Brain (1992), 115, 1045-1059
EFFECTS OF FOCAL TRANSCRANIAL MAGNETIC STIMULATION ON SIMPLE REACTION TIME TO ACOUSTIC, VISUAL AND SOMATOSENSORY STIMULI by ALVARO PASCUAL-LEONE, JOSEP VALLS-SOLE\ ERIC M. WASSERMANN, JOAQUIM BRASIL-NETO, LEONARDO G. COHEN and MARK HALLETT (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, Maryland, USA) SUMMARY
INTRODUCTION
When simple reaction time (RT) to focal transcranial stimulation was compared with RT to acoustic, visual and somatosensory stimuli (Pascual-Leone et al., 1992), RT was longest to a magnetic or electrical stimulus delivered over the contralateral motor cortex at an intensity high enough to induce motor evoked potentials (MEPs) in muscles involved in the response (suprathreshold intensity). Conversely, RT was shortest to subthreshold transcranial stimulation over the same scalp position. This report describes the effects of transcranial magnetic stimulation (TMS)', to which the subjects are not supposed to respond, on RT to acoustic, visual or somatosensory stimuli (go-signal). In RT paradigms, transcranial stimulation.properly delivered in time and space can modify the onset latencies of the responses. Reaction time may be prolonged or shortened depending on the intensity of the stimulus. Suprathreshold transcranial stimuli can delay RT to an auditory go-signal if delivered over the motor cortex close to the expected response time (Day et al., 1989). Transcranial weak direct currents applied over the sensorimotor cortex can shorten RT to go-signals of different modalities (Elbert et al., 1981; Jaeger et al., 1987). Correspondence to: Dr Mark Hallett, Building 10, Room 5N226, NINDS, NIH, Bethesda, MD 20892, USA. © Oxford University Press 1992
Downloaded from by guest on January 25, 2015
In a simple reaction time (RT) paradigm, magnetic stimulation of different intensities was delivered over different scalp positions and at variable delays before (negative) or after (positive) the go-signal. Magnetic stimulation shortened RT to different go-signals (auditory, visual and somatosensory stimuli) by approximately 30 ms when delivered over the motor cortex contralateral to the responding arm at intensities below motor threshold. This effect was maximal at a delay of approximately + 10 ms. A similar effect was found with suprathreshold stimulation to the ipsilateral motor cortex. Magnetic stimulation over other scalp areas did not affect RT regardless of the delay. No differences were found between the effects on elbow flexion and thumb abduction. The shortening of RT was not associated with changes in the timing development of premovement excitability increase in the motor cortex. We conclude that magnetic stimulation shortens RT by inducing an earlier initiation of this excitability increase.
1046
A. PASCUAL-LEONE AND OTHERS
Reaction time can be divided into a first period during which the motor cortex is less excitable, and a second period during which it becomes increasingly excitable, leading to movement onset (Starr et al., 1988). Hallett et al. (1991) have shown that the study of the relative duration of these two periods can provide some understanding of RT abnormalities in patients with Parkinson's disease. Similarly, the effects of transcranial stimulation on RT to different go-signals may be clarified by comparing the duration of these two RT periods in trials with and without transcranial stimulation. METHODS
Downloaded from by guest on January 25, 2015
Reaction time experiments We studied five naive, right-handed normal volunteers (three men and two women), aged 26—42 yrs. An auditory warning signal, used to alert the subject, was followed at random intervals (foreperiod, 1 —5 s) by an auditory, visual or somatosensory go-signal. In response to the go-signal, the subject flexed the right elbow or abducted the right thumb as rapidly as possible. When the response was elbow flexion, the subjects were seated comfortably on a chair with the right arm slightly abducted at the shoulder and flexed 90° at the elbow so that the pronated forearm rested on a horizontal platform. When the response was thumb abduction, the subjects were seated with the right hand supinated and resting on a horizontal platform, the thumb adducted and the elbow flexed at 90°. Each subject completed sets of trials using three different go-signals: a click, a flash and an electrical stimulus to the left index finger. The click was generated by a Grass auditory stimulator and delivered by a loudspeaker suspended 15—20 cm over the subject's head. The flash was generated by a Grass PS22 photic stimulator and delivered at an intensity of 100% of the stimulator's output by a lamp positioned at eye level 30 cm in front of the subject. The electrical stimulus was generated by a Grass electric stimulator and delivered by two surface electrodes taped 3 cm apart to the subject's left index finger. The intensity of the electric stimulus was kept at three times sensory threshold as determined by the method of limits (Gescheider, 1976). Reaction time was measured from the go-signal to the onset of biceps or abductor pollicis brevis (APB) electromyographic (EMG) activity. The EMG was recorded with two surface electrodes taped over the muscle belly. The EMG signal was amplified and filtered (100-2000 Hz) by Grass amplifiers, digitized with a sampling rate of 5000 Hz per channel and rectified. The device delivering the go-signal was triggered with a 100 ms delay after EMG recording began; the total sweep time was - 1 0 0 to 400 ms. All data were collected using an AST personal computer. Transcranial magnetic stimulation was delivered with a Cadwell MES 10 magnetic stimulator equipped with an 8-shaped coil in which each component measured 4.5 cm in diameter. The coil was held flat on the scalp over the position at which TMS induced MEPs of maximal amplitude in the contralateral biceps or APB. (These positions were determined, with the patient at rest, by delivering TMS at an intensity of 100% of the stimulator's output over different scalp areas several times during the experiment.) The handle of the coil was held parallel to the sagittal axis of the subject's head, pointing occipitally. This technique allows relatively focal cortical stimulation (Cohen et al., 1990); the characteristics of the electric field induced in the cortex are discussed elsewhere (Roth et al., 1991). Subthreshold intensity is the highest intensity that did not evoke a MEP in the target muscle at rest (at a recording sensitivity of 50 ^V/division) in five trials. The experiments were performed in sets of 12 trials presented in random order. In each set, one-third of the trials were control trials (go-signal only), one-third were test trials (go-signal plus TMS) and onethird were catch trials (TMS only). In the test trials, TMS was delivered before (negative) or after (positive) the go-signal; delay ranged from - 5 0 ms to +50 ms and was randomly varied in the different trials. The catch trials served to ensure that the subjects were responding to the go-signals and not TMS. The study of each subject was completed in three different recording sessions of 11 sets each (132 trials) using a single go-signal in each session. This procedure was intended to avoid fatigue. The order of the recording sessions for the different go-signals was varied in different subjects. The first set of 12 trials in each recording session was considered a practice set and discarded from analysis. During the practice trials, the subjects were encouraged to perform as rapidly as possible, thus minimizing RT variability.
EFFECT OF TMS ON SIMPLE REACTION TIME
1047
For each subject, we measured RT in the control trials and calculated a mean and standard deviation of RT for each go-signal. In the test trials, we measured RT and calculated a mean and standard deviation of RT for each delay tested. Results across subjects were compared with one-way analysis of variance (ANOVA) repeated for the different go-signals. Comparison of RTs to the different go-signals in control and test trials was performed using one-way ANOVAs collapsing across subjects. Significance level, tested with Scheffc's test, was set at P < 0.05. We also studied the effects of variable intensities of TMS delivered concurrently with the go-signal (delay = 0). The initial stimulus, delivered at subthreshold intensity, was randomly increased or decreased stepwise by 5% of the stimulator's output. Finally, to evaluate the topographic specificity of the effects of TMS on RT, we delivered TMS to F3/4, ipsilateral motor cortex, or P3/4 concurrently with a visual go-signal (delay = 0).
RESULTS
Reaction time experiments All subjects occasionally responded to isolated catch trials (Fig. 1). When this occurred, the entire set of 12 trials was discarded from further analysis because of the possibility that the subject was responding to the magnetic stimulus rather than to the go-signal in the test trials. Errors in catch trials occurred regardless of the go-signal modality, but were significantly more frequent when the go-signal was auditory (Fig. 1). Reaction time with TMS (test trials) was shorter (P < 0.001) than RT without TMS (control trials) regardless of the go-signal modality. The difference between RT in control and test trials, considered to be the amount of RT shortening due to TMS, was approximately 30 ms regardless of the go-signal modality. The results for elbow flexion and for thumb abduction were similar (Table 1). The shortening of RT by TMS started at a delay of —30 ms, was maximal at +5 ms to +10 ms, and lasted up a delay of +30 ms. When the delay was +50 ms or longer, RT was prolonged rather than shortened. The relationship between RT shortening and delay was the same regardless of the
Downloaded from by guest on January 25, 2015
Motor cortex excitability experiments The experimental design was the same as for the RT experiments involving thumb abduction, and the same subjects were studied. The study of APB allowed us to compare our results with those of Starr et al. (1988). In half of the trials, we used the same visual go-signal as in the RT experiments (control trials). In the other half, the go-signal was the same visual stimulus coupled with a subthreshold TMS delivered to the ideal position for evoking MEPs in the contralateral APB (test trials). In both control and test trials, a subthreshold TMS (probing stimulus, S) was delivered at variable times during the RT to assess the probability of evoking MEPs in the APB as a function of the proximity of voluntary EMG onset. The MEP amplitude was expressed as a percentage of the maximal M-response following peripheral electrical nerve stimulation. In the test trials, S was identical in intensity and localization to the TMS coupled with the visual stimulus as part of the go-signal. Transcranial magnetic stimulation was delivered with a Cad well magnetic stimulator capable of delivering single or twin pulses at intervals as short as 30 ms without changes in the amplitude of the pulse. Technical information about this stimulator is presented elsewhere (Pascual-Leone et al., 1991, Appendix 1). The stimulation coil and its position on the scalp were the same as in the RT experiments. In each subject, we recorded 120 trials (60 control and 60 test trials) in a single recording session. We compared RT in control trials with RT in test trials using two-way ANOVA (subject and trial type). To analyse the probability of S evoking an MEP, we aligned the trials at EMG onset (response) and expressed the probability as a function of the interval between S 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 build-up of motor cortex excitability during RT.
1048
A. P A S C U A L L E O N E AND OTHERS
GO-SIGNAL
AUDITORY
VISUAL
SOMATOSENSORY
en en cc 2C-
oCC
i
EFFECTS OF FOCAL TRANSCRANIAL MAGNETIC STIMULATION ON SIMPLE REACTION TIME TO ACOUSTIC, VISUAL AND SOMATOSENSORY STIMULI by ALVARO PASCUAL-LEONE, JOSEP VALLS-SOLE\ ERIC M. WASSERMANN, JOAQUIM BRASIL-NETO, LEONARDO G. COHEN and MARK HALLETT (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, Maryland, USA) SUMMARY
INTRODUCTION
When simple reaction time (RT) to focal transcranial stimulation was compared with RT to acoustic, visual and somatosensory stimuli (Pascual-Leone et al., 1992), RT was longest to a magnetic or electrical stimulus delivered over the contralateral motor cortex at an intensity high enough to induce motor evoked potentials (MEPs) in muscles involved in the response (suprathreshold intensity). Conversely, RT was shortest to subthreshold transcranial stimulation over the same scalp position. This report describes the effects of transcranial magnetic stimulation (TMS)', to which the subjects are not supposed to respond, on RT to acoustic, visual or somatosensory stimuli (go-signal). In RT paradigms, transcranial stimulation.properly delivered in time and space can modify the onset latencies of the responses. Reaction time may be prolonged or shortened depending on the intensity of the stimulus. Suprathreshold transcranial stimuli can delay RT to an auditory go-signal if delivered over the motor cortex close to the expected response time (Day et al., 1989). Transcranial weak direct currents applied over the sensorimotor cortex can shorten RT to go-signals of different modalities (Elbert et al., 1981; Jaeger et al., 1987). Correspondence to: Dr Mark Hallett, Building 10, Room 5N226, NINDS, NIH, Bethesda, MD 20892, USA. © Oxford University Press 1992
Downloaded from by guest on January 25, 2015
In a simple reaction time (RT) paradigm, magnetic stimulation of different intensities was delivered over different scalp positions and at variable delays before (negative) or after (positive) the go-signal. Magnetic stimulation shortened RT to different go-signals (auditory, visual and somatosensory stimuli) by approximately 30 ms when delivered over the motor cortex contralateral to the responding arm at intensities below motor threshold. This effect was maximal at a delay of approximately + 10 ms. A similar effect was found with suprathreshold stimulation to the ipsilateral motor cortex. Magnetic stimulation over other scalp areas did not affect RT regardless of the delay. No differences were found between the effects on elbow flexion and thumb abduction. The shortening of RT was not associated with changes in the timing development of premovement excitability increase in the motor cortex. We conclude that magnetic stimulation shortens RT by inducing an earlier initiation of this excitability increase.
1046
A. PASCUAL-LEONE AND OTHERS
Reaction time can be divided into a first period during which the motor cortex is less excitable, and a second period during which it becomes increasingly excitable, leading to movement onset (Starr et al., 1988). Hallett et al. (1991) have shown that the study of the relative duration of these two periods can provide some understanding of RT abnormalities in patients with Parkinson's disease. Similarly, the effects of transcranial stimulation on RT to different go-signals may be clarified by comparing the duration of these two RT periods in trials with and without transcranial stimulation. METHODS
Downloaded from by guest on January 25, 2015
Reaction time experiments We studied five naive, right-handed normal volunteers (three men and two women), aged 26—42 yrs. An auditory warning signal, used to alert the subject, was followed at random intervals (foreperiod, 1 —5 s) by an auditory, visual or somatosensory go-signal. In response to the go-signal, the subject flexed the right elbow or abducted the right thumb as rapidly as possible. When the response was elbow flexion, the subjects were seated comfortably on a chair with the right arm slightly abducted at the shoulder and flexed 90° at the elbow so that the pronated forearm rested on a horizontal platform. When the response was thumb abduction, the subjects were seated with the right hand supinated and resting on a horizontal platform, the thumb adducted and the elbow flexed at 90°. Each subject completed sets of trials using three different go-signals: a click, a flash and an electrical stimulus to the left index finger. The click was generated by a Grass auditory stimulator and delivered by a loudspeaker suspended 15—20 cm over the subject's head. The flash was generated by a Grass PS22 photic stimulator and delivered at an intensity of 100% of the stimulator's output by a lamp positioned at eye level 30 cm in front of the subject. The electrical stimulus was generated by a Grass electric stimulator and delivered by two surface electrodes taped 3 cm apart to the subject's left index finger. The intensity of the electric stimulus was kept at three times sensory threshold as determined by the method of limits (Gescheider, 1976). Reaction time was measured from the go-signal to the onset of biceps or abductor pollicis brevis (APB) electromyographic (EMG) activity. The EMG was recorded with two surface electrodes taped over the muscle belly. The EMG signal was amplified and filtered (100-2000 Hz) by Grass amplifiers, digitized with a sampling rate of 5000 Hz per channel and rectified. The device delivering the go-signal was triggered with a 100 ms delay after EMG recording began; the total sweep time was - 1 0 0 to 400 ms. All data were collected using an AST personal computer. Transcranial magnetic stimulation was delivered with a Cadwell MES 10 magnetic stimulator equipped with an 8-shaped coil in which each component measured 4.5 cm in diameter. The coil was held flat on the scalp over the position at which TMS induced MEPs of maximal amplitude in the contralateral biceps or APB. (These positions were determined, with the patient at rest, by delivering TMS at an intensity of 100% of the stimulator's output over different scalp areas several times during the experiment.) The handle of the coil was held parallel to the sagittal axis of the subject's head, pointing occipitally. This technique allows relatively focal cortical stimulation (Cohen et al., 1990); the characteristics of the electric field induced in the cortex are discussed elsewhere (Roth et al., 1991). Subthreshold intensity is the highest intensity that did not evoke a MEP in the target muscle at rest (at a recording sensitivity of 50 ^V/division) in five trials. The experiments were performed in sets of 12 trials presented in random order. In each set, one-third of the trials were control trials (go-signal only), one-third were test trials (go-signal plus TMS) and onethird were catch trials (TMS only). In the test trials, TMS was delivered before (negative) or after (positive) the go-signal; delay ranged from - 5 0 ms to +50 ms and was randomly varied in the different trials. The catch trials served to ensure that the subjects were responding to the go-signals and not TMS. The study of each subject was completed in three different recording sessions of 11 sets each (132 trials) using a single go-signal in each session. This procedure was intended to avoid fatigue. The order of the recording sessions for the different go-signals was varied in different subjects. The first set of 12 trials in each recording session was considered a practice set and discarded from analysis. During the practice trials, the subjects were encouraged to perform as rapidly as possible, thus minimizing RT variability.
EFFECT OF TMS ON SIMPLE REACTION TIME
1047
For each subject, we measured RT in the control trials and calculated a mean and standard deviation of RT for each go-signal. In the test trials, we measured RT and calculated a mean and standard deviation of RT for each delay tested. Results across subjects were compared with one-way analysis of variance (ANOVA) repeated for the different go-signals. Comparison of RTs to the different go-signals in control and test trials was performed using one-way ANOVAs collapsing across subjects. Significance level, tested with Scheffc's test, was set at P < 0.05. We also studied the effects of variable intensities of TMS delivered concurrently with the go-signal (delay = 0). The initial stimulus, delivered at subthreshold intensity, was randomly increased or decreased stepwise by 5% of the stimulator's output. Finally, to evaluate the topographic specificity of the effects of TMS on RT, we delivered TMS to F3/4, ipsilateral motor cortex, or P3/4 concurrently with a visual go-signal (delay = 0).
RESULTS
Reaction time experiments All subjects occasionally responded to isolated catch trials (Fig. 1). When this occurred, the entire set of 12 trials was discarded from further analysis because of the possibility that the subject was responding to the magnetic stimulus rather than to the go-signal in the test trials. Errors in catch trials occurred regardless of the go-signal modality, but were significantly more frequent when the go-signal was auditory (Fig. 1). Reaction time with TMS (test trials) was shorter (P < 0.001) than RT without TMS (control trials) regardless of the go-signal modality. The difference between RT in control and test trials, considered to be the amount of RT shortening due to TMS, was approximately 30 ms regardless of the go-signal modality. The results for elbow flexion and for thumb abduction were similar (Table 1). The shortening of RT by TMS started at a delay of —30 ms, was maximal at +5 ms to +10 ms, and lasted up a delay of +30 ms. When the delay was +50 ms or longer, RT was prolonged rather than shortened. The relationship between RT shortening and delay was the same regardless of the
Downloaded from by guest on January 25, 2015
Motor cortex excitability experiments The experimental design was the same as for the RT experiments involving thumb abduction, and the same subjects were studied. The study of APB allowed us to compare our results with those of Starr et al. (1988). In half of the trials, we used the same visual go-signal as in the RT experiments (control trials). In the other half, the go-signal was the same visual stimulus coupled with a subthreshold TMS delivered to the ideal position for evoking MEPs in the contralateral APB (test trials). In both control and test trials, a subthreshold TMS (probing stimulus, S) was delivered at variable times during the RT to assess the probability of evoking MEPs in the APB as a function of the proximity of voluntary EMG onset. The MEP amplitude was expressed as a percentage of the maximal M-response following peripheral electrical nerve stimulation. In the test trials, S was identical in intensity and localization to the TMS coupled with the visual stimulus as part of the go-signal. Transcranial magnetic stimulation was delivered with a Cad well magnetic stimulator capable of delivering single or twin pulses at intervals as short as 30 ms without changes in the amplitude of the pulse. Technical information about this stimulator is presented elsewhere (Pascual-Leone et al., 1991, Appendix 1). The stimulation coil and its position on the scalp were the same as in the RT experiments. In each subject, we recorded 120 trials (60 control and 60 test trials) in a single recording session. We compared RT in control trials with RT in test trials using two-way ANOVA (subject and trial type). To analyse the probability of S evoking an MEP, we aligned the trials at EMG onset (response) and expressed the probability as a function of the interval between S 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 build-up of motor cortex excitability during RT.
1048
A. P A S C U A L L E O N E AND OTHERS
GO-SIGNAL
AUDITORY
VISUAL
SOMATOSENSORY
en en cc 2C-
oCC
i
