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

Abstract

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.

Keywords: 1H-MRS; GABA; NAA; anxiety; cognitive deficits; depression; excitation/inhibition balance; insomnia; long COVID; magnetic resonance spectroscopy.

Figure 1

Histograms depict average increase in symptom severity on a scale from 0 (not at all) to 4 (very much) since recovering from the acute COVID-19 illness (means ± standard errors).

Figure 2

PROMIS (Patient-Reported Outcomes Measurement Information System) [91] comprises a set of short-form scales used to assess seven health domains in PASC (post-acute sequelae of COVID-19) participants. The scores were standardized with a T-score metric based on a normative sample with a mean of 50 (marked with a dotted line) and standard deviation of 10 [96]. PASC participants reported higher anxiety and depression on the two PROMIS scales. The PASC group also reported greater subjective cognitive impairment, as reflected in lower scores on MISCI (Multidimensional Inventory of Subjective Cognitive Impairment) [93], here shown after conversion to PROMIS-compatible T-scores. * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 3

Example of (a) voxel placement in the occipital lobe centered on the median and aligned with the tentorium in the sagittal plane; (b) segmentation of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) for a single participant.

Figure 4

Representative spectra for a single participant: (a) non-edited spectra between 0 and 5 ppm; (b) edited spectra between 2.8 and 4.2 ppm (blue line) along with fitted peaks showing GABA+ and Glx model (red line) and the residuals (black line); (c) reference signal showing the modeling of water from the OFF spectrum.

Figure 5

Group means ± standard errors of GABA+/water and NAA (N-acetylaspartate) for PASC and CNT groups. Controlling for the effect of tissue composition, biological sex, and drinking, the PASC group demonstrated lower values than CNT for both metabolites. * p < 0.05, # p < 0.14.

Figure 6

(a) Mediation analysis model showing the effect of PASC on depression (PROMIS scale) mediated by GABA+/w. (b) Scatterplot indicates that GABA+/w correlates with depression within the PASC group only. Lines represent regression between GABA+/w and depression PROMIS scores on the x-axis. PROMIS: Patient-Reported Outcomes Measurement Information System [91].