Pharmaco-TMS-EEG as a new tool to characterize human cortical excitability and connectivity

Abstract

Excitation and inhibition in human cortex can be measured by transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) by way of specific markers of TMS-evoked muscle and brain responses. It has been shown that this capacity can be strongly enhanced by combining TMS-EMG/EEG with central nervous system (CNS) active drugs. Early studies have systematically investigated the role of a wide variety of CNS active drugs on motor evoked potentials (MEPs) and this knowledge is now partially applied to clinical settings. However, pharmacological alteration of TMS evoked EEG potentials (TEPs), which can provide direct information on cortical excitability and connectivity, has not been systematically elucidated yet. Here, we complement previous findings by using pharmaco-TMSEEG/EMG approaches to explore the physiological signatures of TEPs. In Experiment 1, we studied the effects of the experimental compound S44819, a selective α5-GABAAR antagonist, on TEPs and MEPs in 18 healthy young adults in a phase I study. In experiment 2, we investigated the role of three anti-epileptic drugs (carbamazepine, brivaracetam and tiagabine) on TEPs and MEPs in 15 healthy male adults. 100 mg S44819 enhanced cortical excitability, as denoted by reduction of the amplitude of the N45 TEP component, as well as decrease of the motor threshold; carbamazepine decreased the amplitude of the P25 and P180 TEP components and increased motor threshold; brivaracetam decreased the N100 TEP amplitude and increased MEP threshold; tiagabine had no effect on TEPs and/or MEPs. Results of experiment 1 demonstrated for the first time effects of S44819 in the human cortex, that are relevant as S44819 showed potential to improve plasticity and learning in animal models of cerebral stroke. These findings led to further development of S44819 in a clinical phase II study to test its efficacy in enhancing recovery of function in stroke patients. Results of experiment 2 confirmed and extended previous findings that the P25 TEP component reflects axonal excitability of the corticospinal system, the N100 potential in the non-stimulated hemisphere propagated activity mediated by inhibition of presynaptic neurotransmitter release, and the P180 late activity dependent on voltage-gated sodium channels (VGSCs). We believe that these updated pharmacological characterization of TEPs will prove useful for the understanding of normal and dysfunctional cortical excitability and inhibition of the human brain.