Effects of age on excitability properties in human motor axons Jong Seok Bae a,b , Setsu Sawai a , Sonoko Misawa a , Kazuaki Kanai a , Sagiri Isose a , Kazumoto Shibuya a , Satoshi Kuwabara a, * a Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan b Department of Neurology, Busan Paik Hospital, Inje University, College of Medicine, Busan, Republic of Korea article info Article history: Accepted 20 July 2008 Available online 29 August 2008 Keywords: Age Nerve excitability testing Aging Threshold tracking Axonal excitability Persistent sodium channel Inward rectification abstract Objective: The threshold tracking technique is a new approach to non-invasively assess biophysical prop- erties of axonal membrane in human subjects. The aim of this study was to evaluate the effects of age and gender on excitability properties of human motor axons. Methods: Computerized threshold tracking was used to measure multiple excitability indices in median motor axons of 93 normal subjects (50 men; age, 20–86 years). Results: Regression analyses showed that the higher age was associated with longer strength-duration time constant (p = 0.03), smaller threshold changes in depolarizing threshold electrotonus (p = 0.02), smaller super- normality (p = 0.01), and steeper slope of the current–threshold relationship for hyperpolarizing currents (p < 0.001). There were slight sex differences in rheobase, threshold electrotonus, supernormality, late subnor- mality, and current–threshold slope, though they were significant only in the subgroup with age <50 years. Conclusions: Aging may increase persistent sodium currents, inward rectification, and possibly, outward potassium currents. The combination of changes raises the possibility of slight membrane depolarization in elderly people. For the sex-related differences, further studies will be required with the evaluation of sex hor- monal effects. Significance: Age-related effects on excitability properties are subtle, but should be taken into consideration in the clinical application of nerve excitability testing, particularly in elderly subjects. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction It is generally assumed that aging affects excitability in both the central and peripheral nervous system. In human cortical motor neurons, firing threshold determined with transcranial magnetic stimulation increases progressively with age (Rossini et al., 1992). In spinal motoneurons, experimental animal studies have shown that age-related loss of spinal motoneurons and the compensatory collateral sprouting by surviving neurons (Tomlinson and Irving, 1977) result in changes in discharge patterns and increased electri- cal resistance of the spinal motoneuronal membrane (Engelhardt et al., 1989; Ramirez and Ulfhake, 1992; Roos et al., 1997). Threshold tracking was developed to non-invasively assess the properties of axonal membrane in human subjects (Bostock et al., 1998; Burke et al., 2001; Kuwabara and Misawa, 2004). So far, there are limited data on age-related effects on human peripheral axonal excitability, and previous results were not always consis- tent. Some studies emphasized the effects of non-neural factors (Kiernan et al., 2001), and others suggested age-dependent changes in supernormality and inward rectification (Jankelowitz et al., 2007) or in nodal persistent sodium currents (Tamura et al., 2006). This study was undertaken to investigate the relation- ship of age and gender with multiple axonal excitability indices in a large number of normal subjects. 2. Methods 2.1. Subjects This study included 93 Japanese normal volunteers (50 men). Their age ranged from 20 to 86 years (mean, 47 years). None of them had clinical or electrophysiological evidence of a peripheral nerve disorder and diabetes. All subjects gave an informed consent to the experimental procedures, which had been approved by the Ethics Committee of the Chiba University School of Medicine. 2.2. Multiple excitability measurements using threshold tracking Excitability testing was performed with a computerized pro- gram (QTRAC version 4.3 with multiple excitability protocol TRON- DXM2; copyright, Prof. Hugh Bostock, Institute of Neurology, London, UK) (Kiernan et al., 2000). Compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis 1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.07.005 * Corresponding author. Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160. E-mail address: kuwabara-s@faculty.chiba-u.jp (S. Kuwabara). Clinical Neurophysiology 119 (2008) 2282–2286 Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph