“Differential Cortical Effects of Synaptic versus Extrasynaptic GABAA Receptor Modulation with Lorazepam and Brexanolone: A Randomized, Double-Blind, Placebo-Controlled, Cross-over TMS and EEG Trial.”
Abstract
Aims GABAkines are a diverse class of compounds that modulate γ-aminobutyric acid (GABA) mediated inhibition, yet how their distinct receptor mechanisms translate into neurocircuit-level effects remains unclear. This study leveraged the benzodiazepine (BZD) lorazepam and neuroactive steroid (NAS) brexanolone to explore how synaptic versus combined synaptic and extrasynaptic GABAA receptor modulation differentially impact brain circuitry. Methods This double-blind, placebo-controlled, 4-way crossover study used a multimodal neurophysiology approach combining transcranial magnetic stimulation (TMS) with electromyography (TMS-EMG) and electroencephalography (TMS-EEG), and resting-state pharmaco-electroencephalography (pEEG). Participants received brexanolone (30 or 90 mcg/kg/h 3-hour infusion), lorazepam (2 mg oral), or matching placebo. Outcomes were analyzed using plasma drug concentrations, mixed models for repeated measures and cluster-based permutation testing. Results Brexanolone dose-dependently increased beta and theta power, enhanced long-interval intracortical inhibition (LICI100), and modulated early TMS-evoked potentials (TEPs) in contralateral centroparietal regions. Lorazepam increased beta power, suppressed theta power, and modulated later TEPs in frontocentral areas. Frontal theta power, LICI100 and specific TEP modulation distinguished brexanolone from lorazepam and may serve as NAS-specific biomarkers. Beta power increases correlated with drug exposure for…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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