Facility-measured sleep electroencephalographic microstructures in long COVID

Abstract Study Objectives Sleep electroencephalographic (EEG) microstructures are related to brain functions, providing a window into the unrefreshing, non-restorative sleep and daytime fatigue symptoms in long COVID (LC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We aim to characterize sleep EEG microstructural differences in individuals with LC and age-sex-matched healthy controls (HC), and also ME/CFS, using overnight in-lab facility-measured polysomnography (PSG). Methods 28 LC and 28 HC participants came from a single-center research study. 19 ME/CFS participants came from a single clinical center. Sleep EEG was processed to extract spectral band powers, spindles, slow oscillations (SO, 0.5-1 Hz), spindle-SO coupling, brain age index (BAI), alpha-delta patterns, and infraslow oscillation relative band power (ISO, 0.005-0.03 Hz). Results Compared to HC, LC had higher SO power during wake before sleep and REM sleep. In N2 and N3, LC showed a faster within-spindle frequency drop (chirp) and shorter SO peak duration in the frontal region. LC showed widespread, early spindle-SO coupling phase at SO trough for both fast and slow spindles, with early fast spindle-SO coupling associated with worse sleep quality. ME/CFS shared some differences with LC but had higher SO-uncoupled slow spindle densities in frontal and central regions, more alpha-delta patterns in the first half of the night, and widespread elevated ISO power in the slow sigma band (11-13 Hz). Conclusions These findings suggest that LC and ME/CFS are associated with plausibly pathological sleep EEG microstructure changes, illuminating the pathobiology of post-infectious processes on brain activity. Clinical trial information Trial 1: Sleep and Inflammatory Resolution Pathway, https://clinicaltrials.gov/study/NCT03377543, NCT03377543. Trial 2: Pain in Long COVID-19: the Role of Sleep, https://clinicaltrials.gov/study/NCT05606211, NCT05606211. Statement of Significance People with long COVID (LC) frequently experience sleep disturbances, non-restorative sleep, and fatigue. Sleep electroencephalographic (EEG) microstructures may offer objective markers of subjective sleep quality in LC. Here, we present an in-lab facility-measured sleep study. LC participants exhibited abnormally early spindle-slow oscillation (SO) coupling phase at the trough of the SO, and a faster drop in within-spindle frequency. The abnormally early spindle-SO coupling phase in LC was correlated with worse subjective sleep quality. Similar differences in EEG microstructural patterns were found in people with myalgic encephalomyelitis/chronic fatigue syndrome as well. The results demonstrate candidate electrophysiological abnormalities associated with the fatigue and non-restorative sleep experienced in LC.