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Brain Advance Access originally published online on May 9, 2008
Brain 2008 131(6):1540-1550; doi:10.1093/brain/awn071
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis

Steve Vucic1, Garth A. Nicholson2 and Matthew C. Kiernan1

1Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales and 2University of Sydney, Northcott Neurobiology Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia

Correspondence to: Assoc. Prof. Matthew C. Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia E-mail: m.kiernan{at}unsw.edu.au

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10–15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (–1.2 ± 0.6%) and sporadic ALS patients (–0.7 ± 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 ± 1.5%, P<0.00001) and normal controls (8.5 ± 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, –3.2%; patients 2, –1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.

Key Words: familial ALS; cortical hyperexcitability; SOD-1

Abbreviations: ALSFRS-R, amyotrophic lateral sclerosis function rating scale revised; ANOVA, analysis of variance; CMAP, compound muscle action potentials; CMCT, central motor conduction time; CSP, cortical silent period; FALS, familial amyotrophic lateral sclerosis; ICF, intracortical facilitation; ISI, interstimulus interval; MEP, motor evoked potential; MRC, Medical Research Council; NI, neurophysiological index; RMT, resting motor threshold; SICI, short-interval intracortical inhibition; SOD-1, copper/zinc superoxide-dismutase-1 gene; TMS, transcranial magnetic stimulation

Received December 10, 2007. Revised March 12, 2008. Accepted March 25, 2008.


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