Modafinil reverses hypoexcitability of the motor cortex in narcoleptic patients: a TMS study.

Objective: Although many animal and human studies have been performed, the exact mechanisms of action whereby modafinil promotes wakefulness are still not completely understood. We aimed to investigate the functional effects of modafinil on motor cortex excitability in patients with narcolepsy by means of transcranial magnetic stimulation (TMS) techniques.

Methods: In a double-blind and placebo-controlled design, 24 drug-naive narcoleptic patients with cataplexy and 20 control subjects were administered modafinil or placebo over a period of 4 weeks. TMS was performed twice during the awake state before and at the end of treatment; measures of cortical excitability included central motor conduction time, resting motor threshold, short latency intracortical inhibition (SICI) and intracortical facilitation to paired-TMS. TMS measures were correlated with the conventional neurophysiological method of Multiple Sleep Latency Test (MSLT) and the subjective Epworth Sleepiness Scale (ESS).

Results: As previously reported, motor threshold and SICI were significantly increased in patients with narcolepsy; modafinil reversed this cortical hypoexcitability, but only SICI differences reached statistical significance. The Spearman rank correlation analysis revealed the highest correlation between SICI and the MSLT; a positive correlation was also found between SICI and the ESS, as well as between RMT and both measures of daytime sleepiness.

Conclusions: This represents the first report investigating effects of modafinil on cortical excitability in human narcolepsy. Since SICI is thought to be directly related to GABA(A) intracortical inhibitory activity, we demonstrated that the dose of modafinil that induces a satisfactory wakefulness-promoting response in narcoleptic patients also causes decrease in GABAergic transmission.