Publications

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.

INTRODUCTION: Insomnia is a highly prevalent condition that predisposes individuals to many chronic pain disorders, with most of them showing pronounced sexual dimorphism. We investigated whether experimental insomnia-like sleep disturbances (ESD) affect spontaneous pain and pain sensitivity, and whether sex modulates pain responses.

METHODS: Twenty-four healthy participants (50% females, age 28.3 ± 5.9 years) participated in a study consisting of two 19-day in-laboratory protocols-an ESD protocol consisting of repeated nights of short and disrupted sleep with intermittent nights of undisturbed sleep and a control sleep (CS) protocol consisting of 18 nights with an undisturbed 8-h sleep opportunity. Spontaneous pain was assessed using electronic rating scales during daytime and night-time wake periods. Pain sensitivity was assessed through pressure and heat pain threshold measures every other day of the protocol.

RESULTS: Females responded with higher daytime pain ratings in the ESD compared to the CS condition, while males responded with lower pain ratings (p < 0.05 for condition*sex). Spontaneous pain ratings were higher at night-time than during daytime and worsened across successive nights of sleep disturbances, independent of sex (p < 0.05 for condition*study day*daytime-night-time). Females developed greater pressure pain sensitivity, while males developed greater pain sensitivity to heat in the ESD compared to the CS condition (p < 0.05 for condition*sex).

CONCLUSION: Pain responses to sleep disturbances strongly vary by sex and may contribute to sex differences in the prevalence and symptom burden of many chronic pain conditions. Because the study was not a priori powered on sex, findings are preliminary and require follow-up in larger samples. Findings further suggest to specifically target night-time pain in sleep disturbed individuals, for example, through optimised timing of analgesic-acting medications.

SIGNIFICANCE: Exploration of sex as a modulator suggest that sleep disturbances amplify spontaneous pain and pressure pain sensitivity to a greater extent in females than in males, and this may contribute to females' overrepresentation and disproportionate symptom burden observed for many pain-related disorders for which insomnia is comorbid or a risk factor.

STUDY OBJECTIVES: Persistent post-acute sequelae of SARS-CoV-2 infection, i.e. long COVID, impacts multiple organ systems. While lower blood oxygen is expected when SARS-CoV-2 infects the lungs, hypoxia without pulmonary symptoms may continue after the acute phase. Ventilation and blood oxygen are more vulnerable during sleep, but nocturnal hypoxemia hasn't been studied in people with long COVID in a facility setting using gold-standard polysomnography (PSG).

METHODS: We conducted an observational study with 50 participants (25 long COVID, 25 age-sex-matched healthy controls) using in-laboratory overnight PSG. We calculated the average SpO2, average SpO2 after removing desaturations, the respiratory rate in different sleep periods, and the hypoxic costs using all desaturations.

RESULTS: We found that average SpO2 was lower in participants with long COVID: 1.0% lower after sleep onset (p = .004) and 0.7% lower during REM (p = .002); average SpO2 after removing desaturations was also lower in participants with long COVID: 1.3% lower after sleep onset (p = .002), 0.9% lower during REM (p = .0004), and 1.4% lower during NREM (p = .003); and respiratory rate was 1.4/minute higher in participants with long COVID during REM (p = .005). There were no significant differences in SpO2 and respiratory rate before sleep onset, the within-participant change from before to after sleep onset, or hypoxic costs.

CONCLUSIONS: The results suggest that long COVID had a persistent lower nocturnal blood oxygen saturation, and support the need for a large-scale study of nocturnal hypoxemia in people with long COVID compared to the general population.

Background: Sleep deficiencies, such as manifested in short sleep duration or insomnia symptoms, are known to increase the risk for multiple disease conditions involving immunopathology. Inflammation is hypothesized to be a mechanism through which deficient sleep acts as a risk factor for these conditions. Thus, one potential way to mitigate negative health consequences associated with deficient sleep is to target inflammation. Few interventional sleep studies investigated whether improving sleep affects inflammatory processes, but results suggest that complementary approaches may be necessary to target inflammation associated with sleep deficiencies. We investigated whether targeting inflammation through low-dose acetylsalicylic acid (ASA, i.e., aspirin) is able to blunt the inflammatory response to experimental sleep restriction.

Methods: 46 healthy participants (19F/27M, age range 19-63 years) were studied in a double-blind randomized placebo-controlled crossover trial with three protocols each consisting of a 14-day at-home monitoring phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo). In the sleep restriction/ASA condition, participants took low-dose ASA (81 mg/day) daily in the evening (22:00) during the at-home phase and the subsequent in-laboratory stay. In the sleep restriction/placebo and control sleep/placebo conditions, participants took placebo daily. Each in-laboratory stay started with 2 nights with a sleep opportunity of 8 h/night (23:00-07:00) for adaptation and baseline measurements. Under the two sleep restriction conditions, participants were exposed to 5 nights of sleep restricted to a sleep opportunity of 4 h/night (03:00-07:00) followed by 3 nights of recovery sleep with a sleep opportunity of 8 h/night. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the in-laboratory stay. During each in-laboratory stay, participants had 3 days of intensive monitoring (at baseline, 5^th day of sleep restriction/control sleep, and 2^nd day of recovery sleep). Target variables, including actigraphy-estimated measures of sleep, immune cell function, and C-reactive protein (CRP), were analyzed using generalized linear mixed models.

Results: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<.05 for condition*day) and reduced serum CRP levels (p<.01 for condition) after 5 nights of sleep restriction compared to placebo administration in the sleep restriction condition. Low-dose ASA also reduced the amount of cyclooxygenase (COX)-1/COX-2 double positive cells among LPS-stimulated monocytes after 2 nights of recovery sleep following 5 nights of sleep restriction compared to placebo (p<.05 for condition). Low-dose ASA further decreased wake after sleep onset (WASO) and increased sleep efficiency (SE) during the first 2 nights of recovery sleep (p<.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>.05 for condition).

Conclusion: This study shows that inflammatory responses to sleep restriction can be reduced by preemptive administration of low-dose ASA. This finding may open new therapeutic approaches to prevent or control inflammation and its consequences in those experiencing sleep deficiencies.

Trial Registration: ClinicalTrials.gov NCT03377543.

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC).

OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC.

DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024).

SETTING: 83 enrolling sites.

PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection.

MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests.

RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero.

LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined.

CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC.

PRIMARY FUNDING SOURCE: National Institutes of Health.

STUDY OBJECTIVES: There is strong evidence that sleep disturbances are an independent risk factor for the development of chronic pain conditions. The mechanisms underlying this association, however, are still not well understood. We examined the effect of experimental sleep disturbances (ESDs) on three pathways involved in pain initiation/resolution: (1) the central pain-inhibitory pathway, (2) the cyclooxygenase (COX) pathway, and (3) the endocannabinoid (eCB) pathway.

METHODS: Twenty-four healthy participants (50% females) underwent two 19-day long in-laboratory protocols in randomized order: (1) an ESD protocol consisting of repeated nights of short and disrupted sleep with intermittent recovery sleep; and (2) a sleep control protocol consisting of nights with an 8-hour sleep opportunity. Pain inhibition (conditioned pain modulation, habituation to repeated pain), COX-2 expression at monocyte level (lipopolysaccharide [LPS]-stimulated and spontaneous), and eCBs (arachidonoylethanolamine, 2-arachidonoylglycerol, docosahexaenoylethanolamide [DHEA], eicosapentaenoylethanolamide, docosatetraenoylethanolamide) were measured every other day throughout the protocol.

RESULTS: The central pain-inhibitory pathway was compromised by sleep disturbances in females, but not in males (p < 0.05 condition × sex effect). The COX-2 pathway (LPS-stimulated) was activated by sleep disturbances (p < 0.05 condition effect), and this effect was exclusively driven by males (p < 0.05 condition × sex effect). With respect to the eCB pathway, DHEA was higher (p < 0.05 condition effect) in the sleep disturbance compared to the control condition, without sex-differential effects on any eCBs.

CONCLUSIONS: These findings suggest that central pain-inhibitory and COX mechanisms through which sleep disturbances may contribute to chronic pain risk are sex specific, implicating the need for sex-differential therapeutic targets to effectively reduce chronic pain associated with sleep disturbances in both sexes.

CLINICAL TRIALS REGISTRATION: NCT02484742: Pain Sensitization and Habituation in a Model of Experimentally-induced Insomnia Symptoms. https://clinicaltrials.gov/ct2/show/NCT02484742.

BACKGROUND: Sleep disturbances, as manifested in insomnia symptoms of difficulties falling asleep or frequent nighttime awakenings, are a strong risk factor for a diverse range of diseases involving immunopathology. Low-grade systemic inflammation has been frequently found associated with sleep disturbances and may mechanistically contribute to increased disease risk. Effects of sleep disturbances on inflammation have been observed to be long lasting and remain after recovery sleep has been obtained, suggesting that sleep disturbances may not only affect inflammatory mediators, but also the so-called specialized pro-resolving mediators (SPMs) that actively resolve inflammation. The goal of this investigation was to test for the first time whether the omega-3 fatty acid-derived D- (RvD) and E-series (RvE) resolvins are impacted by prolonged experimental sleep disturbance (ESD).

METHODS: Twenty-four healthy participants (12 F, age 20-42 years) underwent two 19-day in-hospital protocols (ESD/control), separated by > 2 months. The ESD protocol consisted of repeated nights of short and disrupted sleep with intermittent nights of undisturbed sleep, followed by three nights of recovery sleep at the end of the protocol. Under the control sleep condition, participants had an undisturbed sleep opportunity of 8 h/night throughout the protocol. The D- and E-series resolvins were measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

RESULTS: The precursor of the D-series resolvins, 17-HDHA, was downregulated in the ESD compared to the control sleep condition (p <.001 for condition), and this effect remained after the third night of recovery sleep has been obtained. This effect was also observed for the resolvins RvD3, RvD4, and RvD5 (p <.001 for condition), while RvD1 was higher in the ESD compared to the control sleep condition (p <.01 for condition) and RvD2 showed a mixed effect of a decrease during disturbed sleep followed by an increase during recovery sleep in the ESD condition (p <.001 for condition*day interaction). The precursor of E-series resolvins, 18-HEPE, was downregulated in the ESD compared to the control sleep condition (p <.01 for condition) and remained low after recovery sleep has been obtained. This effect of downregulation was also observed for RvE2 (p <.01 for condition), while there was no effect for RvE1 (p >.05 for condition or condition*day interaction). Sex-differential effects were found for two of the D-series resolvins, i.e., RvD2 and RvD4.

CONCLUSION: This first investigation on the effects of experimental sleep disturbance on inflammatory resolution processes shows that SPMs, particularly resolvins of the D-series, are profoundly downregulated by sleep disturbances and remain downregulated after recovery sleep has been obtained, suggesting a longer lasting impact of sleep disturbances on these mediators. These findings also suggest that sleep disturbances contribute to the development and progression of a wide range of diseases characterized by immunopathology by interfering with processes that actively resolve inflammation. Pharmacological interventions aimed at promoting inflammatory resolution physiology may help to prevent future disease risk as a common consequence of sleep disturbances.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02484742.

Epidemiological studies have repeatedly shown that insomnia disorder or symptoms of insomnia are prospectively associated with increased risks for developing a diverse range of medical conditions affecting multiple biological systems. Specifically, insomnia-related disease risks include cardiovascular diseases (Javaheri and Redline, 2017), metabolic diseases, such as type 2 diabetes and metabolic syndrome (Anothaisintawee et al., 2016; Lin et al., 2016), Alzheimer’s disease (Shi et al., 2018), pain (Afolalu et al., 2018), autoimmune diseases (Kok et al., 2016), and cancer (Shi et al., 2020). Insomnia is associated with changes in the regulation of immune, neuroendocrine, and metabolic systems among other physiological consequences, which are thought to mechanistically link insomnia with increased risk for these diseases. The exact pathophysiological mechanisms through which such physiological changes promote disease risk are now intensively studied for some conditions, such as type 2diabetes(Cedernaes et al., 2015; Depner et al., 2014), but less so for others, such as pain or autoimmune conditions (Haack et al., 2020; Zielinski et al., 2019). There is some evidence, however, suggesting that the physiological consequences are most pronounced in insomnia with objective short sleep duration, generally defined as less than 6 h of sleep per night (Vgontzas et al., 2013). For example, the risks of low-grade systemic inflammation, hypertension, or diabetes are greatest in individuals who have insomnia in combination with short sleep (Fernandez-Mendoza et al., 2017; Vgontzas et al., 2013), suggesting that this insomnia phenotype is a biologically more severe form of the disorder.
Fig. 1 depicts immune, neuroendocrine, and metabolic consequences associated with insomnia disorder and their potential role in mediating increased disease risk, which will be reviewed in the following. Autonomic consequences of insomnia (e.g., blood pressure, heart rate variability) will not be discussed here; the interested reader is referred to recent comprehensive reviews (Grimaldi et al., 2019; Nano et al., 2017).

Despite the growing research base examining the benefits and physiological mechanisms of slow-paced breathing (SPB), mindfulness (M), and their combination (as yogic breathing, SPB + M), no studies have directly compared these in a "dismantling" framework. To address this gap, we conducted a fully remote three-armed feasibility study with wearable devices and video-based laboratory visits. Eighteen healthy participants (age 18-30 years, 12 female) were randomized to one of three 8-week interventions: slow-paced breathing (SPB, N = 5), mindfulness (M, N = 6), or yogic breathing (SPB + M, N = 7). The participants began a 24-h heart rate recording with a chest-worn device prior to the first virtual laboratory visit, consisting of a 60-min intervention-specific training with guided practice and experimental stress induction using a Stroop test. The participants were then instructed to repeat their assigned intervention practice daily with a guided audio, while concurrently recording their heart rate data and completing a detailed practice log. The feasibility was determined using the rates of overall study completion (100%), daily practice adherence (73%), and the rate of fully analyzable data from virtual laboratory visits (92%). These results demonstrate feasibility for conducting larger trial studies with a similar fully remote framework, enhancing the ecological validity and sample size that could be possible with such research designs.