Cortical Hyperexcitability More Prominent in Cognitive Impaired ALS


According to the study authors, future longitudinal studies assessing the evolution of cognitive and cortical excitability changes may provide a greater understanding of the importance of cortical circuits in ALS pathogenesis.

Mana Higashihara, PhD

Mana Higashihara, PhD

Recently published data in Neurology revealed that cortical hyperexcitability was more prominent in cognitively impaired patients with amyotrophic lateral sclerosis (ALS), with associations between increases in short interval intracortical inhibition (SICI) and cognitive dysfunction.1

These associations were independent of other transcranial magnetic stimulation (TMS) parameters, disease duration, or motor features. The study, led by Mana Higashihara, PhD, assistant professor, Westmead Clinical School, University of Sydney, collected data on cortical excitability using TMS and cognitive function determined by the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Cognitive impairment was defined by ECAS of less than 105.

In total, 36% of the 40 patients with ALS in the cohort exhibited an abnormal total ECAS score. The prominence of cortical hyperexcitability in cognitively impaired patients with ALS was indicated by an increase in short interval intracortical facilitation (SICF; ECAS≥105, ­–15.3 [±1.7%]; ECAS<105, –20.6 [±1.2%]; P <.01).

Increases in index of excitability (IE; ECAS≥105, 80.9 [±7.8]; ECAS<105, 95.0 [±4.5]; P <.01) and motor evoked potential (MEP) amplitude (ECAS≥105, 28.7 [±3.3%]; ECAS<105, 43.1 [±5.9]; P <.05) also demonstrated the prominence of cortical hyperexcitability in cognitively impaired patients with ALS.

"Longitudinal studies assessing the evolution of cognitive and cortical excitability changes and relating these to structural and functional neuroimaging findings may provide greater understanding of the importance of cortical circuits in ALS pathogenesis, as well as provide information on the role of TMS parameters as outcome biomarkers in future therapeutic trials,” Higashihara et al wrote.

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In patients exhibiting low ALS-specific scores on ECAS (<77), a similar pattern was observed, whereby SICF, IE, and MEP amplitude were increased. A subgroup analysis showed a reduction of SICI in patients exhibiting abnormal verbal fluency, language, and executive scores, accompanied by an increase in SICF.

Higashihara and colleagues also found that SICF was independently associated with the total ECAS (ß = 2.410; P <.05), ALS-specific (ß = 2.328; P <.05) and executive (ß = 2.716; P <.05) subscores when using multivariable regression modelling. Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECASexecutive score >33, 6.2 [±1.3%]; ECASexecutive score <33, 1.5 [±2.1]; P <.01).

The index of excitation was also independently associated with the CMAP amplitude (ß = 2.594, P <0.05) and SI (ß = 3.418, P <0.01), while SICI was correlated with the neurophysiological index (β = -3.027, P < 0.01).

Among patients included in the study, language was the most frequently affected ALS-specific subdomain (32%), followed by executive function (20%) and letter fluency (22%). Additionally, 29% of patients experienced memory dysfunction, an ALS-nonspecific subdomain while visuospatial function was the least affected subdomain (9.8%).

“Given that ECAS is a valid predictor of TDP-43 pathology, the increase in cortical hyperexcitability may be associated with TDP-43 accumulation,” the study authors concluded.

Cortical hyperexcitability has previously been reported as a pathogenic process in ALS, correlating with motor neuron degeneration, disease evolution, and adverse prognosis. In December 2020, a phase 2 randomized controlled trial found that treatment with ezogabine, a once FDA-approved drug for epilepsy, decreases cortical and spinal motor neuron excitability in patients with ALS.2

Lead author Brian J. Wainger, MD, PhD, assistant professor, neurology and anesthesiology, Harvard Medical School, and physician scientist and principal investigator, Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, sat down with NeurologyLive to provide context on the potential of motor neuron excitability in this disease state. Listen below to hear his thoughts.

1. Higashihara M, Pavey N, van den Bos M, Menon P, Kiernan MC, Vucic S. Association of cortical hyperexcitability and cognitive impairment in patients with ALS. Neurology. Published online April 7, 2021. doi: 10.1212/WNL.0000000000011798
2. Wainger BJ, Macklin EA, Vucic S, et al. Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol. Published online November 23, 2020. doi: 10.1001/jamaneurol.2020.4300
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