Findings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle.
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
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.
Background Social restrictions due to COVID-19 might have had a significant impact on mental health. The aim of this study was to assess the prevalence of four emotional domains (nervousness, anger, numbness, physiological arousal) in a sample of citizens during the first pandemic wave in 2020, and their association with sociodemographic characteristics, housing conditions and lifestyle modifications. Methods A cross-sectional study based on a self-administered online questionnaire was set up to investigate emotions. Respondents were recruited through a non-probabilistic snowball sampling approach. The SPAN questionnaire was used to measure emotions in the interviewed population. The association between emotions and independent variables (gender, age, marital status, educational level, working condition, housing condition, COVID-19 positivity, sleep disturbance, increase in alcohol consumption and decrease in physical activity) was assessed through the multivariate Poisson regression. Results A total of 6,675 subjects were included in the analysis. Almost half of respondents (48.9%) experienced nervousness, 41.3% anger, 15.6% numbness and 18.8% physiological arousal. Females were more likely to face nervousness, anger and physiological arousal. For all the outcomes a decreasing trend was observed from younger to older. Singles were more likely to experience numbness compared to married people. Increase in alcohol consumption was associated with nervousness, anger and numbness. Decrease in physical activity was associated with nervousness, anger and physiological arousal. Restless sleep was the variable most associated with all emotional domains. Conclusions The first COVID-19 pandemic wave had a significant emotional impact on this sample, especially among younger people, singles and females. Even without reaching clinical relevance, these emotions could represent a form of psychological distress, which requires the implementation of preventive strategies, in particular regarding lifestyle care.
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