{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:50:34Z","timestamp":1786114234372,"version":"build-2736575974"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    One\u2010third of epilepsy patients remain treatment\u2010resistant, underscoring the need for novel anti\u2010seizure medications (ASMs) and reliable biomarkers of central target engagement. Cortical hyperexcitability is a hallmark of epilepsy, making excitability a valuable pharmacodynamic biomarker for early\u2010phase drug development supporting go\/no\u2010go decision making. Building upon prior transcranial magnetic stimulation (TMS) work in healthy participants, this study aimed to establish TMS\u2010derived endpoints as translational biomarkers of ASM effects in patients. In a randomized, double\u2010blind, placebo\u2010controlled, two\u2010way crossover design, patients with generalized epilepsy on levetiracetam (500\u2009mg twice daily;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200914) or valproic acid (\u22641,000\u2009mg\/day; levetiracetam\u2010na\u00efve,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200912) received a single oral dose of levetiracetam (2000\u2009mg) or placebo. Participants were asked to refrain from their morning ASM dose to minimize background ASM levels while maintaining seizure protection. TMS combined with electromyography (EMG) and electroencephalography (EEG), and resting\u2010state EEG were performed pre\u2010dose, 1.5\u2009h, and 3\u2009h post\u2010dose. Outcomes were analyzed using mixed\u2010effects analysis of covariance or cluster\u2010based permutation testing. Levetiracetam significantly reduced motor\u2010evoked potential (MEP) amplitude, enhanced long\u2010interval intracortical inhibition (LICI), and increased frontal gamma and beta power, with larger effect sizes in levetiracetam\u2010na\u00efve patients. These findings were further supported by linear concentration\u2013response relationships for these endpoints. TMS\u2013EEG revealed group\u2010specific modulation: early TMS\u2010evoked potential components (P30\/N45) in levetiracetam patients vs. later components (N100\/P180) in levetiracetam\u2010na\u00efve patients. These findings build upon prior results, demonstrating that TMS\u2010based biomarkers are sensitive to levetiracetam's acute effects in epilepsy patients with MEP amplitude, LICI, and frontal beta\/gamma power emerging as promising biomarkers, possible also for new ASM development.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70327","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:51:15Z","timestamp":1778734275000},"page":"673-683","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcranial Magnetic Stimulation as a Translational Biomarker in Early\u2010Phase Anti\u2010Seizure Medication Development: A Randomized, Double\u2010Blind, Placebo\u2010Controlled Study in Generalized Epilepsy"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2998-708X","authenticated-orcid":false,"given":"Catherine M. 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