
Statistical procedures
In each trial with go-signal and TMS, we subtracted the delay between the go-signal and the MEP from the individual average RT of the appropriate muscle (APB for the 6:00 task, EPB for the 9:00 task) as determined in the TMS-free trials. The resulting latency indicated when, during the RT, an MEP had occurred. To reveal the time course of MEP amplitudes, the movement direction and the acceleration of TMS-induced thumb movements, we subdivided the RT into bins. To keep the number of samples per bin similar, the bins earlier than 150 ms before the end of the RT were 50 ms wide, and those later than 150 ms before the end of the RT were 30 ms wide, since fewer trials were recorded with TMS early rather than late in the RT.
In each trial, movement direction was determined as an angle
calculated from the arctangents of the first peak acceleration. In
trials with TMS only, this enabled determination of the baseline movement direction; in trials with a go-signal and TMS we could determine the direction of movement during the RT. In trials without TMS, we calculated the individual target direction from the first voluntarily induced peak of each accelerometer recording. In both situations, we performed a trigonometric averaging of movement angles
(see APPENDIX) of trials corresponding both in task and
delay from the go-signal. In each subject, we calculated the deviation (in deg out of 360°) between the average baseline direction and the
average target direction for either task. Similarly, we determined the
deviation of TMS-induced movement directions from the target direction
of the corresponding task (in deg) and normalized it to the baseline
deviation. In each subject, we averaged the deviations from target with
the same latency before the end of the RT. In addition, the nonaveraged
movement directions were analyzed with circular statistics using the
Watson U2-test (Batschelet 1981).
We compared the individual baseline and target directions for either
task, and the movement directions obtained earlier with those obtained
later than 100 ms before the end of RT. In these analyses, the null
hypothesis was that the two sets of data do not differ significantly
from each other in terms of movement direction. Also, we determined the
mean angular deviation as a measure of variability of movement
directions (Batschelet 1981
).
To detect whether the amplitude of the first peak of acceleration changes during the RT, we calculated the length of the vector resulting from the first peaks of acceleration measured by either accelerometer. MEP amplitudes of TMS-induced thumb movements were measured off-line as peak-to-peak amplitudes from APB and EPB. Data were normalized to the individual baseline MEP amplitude that was determined in the trials with TMS, but without go-stimulus.
To compare the time courses of prime mover and nonprime mover, we calculated a repeated measures ANOVA with the internal factors bin and parameter (i.e., normalized MEP amplitude of prime- or nonprime mover, values of both tasks pooled for either parameter).
To determine which bins of averaged movement directions, first peak
accelerations and normalized MEPs differed from baseline, we used
noncorrected t-tests (Perneger 1998). All
data are indicated as mean values ± standard error.
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RESULTS |
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Reaction time (RT)
In the trials without TMS, the average onset of voluntary EMG activity in the APB muscle was 304 ± 5 (SE) ms in the 6:00 task and 298 ± 4 ms in the 9:00 task (t-test, nonsignificant). The average onset of voluntary EMG activity in the EPB muscle was 307 ± 4 ms in the 6:00 task and differed significantly from the onset in the 9:00 task (289 ± 4 ms, t-test).
In trials with TMS, RTs were significantly prolonged. The average RT of the APB muscle was 320 ± 2 ms in the 6:00 task and 312 ± 2 ms in the 9:00 task. The difference between the tasks was significant. For the EPB muscle, average RTs were 326 ± 2 ms in the 6:00 task and 305 ± 2 ms in the 9:00 task. Again, there was a significant difference between tasks.
Simple regression analyses relating RT and the chronological number of the trial did not yield any significant change in RT during the course of the experiment in any subject for any of the investigated muscles, indicating the absence of learning.
Angle of TMS-induced thumb movement
Individual baseline directions as determined in TMS-alone trials and individual target directions are shown in Table 1. In each subject, the directions were consistent with the theoretical directions: the 9:00 task showing a larger variation of target directions than the 6:00 task. Baseline and target directions were generally similar in two successive experimental sessions in the same subject, the overall variability of baseline directions being larger than that of the target directions. Circular statistics (Watson U2-test) confirmed a significant difference between baseline and target directions in both tasks.
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In each subject, TMS-induced movement directions during the RT shifted from baseline direction toward target direction of either task. Hence, the difference between actual movement direction and target direction decreased during the RT. A typical example is shown in Fig. 3. Across subjects, the first bin that was significantly closer to the target than the baseline occurred 61-90 ms before the end of the RT in the 6:00 task and 1-30 ms in the 9:00 task (t-tests). The shift of directions was more complete in the 6:00 task than in the 9:00 task. Circular statistics across subjects confirmed a change of TMS-induced movement direction during the RT for both tasks (Table 1, Fig. 4C). During the RT, the angular deviation increased in subjects 2 (trial 2), 3 (both trials), and 6 (trial 2), it decreased in subject 4 (both trials), and remained essentially unchanged in all other trials and subjects.
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Motor evoked potentials
Across tasks and muscles, we found a significant interaction of muscle × task (repeated-measures ANOVA, F = 35.0, P < 0.0001), confirming the hypothesized task-related predominance of the appropriate muscle. There was neither a significant effect of muscle nor a significant effect of task, ruling out a nonspecific predominance of either muscle or task.
The time courses of the prime mover (APB in 6:00 task, EPB in 9:00 task) and the nonprime mover differed from each other (effect of parameter, F = 42.2, P = 0.007) because the facilitation of the prime mover occurred earlier (post hoc t-test, 151-200 ms) than the facilitation of the nonprime mover (91-120 ms, Fig. 4, A and B).
Acceleration of MEP-induced thumb movement
There was a trend for increasingly accelerated TMS-induced movements during the course of the RT. The first bin that yielded a significant difference from baseline occurred 61-90 ms before the end of the RT in either task (Fig. 4D).
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DISCUSSION |
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Our results provide evidence for an involvement of the human
motor cortex in a selective prime mover facilitation of muscles acting
on the same joint and, as a result of prime mover facilitation, in a
specification of movement direction. We show that the facilitation of
the prime mover precedes a less pronounced facilitation of the nonprime
mover, and that this is the most sensitive measure of direction
specification. The selective facilitation of movement agonists is
consistent with an earlier study (Tomberg 1995) that showed such selective facilitation in two extensors of the index [extensor digitorum (ED) and extensor indicis (EI)]. Looking at one
time point relatively late in the RT of a simple RT task, the author
found a facilitation of ED when an extension of fingers 2 to 5 was
requested, but a facilitation of EI when only an extension of the index
was requested. Our findings extend Tomberg's data in that two
muscles acting on a single joint were studied in the present paper (as
well as exploring the full time course).
With conditioning-test paired pulse TMS, a recent study has shown
reduced activity of intracortical inhibition during movement preparation (Reynolds and Ashby 1999). Inhibition was
only reduced in the movement agonist (hand extensors), but not in the
antagonist (hand flexors). This underlines the cortical origin of the
selective agonist facilitation.
Determining movement direction has been studied by Ghez et
al. (1997). These authors investigated a two-choice RT task in which subjects were forced to move before the end of their ordinary RT,
i.e., before the end of full movement planning. As a parameter for the
degree of planning, they used the directional correctness of movements.
For early parts of movement planning (forced movement times shorter
than 80 ms after the go-signal), they found no directional specificity
of movements. For later parts of planning (forced movement times
ranging from 81 to 200 ms), there was a trend to increase correctness
of movements; with forced movement times longer than 200 ms after the
go-signal, the proportion of correctly directed movements sharply
increased. Findings from their study are consistent with ours in that
the first sign of directional specification was approximately 100 ms
after the go signal (increase of the excitability of the prime mover
200 ms before the end of the reaction time with a total reaction time
of about 300 ms).
In primate studies (Georgopoulos and Pellizer 1995;
Georgopoulos et al. 1989
), the authors investigated
choice RT tasks in monkeys and described a gradual build-up of the
"population vector" as calculated over a sample of single-cell
recordings. The authors concluded that in movement preparation of
primates, the primary motor cortex is involved in processing the motor
program. This population vector change in response to a visual target
was observed within 150 to 100 ms before movement onset; this time
window is similar to our data regarding specification of movement
direction in humans. Consistent with this, Gold and Shadlen provided
evidence for a gradual determination of the direction of a forthcoming eye movement by microstimulating the monkey's frontal eye field (Gold and Shadlen 2000
).
In both tasks of our study, significant facilitation of muscles
occurred earlier than the significant shift in the direction of evoked
movements. Pooling the tasks confirmed that facilitation of the prime
mover preceded the directional change. We conclude that the rise in
excitability anticipates the directional change detected with the
methods employed here and hypothesize that a certain level of
facilitation of the predominant muscle is necessary to generate a
kinematic change. In addition, the prime mover facilitation was more
pronounced and preceded that of the nonprime mover. This points to a
very early and economical way to facilitate muscles acting on the same
joint, at least for the concentric movements studied here. This
suggests a relative inhibition of competing motor programs (Mink
1996), even at early stages of motor planning.
In conclusion, our data expand evidence for a specific motor cortex facilitation of muscles acting on the same joint. They demonstrate that in the preparatory phase of voluntary movement this increased excitability of the predominant muscle precedes that of the nonpredominant muscle and results in a gradual change of movement direction encoded within the human motor cortex.
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APPENDIX |
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The direction of movement was determined in each trial as an
angle calculated from arctangens of the first peak accelerations. The
formula is as follows: for acc1 > 0: m = arctan
acc1/acc2; for acc1 < 0: m = + (arctan acc1/acc2). There are two undefined cases, acc2 = 0 and
acc1 < 0 is defined as 270°, acc2 = 0 and acc1 > 0 is defined as 90°. If the resulting value is negative, add
2
. For angular transformation divide by
*
180. To conform the resulting angle to the usual coordinate system as
depicted in Fig. 2D, 90° was subtracted from all angles.
The trigonometric average movement direction across a sample of trials
was calculated following the formula: for c > 0:
m = arctan s/c; for
c < 0: m =
+ (arctan
s/c), where m is the average movement
direction, s is the arithmetical average of the sine of each
trial, c is the arithmetical average of the cosine of each
trial, and
= 3.142.
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ACKNOWLEDGMENTS |
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The authors appreciate the skillful editing of D. G. Schoenberg, M.Sc.
M. Sommer was supported in part by the German Academic Exchange Service (DAAD); J. Classen was supported by the Deutsche Forschungsgemeinschaft (DFG Grant Cl 95/2-2).
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FOOTNOTES |
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Address for reprint requests: M. Hallett, NIH, NINDS, Medical Neurology Branch, Bldg. 10, Rm. 5N226, 10 Center Dr. MSC1428, Bethesda, MD 20892-1428 (E-mail: hallettm{at}ninds.nih.gov).
Received 9 November 2000; accepted in final form 5 June 2001.
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REFERENCES |
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