Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA/glutamate balance

Abstract

Sodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABAB receptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate (Glu) in the anterior cingulate cortex (ACC). Sixteen healthy male volunteers received 50mg/kg GHB p.o. or placebo at 02:30am to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00am of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared to placebo. This SN-rCEN coupling was significantly associated with changes in GABA and GABA/Glu levels in the ACC (pall<0.05). The proposed framework allows to identify a neural pattern of pharmacological modulation of the SN, which may serve as a neurobiological signature of the wake-promoting effects of GHB.