Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype

Hatice Tankisi; Anna Bystrup Jacobsen; Gaia Fanella; Bülent Cengiz; Hasan Kılınç; Jose Manuel Matamala; Javier Moreno-Roco; Agessandro Abrahao; Lorne Zinman; Martin Koltzenburg; James Howells; Gintaute Samusyte; Friedemann Awiszus; Hugh Bostock

doi:10.1016/j.clinph.2025.2110770

Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype

Clin Neurophysiol. 2025 May 25:176:2110770. doi: 10.1016/j.clinph.2025.2110770. Online ahead of print.

Affiliations

¹ Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark.
² Department of Neurology, Gazi University Faculty of Medicine, Beşevler, 06500 Ankara, Turkey; NOROM, Neuroscience and Neurotechnology Center of Excellence, Besevler, Ankara, Turkey.
³ Department of Neurological Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
⁴ Division of Neurology, Department of Medicine and Harquail Centre for Neuromodulation, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
⁵ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, Queen Square, WC1N 3BG London, United Kingdom; Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG London, United Kingdom.
⁶ Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁷ Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁸ Neuromuscular Research Group, Department of Orthopaedics, Otto-von-Guericke Universität, D-39120 Magdeburg, Germany.
⁹ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N 3BG London, United Kingdom. Electronic address: H.Bostock@ucl.ac.uk.

PMID: 40482593
DOI: 10.1016/j.clinph.2025.2110770

Abstract

Objective: To investigate the relationship between short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF) and amyotrophic lateral sclerosis (ALS) phenotype, using threshold-tracking transcranial magnetic stimulation (TMS).

Methods: A new paired-pulse TMS protocol was applied to 49 patients with ALS and 49 age-matched healthy controls. Motor evoked potentials (MEPs) were recorded from first dorsal interosseus muscle, while paired pulses were delivered at interstimulus intervals (ISI) of 1.0, 2.5 or 3.0 ms, with stimuli related to the resting motor threshold for a 200 µV MEP. For each ISI, 6 SICI and 3 SICF pulse pairs with different conditioning stimuli were randomised and interleaved with test-alone stimuli.

Results: ALS phenotypes were characterised as Pyramidal (n = 12, with prominent upper motor neuron signs), Classic (n = 20, with limb onset), or Bulbar (n = 17). Compared with healthy controls, Bulbar patients had significantly less inhibition at all ISIs, while SICI in Pyramidal patients was normal, and in Classic patients intermediate. The only SICF abnormalities independent of the changes in SICI were less facilitation in Pyramidal patients at ISIs 1 and 3 ms.

Conclusion: Changes in SICI and SICF depend on ALS phenotype.

Significance: ALS phenotypes should be matched between treatment and placebo arms of clinical trials.

Keywords: Amyotrophic lateral sclerosis; Short-interval intracortical facilitation; Short-interval intracortical inhibition; Threshold-tracking TMS; Upper motor neuron score.