Conventional electrophysiological tests of nerve function focus on the number of conducting fibers and their conduction velocity. These tests are sensitive to the integrity of the myelin sheath, but provide little information about the axonal membrane. Threshold tracking techniques, in contrast, test nerve excitability, which depends on the membrane properties of the axons at the site of stimulation. These methods are sensitive to membrane potential, and to changes in membrane potential caused by activation of ion channels and electrogenic ion pumps, including those under the myelin sheath. This review describes the range of threshold tracking techniques that have been developed for the study of human nerves in vivo: resting threshold is compared with the threshold altered by a change in environment (e.g., ischemia), by a preceding single impulse (e.g., refractoriness, superexcitability) or impulse train, or by a subthreshold current (e.g., threshold electrotonus). Few clinical studies have been reported so far, mainly in diabetic neuropathy and motor neuron disease. Threshold measurements seem well suited for studies of metabolic and toxic neuropathies but insensitive to demyelination. Until suitable equipment becomes more widely available, their full potential is unlikely to be realized.

Threshold tracking techniques in the study of human peripheral nerve.

Excitability of human axons.

Multiple nerve excitability measurements have been proposed for clinical testing of nerve function, since excitability measures can provide evidence of altered axonal membrane properties and are complementary to conventional nerve conduction studies. An important determinant of excitability is membrane potential, and this study was undertaken to determine the changes in a range of excitability properties associated with alterations in membrane potential. Membrane potential was varied directly using DC polarizing currents and indirectly by ischaemia. The median nerve was stimulated at the wrist and the resultant compound muscle action potentials recorded from abductor pollicis brevis. Stimulus-response behaviour, strength-duration time constant (tau(SD)), threshold electrotonus to 100-ms polarizing currents, a current-threshold relationship and the recovery of excitability following supramaximal activation were each followed in four normal subjects during the two manoeuvres, using a recently described protocol. Membrane depolarization and ischaemia produced an increase in axonal excitability, an increase in the slope of the current-threshold relationship, a 'fanning in' of responses during threshold electrotonus, a decrease in super-excitability, and increases in both tau(SD) and the refractory period. Changes in the opposite direction occurred with membrane hyperpolarization and during the post-ischaemic period. One excitability parameter differentiated between the direct and indirect changes in membrane potential: late subexcitability was sensitive to polarizing currents but relatively insensitive to ischaemia, probably because of compensatory changes in extracellular potassium ions. These results should enable multiple excitability measurements to be used as a tool to identify changes in axonal membrane potential in neuropathy.

Effects of membrane polarization and ischaemia on the excitability properties of human motor axons

Mutations that reduce the function of KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. These channels are present in nodes of Ranvier in rat brain and nerve and have been proposed to mediate the slow nodal potassium current I(Ks). We have used immunocytochemistry, electrophysiology and pharmacology to test this hypothesis and to determine the contribution of KCNQ channels to nerve excitability in the rat. When myelinated nerve fibres of the sciatic nerve were examined by immunofluorescence microscopy using antibodies against KCNQ2 and KCNQ3, all nodes showed strong immunoreactivity for KCNQ2. The nodes of about half the small and intermediate sized fibres showed labelling for both KCNQ2 and KCNQ3, but nodes of large fibres were labelled by KCNQ2 antibodies only. In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 (IC50 = 2.2 microm) and linopirdine (IC50 = 5.5 microm) completely inhibited I(Ks), as did TEA (IC50 = 0.22 mm). The KCNQ channel opener retigabine (10 microm) shifted the activation curve to more negative membrane potentials by -24 mV, thereby increasing I(Ks). In isotonic KCl 50% of I(Ks) was activated at -62 mV. The activation curve shifted to more positive potentials as [K+]o was reduced, so that the pharmacological and biophysical properties of I(Ks) were consistent with those of heterologously expressed homomeric KCNQ2 channels. The ability of XE991 to selectively block I(Ks) was further exploited to study I(Ks) function in vivo. In anaesthetized rats, the excitability of tail motor axons was indicated by the stimulus current required to elicit a 40% of maximal compound muscle action potential. XE991 (2.5 mg kg(-1) i.p.) eliminated all nerve excitability functions previously attributed to I(Ks): accommodation to 100 ms subthreshold depolarizing currents, the post-depolarization undershoot in excitability, and the late subexcitability after a single impulse or short trains of impulses. Due to reduced spike-frequency adaptation after XE991 treatment, 100 ms suprathreshold current injections generated long trains of action potentials. We conclude that the nodal I(Ks) current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2006.106815

KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier.

Neuropathy is a common complication of end-stage kidney disease (ESKD), typically presenting as a distal symmetrical process with greater lower-limb than upper-limb involvement. The condition is of insidious onset, progressing over months. and has been estimated to be present in 60%-100% of patients on dialysis. Neuropathy generally only develops at glomerular filtration rates of less than 12 ml/min. The most frequent clinical features reflect large-fiber involvement, with paresthesias, reduction in deep tendon reflexes, impaired vibration sense, muscle wasting, and weakness. Nerve conduction studies demonstrate findings consistent with a generalized neuropathy of the axonal type. Patients may also develop autonomic features, with postural hypotension, impaired sweating, diarrhea, constipation, or impotence. The development of uremic neuropathy has been related previously to the retention of neurotoxic molecules in the middle molecular range, although this hypothesis lacked formal proof. Studies utilizing novel axonal excitability techniques have recently shed further light on the pathophysiology of this condition. Nerves of uremic patients have been shown to exist in a chronically depolarized state prior to dialysis, with subsequent improvement and normalization of resting membrane potential after dialysis. The degree of depolarization correlates with serum K(+), suggesting that chronic hyperkalemic depolarization plays an important role in the development of nerve dysfunction in ESKD. These recent findings suggest that maintenance of serum K(+) within normal limits between periods of dialysis, rather than simple avoidance of hyperkalemia, is likely to reduce the incidence and severity of uremic neuropathy.

Uremic neuropathy: clinical features and new pathophysiological insights.

1. We have previously studied accommodation in rat and human motor axons by testing excitability with combinations of long and short current pulses. We found that normally polarized axons accommodate slowly and partially (over about 50 ms) to subthreshold depolarizing currents, and that the principal mechanism is the activation of slow potassium channels (Bostock & Baker, 1988). To understand the response of human nerves to ischaemia, we have now extended these observations to axons already depolarized before the testing currents were applied. 2. Rat ventral root axons were depolarized by passing continuous currents or by raising the extracellular potassium concentration. Human forearm nerves were depolarized by ischaemia, induced by inflating a sphygmomanometer cuff on the upper arm. Depolarized rat and human motor axons accommodated much more rapidly and completely than normally polarized axons (e.g. accommodation in rat axons was 50% complete within 2 ms at about 15 mV depolarized to rest). 3. The fast component of accommodation in depolarized rat fibres was not blocked by tetraethylammonium ions or 4-aminopyridine, was not accompanied by a conductance or potential change, and had a time constant of 1.7 ms at 30 degrees C. It was attributed to inactivation of closed sodium channels. 4. In depolarized rat fibres exhibiting fast accommodation, a brief rise in excitability was seen at the break of an anodal current. Our prediction that human motor axons would show anode-break excitation during ischaemia was readily confirmed. 5. The results are discussed in relation to Hill's (1936) mathematical description of accommodation in nerve, and it is concluded that his description is only applicable to depolarized axons.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1989.sp017589

Depolarization changes the mechanism of accommodation in rat and human motor axons.

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Depolarization changes the mechanism of accommodation in rat and human motor axons.