{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T02:44:24Z","timestamp":1782355464812,"version":"3.54.5"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof\u2010of\u2010mechanism in early\u2010phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double\u2010blind, placebo\u2010controlled, 4\u2010way cross\u2010over study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In 16 healthy male subjects, single\u2010 and paired\u2010pulse TMS\u2010EMG\u2013EEG measurements were performed predose and 1.5, 7 and 24\u2009hours postdose. Treatment effects on motor\u2010evoked potential, short and long intracortical inhibition and TMS\u2010evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster\u2010based permutation analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that motor\u2010evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] \u2212378.4\u00a0\u03bcV; 95%CI: \u2212644.3, \u2212112.5\u00a0\u03bcV; <jats:italic>P<\/jats:italic>\u00a0&lt;\u2009.01), valproic acid (ED \u2212268.8\u00a0\u03bcV; 95%CI: \u2212532.9, \u22124.6\u00a0\u03bcV; <jats:italic>P<\/jats:italic>\u00a0=\u2009.047) and lorazepam (ED \u2212330.7\u00a0\u03bcV; 95%CI: \u2212595.6, \u221265.8\u00a0\u03bcV; <jats:italic>P<\/jats:italic>\u00a0=\u2009.02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED \u221260.3%; 95%CI: \u221287.1%, \u221233.5%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u2009.001) and lorazepam (ED \u221268.2%; 95%CI: \u221294.7%, \u221241.7%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u2009.001) at a 50\u2010ms interstimulus interval. Levetiracetam increased TMS\u2010evoked potential component N45 (<jats:italic>P<\/jats:italic>\u00a0=\u2009.004) in a central cluster and decreased N100 (<jats:italic>P<\/jats:italic>\u00a0&lt;\u2009.001) in a contralateral cluster.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS\u2010EMG\u2013EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15232","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T01:14:40Z","timestamp":1642122880000},"page":"2926-2937","source":"Crossref","is-referenced-by-count":12,"title":["Transcranial magnetic stimulation as biomarker of excitability in drug development: A randomized, double\u2010blind, placebo\u2010controlled, cross\u2010over study"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-924X","authenticated-orcid":false,"given":"Titia Q.","family":"Ruijs","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center (LUMC)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-5088","authenticated-orcid":false,"given":"Jules A. 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