Clinical Neurophysiology 120 (2009) 1–2

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Clinical Neurophysiology

journal homepage: www.elsevier .com/locate /c l inph

Editorial

Physiological differences in excitability among human axons

See Article, pages 167–173

The main role of axons is to transmit nerve impulse securely,and nerve conduction velocities measured in the same segmentsare similar among upper or lower limb nerves in routine nerve con-duction studies. However, excitability properties of different axonsare not identical. The properties of axons are determined by anumber of factors (Burke et al., 2001). First, anatomical factorssuch as axonal size and internodal length largely affect the proper-ties. Compared with proximal or intermediate axons along thenerve, distal axons have the shorter internodes that lead to greateraxonal resistance (referred as the Barrett–Barrett resistance; Bar-rett and Barrett, 1982) and to other changes in passive membraneproperties such as smaller nodal area and thinner myelin. Second,there are substantial differences in excitability properties betweenmotor and sensory axons in human nerves. Large myelinated sen-sory axons have a greater persistent sodium current and inwardrectification than alpha-motor axons (Bostock et al., 1998). Becauseof these modality-dependent differences, ectopic activity occursmore easily with cutaneous afferents, and indeed peripheral neu-ropathy produces paresthesias much more readily than fascicula-tion or muscle cramp. Finally, there is evidence that axonalexcitability properties are adapted to the pattern and extent of im-pulse traffic normally carried by the corresponding axons. Thereare differences in excitability between sensory axons innervatingdifferent skin regions; median sensory axons have a more promi-nent slow potassium conductance and inward rectification thansural sensory axons (Lin et al., 2000). Accordingly, axonal excitabil-ity depends on (1) site-dependent changes along the nerve, (2) mo-tor-sensory (modality-dependent) differences, and (3) biophysicalchanges in ion channel expression associated with functionaladaptation.

In this issue of Clinical Neurophysiology, a paper by Jankelowitzand Burke (2008) demonstrated differences in excitability proper-ties between motor axons innervating the flexor carpi radialis(FCR) and abductor pollicis brevis (APB), both muscles being inner-vated by the same median nerve. Excitability measurements wereperformed at the elbow portion of the median nerve for FCR axonsand wrist for APB axons. Compared with APB axons, FCR motor ax-ons showed reduced threshold changes, produced by subthresholddepolarizing conditioning currents in threshold electrotonus (fan-ning-in), reduced supernormality, and increased refractoriness.The authors suggest that the combination of these changes inexcitability indices cannot be explained by length-dependentchanges alone, but raise the possibility that FCR axons may be rel-atively depolarized compared with APB axons. They also showedsimilar differences in FCR- and APB axons at the elbow, examiningthe same site of the same median nerve. The biological significance

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of these differences is unclear at present, but it is important thateven at the same site of the same nerve, excitability of motor axonsis significantly different according to their innervated muscles.

These muscle-dependent differences in excitability properties ofmotor axons could be of clinical relevance, because the differencescan lead to different responses to injury or disease. For example, inamyotrophic lateral sclerosis (ALS), muscle wasting predominantlyaffects the ‘‘thenar complex” including APB and first dorsal interos-seous (FDI) muscles with relative sparing of the abductor digiti min-imi (ADM) (Kuwabara et al., 2008). This peculiar pattern ofdissociated atrophy of the intrinsic hand muscles has been termedthe ‘‘split hand” by Wilbourn (2000). FDI and ADM are innervatedby 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-motoraxons at the wrist in normal subjects, and found that FDI axonsmay have more prominent persistent sodium currents and lesspotassium currents (Bae et al., 2008). These physiological differ-ences are exactly consistent with the changes in properties re-ported in ALS (Bostock et al., 1995; Kanai et al., 2006). Previousexcitability studies have suggested increased persistent sodiumcurrents and decreased potassium currents in ALS, and bothchanges increase axonal excitability, presumably resulting in gen-eration of fasciculations, and possibly, motoneuronal death. Thesefindings raise the possibility that axons with physiologically higherexcitability are more preferentially involved in ALS. It would be ofinterest to investigate other intra-nerve differences in excitabilityproperties and in responses to disease.

Computerized nerve excitability testing (threshold tracking) isstill in its infancy, and it has not been established whether it willearn a place in the clinic alongside nerve conduction studies andelectromyography. However, excitability testing is undoubtedlycapable of yielding answers about the biophysical state of thetested axons as evidenced by the paper of Jankelowitz and Burke(2008) presented in this issue of the journal. The advantage ofexcitability testing is that it can be reasonably expected to leadto developments of novel pharmacologic treatment by modulatingaxonal excitability. Once a specific ionic conductance is identified,blocking or activating it may provide a new therapeutic option in avariety of neuromuscular disorders.

References

Bae JS, Sawai S, Misawa S, Kanai K, Isose S, Kuwabara S. Differences in excitabilityproperties of FDI and ADM motor axons. Muscle Nerve 2008.

Barrett EF, Barrett JN. Intracellular recording from vertebrate myelinated axons:mechanisms of the depolarizing afterpotential. J Physiol (Lond)1982;323:117–44.

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2 Editorial / Clinical Neurophysiology 120 (2009) 1–2

Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of humanperipheral nerve. Muscle Nerve 1998;21:137–58.

Bostock H, Sharief MK, Reid G, Murray NM. Axonal ion channel dysfunction inamyotrophic lateral sclerosis. Brain 1995;118:217–25.

Burke D, Kiernan MC, Bostock H. Excitability of human axons. Clin Neurophysiol2001;112:1575–85.

Jankelowitz S, Burke D. Axonal excitability in the forearm: normal data anddifferences along the median nerve. Clin Neurophysiol 2008;120:167–73.

Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, et al.Altered axonal excitability properties in amyotrophic lateral sclerosis:impaired potassium channel function related to disease stage. Brain2006;129:953–62.

Kuwabara S, Sonoo M, Komori T, Shimizu T, Hirashima F, Inaba A, et al. Dissociatedsmall hand muscle atrophy in amyotrophic lateral sclerosis: frequency, extent,and specificity. Muscle Nerve 2008;37:426–30.

Lin CS, Mogyoros I, Kuwabara S, Cappelen-Smith C, Burke D. Accommodation todepolarizing and hyperpolarizing currents in cutaneous afferents ofthe human median and sural nerves. J Physiol (Lond) 2000;529:483–92.

Wilbourn AJ. The split hand syndrome. Muscle Nerve 2000;23:138.

Satoshi KuwabaraDepartment of Neurology, Graduate School of Medicine,

Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670,Japan

Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160E-mail address: kuwabara-s@faculty.chiba-u.jp