Geevasinga N, Menon P, Nicholson GA, Ng K, Howells J, Kril JJ, Yiannikas C, Kiernan MC, Vucic S. Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Nov;72(11):1268-74. PubMed.
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University of British Columbia
Vucic and colleagues in Australia have, over the last decade, published extensively on hyperexcitability in ALS, and there can be little debate regarding the validity of the phenomenon. The sophisticated physiology used to investigate ALS-related hyperexcitability indicates that it reflects a combination of reduced inhibition from impaired GABA functioning and increased glutamate activity. The present study confirms the presence of cortical hyperexcitability in symptomatic patients with C9ORF72 familial ALS (FALS), as has been previously noted in ALS patients with other genetic mutations, suggesting that cortical hyperexcitability is of pathophysiological importance in ALS, as well as in sporadic ALS (SALS), irrespective of underlying genetic status.
However, cortical excitability is normal in asymptomatic FALS, independent of the type of mutation, so the development of hyperexcitability in FALS is a late feature, possibly mediating neuronal degeneration via a transsynaptic anterograde process. It is important that this latency has been established, because protective therapy aimed at preventing or reducing hyperexcitability in the presymptomatic period will likely be of no avail. Furthermore, detecting cortical hyperexcitability as a marker of presymptomatic FALS or SALS is not going to be useful. However, cortical hyperexcitability in ALS is an interesting phenomenon, and much still remains to be learned about it. It may turn out that reduced inhibition (GABA impairment) is the crucial element, which could be of value as an early, presymptomatic disease marker.
View all comments by Andrew EisenChiba University
Chiba University
Motor Cortical Hyperexcitability and Neuronal Death in Familial and Sporadic Amyotrophic Lateral Sclerosis
Widespread fasciculations are a prominent clinical feature in patients with ALS, indicating abnormally increased excitability and spontaneous firing of lower motor neurons/axons. Fasciculations often arise from the motor nerve terminals, and partly from spinal motor neurons (de Carvalho et al., 2013). These findings suggest altered excitability occurs in both the distal motor axons and cell body of lower motor neurons.
Over the past 20 years, our understanding of the ionic pathogenesis for fasciculations has been expanded. Peripheral motor axonal excitability studies with a threshold-tracking technique have shown increased nodal persistent sodium currents and reduced potassium currents in ALS patients, both changes leading to increased axonal excitability, and thereby generation of fasciculations (Kanai et al., 2006).
Separately, a long and ongoing debate regarding the processes underlying motor neuronal death in ALS continues, and corticomotoneuronal hyperexcitability via an anterograde trans-synaptic glutaminergic process has been proposed as an underlying mechanism (Eisen et al., 1992). Support for this primary cortical involvement hypothesis has been provided by TMS studies establishing that cortical hyperexcitability was an early event of patients with sporadic ALS; TMS has shown hyperexcitability of the motor cortical circuitry (Vucic et al., 2013). Specifically, short-interval intracortical inhibition (SICI) with paired pulse TMS threshold tracking was significantly reduced in patients with sporadic ALS, and in those with familial ALS caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene. This reflects changes in intrinsic motor cortical circuits presumably mediated by altered actions in GABAergic neurotransmission (Vucic et al., 2008).
The present study nicely demonstrated this in asymptomatic carriers and patients with C9ORF72 ALS. The authors measured SICI with TMS threshold tracking, and found that the results largely paralleled clinical states; patients with C9ORF72 expansion had significantly reduced SICI, and motor cortical hyperexcitability very similar to people with sporadic ALS. In contrast, asymptomatic carriers showed normal SICI. These findings strongly suggest that the onset of ALS is closely associated with cortical hyperexcitability of the motor cortex. The disinhibition may be caused by loss of GABAergic inhibitory interneurons in the motor cortex. Further studies will be required to elucidate the mechanisms for the altered cortical function.
Another important finding is that markedly reduced SICI in C9ORF72 ALS patients is exactly the same as those observed in familial ALS patients with different genetic mutations such SOD-1 mutation (Vucic et al., 2008). This suggests that sporadic ALS and familial ALS with different genetic status share a common pathophysiological mechanism. For both sporadic and familial ALS, suppression of neuronal and axonal excitability of cortical, as well as spinal, motor neurons could be a neuro-protective strategy. Stabilization of the neuronal membrane with persistent sodium channel blockers or potassium channel openers will be therapeutic options for the total population of ALS.
References:
de Carvalho M, Swash M. Origin of fasciculations in amyotrophic lateral sclerosis and benign fasciculation syndrome. JAMA Neurol. 2013 Dec;70(12):1562-5. PubMed.
Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T, Bostock H. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8 PubMed.
Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron?. Muscle Nerve. 1992 Feb;15(2):219-24. PubMed.
Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1161-70. Epub 2012 Dec 21 PubMed.
Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain. 2008 Jun;131(Pt 6):1540-50. Epub 2008 May 9 PubMed.
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