Electroencephalography and clinical Neurophysiology , 85 (1992) 95-101
95
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/92/$05.00
ELMOCO 90244
Afferent conditioning of motor evoked potentials following transcranial magnetic stimulation of motor cortex in normal subjects T. Kasai *, K.C. Hayes, D.L. Wolfe and R.D. Allatt Department of Physical Medicine and Rehabilitation, Parkwood Hospital, University of Western Ontario, London, Ont. (Canada) (Accepted for publication: 5 August 1991)
Summary The present study determined the effects of percutaneous electrical stimulation of the plantar surface on motor evoked potentials (MEPs) in tibialis anterior (TA) and soleus (SOL) of normal subjects following transcranial magnetic stimulation of motor cortex. The conditioning stimulation consisted of a 20 msec train of electrical pulses (500 Hz; 0.1 msec rectangular) delivered to the medial border of the sole of the foot at an intensity just subthreshold for evoking a flexion reflex. The conditioning (C) stimulation preceded the test (T) cortical stimulation by intervals of 20-130 msec. Magnetic stimulation of motor cortex (Cadwell MES-10) was delivered through a 9.5 cm focal point coil positioned tangential to the scalp and located with the rim over vertex. Five healthy adults served as subjects and each was investigated on at least 2 occasions. At C-T intervals 20-50 msec there was a mild inhibition of MEPs in both TA and SOL. This was followed by marked facilitation ( > 300%) of MEPs at C-T intervals 50-85 msec in both TA and SOL in all subjects. At longer C-T intervals > 110 msec, there was an inhibition of MEPs in TA but not in SOL. Based on the time course of these 3 phases of MEP amplitude modulation, and different stimulation thresholds for each phase, it appears that separate neurophysiological processes underlie each phase of MEP modulation. These observations also suggest that percutaneous electrical stimulation may be useful as a means of enhancing low amplitude or subliminal MEPs in normal subjects or patients with myelopathy. Key words: Motor evoked potentials; Conditioning; Flexion reflex
L
Transcranial stimulation of the human motor cortex is now recognized as a viable diagnostic tool for examining the structural integrity and conduction properties of corticospinal pathways (Merton and Morton 1980; Merton et al. 1982; Barker et al. 1985a,b, 1986, 1988; Mills et al. 1987). Prolonged latencies of the evoked muscle response (motor evoked potentials - MEPs), and reduced amplitude of response, have been reported in cases of multiple sclerosis (Cowan et al. 1984; Mills and Murray 1985), motor neuron disease (Ingram and Swash 1986), spinal cord compression (Caramia et al. 1988; Ingram 1988), and following spinal cord trauma (Gianutsos et al. 1987; Thompson et al. 1987; Dimitrijevi6 et al. 1988). In paretic spinal cord injured patients the MEPs typically have an abnormally high stimulation threshold and low amplitude of response and the risk of false negative interpretation of absent responses is high (Hayes et al. 1991). MEPs evoked from lower limb
Correspondence to: Dr. T. Kasai, c / o Dr. K.C. Hayes, Dept. of Physical Medicine and Rehabilitation, Parkwood Hospital, 801 Commissioners Rd. E., London, Ont. N6C 5J1 (Canada). * Current address: Dept. of Human Movement, Hiroshima University, 1-1-89, Higashisendamachi, Naka-ku, Hiroshima 730, Japan.
musculature are especially difficult to elicit, even in some subjects with intact corticosi~inal pathways, because of the relatively small area and deep location of the lower leg cortical representation on the mesial surface of the cerebral hemispheres. In view of these methodological constraints, we have undertaken a series of studies of techniques for reinforcing the amplitude of MEPs, with special consideration being given to those techniques which are applicable to patients with paraplegia or quadriplegia (Hayes et al. 1991, 1992; Kawakita et al. 1991). The present investigation was designed to determine the time course and extent of MEP amplitude modulation in lower limb muscles following percutaneous electrical stimulation of the medial plantar nerve. Specifically we examined the conditioning effects of a train of high frequency (500 Hz) electrical stimuli (0.1 msec rectangular pulse: 20 msec train) delivered percutaneously to the medial border of the sole of the foot. These stimulus parameters have previously been reported to be optimal for evoking a flexion reflex in tibialis anterior (Shahani and Young 1971). By adjusting the intensity of stimulation to be subthreshold for evoking a flexion reflex, and varying the interval between percutaneous electrical and cortical stimulation (C-T interval), it was possible to establish the modulat-
96 ing influence of subliminal electrical stimulation on MEPs elicited f r o m soleus (SOL) and tibialis anterior (TA). The present study was conducted on normal subjects. Elsewhere we describe a parallel series of studies conducted on patients with spinal cord injuries (Hayes et al. 1992).
Methods
Subjects J Five healthy adults (4 males; 1 female) provided informed consent to participate in the study. The subjects were aged 21-44 years and none had any known neurological deficit. Each subject was screened for a personal or family history of epilepsy and cardiovascular disease that would contraindicate their undergoing transcranial magnetic stimulation of motor cortex. Each subject was examined on 2 separate occasions, and one subject was investigated on 6 different days in order to examine the reproducibility of the observed results. Cortical stimulation Transcranial magnetic stimulation of the motor cortex (70-100% maximum intensity) was delivered from a Cadwell MES-10 stimulator through a focal point stimulating coil electrode with effective radius 4.75 cm. The coil was positioned tangential to the scalp, with the rim over Cz (vertex) of the 10-20 international system for EEG recording (cf., Jasper 1958). This site is optimal for evoking responses in lower limb muscles. The orientation of the stimulating coil was maintained constant to ensure the same initial direction of current (counter clockwise) on each stimulation. The wave form of each 100/zsec stimulation pulse of the Cadwell MES-10 is that of a damped 5000 Hz, 5-cycle sine wave. At 100% intensity the peak magnetic induction is nominally 2.2 Tesla and the peak voltage is 187 V. The generated field has an associated magnetic flux of 0.25 webers (rms). In order to minimize risk of saturating the MEP amplitude with reinforcement, cortical stimulation intensity was adjusted to yield ~ 90 msec was preserved. When the group data were ensemble-averaged these temporal variations attenuated the depth of suppression or facilitation but the overall pattern of MEP amplitude changes was generally preserved (see Fig. 2). The peak facilitation at C-T: 70 msec (~ = 1.08 mV) represented a 385% increase over the group mean MEP amplitude in the unconditioned control condition (~ = 0.28 mV). The suprathreshold flexion reflex responses for all subjects occurred between 70 and 76 msec. Fig. 2A illustrates the averaged group conditioning profile for TA. At C-T: 50-85 msec the mean amplitude (%) exceeded the control (~ + 2.0 [standard error: S.E.]) and at C-T: 120-150 msec the mean amplitude
approached the 95% confidence limits ~ - 2.0 (S.E.). Post hoc t tests of the differences at C-T: 70 msec and 160 msec confirmed the statistical significance ( P < 0.05) of these observations.
600
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90 msec there was no evidence of suppressed MEP amplitude; instead there was marginal evidence of a late facilitation at C-T: 150 msec.
Reproducibility of MEP modulation One subject was examined on 6 separate days in order to determine the reproducibility of the conditioning effects. The overall pattern of 3 distinct phases of MEP amplitude modulation was clearly reproducible across all days of testing.
Effects of conditioning stimulus intensity The intensity of the conditioning stimulation was systematically varied in 2 subjects in order to determine the stimulation threshold for each of the 3 phases of MEP amplitude modulation. Fig. 3 shows the effect of changes in the intensity of stimulation when delivered at select C-T intervals corresponding to the 3 phases of MEP amplitude change in TA, i.e., at C-T: 40 msec; C-T: 70 msec; and C-T: 110 msec. The early suppression of MEP amplitude in T A was labile and was only cle~arly evident at high stimulation intensities, i.e., 4.3 x STH. The stimulation threshold for the second phase, i.e., facilitation of MEP amplitude at C-T: 70 msec, occurred at 3.2 × STH. The late phase of
• C-T: 4 0 m s • C-T: 7 0 m s • C-T: II0 rn~ 0 Conl~rol
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Strength of Condititming Slimuhm (xb~'H) Fig. 3. Threshold determination for each phase of MEP amplitude modulation. Abscissa shows strength of conditioning stimulation in terms of sensory threshold (x STH). Arrows indicate appearance of early inhibition C-T: 40 msec at 4.3 x STH; facilitation C-T: 70 msec at 3.2 x STH and late inhibition C-T: 40 msec at 1.6 x STH. Horizontal line shows unconditioned control MEP value (100%) and vertical bars represent standard deviation of repeated measurements in 1 subject.
MEP suppression had the lowest stimulation threshold and appeared at 1.6 x STH. The reduction in MEP amplitude became progressively more apparent at higher intensities of stimulation. Similar results were obtained from both subjects.
Discussion
The present investigation was designed to explore the feasibility of using subliminal electrical percutaneous stimulation as a means of facilitating low amplitude MEPs evoked from T A and SOL. MEPs evoked by transcranial magnetic stimulation of motor cortex are compound muscle action potentials considered to result from the (indirect) activation of corticospinal neurons (Day et al. 1987a). The descending corticospinal volley consisting of " I " waves (Day et al. 1987b) in turn activates the target alpha motoneurons directly or via interneurons. The results of the present study showed that conditioning MEPs in T A with preceding subthreshold electrical stimulation of the plantar surface yielded a well defined pattern of amplitude modulation of the MEPs in normal subjects. Prominent in this pattern was a clear facilitation of the MEP amplitude at C-T intervals 50-85 msec. Before and after the facilitation there was clear evidence of depressed MEP amplitude suggestive of inhibition. The early (C-T: 20-50 msec) reduction in MEP amplitude and the facilitation (C-T: 50-85 msec) were also apparent, although to a lesser degree, in SOL and in this muscle the late (C-T: > 100 msec) inhil~ition was not present. For the purposes of discussion we will refer to the 3 phases of MEP amplitude modulation as phase 1 (C-T: 20-50 msec), phase 2 (C-T: 50-85 msec) and phase 3 (C-T: > 100 msec). Given the time course and the different stimulation threshold for the various phases it appears these effects are mediated by independent neurophysiological processes. Phase 1, the early suppression of MEP amplitude in T A and SOL evident at high stimulation threshold, is most probably mediated by the action of high threshold cutaneous afferents. Its short latency (20-50 msec) indicates reflex effects through a segmental pathway. In the cat it has been shown that high threshold cutaneous afferent fibers excite Ia and Ib inhibitory interneurons projecting to motoneurons (Hultborn 1972; Lundberg et al. 1975) and that these interneurons may also be excited by corticospinal neurons (Lundberg and Voorhoeve 1962; Jankowska and Tanaka 1974; Jankowska et al. 1975). The Ia and Ib inhibitory interneurons may thus be the site of convergence of cutaneous afferent input from the percutaneous plantar stimulation and the descending volley of corticospinal input from the transcranial magnetic stimulation of motor cortex. Similar short latency in-
C O N D I T I O N I N G O F MEPs
hibitory effects of cutaneous stimulation have been observed on H-reflexes in the tibialis anterior in man (Delwaide et al. 1981; Delwaide and Crenna 1984; Kasai et al. 1991). Phase 2, facilitation of MEPs in both TA and SOL (C-T: 50-90 msec) occurred at a lower stimulation threshold (3.2 × STH) and was therefore probably mediated by lower threshold cutaneous (or muscle) afferents than those involved in phase 1 inhibition. The time course of this facilitation embraces the latency of the early EMG component of the flexion reflex evoked by higher intensity cutaneous stimulation. The latency of the early flexion reflex in TA in the present subjects varied between 60 and 90 msec and this is comparable to previous reports (Shahani 1968; Dimitrijevi6 and Nathan 1970; Shahani and Young 1971; Faganel 1973). If one assumes an average early flexion reflex component to occur at ~ 75 msec and the fastest conduction along the TA alpha motoneurons to take ~ 15 msec, then the conditioning afferent effects are being manifest on the alpha motoneuron pool, ~60 msec after the onset of cutaneous stimulation 1. Given that the latency of the MEP in the normal relaxed TA is 27-29 msec (Eisen et al. 1990; Kawakita et al. 1991), and that includes 13-15 msec for central conduction to lumbar segments (Robinson et al. 1988; Rossini and Caramia 1988), then for there to be a convergence of corticospinal and cutaneous afferent effects at the segmental level of the TA motoneuron pool the cortical stimulation would have to be delivered ,,,45 msec after the onset of cutaneous stimulation. This reasoning is generally consistent with the observed onset of facilitation of the MEPs in TA at SOL at a C-T: ~ 50 msec in the present study; the actual onset time may have been delayed slightly ( ~ 5 msec) by the competing phase 1 inhibition. The 20 msec train of percutaneous stimulation would be expected to ensure a prolonged afferent discharge. Similarly, cortical stimulation gives rise to a temporally dispersed volley of I waves (Day et al. 1987a,b). The convergence of these temporally dispersed inputs could explain the time course of MEP facilitation and the polyphasic nature of the evoked response. Again, the temporal characteristics of the MEP facilitation concur with similar effects of cutaneous stimulation on H-reflexes and EMG (Delwaide et al. 1981; Meinck et al. 1981, 1983, 1985; Kasai et al. 1991). The phase 3 suppression of MEP amplitude in TA at C-T: > 110 msec occurred at the lowest percuta-
1 C u t a n e o u s and muscle afferents in the tibial nerve are estimated to conduct at 52.8 +_3.2 m / s e c and 54.7 + 3.4 m / s e c respectively (Macefield et al. 1989).
99
neous stimulation intensity. This effect appears to be an inhibition mediated by low threshold cutaneous afferents which, on the basis of the relatively long latency of their effects, may involve slowly conducting neurons or involve long polysynaptic pathways possibly involving suprasegmental centers. The exact neurophysiological basis for this component of cutaneomuscular reflex organization is far from being established (Meinck et al. 1985). Indeed the relative contribution of segmental and suprasegmental pathways to the overall flexor reflex organization remains speculative even though useful models have been proposed to help explain some of the observed properties (Meinck et al. 1985). In previous work Deletis et al. (1987) reported that the amplitude of MEPs in flexor digitorum longus could be enhanced by percutaneous conditioning stimulation of the tibial nerve in the popliteal fossa. Intervals C-T: 55-85 msec were most effective. The facilitation was considered due to proprioceptive afferent volleys modifying the excitability of the motor cortex. Troni et al. (1988) reported differential conditioning effects of mixed proprioceptive and exteroreceptive input and pure exteroceptive volleys on MEPs in thenar muscles. Whereas strong conditioning effects were noted following stimulation of mixed nerves, no facilitation of MEPs was observed with pure exteroreceptive stimulation. The putative site of facilitation, i.e., motor cortex, was inferred from the observations that F waves, indicative of alpha motoneuron excitability, were unaltered by the conditioning volleys. Day et al. (1988) subsequently reported that MEPs evoked in the first dorsal interosseus muscle by electrical stimulation of motor cortex were modulated with a time course that was similar to cutaneous reflex effects, whereas MEPs evoked by magnetic stimulation of cortex were modified with a different time course. This was interpreted as support for the hypothesis that cutaneous input has a direct effect on excitability of motor cortical neurons. The present study was designed to characterize a means for reinforcement of MEPs rather than to shed light on the specific site of facilitation or the specific afferents (cutaneous or proprioceptive) involved. It remains to be definitively established whether the MEP facilitation at C-T: 50-85 msec is manifest at spinal or cortical levels. Cutaneous afferent volleys from the plantar surface lead to flexor reflexes with a latency of ~70 msec in spinal cord injured patients (Riddoch 1917; Dimitrijevi6 and Nathan 1970; Shahani and Young 1971) and a segmental contribution to the flexor reflex is well established (Riddoch 1917; Dimitrijevi6 and Nathan 1970). The possibility exists therefore for convergence of cutaneous (or proprioceptive) and magnetically evoked corticofugal volleys to occur at the spinal level in normal man. It may be that there exists facilitation at spinal as well as supraspinal sites and
100
together these underlie the marked enhancement of MEP amplitude seen in the present study.
References Barker, A.T., Freeston, I.L., Jalinous, R. and Jarratt, J.A. Noninvasire stimulation of motor pathways within the brain using timevarying magnetic fields. Electroenceph. clin. Neurophysiol., 1985a, 61: 245-246. Barker, A.T., Jalinous, R. and Freeston, I.L. Non-invasive magnetic stimulation of the human motor cortex. Lancet, 1985b, i: 11061107. Barker, A.T., Freeston, I.L., Jalinous, R. and Jarratt, J.A. Clinical evaluation of conduction time measurements in central motor pathways using magnetic stimulation of the human brain. Lancet, 1986, i: 1325-1326. Barker, A.T., Freeston, I.L., Jalinous, R. and Jarratt, J.A. Magnetic stimulation in clinical practice In: P.M. Rossini and C.D. Marsden (Eds.), Neurology and Neurobiology. Vol. 41. Non-lnvasive Stimulation of Brain and Spinal Cord Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 231-241. Caramia, M.D., Zarola, F., Spadaro, M., Pardal, A.M. and Bernardi, G. Neurophysiological testing of the central impulse propagation characteristics in patients with sensorimotor disorders. In: P.M. Rossini and C.D. Marsden (Eds.), Neurology and Neurobiology. Vol. 41. Non-Invasive Stimulation of Brain and Spinal Cord Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 193-206. Cowan, J.M.A., Dick, J.P.R., Day, B.L., Rothwell, J.C., Thompson, P.D. and Marsden, C.D. Abnormalities in central motor pathway conduction in multiple sclerosis. Lancet, 1984, ii: 304-307. Day, B.L., Thompson, P.D., Dick, J.P.D., Nakashima, K. and Marsden, C.D. Different sites of action of electrical and magnetic stimulation of the human brain. Neurosci. Lett., 1987a, 75: 101106. Day, B.L., Rothwell, J.C., Thompson, P.D., Dick, J.P.R., Cowan, J.M.A., Berardelli, A. and Marsden, C.D. Motor cortex stimulation in intact man. 2. Multiple descending volleys. Brain, 1987b, 110: 1191-1209. Day, B.L., Dressier, D., Maertens de Noordhout, A., Marsden, C.D., Nakajima, K., Rothwell, J.C. and Thompson, P.D. Differential effect of cutaneous stimuli on responses to electrical or magnetic stimulation of the human brain. J. Physiol. (Lond.), 1988, 399: 68P. Deletis, V., Dimitrijevir, M.R. and Sherwood, A.M. Effects of electrically induced afferent input from limb nerves on the excitability of the human motor cortex. Neurosurgery, 1987, 20: 195-197. Delwaide, P.J. and Crenna, P. Cutaneous nerve stimulation and motoneuronal excitability. II. Evidence for non-segmental influences. J. Neurol. Neurosurg. Psychiat., 1984, 47: 190-196. Delwaide, P.J., Crenna, P. and Fleron, M.H. Cutaneous nerve stimulation and motoneuronal excitability. I. Soleus and tibialis anterior excitability after ipsilateral and contralateral sural nerve stimulation. J. Neurol. Neurosurg. Psychiat., 1981, 44: 699-707. Dimitrijevi(~, M.R. and Nathan, P.W. Studies of spasticity in man. 4. Changes in flexion reflex with repetitive cutaneous stimulation in spinal man. Brain, 1970, 93: 743-768. Dimitrijevir, M.R., Eaton, W.J., Sherwood, A.M. and Van der Linden, C. Assessment of corticospinal tract integrity in human chronic spinal cord injury. In: P.M. Rossini and C.D. Marsden (Eds.), Neurology and Neurobiology. Vol. 41. Non-Invasive Stimulation of Brain and Spinal Cord Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 243-253.
T. KASAI ET AL. Eisen, A.A. and Shtybel, W. AAEM minimonograph no. 35: Clinical experience with transcranial magnetic stimulation. Muscle Nerve, 1990, 13: 995-1011. Faganel, J. Electromyographic analysis of human flexion reflex components. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology. Karger, Basel, 1973: 730-733. Gassel, M.M. and Ott, K.H. Local sign and late effects on motoneuron excitability of cutaneous stimulation in man. Brain, 1970, 93: 95-106. Gianutsos, J., Eberstein, A., Ma, D., Holland, T. and Goodgold, J. A noninvasive technique to assess completeness of spinal cord lesions in humans. Exp. Neurol., 1987, 98: 34-40. Hayes, K.C., Allatt, R.D., Wolfe, D.L., Kasai, T. and Hsieh, J. Reinforcement of motor evoked potentials in patients with spinal cord injury. In: W.J. Levy, R.Q. Cracco and J. Rothwell (Eds.), Magnetic Motor Stimulation: Basic Principles and Clinical Experience (EEG Suppl. 43). Elsevier, Amsterdam, 1991: 308-325. Hayes, K.C., Allatt, R.D., Wolfe, D.L., Kasai, T. and Hsieh, J. Reinforcement of subliminal flexion reflexes by transcranial magnetic stimulation of motor cortex in subjects with spinal cord injury. Electroenceph. clin. Neurophysiol., 1992, 85: 102-109. Hultborn, H. Convergence on interneurones in reciprocal Ia inhibitory pathway to motoneurones. Acta Physiol. Scand., 1972, 85 (Suppl. 375): 1-42. Ingram, D.A. Central motor conduction in neurological disorders: studies with electrical and magnetic brain stimulation. In: P.M. Rossini and C.D. Marsden (Eds.), Non-lnvasive Stimulation of Brain and Spinal Cord: Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 207-218. Ingram, D.A. and Swash, M. Central motor conduction is abnormal in motor neurones disease. J. Neurol. Neurosurg. Psychiat., 1986, 49: 474. Jankowska, E. and Tanaka, R. Neural mechanism of the disynaptic inhibition evoked in primate spinal motoneurones from the cortical tract. Brain Res., 1974, 75: 163-166. Jankowska, E., Padel, Y. and Tanaka, R. Projections of pyramidal tract cells to alpha-motoneurones innervating hind-limb muscles in the monkey. J. Physiol. (Lond.), 1975, 249: 637-667. Jasper, H.H. The ten-twenty electrode system of the International Federation. Electroenceph. clin. Neurophysiol., 1958, 10: 371375. Kasai, T., Manabe, M. and Tanaka, R. Cutaneous and muscular afferent effects on ankle extensor and flexor motoneurones in man. 1991, Unpublished. Kawakita, H., Kameyama, O., Ogawa, R., Hayes, K.C. and Wolfe, D.L. Reinforcement of motor evoked potentials by remote muscle contraction. J. Electromyogr. Kinesiol., 1991, 1: 1-10. Kugelberg, E. Demonstration of A and C fibre components in the Babinksi plantar response and the pathological flexion reflex. Brain, 1948, 71: 304-319. Lundberg, A. and Voorhoeve, P. Effects from the py~'amidal tract on spinal reflex arcs. Acta Physiol. Scand., 1962, 56: 201-219. Lundberg, A., Malmgren, K. and Schomburg, E.D. Convergence from Ib cutaneous and joint afferents in reflex pathways to motoneurones. Brain Res., 1975, 86: 81-84. Macefield, G., Gandevia, C. and Burke, D. Conduction velocities of muscle and cutaneous afferents in the upper and lower limbs of human subjects. Brain, 1989, 112: 1519-1532. Meinck, H.M., Piesiur-Strehlow, B. and Koehler, W. Some principles of flexor reflex generation in human leg muscles. Electroenceph. clin. Neurophysiol., 1981, 52: 140-150. Meinck, H.M., Benecke, R., Kuster, S. and Conrad, B. Cutaneomuscular (flexor) reflex organization in normal man and in patients with motor disorders. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Raven Press, New York, 1983: 787-796.
CONDITIONING OF MEPs Meinck, H.M., Kusters, S., Benecke, R. and Conrad, B. The flexor reflex-influence of stimulus parameters on the reflex response. Electroenceph. clin. Neurophysiol., 1985, 61: 287-298. Merton, P.A. and Morton, H.B. Stimulation of the cerebral cortex in the intact human subject. Nature, 1980, 285: 227. Merton, P.A., Morton, H.B., Hill, D.K. and Marsden, C.D. Scope of a technique for electrical stimulation of human brain, spinal cord and muscle. Lancet, 1982, ii: 597-600. Mills, K.R. and Murray, N.M.F. Corticospinal tract conduction time in multiple sclerosis. Ann. Neurol., 1985, 18: 601-605. Mills, K.R., Murray, N.M.F. and Hess, C.W. Magnetic and electrical transcranial brain stimulation: physiological mechanisms and clinical applications. Neurosurgery, 1987, 20: 164-168. Riddoch, G. The reflex functions of the completely divided spinal cord in man, compared with those associated with less severe lesions. Brain, 1917, 40: 264-402. Robinson, L.R., Jantra, P. and MacLean, I.C. Central motor conduction times using transcranial stimulation and F wave latencies. Muscle Nerve, 1988, 11: 174-180. Rossini, P.M. and Caramia, M.D. Methodological and physiological
101 considerations on the electric or magnetic transcranial stimulation In: P.M. Rossini and C.D. Marsden (Eds.), Non-lnvasive Stimulation of Brain and Spinal Cord: Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 37-65. Shahani, B. Effects of sleep on human reflexes with a double component. J. Neurol. Neurosurg. Psychiat., 1968, 31: 574-577. Shahani, B. and Young, R.R. Human flexor reflexes. J. Neurol. Neurosurg. Psychiat., 1971, 34: 616-627. Thompson, P.D., Dick, J.P.R., Asselman, P., Griffin, G.B., Day, B.L., Rothwell, J.C., Sheehy, M.P. and Marsden, C.D. Examination of motor function in lesions of the spinal cord by stimulation of the motor cortex. Ann. Neurol., 1987, 21: 389-396. Troni, W., Cantello, R., De Mattei, M. and Bergamini, L. Muscle responses elicited by cortical stimulation in the human hand: differential conditioning by activation of the proprioceptive and exteroceptive fibers of the median nerve. In: P.M. Rossini and C.D. Marsden (Eds.), Neurology and Neurobiology. Vol. 41. Non-Invasive Stimulation of Brain and Spinal Cord: Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 73-83.
95
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/92/$05.00
ELMOCO 90244
Afferent conditioning of motor evoked potentials following transcranial magnetic stimulation of motor cortex in normal subjects T. Kasai *, K.C. Hayes, D.L. Wolfe and R.D. Allatt Department of Physical Medicine and Rehabilitation, Parkwood Hospital, University of Western Ontario, London, Ont. (Canada) (Accepted for publication: 5 August 1991)
Summary The present study determined the effects of percutaneous electrical stimulation of the plantar surface on motor evoked potentials (MEPs) in tibialis anterior (TA) and soleus (SOL) of normal subjects following transcranial magnetic stimulation of motor cortex. The conditioning stimulation consisted of a 20 msec train of electrical pulses (500 Hz; 0.1 msec rectangular) delivered to the medial border of the sole of the foot at an intensity just subthreshold for evoking a flexion reflex. The conditioning (C) stimulation preceded the test (T) cortical stimulation by intervals of 20-130 msec. Magnetic stimulation of motor cortex (Cadwell MES-10) was delivered through a 9.5 cm focal point coil positioned tangential to the scalp and located with the rim over vertex. Five healthy adults served as subjects and each was investigated on at least 2 occasions. At C-T intervals 20-50 msec there was a mild inhibition of MEPs in both TA and SOL. This was followed by marked facilitation ( > 300%) of MEPs at C-T intervals 50-85 msec in both TA and SOL in all subjects. At longer C-T intervals > 110 msec, there was an inhibition of MEPs in TA but not in SOL. Based on the time course of these 3 phases of MEP amplitude modulation, and different stimulation thresholds for each phase, it appears that separate neurophysiological processes underlie each phase of MEP modulation. These observations also suggest that percutaneous electrical stimulation may be useful as a means of enhancing low amplitude or subliminal MEPs in normal subjects or patients with myelopathy. Key words: Motor evoked potentials; Conditioning; Flexion reflex
L
Transcranial stimulation of the human motor cortex is now recognized as a viable diagnostic tool for examining the structural integrity and conduction properties of corticospinal pathways (Merton and Morton 1980; Merton et al. 1982; Barker et al. 1985a,b, 1986, 1988; Mills et al. 1987). Prolonged latencies of the evoked muscle response (motor evoked potentials - MEPs), and reduced amplitude of response, have been reported in cases of multiple sclerosis (Cowan et al. 1984; Mills and Murray 1985), motor neuron disease (Ingram and Swash 1986), spinal cord compression (Caramia et al. 1988; Ingram 1988), and following spinal cord trauma (Gianutsos et al. 1987; Thompson et al. 1987; Dimitrijevi6 et al. 1988). In paretic spinal cord injured patients the MEPs typically have an abnormally high stimulation threshold and low amplitude of response and the risk of false negative interpretation of absent responses is high (Hayes et al. 1991). MEPs evoked from lower limb
Correspondence to: Dr. T. Kasai, c / o Dr. K.C. Hayes, Dept. of Physical Medicine and Rehabilitation, Parkwood Hospital, 801 Commissioners Rd. E., London, Ont. N6C 5J1 (Canada). * Current address: Dept. of Human Movement, Hiroshima University, 1-1-89, Higashisendamachi, Naka-ku, Hiroshima 730, Japan.
musculature are especially difficult to elicit, even in some subjects with intact corticosi~inal pathways, because of the relatively small area and deep location of the lower leg cortical representation on the mesial surface of the cerebral hemispheres. In view of these methodological constraints, we have undertaken a series of studies of techniques for reinforcing the amplitude of MEPs, with special consideration being given to those techniques which are applicable to patients with paraplegia or quadriplegia (Hayes et al. 1991, 1992; Kawakita et al. 1991). The present investigation was designed to determine the time course and extent of MEP amplitude modulation in lower limb muscles following percutaneous electrical stimulation of the medial plantar nerve. Specifically we examined the conditioning effects of a train of high frequency (500 Hz) electrical stimuli (0.1 msec rectangular pulse: 20 msec train) delivered percutaneously to the medial border of the sole of the foot. These stimulus parameters have previously been reported to be optimal for evoking a flexion reflex in tibialis anterior (Shahani and Young 1971). By adjusting the intensity of stimulation to be subthreshold for evoking a flexion reflex, and varying the interval between percutaneous electrical and cortical stimulation (C-T interval), it was possible to establish the modulat-
96 ing influence of subliminal electrical stimulation on MEPs elicited f r o m soleus (SOL) and tibialis anterior (TA). The present study was conducted on normal subjects. Elsewhere we describe a parallel series of studies conducted on patients with spinal cord injuries (Hayes et al. 1992).
Methods
Subjects J Five healthy adults (4 males; 1 female) provided informed consent to participate in the study. The subjects were aged 21-44 years and none had any known neurological deficit. Each subject was screened for a personal or family history of epilepsy and cardiovascular disease that would contraindicate their undergoing transcranial magnetic stimulation of motor cortex. Each subject was examined on 2 separate occasions, and one subject was investigated on 6 different days in order to examine the reproducibility of the observed results. Cortical stimulation Transcranial magnetic stimulation of the motor cortex (70-100% maximum intensity) was delivered from a Cadwell MES-10 stimulator through a focal point stimulating coil electrode with effective radius 4.75 cm. The coil was positioned tangential to the scalp, with the rim over Cz (vertex) of the 10-20 international system for EEG recording (cf., Jasper 1958). This site is optimal for evoking responses in lower limb muscles. The orientation of the stimulating coil was maintained constant to ensure the same initial direction of current (counter clockwise) on each stimulation. The wave form of each 100/zsec stimulation pulse of the Cadwell MES-10 is that of a damped 5000 Hz, 5-cycle sine wave. At 100% intensity the peak magnetic induction is nominally 2.2 Tesla and the peak voltage is 187 V. The generated field has an associated magnetic flux of 0.25 webers (rms). In order to minimize risk of saturating the MEP amplitude with reinforcement, cortical stimulation intensity was adjusted to yield ~ 90 msec was preserved. When the group data were ensemble-averaged these temporal variations attenuated the depth of suppression or facilitation but the overall pattern of MEP amplitude changes was generally preserved (see Fig. 2). The peak facilitation at C-T: 70 msec (~ = 1.08 mV) represented a 385% increase over the group mean MEP amplitude in the unconditioned control condition (~ = 0.28 mV). The suprathreshold flexion reflex responses for all subjects occurred between 70 and 76 msec. Fig. 2A illustrates the averaged group conditioning profile for TA. At C-T: 50-85 msec the mean amplitude (%) exceeded the control (~ + 2.0 [standard error: S.E.]) and at C-T: 120-150 msec the mean amplitude
approached the 95% confidence limits ~ - 2.0 (S.E.). Post hoc t tests of the differences at C-T: 70 msec and 160 msec confirmed the statistical significance ( P < 0.05) of these observations.
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90 msec there was no evidence of suppressed MEP amplitude; instead there was marginal evidence of a late facilitation at C-T: 150 msec.
Reproducibility of MEP modulation One subject was examined on 6 separate days in order to determine the reproducibility of the conditioning effects. The overall pattern of 3 distinct phases of MEP amplitude modulation was clearly reproducible across all days of testing.
Effects of conditioning stimulus intensity The intensity of the conditioning stimulation was systematically varied in 2 subjects in order to determine the stimulation threshold for each of the 3 phases of MEP amplitude modulation. Fig. 3 shows the effect of changes in the intensity of stimulation when delivered at select C-T intervals corresponding to the 3 phases of MEP amplitude change in TA, i.e., at C-T: 40 msec; C-T: 70 msec; and C-T: 110 msec. The early suppression of MEP amplitude in T A was labile and was only cle~arly evident at high stimulation intensities, i.e., 4.3 x STH. The stimulation threshold for the second phase, i.e., facilitation of MEP amplitude at C-T: 70 msec, occurred at 3.2 × STH. The late phase of
• C-T: 4 0 m s • C-T: 7 0 m s • C-T: II0 rn~ 0 Conl~rol
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Strength of Condititming Slimuhm (xb~'H) Fig. 3. Threshold determination for each phase of MEP amplitude modulation. Abscissa shows strength of conditioning stimulation in terms of sensory threshold (x STH). Arrows indicate appearance of early inhibition C-T: 40 msec at 4.3 x STH; facilitation C-T: 70 msec at 3.2 x STH and late inhibition C-T: 40 msec at 1.6 x STH. Horizontal line shows unconditioned control MEP value (100%) and vertical bars represent standard deviation of repeated measurements in 1 subject.
MEP suppression had the lowest stimulation threshold and appeared at 1.6 x STH. The reduction in MEP amplitude became progressively more apparent at higher intensities of stimulation. Similar results were obtained from both subjects.
Discussion
The present investigation was designed to explore the feasibility of using subliminal electrical percutaneous stimulation as a means of facilitating low amplitude MEPs evoked from T A and SOL. MEPs evoked by transcranial magnetic stimulation of motor cortex are compound muscle action potentials considered to result from the (indirect) activation of corticospinal neurons (Day et al. 1987a). The descending corticospinal volley consisting of " I " waves (Day et al. 1987b) in turn activates the target alpha motoneurons directly or via interneurons. The results of the present study showed that conditioning MEPs in T A with preceding subthreshold electrical stimulation of the plantar surface yielded a well defined pattern of amplitude modulation of the MEPs in normal subjects. Prominent in this pattern was a clear facilitation of the MEP amplitude at C-T intervals 50-85 msec. Before and after the facilitation there was clear evidence of depressed MEP amplitude suggestive of inhibition. The early (C-T: 20-50 msec) reduction in MEP amplitude and the facilitation (C-T: 50-85 msec) were also apparent, although to a lesser degree, in SOL and in this muscle the late (C-T: > 100 msec) inhil~ition was not present. For the purposes of discussion we will refer to the 3 phases of MEP amplitude modulation as phase 1 (C-T: 20-50 msec), phase 2 (C-T: 50-85 msec) and phase 3 (C-T: > 100 msec). Given the time course and the different stimulation threshold for the various phases it appears these effects are mediated by independent neurophysiological processes. Phase 1, the early suppression of MEP amplitude in T A and SOL evident at high stimulation threshold, is most probably mediated by the action of high threshold cutaneous afferents. Its short latency (20-50 msec) indicates reflex effects through a segmental pathway. In the cat it has been shown that high threshold cutaneous afferent fibers excite Ia and Ib inhibitory interneurons projecting to motoneurons (Hultborn 1972; Lundberg et al. 1975) and that these interneurons may also be excited by corticospinal neurons (Lundberg and Voorhoeve 1962; Jankowska and Tanaka 1974; Jankowska et al. 1975). The Ia and Ib inhibitory interneurons may thus be the site of convergence of cutaneous afferent input from the percutaneous plantar stimulation and the descending volley of corticospinal input from the transcranial magnetic stimulation of motor cortex. Similar short latency in-
C O N D I T I O N I N G O F MEPs
hibitory effects of cutaneous stimulation have been observed on H-reflexes in the tibialis anterior in man (Delwaide et al. 1981; Delwaide and Crenna 1984; Kasai et al. 1991). Phase 2, facilitation of MEPs in both TA and SOL (C-T: 50-90 msec) occurred at a lower stimulation threshold (3.2 × STH) and was therefore probably mediated by lower threshold cutaneous (or muscle) afferents than those involved in phase 1 inhibition. The time course of this facilitation embraces the latency of the early EMG component of the flexion reflex evoked by higher intensity cutaneous stimulation. The latency of the early flexion reflex in TA in the present subjects varied between 60 and 90 msec and this is comparable to previous reports (Shahani 1968; Dimitrijevi6 and Nathan 1970; Shahani and Young 1971; Faganel 1973). If one assumes an average early flexion reflex component to occur at ~ 75 msec and the fastest conduction along the TA alpha motoneurons to take ~ 15 msec, then the conditioning afferent effects are being manifest on the alpha motoneuron pool, ~60 msec after the onset of cutaneous stimulation 1. Given that the latency of the MEP in the normal relaxed TA is 27-29 msec (Eisen et al. 1990; Kawakita et al. 1991), and that includes 13-15 msec for central conduction to lumbar segments (Robinson et al. 1988; Rossini and Caramia 1988), then for there to be a convergence of corticospinal and cutaneous afferent effects at the segmental level of the TA motoneuron pool the cortical stimulation would have to be delivered ,,,45 msec after the onset of cutaneous stimulation. This reasoning is generally consistent with the observed onset of facilitation of the MEPs in TA at SOL at a C-T: ~ 50 msec in the present study; the actual onset time may have been delayed slightly ( ~ 5 msec) by the competing phase 1 inhibition. The 20 msec train of percutaneous stimulation would be expected to ensure a prolonged afferent discharge. Similarly, cortical stimulation gives rise to a temporally dispersed volley of I waves (Day et al. 1987a,b). The convergence of these temporally dispersed inputs could explain the time course of MEP facilitation and the polyphasic nature of the evoked response. Again, the temporal characteristics of the MEP facilitation concur with similar effects of cutaneous stimulation on H-reflexes and EMG (Delwaide et al. 1981; Meinck et al. 1981, 1983, 1985; Kasai et al. 1991). The phase 3 suppression of MEP amplitude in TA at C-T: > 110 msec occurred at the lowest percuta-
1 C u t a n e o u s and muscle afferents in the tibial nerve are estimated to conduct at 52.8 +_3.2 m / s e c and 54.7 + 3.4 m / s e c respectively (Macefield et al. 1989).
99
neous stimulation intensity. This effect appears to be an inhibition mediated by low threshold cutaneous afferents which, on the basis of the relatively long latency of their effects, may involve slowly conducting neurons or involve long polysynaptic pathways possibly involving suprasegmental centers. The exact neurophysiological basis for this component of cutaneomuscular reflex organization is far from being established (Meinck et al. 1985). Indeed the relative contribution of segmental and suprasegmental pathways to the overall flexor reflex organization remains speculative even though useful models have been proposed to help explain some of the observed properties (Meinck et al. 1985). In previous work Deletis et al. (1987) reported that the amplitude of MEPs in flexor digitorum longus could be enhanced by percutaneous conditioning stimulation of the tibial nerve in the popliteal fossa. Intervals C-T: 55-85 msec were most effective. The facilitation was considered due to proprioceptive afferent volleys modifying the excitability of the motor cortex. Troni et al. (1988) reported differential conditioning effects of mixed proprioceptive and exteroreceptive input and pure exteroceptive volleys on MEPs in thenar muscles. Whereas strong conditioning effects were noted following stimulation of mixed nerves, no facilitation of MEPs was observed with pure exteroreceptive stimulation. The putative site of facilitation, i.e., motor cortex, was inferred from the observations that F waves, indicative of alpha motoneuron excitability, were unaltered by the conditioning volleys. Day et al. (1988) subsequently reported that MEPs evoked in the first dorsal interosseus muscle by electrical stimulation of motor cortex were modulated with a time course that was similar to cutaneous reflex effects, whereas MEPs evoked by magnetic stimulation of cortex were modified with a different time course. This was interpreted as support for the hypothesis that cutaneous input has a direct effect on excitability of motor cortical neurons. The present study was designed to characterize a means for reinforcement of MEPs rather than to shed light on the specific site of facilitation or the specific afferents (cutaneous or proprioceptive) involved. It remains to be definitively established whether the MEP facilitation at C-T: 50-85 msec is manifest at spinal or cortical levels. Cutaneous afferent volleys from the plantar surface lead to flexor reflexes with a latency of ~70 msec in spinal cord injured patients (Riddoch 1917; Dimitrijevi6 and Nathan 1970; Shahani and Young 1971) and a segmental contribution to the flexor reflex is well established (Riddoch 1917; Dimitrijevi6 and Nathan 1970). The possibility exists therefore for convergence of cutaneous (or proprioceptive) and magnetically evoked corticofugal volleys to occur at the spinal level in normal man. It may be that there exists facilitation at spinal as well as supraspinal sites and
100
together these underlie the marked enhancement of MEP amplitude seen in the present study.
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