Physiological differences in excitability among human axons

The main role of axons is to transmit nerve impulse securely, and nerve conduction velocities measured in the same segments are similar among upper or lower limb nerves in routine nerve conduction studies. However, excitability properties of different axons are not identical. The properties of axons are determined by a number of factors (Burke et al., 2001). First, anatomical factors such as axonal size and internodal length largely affect the properties. Compared with proximal or intermediate axons along the nerve, distal axons have the shorter internodes that lead to greater axonal resistance (referred as the Barrett–Barrett resistance; Barrett and Barrett, 1982) and to other changes in passive membrane properties such as smaller nodal area and thinner myelin. Second, there are substantial differences in excitability properties between motor and sensory axons in human nerves. Large myelinated sensory axons have a greater persistent sodium current and inward rectification than alpha-motor axons (Bostock et al., 1998). Because of these modality-dependent differences, ectopic activity occurs more easily with cutaneous afferents, and indeed peripheral neuropathy produces paresthesias much more readily than fasciculation or muscle cramp. Finally, there is evidence that axonal excitability properties are adapted to the pattern and extent of impulse traffic normally carried by the corresponding axons. There are differences in excitability between sensory axons innervating different skin regions; median sensory axons have a more prominent slow potassium conductance and inward rectification than sural sensory axons (Lin et al., 2000). Accordingly, axonal excitability depends on (1) site-dependent changes along the nerve, (2) motor-sensory (modality-dependent) differences, and (3) biophysical changes in ion channel expression associated with functional adaptation.

In this issue of Clinical Neurophysiology, a paper by Jankelowitz and Burke (2008) demonstrated differences in excitability properties between motor axons innervating the flexor carpi radialis (FCR) and abductor pollicis brevis (APB), both muscles being innervated by the same median nerve. Excitability measurements were performed at the elbow portion of the median nerve for FCR axons and wrist for APB axons. Compared with APB axons, FCR motor axons showed reduced threshold changes, produced by subthreshold depolarizing conditioning currents in threshold electrotonus (fanning-in), reduced supernormality, and increased refractoriness. The authors suggest that the combination of these changes in excitability indices cannot be explained by length-dependent changes alone, but raise the possibility that FCR axons may be relatively depolarized compared with APB axons. They also showed similar differences in FCR- and APB axons at the elbow, examining the same site of the same median nerve. The biological significance of these differences is unclear at present, but it is important that even at the same site of the same nerve, excitability of motor axons is significantly different according to their innervated muscles.

These muscle-dependent differences in excitability properties of motor axons could be of clinical relevance, because the differences can lead to different responses to injury or disease. For example, in amyotrophic lateral sclerosis (ALS), muscle wasting predominantly affects the “thenar complex” including APB and first dorsal interosseous (FDI) muscles with relative sparing of the abductor digiti minimi (ADM) (Kuwabara et al., 2008). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles has been termed the “split hand” by Wilbourn (2000). FDI and ADM are innervated by the same ulnar nerve and spinal segments (C8-T1).

With a concept similar to that of Jankelowitz and Burke (2008), a recent study has compared excitability of FDI- and ADM-motor axons at the wrist in normal subjects, and found that FDI axons may have more prominent persistent sodium currents and less potassium currents (Bae et al., 2008). These physiological differences are exactly consistent with the changes in properties reported in ALS (Bostock et al., 1995, Kanai et al., 2006). Previous excitability studies have suggested increased persistent sodium currents and decreased potassium currents in ALS, and both changes increase axonal excitability, presumably resulting in generation of fasciculations, and possibly, motoneuronal death. These findings raise the possibility that axons with physiologically higher excitability are more preferentially involved in ALS. It would be of interest to investigate other intra-nerve differences in excitability properties and in responses to disease.

Computerized nerve excitability testing (threshold tracking) is still in its infancy, and it has not been established whether it will earn a place in the clinic alongside nerve conduction studies and electromyography. However, excitability testing is undoubtedly capable of yielding answers about the biophysical state of the tested axons as evidenced by the paper of Jankelowitz and Burke (2008) presented in this issue of the journal. The advantage of excitability testing is that it can be reasonably expected to lead to developments of novel pharmacologic treatment by modulating axonal excitability. Once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option in a variety of neuromuscular disorders.