Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID, 2026, Sun et al.

[SNT Gatchaman]

Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID

Spoiler: Authors

Haoqi Sun; Rammy Dang; Peng Li; Wenzhong Xiao; Jennifer Scott-Sutherland; Kenneth C Sassower; M Brandon Westover; Donna Felsenstein; Robert J Thomas; Monika Haack; Janet M Mullington

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.

Web | DOI | PDF | Sleep | Paywall

 

[Ash]

@SNT Gatchaman do you rate this?

 

[SNT Gatchaman]

Yes, as far as I follow it. They're trying to demonstrate objective data to correlate with subjective poor and unrefreshing sleep. There's quite a lot of complex EEG terminology, which we might have to find some review papers to follow. The thalamus and the locus coeruleus pop up. I'll put some summary quotes up.

 

[SNT Gatchaman]

Acknowledgements

Work was supported by the Open Medicine Foundation and Patient-Led Collaborative (to JMM and WX) and the NHLBI/NINDS/NIAID RECOVER Initiative research studies at Beth Israel Deaconess Medical Center (JMM). Additional research support was provided by the NIH

Disclosure

MBW is a co-founder, serves as a scientific advisor and consultant to, and has a personal equity interest in Beacon Biosignals.

Limitations

First, the sample size was modest. The control group was drawn from historical cohorts and had stricter exclusion criteria than the LC group.

Second, some LC participants were taking medications, such as antidepressants and hypnotics (Table S2). As shown in Table S3, within the LC group, pain medication is associated with a more negative spindle chirp, which could explain the more negative spindle chirp in the LC group than in the HC group in Table 2. Similarly, some LC participants had pre-COVID comorbidities, such as sleep apnea, insomnia, depression or anxiety, and headache or migraine (Table S2). However, we did not find common sleep patterns in Table S4 compared with those in Table 2, indicating the results are less affected by pre-COVID comorbidities.

In general, a larger sample size is required to adequately account for medications and comorbidities. Third, although in-lab facility-measured polysomnography is the gold standard for recording sleep, a first-night effect can occur, particularly in terms of total sleep time, which may not accurately reflect habitual sleep patterns.

 

[SNT Gatchaman]

Introduction —

A major challenge is the lack of objective biomarkers that capture the hallmark symptom of non-restorative sleep despite relatively modest abnormalities in conventional sleep architecture.

Electroencephalographic (EEG) microstructures of sleep are explicitly related to brain and body functions […] going beyond the known subjective sleep quality and sleep architectural changes (macrostructure) in LC. Importantly, EEG microstructure metrics may help bridge the long-recognized discrepancy between subjective sleep quality and objective polysomnographic measures such as N3 duration or wake after sleep onset (WASO).

For example, delta band power in non-rapid eye movement (NREM) stage 3 (N3) reflects the net effect of circadian and sleep homeostasis; its reduction across the sleep period reflects plasticity homeostasis; spindles and their coupling to slow oscillations (SO, 0.5-1Hz) are related to memory consolidation; alpha-delta (alpha intrusion) is associated with chronic fatigue; and infraslow oscillations (ISO) associated with norepinephrine-induced glymphatic clearance.

Methods —

This was an observational study. Participants were recruited through internet advertisements, physical flyers in the Greater Boston Area, postings on ClinicalTrials.gov, and referrals from clinicians at the Critical Illness and COVID-19 Survivorship Clinic

The HCs were a convenience sample of individuals from past studies who enrolled in a study of sleep in healthy people31, hence having different exclusion criteria than the LC participants. Controls were 1:1 matched by sex and age (±5 years) to the LC participants.

The ME/CFS patient cohort was obtained from Massachusetts General Hospital (MGH) in 2022.

 

[SNT Gatchaman]

Results —

The cohort consisted of 28 LC participants and 28 age-sex-matched HC participants. […] Participants were about 37 to 38 years old on average, with 71.4% being female. By design, there were no significant differences in age and sex.

The LC group had reduced total sleep time, about 8% lower sleep efficiency, about three times longer sleep latency, spent less time in REM sleep, mainly during the second half of the night, and had approximately twice the REM latency than HC. The lower REM duration in LC is not a byproduct of reduced total sleep time, since the REM percent is also lower.

We did not find significant differences between HC and LC in alpha-delta patterns (p = 0.58), brain age index (BAI, +0.4 years in HC and +1.0 years in LC, p = 0.39), or overnight delta power reduction (p = 0.54).

There was no difference in the spindle density, amplitude, frequency, or duration between HC and LC.

The duration of the SO [Slow Oscillation] positive peak was shorter in LC at 0.45 seconds compared to HC at 0.50 seconds (p < 0.001). Meanwhile, the SO rising slope was steeper in the LC at 326.3uV/s than in the HC at 264.3uV/s (p < 0.01).

The ME/CFS participants were about 41 years old on average, and 74% were female. There were no significant differences in age and sex compared to HC.

Compared to HC, the ME/CFS group had about 5% lower sleep efficiency, about three times longer sleep latency, less time spent in REM regardless of the first or second half of the night, about twice the REM latency, and more continuous N1.

When comparing the spindle and SO patterns to HC, similar to LC, the widespread phase advance in ME/CFS was present in both fast and slow spindles, with the most pronounced effect observed in fast spindles. […] For the fast spindles, the ME/CFS group also had a more negative fast spindle chirp compared to the controls, a pattern similar to that seen in the LC group.

ME/CFS patients had a lower frontal delta power at wake before sleep onset than LC patients (ME/CFS median 15.5dB, LC median 20.5dB, p < 0.001); ME/CFS patients also had a higher alpha-to-delta ratio in the occipital region in the first half of NREM sleep than LC patients (ME/CFS median 0.35, LC median 0.21, p = 0.009) that similarly became insignificant after Bonferroni correction.

 

[SNT Gatchaman]

Discussion —

One key finding is that spindle morphology differed between groups, despite density, amplitude, duration, and frequency being similar. The spindle morphological differences include a more negative spindle chirp (rate of IF [Instantaneous Frequency] change), a weaker correlation between IF and SO [Slow Oscillation] phase, and an advanced SO-coupling phase in LC.

Spindles are generated in the thalamus, propagated to the cortex, and form a feedback loop between the cortex and thalamus. Although the impairment mechanism is unknown in LC, the thalamocortical feedback loop is possibly impaired by a few mechanisms, e.g., 1) an excitation/inhibition imbalance from a glial pro-inflammatory responses to viral infection; 2) mitochondrial impairment 3) redox-stress from a lower nocturnal SpO2, all contributing to impaired synchronization of spike timing at the dendritic level. Therefore, there could be an insufficient “push” for spindle activity, as reflected in an abnormal coupling phase.

Interestingly, spindle characteristics in ME/CFS and LC share differences in terms of spindle chirp and advanced spindle-SO coupling phase, while also showing distinct differences in increased SO-uncoupled slow spindle density in frontal and central regions, compared with HC.

ME/CFS patients may have reduced efficiency in producing fast spindles that support brain health compared to LC patients.

Notably, the alpha-delta pattern (alpha intrusion) was not different in LC but was higher in the ME/CFS group before the Bonferroni correction. The alpha-delta pattern is well known for its correlation with fatigue, non-refreshing sleep, and fibromyalgia. However, the neural basis of the alpha-delta pattern remains poorly understood.

The ISO [Infraslow Oscillation] relative power was higher in LC participants at the frontal regions from the slow spindle band. ISO has been found to correlate with the rhythmic release of norepinephrine from the locus coeruleus, which enables glymphatic clearance and boosts the flow of blood and cerebrospinal fluid. Our previous work, comparing blood oxygen levels (SpO2) in the same cohort, showed lower baseline SpO2 in LC participants. Therefore, one hypothesis is that the increase in ISO may reflect a compensatory mechanism to maintain the required total oxygen by increasing blood volume, because of reduced blood oxygen saturation.

No difference was found in the sleep EEG-based brain age index (BAI). BAI is driven by a selected set of age-dependent sleep EEG features, including delta power, delta-to-alpha ratio, delta-to-theta ratios, spindle density, spindle-SO coupling overlap, and power and waveform kurtosis (measures bursts) in N2 and N3, and alpha power in N1. These patterns were not different between HC and LC, suggesting that LC may represent differences in specific neural dynamics that are insensitive to age.

The associations between sleep EEG microstructures and the subjective sleep quality measures provide new insights. The fast spindle-SO coupling phase, being significantly phase-advanced in LC, is positively correlated with higher diary-based rest quality in LC. Therefore, the fast spindle-SO coupling phase may serve as a marker of the severity of LC-related sleep quality and fatigue.

 

[SNT Gatchaman]

Spindles are generated in the thalamus, propagated to the cortex, and form a feedback loop between the cortex and thalamus. Although the impairment mechanism is unknown in LC, the thalamocortical feedback loop is possibly impaired by a few mechanisms, e.g., 1) an excitation/inhibition imbalance from a glial pro-inflammatory responses to viral infection; 2) mitochondrial impairment 3) redox-stress from a lower nocturnal SpO2, all contributing to impaired synchronization of spike timing at the dendritic level. Therefore, there could be an insufficient “push” for spindle activity, as reflected in an abnormal coupling phase.

Perhaps we could add AMPA / fast glutamergic thalamic synapse dysregulation to that list, although I don't know if the increased AMPA density described in Systemic increase of AMPA receptors associated with cognitive impairment of long COVID (2025) could be in the right direction in terms of excitation/inhibition imbalance.

Just looking at this week's news in brief posting there are five LC neuro paper all arguing against neuroinflammation and most describing vascular dysfunction.

Spoiler: Neuro papers

Vascular Inflammation in Neuropsychiatric Long COVID — McAlpine et al
"We identified a novel and distinct vascular inflammatory signature in Long COVID, characterized by elevations in endothelial adhesion–related biomarkers (α-2 macroglobulin, sL-selectin), suggesting a mechanism of endothelial activation rather than residual post-acute inflammation."
Article | Thread

Cerebrovascular recovery drives restoration of neurometabolite levels after mild COVID-19 — Coe et al
"We showed that GM CVR delay was associated with tCho, tCr, and tNAA levels in the thalamic region" "Unlike CVR delay itself, the concentrations of these metabolites did not exhibit spontaneous normalization as a function of post-infection time, but rather appeared to depend on vascular recovery."
Article | Thread

Reduced cortical brain perfusion following COVID-19 infection: impact of COVID-19 severity and relation to memory performance — Palmer et al
"Gray matter perfusion also uniquely predicted pattern separation performance" "the lack of prolonged damage to the white matter provides further support that disrupted perfusion is at least one of the prominent drivers of cognitive sequelae"
Article | Thread

Association between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET study — Tuomaala et al
"We found no evidence of increased TSPO availability or elevated serum biomarkers indicative of CNS damage in LC patients experiencing psychiatric and cognitive symptoms on average 17 months post-infection." "These findings suggest that persistent LC symptoms are unlikely to be driven by ongoing elevated neuroinflammation."
Article | Thread

Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity — Visser et al
"Our results revealed changes in thalamic somatomotor connectivity to be mainly driven by neurocognitive complaints rather than neuroinflammatory activity."
Article | Thread

The ISO [Infraslow Oscillation] relative power was higher in LC participants at the frontal regions from the slow spindle band. ISO has been found to correlate with the rhythmic release of norepinephrine from the locus coeruleus, which enables glymphatic clearance and boosts the flow of blood and cerebrospinal fluid. Our previous work, comparing blood oxygen levels (SpO2) in the same cohort, showed lower baseline SpO2 in LC participants. Therefore, one hypothesis is that the increase in ISO may reflect a compensatory mechanism to maintain the required total oxygen by increasing blood volume, because of reduced blood oxygen saturation.

Our thread for that paper is Facility-measured nocturnal hypoxemia and sleep among adults with long COVID versus age- and sex-matched healthy adults: a preliminary observational study (2025)