Elsevier

Clinical Neurophysiology

Volume 112, Issue 9, September 2001, Pages 1575-1585
Clinical Neurophysiology

Review
Excitability of human axons

https://doi.org/10.1016/S1388-2457(01)00595-8Get rights and content

Abstract

The excitability of human axons can be studied reliably using the technique of threshold tracking, which allows the strength of a test stimulus to be adjusted by computer to activate a defined fraction of the maximal nerve or muscle action potential. The stimulus current that just evokes the target response is considered the ‘threshold’ for that response. More useful than the resting threshold are other indices of axonal excitability derived from pairs of threshold measurements, such as refractoriness, supernormality, strength-duration time constant and ‘threshold electrotonus’ (i.e. the changes in threshold produced by long-lasting depolarizing or hyperpolarizing current pulses). Each of these measurements depends on membrane potential and on other biophysical properties of the axons. Together they can provide new information about the pathophysiology underlying abnormalities in excitability in neuropathy.

Introduction

When axons are diseased or damaged, disturbed axonal excitability may result in the inability to maintain conduction of a meaningful impulse train (Bostock and Grafe, 1985, Burke et al., 1997, Inglis et al., 1998, Cappelen-Smith et al., 2000, Kaji et al., 2000). Alternatively ectopic activity may develop at a focus of hyperexcitability leading to symptoms of paraesthesiae, or pain or fasciculation (Lance et al., 1979, Ochoa and Torebjörk, 1980, Nyström and Hagbarth, 1981, Culp and Ochoa, 1980, Nordin et al., 1984, Waxman et al., 1999, Mogyoros et al., 2000). The abnormalities of axonal excitability that underlie conduction block and ectopic impulse activity are not adequately explored by routine nerve conduction studies. In routine diagnostic studies, only latency or conduction velocity can be measured accurately but, while such measurements may be very useful in defining pathology, they provide little insight into underlying disease mechanisms because a number of morphological and functional changes can prolong latency (Table 1). Increasingly the technique of ‘threshold tracking’ is being used in research and clinical studies on large myelinated axons (Bostock et al., 1998, Kiernan et al., 2000), and Table 2 lists some of the neuropathic disturbances that have been so studied. This paper reviews some of the determinants of the excitability of large myelinated axons and the mechanisms underlying the excitability properties that can be studied in vivo in human subjects.

Section snippets

Threshold tracking methods

The electrical excitability of an axon is defined by the threshold current that just excites it. Threshold determination is a trial-and-error process, and best achieved using a computer to control the output of a current source, depending on the response of the axon or group of axons stimulated. The interested reader is referred to a recent review of ‘threshold tracking’ for a detailed discussion of the technique (Bostock et al., 1998). For single axons, ‘threshold’ is estimated as the stimulus

Axonal excitability depends on nodal and internodal ion channels

The action potential of human myelinated axons can be modelled successfully using only the properties of transient Na+ channels (Schwarz et al., 1995). Other channels are activated during and after the action potential. Some contribute to resting membrane potential and thereby determine the threshold for action potential generation. Ion channels are not evenly distributed along a myelinated axon (Fig. 1). The density of Na+ channels at the node of Ranvier is ∼30 times the density on the

The internode is not isolated and its properties set the resting membrane potential

Changes in potential of the node spread to the internode, but slowly because of the resistance of the myelin sheath and the large capacitance of the internodal axolemma. This results in slow activation/deactivation of voltage-dependent channels on the internodal membrane. Although Na+ channel density is insufficient for the internodal membrane to generate an action potential, the changes in resistance of the internodal membrane and in the current stored on it will affect the behaviour of the

Some internodal conductances can be studied using ‘threshold electrotonus’

The technique that provides most insight into internodal conductances in human subjects in vivo is ‘threshold electrotonus’ (Bostock and Baker, 1988). This term was coined for the changes in threshold produced by long-lasting DC pulses (Fig. 2), because under most circumstances, the changes in threshold largely parallel the underlying electrotonic changes in membrane potential. Conventionally, threshold electrotonus is plotted such that an increase in excitability (i.e. a threshold reduction)

Excitability fluctuates after an action potential

Following an action potential, large myelinated axons are absolutely refractory for 0.5–1.0 ms, during which they cannot generate another action potential no matter how strong the depolarizing stimulus. The axons are then relatively refractory for some 3–4 ms, during which a stronger than normal depolarizing stimulus is required to generate an action potential. As refractoriness subsides, axons pass into a phase of supernormality (or superexcitability) during which the stimulus necessary to

Excitability properties reflect membrane potential

It is not possible to measure membrane potential in intact human axons, but it is possible to obtain indirect evidence about membrane potential by studying excitability indices that are dependent on membrane potential. Each of the indices below can be altered by factors other than membrane potential, but it is a reasonable conclusion that membrane potential is different when these indices undergo changes in the appropriate direction and by the appropriate extent.

Axons are not identical

The sensitivity of an axon to stresses such as ischaemia differs along the course of the axon (Bostock et al., 1991a) but few biophysical differences have been identified so far at different sites along the same nerve (Mogyoros et al., 1999, Kuwabara et al., 2000). However, there is good evidence for subtle biophysical differences between axons of different modality, perhaps because their discharge rates and discharge patterns differ.

Conducting trains of impulses alters axonal excitability

As illustrated in Fig. 3, the generation of an action potential at the node of Ranvier sets up a sequence of oscillating changes in membrane potential which, following a single action potential, are commonly referred to as the recovery cycle. Trains of impulses result in summation of these effects, compensatory mechanisms to correct the altered distribution Na+ and K+ ions on either side of the membrane (e.g. activation of the Na+/K+ pump) and the secondary effects of processes designed to

Of what clinical value are measurements of axonal excitability?

As a clinical tool, measurements of axonal excitability are still in their infancy, the physiological and technical factors that can affect the measurements are being explored, clinically useful protocols are being developed, and their variability in normal subjects is being assessed. To be useful clinically, testing should assess multiple indices relatively quickly, so that the procedures can be used, when appropriate, to supplement conventional nerve conduction studies. This rationale

Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia. MCK was recipient of a C.J. Martin/R.G. Menzies Travelling Fellowship of the National Health and Medical Research Council of Australia.

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