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

Darmani, Ghazaleh; Bergmann, Til Ole; Zipser, Carl Moritz; Baur, Dirk G.; Müller‐Dahlhaus, Florian; Ziemann, Ulf

doi:10.1002/hbm.24448

Cited by 73 publications

(55 citation statements)

References 87 publications

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“…XEN1101 is a novel potassium channel opener with the same mechanism of action as retigabine. We hypothesized that XEN1101 would show TMS‐EDM effects, modulating cortical excitability consistent with previous TMS studies of AEDs . As predicted, we found that XEN1101 had strong effects on RMT and TEPs, which suggests that it reduces cortical excitability.…”

Section: Introductionsupporting

confidence: 86%

TMS as a pharmacodynamic indicator of cortical activity of a novel anti‐epileptic drug, XEN1101

Premoli

Rossini

Goldberg

et al. 2019

Ann Clin Transl Neurol

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Objective: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. Methods: TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. Results: Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. Interpretation: Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform earlystage clinical trials. 2164

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Section: Introductionsupporting

confidence: 86%

TMS as a pharmacodynamic indicator of cortical activity of a novel anti‐epileptic drug, XEN1101

Premoli

Rossini

Goldberg

et al. 2019

Ann Clin Transl Neurol

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“…Pharmacological studies targeting inhibitory receptors have provided evidence that certain TEP peaks around 45 and 100 ms are sensitive to changes in GABAergic neurotransmission 13,14 , whereas peaks at 30 ms, 45 ms and 180 ms are sensitive to anti-epileptic drugs targeting voltage-gated sodium channels 51,52 . However, the sensitivity of TEPs to changes in excitatory neurotransmission is less clear.…”

Section: Effects Of Dextromethorphan On Tepsmentioning

confidence: 99%

The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Rogasch

Zipser

Darmani

et al. 2020

Sci Rep

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Measuring the brain's response to transcranial magnetic stimulation (TMS) with electroencephalography (EEG) offers unique insights into the cortical circuits activated following stimulation, particularly in non-motor regions where less is known about TMS physiology. However, the mechanisms underlying TMS-evoked EEG potentials (TEPs) remain largely unknown. We assessed TEP sensitivity to changes in excitatory neurotransmission mediated by n-methyl-d-aspartate (NMDA) receptors following stimulation of non-motor regions. In fourteen male volunteers, resting EEG and TEPs from prefrontal (PFC) and parietal (PAR) cortex were measured before and after administration of either dextromethorphan (NMDA receptor antagonist) or placebo across two sessions in a doubleblinded pseudo-randomised crossover design. At baseline, there were amplitude differences between PFC and PAR TEPs across a wide time range (15-250 ms), however the signals were correlated after ~80 ms, suggesting early peaks reflect site-specific activity, whereas late peaks reflect activity patterns less dependent on the stimulated sites. Early TEP peaks were not reliably altered following dextromethorphan compared to placebo, although findings were less clear for later peaks, and low frequency resting oscillations were reduced in power. Our findings suggest that early TEP peaks (<80 ms) from PFC and PAR reflect stimulation site specific activity that is largely insensitive to changes in NMDA receptor-mediated neurotransmission.Transcranial magnetic stimulation (TMS) is a brain stimulation method capable of non-invasively activating cortical neurons across the scalp in humans via electromagnetic induction 1 . A single TMS pulse evokes a series of time-locked peaks and troughs in electroencephalographic (EEG) recordings of brain activity 2 , which are commonly known as TMS-evoked EEG potentials (TEPs). TEPs are reliable within and between sessions 3-5 , are sensitive to changes in TMS parameters such as intensity 4 and pulse shape 6 , and differ depending on the cortical site stimulated 4,7 . In addition, TEPs are sensitive to changes in cortical properties resulting from differing brain states, plasticity-inducing brain stimulation paradigms, and brain disorders 8 . As such, TMS-EEG is emerging as a powerful method for investigating cortical dynamics in health and disease.Despite the recent uptake of TMS-EEG within the brain stimulation field, it remains largely unclear what physiological properties underlie the size, shape and distribution of TEPs, thereby limiting their interpretability. Current hypotheses suggest that TEPs primarily reflect fluctuations in cortical excitability resulting from excitatory and inhibitory neurotransmission at the site of stimulation, as well as the propagation of activation through www.nature.com/scientificreports www.nature.com/scientificreports/ PFC (15-45 ms) 60 [18-133] 73 [40-103] 0.93 [0.81-0.99] 0.135 PFC (95-125 ms) 80 [24-129] 59 [20-110] 0.88 [0.68-0.99] 0.077 PFC (175-205 ms) 80 [37-123] 51 [21-122] 0.84 [0.69-0.99] 0....

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“…In most studies that have employed TMS to perturb or modify brain activity, behavioural or physiological data are typically collected over experimental sessions that last up to an hour or more (e.g. Darmani et al, 2018;Herring et al, 2015;Salminen-Vaparanta et al, 2013). The implicit assumption is that participants' levels or alertness remain relatively consistent for the duration of the testing session.…”

Section: Introductionmentioning

confidence: 99%

Alertness fluctuations during task performance modulate cortical evoked responses to transcranial magnetic stimulation

Noreika

Kamke

Canales‐Johnson

et al. 2017

Preprint

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Transcranial magnetic stimulation (TMS) has been widely used in human cognitive neuroscience to examine the causal role of distinct cortical areas in perceptual, cognitive and motor functions. However, it is widely acknowledged that the effects of focal cortical stimulation on behaviour can vary substantially between participants and even from trial to trial within individuals. Here we asked whether spontaneous fluctuations in alertness can account for the variability in behavioural and neurophysiological responses to TMS. We combined single-pulse TMS with neural recording via electroencephalography (EEG) to quantify changes in motor and cortical reactivity with fluctuating levels of alertness defined objectively on the basis of ongoing brain activity. We observed rapid, non-linear changes in TMS-evoked neural responses – specifically, motor evoked potentials and TMS-evoked cortical potentials – as EEG activity indicated decreasing levels of alertness, even while participants remained awake and responsive in the behavioural task.IMPACT STATEMENTA substantial proportion of inter-trial variability in neurophysiological responses to TMS is due to spontaneous fluctuations in alertness, which should be controlled for during experimental and clinical applications of TMS.

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

Cited by 73 publications

References 87 publications

TMS as a pharmacodynamic indicator of cortical activity of a novel anti‐epileptic drug, XEN1101

TMS as a pharmacodynamic indicator of cortical activity of a novel anti‐epileptic drug, XEN1101

The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Alertness fluctuations during task performance modulate cortical evoked responses to transcranial magnetic stimulation

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