No abstract

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.

Introduction Sleep disturbances deteriorate immune function by not only affecting pro-inflammatory pathways, but also inflammatory resolution pathways, which actively terminate inflammation. It is assumed that slow wave sleep (SWS) amount and slow wave activity (SWA) convey the immune-supportive functions of sleep. We investigated whether changes in SWS induced by experimental sleep disturbance followed by recovery sleep predict changes in inflammatory resolution mediators. Methods The randomized controlled within-subjects trial (N=24, 20-42 years, 12 women) consisted of two 19-day in-hospital protocols (experimental sleep disturbance/control). After three nights of baseline sleep (8h/night), participants in the experimental sleep disturbance condition were exposed to three cycles of three nights of disturbed sleep (delayed sleep-onset, hourly sleep disruption, advanced sleep-offset) followed by one night of 8h-recovery sleep. The protocol ended with three nights of recovery sleep. In the control condition, participants had uninterrupted sleep (8h/night). Sleep (PSG) and resolvin lipid mediators in plasma (1100h, LC-MS/MS) were assessed at baseline, during the last cycle of sleep disturbance, and during/after the first and third night of final recovery sleep. Data were analyzed using generalized linear mixed models and Pearson/Spearman correlations. Results As expected, SWS amount decreased during experimental sleep disturbance and increased during the first recovery sleep night (p<.001). Similarly, resolvin (Rv) D2 and RvD3 decreased during sleep disturbance and RvD2 increased with subsequent recovery sleep (p<.001). The SWS response did not correlate with the resolvin response to sleep disturbance or to recovery sleep. However, the NREM sleep response correlated with the resolvin response during the third recovery sleep night, i.e., a greater NREM response was associated with a greater RvD2 and RvD3 response (r=.68, p=.002; r=.58, p=.012). In contrast, a greater REM sleep response was associated with a lower resolvin response (r=−.63, p=.005; r=−.66, p=.003). Conclusion These data suggest that during recovery from sleep disturbance, NREM rather than REM sleep promotes inflammatory resolution, thereby acting as the sleep state that protects against low-grade systemic inflammation, which has been frequently observed as a consequence of sleep disturbances. Analysis whether SWA is related to inflammatory resolution is in progress. Support (if any) NIH/NINDS R01-NS091177; NIH/NCRR UL1-RR02758, M01-RR01032; German Research Foundation (DFG) EN1291/1-1.

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 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:(a) an experimental sleep disturbance protocol consisting of repeated nights of short and disrupted sleep with intermittent recovery sleep; and (b) 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 (LPS-stimulated and spontaneous), and eCBs (AEA, 2-AG, DHEA, EPEA, DTEA) 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 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.