Abstract
Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.
Highlights
The development of a high percentage of central nervous system (CNS) active drugs could fail due to safety concerns and toxicology issues in preclinical studies
The EEG responses to Transcranial magnetic stimulation (TMS) averaged in the time domain are called TMS-evoked EEG potentials (TEPs), which are a reliable alternating sequence of positive (P) and negative (N) peaks at approximately 25 (P25), 45 (N45), 60 (P60), 100 (N100) and 180 (P180) milliseconds after stimulation of the human primary motor cortex (M1)[5]
Pharmacological studies investigating the inhibitory GABAergic pathways showed that the N45 and N100 peaks are associated with GABA-A11,12 and GABA-B11 receptor-mediated neurotransmission, respectively
Summary
The development of a high percentage of central nervous system (CNS) active drugs could fail due to safety concerns and toxicology issues in preclinical studies. The evaluation of pharmacodynamic properties in vivo can be achieved with positron emission tomography (PET) or drug distribution to the CNS by analysing cerebrospinal fluid (CSF) samples; these methods are invasive, expensive and not always available For all these reasons, the development and validation of simple, fast and reliable markers is a paramount challenge. Time–frequency decomposition of the TMS-EEG signal reveals TMS-induced oscillations which, in contrast with the TEP, contain information not necessarily phase locked to the stimulus[8] Their typical profile following M1 stimulation is characterized by an early increase of delta, theta, alpha and beta band power up to 200 ms, followed by alpha and beta suppression[9] (often termed de-synchronization) with a final increase in beta p ower[10]. Together with TEPs, spontaneous and TMS-related oscillations are of great potential value for inferring mechanisms and confirming specific target engagement
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