Abstract. Fatigue of voluntary muscular effort is a com, plex and multifaceted phenomenon. Fatigue of peripher- al nervous system components, including the ...
Exp Brain Res (1993) 93:181-184
Experimental BrainResearch 9 Springer-Verlag 1993
Research Note Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue Joaquim P. Brasil-Neto, Alvaro Pascual-Leone, Josep Vails-Sol6, Angel Cammarota, Leonardo G. Cohen, Mark Hallett Human Cortical Physiology Unit, Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5N226, Bethesda, MD 20892, USA Received: 4 August 1992 / Accepted: 5 November 1992
Abstract. Fatigue o f v o l u n t a r y m u s c u l a r effort is a c o m , plex a n d multifaceted p h e n o m e n o n . Fatigue o f peripheral nervous system c o m p o n e n t s , including the contractile a p p a r a t u s and the n e u r o m u s c u l a r junction, has been well studied. Central nervous system c o m p o n e n t s also fatigue, but studies have lagged for w a n t o f objective methods. Transcranial magnetic stimulation is a relatively new technique t h a t c a n be used to assess central nervous system excitability f r o m the m o t o r cortex to the a l p h a - m o t o n e u r o n . In six n o r m a l volunteers, including four o f the investigators, the amplitudes o f m o t o r evoked potentials elicited by transcranial magnetic stimulation were transiently decreased after exercise, indicating fatigue o f m o t o r p a t h w a y s in the central n e r v o u s system. T h e decrease in amplitude was associated with a feeling o f fatigue. The m e c h a n i s m o f this p h e n o m e n o n is a p p a r e n t l y decreased efficiency in the generation o f the m o t o r c o m m a n d in the m o t o r cortex. Key words: Transcranial magnetic stimulation - M o t o r evoked potentials - Exercise - Fatigue - H u m a n
Introduction Cortical excitability in h u m a n s m a y be affected by b o t h pathological a n d physiological processes. In epilepsy, the m o t o r cortex shows increased excitability to transcranial magnetic stimulation ( T M S ; Reutens and Berkovic 1992). In cortical m y o c l o n u s , increased excitability o f the s e n s o r i m o t o r cortex is d e m o n s t r a t e d with the recording o f giant s o m a t o s e n s o r y evoked potentials ( D a w s o n 1947; Halliday 1980) and large cortical potentials associated with s p o n t a n e o u s or action-induced jerks (Hallett et al. 1979). In n o r m a l subjects, the amplitudes o f m o t o r evoked potentials ( M E P s ) in response to T M S , at any given stimulus intensity, are increased when the target muscle is voluntarily preactivated ( M e r t o n et al. 1982; Correspondence to: M. Hallett
Hess et al. 1986; C h i a p p a et al. 1991). Heretofore, however, the effects o f fatigue on the amplitudes o f M E P s to T M S or transcranial electrical stimulation (TES) have n o t been described. We report here a transient decrease in the amplitude o f M E P s to T M S following a period o f repetitive muscle activation to the point o f subjective fatigue in healthy h u m a n s .
Materials and methods We studied six normal men, including four of the investigators. The protocol was approved by the clinical research subpanel, and the subjects gave their written informed consent for the studies. The subject was comfortably seated ; his right forearm was supinated on a table, and the dorsal aspect of the wrist was kept on the edge of the table so that he could make full-range movements of wrist flexion and wrist extension while holding a 7.5-1b (3.4 kg) dumbbell weight. Surface electrodes (DISA 13K60) were placed on the skin overlying the flexor carpi radialis, and MEPs, maximal M waves, and H-reflexes were recorded on an electromyograph (Dantec Counterpoint) with a gain from 50 ~tV to 1 mV/division. The median nerve was stimulated with square-wave electrical pulses, 0.5 ms in duration, applied just above the elbow crease. A figure 8-shaped magnetic coil driven by a Cadwell MES-10 magnetic stimulator was placed over the optimal scalp position for eliciting MEPs in the flexor carpi radialis; the stimulus intensity was 10% above the subject's motor threshold (the lowest intensity capable of eliciting in ten consecutive trials at least five MEPs with an amplitude of at least 50 gV). An electrical stimulator (Digitimer D-180) was used to deliver pulses, 50 gs in duration, at an intensity 10% above the subject's motor threshold for TES. Stimulation was monopolar (Rossini and Caramia 1988): the cathode was a ground strap (Dantec Velcro band) tightly fastened around the head, and the anode was a disk electrode, 0.5 cm in diameter, placed on the optimal scalp position. Pre-exercise sets of eight maximal M waves, eight H-reflexes, and eight MEPs to trains of TES and TMS, delivered at a frequency of 0.2 Hz, were recorded. The weight was then placed in the subject's hand, and he was asked to make wrist movements, at a rate of 1 per second (kept by a metronome), until he felt too fatigued to carry on with the task. The weight was removed, electromyographic (EMG) activity was monitored on an oscilloscope to ensure that the muscle was fully relaxed after the exercise, and new sets of eight maximal M waves, eight H-reflexes, and eight MEPs to TMS and TES were recorded. In three subjects, the sequence was such that TMS
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was performed before TES, and in the other three subjects, TES was performed before TMS. A similar procedure was performed on a different day in three of the subjects, who exercised for 30 s and then rested while sets of four MEPs in response to TMS, four maximal M waves, and four H-reflexes were recorded. This sequence was repeated at least five times.
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All subjects had progressive difficulty maintaining movemerit regularity and avoiding involuntary changes in the originally intended h a n d trajectory. The smoothness and precision o f the wrist m o v e m e n t s progressively deteriorated, with a tendency to wrist adduction, placement o f the contralateral h a n d on the test table for stabilization, and synkinetic activation o f various muscle groups, including respiratory muscles.
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Fig. 2. A Scattergram of motor evoked potential (MEP) amplitudes to transcranial magnetic stimulation (TMS) in 30-s periods of exercise in subject 2. Note the "central postactivation facilitation" of the initial MEPs in each group of four, followed by "central postexercise exhaustion." Arrows indicate the exercise periods. B The 4th: 1st ratio of MEP amplitudes in three subjects before exercise (C) and after each 30-s period of exercise (El-E5). The bars on the right are mean (_+SD) 4th:lst ratios before and after all exercise periods for subject 3. * P < 0.01, paired t test
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(MEPs) in response to transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) in both fresh and fatigued muscle of one subject. These traces are from the first four MEPs in the series of eight9 In the fatigued muscle, the MEP amplitude decreased progressively with TMS, but not TES. B Mean (• changes in amplitude, expressed as a percentage of preexercise values, for maximal M responses~ H-reflexes, and MEPs to TMS and TES in six normal subjects after exercise
The amplitude o f M E P s evoked by T M S immediately after the fatiguing task decreased progressively over the train o f test stimuli, but the same effect was n o t observed with TES (Fig. 1 A). The decrease occurred in the absence o f any m a r k e d changes in the amplitudes o f the M wave or H-reflexes, indicating that a l p h a - m o t 9 excitability was u n c h a n g e d and nerve c o n d u c t i o n , neuromuscular transmission, and muscle m e m b r a n e excitability were n o t altered. The m e a n amplitudes o f M E P s to T M S after exercise were significantly lower than the preexercise values (Fig. 1 B). A l t h o u g h the amplitudes o f M E P s to TES increased in two subjects, the overall result was a decrease in the amplitudes (Fig. 1 B). There was also a decrease in the m e a n amplitude o f M E P s recorded serially during the intervals between 30-s sessions o f the same wrist-flexion exercises p e r f o r m e d by the three subjects. Immediately after the 30-s periods o f exercise, however, the amplitudes o f the first one or two M E P s increased (central postactivation facilitation),
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but once the subject felt fatigued the increase stopped (central postexercise exhaustion). There was no increase in baseline EMG activity. We calculated the ratio between the amplitude of the fourth MEP and the amplitude of the first MEP (4th: 1st ratio) in each set of four MEPs. Mean 4th: 1st ratios in sets of MEPs recorded in the absence of exercise were significantly higher than those with interpolated periods of exercise (Fig. 2). Discussion
The clear and progressive decrease in the amplitudes of MEPs produced by TMS, but not TES, after repetitive activation to perform the required movement strongly suggests that intracortical mechanisms are involved in the decrease. This conclusion is based on the different loci of action proposed for the different methods of stimulation, with TES acting preferentially on the axon hillock of corticospinal motoneurons, and TMS activating these neurons mostly presynaptically, through intracortical connections (Amassian et al. 1987; Day et al. 1987). An alternative explanation would be that the more impressive decrease in MEP amplitudes with TMS than with TES might be due to greater fatiguability of those muscles that contributed the most to the generation of MEPs to TMS. However, the maximal M wave recorded after supramaximal stimulation of the median nerve at the elbow should also have decreased in amplitude if muscle fatigue led to smaller potentials arising from any muscle or group of muscles. Therefore, the absence of changes in the maximal M response does not support this explanation. Fatigue of sustained maximal voluntary contractions is accompanied by a decline in surface-recorded EMG activity, which suggests that loss of force also results from reduced muscle activation, in addition to failure of muscle contractile mechanisms (Bigland-Ritchie et al. 1983). However, the firing rate of the central neuronal drive might decrease, because, once fatigued, the muscle can respond with the same contractile force to neuronal inputs reaching it at lower frequencies owing to an increase in muscle relaxation time (Bigland-Ritchie et al. 1983). Thus the decrease in MEP amplitudes may have been caused by a compensatory response of the central nervous system (CNS) to changes in mechanical function caused by exercise. This explanation seems unlikely, though, because early in the process of fatigue development, the initial MEP was often enhanced, but the later MEPs were reduced. On the basis of this amplitude difference between the initial and later MEPs in a series, one could argue that habituation, relaxation of the subject, or anticipation could be the responsible factor. This seems rather unlikely, however, as we have never observed such a phenomenon when delivering a series of stimuli to the same scalp position nor when moving from one stimulus position to another, during the course of noninvasive mapping of the human motor cortex (Cohen et al. 1991 ; Brasil-Neto et al. 1992). Alternatively, the decrease in MEP amplitudes may have resulted from a change in the specific force-generat-
ing strategies adopted by the motor system, involving motor pathways and structures other than the fast corticospinal tracts for the production of the required movements. Studies of poststimulus time histograms (Brower et al. 1989) indicate that additional synaptic input to motoneurons in order to maintain a stronger muscle contraction might come from fiber systems other than the fast corticospinal pathways activated by TMS. However, given the increase in amplitude of the initial MEP in a series of stimuli delivered after each period of exercise, this explanation also seems unlikely. In a further interpretation, the decrease in MEP amplitudes could be a neurophysiological sign of fatigue of CNS structures. At the level of the neuromuscular junction, there are effects that can be detected by changes in the amplitude of the compound muscle action potential to repetitive peripheral nerve stimulation whenever there is a decrease in the safety factor, as in myasthenia gravis. Exercise before fatigue results in the release of an excess of acetylcholine and an increase in the amplitude of the end-plate potential, accounting for facilitation of subsequent muscle contractions. Conversely, postexercise exhaustion results from depletion of the immediately available pool of acetylcholine (Oh 1988). In our study, the production of a decrease in MEP amplitudes only by trains of TMS and the presence of postactivation facilitation and exhaustion phenomena are compatible with effects related to the accumulation and depletion of neurotransmitters. The neural structures involved in these processes are probably located in the CNS at a level upstream of the corticospinal neurons, because the H-reflexes did not change, and TES did not produce consistent changes. Attempts to modify the postexercise depression of MEP amplitudes pharmacologically (e.g., by the administration of apomorphine) might shed some light on the physiological mechanisms of the phenomenon. We plan to study postexercise depression of MEPs in patients with Parkinson's disease, multiple sclerosis, and chronic fatigue syndrome to assess the fatigue associated with these diseases.
Acknowledgements. We thank B.J. Hessie for skillful editing, and Nguyet Dang for technical support during the experiments.
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