Cortical GABA Levels Are Reduced in Post-Acute COVID-19 Syndrome.

After recovering from the acute COVID-19 illness, a substantial proportion of people continue experiencing post-acute sequelae of COVID-19 (PASC), also termed "long COVID". Their quality of life is adversely impacted by persistent cognitive dysfunction and affective distress, but the underlying neural mechanisms are poorly understood. The present study recruited a group of mostly young, previously healthy adults (24.4 ± 5.2 years of age) who experienced PASC for almost 6 months following a mild acute COVID-19 illness. Confirming prior evidence, they reported noticeable memory and attention deficits, brain fog, depression/anxiety, fatigue, and other symptoms potentially suggestive of excitation/inhibition imbalance. Proton magnetic resonance spectroscopy (1H-MRS) was used to examine the neurochemical aspects of cell signaling with an emphasis on GABA levels in the occipital cortex. The PASC participants were compared to a control (CNT) group matched in demographics, intelligence, and an array of other variables. Controlling for tissue composition, biological sex, and alcohol intake, the PASC group had lower GABA+/water than CNT, which correlated with depression and poor sleep quality. The mediation analysis revealed that the impact of PASC on depression was partly mediated by lower GABA+/water, indicative of cortical hyperexcitability as an underlying mechanism. In addition, N-acetylaspartate (NAA) tended to be lower in the PASC group, possibly suggesting compromised neuronal integrity. Persistent neuroinflammation may contribute to the pathogenesis of PASC-related neurocognitive dysfunction.

Cortical GABA levels are reduced in young adult binge drinkers: Association with recent alcohol consumption and sex.

Binge drinking refers to a pattern of alcohol intake that raises blood alcohol concentration to or above legal intoxication levels. It is common among young adults and is associated with health risks that scale up with alcohol intake. Acute intoxication depresses neural activity via complex signaling mechanisms by enhancing inhibition mediated by gamma-amino butyric acid (GABA), and by decreasing excitatory glutamatergic effects. Evidence primarily rooted in animal research indicates that the brain compensates for the acute depressant effects under the conditions of habitual heavy use. These neuroadaptive changes are reflected in neural hyperexcitability via downregulated inhibitory signaling, which becomes apparent as withdrawal symptoms. However, human evidence on the compensatory reduction in GABA signaling is scant. The neurochemical aspect of this mechanistic model was evaluated in the present study with proton magnetic resonance spectroscopy (1H-MRS) which is sensitive to GABA plus macromolecule signal (GABA + ). Furthermore, we examined sex differences in GABA + levels as a function of a recent history of binge drinking, given interactions between endogenous neurosteroids, GABA signaling, and alcohol. The study recruited young adult women and men (22.2 ± 2.8 years of age) who were classified as binge drinkers (BDs, N = 52) if they reported ≥ 5 binge episodes in the previous six months. Light drinkers (LDs, N = 49) reported drinking regularly, but not exceeding ≤ 2 binge episodes in the past six months. GABA-edited 1H-MR spectra were acquired from the occipital cortex at 3 T with the MEGA-PRESS sequence. GABA + signal was analyzed relative to water and total creatine (Cr) levels as a function of binge drinking history and sex. Controlling for within-voxel tissue composition, both GABA + indices showed decreased GABA + levels in BDs relative to LDs. The reduced GABA + concentration was associated with occasional high-intensity drinking in the BD group. This evidence is consistent with compensatory GABA downregulation that accompanies alcohol misuse, tipping the excitation/inhibition balance towards hyperexcitability. Analysis of the time course of GABA + neuroplasticity indicated that GABA + was lowest when measured one day after the last drinking occasion in BDs. While the BD vs LD differences were primarily driven by LD women, there was no interaction between Sex and a history of binge drinking. GABA + was higher in LD women compared to LD men. Aligned with the allostasis model, the mechanistic compensatory GABA downregulation observed in young emerging adults engaging in occasional binge drinking complements direct neural measures of hyperexcitability in BDs. Notably, these results suggest that neuroadaptation to alcohol is detectable at the levels of consumption that are within a normative range, and may contribute to adverse health outcomes.

Local and network-level dysregulation of error processing is associated with binge drinking.

Binge drinking refers to the pattern of alcohol consumption that brings blood alcohol levels to or above legal intoxication levels. Commonly practiced by young adults, it is associated with neurofunctional alterations, raising health-related concerns. Executive deficits may contribute to the inability to refrain from excessive alcohol intake. As a facet of cognitive control, error processing allows for flexible modification of behavior to optimize future outcomes. It is highly relevant to addiction research, as a failure to inhibit excessive drinking results in relapses, which is a hallmark of alcohol use disorder. However, research on local and system-level neural underpinnings of inhibition failures as a function of binge drinking is limited. To address these gaps, functional magnetic resonance imaging (fMRI) was used to examine local changes and interregional functional connectivity during response inhibition errors on a Go/NoGo task. Young adult binge drinkers (BDs) performed equally well as light drinkers (LDs), a group of demographically matched individuals who drink regularly but in low-risk patterns. In contrast, BDs exhibited greater fMRI activity to inhibition errors contrasted with correct NoGo trials in the rostral anterior (rACC) and posterior cingulate cortices (PCC), as well as right middle frontal gyrus (R-MFG). Furthermore, BDs showed increased connectivity between the rACC and right lateral prefrontal cortex, in addition to greater connectivity between the R-MFG and the left ventrolateral and superior frontal cortices. Imaging indices were positively correlated only with alcohol-related measures, but not with those related to moods, disposition, or cognitive capacity. Taken together, greater error-related activity and expanded functional connectivity among prefrontal regions may serve a compensatory role to maintain efficiency of inhibitory control. Aligned with prominent models of addiction, these findings accentuate the importance of top-down control in maintaining low-risk drinking levels. They provide insight into potentially early signs of deteriorating cognitive control functions in BDs and may help guide intervention strategies aimed at preventing excessive drinking habits.

Binge drinking is associated with altered resting state functional connectivity of reward-salience and top down control networks.

Binge drinking is characterized by bouts of high-intensity alcohol intake and is associated with an array of health-related harms. Even though the transition from occasional impulsive to addictive alcohol use is not well understood, neurobiological models of addiction suggest that repeated cycles of intoxication and withdrawal contribute to the development of addiction in part through dysregulation of neurofunctional networks. Research on the neural sequelae associated with binge drinking is scant but resting state functional connectivity (RSFC) studies of alcohol use disorders (AUD) indicate that the development and maintenance of long-term excessive drinking may be mediated by network-level disruptions. The present study examined RSFC in young adult binge (BD) and light (LD) drinkers with seeds representing the networks subserving reward (the nucleus accumbens and caudate nucleus), salience (anterior cingulate cortex, ACC), and executive control (inferior frontal cortex, IFC). BDs exhibited enhanced connectivity between the striatal reward areas and the orbitofrontal cortex and the ACC, which is consistent with AUD studies and may be indicative of alcohol-motivated appetitive behaviors. Conversely, BDs demonstrated lower connectivity between the IFC and hippocampus which was associated with higher craving. This may indicate impaired ability to suppress unwanted thoughts and a failure to employ memory of the harmful consequences of heavy drinking in prospective plans and intentions. The observed greater connectivity of the reward/salience network and the lower prefrontal-hippocampal connectivity were associated with hazardous drinking levels indicating that dysregulation of neurofunctional networks may underlie binge drinking patterns.