Nocturnal Sodium Oxybate Treatment Functional Network Changes Associated With Anterior Cingulate GABA

Francesco Bavato, MD

Recently published in Cerebral Cortex, findings from a study demonstrated that anterior cingulate γ-aminobutyric acid (GABA) was associated with subacute changes in brain functional network connectivity following nocturnal sodium oxybate (GHB; Xyrem; Jazz Pharmaceuticals) treatment. These results provide evidence of the persisting internetwork connectivity changes in the morning following a nocturnal therapeutic dose of GHB, a therapeutic often used for patients with narcolespy.¹

Among 16 healthy men, a significant effect was observed in the internetwork connectivity of the right central executive network (rCEN) with the salience network (SN) (one sample t-test: P = .038), which was not present in the placebo group (one sample t-test: P = .460). Also, rCEN-SN internetwork connectivity was significantly higher in the GHB group compared with placebo (paired t-test: P = 0.017, Cohen d = 0.49, respectively). Thus, this SN-rCEN coupling was significantly associated with changes in GABA levels in the anterior cingulate cortex (ACC) (all, P<.05).

“The observed alteration in connectivity pattern seem to indicate a modulation of the balancing function of the SN between the [default mode network] and the [central executive network], toward a more externally oriented brain state, which is in line with GHB’s ability to improve next day waking functions. We also described a GHB-induced positive interaction of GABA/Glu balance in the ACC with whole-brain connectivity changes,” lead author Francesco Bavato, MD, a postdoctoral researcher in the department of psychiatry, psychotherapy, and psychosomatics at the Psychiatric University Hospital Zurich of the University of Zurich, and colleagues wrote.¹

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Investigators conducted 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 in the ACC. There were 2 experimental nights investigating GHB versus placebo which were separated by a washout phase of 7 days. The participants wore an actimeter on the nondominant arm and kept a sleep–wake diary. At each experimental night, study participants were awoken at 2:30 AM to receive 50 mg/kg of GHB or placebo, representing the maximal therapeutic starting dose for narcolepsy. Following the treatment, researchers performed the fMRI resting state scans in the morning after both experimental nights.

In the generalized linear regression models, findings revealed that ΔrsFC of the rCEN-SN was significantly associated with ΔGABA (B = 2.69; SE = 1.10; 95% CI, 0.54-4.84; P = .014) and not with ΔGlu (B = –0.47; SE = 0.44; 95% CI, −1.33, 0.39; P = .284), following the correction for experimental session order. Notably, these models demonstrated no significant effects of condition in GHB compared with the placebo and experimental session order on morning self-report questionnaire EWL-60 subscale scores (all, P > 0.13).

Limitations of the study included that the final sample size since 4 individuals were excluded in the analysis which resulted in lower statistical power and limited the generalizability of the results. Authors noted that MRS-data limited their investigation to the ACC and that neurochemical alterations could have also occurred in other crucial SN hubs such as the anterior insula. As such, the relevance of mesolimbic dopamine levels for SN regulation might contribute to the effects of GHB on rsFC. Researchers also noted that study sample had only young healthy men as participants, with reason to avoid any interference of hormonal fluctuations during the menstrual cycle on metabolite levels in the brain.

“Thus, our findings support the idea of an excitatory/inhibitory equilibrium in the ACC to be actively involved in the modulation of rsFC on a large-scale level. Future research should clarify the generalizability of these findings to other stimulant and/or sedative drugs affecting GABA and Glu homeostasis and further assess correlations with cognitive and behavioral effects in clinical populations,” Bavato et al wrote.¹

REFERENCES
 1. Bavato F, Esposito F, Dornbierer DA, et al. Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA. Cereb Cortex. 2023;33(12):8046-8055. doi:10.1093/cercor/bhad097