Cannabidiol Lacks Direct Effect on Cortical Excitability: A Randomized, Double Blind, Placebo Controlled, 3-Way Crossover Trial.

Cannabidiol (CBD) is approved as an adjunctive treatment of seizures associated with Dravet syndrome, Lennox-Gastaut Syndrome, and tuberous sclerosis. Its therapeutic and adverse effects are thought to arise, at least partly, from a pharmacokinetic interaction with clobazam, another anti-seizure medication (ASM). The goal of this study was to evaluate the intrinsic anti-epileptic and sedative properties of CBD.

Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects.

TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine-1-Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects.

Current anti-epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment-resistant. Drugs targeting the sphingosine-1-phosphate receptor show potential anti-convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti-epileptic potential. TRV045 is a selective sphingosine-1-phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability.

Machine Learning Techniques for Developing Remotely Monitored Central Nervous System Biomarkers Using Wearable Sensors: A Narrative Literature Review.

Background: Central nervous system (CNS) disorders benefit from ongoing monitoring to assess disease progression and treatment efficacy. Mobile health (mHealth) technologies offer a means for the remote and continuous symptom monitoring of patients. Machine Learning (ML) techniques can process and engineer mHealth data into a precise and multidimensional biomarker of disease activity.

Transcranial magnetic stimulation as biomarker of excitability in drug development: A randomized, double-blind, placebo-controlled, cross-over study.

Aims: The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof-of-mechanism in early-phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double-blind, placebo-controlled, 4-way cross-over study.

Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation.

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans.

Spatiotemporal Dynamics of Single and Paired Pulse TMS-EEG Responses.

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain.

Infraslow activity as a potential modulator of corticomotor excitability.

Fluctuations in cortical excitability are a candidate mechanism involved in the trial-to-trial variation of motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS). We explore whether infraslow EEG activity (<0.1 Hz) modulates corticomotor excitability by evaluating the presence of temporal and phase clustering of TMS-induced MEPs.

Resting Motor Threshold, MEP and TEP Variability During Daytime.

Humans show a variation in physiological processes during the day. To reliably assess (changes in) cortical excitability with transcranial magnetic stimulation (TMS), it is relevant to know the natural variation in TMS readouts during the day. In case of significant daytime variations, this should be taken into account when scheduling (follow-up) measurements.

Accurate Coil Positioning is Important for Single and Paired Pulse TMS on the Subject Level.

Function-guided navigation is commonly used when assessing cortical excitability using transcranial magnetic stimulation (TMS). However, the required accuracy, stability and the effect of a change in coil positioning are not entirely known. This study investigates the accuracy of function-guided navigation for determining the hotspot.

Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study.

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus).

Fluid Resuscitation in Septic Patients Improves Systolic but not Diastolic Middle Cerebral Artery Flow Velocity.

To investigate the effects of fluid resuscitation on cerebral hemodynamics in sepsis, the following set of transcranial Doppler (TCD) parameters was used: maximal change in flow velocity (FV) during stroke onset (acc), maximal FV during first (sys1) or second (sys2) phase of systole and mean diastolic FV (dias@560). We aim to evaluate changes in cerebral hemodynamics that result from (i) sepsis and (ii) adequate fluid resuscitation in critically ill septic patients. In the majority of 16 septic patients sys2 was initially absent but reappeared during the period of fluid resuscitation; whereas sys2 absence was never seen in healthy controls.

Repeatability of long intracortical inhibition in healthy subjects.

Objectives: Transcranial magnetic stimulation (TMS) is widely used to assess cortical excitability. To detect changes in excitability with longitudinal studies, it is important to validate the repeatability of excitability measures within a subject between different sessions. Repeatability studies on long intracortical inhibition (LICI) are limited and reported agreement ranges from poor to good.

Single and paired pulse transcranial magnetic stimulation in drug naïve epilepsy.

Transcranial magnetic stimulation (TMS) measures cortical excitability and is therefore potentially suitable as an additional tool for epilepsy diagnostics and therapy evaluation. In this review we discuss the application of TMS in epilepsy research and systematically analyze single and paired pulse TMS outcomes from 31 drug naïve patient studies. Despite a large variety in used TMS protocols, there was no relation between specific protocol aspects and the occurrence of significant results.