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Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement
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Electroencephalography and clinical Neurophysiology, 1988, 70:26-32 Elsevier Scientific Publishers Ireland, Ltd.
EEG 03462
Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement A. Starr, M. Caramia, F. Zarola and P.M. Rossini Laboratory of Clinical Neurophysiology, Dept. of Public Health, Hnd University of Rome, Via Orazio Raimondo, 00173 Rome (Italy)
(Accepted for publication: 13 October 1987)
Summary The time course of facilitation of motor evoked potentials (MEPs) to transcranial electrical stimulation delivered at varying intervals near the onset of a voluntary ballistic movement was studied in 4 normal subjects. MEPs were recorded from the left thenar muscles to unifocal anodal stimulation of the right scalp overlying the hand motor area delivered every 8-10 sec. A click, occasionally associated with the scalp stimulation (P = 0.3-0.6), was the signal for the subject to make a brief thumb press on a piston at short latency. The timing of the scalp stimulus and the click was adjusted so that the former occurred approximately between 100 msec before and 100 msec after the onset of the voluntary movement signaled by the EMG in the thenar muscles. MEPs were not detected when the scalp was stimulated 80 msec or more before onset of voluntary movement and then appeared with increasing probability as the time interval before movement shortened. The amplitudes of MEPs in the 80-40 msec period preceding movement onset were small ( < 20% of maximum) and achieved maximum values 20 msec after movement onset. Key words: Voluntary movement; Motor cortex excitability; Non-invasive electrical stimulation; (Human) N o n - i n v a s i v e transcranial electrical s t i m u l a t i o n of cerebral m o t o r areas in h u m a n beings is a relatively new neurophysiological technique (Merton a n d M o r t o n 1980a,b; M a r s d e n et al. 1981, 1982; M e r t o n et al. 1982; Rossini et al. 1985a, b; A m a s s i a n a n d Cracco 1987) that might provide a m e a n s for elucidating some of the m o t o r control m e c h a n i s m s in h u m a n s . I n d i v i d u a l a n o d a l stimuli of relatively high intensity a n d short d u r a t i o n applied to the appropriate scalp region elicit motor evoked potentials (MEPs) in the h a n d muscles of the relaxed contralateral u p p e r limb at a latency of approximately 2 0 - 2 4 msec a n d with an amplitude of several h u n d r e d microvolts. W h e n the current strength is reduced below threshold, M E P s are not elicited. However, facilitation of such a subthreshold electrical stimulus will occur if the h a n d muscles contralateral to the stimulus site are
c o n t r a c t e d d u r i n g the stimulus period. Thus, a previously ineffective electrical stimulus will elicit M E P s of high a m p l i t u d e ( > 1 mV) a n d short latency (17-21 msec) if applied d u r i n g such a muscle c o n t r a c t i o n ( M e r t o n et al. 1982; Rossini et al. 1985a,b). The present study examines the time course of M E P facilitation d u r i n g voluntary, isotonic, ballistic m o v e m e n t of t h u m b opposition. It is k n o w n from sensory evoked potential studies that v o l u n t a r y m o v e m e n t s will alter the processing of sensory signals b y s e n s o r i m o t o r cortex for up to 75 msec prior to the onset of v o l u n t a r y movem e n t s ( C o h e n a n d Starr 1987). We wished to d e t e r m i n e whether facilitation of electrical stimulation of m o t o r areas also occurs prior to the i n i t i a t i o n of a ballistic v o l u n t a r y c o n t r a c t i o n and, if so, for what length of time before m o v e m e n t onset.
This research was partially supported by a CNR Research Grant No. 8500371.
Materials and methods
Correspondence to: Dr. A. Starr, Department of Neurology, University of California Irvine, Irvine, CA 92717 (U.S.A.).
F o u r healthy volunteers from the l a b o r a t o r y staff (2 females, 2 males, age range 2 4 - 3 7 years,
0013-4649/88/$03.50 © 1988 Elsevier Scientific Publishers Ireland, Ltd.
NON-INVASIVE STIMULATIONOF HUMAN MOTOR CORTEX including some of the authors) were examined after having obtained their informed consents. MEPs were recorded via a surface electrode placed on the left thenar eminence over the opponens pollicis muscle and referenced to another electrode over the muscle's tendon. A bandpass of 20-2000 Hz and a signal amplification of 0.5-5 m V / d i v were employed. The onset of thumb movement was defined by measuring the pressure exerted by the left thumb on a syringe piston connected with a pressure meter (OTE-2080) with an output signal of 5 V / 2 0 0 - 4 0 0 mm Hg. Tracings of E M G activity and of pressure (linear and integrated) were simultaneously acquired over a 500 msec time base (sampling rate of 2 - 4 kHz/channel) and stored on flexible diskettes for off-line analysis (OTE-Basis). The subject lay on a bed with closed eyes, holding the syringe in the left hand. H e / s h e was trained to briefly press the piston as rapidly as possible following the presentation of a click delivered to the right ear by a small earphone. At all other times the hand was to be relaxed. Relaxation was aided by acoustic feedback from the E M G amplifier. The scalp electrical stimulus was a rectangular anodal pulse of brief duration (150 /~sec; 5 /~sec rise time) applied through an EEG electrode attached to the scalp, contralateral to the hand that was to be moved, 6-7 cm lateral to the vertex (Cz) and 1 cm in front of a line joining Cz to the earlobe. The cathode consisted of 8 EEG silver chloride disks attached to the scalp at 7-8 cm intervals along a line 2 cm superior to a horizontal plane passing through the nasion and inion. The impedances of the electrodes were adjusted to a balanced value of about 2 kl2 by abrading the skin and filling them with electroconductive jelly. The pericranial electrodes were then interconnected via short bridges and attached by a single cable to the stimulator's negative pole. The experimental protocol consisted of stimulating the motor areas at intervals between 7.95 and 9.99 sec. The stimulus intensity was adjusted to elicit reproducible MEPs when the thenar muscle was slightly contracted, but not to provoke any EMG response when it was relaxed. Stimulus intensities employed ranged from 77 to 103 mA.
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Once a stimulus intensity was selected for a subject, that level was maintained throughout the experiment. The electrical stimuli were randomly preceded by a click (probability ranging from 0.3 to 0.6), which was the command for the subject to make a rapid press of the syringe piston with the thumb. The movement was brief comprising up to 300 msec of E M G activity from the thenar muscles. The time interval between the click and the onset of E M G activity in the thenar muscles was initially selected for each subject by first defining the latency of onset of the muscle potentials to the clicks presented alone. Then a click-to-stimulus interval was selected such that the scalp electrical stimulus usually occurred from approximately 100 msec before to 100 msec after the onset of E M G activity in the thenar muscle. The EMG of thenar muscle and the pressure transducer's output were recorded with each trial of electrical stimulation, whether or not accompanied by the click. The individual trials were then analyzed to define: (1) the time interval between the scalp stimulus and the onset of the reaction time of the thenar muscles; (2) the presence or absence of an MEP to the scalp stimulus; (3) the amplitude of the MEP; (4) the latency of the MEP. For those trials in which the onset of the E M G of reaction time was difficult to define, the latency of the pressure transducer signaling motion was employed after subtracting a constant of 30 msec, representing the average time delay between E M G onset and pressure transducer output. The latency interval between E M G activity in thenar muscle and thumb movement as measured by the pressure transducer has been ascribed to excitation-contraction coupling delays of motor fibers and, less importantly, to the piston's load opposing the presssure (Kernell 1983). Those trials in which spontaneous E M G activity was present were not included in the analysis. In each subject the number of trials containing a scalp stimulus without a warning click ranged between 51 and 102, while those paired with the click ranged between 76 and 204.
Data analysis The probability of the scalp electrical stimuli eliciting a MEP was calculated for the - 1 0 0 to + 100 msec epoch in 10 msec steps. Time 0 corre-
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A. STARR ET AL.
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sponded to the onset of the EMG activity. At least 3 MEPs recorded within each 10 msec epoch (latency variability was equal to or less than, 3
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Pig. 1. Changes in a single subject in both the probability of appearance of motor evoked potentials (MEPs) in thenar muscles and in their amplitude to motor cortex stimulation as the timing of the cortical stimulus approached the onset of a voluntary movement of the thumb. The time interval in msec between the cortical stimulus and movement onset is indicated to the left. Upper trace of each pair contains the output of the pressure transducer; the lower trace contains the EMG from thenar muscle. Two or 3 examples are superimposed for each time interval. The small vertical bars near the begilming of the EMG tracing (labeled 'S' in the - 1 0 0 msec epoch) mark the occurrence of the scalp stimulus; filled circles represent the onset of EMG activity of the voluntary thumb movement (labeled 'MOVE' in the - 1 0 0 msec epoch). Arrows signal the MEP. Note that in this subject a tiny MEP first appears when scalp stimulation precedes EMG onset of the voluntary movement by 70 msec, The amplitude of the MEP progressively increases as the time separation between the scalp stimulus and EMG onset decreases. The amplitude cahbration is 100 gV for the EMG tracings for the intervals from - 1 0 0 through - 5 0 msec, 200 gV for the - 40 and - 30 msec intervals and 400 #V for the - 20 and - 5 msec intervals.
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Fig. 3. Histogram showing the mean and standard deviation of amplitudes of MEPs evoked before movement, expressed as percentages of the MEP amplitude evoked close to EMG onset (the - 1 0 to +10 msec epoch) for the 4 subjects. Standard deviations were not calculated in the - 80 to - 60 msec epochs because of the small numbers of observations. Note the slow increase in amplitude up to the - 20 msec epoch and the steep increments thereafter.
NON-INVASIVE STIMULATION OF H U M A N MOTOR CORTEX
msec) were superimposed after aligning the stimulus artifact. MEP amplitudes were measured between the initial negative deflection and the peak of the next major positive trough. Since absolute amplitudes varied between subjects, the amplitude of MEP was calculated for each subject relative to the maximal MEP amplitude encountered during the E M G burst accompanying voluntary thumb movement. The latencies of MEPs were measured to the onset and to the peak of the initial negative deflection. Amplitude ratios and latencies of MEPs during the movement condition were then plotted against the time interval separating the scalp stimulus from the initiation of the EMG activity.
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in the - 8 0 to - 6 0 msec epoch followed by a steep increment between - 6 0 and - 4 0 msec. From - 4 0 msec to + 100 msec every scalp stimulus evoked an MEP in every subject (Fig. 2). MEP amplitudes in the - 8 0 to - 4 0 msec interval were small (less than 30% of maximal values) and then rapidly increased in size in the - 4 0 to 0 msec epoch (up to 80% of maximal value, Fig. 3). MEPs recorded close to the onset of the E M G activity represent about 80% of the maximal amplitudes of MEPs obtained in the + 20 to + 70 msec period following E M G onset. Latency analysis showed up to a 6 msec reduction in the negative deflection of MEP onset between the - 8 0 and the - 2 0 msec periods (Fig. 4). The latency remained stable thereafter.
Results Unifocal anodal scalp stimulation never elicited MEPs when the hand was relaxed or when the time interval separating the scalp stimulation from E M G onset exceeded 80 msec (Figs. 1 and 2). The probability of eliciting MEPs increased gradually
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Fig. 4. The insert shows MEPs to scalp stimuli from a single subject at 70 and 20 msec between the onset EMG activity (number on the left of each tracing) and the application of the scalp stimulus (vertical mark at left of trace). Note the slight shortening of MEP latency. The graph contains results from 4 subjects. MEP latency is plotted as a function of the interval between the scalp stimulus and the onset of the EMG indicating voluntary movement. The MEP latency gradually shifts approximately 5 msec.
Discussion Previous papers on transcranial electrical stimulation of the motor area suggest that the current engages large Betz cell axons in the motor cortex or just subcortically which, in turn, activate large spinal alpha motoneurons and their fastpropagating peripheral nerve fibers governing the large motor units to produce the initial negativity of the MEPs (Rossini et al. 1985b, 1987). However, it is unclear how voluntary contraction of the muscles remarkably enhances MEP amplitude while slightly reducing its latency (Merton et al. 1982; Marsden et al. 1983; Rossini et al. 1985a,b). In the present experiments we found MEPs to be facilitated for up to 80 msec before the appearance of an E M G in the thenar muscles of the hand contralateral to the stimulated hemisphere as the subject moved the thumb during a simple reaction time to a click. The facilitation was evidenced in 2 ways. First, electrical currents subthreshold for evoking an MEP, if the thumb were relaxed, became capable of evoking MEPs with varying probability up to 80 msec before the onset of the E M G signaling a voluntary contraction. Secondly, the amplitude of the MEP increased and its latency shortened as the stimulus approached the time of the E M G onset. The time course of facilitation approximates
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that found in monkey pyramidal neurons of primary and supplementary sensorimotor areas, which begin to discharge between 120 and 50 msec before movement onset and show an increasing rate of firing as the interval to the onset of movement shortens (Evarts 1966; Brinkman and Porter 1975; Kubota and Hamada 1979; Fromm 1983; Sanes and Evarts 1983). It also resembles the monosynaptic spinal reflex facilitation which appears about 80 msec before the onset of a movement of the same muscle (Gottlieb et al. 1970; Pierrot-Deseilligny et al. 1971) and which disappears after lesioning the pyramidal tract (Ioffe 1973). We would expect that the increasing rate of discharge of pyramidal neurons found in animals would also occur in humans (Lee et al. 1986) and be accompanied by a lowering of those neurons' thresholds to electric anodal currents applied through the scalp. Thus, the electrical stimulus delivered in the premovement period should elicit an increasing amount of synchronously descending impulses along the fast propagating corticospinal tracts as both the number of pyramidal tract neurons engaged by the stimulus and their rates of firing increase. The small amplitudes and relatively longer latencies of MEPs gathered during the - 8 0 to - 4 0 msec epoch compared to those of the - 4 0 to 0 msec epoch must be accounted for by 2 separate or overlapping mechanisms. The first is mainly cortical and is based upon the fact that, in animals, cortico-spinal output evoked by an electrical stimulus to motor cortex consists of a volley of descending discharges that can last up to 8 msec (Patton and Amassian 1954; Gorman 1966). We suggest that in the - 8 0 to - 4 0 msec epoch, the initial portion of this descending volley depolarizes a small number of alpha motoneurons either through direct input to the motoneurons or through removal of presynaptic inhibition on Ia terminals (Porter and Muir 1971; Eichenberger and Ruegg 1984). However, depolarization of these spinal motoneurons, sufficient to cause their discharge and MEPs, must wait upon the additional depolarizing effects of subsequent descending volleys. Thus, in the - 8 0 to - 4 0 msec period the MEPs recorded in the thenar muscles will have a relatively long onset latency and a small ampli-
A. STARR ET AL.
tude. In the - 4 0 to 0 msec epoch there will be more anterior horn cells sufficiently depolarized (due to the increasing amount of descending impulses) to allow the initial volleys of electrically induced motor tract activity to cause a discharge, thereby both shortening the latency and increasing the amplitude of the thenar MEPs. The second mechanism is mostly spinal and reflects the 'size principle' of motoneuron activation (Henneman et al. 1965). At the initiation of a voluntary movement of low force, small spinal alpha motoneurons are recruited before the larger ones because of the formers' lower thresholds of excitation (Kernell 1966, 1983). Since the small spinal alpha motoneurons activate the small motor units in muscle through relatively slowly propagating motor axons (Desmedt and Godaux 1979), the resulting MEPs in the - 8 0 to - 4 0 msec period will be of low amplitudes and relatively long latencies. The further amplitude increments of MEPs, occurring after movement has actually developed (i.e., in the + 20 to + 70 msec period), could be due to the facilitation of spinal motoneurons, and possibly cortical motoneurons, secondary to the discharge of muscle and joint receptors in the contracted thenar muscles and their subsequent excitatory feedback to these motoneurons. The analysis of the relative roles of cortical, spinal, and reafferent mechanisms on the changes in amplitude and latency of the MEPs evoked in thenar muscles around the period of voluntary movement of the thumb will be presented in a subsequent paper. The temporal features of excitability changes of human motor cortex that precede a voluntary movement can be related to EEG evidence of neural changes preceding the performance of voluntary movements. Firstly, riding on a long lasting bilateral negative potential beginning up to 1 sec before movement onset (Kornhuber and Deecke 1965) there is a brief negative potential that precedes movement onset by 50-100 msec recorded over the precentral regions mainly contralateral to the moving limb (Barrett et al. 1985). This potential has temporal features resembling the facilitation of MEPs reported in the present study. Secondly, some of the components of
NON-INVASIVE STIMULATION OF HUMAN MOTOR CORTEX somatosensory evoked potentials are a t t e n u a t e d over sensorimotor cortical regions for up to 75 msec before a v o l u n t a r y m o v e m e n t in the same period as MEPs are facilitated ( C o h e n a n d Starr 1987). The definition of a n excitability change in motor cortex in the 60 msec period before m a k i n g a v o l u n t a r y m o v e m e n t needs to be considered relative to the total time involved in processing a sensory signal for a m o t o r response. The average reaction time of our subjects (using the onset of the E M G of the muscle to be moved) was approximately 150 msec. A p p r o x i m a t e l y 20 msec of this time represents the c o n d u c t i o n time of large cortico-spinal tracts projecting to the h a n d m o t o n e u r o n s in the spinal cord a n d the latters' c o n d u c t i o n time to the muscle fibers of the t h u m b (Rossini et al. 1985a). A n o t h e r 10 msec is required, at a m i n i m u m , for an acoustic stimulus like a click to activate cells in p r i m a r y auditory cortex (Celesia 1976). T h u s a p p r o x i m a t e l y 120 msec r e m a i n between the arrival of an acoustic i n p u t to p r i m a r y a u d i t o r y cortex a n d the beginn i n g of an o u t p u t from m o t o r areas triggering the onset of E M G activity in thenar muscles. The excitability changes in threshold of m o t o r cortex to scalp electrical stimulation revealed in this study, while evident 80 msec prior to onset of E M G activity, only achieve substantial proportions, b o t h with regard to p r o b a b i l i t y of occurrence of the M E P a n d its amplitude, 4 0 - 6 0 msec prior to E M G onset. Thus, the a p p r o x i m a t e l y 6 0 - 8 0 msec r e m a i n i n g m u s t reflect the time available for other n e u r a l processes related to the prod u c t i o n of v o l u n t a r y m o v e m e n t in structures remote from the p r i m a r y auditory cortex a n d cortical and spinal m o t o n e u r o n s . Our findings are in agreement with experimental animal data i n d i c a t i n g that the m o t o r cortex p r o b a b l y functions primarily as the final o u t p u t site of the m o t o r system. The evolution of the p r o g r a m of m o t o r action, even for a simple behavior such as a reaction time, p r o b a b l y occurs in structures remote from p r i m a r y m o t o r cortex. The study of the time course of h u m a n m o t o r system excitability preceding a v o l u n t a r y m o v e m e n t m a y provide insight into m e c h a n i s m s of m o t o r disorders.
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References Amassian, V.E. and Cracco, R.Q. Human cerebral cortical responses to contralateral transcranial stimulation. Neurosurgery, 1987, in press. Barrett, G., Shibasaki, H. and Neshige, R. A computer-assisted method for averaging movement-related cortical potentials with respect to EMG onset. Electroenceph. clin. Neurophysiol., 1985, 60: 276-281. Brinkman, C. and Porter, R. Supplementary motor area in the monkey: activity of neurons during performance of a learned motor task. J. Neurosurg., 1975, 42: 681-709. Brinkman, C. and Porter, R. Supplementary motor area and premotor area of monkey cerebral cortex: functional organization and activities of simple neurons during performance of a learned movement. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 393-420. Celesia, G.G. Organization of auditory cortical areas in man. Brain, 1976, 99: 403-414. Cohen, L. and Starr, A. Localization, timing and specificity of gating of somatosensory evoked potentials during active movement in man. Brain, 1987, 110: 451-468. Desmedt, J.E. and Godaux, E. Recruitment patterns of single motor units in human masseter muscle during brisk jaw clenching. Arch. Oral. Biol., 1979, 14: 171-178. Eichenberger, A. and Ruegg, D.G. Relation between the specific H-reflex facilitation preceding voluntary movement and movement parameters in man. J. Physiol. (Lond.), 1984, 347: 545-559. Evarts, E.V. Pyramidal tract activity to force exerted during voluntary movement. J. Neurophysiol., 1966, 19: 10111027. Fromm, C. Contrasting properties of pyramidal tract neurons located in the precentral or postcentral areas and of corticarubral neurons in the behaving monkey. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 329-346. Gorman, A.L.F. Differential patterns of activation of the pyramidal system elicited by surface anodal and cathodal cortical stimulation. J. Neurophysiol., 1966, 29: 547-564. Gottlieb, G.L., Argawai, G.C. and Stark, L. Interactions between voluntary and postural mechanisms of the human motor system. J. Neurophysiol., 1970, 33: 365-381. Henneman, E., Somjen, G. and Carpenter, D.O. Functional significance of cell size in spinal motoneurons. J. Neurophysiol., 1965, 28: 560-580. Ioffe, M.E. Supraspinal influences on spinal mechanisms activated prior to a learned movement. Acta Neurobiol. Exp., 1973, 33: 729-741. Jones, E.C., Coulter, J.D. and Wise, S.P. Commissural columns in the sensory-motor cortex of monkeys. J. Comp. Neurol., 1979, 188: 113-136. Kernell, D. Input resistance, electrical excitability and size of ventral horn cells in the cat spinal cord. Science, 1966, 152: 1637-1640. Kernell, D. Functional properties of spinal motoneurons and
32 gradation of muscle force. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 213-226. Kornhuber, H.H. und Deecke, L. Hirnpotential~inderungen bei Willktirbewegungen und passiven Bewegungen des Menschen: Bereitschaftspotential und reafferente Potentiale. Pfluegers Arch. Ges. Physiol., 1965, 284: 1-17. Kubota, K. and Hamada, I. Preparatory activity of monkey pyramidal tract neurons related to quick movement onset during visual tracking performance. Brain Res., 1979, 168: 435-439. Lee, B.I., Liiders, H., Lesser, R.P., Dinner, D.S. and Morris, H.H. Cortical potentials related to voluntary and passive finger movements recorded from subdural electrodes in humans. Ann. Neurol., 1986, 20: 32-37. Marsden, C.D., Merton, P.A. and Morton, H.B. Maximal twitches from stimulation of motor cortex in man. J. Physiol. (Lond.), 1981, 312: 5P. Marsden, C.D., Merton, P.A. and Morton, H.B. Percutaneous stimulation of the spinal cord and brain: pyramidal tract conduction velocities in man. J. Physiol. (Lond.), 1982, 238: 6P. Marsden, C.D., Merton, P.A. and Morton, H.B. Direct electrical stimulation of corticospinal pathways through the intact scalp in human subjects. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Human Disease. Raven Press, New York, 1983: 387-391. Merton, P.A. and Morton, H.B. Stimulation of the cerebral cortex in the intact human subject. Nature (Lond.), 1980a, 285: 227. Merton, P.A. and Morton, H.B. Electrical stimulation of human motor and visual cortex through the scalp. J. Physiol. (Lond.), 1980b, 305: 9P-10P. Merton, P.A., Morton, H.B., Hill, D.K. and Marsden, C.D.
A. STARR ET AL. Scope of a technique for electrical stimulation of human brain, spinal cord, and muscle. Lancet, 1982, ii: 587-600. Patton, H.D. and Amassian, V.E. Single and multiple unit analysis of cortical stage of pyramidal tract activation. J. Neurophysiol., 1954, 29: 547-564. Pierrot-Deseilligny, E., Lacer, P. et Stark, L. Amplitude et variabilit6 des r6flexes monosynaptiques avant un mouvement volontaire. Physiol. Behav., 1971, 7: 495-508. Porter, R. and Muir, R.B. The meaning for motoneurons of the temporal pattern of natural activity in pyramideal tract neurons of conscious monkey. Brain Res., 1971, 34: 127-142. Rossini, P.M., Di Stefano, E. and Stanzione, P. Nerve impulse propagation along central and peripheral fast conducting motor and sensory pathways in man. Electroenceph. clin. Neurophysiol., 1985a, 60: 320-334. Rossini, P.M., Marciani, M.G., Caramia, M., Roma, V. and Zarola, F. Nervous propagation along 'central' motor pathways in intact man: characteristics of motor responses to 'bifocal' and 'unifocal' spine and scalp non-invasive stimulation. Electroenceph. clin. Neurophysiol., 1985b, 61: 272-286. Rossini, P.M., Caramia, M. and Zarola, F. Central motor tract propagation in man: studies with non-invasive, unifocal scalp stimulation. Brain Res., 1987, in press. Sanes, J. and Evarts, E. Regulatory role of proprioceptive input in motor control of phasic or maintained voluntary contractions in man. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 47-60. Tanji, J. and Kurata, K. Functional organization of the supplementary motor areas. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 421-431.
Electroencephalography and clinical Neurophysiology, 1988, 70:26-32 Elsevier Scientific Publishers Ireland, Ltd.
EEG 03462
Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement A. Starr, M. Caramia, F. Zarola and P.M. Rossini Laboratory of Clinical Neurophysiology, Dept. of Public Health, Hnd University of Rome, Via Orazio Raimondo, 00173 Rome (Italy)
(Accepted for publication: 13 October 1987)
Summary The time course of facilitation of motor evoked potentials (MEPs) to transcranial electrical stimulation delivered at varying intervals near the onset of a voluntary ballistic movement was studied in 4 normal subjects. MEPs were recorded from the left thenar muscles to unifocal anodal stimulation of the right scalp overlying the hand motor area delivered every 8-10 sec. A click, occasionally associated with the scalp stimulation (P = 0.3-0.6), was the signal for the subject to make a brief thumb press on a piston at short latency. The timing of the scalp stimulus and the click was adjusted so that the former occurred approximately between 100 msec before and 100 msec after the onset of the voluntary movement signaled by the EMG in the thenar muscles. MEPs were not detected when the scalp was stimulated 80 msec or more before onset of voluntary movement and then appeared with increasing probability as the time interval before movement shortened. The amplitudes of MEPs in the 80-40 msec period preceding movement onset were small ( < 20% of maximum) and achieved maximum values 20 msec after movement onset. Key words: Voluntary movement; Motor cortex excitability; Non-invasive electrical stimulation; (Human) N o n - i n v a s i v e transcranial electrical s t i m u l a t i o n of cerebral m o t o r areas in h u m a n beings is a relatively new neurophysiological technique (Merton a n d M o r t o n 1980a,b; M a r s d e n et al. 1981, 1982; M e r t o n et al. 1982; Rossini et al. 1985a, b; A m a s s i a n a n d Cracco 1987) that might provide a m e a n s for elucidating some of the m o t o r control m e c h a n i s m s in h u m a n s . I n d i v i d u a l a n o d a l stimuli of relatively high intensity a n d short d u r a t i o n applied to the appropriate scalp region elicit motor evoked potentials (MEPs) in the h a n d muscles of the relaxed contralateral u p p e r limb at a latency of approximately 2 0 - 2 4 msec a n d with an amplitude of several h u n d r e d microvolts. W h e n the current strength is reduced below threshold, M E P s are not elicited. However, facilitation of such a subthreshold electrical stimulus will occur if the h a n d muscles contralateral to the stimulus site are
c o n t r a c t e d d u r i n g the stimulus period. Thus, a previously ineffective electrical stimulus will elicit M E P s of high a m p l i t u d e ( > 1 mV) a n d short latency (17-21 msec) if applied d u r i n g such a muscle c o n t r a c t i o n ( M e r t o n et al. 1982; Rossini et al. 1985a,b). The present study examines the time course of M E P facilitation d u r i n g voluntary, isotonic, ballistic m o v e m e n t of t h u m b opposition. It is k n o w n from sensory evoked potential studies that v o l u n t a r y m o v e m e n t s will alter the processing of sensory signals b y s e n s o r i m o t o r cortex for up to 75 msec prior to the onset of v o l u n t a r y movem e n t s ( C o h e n a n d Starr 1987). We wished to d e t e r m i n e whether facilitation of electrical stimulation of m o t o r areas also occurs prior to the i n i t i a t i o n of a ballistic v o l u n t a r y c o n t r a c t i o n and, if so, for what length of time before m o v e m e n t onset.
This research was partially supported by a CNR Research Grant No. 8500371.
Materials and methods
Correspondence to: Dr. A. Starr, Department of Neurology, University of California Irvine, Irvine, CA 92717 (U.S.A.).
F o u r healthy volunteers from the l a b o r a t o r y staff (2 females, 2 males, age range 2 4 - 3 7 years,
0013-4649/88/$03.50 © 1988 Elsevier Scientific Publishers Ireland, Ltd.
NON-INVASIVE STIMULATIONOF HUMAN MOTOR CORTEX including some of the authors) were examined after having obtained their informed consents. MEPs were recorded via a surface electrode placed on the left thenar eminence over the opponens pollicis muscle and referenced to another electrode over the muscle's tendon. A bandpass of 20-2000 Hz and a signal amplification of 0.5-5 m V / d i v were employed. The onset of thumb movement was defined by measuring the pressure exerted by the left thumb on a syringe piston connected with a pressure meter (OTE-2080) with an output signal of 5 V / 2 0 0 - 4 0 0 mm Hg. Tracings of E M G activity and of pressure (linear and integrated) were simultaneously acquired over a 500 msec time base (sampling rate of 2 - 4 kHz/channel) and stored on flexible diskettes for off-line analysis (OTE-Basis). The subject lay on a bed with closed eyes, holding the syringe in the left hand. H e / s h e was trained to briefly press the piston as rapidly as possible following the presentation of a click delivered to the right ear by a small earphone. At all other times the hand was to be relaxed. Relaxation was aided by acoustic feedback from the E M G amplifier. The scalp electrical stimulus was a rectangular anodal pulse of brief duration (150 /~sec; 5 /~sec rise time) applied through an EEG electrode attached to the scalp, contralateral to the hand that was to be moved, 6-7 cm lateral to the vertex (Cz) and 1 cm in front of a line joining Cz to the earlobe. The cathode consisted of 8 EEG silver chloride disks attached to the scalp at 7-8 cm intervals along a line 2 cm superior to a horizontal plane passing through the nasion and inion. The impedances of the electrodes were adjusted to a balanced value of about 2 kl2 by abrading the skin and filling them with electroconductive jelly. The pericranial electrodes were then interconnected via short bridges and attached by a single cable to the stimulator's negative pole. The experimental protocol consisted of stimulating the motor areas at intervals between 7.95 and 9.99 sec. The stimulus intensity was adjusted to elicit reproducible MEPs when the thenar muscle was slightly contracted, but not to provoke any EMG response when it was relaxed. Stimulus intensities employed ranged from 77 to 103 mA.
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Once a stimulus intensity was selected for a subject, that level was maintained throughout the experiment. The electrical stimuli were randomly preceded by a click (probability ranging from 0.3 to 0.6), which was the command for the subject to make a rapid press of the syringe piston with the thumb. The movement was brief comprising up to 300 msec of E M G activity from the thenar muscles. The time interval between the click and the onset of E M G activity in the thenar muscles was initially selected for each subject by first defining the latency of onset of the muscle potentials to the clicks presented alone. Then a click-to-stimulus interval was selected such that the scalp electrical stimulus usually occurred from approximately 100 msec before to 100 msec after the onset of E M G activity in the thenar muscle. The EMG of thenar muscle and the pressure transducer's output were recorded with each trial of electrical stimulation, whether or not accompanied by the click. The individual trials were then analyzed to define: (1) the time interval between the scalp stimulus and the onset of the reaction time of the thenar muscles; (2) the presence or absence of an MEP to the scalp stimulus; (3) the amplitude of the MEP; (4) the latency of the MEP. For those trials in which the onset of the E M G of reaction time was difficult to define, the latency of the pressure transducer signaling motion was employed after subtracting a constant of 30 msec, representing the average time delay between E M G onset and pressure transducer output. The latency interval between E M G activity in thenar muscle and thumb movement as measured by the pressure transducer has been ascribed to excitation-contraction coupling delays of motor fibers and, less importantly, to the piston's load opposing the presssure (Kernell 1983). Those trials in which spontaneous E M G activity was present were not included in the analysis. In each subject the number of trials containing a scalp stimulus without a warning click ranged between 51 and 102, while those paired with the click ranged between 76 and 204.
Data analysis The probability of the scalp electrical stimuli eliciting a MEP was calculated for the - 1 0 0 to + 100 msec epoch in 10 msec steps. Time 0 corre-
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A. STARR ET AL.
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sponded to the onset of the EMG activity. At least 3 MEPs recorded within each 10 msec epoch (latency variability was equal to or less than, 3
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Pig. 1. Changes in a single subject in both the probability of appearance of motor evoked potentials (MEPs) in thenar muscles and in their amplitude to motor cortex stimulation as the timing of the cortical stimulus approached the onset of a voluntary movement of the thumb. The time interval in msec between the cortical stimulus and movement onset is indicated to the left. Upper trace of each pair contains the output of the pressure transducer; the lower trace contains the EMG from thenar muscle. Two or 3 examples are superimposed for each time interval. The small vertical bars near the begilming of the EMG tracing (labeled 'S' in the - 1 0 0 msec epoch) mark the occurrence of the scalp stimulus; filled circles represent the onset of EMG activity of the voluntary thumb movement (labeled 'MOVE' in the - 1 0 0 msec epoch). Arrows signal the MEP. Note that in this subject a tiny MEP first appears when scalp stimulation precedes EMG onset of the voluntary movement by 70 msec, The amplitude of the MEP progressively increases as the time separation between the scalp stimulus and EMG onset decreases. The amplitude cahbration is 100 gV for the EMG tracings for the intervals from - 1 0 0 through - 5 0 msec, 200 gV for the - 40 and - 30 msec intervals and 400 #V for the - 20 and - 5 msec intervals.
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Fig. 3. Histogram showing the mean and standard deviation of amplitudes of MEPs evoked before movement, expressed as percentages of the MEP amplitude evoked close to EMG onset (the - 1 0 to +10 msec epoch) for the 4 subjects. Standard deviations were not calculated in the - 80 to - 60 msec epochs because of the small numbers of observations. Note the slow increase in amplitude up to the - 20 msec epoch and the steep increments thereafter.
NON-INVASIVE STIMULATION OF H U M A N MOTOR CORTEX
msec) were superimposed after aligning the stimulus artifact. MEP amplitudes were measured between the initial negative deflection and the peak of the next major positive trough. Since absolute amplitudes varied between subjects, the amplitude of MEP was calculated for each subject relative to the maximal MEP amplitude encountered during the E M G burst accompanying voluntary thumb movement. The latencies of MEPs were measured to the onset and to the peak of the initial negative deflection. Amplitude ratios and latencies of MEPs during the movement condition were then plotted against the time interval separating the scalp stimulus from the initiation of the EMG activity.
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in the - 8 0 to - 6 0 msec epoch followed by a steep increment between - 6 0 and - 4 0 msec. From - 4 0 msec to + 100 msec every scalp stimulus evoked an MEP in every subject (Fig. 2). MEP amplitudes in the - 8 0 to - 4 0 msec interval were small (less than 30% of maximal values) and then rapidly increased in size in the - 4 0 to 0 msec epoch (up to 80% of maximal value, Fig. 3). MEPs recorded close to the onset of the E M G activity represent about 80% of the maximal amplitudes of MEPs obtained in the + 20 to + 70 msec period following E M G onset. Latency analysis showed up to a 6 msec reduction in the negative deflection of MEP onset between the - 8 0 and the - 2 0 msec periods (Fig. 4). The latency remained stable thereafter.
Results Unifocal anodal scalp stimulation never elicited MEPs when the hand was relaxed or when the time interval separating the scalp stimulation from E M G onset exceeded 80 msec (Figs. 1 and 2). The probability of eliciting MEPs increased gradually
26
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Fig. 4. The insert shows MEPs to scalp stimuli from a single subject at 70 and 20 msec between the onset EMG activity (number on the left of each tracing) and the application of the scalp stimulus (vertical mark at left of trace). Note the slight shortening of MEP latency. The graph contains results from 4 subjects. MEP latency is plotted as a function of the interval between the scalp stimulus and the onset of the EMG indicating voluntary movement. The MEP latency gradually shifts approximately 5 msec.
Discussion Previous papers on transcranial electrical stimulation of the motor area suggest that the current engages large Betz cell axons in the motor cortex or just subcortically which, in turn, activate large spinal alpha motoneurons and their fastpropagating peripheral nerve fibers governing the large motor units to produce the initial negativity of the MEPs (Rossini et al. 1985b, 1987). However, it is unclear how voluntary contraction of the muscles remarkably enhances MEP amplitude while slightly reducing its latency (Merton et al. 1982; Marsden et al. 1983; Rossini et al. 1985a,b). In the present experiments we found MEPs to be facilitated for up to 80 msec before the appearance of an E M G in the thenar muscles of the hand contralateral to the stimulated hemisphere as the subject moved the thumb during a simple reaction time to a click. The facilitation was evidenced in 2 ways. First, electrical currents subthreshold for evoking an MEP, if the thumb were relaxed, became capable of evoking MEPs with varying probability up to 80 msec before the onset of the E M G signaling a voluntary contraction. Secondly, the amplitude of the MEP increased and its latency shortened as the stimulus approached the time of the E M G onset. The time course of facilitation approximates
30
that found in monkey pyramidal neurons of primary and supplementary sensorimotor areas, which begin to discharge between 120 and 50 msec before movement onset and show an increasing rate of firing as the interval to the onset of movement shortens (Evarts 1966; Brinkman and Porter 1975; Kubota and Hamada 1979; Fromm 1983; Sanes and Evarts 1983). It also resembles the monosynaptic spinal reflex facilitation which appears about 80 msec before the onset of a movement of the same muscle (Gottlieb et al. 1970; Pierrot-Deseilligny et al. 1971) and which disappears after lesioning the pyramidal tract (Ioffe 1973). We would expect that the increasing rate of discharge of pyramidal neurons found in animals would also occur in humans (Lee et al. 1986) and be accompanied by a lowering of those neurons' thresholds to electric anodal currents applied through the scalp. Thus, the electrical stimulus delivered in the premovement period should elicit an increasing amount of synchronously descending impulses along the fast propagating corticospinal tracts as both the number of pyramidal tract neurons engaged by the stimulus and their rates of firing increase. The small amplitudes and relatively longer latencies of MEPs gathered during the - 8 0 to - 4 0 msec epoch compared to those of the - 4 0 to 0 msec epoch must be accounted for by 2 separate or overlapping mechanisms. The first is mainly cortical and is based upon the fact that, in animals, cortico-spinal output evoked by an electrical stimulus to motor cortex consists of a volley of descending discharges that can last up to 8 msec (Patton and Amassian 1954; Gorman 1966). We suggest that in the - 8 0 to - 4 0 msec epoch, the initial portion of this descending volley depolarizes a small number of alpha motoneurons either through direct input to the motoneurons or through removal of presynaptic inhibition on Ia terminals (Porter and Muir 1971; Eichenberger and Ruegg 1984). However, depolarization of these spinal motoneurons, sufficient to cause their discharge and MEPs, must wait upon the additional depolarizing effects of subsequent descending volleys. Thus, in the - 8 0 to - 4 0 msec period the MEPs recorded in the thenar muscles will have a relatively long onset latency and a small ampli-
A. STARR ET AL.
tude. In the - 4 0 to 0 msec epoch there will be more anterior horn cells sufficiently depolarized (due to the increasing amount of descending impulses) to allow the initial volleys of electrically induced motor tract activity to cause a discharge, thereby both shortening the latency and increasing the amplitude of the thenar MEPs. The second mechanism is mostly spinal and reflects the 'size principle' of motoneuron activation (Henneman et al. 1965). At the initiation of a voluntary movement of low force, small spinal alpha motoneurons are recruited before the larger ones because of the formers' lower thresholds of excitation (Kernell 1966, 1983). Since the small spinal alpha motoneurons activate the small motor units in muscle through relatively slowly propagating motor axons (Desmedt and Godaux 1979), the resulting MEPs in the - 8 0 to - 4 0 msec period will be of low amplitudes and relatively long latencies. The further amplitude increments of MEPs, occurring after movement has actually developed (i.e., in the + 20 to + 70 msec period), could be due to the facilitation of spinal motoneurons, and possibly cortical motoneurons, secondary to the discharge of muscle and joint receptors in the contracted thenar muscles and their subsequent excitatory feedback to these motoneurons. The analysis of the relative roles of cortical, spinal, and reafferent mechanisms on the changes in amplitude and latency of the MEPs evoked in thenar muscles around the period of voluntary movement of the thumb will be presented in a subsequent paper. The temporal features of excitability changes of human motor cortex that precede a voluntary movement can be related to EEG evidence of neural changes preceding the performance of voluntary movements. Firstly, riding on a long lasting bilateral negative potential beginning up to 1 sec before movement onset (Kornhuber and Deecke 1965) there is a brief negative potential that precedes movement onset by 50-100 msec recorded over the precentral regions mainly contralateral to the moving limb (Barrett et al. 1985). This potential has temporal features resembling the facilitation of MEPs reported in the present study. Secondly, some of the components of
NON-INVASIVE STIMULATION OF HUMAN MOTOR CORTEX somatosensory evoked potentials are a t t e n u a t e d over sensorimotor cortical regions for up to 75 msec before a v o l u n t a r y m o v e m e n t in the same period as MEPs are facilitated ( C o h e n a n d Starr 1987). The definition of a n excitability change in motor cortex in the 60 msec period before m a k i n g a v o l u n t a r y m o v e m e n t needs to be considered relative to the total time involved in processing a sensory signal for a m o t o r response. The average reaction time of our subjects (using the onset of the E M G of the muscle to be moved) was approximately 150 msec. A p p r o x i m a t e l y 20 msec of this time represents the c o n d u c t i o n time of large cortico-spinal tracts projecting to the h a n d m o t o n e u r o n s in the spinal cord a n d the latters' c o n d u c t i o n time to the muscle fibers of the t h u m b (Rossini et al. 1985a). A n o t h e r 10 msec is required, at a m i n i m u m , for an acoustic stimulus like a click to activate cells in p r i m a r y auditory cortex (Celesia 1976). T h u s a p p r o x i m a t e l y 120 msec r e m a i n between the arrival of an acoustic i n p u t to p r i m a r y a u d i t o r y cortex a n d the beginn i n g of an o u t p u t from m o t o r areas triggering the onset of E M G activity in thenar muscles. The excitability changes in threshold of m o t o r cortex to scalp electrical stimulation revealed in this study, while evident 80 msec prior to onset of E M G activity, only achieve substantial proportions, b o t h with regard to p r o b a b i l i t y of occurrence of the M E P a n d its amplitude, 4 0 - 6 0 msec prior to E M G onset. Thus, the a p p r o x i m a t e l y 6 0 - 8 0 msec r e m a i n i n g m u s t reflect the time available for other n e u r a l processes related to the prod u c t i o n of v o l u n t a r y m o v e m e n t in structures remote from the p r i m a r y auditory cortex a n d cortical and spinal m o t o n e u r o n s . Our findings are in agreement with experimental animal data i n d i c a t i n g that the m o t o r cortex p r o b a b l y functions primarily as the final o u t p u t site of the m o t o r system. The evolution of the p r o g r a m of m o t o r action, even for a simple behavior such as a reaction time, p r o b a b l y occurs in structures remote from p r i m a r y m o t o r cortex. The study of the time course of h u m a n m o t o r system excitability preceding a v o l u n t a r y m o v e m e n t m a y provide insight into m e c h a n i s m s of m o t o r disorders.
31
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