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. 2020 May;7(5):733-741.
doi: 10.1002/acn3.51039. Epub 2020 Apr 18.

Cortical hyperexcitability evolves with disease progression in ALS

Parvathi Menon  1 , Mana Higashihara  1 , Mehdi van den Bos  1 , Nimeshan Geevasinga  1 , Matthew C Kiernan  2 , Steve Vucic  1
Affiliations

Cortical hyperexcitability evolves with disease progression in ALS

Parvathi Menon et al. Ann Clin Transl Neurol. 2020 May.

Abstract

Objective: Cortical hyperexcitability has been established as an early feature of amyotrophic lateral sclerosis (ALS). The evolution of cortical hyperexcitability with ALS progression remains to be fully elucidated. This study aims to investigate changes in cortical function in ALS with disease progression.

Methods: Cortical function assessed by threshold tracking transcranial magnetic stimulation (TMS) along with clinical phenotyping was prospectively undertaken on 444 patients presenting with suspected ALS (345 ALS; 99 neuromuscular mimics). Disease stage was defined as follows: (1) King's clinical staging system and (2) proportion of disease duration statistically categorized into tertials.

Results: Cortical hyperexcitability was evident across all ALS stages, being more prominent in later stages of ALS as indicated by increased motor-evoked potential amplitude (P < 0.05), as well as longer disease duration as reflected by reduced short-interval intracortical inhibition (P < 0.05). Prolonged central motor conduction time was evident with disease progression. These changes were accompanied by reduction in neurophysiological index (P < 0.001) and compound muscle action potential amplitude (P < 0.01), progressive muscle weakness (P < 0.001), and decline in the ALS functional rating scale (P < 0.001).

Interpretation: This study established an increase in cortical hyperexcitability with increased disease duration in ALS, mediated by cortical disinhibition and direct increase in corticomotoneuronal excitability.

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Conflict of interest statement

Prof MCK reports being editor of Journal of Neurology Neurosurgery and Psychiatry. Prof SV reports receiving honoraria from Merck Serono Australia, CSL Australia, and Biogen Pty Ltd Australia. There are no other conflicts of interest to report.

Figures

Figure 1
Figure 1
There was a significant reduction in mean short‐interval intracortical inhibition (SICI), between interstimulus intervals (ISI) 1 and 7 msec, in amyotrophic lateral sclerosis (ALS) patients when compared with neuromuscular controls. The reduction in SICI was comparable across the King’s clinical stages in ALS patients. NS, Nonsignificant; ***P < 0.001.
Figure 2
Figure 2
Longitudinal studies in a cohort of amyotrophic lateral sclerosis (ALS) patients (N = 23) disclosed a significant reduction in mean short‐interval intracortical inhibition (SICI), between interstimulus intervals (ISI) 1 and 7 msec, with greater disease duration. NS, Nonsignificant; *P < 0.05.
Figure 3
Figure 3
(A) The motor‐evoked potential (MEP) amplitude was significantly increased in amyotrophic lateral sclerosis (ALS) patients classified as King’s stage 3 when compared with King’s stages 1, 2, and neuromuscular controls. (B) The increase in MEP amplitude was significant in ALS patients classified as intermediate and longer disease duration. NS‐ Nonsignificant; *P < 0.05; ***P < 0.001.
Figure 4
Figure 4
Changes in transcranial magnetic stimulation (TMS) parameters with Kings clinical stages and disease duration. Short‐interval intracortical inhibition (SICI) was significantly increased at baseline and remained stable across King’s stages but increased with disease duration. Intracortical facilitation (ICF) was increased while cortical silent period (CSP) duration was reduced at baseline and did not change with Kings clinical stages or disease duration. The motor‐evoked potential (MEP) amplitude was increased at baseline and increased with Kings clinical stages and disease duration. The resting motor threshold (RMT) was comparable with controls and did not evolve with Kings clinical stage or disease duration.
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References

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