{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:43:19Z","timestamp":1790793799263,"version":"4.1.0"},"reference-count":187,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T00:00:00Z","timestamp":1722211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.<\/jats:p>","DOI":"10.3390\/brainsci14080760","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T11:11:25Z","timestamp":1722337885000},"page":"760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7243-644X","authenticated-orcid":false,"given":"Aicee Dawn","family":"Calma","sequence":"first","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"van den Bos","sequence":"additional","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9636-4391","authenticated-orcid":false,"given":"Nathan","family":"Pavey","sequence":"additional","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4495-6314","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Santos Silva","sequence":"additional","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"},{"name":"Department of Neurosciences and Mental Health, Unidade Local de Sa\u00fade de Santa Maria, 1649-028 Lisbon, Portugal"},{"name":"Faculdade de Medicina-Instituto de Medicina Molecular, Centro de Estudos Egas Moniz, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvathi","family":"Menon","sequence":"additional","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Vucic","sequence":"additional","affiliation":[{"name":"Brain and Nerve Research Center, The University of Sydney, Sydney 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Kiernan","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrneurol.2016.140","article-title":"Pathophysiological and diagnostic implications of cortical dysfunction in ALS","volume":"12","author":"Geevasinga","year":"2016","journal-title":"Nat. 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