Brain, Vol. 123, No. 5, 992-1000,
May 2000
© 2000 Oxford University Press
The effects of a volatile anaesthetic on the excitability of human corticospinal axons
Departments of Clinical Neurophysiology, Anaesthesia and Intensive Care, and Orthopaedics, Prince of Wales Hospital and Sydney Children's Hospital, and Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia
Correspondence to:
Professor David Burke, Prince of Wales Medical Research Institute, High Street, Randwick, NSW, Australia E-mail: d.burke{at}unsw.edu.au
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Abstract |
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The recovery of excitability following a conditioning volley and the strength–duration properties of corticospinal axons were measured in 10 neurologically normal patients in whom corticospinal function was being monitored during scoliosis surgery. Corticospinal volleys were produced using transcranial electrical stimulation of the motor cortex, and recorded from the spinal cord using epidural leads. Administration of a volatile anaesthetic, sevoflurane 2%, increased the threshold current required to produce a submaximal test volley by 35.8% (P = 0.0005), indicating that the anaesthetic depressed the excitability of the site at which the transcranial stimulus activated the corticospinal system. Following a strong transcranial stimulus, axons were relatively refractory for conditioning–test intervals up to ~2.5 ms, and then superexcitable for intervals of >10 ms. In two patients, the time course and extent of refractoriness and superexcitability did not differ when receiving sevoflurane 2% and after its withdrawal. Strength–duration properties were determined by measuring the stimulus current required to produce a submaximal corticospinal volley of fixed amplitude using test stimuli of different duration, from 50 µs to 1 ms. Strength–duration curves were well described by a hyperbolic function, with which there is a linear relationship between stimulus charge and stimulus duration. In the absence of sevoflurane, the strength–duration time constant (
SD) was 432.2 ± 70.5 µs. When sevoflurane 2% was administered to 6 patients, SD decreased to 203.7 ± 93.8 µs, a change that was significant (P = 0.04). The decrease in SD was accompanied by an increase in rheobase. These findings imply that the lowest-threshold component of the corticospinal volley produced by transcranial electrical stimulation probably arises from nodes of Ranvier of corticospinal axons, where it would not be affected by changes in the excitability of cortical neurons. It is suggested that the increase in threshold produced by sevoflurane is due to depression of Na+ currents at the nodes of Ranvier of corticospinal axons. corticospinal axons; axonal excitability; anaesthetics; Na+ channels; transcranial stimulation
SD = strength–duration time constant
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Introduction |
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Using transcranial electrical stimulation, it is possible to excite corticospinal axons directly and, with weak stimuli, the evoked volley is generated at or near the corticospinal neuron (Burke et al., 1990
; Hicks et al., 1992; Rothwell et al., 1994). The excitability of an axon can limit its maximal firing rate, and focal abnormalities of excitability can contribute to both conduction block and ectopic impulse activity. On the one hand, intermittent conduction block could be responsible for some of the fluctuations in the deficit of patients with, for example, multiple sclerosis (McDonald, 1995; Waxman et al., 1995) while, on the other hand, there is evidence that the excitability of corticospinal pathways may be increased in motor neuron disease (Kohara et al., 1996; Eisen et al., 1998). In addition, transcranial stimulation is now being performed using pulse trains in clinical and research studies (Berardelli et al., 1998, 1999; Chen et al., 1998) and for intraoperative monitoring (Jones et al., 1996; Pechstein et al., 1998; Ubags et al., 1998): in such instances, the evoked corticospinal volley transmitted to the spinal motor neuron pool will depend on the ability of the stimulated elements to respond repetitively. However, apart from studies in which the behaviour of corticospinal axons has been inferred from recordings of compound muscle action potentials, there are no data in the literature on the excitability of human corticospinal axons.
In the main, general anaesthetics are thought to operate by interfering with synaptic transmission within the brain, but such agents also have effects on Na+ channels (Berg-Johnsen and Langmoen, 1986; Fujiwara et al., 1988; Frenkel et al., 1993; Urban, 1993; Rehberg et al., 1996). As a result, it should be possible to depress the excitability of corticospinal axons by altering anaesthetic levels. In this respect, the response to direct stimulation of corticospinal axons (the `D' wave) is decreased by volatile anaesthetics when the D wave is liminal, regardless of whether it is produced by transcranial electrical stimulation (Hicks et al., 1992) or magnetic stimulation (Burke et al., 1993). This sensitivity could be due to an anaesthetic effect on axonal excitability, though previously it was interpreted as indicating that the liminal D wave arose at or near the axon hillock and was, thereby, sensitive to changes in excitability of cortical neurons (Hicks et al., 1992; Burke et al., 1993).
The present study was undertaken to measure directly some aspects of axonal excitability for corticospinal axons and to determine whether they were altered by a volatile anaesthetic, sevoflurane. The results indicate that sevoflurane has little effect on some excitability measures but can alter strength–duration behaviour. This could be due to an effect on a conductance active at resting membrane potential, a `threshold' conductance, possibly mediated by persistent Na+ channels.
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Methods |
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Data were gathered during operations to correct scoliosis on 10 neurologically normal adolescents (eight female, two male, aged 8–17 years). The patients and their parents gave informed consent to the procedures, which had the approval of the Research Ethics Committee of the South Eastern Sydney Area Health Service (Eastern Division).
Monitoring technique
In each patient, spinal cord function was monitored intraoperatively by stimulating the motor cortex using transcranial electrical pulses simultaneously with both tibial nerves in the popliteal fossae, much as described previously (Burke et al., 1992). The descending corticospinal volley and the ascending somatosensory volley were recorded at two levels (Fig. 1), using bipolar electrodes inserted into the epidural space and advanced to overlie the cervical and lumbosacral enlargements. The transcranial stimuli were delivered through low-impedance uninsulated spiral needle electrodes inserted into the scalp, initially at an intensity sufficient to produce a simple D wave of maximal amplitude. The descending corticospinal volley reached the low-cervical electrode after 3–4 ms and the low-thoracic electrode some 3–4 ms later, while the ascending somatosensory volley reached the low-thoracic electrode first, at ~12–13 ms. As shown in Fig. 1, the volleys could be distinguished clearly by latency and direction of propagation. However, when the excitability of corticospinal axons was being studied, the peripheral nerve stimulus was turned off, and attention was focused on the upper (cervical) recording electrode, where the D wave was usually larger.
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Anaesthesia
After intubation, the patients were anaesthetized with a 70%/30% nitrous oxide/oxygen mixture, supplemented with fentanyl and midazolam or, in some subjects, propofol, with full muscle relaxation using atracurium or vecuronium. Sevoflurane was introduced as an additional agent in the majority of studies or to replace propofol, and observations were made of its effects when the end-tidal concentration had been stable for 10 min, as measured using a Datex Capnomac Ultima (Datex Instrumentarium, Helsinki, Finland). Excitability measurements were made only when anaesthetic level, temperature, arterial blood pressure, pulse and end-tidal CO2 were stable. It should be noted that the patients remained anaesthetized even after the withdrawal of sevoflurane. The presence of background anaesthetic implies that the present data may not reflect the properties of corticospinal axons in awake subjects.
Recovery cycle
The recovery of excitability of corticospinal axons was measured for 10 ms after a strong conditioning stimulus that produced a maximal or near-maximal simple D wave (as in Fig. 1
), delivered by a Digitimer D185 stimulator (Digitimer, Welwyn Garden City, UK). The paradigm involved an amplitude-based measurement in which changes in excitability produced changes in amplitude of the test volley to a constant submaximal test stimulus. The conditioning and test stimuli were square-wave pulses of duration 50 µs delivered from a constant-voltage source. The test stimulus was delivered by a second D185 stimulator, and its intensity was adjusted so that, when the test stimulus was delivered by itself, the amplitude of the resulting D wave was 30–50% of the response produced by the conditioning stimulus (Fig. 2). The conditioning potentials were ~12–35 µV in different patients and the unconditioned test potentials ~5–15 µV. The conditioning–test interval was varied from 1 ms to 9.9 ms by delaying the stimulus from the second D185. The longest interstimulus interval from the D185 is 9.9 ms, so that intervals that would have sampled late subnormality were not studied. Each recording consisted of an average of 8–10 repetitions using a stimulus repetition rate of once per 3 s. To ensure that conditions had remained stable during the excitability measurements, the unconditioned test potential was measured before and after the recovery cycle and varied by <10%.
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Strength–duration properties
To measure strength–duration properties, square-wave pulses of different duration were delivered from a constant-current source to produce a test D wave, the amplitude of which was usually 5–15 µV, 30–50% of the amplitude of the maximal simple D wave. These stimuli were delivered from a Digitimer DS7A (Digitimer), modified to increase maximal output and to allow 12 different stimulus durations (50, 75, 100, 125, 150, 200, 250, 300, 400, 500, 750 and 1000 µs). The current required to produce a test D wave of the target amplitude was determined by adjusting the stimulus intensity manually, so that initially consecutive single responses were of the desired size, and this was then confirmed for each recording using averages of 8–10 responses. Measurements were made from the averaged responses.
The strength–duration curves for peripheral nerve axons of the rat (Bostock, 1983) and human subjects (Mogyoros et al., 1996) are hyperbolic and follow Weiss' formula, according to which there is a linear relationship between stimulus charge (in µC, equal to the intensity of a stimulus in mA multiplied by its duration in ms) and stimulus duration (Weiss, 1901). The strength–duration time constant (SD) reflects the speed with which threshold current decreases as stimulus duration increases. In Weiss' formulation, it equates to chronaxie and is given by the intercept of the regression line on the duration axis of the charge–duration plot. Rheobase is the threshold current for an infinitely long stimulus and, in Weiss' formulation, it is given by the slope of the regression line. As presented in Results, human corticospinal axons behaved in much the same way as has been seen previously with human peripheral nerve axons (Mogyoros et al., 1996). However, only qualitative statements can be made about rheobase in the present experiments because stimulation was transcranial and the distance to the corticospinal axons and the impedance of scalp, skull and other tissues are likely to be different for different subjects.
The amplitude of the D wave was measured from negative peak to the following positive peak. Data are given as mean ± standard error of the mean and were compared using Student's t-test for paired data. Probabilities are given for two-tailed comparisons.
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Results |
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The recovery cycle was measured for four patients receiving sevoflurane 2%, and in two of the patients these studies were repeated after its withdrawal. Strength–duration curves were measured for all 10 patients when not on sevoflurane, and for six of these the studies were repeated when the patients were receiving sevoflurane 2% (and sometimes lower doses). In three of the six patients, the initial strength–duration measurements were made under sevoflurane, which was then withdrawn. In the remaining three patients, the initial measurements were made before introduction of sevoflurane, and measurements were also obtained after its withdrawal. In all, 24 measurements of strength–duration properties were made in the 10 patients.
Effects of sevoflurane on the threshold for a target D wave
As assessed using unconditioned test stimuli of 0.1 ms duration, sevoflurane increased the threshold for a submaximal D wave (30–50% of maximal) from 112.4 ± 13.2 to 152.7 ± 13.8 mA. The 35.8% increase in threshold was statistically significant (P = 0.0005). These data complement previous findings that volatile anaesthetics (isoflurane and enflurane) can reduce the size of the D wave produced by transcranial stimuli of constant intensity, whether the stimulation is electrical (Hicks et al., 1992) or magnetic (Burke et al., 1993).
Recovery cycle
Figure 2 shows raw data for one patient. In Fig. 2A, the D wave produced by a fixed submaximal stimulus falls within the relatively refractory period at conditioning–test intervals of 1.5 and 2 ms, but for conditioning–test intervals of 3–8 ms it falls within the supernormal period. Supernormal excitability is greatest at 5 ms (Fig. 2B). In Fig. 2B the traces from Fig. 2A are superimposed, and Fig. 2C shows the unconditioned test potential recorded after the sequences in Figs 2A and B.
Figure 3 shows the normalized recovery cycles for four patients. No test potential could be recorded when the conditioning–test interval was 1 ms. The relatively refractory period lasted 2–3 ms, and thereafter corticospinal axons developed supernormal excitability, such that the test D wave to the conditioned stimulus was greater than to the unconditioned stimulus. The amplitude of the conditioned D wave reached 140–190% of the unconditioned D wave at 5–6 ms. Supernormal excitability decayed only slightly (by 9.9 ms). Longer conditioning–test intervals were not studied and, as a consequence, the studies provided no data on the late subnormal period.
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In two patients, studies were performed both with sevoflurane and after its withdrawal (Fig. 4
). In one (female, aged 14 years, square symbols), the intensity of the test stimulus was the same for both measurements. The unconditioned D wave was 15 µV when on sevoflurane and 24 µV after withdrawal. However, when normalized to the amplitude of the unconditioned D wave, the curves on and off sevoflurane were similar (Fig. 4B, square symbols). In the second patient (Fig. 4B, circles), the test stimulus was reduced so that the unconditioned test D waves were of similar size on and off the anaesthetic. Again, the recovery curves were similar. These findings indicate that sevoflurane has little effect on the mechanisms responsible for the recovery cycle (or at least for the first 10 ms thereof).
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Strength–duration properties
The strength–duration data conformed to the hyperbolic function predicted by Weiss (1901) in all 24 measurements, with a linear relationship between threshold charge and stimulus duration, as in Figs 5–7
. The regression coefficients were high, with R2 values ranging from 0.9725 to 0.9980 (mean 0.9922). Using data recorded after the withdrawal of sevoflurane for three patients, SD without sevoflurane was 432.2 ± 70.5 µs for the 10 patients. In two patients, it was confirmed that there was little difference in SD when test D waves of different amplitude were used (Fig. 5), even though rheobase was, of necessity, greater for the larger test D wave. These data suggest that the anaesthesia-induced changes in SD described below cannot be attributed to small differences in the target D waves [and also that the anaesthesia-induced increase in threshold of ~35.8% (see above) was not due to a reduction in stimulus efficacy because of current shunting].
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Sevoflurane decreased
SD and increased rheobase. In three patients, strength–duration properties were measured before, during and after administration of sevoflurane 2% (Fig. 6), and in the other three patients studies were performed during and after withdrawal of sevoflurane 2% (Figs 7A and B). Considering the nine possible comparisons, sevoflurane decreased SD by 226.9 ± 65.0 µs (P = 0.0109). It proved difficult to obtain readings of 0% after withdrawal of sevoflurane, indicating that there was some residual sevoflurane in the system. Accepting this, the values before and after sevoflurane were averaged for each of the six patients to provide a single comparison with the recordings obtained when receiving servoflurane: SD was 203.7 ± 41.0 µs when on sevoflurane 2% and 422.2 ± 93.8 µs when not on it (P = 0.0444).
Dose-dependency was not studied formally, but SD was similar when receiving sevoflurane 1 and 2% (Fig. 7A). Similarly, strength–duration curves were similar with sevoflurane 0.25 and 0.2% (Fig. 7B). These findings suggest that the depressant effect of sevoflurane probably follows a sigmoid relationship with maximal sensitivity at ~0.5–1.0%.
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Discussion |
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This paper documents for the first time aspects of the excitability of human corticospinal axons. Both the recovery of excitability after a conditioning discharge and the strength–duration properties of corticospinal axons are comparable to those of peripheral nerve axons (Ng et al., 1987
; Kiernan et al., 1996; Mogyoros et al., 1996) and, as discussed below, this similarity is consistent with stimulation at nodes of Ranvier of corticospinal axons. Sevoflurane increased axonal threshold and altered strength–duration properties but did not alter the recovery cycle. As discussed below, these findings have implications for the site and mechanisms through which sevoflurane alters axonal threshold, and also for the site of initiation of the D wave in the corticospinal system.
Recovery cycle
Sevoflurane produced no clear change in refractoriness or supernormality. Refractoriness depends largely on the recovery of Na+ channels from inactivation (Hodgkin and Huxley, 1952). Based on in vitro studies (e.g. Rehberg et al., 1996), one might have expected sevoflurane to have increased steady-state Na+ channel inactivation. If this occurred, it was insufficient to alter refractoriness and probably played little role in the sevoflurane-induced threshold increase. In myelinated axons, both peripheral and central, supernormal excitability is due to the passive discharge of current stored on the internodal axolemma, through a low-resistance pathway through or under the myelin sheath (Barrett and Barrett, 1982; Blight and Someya, 1985; Bowe et al., 1987). The extent of supernormality can be altered by mechanisms that alter the status of voltage-dependent K+ channels in the paranodal region (David et al., 1992, 1993, 1995). Blocking paranodal K+ channels increases the resistance of the internodal membrane, thereby increasing the depolarizing afterpotential responsible for supernormal excitability. Similarly, axonal depolarization and hyperpolarization will open and close these K+ channels and, as a result, supernormality varies with membrane potential.
Refractoriness is even more sensitive to changes in membrane potential (Burke et al., 1998): a depolarizing shift will increase the extent of Na+ channel inactivation and a hyperpolarizing shift will decrease it. Accordingly, refractoriness and supernormality can be used as indirect indicators of membrane potential (Bostock et al., 1998).
The lack of an anaesthesia-induced change in the recovery cycle suggests that the increase in axonal threshold was not due to or associated with an increase in Na+ channel inactivation, blockage of paranodal K+ channels, or a direct or indirect change in membrane potential.
Site of action of sevoflurane and site of initiation of the threshold D wave
It has been suggested previously that the depressant effect of volatile anaesthetics might be due to depression of excitability of motoneurons in the motor cortex, on the assumption that the threshold D wave was initiated at the axon hillock and would therefore be sensitive to anaesthetic-induced changes in neuronal excitability (Hicks et al., 1992; Burke et al., 1993). If the depression of cortical excitability was associated with neuronal hyperpolarization due, for example, to withdrawal of background excitation, it would be reasonable to expect sevoflurane to alter the recovery cycle. However, as discussed above, sevoflurane decreases excitability without altering refractoriness or supernormality, findings that would be expected if the site of initiation of the D wave was sufficiently remote from the neuronal cell body that it was not sensitive to changes in motor cortex excitability. Similarly, it would be expected that the excitability properties of the D wave would be similar to those of peripheral nerve axons.
Little is known about axonal excitability at the first heminode of the initial segment. However, it would be reasonable to expect both strength–duration properties (which reflect properties of the exposed nodal membrane) and supernormality (which reflects internodal properties) to differ from those at a mid-axonal site because, at the heminode, much more membrane is exposed and there is only one myelin segment. The similarity of the studied properties to those of peripheral nerve axons argues in favour of D wave initiation at a conventional node of Ranvier. The present findings are therefore consistent with the view of Amassian and colleagues that the threshold D wave arises from nodes of Ranvier in corticospinal axons close to the cell body, and that the action of sevoflurane is probably at nodes of Ranvier (Amassian et al., 1987).
Effects of sevoflurane on Na+ channels and on SD
Volatile anaesthetics, including sevoflurane, have complex effects on Na+ channels, both in peripheral nerves and the brain (Berg-Johnsen and Langmoen, 1986; Fujiwara et al., 1988; Frenkel et al., 1993; Urban, 1993; Rehberg et al., 1996), and these include a reduced peak Na+ current that is not voltage-sensitive and a shift of steady-state Na+ inactivation in the hyperpolarizing direction. The lack of change in refractoriness in the present study provides no evidence for altered Na+ channel inactivation. However, it is possible that the effects on SD result from a block of Na+ currents, particularly those through persistent Na+ channels, at least if the strength–duration behaviour of corticospinal axons results from the same mechanisms as in peripheral nerves.
In peripheral nerves, strength–duration properties are due to passive membrane properties and any conductance that is open at resting membrane potential and can thereby affect threshold behaviour (Bostock and Rothwell, 1997). The likely conductance is a persistent Na+ conductance, i.e. a Na+ channel that has fast kinetics but fails to inactivate (or does so very slowly). Channels with the appropriate properties on neurons within the CNS are well documented (Crill, 1996), and have been identified in rat optic nerve axons (Stys et al., 1993) and rat dorsal root ganglia (Baker and Bostock, 1997, 1998, 1999).
A decrease in SD could result from a hyperpolarizing change in membrane potential or from anaesthetic blockage of Na+ channels. The slope of the relationship between SD and axonal excitability is low for peripheral nerve axons (Burke et al., 1998). If there is a similar relationship for corticospinal axons, there would need to be a very large hyperpolarizing change in excitability to explain the reduction in SD. Such a change would have produced large changes in refractoriness and supernormality, and the absence of an appropriate change in these indicators of membrane potential is therefore pertinent. On the other hand, volatile anaesthetics can block Na+ currents in clinically relevant concentrations, and this remains the most parsimonious explanation for the present findings.
We conclude that the increase in threshold for the D wave probably results from suppression by sevoflurane of Na+ currents, particularly those associated with persistent Na+ channels, at nodes of Ranvier of corticospinal axons.
Implications for the clinical use of trains of transcranial stimuli
The present data indicate that the corticospinal volleys produced by each shock in a train of transcranial stimuli will not be identical. The study has documented this for the D wave but the situation is likely to be similar for I waves (though the time course of the excitability changes in axons of corticocortical interneurons probably differs from that seen in the present study).
The present data also indicate that less electrical energy (i.e. charge) is delivered to the patient if pulses are of brief duration. Despite the higher stimulus intensity, the patient is subjected to less electrical energy the shorter the pulse, and this has implications when monitoring corticospinal function intraoperatively using transcranial electrical stimuli. This does not imply that long stimulus durations are less safe than short durations; nevertheless, stimulus duration should be a consideration when setting up an intraoperative monitoring service.
It has been suggested recently that there is greater expression of persistent Na+ channels on motor axons in the peripheral nerves of patients with amyotrophic lateral sclerosis (Mogyoros et al., 1998). Greater expression of this conductance on corticospinal axons could contribute to motor hyperexcitability and possibly to fasciculation of central origin (Kohara et al., 1996; Eisen et al., 1998). The present techniques might allow this possibility to be explored directly when such patients undergo surgery.
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Acknowledgments |
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The authors thank Mr John R. Smale (Digitimer Ltd) for the loan of specially modified equipment for these studies. These studies were supported by the National Health & Medical Research Council of Australia.
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Received September 17, 1999. Revised November 24, 1999. Accepted December 1, 1999.
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 V D. Lazzaro, A Oliviero, P Profice, M Meglio, B Cioni, P Tonali, and J C Rothwell Descending spinal cord volleys evoked by transcranial magnetic and electrical stimulation of the motor cortex leg area in conscious humans J. Physiol., December 15, 2001; 537(3): 1047 - 1058. [Abstract] [Full Text] [PDF]
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 C. B. Dobson, F. Villagra, G. J. Clowry, M. Smith, S. Kenwrick, D. Donnai, S. Miller, and J. A. Eyre Abnormal corticospinal function but normal axonal guidance in human L1CAM mutations Brain, December 1, 2001; 124(12): 2393 - 2406. [Abstract] [Full Text] [PDF]
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T. D Sanger, R. R Garg, and R. Chen Interactions between two different inhibitory systems in the human motor cortex J. Physiol., January 15, 2001; 530(2): 307 - 317. [Abstract] [Full Text] [PDF]
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