Gamma‐hydroxybutyrate increases brain resting‐state functional connectivity of the salience network and dorsal nexus in humans

Abstract

&NA; According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting‐state functional connectivity (rsFC) of these networks enables the elucidation of drug‐induced brain alterations. Gamma‐hydroxybutyrate (GHB) is a GHB/GABA‐B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo‐controlled, double‐blind, randomized, cross‐over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN‐, SN‐, CEN‐, and dorsal nexus‐rsFC measured by functional magnet resonance imaging and applying independent component as well as seed‐based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN‐, and CEN‐rsFC remained largely unchanged under GHB, but the drug increased SN‐DMN‐rsFC and SN‐dorsal nexus‐rsFC, while dorsal nexus‐rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN‐dorsal nexus‐rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN‐dorsal nexus‐rsFC was demonstrated to be a potential signature of the sedative component of the drug effect. HighlightsGHB increases salience network functional connectivity to the default mode network in humans.GHB increases salience network functional connectivity to the dorsal nexus in humans.GHB increases dorsal nexus functional connectivity to the right salience and the right executive control network in humans.Sedation is mediated by increased salience network functional connectivity to the dorsal nexus.