Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans.

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, 5th day of sleep restriction/control sleep, and 2nd day of recovery sleep). Variables, including pro-inflammatory immune cell function, C-reactive protein (CRP), and actigraphy-estimated measures of sleep, were analyzed using generalized linear mixed models. RESULTS: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<0.05 for condition*day) and reduced serum CRP levels (p<0.01 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<0.05 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<0.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>0.05 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.

Timing of restricted sleep: mood and neurobehavioral outcomes in healthy sleepers.

Study Objective: To evaluate how nocturnal timing of sleep restriction affects vigilant attention and mood in healthy controls with normal sleep-wake patterns. Methods: A convenience sample from two controlled sleep restriction protocols were used to investigate the difference between 4 hours of sleep early in the night, versus 4 hours late in the night. Volunteers stayed in a hospital setting and were randomized to one of the three conditions: a control (8 hours of sleep each night), an early short sleep (ESS, 2300-0300 hours), and a late short sleep (LSS, 0300-0700 hours). Participants were evaluated with psychomotor vigilance task (PVT) and mood ratings via visual analog scales. Results: Short sleep conditions led to greater performance decrements than control on PVT. LSS performance impairments were greater than control (lapses, p = 0.011; median RT, p = 0.029; fastest 10%, p = 0.038; reciprocal RT, p = 0.014; and reciprocal 10%, p = 0.005), but had higher positive mood ratings (p = 0.005). LSS also had higher positive mood ratings compared with ESS (p < 0.001). Conclusions: The data underscore the negative mood impact of waking at an adverse circadian phase, for healthy controls. In addition, the paradoxical relationship between mood and performance seen in LSS raises concerns that staying up late and waking at the usual rise time may be rewarding in terms of mood, but nonetheless have performance consequences that may not be fully recognized.

Alterations of pain pathways by experimental sleep disturbances in humans: central pain-inhibitory, cyclooxygenase, and endocannabinoid pathways.

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.

Differential effects of an experimental model of prolonged sleep disturbance on inflammation in healthy females and males.

Sleep disturbances, including disrupted sleep and short sleep duration, are highly prevalent and are prospectively associated with an increased risk for various widespread diseases, including cardiometabolic, neurodegenerative, chronic pain, and autoimmune diseases. Systemic inflammation, which has been observed in populations experiencing sleep disturbances, may mechanistically link disturbed sleep with increased disease risks. To determine whether sleep disturbances are causally responsible for the inflammatory changes reported in population-based studies, we developed a 19-day in-hospital experimental model of prolonged sleep disturbance inducing disrupted and shortened sleep. The model included delayed sleep onset, frequent nighttime awakenings, and advanced sleep offset, interspersed with intermittent nights of undisturbed sleep. This pattern aimed at providing an ecologically highly valid experimental model of the typical sleep disturbances often reported in the general and patient populations. Unexpectedly, the experimental sleep disturbance model reduced several of the assessed proinflammatory markers, namely interleukin(IL)-6 production by monocytes and plasma levels of IL-6 and C-reactive protein (CRP), presumably due to intermittent increases in the counterinflammatory hormone cortisol. Striking sex differences were observed with females presenting a reduction in proinflammatory markers and males showing a predominantly proinflammatory response and reductions of cortisol levels. Our findings indicate that sleep disturbances causally dysregulate inflammatory pathways, with opposing effects in females and males. These results have the potential to advance our mechanistic understanding of the pronounced sexual dimorphism in the many diseases for which sleep disturbances are a risk factor.

Heart rate variability rebound following exposure to persistent and repetitive sleep restriction.

While it is well established that slow-wave sleep electroencephalography (EEG) rebounds following sleep deprivation, very little research has investigated autonomic nervous system recovery. We examined heart rate variability (HRV) and cardiovagal baroreflex sensitivity (BRS) during four blocks of repetitive sleep restriction and sequential nights of recovery sleep. Twenty-one healthy participants completed the 22-day in-hospital protocol. Following three nights of 8-hr sleep, they were assigned to a repetitive sleep restriction condition. Participants had two additional 8-hr recovery sleep periods at the end of the protocol. Sleep EEG, HRV, and BRS were compared for the baseline, the four blocks of sleep restriction, and the second (R2) and third (R3) nocturnal recovery sleep periods following the last sleep restriction block. Within the first hour of each sleep period, vagal activation, as indexed by increase in high frequency (HF; HRV spectrum analysis), showed a rapid increase, reaching its 24-hr peak. HF was more pronounced (rebound) in R2 than during baseline (p < 0.001). The BRS increased within the first hour of sleep and was higher across all sleep restriction blocks and recovery nights (p = 0.039). Rebound rapid eye movement sleep was observed during both R2 and R3 (p = 0.004), whereas slow-wave sleep did not differ between baseline and recovery nights (p > 0.05). Our results indicate that the restoration of autonomic homeostasis requires a time course that includes at least three nights, following an exposure to multiple nights of sleep curtailed to about half the normal nightly amount.