ReviewExcitability of human axons
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.
References (78)
Axonal flip-flops and oscillators
Trends Neurosci
(2000)Computer simulation of action potentials and afterpotentials in mammalian myelinated axons: the case for a lower resistance myelin sheath
Neuroscience
(1985)- et al.
Evidence for two types of potassium channel in human motor axons in vivo
Brain Res
(1988) - et al.
The association of the supernormal period and the depolarizing afterpotential in myelinated frog and rat sciatic nerve
Neuroscience
(1987) - et al.
Nomenclature of voltage-gated sodium channels
Neuron
(2000) - et al.
Strength-duration properties and their voltage dependence at different sites along the median nerve
Clin Neurophysiol
(1999) - et al.
Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns
Pain
(1984) - et al.
Microelectrode recordings from transected nerves in amputees with phantom limb pain
Neurosci Lett
(1981) - et al.
The time constants of motor and sensory peripheral nerve fibers measured with the method of latent addition
Electroenceph clin Neurophysiol
(1994) - et al.
Is resistance to ischaemia of motor axons in diabetic subjects due to membrane depolarization?
J Neurol Sci
(1990)
Threshold tracking provides a rapid indication of ischaemic resistance in motor axons of diabetic subjects
Electroenceph clin Neurophysiol
Changes in excitability of human cutaneous afferents following prolonged high-frequency stimulation
Brain
Depolarization changes the mechanism of accommodation in rat and human motor axons
J Physiol (Lond)
Low-threshold, persistent sodium current in rat large dorsal root ganglion neurons in culture
J Neurophysiol
Inactivation of macroscopic late Na+ current and characteristics of unitary late Na+ currents in sensory neurons
J Neurophysiol
Function and distribution of 3 types of rectifying channel in rat spinal root myelinated axons
J Physiol (Lond)
Intracellular recording from vertebrate myelinated axons: mechanism of depolarizing afterpotential
J Physiol (Lond)
The physiology of single human nerve fibres
Post-tetanic excitability changes and ectopic discharges in a human motor axon
Brain
Activity-dependent excitability changes in normal and demyelinated rat spinal root axons
J Physiol (Lond)
Latent addition in motor and sensory fibres of human peripheral nerve
J Physiol (Lond)
Changes in excitability and accommodation of human motor axons following brief periods of ischaemia
J Physiol (Lond)
Changes in excitability of human motor axons underlying post-ischaemic fasciculations: evidence for two stable states
J Physiol (Lond)
Differences in behaviour of sensory and motor axons following release of ischaemia
Brain
Axonal ion channel dysfunction in amyotrophic lateral sclerosis
Brain
Threshold tracking techniques in the study of human peripheral nerve
Muscle Nerve
Susceptibility to conduction block: differences in the biophysical properties of cutaneous afferents and motor axons
Quantitative description of the voltage dependence of axonal excitability in human cutaneous afferents
Brain
Sodium channel Na(v)1.6 is localized at nodes of Ranvier, dendrites, and synapses
Proc Natl Acad Sci USA
Activity-dependent hyperpolarization and conduction block in chronic inflammatory demyelinating polyneuropathy
Ann Neurol
Evidence that action potentials activate an internodal potassium conductance in lizard myelinated axons
J Physiol (Lond)
Electrical and morphological factors influencing the depolarizing after-potential in rat and lizard myelinated axons
J Physiol (Lond)
Changes in nerve potentials produced by rapidly repeated stimuli and their relation to the responsiveness of nerve to stimulation
Am J Physiol
Diversity of mammalian voltage-gated sodium channels
Ann N Y Acad Sci
Changes in excitability indices of cutaneous afferents produced by ischaemia in human subjects
J Physiol (Lond)
Ischaemic changes in refractoriness of human cutaneous afferents under threshold-clamp conditions
J Physiol (Lond)
Clinical phase I study of Paclitaxel followed by Cisplatin in advanced head and neck squamous cell carcinoma
Semin Oncol
A quantitative description of membrane current as its application to conduction and excitation in nerve
J Physiol (Lond)
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