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MS 11046 Received 25 April 2000; accepted after revision 9 October 2000.
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ABSTRACT |
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SD)) were measured using threshold tracking. Impulse transmission was assessed using supramaximal stimuli.
SD, all of which lasted ~10 min and indicate axonal hyperpolarization. However, immediately after the contraction there was an unexpected increase in refractoriness. The post-contraction increase in refractoriness could not be mimicked by an imposed ramp of hyperpolarization that produced changes in the other indices to an extent that was similar to voluntary contraction.
SD following voluntary contraction differed significantly from those recorded during the hyperpolarization produced by DC current. It is argued that these differences probably result from extra-axonal K+ accumulation with the voluntary contraction but not with the DC polarization.
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INTRODUCTION |
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When conducting a long train of impulses, axons undergo hyperpolarization due to activation of the electrogenic Na+-K+ pump (Gasser, 1935; Bostock & Grafe, 1985; Gordon et al. 1990; Kiernan et al. 1997). It has recently been shown that natural activity induced by voluntary contraction of a muscle causes substantial hyperpolarization of active motor axons (Vagg et al. 1998). This hyperpolarization could be a limiting factor for impulse conduction if the safety margin is lowered by pathology (Bostock & Grafe, 1985) or in axonal branch points where the safety factor is physiologically low (Parnas, 1972; Grossman et al. 1979; Parnas & Segev, 1979; Waxman & Wood, 1984; Stoney, 1985, 1990). An activity-dependent change in impulse transmission may be responsible for muscle fatigue and weakness in patients with demyelinating neuropathy (Kaji et al. 2000).
However, voluntary contractions can have complex effects on axons other than through the pump-induced change in membrane potential. For example, voluntary contraction may have secondary effects due to abnormal ion accumulation. The impulse load during contraction could lead to an intracellular accumulation of Na+ which could reduce the sodium equilibrium potential (Rasminsky & Sears, 1972), and an extracellular accumulation of K+ which could increase excitability (Bostock et al. 1991). Voluntary contractions also affect glycolytic and oxidative metabolism and other energy-dependent processes within muscle fibres (Burke et al. 1971) and, presumably, within motor axons. Anaerobic glycolysis causes intracellular acidosis and can secondarily depress fast K+ conductance (Schneider et al. 1993), though this has been demonstrated only under hyperglycaemic conditions.
The present study was undertaken to investigate whether voluntary contraction produces a significant impairment in impulse transmission in normal motor axons and whether mechanisms other than pump-induced membrane hyperpolarization contribute to the changes in axonal excitability. The effects produced by voluntary efforts were compared with those of continuous hyperpolarizing currents. The data suggest that both manoeuvres cause axonal hyperpolarization associated with appropriate changes in axonal excitability at the stimulus site, but voluntary contractions produced additional changes in axonal properties, impairing the refractory period of transmission such that there is transmission failure for the second of a pair of closely spaced impulses.
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METHODS |
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Twenty-one experiments were performed in 11 healthy volunteers, aged 25-55 years (mean age, 35 years). The subjects had no clinical or electrophysiological evidence of a peripheral nerve disorder, and gave informed consent to the study procedures, which had the approval of the Committee on Experimental Procedures Involving Human Subjects, University of New South Wales.
Compound muscle action potentials (CMAPs) were recorded from the abductor pollicis brevis (APB) after median nerve stimulation at the wrist using bipolar self-adhesive surface electrodes (Red-Dot; 3M Canada, London, Ontario, Canada). The reference electrode for nerve stimulation was placed 10 cm proximal to the active electrode over forearm muscles. The amplitude of the CMAP was measured on-line by computer from baseline to negative peak. In 15 experiments subjects performed maximal isometric voluntary contractions against resistance provided by one of the authors. The subjects were encouraged to maintain their effort for 1 min.
Contraction induced changes in axonal excitability
In six subjects, the changes in excitability indices (threshold, refractoriness, supernormality and strength-duration time constant) were measured using the threshold-tracking technique, as previously described (Bostock & Baker, 1988; Bostock et al. 1998; Burke et al. 1998; Grosskreutz et al. 1999). Briefly, a computerized threshold-tracking procedure (QTRAC20, Institute of Neurology, London, UK) was used to follow axonal excitability. The stimulus intensity was adjusted using 'proportional tracking' in order to keep the CMAPs at 70 % of maximum. With proportional tracking, the change in stimulus current was proportional to the error between the recorded response and the target CMAP (70 % of maximum).
Different stimulus combinations were used to allow measurements of threshold, refractoriness and supernormality, and off-line calculation of strength-duration time constant (SD). The stimulus current required to produce the test CMAP (i.e. the threshold for the CMAP) was measured using single stimuli of 0·1 and 1·0 ms duration. From these data, SD was calculated using the Weiss formula (Mogyoros et al. 1996). Axonal excitability during the relatively refractory period and the supernormal period were sampled at conditioning-test intervals of 2 and 7 ms, respectively, using a test stimulus of 0·1 ms duration, preceded by a supramaximal conditioning stimulus. The conditioned CMAP was measured after the response to the supramaximal conditioning stimulus had been subtracted on-line (as in Fig. 4C), because the maximal conditioning CMAP was superimposed on the test CMAP. The 7 ms interval was chosen because supernormal excitability is maximal at this interval (Kiernan et al. 1996).
The above indices of axonal excitability are sensitive to membrane potential (Bostock et al. 1998; Burke et al. 1998). For example, with axonal hyperpolarization, refractoriness decreases and threshold, supernormality and SD increase. The post-contraction increase in threshold indicates the extent by which it was necessary to increase stimulus current to produce the test CMAP. Refractoriness and supernormality were expressed as the increase or the decrease, respectively, in stimulus current below the unconditioned intensity necessary to produce the target CMAP, normalized to the unconditioned test stimulus (i.e. (conditioned threshold - unconditioned threshold)/unconditioned threshold).
In nine subjects, the effects of a voluntary contraction on impulse transmission were studied using supramaximal test stimuli delivered by themselves or following identical conditioning stimuli (see Fig. 4C). To ensure that stimulus intensity was sufficient to produce a maximal CMAP even after voluntary effort or applying hyperpolarizing currents had depressed axonal excitability, two supramaximal stimuli of 0·2 ms duration were used: the intensity of the first stimulus was set well above that required to produce a maximal CMAP, and that of the second stimulus was 20 % stronger than the first (Fig. 4A). If stimuli of different intensity produced potentials of identical amplitude, the CMAPs were considered maximal (Fig. 4B; Kiernan et al. 1999). A pair of supramaximal stimuli was delivered at conditioning-test intervals of 2, 3, 4, 5, 7, 10 and 15 ms, to investigate the time course of any changes in impulse transmission. In addition the amplitude of the CMAP produced by a constant submaximal stimulus, initially producing a CMAP 70 % of maximum, was measured as an indication of the time course of the change in axonal excitability. Accordingly, there were 10 stimulus channels: 1, supramaximal stimulus; 2, supramaximal stimulus (with intensity of 20 % stronger than that of channel 1); 3, submaximal stimulus producing a CMAP 70 % of maximum; 4-10, paired supramaximal stimuli delivered at conditioning-test intervals of 2, 3, 4, 5, 7, 10 and 15 ms.
Effects of hyperpolarization on axonal excitability
In six subjects, the effects of continuous hyperpolarizing currents were studied using a 10 min decreasing current ramp designed to mimic the hyperpolarization that occurs after voluntary contractions. In this artificial hyperpolarization, the maximal intensity of hyperpolarizing currents was set to 10 or 20 % of that required to produce a test CMAP of 70 % maximum using an unconditioned test stimulus of 1·0 ms duration. The intensity of hyperpolarizing currents gradually decreased from this level over 10 min. The relationship between threshold (or 'excitability', which was defined as the reciprocal of threshold) and refractoriness, supernormality or SD was followed before and during the hyperpolarizing current ramp.
Skin temperature, measured near the stimulating site, ranged from 31·8 to 33·2°C (mean, 32·6°C). For each subject, threshold, amplitude or latency data were normalized to the precontraction value. All data are given as means ± S.E.M.
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RESULTS |
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In the experiments below, conclusions about changes in axonal excitability at the site of the stimulus application (i.e. mid-axon) were made by measuring changes in the current required to produce a fixed submaximal CMAP, 70 % of maximum (threshold tracking, Figs 1-3), or by measuring the change in amplitude of a submaximal CMAP produced by a fixed submaximal stimulus (Fig. 5A). To document impairment of impulse transmission, it was necessary to eliminate the effects of these changes in excitability at the site of stimulation and, for such studies, supramaximal stimuli were delivered as single and paired stimuli (Figs 4-6).
Using threshold tracking, a number of excitability indices were measured, all of which should change appropriately with changes in membrane potential at the stimulus site: threshold, refractoriness, supernormality and SD, as described in Methods. Refractoriness was measured during the relatively refractory period, at the 2 ms conditioning- test interval, as the increase in current required to produce the target CMAP. Supernormality was measured during the supernormal period, 7 ms after the conditioning stimulus, as the decrease in current required to produce the target CMAP, and is therefore expressed as a negative value. SD was calculated off-line from the threshold currents for an unconditioned CMAP of 70 % maximum, using test stimuli of 0·1 and 1·0 ms duration. It reflects the rate at which threshold current decreases as the duration of the test stimulus increases.
Changes in axonal excitability produced by voluntary contraction and hyperpolarizing current
In six subjects, the effects of voluntary contraction on threshold, refractoriness, supernormality and SD were studied. Maximal voluntary contraction for 1 min significantly increased the threshold of the active motor axons (Figs 1 and 2), whether tested with stimuli of 0·1 or 1·0 ms duration. The threshold increases were 17 ± 6 % using the 0·1 ms stimuli (P < 0·01; Student's paired t test), and 22 ± 5 % using the 1·0 ms stimuli (P < 0·001). The threshold change was maximal immediately after the maximal contraction, and gradually returned to the precontraction level over 10 min. The increase in threshold following voluntary contractions was associated with an increase in supernormality and a decrease in SD (Figs 1 and 2). The changes in the axonal excitability indices suggest axonal hyperpolarization (Bostock et al. 1998; Burke et al. 1998; Vagg et al. 1998), but there was a paradoxical increase in refractoriness in all six subjects. Refractoriness is sensitive to membrane potential and would be expected to decrease during hyperpolarization (Bostock et al. 1998; Burke et al. 1998; Grosskreutz et al. 1999). Figure 1B shows that there was a prominent increase in refractoriness in a single subject when the conditioning-test stimulus interval was 2 ms. The conditioned threshold increased abruptly and could not be measured for 3 min but then decreased equally abruptly to a level below the precontraction level. The time course is shown in Fig. 2B for each of the six subjects, in one of whom the abrupt change lasted 8-9 min. It can be appreciated that the transient increase in refractoriness was riding on a reduced background level, raising the possibility that a transient phenomenon was superimposed on an underlying decrease in refractoriness. The next study was therefore performed to measure the changes in excitability produced by membrane hyperpolarization.
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 ) and a 10 % continuous hyperpolarizing current ( ) in a single subject
A, threshold changes measured using test stimuli of 1·0 ms duration. B, refractoriness measured using a 0·1 ms test stimulus delivered 2 ms after a supramaximal conditioning stimulus. Note that following voluntary effort (VC in D, applies also to A-C) there was an abrupt increase in the conditioned threshold for 3 min, superimposed on a long-lasting decrease. The dashed line in B indicates the pre-contraction value. C, supernormality measured during the supernormal period using a 0·1 ms test stimulus delivered 7 ms after a supramaximal stimulus. In B and C, the change is expressed as a percentage of the unconditioned threshold. D, | ||
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Figure layout as for Fig. 1. Data have been averaged over consecutive 15 s intervals. A, C and D, means ± S.E.M. for 6 subjects. B, changes in refractoriness for each of the 6 subjects (different symbol for each). The large filled circles represent the mean precontraction refractoriness (± S.E.M.) and mean refractoriness 11 min after the contraction. For each subject the transient post-contraction increase in refractoriness was superimposed on a decrease in refractoriness. | ||
Continuous hyperpolarizing currents were applied to the median nerve at the wrist and had qualitatively similar effects on threshold, supernormality and SD to those produced by voluntary contraction (Figs 2 and 3). Using the 1·0 ms test stimulus, the increase in threshold produced by 10 % hyperpolarizing currents was almost identical to that produced by voluntary contraction (20 ± 2 vs. 22 ± 5 %, respectively), and was associated with appropriate changes in the other excitability indices: a decrease in refractoriness, an increase in supernormality and an increase in SD, all of which would be expected with membrane hyperpolarization. The 20 % hyperpolarizing current increased the 1 ms threshold by 52 ± 2 % and was associated with appropriately greater changes in refractoriness, supernormality and SD.
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Figure layout as for Fig. 1. Means ± S.E.M. for 6 subjects. The intensity of artificial hyperpolarization was maximal (10 % of current required to produce a CMAP that was 50 % of maximum) at 5 min and gradually decreased over 10 min. Data have been averaged over consecutive 15 s intervals. | ||
The similarity in the changes in excitability indices produced by the 10 % hyperpolarizing current and voluntary contraction supports the view that voluntary activity does produce axonal hyperpolarization. However, voluntary contraction was associated with a paradoxical increase in the conditioned threshold when the conditioning-test interval was short (2 ms). This would be explicable if there was failure of transmission of the second impulse of the pair when the conditioning-test interval was short, i.e. that voluntary activity increased the 'refractory period of transmission' (McDonald & Sears, 1970) even though it decreased axonal refractoriness at mid-axonal sites. To determine whether this was the case, a pair of supramaximal stimuli was used in subsequent experiments.
Changes in transmission of volleys produced by single and paired stimuli
In nine subjects, the amplitude of the maximal CMAP was measured before and after voluntary contraction using single stimuli and pairs of stimuli with different conditioning-test intervals. To ensure that stimuli remained truly supramaximal after the contraction, two stimuli of different intensity were delivered to produce identical CMAPs (Fig. 4A). Figure 4 shows the original data for a single subject, for whom contraction-induced changes in the maximal CMAP were greatest. The unconditioned maximal CMAP measured 
6 mV but decreased to 5 mV after the contraction (Fig. 4A). Prior to the contraction, the amplitude of maximal conditioned CMAPs varied with conditioning- test interval, least at 2 ms, recovering to the unconditioned level by 10 ms, and slightly greater than the unconditioned level at 15 ms. These changes in amplitude do not mirror the changes in axonal recovery as reflected in the latency of the same CMAPs (Fig. 5) and are presumably due to dispersion of the compound EMG potential, probably due to changes in the propagation velocity of muscle fibre action potential (Stålberg, 1966; Stålberg & Ekstedt, 1973). Figure 4B and D shows the post-contraction changes in the maximal conditioned CMAP. The conditioned CMAP could not be recorded at the 2 ms interval and, at the 3 ms and 4 ms intervals, it was depressed more than the unconditioned CMAP in Fig. 4A.
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A, changes in amplitude of unconditioned compound muscle action potential (CMAP) recorded from the abductor pollicis brevis in a single subject. To prove that stimulus intensity remained supramaximal after contraction, a second stimulus (stimulus 2) was introduced after the contraction. Stimulus 2 was set 20 % stronger than stimulus 1. B, amplitudes of conditioned CMAPs produced by supramaximal stimuli at conditioning-test intervals of 2-15 ms. C, unconditioned and conditioned CMAPs to supramaximal stimuli before maximal voluntary contraction. Traces are, from top to bottom, maximal CMAP to an unconditioned supramaximal stimulus, CMAP to an even stronger supramaximal stimulus, responses to supramaximal conditioning and test stimuli (interval 2 ms), the CMAP to the conditioned stimulus (determined by subtracting the unconditioned CMAP from the response to the conditioning and test stimulus pair). D, post-contraction changes in the conditioned CMAP (30, 60 and 90 s after the end of the contraction). | ||
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A, latency of the CMAP, measured to half-peak, normalized to the latency of unconditioned response. Pre-contraction data were obtained over 2 min before the contraction, and post-contraction data from 2-4 min after the end of the contraction. B, amplitude of the conditioned CMAP to supramaximal stimuli. Note the recovery of latency is much quicker than that of amplitude. All data points represent means ± S.E.M. for 9 subjects. (The symbols are often larger than the error bars.) | ||
In Fig. 6, the mean data are shown for the nine subjects. The amplitudes of the conditioned CMAPs in B were normalized to the precontraction values. There was, on average, little change in the unconditioned maximal CMAP amplitude (3·8 ± 3·3 %; Fig. 6B, open circles), but the conditioned maximal CMAP was significantly decreased at conditioning-test intervals of 2-4 ms (Fig. 6B; P < 0·0001 for the 2 ms interval, P < 0·001 for 3 ms and P < 0·01 for 4 ms; Student's paired t test). The decreases were maximal immediately after the end of contraction, and returned to the precontraction level in 3 min. The recovery time differed from that of axonal excitability which took over 10 min (Fig. 6A).
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Means ± S.E.M. for 9 subjects. A, amplitude of CMAP elicited by a constant submaximal stimulus which initially produced a CMAP 70 % of maximal. B, amplitudes of the conditioned CMAP produced by supramaximal test stimuli delivered 2, 3 and 4 ms after supramaximal conditioning stimului. In A, amplitude was normalized to that of the maximal CMAP. In B, the conditioned CMAPs were normalized to their pre-contraction values. | ||
Figure 5 illustrates the recovery cycle of axonal excitability based on changes in latency to half peak of the conditioned maximal CMAP (Stys & Ashby, 1992) before and after voluntary effort. Latency was normalized to the unconditioned value and is plotted for the conditioning-test intervals of 2-15 ms, with refractoriness at the 2 ms interval and supernormality from 4 to 15 ms. There was little difference in the curves, presumably because axonal hyperpolarization produced little change in latency. Changes in latency do not always provide an unambiguous indication of axonal excitability (Burke et al. 1995; Bostock et al. 1998), but the data still indicate that recovery of axonal excitability after a conditioning stimulus was probably much more rapid than the recovery of CMAP amplitude (Fig. 5B).
Relationship of supernormality or SD to axonal excitability
Figure 7 shows the relationships of supernormality and SD to axonal excitability measured for the first 10 min after the end of the voluntary contractions, or for first 10 min after the start of continuous hyperpolarizing current for four subjects who were studied in both experiments. The relationships using all six subjects for the two experiments were similar. Excitability was defined as the reciprocal of threshold. There were linear relationships between excitability and supernormality or SD. The relationships were identical for the 10 % and 20 % hyperpolarizing currents apart from the greater change in threshold produced by the latter. The 10 % data are plotted in Fig. 7 because the threshold changes were similar to those produced by the voluntary contraction.
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SD; B)
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For both supernormality and SD the slopes of the relationships with axonal excitability were significantly steeper for the changes produced by voluntary contractions than by continuous hyperpolarizing currents (0·3752 and 0·2551 for A and 0·4575 and 0·3114 for B, respectively; P < 0·0001 for both).
In Fig. 8 the changes in supernormality are plotted against the changes in SD for the two manoeuvres. The relationships were similar. These findings indicate that the differences in these two parameters were proportional, and suggest that there may have been a background difference in membrane potential produced by voluntary contraction and by DC current.
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Relationships between supernormality and | ||
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DISCUSSION |
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The present study has demonstrated that, following maximal voluntary contraction of a normal muscle, the transmission of a pair of closely spaced impulses is impaired sufficiently to cause conduction failure of the second impulse, and suggests that the changes in axonal excitability induced by voluntary contractions are not solely due to changes in membrane potential. Apart from refractoriness, the changes in excitability properties produced by voluntary contractions were qualitatively similar to (but quantitatively different from) those produced by hyperpolarizing currents, indicating that motor axons hyperpolarize during voluntary activity. However, the findings suggest that, besides Na+-K+ pump-induced membrane hyperpolarization, voluntary contractions have additional effects on impulse transmission and axonal excitability.
Refractory period of transmission
Following maximal voluntary contractions, there was, on average, only a small change in the amplitude of the unconditioned maximal CMAP (3·8 %, Fig. 6B). However, the amplitude of the conditioned maximal CMAP was significantly reduced when the conditioning-test interval was short (Figs 4B and 5B). This occurred even though the test stimulus was supramaximal (Fig. 4A) and indicates transmission failure for the second impulse. Conduction block for the test potential can explain the paradoxical increase in threshold of the test CMAPs at the 2 ms conditioning-test interval (Figs 1 and 2). This transmission failure developed following voluntary contraction but not during continuous hyperpolarizing currents delivered to the axons.
For the thenar muscles, the maximal firing rates of motor units are approximately 30 Hz during voluntary contractions (Bellemare et al. 1983), although occasionally they reach 100 Hz (Marsden et al. 1971). Such rates are not sustained, falling to 15 Hz within 1 min (Bigland-Ritchie et al. 1983). Our results confirm that these impulse loads can lead to substantial hyperpolarization of the active axons (Vagg et al. 1998), but it is unlikely that such rates have significant effects on neuromuscular transmission: it has been described that, in sustained maximal voluntary contractions, there is no decline in the potentials of single motor units or the ulnar CMAP (Bigland-Ritchie et al. 1982) and, in agreement with this, there was only a small change in the maximal unconditioned CMAP (Fig. 5B). The refractory periods in patients with myasthenia gravis are normal (Kimura, 1983) suggesting that transmission of two impulses with a short interval are not impaired even if the safety margin for neuromuscular transmission is reduced.
The refractory period of transmission depends not only on refractoriness of the axon at the stimulus site, but also on the ability of the remainder of the nerve to transmit impulses (Bostock et al. 1998). The term, refractory period of transmission (RPT), was coined by McDonald & Sears (1970) when studying the ability of single fibres to transmit pairs of impulses through a focal demyelinated lesion in the dorsal columns of the cat, and was subsequently defined as the maximal interval between two impulses at which there was failure to conduct the second impulse (Smith, 1980; see also Felts et al. 1997). As defined, the RPT will increase when the security of impulse transmission is lowered (Bostock et al. 1998). Accordingly, it is likely that the transmission failure of the second of the pair of impulses occurred distal to the stimulus site. While transmission failure can occur at a number of pre- and post-synaptic sites (Sieck & Prakash, 1995), perhaps even in the muscle fibre itself, we speculate that the relevant site in the present experiments was the terminal axon, possibly at branch points.
The motor nerve terminals have different anatomical and biophysical characteristics from those of the nerve trunk. Each motor axon has several branching points in the preterminal segments, and the safety factor for impulse conduction is physiologically lower at the branching points (Westerfield et al. 1978; Stoney, 1985, 1990) where the driving current needs to activate two nodes of Ranvier. Na+ channels are practically absent from the terminal part of motor nerve endings of mouse, frog and lizard, and active depolarization at the last node of Ranvier invades electrotonically the presynaptic terminal (Brigant & Mallart, 1982; Mallart, 1984, 1985; Lindgren & Moore 1989; see however Konishi & Sears, 1984). In crayfish axons, high-frequency stimulation produces abrupt conduction block after 40-80 stimuli, probably due to failure of invasion of the nerve action potential into the branches of the motor nerve terminal (Parnas, 1972). In addition, the thin unmyelinated portion of the nerve terminal may be more susceptible to metabolic changes such as acidosis and anaerobic glycolysis, associated with the impulse load produced by maximal voluntary contractions.
Voltage-dependent changes in supernormality and SD
This study suggests that the changes in supernormality and SD produced by voluntary contraction are greater than those produced by hyperpolarizing current (Fig. 7). A caveat on this conclusion is that these indices are quite variable within the same subject on different days (Mogyoros et al. 2000), but the differences were still reproducible across subjects, and statistically significant. The greater sensitivity of these indices to axonal excitability suggests that additional mechanisms other than the change in membrane potential are brought into play by activity. This is not surprising. The changes in axonal excitability produced by voluntary activity largely result from activation of the Na+-K+ pump, driven by the extracellular accumulation of K+ ions and intracellular accumulation of Na+ ions. The former, in particular, could be quite relevant.
Activity leads to an extracellular accumulation of K+ in the restricted diffusion space under the myelin sheath, and this could result in local depolarization and the activation of voltage-dependent K+ channels (Brismar, 1981; David et al. 1992, 1993; Kapoor et al. 1993). When the K+ concentration outside the internodal axolemma is elevated so that the transaxonal electrochemical gradient of K+ is reversed, activation of K+ channels can produce a prolonged negative afterpotential (David et al. 1992, 1993), and presumably thereby enhanced supernormality. Markedly enhanced supernormality has actually been demonstrated when human motor axons are tetanized at 300 Hz for up to 30 min (Bostock & Bergmans, 1994). Assuming that the change in potential of the internodal membrane affects nodal properties, such as SD, this mechanism could explain the greater sensitivity of supernormality and SD to excitability following voluntary activity.
Functional implications
Our results show that maximal voluntary contraction causes transmission failure of a pair of impulses in healthy motor axons when the stimulus interval is short (2-4 ms). Given that intervals of 2-4 ms correspond to impulse rates of 250-500 Hz, it is unlikely that conduction failure sufficient to cause motor weakness would occur under natural conditions for healthy axons through this mechanism. However, further impairment of the refractory period of transmission in pathological states could result in significant impairment of motor function. The blood-nerve barrier is anatomically deficient at nerve terminals (Olsson, 1969), and terminals are preferentially involved in immune-mediated demyelinating neuropathy such as Guillain-Barré syndrome (Brown & Snow, 1991). Assessment of the refractory period of transmission could be a sensitive measure of the safety margin for impulse conduction in the distal nerve terminals, if stimulation at 1 Hz fails to reveal impaired conduction in routine clinical electrophysiological testing.
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REFERENCES |
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This study was supported by the National Health and Medical Research Council of Australia, the National Multiple Sclerosis Association of Australia, and Uehara Memorial Foundation (Japan).
Corresponding author
S. Kuwabara: Prince of Wales Medical Research Institute, High Street, Randwick, Sydney, NSW 2031, Australia.
Email: kuwabara{at}med.m.chiba-u.ac.jp
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