Lamotrigine and levetiracetam exert a similar modulation of TMS‐evoked EEG potentials

Abstract

SummaryObjectiveAntiepileptic drug (AED) treatment failures may occur because there is insufficient drug in the brain or because of a lack of relevant therapeutic response. Until now it has not been possible to measure these factors. It has been recently shown that the combination of transcranial magnetic stimulation and electroencephalography (TMS‐EEG) can measure the effects of drugs in healthy volunteers. TMS‐evoked EEG potentials (TEPs) comprise a series of positive and negative deflections that can be specifically modulated by drugs with a well‐known mode of action targeting inhibitory neurotransmission. Therefore, we hypothesized that TMS‐EEG can detect effects of two widely used AEDs, lamotrigine and levetiracetam, in healthy volunteers.MethodsFifteen healthy subjects participated in a pseudo‐randomized, placebo‐controlled, double‐blind, crossover design, using a single oral dose of lamotrigine (300 mg) and levetiracetam (3,000 mg). TEPs were recorded before and 120 min after drug intake, and the effects of drugs on the amplitudes of TEP components were statistically evaluated.ResultsA nonparametric cluster‐based permutation analysis of TEP amplitudes showed that AEDs both increased the amplitude of the negative potential at 45 msec after stimulation (N45) and suppressed the positive peak at 180 msec (P180). This is the first demonstration of AED‐induced modulation of TMS‐EEG measures.SignificanceDespite the different mechanism of action that lamotrigine and levetiracetam exert at the molecular level, both AEDs impact the TMS‐EEG response in a similar way. These TMS‐EEG fingerprints observed in healthy subjects are candidate predictive markers of treatment response in patients on monotherapy with lamotrigine and levetiracetam.

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

“…A decrease in P180 amplitude was observed after lamotrigine intake, both with and without adjusting stimulus intensity to compensate for RMT change (Premoli, Biondi, et al, ; Premoli, Costantini, et al, ). Our results complement these findings, as CBZ reduced P180 amplitude both with and without adjusting stimulation intensity.…”

“…The N100 is thought to be a marker of GABABergic inhibition due to the enhancing effect of baclofen, a specific GABAB receptor agonist, on N100 amplitude at the site of stimulation (Premoli, Castellanos, et al, ). On the other hand, benzodiazepines (Premoli, Castellanos, et al, ) and levetiracetam (Premoli, Biondi, et al, ) resulted in N100 amplitude depression in the nonstimulated hemisphere. The present results of BRV, showing N100 amplitude depression in M1 area of the nonstimulated hemisphere (Figure ) are in full agreement with those previous findings.…”

“…One way to characterize the physiology of these TEPs is to test their changes in healthy subjects under challenge with central nervous system active drugs, which have specific modes action (Ziemann et al, ). Neurotransmission through the gamma‐butyric acid type A (GABAA) receptor contributes to the N45 potential because positive modulators at the GABAA receptor, such as benzodiazepines and zolpidem, and the SV2A ligand levetiracetam increased the N45 potential amplitude (Premoli et al, ; Premoli, Biondi, Carlesso, Rivolta, & Richardson, ; Premoli, Costantini, Rivolta, Biondi, & Richardson, ), whereas S44819, a specific antagonist of the alpha‐5 subunit bearing subtype of the GABAA receptor decreased it (Darmani et al, ). Moreover, neurotransmission through the GABAB receptor contributes to the N100 potential because baclofen, a specific agonist at the GABAB receptor, increased the N100 potential amplitude at the site of stimulation (Premoli, Castellanos, et al, ).…”

Transcranial magnetic stimulation with electroencephalography: methodology, applications for research and cilinics

“…Также показана возможная связь с тормозными процессами для компонента N45 -с работой рецеп-торов ГАМК-А, для компонента P60 -связь с систе-мой ГАМК-В. ТМС-ЭЭГ открыла новую эру иссле-дований в фармакологии, позволяя локально оценивать модуляцию компонент ТМС-ЭЭГ при воз-действии различных фармакологических препаратов с выявлением их точечных эффектов [40]. Результаты исследований связи разных компонент ТМС-ВП с нейромедиаторными системами и действием пре-паратов представлены в обзоре [41].…”

“…У детей с СДВГ компонента N100 была меньше по амплитуде, чем у здоровых детей в контрольной группе [65]. Активно изучаются возможности ТМС-ЭЭГ при эпилепсии для иденти-фикации эпилептогенной зоны, предсказания эффек-тивности антиэпилептических препаратов [40,67] и эффективности инвазивной нейромодуляторной терапии [59,66,68].…”