Brain Advance Access originally published online on July 10, 2006
Brain 2006 129(9):2436-2446; doi:10.1093/brain/awl172
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Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease
Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales and Institute of Neurological Sciences, Prince of Wales Hospital Randwick, Sydney, Australia
Correspondence to: Matthew C. Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia E-mail: M.kiernan{at}unsw.edu.au
The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 ± 0.8%; controls = 8.5 ± 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus–response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = –0.6) and neurophysiological index (r = –0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = –0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.
Key Words: cortical hyperexcitability; MND; threshold tracking
Abbreviations:
AHC, anterior horn cell; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Score—Revised; APB, abductor pollicis brevis; CMAP, compound muscle action potential; CMCT, central motor conduction time; CSP, cortical silent period; ISI, interstimulus interval; MEP, motor-evoked potential; MND, motor neuron disease; NI, neurophysiological index; RMT, resting motor threshold; SICI, short-interval intracortical inhibition; SR, stimulus–response; 
SD, strength–duration time constant; TMS, transcranial magnetic stimulation; UMN, upper motor neuron
Received February 15, 2006. Revised May 25, 2006. Accepted June 2, 2006.
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