Topiramate Selectively Decreases Intracortical Excitability in Human Motor Cortex

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Abstract
Summary: Purpose: Topiramate (TPM) is a novel drug with broad antiepileptic effect in children and adults. In vitro studies suggest activity as sodium‐channel blocker, as γ‐aminobutyric acid type A (GABAA)‐receptor agonist and as non–N‐methyl‐D‐aspartate (NMDA)‐glutamate receptor antagonist. Methods: With transcranial magnetic stimulation (TMS), we evaluated which of the mechanisms of action of TPM detected in vitro are relevant for the modulation of human motor cortex excitability. In a double‐blind, placebo‐controlled, crossover study design, we investigated the effect of single oral doses of 50 mg and 200 mg TPM on motor thresholds, cortical silent period (CSP), and on intracortical inhibition (ICI) and intracortical facilitation (ICF) in 20 healthy subjects. Results: A significant dose‐dependent increase of ICI was noticed after 200 mg TPM as compared with placebo at short interstimulus intervals of 2 to 4 ms. TPM had no effect on motor thresholds or the CSP. Conclusions: We conclude that a single dose of TPM selectively increases ICI by GABAAergic and/or glutamatergic mechanisms without a relevant influence on measures, depending on ion‐channel blockade or GABAB‐receptor activity. The decrease of intracortical excitability (as measured by ICI and ICF) caused by TPM may correlate with its lack of proconvulsive potential in idiopathic generalized epilepsy, because drugs without this action or with less pronounced action may exacerbate seizures in this condition.