Showing papers by "David Burke published in 2000"

Multiple measures of axonal excitability: A new approach in clinical testing

Abstract: From measurements of nerve excitability and the changes in excitability produced by nerve impulses and conditioning currents, it is possible to infer information about the membrane potential and biophysical properties of peripheral axons. Such information cannot be obtained from conventional nerve conduction studies. This article describes a new method that enables several such measurements to be made on a motor nerve quickly and reproducibly, with minimal operator intervention. The protocol measures stimulus-response behavior using two stimulus durations (from which the distribution of strength-duration time constants can be estimated), threshold electrotonus to 100-ms polarizing currents, a current-threshold relationship (indicating inward and outward rectification), and the recovery of excitability following supramaximal activation. The method was tested on 30 healthy volunteers, stimulating the median nerve at the wrist and recording from the abductor pollicis brevis. The results were comparable with previously published normal data, but the recordings took less than 10 min. The convenience and brevity of the new method make it appropriate for routine clinical use.

Activity-dependent hyperpolarization and conduction block in chronic inflammatory demyelinating polyneuropathy.

Abstract: Voluntary activity produces activity-dependent hyperpolarization of the active motor axons. The present study investigated whether this hyperpolarization produces conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP). Studies were performed in 10 healthy control subjects, 7 patients with CIDP, and 3 patients with multifocal motor neuropathy. The compound muscle action potential (CMAP) of the abductor pollicis brevis was recorded in response to supramaximal stimuli to the median nerve at the wrist, alternating with measurements of axonal excitability. After a maximal voluntary contraction for 60 seconds, the amplitude of the maximal CMAP was significantly reduced in symptomatic CIDP patients by 40%, but there were only slight changes in the CMAPs of healthy controls, asymptomatic CIDP patients, and multifocal motor neuropathy patients. In symptomatic CIDP patients, the activity-dependent conduction block paralleled the activity-dependent hyperpolarization and was presumably precipitated by it. In these patients, the safety margin for impulse conduction was estimated to be about 12%. Activity-dependent conduction block may be clinically important in chronic demyelinating diseases and can be demonstrated electrophysiologically if testing occurs across pathological sites.

Excitability properties of median and peroneal motor axons.

Abstract: Threshold tracking was used to compare excitability properties (stimulus–response curves, strength–duration properties, recovery cycle, and threshold electrotonus) of median motor axons at the wrist and peroneal motor axons at the ankle in 12 healthy subjects. Stimulus–response curves and strength–duration properties were similar, though higher stimulus intensities were required for peroneal axons. However, there were significant differences in the recovery cycle of excitability following a conditioning stimulus and in threshold electrotonus. In the recovery cycle, median axons had significantly greater supernormality and late subnormality. In threshold electrotonus, the initial slow threshold changes in response to subthreshold depolarizing and hyperpolarizing currents (S1) were significantly greater in median axons, and there was also greater accommodation to depolarizing currents (S2) and greater threshold undershoot after depolarization. Similar differences in supernormality and the S1 phase of threshold electrotonus were found between peroneal axons at ankle and knee, suggesting that these properties may be dependent on nerve length. When median motor axons at the wrist were compared with peroneal motor axons at the knee, there were no differences in refractoriness and supernormality and only small differences in S1, but the late subnormality and undershoot were significantly greater in the median axons. These findings suggest that, in addition to any length-dependent differences, peroneal axons have a less prominent slow K+ conductance. We conclude that the properties of different motor axons are not identical and their responses to injury or disease may therefore differ. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1365–1373, 2000.

The effects of a volatile anaesthetic on the excitability of human corticospinal axons

Abstract: 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 (τSD) was 432.2 ± 70.5 μs. When sevoflurane 2% was administered to 6 patients, τSD decreased to 203.7 ± 93.8 μs, a change that was significant ( P = 0.04). The decrease in τSD 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.

Accommodation to depolarizing and hyperpolarizing currents in cutaneous afferents of the human median and sural nerves.

Abstract: A previous study presented evidence that nodal slow K+ conductances are expressed less on cutaneous afferents in the sural nerve than on cutaneous afferents in the median nerve (Lin et al. 2000). The density of slow K+ channels at the node of Ranvier is some 25 times that in the internode but there is much more internodal membrane than nodal, such that the absolute number of slow K+ channels is much greater on the internodal membrane. Their kinetics are such that they probably contribute little to the repolarization after an action potential, but they can produce accommodation to maintained depolarizing stimuli and, thereby, spike-frequency adaptation (Bostock, 1995). The only method with which to examine the behaviour of internodal conductances in human subjects is threshold electrotonus (Bostock & Baker, 1988; Bostock et al. 1998), in which the threshold changes produced by prolonged subthreshold depolarizing or hyperpolarizing currents are measured. The threshold changes generally parallel the electrotonic potentials responsible for them, hence the term ‘threshold electrotonus’. Because externally applied currents have a greater effect on large diameter than on small diameter axons, threshold electrotonus studies properties of primarily the larger axons in the nerve. In threshold electrotonus studies, activation of the slow K+ conductance is probably the major factor producing accommodation to prolonged depolarizing currents (Bostock, 1995; Bostock et al. 1998). However, it is not the only internodally located conductance that can be investigated using threshold electrotonus. Inward rectification is activated by hyperpolarizing currents and acts to limit the degree of hyperpolarization, its biological role probably being to offset the activity-dependent hyperpolarization that occurs when axons conduct impulse trains (Pape, 1996). In the human median nerve, inward rectification is expressed more on sensory axons than on motor axons, such that motor axons undergo greater hyperpolarization following release of ischaemia (Bostock et al. 1994) and following repetitive activity (Vagg et al. 1998). This and other biophysical differences between sensory and motor axons can explain differences in susceptibility to conduction block in demyelinating neuropathies (Kaji et al. 2000; Cappelen-Smith et al. 2000). The present study was undertaken using threshold electrotonus to explore whether there are differences between cutaneous afferents in the median and sural nerves in these two predominantly internodal conductances: a slow K+ conductance, responsible for accommodation to depolarizing stimuli, and inward rectification, responsible for accommodation to hyperpolarizing stimuli. The data indicate that the two nerves respond differently to prolonged subthreshold currents but that when this factor is taken into account differences still exist, suggesting that both accommodating conductances are expressed less on sural afferents than on median afferents. Accordingly, it would be expected that afferents in the upper and lower limbs respond differently to stress.

Recovery of excitability of cutaneous afferents in the median and sural nerves following activity

Abstract: In acquired polyneuropathies, symptoms and signs are typically distal and symmetrical, more prominent in the lower limbs than the upper limbs. This study was undertaken to measure the extent of the decrease in excitability produced by single impulses and by impulse trains in cutaneous afferents in the median and sural nerves, and to compare the resulting changes in excitability of these afferents. Threshold tracking was used in 10 healthy subjects to measure the changes in threshold for a compound sensory action potential of 50% maximum produced by conditioning stimuli. Following a single supramaximal conditioning stimulus, the threshold changes occurring during the refractory and supernormal periods were identical for the two nerves, but there was a greater increase in threshold during the late subnormal period for median afferents. Following a train of 10 supramaximal conditioning stimuli, threshold increased by approximately 40% for median afferents and by approximately 20% for sural afferents. These differences are consistent with differences in a slow K(+) conductance. It is suggested that the hypo-excitability produced by brief trains of impulses may be sufficient to disturb conduction in diseased nerve fibers, and that the lesser expression of slow K(+) conductances on cutaneous afferents in the sural nerve could render them more sensitive to depolarizing stresses than median afferents. This could be a factor in the ease with which sural afferents become ectopically active in polyneuropathies.

Strength-duration properties and their voltage dependence as measures of a threshold conductance at the node of Ranvier of single motor axons.

Abstract: In a number of clinical studies, measurement of axonal strength-duration properties has been used to provide indirect insight into conductances at the node of Ranvier, particularly persistent Na(+) conductance. However, the specificity of any changes is limited because other factors can affect strength-duration behavior. The present study was undertaken to define the relationship between different strength-duration measures at rest and at different membrane potentials, and also to determine the limits within which strength-duration behavior can be used as a measure of nodal conductances. The strength-duration time constant (tau(SD)) and rheobase of 20 single motor units in the flexor carpi ulnaris were calculated from thresholds defined using threshold tracking. "True" rheobase and rheobasic latencies were measured using test stimuli of 100-ms duration. For ten units, the technique of latent addition was used to measure threshold changes directly attributable to nodal conductances, and for six units these were compared with strength-duration properties at different membrane potentials. The data indicate that measurements of tau(SD) and rheobase can provide sensitive indicators of conductances present at the node of Ranvier when membrane potential changes. There is a reciprocal relationship between tau(SD) and rheobase for single motor units at different membrane potentials, and this relationship may allow changes in tau(SD) due to depolarization and demyelination to be differentiated.

Ischaemic changes in refractoriness of human cutaneous afferents under threshold‐clamp conditions

Abstract: Peripheral nerves are commonly subjected to ischaemic insults. The physiological consequences of ischaemic insults and their underlying mechanisms have been the subject of recent investigations in human subjects using threshold-tracking techniques (Bostock et al. 1991a,b, 1994; Mogyoros et al. 1997). During ischaemia, axons depolarize and their excitability increases until conduction block ensues, when they become inexcitable. As axonal excitability increases, there are changes in other properties consistent with axonal depolarization: refractoriness increases, supernormal excitability decreases, and the strength-duration time constant (τSD) increases. Axons hyperpolarize on release of ischaemia but, paradoxically, may develop quite intense ectopic activity, such that subjects experience strong paraesthesiae and fasciculations (Bostock et al. 1991a,b, 1994). Some of the changes in nerve excitability produced by ischaemia and its release can be adequately reproduced by injecting polarizing current to depolarize or hyperpolarize axons (Bostock et al. 1991a, 1998; Horn et al. 1996). However, ischaemia has effects on refractoriness that cannot be explained merely by the change in membrane potential, while the release of ischaemia has effects on supernormality that are similarly difficult to explain (Grosskreutz et al. 1999). Specifically, during ischaemia there was a disproportionate increase in refractoriness that was dependent on the duration of ischaemia, and was interpreted as the result of interference with the processes underlying refractoriness (presumably recovery of Na+ channels from inactivation) by an accumulating metabolite produced by ischaemia. On release of ischaemia, supernormality was disproportionately enhanced and less responsive to induced changes in axonal excitability, as if paranodal K+ channels (the activity of which influences the extent of supernormal excitability; see Baker et al. 1987; David et al. 1995) were blocked. In the present study, a technique was developed to control the excitability of human axons, the intention being to keep axonal excitability at the pre-ischaemic control level so that the typical ischaemic and post-ischaemic changes in threshold would not occur. Measurements of other indices of axonal excitability were then undertaken during intermittent threshold compensation or continuous threshold clamp to see whether the ischaemic changes in these indices were similarly controlled. A threshold-clamp technique has previously been used by Bostock & Grafe (1985) to counteract the hyperpolarization and, thereby, conduction block that resulted when acutely demyelinated rat ventral root axons were activated repetitively. However, such a technique has not previously been used in human subjects.