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

ABSTRACT: Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco-physiological characterization of TEPs will facilitate utilization of TMS-EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.

SUBMITTER: Darmani G

PROVIDER: S-EPMC6865504 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Darmani Ghazaleh G Bergmann Til O TO Zipser Carl C Baur David D Müller-Dahlhaus Florian F Ziemann Ulf U

Human brain mapping 20181213 4

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action ...[more]

PMID: 30549127

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Project description:Alpha-5 gamma-aminobutyric acid type A receptors (α5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebo-controlled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS-EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific α5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke.Significance statementThe extrasynaptic α-5 gamma-aminobutyric acid type A receptor (α5-GABAAR) regulates neuronal excitability through tonic inhibition in the mammalian brain. Tonic inhibition is important for many fundamental processes such as plasticity and learning. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. This study demonstrates that S44819, a selective α5-GABAAR antagonist, increases cortical excitability in healthy human subjects, as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography. Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods. The actions of S44819 may be suitable to improve plasticity and learning.

Project description:Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography applied to the primary motor cortex provides two parameters for cortical excitability: motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). This study aimed to evaluate the effects of systematic coil shifts on both the TEP N100 component and MEPs in addition to the relationship between both parameters. In 12 healthy adults, the center of a standardized grid was fixed above the hot spot of the target muscle of the left primary motor cortex. Twelve additional positions were arranged in a quadratic grid with positions between 5 and 10 mm from the hot spot. At each of the 13 positions, TMS single pulses were applied. The topographical maximum of the resulting N100 was located ipsilateral and slightly posterior to the stimulation site. A source analysis revealed an equivalent dipole localized more deeply than standard motor cortex coordinates that could not be explained by a single seeded primary motor cortex dipole. The N100 topography might not only reflect primary motor cortex activation, but also sum activation of the surrounding cortex. N100 amplitude and latency decreased significantly during stimulation anterior-medial to the hot spot although MEP amplitudes were smaller at all other stimulation sites. Therefore, N100 amplitudes might be suitable for detecting differences in local cortical excitability. The N100 topography, with its maximum located posterior to the stimulation site, possibly depends on both anatomical characteristics of the stimulated cortex and differences in local excitability of surrounding cortical areas. The less excitable anterior cortex might contribute to a more posterior maximum. There was no correlation between N100 and MEP amplitudes, but a single-trial analysis revealed a trend toward larger N100 amplitudes in trials with larger MEPs. Thus, functionally efficient cortical excitation might increase the probability of higher N100 amplitudes, but TEPs are also generated in the absence of MEPs.

Dataset Information

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

Publications

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

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