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Effects of somatosensory input on central fatigue: a pilot study
Clinical Neurophysiology 111 (2000) 1843±1846
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Effects of somatosensory input on central fatigue: a pilot study Jens D. Rollnik*, Margot Schubert, Julia Albrecht, Kai Wohlfarth, Reinhard Dengler Department of Neurology and Clinical Neurophysiology, Medical School of Hannover, 30623 Hannover, Germany Accepted 28 June 2000
Abstract Objective: Depression of motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS) may be a sign of central motor fatigue. As a pilot study, we have examined whether post-exercise MEP depression can be compensated by application of sensory stimuli prior to TMS. Methods: We studied 15 healthy volunteers (aged 21±28 years) who were required to perform an exercise protocol of ankle dorsi¯exion until force fell below 66% of maximum force. MEPs were recorded from the right tibialis anterior muscle. Prior to TMS, electrical stimuli were applied to the ipsilateral sural nerve with an individual interstimulus interval between 50 and 80 ms. Results: MEP areas decreased after exercise. When a sensory stimulus was administered MEPs did not change. Conclusion: We conclude that the effects of central fatigue may be in¯uenced by application of sensory stimuli. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Fatigue; Sensory stimulation; Facilitation; Transcranial magnetic stimulation; Central nervous system
1. Introduction Several variables may in¯uence motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). Among these are executed or intended muscle contraction, sensory factors, prefrontal in¯uences, and central motor fatigue (Deletis et al., 1992; Nielsen et al., 1997; Rollnik et al., 2000; Schubert et al., 1998). Fatigue of the motor system is characterized by a decrease of force generated by the neuromuscular system during sustained or repeated muscle activity. Central motor fatigue leads to a post-exercise depression of MEPs and results from reduced neural drive proximal to the anterior horn cell (Brasil-Neto et al., 1993, 1994; Deuschl et al., 1991). The origin of central fatigue is still a matter of discussion, but some authors suggested that the frontal cortex and basal ganglia might be involved (Roelcke et al., 1997). Several studies have investigated facilitation of MEPs. For instance, voluntary background contraction or posture exerts a facilitatory effect upon compound muscle action potentials of the upper and lower limbs elicited by TMS or transcranial electrical stimulation (Ackermann et al., 1991; Benecke et al., 1988; Day et al., 1987; Hess et al., 1987; Merton et al., 1982; Rossini et al., 1985). MEPs may * Corresponding author. Tel.: 149-511-532-3558; fax 149-511-5322415. E-mail address: [email protected] (J.D. Rollnik).
be facilitated by sensory stimulation prior to TMS (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). Short-interval facilitation, which is supposed to be mediated through spinal mechanisms, takes place when a sensory stimulus is applied some 10 ms prior to TMS. Long-interval facilitation reaches its optimum between 30 and 50 ms for upper and 50 to 80 ms for lower limbs and is probably mediated through cortical neurons (Nielsen et al., 1997). Sensory stimulation appears to play an important role in modulating the output of the human motor cortex (Edwards, 1981). Both single sensory stimuli and vibration can in¯uence excitability of a motoneurons (Claus et al., 1988). The aim of our pilot study was to investigate whether post-exercise MEP depression (which may be considered a sign of central fatigue) can be in¯uenced by facilitating sensory stimuli prior to TMS.
2. Methods We studied 15 healthy right-handed volunteers (9 men and 6 women), aged 21±28 years (mean 24.7, SD 2:2). All subjects gave written informed consent to the experimental procedure. Subjects lay on a bed with hip ¯exed to 908, the knee ¯exed to 908, and the ankle at 1008. A strain
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(00)00385-0
CLINPH 2000584
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J.D. Rollnik et al. / Clinical Neurophysiology 111 (2000) 1843±1846
body temperature was obtained before and after the experiment (to exclude temperature- induced changes of nerve conduction velocity). The subjects had to perform an exercise protocol (dorsi¯exion of the foot) at a level of 70% of baseline maximum force (6 s exercise, 4 s rest) until force fell below 66% of maximum force, which was set as the endurance limit. Maximum force was determined as the strongest force from 3 consecutive trials with a duration of 1 s (prior to the experiment, at baseline). We measured maximum force, areas of recti®ed MEPs, total motor conduction time from cortex to muscle (TMCT) and peripheral motor conduction times (PMCT) using the conventional F-wave technique before, immediately after (within 15±30 s), and 15 and 30 min after the exercise. Central motor conduction time (CMCT) was computed by the formula CMCT TMCT 2 PMCT. Because of huge data variation we used non-parametric tests, employing Kruskal-Wallis and Friedman tests. Differences were regarded as signi®cant with P , 0:05. Force and MEP measures were expressed as a percentage of pre-exercise (baseline) values.
gauge was attached to the right ankle and foot in order to perform force measurements of ankle dorsi¯exion. Single electrical stimuli of the sural nerve were applied by surface electrodes placed at the lateral malleolus. Duration of the stimulus was 0.1 ms and the intensity was two times perception threshold. Using a D4030 Digitimer (Digitimer Ltd., Hertfordshire, UK), the conditioning sensory stimuli were given at individually determined interstimulus intervals (50±80 ms prior to TMS) that had produced MEPs with the largest areas in prior trials, i.e. the strongest facilitation. For this purpose, intervals between 40 and 100 ms were tested in random order and steps of 10 ms in each subject. The interval with the strongest MEP facilitation was used as the interstimulus interval throughout the experiment. During the experiment a sensory stimulus preceded TMS in 10 of 20 trials (in random order). Transcranial magnetic stimuli (MagStim 200; MagStim Co. Ltd., Whitland, UK) were applied over the vertex with a double-cone coil (current in the coil was directed anteriorly). The position of the coil was systematically adjusted before the start of each experiment to ®nd the optimum location for the tibialis anterior muscle (up to 2 cm lateral to the vertex). MEPs were recorded from the right tibialis anterior and gastrocnemius muscles with surface EMG electrodes at rest, which was controlled by EMG loudspeakers to avoid facilitation by pre-activation. The intensity of TMS was set at 20% above the motor threshold (MT). In order to determine MT at rest we usually started with 40% of maximum stimulator output, increasing stepwise in 5% intervals (Claus, 1990). When MEPs could be evoked, stimulus intensity was reduced in steps of 1±2% until MT could be identi®ed (lowest intensity which produced 3 responses with an amplitude of at least 50 mV in 4 trials). The abovementioned 20 transcranial magnetic stimuli were given at a rate of 0.2±0.3 Hz. Magnetic stimulation was followed immediately by supramaximal electrical stimuli (1 Hz) applied to the right peroneal nerve to evoke the M wave and 10 F waves in the right tibialis anterior muscle. Oral
We found that maximum force was signi®cantly reduced after exercise (Friedman-test: x2 18:24, d´f´ 3; P , 0:001; Fig. 1). Immediately after exercise, force was decreased to a mean of 69.9% (SD 9:8) of pre-exercise values. 15 min after exercise maximum force increased to 90.8% (SD 14:2), and 30 min after exercise to 93.3% (SD 14:5) of baseline levels. The endurance limit was reached after a mean of 5.9 min (SD 7:3; range 2.5±30 min). In the absence of sensory stimulation, areas of recti®ed MEPs from the tibialis anterior muscle decreased immediately after exercise (Fig. 2) to 88.2% (SD 50:5), to 62.1%
Fig. 1. Maximum force immediately after the exercise (0), and 15 and 30 min post-exercise. Force values are expressed as percentage of baseline maximum force (pre-exercise maximum force). Standard deviation is indicated on top of bars.
Fig. 2. Areas of recti®ed MEPs with and without conditioning electrical stimulation of the sural nerve. MEP area values are expressed as percentage of pre-exercise values. Post-exercise there was a signi®cant decrease of MEP areas when no sensory stimulation took place. No signi®cant changes could be observed when there was an electrical stimulus prior to TMS. Areas were signi®cantly higher after 15 and 30 min when electrical stimulation was performed. Standard deviation is indicated on top of bars.
3. Results
J.D. Rollnik et al. / Clinical Neurophysiology 111 (2000) 1843±1846
(SD 33:7) after 15 min, and to 81.0% (SD 64:0) after 30 min. This MEP area reduction was highly signi®cant (Friedman-test: mean rank 3.50 before exercise, 2.58 immediately after exercise, 1.75 after 15 min, and 2.17 after 30 min; x2 12:10, d´f´ 3, P 0:007). When an electrical stimulus preceded TMS (Fig. 2) areas of recti®ed MEPs did not change signi®cantly (92.4% (SD 44:8) immediately after exercise, 82.2% (SD 32:9) after 15 min, and 95.2% (SD 41:2) after 30 min; x2 1:84, d´f´ 3, not signi®cant). Comparing MEP areas with and without prior electrical stimulation (using Kruskal-Wallis tests), we could not ®nd signi®cant differences at baseline (x2 1:47, d´f´ 1, not signi®cant) and immediately after exercise (x2 2:95, d´f´ 1, P 0:086), but 15 min (x2 4:05, d´f´ 1, P 0:044) and 30 min (x2 5:22, d´f´ 1, P 0:022) later, MEP areas were signi®cantly higher with conditioning sural stimulation (for example, see Fig. 3).
Fig. 3. Examples of MEPs (recorded from the right tibialis anterior muscle) with and without sural nerve stimulation. Subject J (female, 24 years), 15 min after exercise. Lines A1 and A5, without sural nerve stimulation (MEP areas: 44.8 and 49.3 mV/ms, respectively); lines A3 and A7, with conditioning stimulus (MEP areas: 84.3 and 81.5 mV/ms, respectively).
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M and F waves, TMCT and CMCT did not change before and after exercise. Oral body temperature pre- and postexercise did not change. We could not ®nd signi®cant MEP changes induced by exercise or by electrical stimulation in the antagonist muscle (gastrocnemius muscle) either. 4. Discussion After an exhausting exercise, central fatigue may occur leading to post-exercise MEP depression without M-wave changes (Deletis et al., 1992; Schubert et al., 1998). The results of our study are in line with similar studies demonstrating an exercise-induced decrease of MEP areas (BrasilNeto et al., 1993, 1994; Dengler et al., 1995). Consistent with this ®nding, the maximum force that can be taken as an indicator of fatigue was also decreased. It is well known that sensory stimuli may facilitate MEPs (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). This MEP facilitation follows sensory stimulation at short and long intervals. Short-interval facilitation is believed to arise on a spinal level, whereas long-interval facilitation is probably mediated through cortical mechanisms (Nielsen et al., 1997). We know from long-latency responses (LLR) that they follow a transcortical pathway as a servo loop mechanism for modifying motor programs (Mariorenzi et al., 1991). The duration of these intervals is dependent on the subject's height. Therefore, the interstimulus intervals were carefully determined for each subject in our experiment. In line with other studies, we found that sensory stimulation (50±80 ms before TMS) leads to a facilitation of MEPs (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). Using these individually determined interstimulus intervals, we found that sensory stimuli elevated previously depressed MEPs (when central fatigue is assumed). From the fact that we did not observe any changes in the antagonist muscle we can conclude that the facilitatory effect of sensory stimuli was mainly limited to the corticospinal neurons representing the fatigued muscle. The site of this effect cannot be determined easily. The results of our study indicate that it is not the neuromuscular junction (unchanged M responses). The fact that the latencies used were within range of long-interval facilitation suggests that cortical mechanisms may be involved (Nielsen et al., 1997). The transcortical hypothesis of long-latency responses also gives weight to this interpretation (Mariorenzi et al., 1991). Further, TMS mainly excites neurons presynaptic to corticospinal neurons located in frontal areas (Claus et al., 1988; Day et al., 1987). The processing of facilitation and fatigue might take place in these neurons. In addition, the dorsolateral prefrontal cortex (DLPFC) is essential in central motor control (Rollnik et al., 2000). In a previous study, we demonstrated that activation of DLPFC
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using rapid-rate repetitive TMS may induce MEP depression. This ®nding re¯ects that the DLPFC is able to reduce motor cortex excitability. Further, sensory information might be transmitted to frontal areas and thus reduces its inhibiting in¯uence. It should be noticed that DLPFC is also involved in mood regulation (George et al., 1997). Activation of left DLPFC (using rapid-rate repetitive TMS) may improve depressive symptoms (George et al., 1997). In addition, the importance of frontal cortical areas in sensorimotor integration is immense: Proprioceptive input arrives in parietal primary sensory, and in frontal primary and nonprimary motor areas (Mariorenzi et al., 1991; Rossini et al., 1987). In addition, there are a few observations that the frontal cortex plays a crucial role in the phenomenon of central fatigue. Roelcke et al. (1997) demonstrated a reduced glucose metabolism in the frontal cortex and basal ganglia of MS patients with fatigue. In conclusion, we were able to demonstrate that sensory input may partially compensate fatigue-induced MEP depression. There are good reasons to believe that this mechanism could be mediated through a transcortical loop involving frontal cortical areas. Further studies on this topic, combining neurophysiological methods with functional imaging, are strongly encouraged. References Ackermann H, Scholz E, Koehler W, Dichgans J. In¯uence of posture and voluntary background contraction upon compound muscle action potentials from anterior tibial and soleus muscle following transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 1991;81:71±80. Benecke R, Meyer BU, GoÈhmann M, Conrad B. Analysis of muscle responses elicited by transcranial magnetic stimulation of the corticospinal system in man. Electroencephalogr Clin Neurophysiol 1998;69:412±422. Brasil-Neto JP, Pascual-Leone A, Valls-Sole J, Cammarota A, Cohen LG, Hallett M. Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue. Exp Brain Res 1993;93:181±184. Brasil-Neto JP, Cohen LG, Hallett M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994;17:713±719. Claus D. Central motor conduction: method and normal results. Muscle Nerve 1990;13:1125±1132. Claus D, Mills KR, Murray NMF. The in¯uence of vibration on the excitability of alpha motoneurones. Electroencephalogr Clin Neurophysiol 1988;69:431±436. Date M, Schmid UD, Hess CW, Schmid J. In¯uence of peripheral nerve stimulation on the responses in small hand muscles to transcranial magnetic cortex stimulation. Electroencephalogr Clin Neurophysiol Suppl 1991;43:212±223. Day BL, Thompson PD, Dick JP, Nakashima K, Marsden CD. Different sites of action of electrical and magnetic stimulation of the human brain. Neurosci Lett 1987;75:101±106. Day BL, Dressler D, Maertens de Noordhout A, Nakashima K, Rothwell JC, Thompson PD. Electric and magnetic stimulation of human motor cortex: EMG and single motor unit studies. J Physiol 1989;41:449±473.
Deletis V, Schild JH, Beric A, Dimitrijevic MR. Facilitation of motor evoked potentials by somatosensory afferent stimulation. Electroencephalogr Clin Neurophysiol 1992;85:302±310. Dengler R, Schubert M, Wohlfarth K, Czapowski D. An approach to study the role of the corticospinal tract in central fatigue. Electroencephalogr Clin Neurophysiol 1995;97:S58. Deuschl G, Michels R, Berardelli A, Schenck E, Inghilleri M, LuÈcking CH. Effects of electric and magnetic transcranial stimulation on long latency re¯exes. Exp Brain Res 1991;83:403±410. Edwards RHT. Human muscle function and fatigue. In: Porter R, Whelan J, editors. Human muscle fatigue physiological mechanisms, London: Pitman Medical, 1981. pp. 1±18. George MS, Wassermann EM, Kimbrell TA, Little JT, Williams WE, Danielson AL, Greenberg BD, Hallett M. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry 1997;12:1752±1756. Hamdy S, Rothwell JC, Aziz Q, Singh KD, Thompson DG. Long-term reorganization of human motor cortex driven by short-term sensory stimulation. Nat Neurosci 1998;1:64±68. Hess CW, Mills KR, Murray NMF. Responses in small hand muscles from magnetic stimulation of the human brain. J Physiol 1987;388:397±419. Kasai T, Hayes KC, Wolfe DL, Allatt RD. Afferent conditioning of motor eveoked potentials following transcranial magnetic stimulation of motor cortex in normal subjects. Electroencephalogr Clin Neurophysiol 1992;85:95±101. Mariorenzi R, Zarola F, Caramia MD, Paradiso C, Rossini PM. Non-invasive evaluation of central motor tract excitability changes following peripheral nerve stimulation in healthy humans. Electroencephalogr Clin Neurophysiol 1991;81(2):90±101. Merton PA, Morton HB, Hill DK, Marsden CD. Scope of a technique for electrical stimulation of human brain, spinal cord, and muscle. Lancet 1982:597±600. Nielsen J, Petersen N, Fedirchuk B. Evidence suggesting a transcortical pathway from cutaneous foot afferents to tibialis anterior motoneurones in man. J Physiol 1997:473±484. Pereon Y, Guiheneuc P. Late facilitations of motor evoked potentials by contralateral mixed nerve stimulation. Electroencephalogr Clin Neurophysiol 1995;97:126±130. Roelcke U, Kappos L, Lechner-Scott J, Brunnschweiler H, Huber S, Ammann W, Plohmann A, Dellas S, Maguire RP, Missimer J, Radu EW, Steck A, Leenders KL. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18 F-¯urodeoxyglucose positron emission tomography study. Neurology 1997;48(6):1566±1571. Rollnik JD, Schubert M, Dengler R. Subtreshold prefrontal repetitive transcranial magnetic stimulation reduces motor cortex excitability. Muscle Nerve 2000;23(1):112±114. Rossini PM, Marciani MG, Caramia M, Roma V, 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. Electroencephalogr Clin Neurophysiol 1985;61:272±286. Rossini PM, Gigli GL, Marciani MG, Zarola F, Caramia M. Non-invasive evaluation of input-output characteristics of sensorimotor cerebral areas in healthy humans. Electroencephalogr Clin Neurophysiol 1987;68:88± 100. Schubert M, Wohlfarth K, Rollnik JD, Dengler R. Walking and fatigue in multiple sclerosis: the role of the corticospinal system. Muscle Nerve 1998;21:1068±1070. Wolfe DL, Hayes KC. Conditioning effects of sural nerve stimulation on short and long latency motor evoked potentials in lower limb muscles. Electroencephalogr Clin Neurophysiol 1995;97:11±17.
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Effects of somatosensory input on central fatigue: a pilot study Jens D. Rollnik*, Margot Schubert, Julia Albrecht, Kai Wohlfarth, Reinhard Dengler Department of Neurology and Clinical Neurophysiology, Medical School of Hannover, 30623 Hannover, Germany Accepted 28 June 2000
Abstract Objective: Depression of motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS) may be a sign of central motor fatigue. As a pilot study, we have examined whether post-exercise MEP depression can be compensated by application of sensory stimuli prior to TMS. Methods: We studied 15 healthy volunteers (aged 21±28 years) who were required to perform an exercise protocol of ankle dorsi¯exion until force fell below 66% of maximum force. MEPs were recorded from the right tibialis anterior muscle. Prior to TMS, electrical stimuli were applied to the ipsilateral sural nerve with an individual interstimulus interval between 50 and 80 ms. Results: MEP areas decreased after exercise. When a sensory stimulus was administered MEPs did not change. Conclusion: We conclude that the effects of central fatigue may be in¯uenced by application of sensory stimuli. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Fatigue; Sensory stimulation; Facilitation; Transcranial magnetic stimulation; Central nervous system
1. Introduction Several variables may in¯uence motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). Among these are executed or intended muscle contraction, sensory factors, prefrontal in¯uences, and central motor fatigue (Deletis et al., 1992; Nielsen et al., 1997; Rollnik et al., 2000; Schubert et al., 1998). Fatigue of the motor system is characterized by a decrease of force generated by the neuromuscular system during sustained or repeated muscle activity. Central motor fatigue leads to a post-exercise depression of MEPs and results from reduced neural drive proximal to the anterior horn cell (Brasil-Neto et al., 1993, 1994; Deuschl et al., 1991). The origin of central fatigue is still a matter of discussion, but some authors suggested that the frontal cortex and basal ganglia might be involved (Roelcke et al., 1997). Several studies have investigated facilitation of MEPs. For instance, voluntary background contraction or posture exerts a facilitatory effect upon compound muscle action potentials of the upper and lower limbs elicited by TMS or transcranial electrical stimulation (Ackermann et al., 1991; Benecke et al., 1988; Day et al., 1987; Hess et al., 1987; Merton et al., 1982; Rossini et al., 1985). MEPs may * Corresponding author. Tel.: 149-511-532-3558; fax 149-511-5322415. E-mail address: [email protected] (J.D. Rollnik).
be facilitated by sensory stimulation prior to TMS (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). Short-interval facilitation, which is supposed to be mediated through spinal mechanisms, takes place when a sensory stimulus is applied some 10 ms prior to TMS. Long-interval facilitation reaches its optimum between 30 and 50 ms for upper and 50 to 80 ms for lower limbs and is probably mediated through cortical neurons (Nielsen et al., 1997). Sensory stimulation appears to play an important role in modulating the output of the human motor cortex (Edwards, 1981). Both single sensory stimuli and vibration can in¯uence excitability of a motoneurons (Claus et al., 1988). The aim of our pilot study was to investigate whether post-exercise MEP depression (which may be considered a sign of central fatigue) can be in¯uenced by facilitating sensory stimuli prior to TMS.
2. Methods We studied 15 healthy right-handed volunteers (9 men and 6 women), aged 21±28 years (mean 24.7, SD 2:2). All subjects gave written informed consent to the experimental procedure. Subjects lay on a bed with hip ¯exed to 908, the knee ¯exed to 908, and the ankle at 1008. A strain
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(00)00385-0
CLINPH 2000584
1844
J.D. Rollnik et al. / Clinical Neurophysiology 111 (2000) 1843±1846
body temperature was obtained before and after the experiment (to exclude temperature- induced changes of nerve conduction velocity). The subjects had to perform an exercise protocol (dorsi¯exion of the foot) at a level of 70% of baseline maximum force (6 s exercise, 4 s rest) until force fell below 66% of maximum force, which was set as the endurance limit. Maximum force was determined as the strongest force from 3 consecutive trials with a duration of 1 s (prior to the experiment, at baseline). We measured maximum force, areas of recti®ed MEPs, total motor conduction time from cortex to muscle (TMCT) and peripheral motor conduction times (PMCT) using the conventional F-wave technique before, immediately after (within 15±30 s), and 15 and 30 min after the exercise. Central motor conduction time (CMCT) was computed by the formula CMCT TMCT 2 PMCT. Because of huge data variation we used non-parametric tests, employing Kruskal-Wallis and Friedman tests. Differences were regarded as signi®cant with P , 0:05. Force and MEP measures were expressed as a percentage of pre-exercise (baseline) values.
gauge was attached to the right ankle and foot in order to perform force measurements of ankle dorsi¯exion. Single electrical stimuli of the sural nerve were applied by surface electrodes placed at the lateral malleolus. Duration of the stimulus was 0.1 ms and the intensity was two times perception threshold. Using a D4030 Digitimer (Digitimer Ltd., Hertfordshire, UK), the conditioning sensory stimuli were given at individually determined interstimulus intervals (50±80 ms prior to TMS) that had produced MEPs with the largest areas in prior trials, i.e. the strongest facilitation. For this purpose, intervals between 40 and 100 ms were tested in random order and steps of 10 ms in each subject. The interval with the strongest MEP facilitation was used as the interstimulus interval throughout the experiment. During the experiment a sensory stimulus preceded TMS in 10 of 20 trials (in random order). Transcranial magnetic stimuli (MagStim 200; MagStim Co. Ltd., Whitland, UK) were applied over the vertex with a double-cone coil (current in the coil was directed anteriorly). The position of the coil was systematically adjusted before the start of each experiment to ®nd the optimum location for the tibialis anterior muscle (up to 2 cm lateral to the vertex). MEPs were recorded from the right tibialis anterior and gastrocnemius muscles with surface EMG electrodes at rest, which was controlled by EMG loudspeakers to avoid facilitation by pre-activation. The intensity of TMS was set at 20% above the motor threshold (MT). In order to determine MT at rest we usually started with 40% of maximum stimulator output, increasing stepwise in 5% intervals (Claus, 1990). When MEPs could be evoked, stimulus intensity was reduced in steps of 1±2% until MT could be identi®ed (lowest intensity which produced 3 responses with an amplitude of at least 50 mV in 4 trials). The abovementioned 20 transcranial magnetic stimuli were given at a rate of 0.2±0.3 Hz. Magnetic stimulation was followed immediately by supramaximal electrical stimuli (1 Hz) applied to the right peroneal nerve to evoke the M wave and 10 F waves in the right tibialis anterior muscle. Oral
We found that maximum force was signi®cantly reduced after exercise (Friedman-test: x2 18:24, d´f´ 3; P , 0:001; Fig. 1). Immediately after exercise, force was decreased to a mean of 69.9% (SD 9:8) of pre-exercise values. 15 min after exercise maximum force increased to 90.8% (SD 14:2), and 30 min after exercise to 93.3% (SD 14:5) of baseline levels. The endurance limit was reached after a mean of 5.9 min (SD 7:3; range 2.5±30 min). In the absence of sensory stimulation, areas of recti®ed MEPs from the tibialis anterior muscle decreased immediately after exercise (Fig. 2) to 88.2% (SD 50:5), to 62.1%
Fig. 1. Maximum force immediately after the exercise (0), and 15 and 30 min post-exercise. Force values are expressed as percentage of baseline maximum force (pre-exercise maximum force). Standard deviation is indicated on top of bars.
Fig. 2. Areas of recti®ed MEPs with and without conditioning electrical stimulation of the sural nerve. MEP area values are expressed as percentage of pre-exercise values. Post-exercise there was a signi®cant decrease of MEP areas when no sensory stimulation took place. No signi®cant changes could be observed when there was an electrical stimulus prior to TMS. Areas were signi®cantly higher after 15 and 30 min when electrical stimulation was performed. Standard deviation is indicated on top of bars.
3. Results
J.D. Rollnik et al. / Clinical Neurophysiology 111 (2000) 1843±1846
(SD 33:7) after 15 min, and to 81.0% (SD 64:0) after 30 min. This MEP area reduction was highly signi®cant (Friedman-test: mean rank 3.50 before exercise, 2.58 immediately after exercise, 1.75 after 15 min, and 2.17 after 30 min; x2 12:10, d´f´ 3, P 0:007). When an electrical stimulus preceded TMS (Fig. 2) areas of recti®ed MEPs did not change signi®cantly (92.4% (SD 44:8) immediately after exercise, 82.2% (SD 32:9) after 15 min, and 95.2% (SD 41:2) after 30 min; x2 1:84, d´f´ 3, not signi®cant). Comparing MEP areas with and without prior electrical stimulation (using Kruskal-Wallis tests), we could not ®nd signi®cant differences at baseline (x2 1:47, d´f´ 1, not signi®cant) and immediately after exercise (x2 2:95, d´f´ 1, P 0:086), but 15 min (x2 4:05, d´f´ 1, P 0:044) and 30 min (x2 5:22, d´f´ 1, P 0:022) later, MEP areas were signi®cantly higher with conditioning sural stimulation (for example, see Fig. 3).
Fig. 3. Examples of MEPs (recorded from the right tibialis anterior muscle) with and without sural nerve stimulation. Subject J (female, 24 years), 15 min after exercise. Lines A1 and A5, without sural nerve stimulation (MEP areas: 44.8 and 49.3 mV/ms, respectively); lines A3 and A7, with conditioning stimulus (MEP areas: 84.3 and 81.5 mV/ms, respectively).
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M and F waves, TMCT and CMCT did not change before and after exercise. Oral body temperature pre- and postexercise did not change. We could not ®nd signi®cant MEP changes induced by exercise or by electrical stimulation in the antagonist muscle (gastrocnemius muscle) either. 4. Discussion After an exhausting exercise, central fatigue may occur leading to post-exercise MEP depression without M-wave changes (Deletis et al., 1992; Schubert et al., 1998). The results of our study are in line with similar studies demonstrating an exercise-induced decrease of MEP areas (BrasilNeto et al., 1993, 1994; Dengler et al., 1995). Consistent with this ®nding, the maximum force that can be taken as an indicator of fatigue was also decreased. It is well known that sensory stimuli may facilitate MEPs (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). This MEP facilitation follows sensory stimulation at short and long intervals. Short-interval facilitation is believed to arise on a spinal level, whereas long-interval facilitation is probably mediated through cortical mechanisms (Nielsen et al., 1997). We know from long-latency responses (LLR) that they follow a transcortical pathway as a servo loop mechanism for modifying motor programs (Mariorenzi et al., 1991). The duration of these intervals is dependent on the subject's height. Therefore, the interstimulus intervals were carefully determined for each subject in our experiment. In line with other studies, we found that sensory stimulation (50±80 ms before TMS) leads to a facilitation of MEPs (Date et al., 1991; Day et al., 1989; Hamdy et al., 1998; Dengler et al., 1995; Kasai et al., 1992; Pereon and Guiheneuc, 1995; Wolfe and Hayes, 1995). Using these individually determined interstimulus intervals, we found that sensory stimuli elevated previously depressed MEPs (when central fatigue is assumed). From the fact that we did not observe any changes in the antagonist muscle we can conclude that the facilitatory effect of sensory stimuli was mainly limited to the corticospinal neurons representing the fatigued muscle. The site of this effect cannot be determined easily. The results of our study indicate that it is not the neuromuscular junction (unchanged M responses). The fact that the latencies used were within range of long-interval facilitation suggests that cortical mechanisms may be involved (Nielsen et al., 1997). The transcortical hypothesis of long-latency responses also gives weight to this interpretation (Mariorenzi et al., 1991). Further, TMS mainly excites neurons presynaptic to corticospinal neurons located in frontal areas (Claus et al., 1988; Day et al., 1987). The processing of facilitation and fatigue might take place in these neurons. In addition, the dorsolateral prefrontal cortex (DLPFC) is essential in central motor control (Rollnik et al., 2000). In a previous study, we demonstrated that activation of DLPFC
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using rapid-rate repetitive TMS may induce MEP depression. This ®nding re¯ects that the DLPFC is able to reduce motor cortex excitability. Further, sensory information might be transmitted to frontal areas and thus reduces its inhibiting in¯uence. It should be noticed that DLPFC is also involved in mood regulation (George et al., 1997). Activation of left DLPFC (using rapid-rate repetitive TMS) may improve depressive symptoms (George et al., 1997). In addition, the importance of frontal cortical areas in sensorimotor integration is immense: Proprioceptive input arrives in parietal primary sensory, and in frontal primary and nonprimary motor areas (Mariorenzi et al., 1991; Rossini et al., 1987). In addition, there are a few observations that the frontal cortex plays a crucial role in the phenomenon of central fatigue. Roelcke et al. (1997) demonstrated a reduced glucose metabolism in the frontal cortex and basal ganglia of MS patients with fatigue. In conclusion, we were able to demonstrate that sensory input may partially compensate fatigue-induced MEP depression. There are good reasons to believe that this mechanism could be mediated through a transcortical loop involving frontal cortical areas. Further studies on this topic, combining neurophysiological methods with functional imaging, are strongly encouraged. References Ackermann H, Scholz E, Koehler W, Dichgans J. In¯uence of posture and voluntary background contraction upon compound muscle action potentials from anterior tibial and soleus muscle following transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 1991;81:71±80. Benecke R, Meyer BU, GoÈhmann M, Conrad B. Analysis of muscle responses elicited by transcranial magnetic stimulation of the corticospinal system in man. Electroencephalogr Clin Neurophysiol 1998;69:412±422. Brasil-Neto JP, Pascual-Leone A, Valls-Sole J, Cammarota A, Cohen LG, Hallett M. Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue. Exp Brain Res 1993;93:181±184. Brasil-Neto JP, Cohen LG, Hallett M. Central fatigue as revealed by postexercise decrement of motor evoked potentials. Muscle Nerve 1994;17:713±719. Claus D. Central motor conduction: method and normal results. Muscle Nerve 1990;13:1125±1132. Claus D, Mills KR, Murray NMF. The in¯uence of vibration on the excitability of alpha motoneurones. Electroencephalogr Clin Neurophysiol 1988;69:431±436. Date M, Schmid UD, Hess CW, Schmid J. In¯uence of peripheral nerve stimulation on the responses in small hand muscles to transcranial magnetic cortex stimulation. Electroencephalogr Clin Neurophysiol Suppl 1991;43:212±223. Day BL, Thompson PD, Dick JP, Nakashima K, Marsden CD. Different sites of action of electrical and magnetic stimulation of the human brain. Neurosci Lett 1987;75:101±106. Day BL, Dressler D, Maertens de Noordhout A, Nakashima K, Rothwell JC, Thompson PD. Electric and magnetic stimulation of human motor cortex: EMG and single motor unit studies. J Physiol 1989;41:449±473.
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