Nocturnal sodium oxybate increases the anterior cingulate cortex magnetic resonance glutamate signal upon awakening

Abstract

Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ-hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB-enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double-blind cross-over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography-defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two-dimensional, J-resolved, point-resolved magnetic resonance spectroscopy (PRESS) localisation at 3-Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB-enhanced sleep in all participants in whom good-quality spectroscopy data were available (n = 16; pFDR < 0.002). Further, global vigilance (10th-90th inter-percentile range on the PVT) was improved (pFDR < 0.04) and median PVT response time was shorter (pFDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro-vigilant efficacy in disorders of hypersomnolence.

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

“…Importantly, we did not find any significant effects of GHB on the subjective mental state in this study. However, we observed increased sustained vigilant attention (assessed with a 10-min visual psychomotor vigilance test), which was tested in the same experiment and reported in a previous publication ( Dornbierer et al. 2023 ).…”

“…In contrast, the post-acute behavioral effects of nocturnal 50 mg/kg oral GHB included activation and vigilance enhancement ( Robinson and Keating 2007 ; Buchele et al. 2018 ; Dornbierer et al. 2023 ).…”

“…To investigate how the reported modulation of rsFC alterations relate to the neurochemical brain homeostasis, we analyzed previously published data of MRS from an ACC-seed assessed in the same individuals and from the same experiment ( Dornbierer et al. 2023 ).…”

“…2019a ), kynurenine pathway metabolites ( Dornbierer et al. 2019b ), and post-awakening brain metabolite signals and vigilance ( Dornbierer et al. 2023 ) were also assessed in the experiment and published elsewhere.…”

“…A single voxel (sv-) MRS was performed at each experimental session immediately before the fMRI paradigm, using two-dimensional J-resolved spectroscopy combined with PRESS localization (2D-JPRESS) sequence. The voxel with an effective size of 14.8 cm 3 was placed in the anterodorsal portion of the ACC (see MRS-protocol details in a separate publication and in Supplementary Material ; Dornbierer et al. 2023 ).…”