Publications

BACKGROUND: Poor sleep and pain perpetuate each other through a feed-forward cycle. While mechanisms driving this cycle remain poorly understood, they appear to involve inflammatory pathways. We investigated whether pre-emptive administration of low-dose acetylsalicylic acid (ASA, aspirin), which targets multiple inflammatory pathways, attenuates the pain response to a sleep restriction challenge in healthy adults.

METHODS: Forty-six participants completed a randomized, double-blind crossover protocol consisting of three conditions: sleep restriction/ASA, sleep restriction/placebo, and control sleep/placebo. Each participant completed all three conditions in randomized order. Study medication was administered throughout both the 14-day at-home phase and the subsequent 11-day laboratory stay. Sleep restriction consisted of five consecutive nights of 4-h sleep opportunity. Pain measures included spontaneous daily pain ratings and quantitative sensory testing assessing pain thresholds, pain tolerance, and central pain modulation (inhibition and facilitation).

RESULTS: Low-dose ASA intake for 14 days did not affect baseline assessments of spontaneous pain, pain sensitivity, or modulation (p > 0.05). However, ASA attenuated the pain response to sleep restriction, as evidenced by lower widespread and muscle pain ratings (p = 0.040, p = 0.009 for condition effect) and less impaired central pain inhibition (p = 0.020 for condition × day effect) compared to placebo.

CONCLUSIONS: Pre-emptive low-dose ASA attenuated pain responses to sleep restriction, particularly widespread pain and impaired central pain inhibition, consistent with modulation of nociplastic-like pain mechanisms. Elucidating the mechanisms underlying this effect of ASA could help inform the development of targeted strategies for individuals who experience recurrent short or disrupted sleep and may be at increased risk for chronic pain.

SIGNIFICANCE STATEMENT: Pre-emptive low-dose acetylsalicylic acid attenuated increases in spontaneous pain, heat pain sensitivity, and impaired central pain inhibition induced by experimental sleep restriction in healthy individuals. These findings suggest that inflammatory modulation may contribute to pain responses following sleep restriction and highlight a potential pathway for mitigating the sleep-related pain vulnerability.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT03377543).

INTRODUCTION: This was a pilot study designed to test the hypothesis that bedtime administration of acetylsalicylic acid (ASA) lowers BP through sleep improvements that impact the inflammatory, and renin-angiotensin-aldosterone system (RAAS). We predicted that ASA would enhance sleep consolidation and lower sympathetic activation, protecting against the physiological stress of fragmented sleep.

METHODS: Seven participants (5F, 2M, mean age 25.71 ± 4.03 years, body mass index (BMI) 22.40 ± 1.91 kg/m2) completed this within-subject, double-blind, balanced study involving 2 × 5 in-patient days. Participants were randomized to daily intake of ASA (81 mg/day) or placebo at bedtime for 2 weeks before each hospital research stay that included 1 baseline (BL) night, 2 nights of an experimental sleep disturbance (ESD) protocol and finally, 1 night of recovery sleep. The ESD protocol included 1-h delayed sleep onset, fragmentation of sleep with 5 × 20-min awakenings, and a 1-h earlier lights on time.

RESULTS: ASA did not decrease BP following the 2-week at-home ASA administration, nor during ESD. Evening renin was significantly reduced (p = .048), compared to placebo after 2 weeks of ASA. Mood and well-being improved after 2 weeks of ASA. There were statistical trends toward decreased 24-h average heart rate (p = .053), and increased heart rate variability (p = .080). When challenged with the ESD protocol, ASA was associated with a longer duration of individual slow waves (p = .013), lower 24-h average HR (p < .001) and a trend to greater non-rapid eye movement delta power (p = .061).

CONCLUSIONS: This pilot study is the first investigation exploring effects of ASA on renal & hemodynamic parameters at night, implicating sleep as an important mechanistic factor.

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 INFORMATIONTrial 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.

BACKGROUND: Sleep disturbance, which is a common symptom in Long COVID, promotes a pro-inflammatory state and dysregulates lipid-derived specialized pro-resolving mediators (SPMs), presumably contributing to chronic unresolved inflammation. This study aimed to investigate the role of sleep disturbance in inflammatory resolution in Long COVID.

METHODS: We studied 39 participants (30F/9M, age range 22-68 years), including 31 individuals with Long COVID and 8 SARS-CoV-2-infected controls, who did not develop Long COVID. The study consisted of a 14-day at-home phase followed by a 1-day (24-h) in-laboratory stay. Sleep disturbance was assessed using PROMIS Sleep Disturbance T-scores. During the in-laboratory stay, a fasting morning blood sample was taken for assessment of lipid mediators. Data were analyzed using generalized linear mixed models.

RESULTS: Participants with Long COVID reported higher sleep disturbance than controls (p<.001). Pro-inflammatory lipid pathways were upregulated in Long COVID compared to control, as indicated by higher prostaglandin E2 (PGE2) levels (p<.05). Long COVID participants with high sleep disturbance (PROMIS Sleep Disturbance T-score ≥60) had lower SPM levels, including the precursor of D-series resolvins 17-hydroxydocosahexaenoic acid (17-HDHA), 17R/S-resolvin D1 (17R/S-RvD1), 15R-lipoxin B4 (15R-LXB4), and protectin D1n-3 DPA (PD1n-3 DPA) than those with low sleep disturbance (T-score <60) (p<.05).

CONCLUSIONS: This study suggests that sleep disturbance may contribute to chronic inflammation in Long COVID by compromising certain inflammatory resolution pathways. Promoting inflammatory resolution physiology in particular in those individuals with Long COVID suffering from sleep disturbance may serve as a mechanistic target to mitigate inflammation and symptom burden in Long COVID.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05606211.

INTRODUCTION: Sleep deficiency is known to increase the risk for multiple disease conditions involving immunopathology, in which inflammation is thought to be a mechanism for disease development. Thus, one potential way to mitigate negative health consequences of deficient sleep is to target inflammation. We investigated whether low-dose acetylsalicylic acid (ASA, aspirin) administration prior to and during exposure to an experimental sleep restriction challenge affects cellular immune responses to sleep restriction.

METHODS: We studied 46 healthy humans (19F/27M, age range 19-63 years) in a randomized trial with 3 protocols each consisting of a 14-day at-home phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo) with daily ASA (81 mg/day) or placebo intake across the entire study period (at-home and in-laboratory). During in-laboratory stays, sleep opportunity under both sleep restriction conditions was 8 h during 2 pre-challenge nights, 4 h during 5 nights of restricted sleep, and 8 h during 3 nights of recovery sleep. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the protocol. Blood samples were analyzed prior to and following 5 nights of sleep restriction/control sleep, and after 2 nights of recovery sleep. Data were analyzed using generalized linear mixed models.

RESULTS: Experimental sleep restriction increased WBC, lymphocyte, monocyte, eosinophil, basophil, CD4 T cell counts, and the CD4/CD8 T cell ratio compared to control sleep under placebo (p<.01). Low-dose ASA had no effect at pre-challenge for most cell types. However, low-dose ASA attenuated the eosinophil and basophil responses to sleep restriction and reduced elevation of the CD4/CD8 T cell ratio (p<.01). Monocyte counts stayed elevated after 2 nights of recovery sleep in the sleep restriction/ASA condition compared to control sleep, whereas monocyte counts recovered under placebo intake (p<.01).

CONCLUSION: The present study shows that low-dose ASA can counteract certain cellular immune responses to sleep restriction, in particular elevations in eosinophil and basophil counts as well as the CD4/CD8 T cell ratio, while not affecting most immune cell counts prior to the sleep restriction challenge.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03377543.

Wearables yield a wide array of sleep-related measures that are relevant to Long COVID. We leveraged wearables-derived sleep measures (WDSM) to identify differences between individuals with Long COVID (LC) versus individuals with possible or no LC in the RECOVER adult cohort. We found significant associations between LC and reduced heart rate variability measured during sleep and increased nightly variability in sleep duration after adjusting for confounders. Moreover, LC was independently associated with lower sleep efficiency, greater variability of nighttime sleep timing, higher resting heart rate, lower respiratory rate during rapid eye movement (REM) sleep, prolonged REM sleep onset latency, worse global physical and mental health. Cluster analysis identified distinct multidimensional patterns of WDSM that are associated with LC and quality of life. Together, the strong association between WDSM, or WDSM clusters, with LC provides a potential biomarker for future validation efforts to detect LC and monitor treatment effectiveness.

a) Purpose of review:

Current knowledge on inflammatory and central pain-modulatory pathways as potential mechanisms linking sleep disturbances with pain, and the role of sex in modulating these pathways will be reviewed.

b) Recent findings: There is increasing evidence that the degree to which inflammatory and pain-modulatory pathways are affected by sleep disturbances are modulated by sex, with recent studies suggesting a greater pro-inflammatory response in males compared to females, and a stronger impairment of pain-inhibitory pathways in females compared to males.  

c) Summary: Knowledge on sex-differential activations of pain pathways by sleep disturbances has important therapeutic implications and may require different mechanism-based therapies to treat pain in both sexes effectively. The development of specific therapeutics that complement traditional sleep-improving therapies has the potential to better mitigate pain associated with sleep disturbances and interrupt the transition to pain chronicity in both sexes.

Wearables yield a wide array of sleep-related measures that are relevant to Long COVID. We leveraged wearables-derived sleep measures (WDSM) to identify differences between individuals with Long COVID (LC) versus individuals with possible or no LC in the RECOVER adult cohort. We found significant associations between LC and reduced heart rate variability measured during sleep and increased nightly variability in sleep duration after adjusting for confounders. Moreover, LC was independently associated with lower sleep efficiency, greater variability of nighttime sleep timing, higher resting heart rate, lower respiratory rate during rapid eye movement (REM) sleep, prolonged REM sleep onset latency, worse global physical and mental health. Cluster analysis identified distinct multidimensional patterns of WDSM that are associated with LC and quality of life. Together, the strong association between WDSM, or WDSM clusters, with LC provides a potential biomarker for future validation efforts to detect LC and monitor treatment effectiveness.