Abstract Objective Cenobamate (CNB) is an effective antiseizure medication, though its mechanisms of efficacy remain incompletely understood. We assessed changes in cortical responses to transcranial magnetic stimulation (TMS) following CNB treatment. Methods We recruited people with drug‐resistant focal epilepsy scheduled to start add‐on CNB in a tertiary epilepsy center. We performed TMS coupled with electromyography (EMG) and electroencephalography (EEG) at baseline, at 100 mg/day and at the maximum tolerated or minimum effective dose. Participants were categorized as responders (≥50% seizure reduction) or nonresponders. We used linear mixed models and cluster‐based permutation tests to assess CNB effects on resting motor thresholds (rMTs), intracortical inhibition and the amplitude, mean field power and event‐related spectral perturbation of TMS‐evoked EEG potentials (TEPs). For TMS measures that were significantly affected by CNB dose ( p < 0.05), we assessed differences between responders and non‐responders and correlations with seizure frequency. Results Twenty‐eight participants completed the study (16 females; median age, 50 years). rMT ( p < 0.01) increased and cortical silent period (CSP) lengthened ( p = 0.03) with increasing CNB dose. These changes did not differ between responders and nonresponders, nor did they correlate with reduced seizure frequency. Short‐ and long‐interval intracortical inhibition, as well as all TEP parameters, remained unchanged. Conclusion While CSP lengthening may merely reflect higher stimulation intensities, rMT increases align with CNB's suggested modulation of sodium channels. Significance rMT changes that are independent of clinical response suggest that sodium channel effects do not fully account for the therapeutic efficacy of CNB. Plain Language Summary We used magnetic brain stimulation in people with epilepsy to find out how the antiseizure medication cenobamate affects brain activity. As its dose increased, cenobamate raised the stimulation strength required to activate a muscle, known as the resting motor threshold (rMT). These changes did not predict a reduction in seizures. This suggests that cenobamate's effectiveness involves more than its effects on mechanisms linked to the rMT.
Gefferie et al. (Thu,) studied this question.