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Pain can be both a cause and a consequence of sleep deficiency. This bidirectional relationship between sleep and pain has important implications for clinical management of patients, but also for chronic pain prevention and public health more broadly. The review that follows will provide an overview of the neurobiological evidence of mechanisms thought to be involved in the modulation of pain by sleep deficiency, including the opioid, monoaminergic, orexinergic, immune, melatonin, and endocannabinoid systems; the hypothalamus-pituitary-adrenal axis; and adenosine and nitric oxide signaling. In addition, it will provide a broad overview of pharmacological and non-pharmacological approaches for the management of chronic pain comorbid with sleep disturbances and for the management of postoperative pain, as well as discuss the effects of sleep-disturbing medications on pain amplification.

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, \"Sleep Insufficiency, Circadian Misalignment, and the Immune Response,\" to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

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.

Fibromyalgia (FM) is a chronic widespread pain disorder characterized by negative affect, sleep disturbance, and fatigue. This uncontrolled pilot study investigated the efficacy of daily yoga-based exercise to improve FM symptoms and explored baseline phenotypic characteristics associated with the greatest benefit. FM patients (n=46, with 36 completers) reported psychosocial functioning and a range of FM symptoms using validated instruments before and after participation in Satyananda yoga, which included weekly in-person pain-tailored group classes for 6 weeks and daily home yoga video practice. Changes in FM symptoms from pre- to post-yoga were variable amongst participants. Group means for pain decreased, as reported by average daily diary and Brief Pain Inventory, with greater home practice minutes associated with a greater decrease in pain. Average daily ratings of sleep and fatigue improved. Pain catastrophizing was decreased overall, with greater change correlated to a decrease in FM symptoms. We did not observe any group mean changes in actigraphy sleep efficiency, Patient-Reported Outcomes Measurement Information System-anxiety and the Revised Fibromyalgia Impact Questionnaire. Multilevel Modeling analysis revealed a significant interaction between anxiety and catastrophizing for end-study sleep efficiency, fatigue, and pain, such that patients with higher baseline catastrophizing and lower baseline anxiety reported less pain and fatigue, and higher sleep efficiency after the sixth week of yoga practice. This pilot study suggests that yoga may reduce pain and catastrophizing, as well as improve sleep, but these changes were modest across study participants. Greater uptake of home yoga practice as well as a phenotype of higher baseline catastrophizing combined with lower baseline anxiety were associated with greater impact. Future randomized, controlled trials comparing different types of yoga or exercise will allow determination of the most effective treatments for FM and allow closer targeting to the patients who will benefit most from them.

Tumor Treating Fields (TTFields) are delivered by transducer arrays applied to scalp or body surface for treatment of multiple malignancies. Dermatologic complications are thought to be related to hydrogel situated between the electrodes and scalp or skin to facilitate electric field penetration. High intensity of TTFields on these surfaces may also be a contributing factor. We explored conductivity changes in the hydrogel and skin to improve TTFields coverage and penetration. Magnetic resonance imaging datasets from 12 glioblastoma patients and attenuation-corrected positron emission tomography-computed tomography datasets from 3 non-small cell lung and 2 ovarian carcinoma patients were used to segment anatomic structures. Finite element mesh models were generated and solved for distribution of applied electric fields, rate of energy deposition, and current density at the gross tumor volume (GTV) and clinical target volume (CTV). Electric field-volume, specific absorption rate-volume, and current density-volume histograms were generated, by which plan quality metrics were used to evaluate relative differences in field coverage between models at various hydrogel and skin conductivities. By varying conductivity of hydrogel, TTFields coverage at GTV or CTV increased up to 0.5 S/m for head and 1.0 S/m for thorax and pelvis models, and no additional increase was observed beyond these saturation points. Although scalp hotspots increased or decreased by +1.5%, -0.1%, and -0.9% in E , SAR , and CD , the skin hotspots increased by as much as +23.5%, +45.7%, and +20.6%, respectively. When altering conductivity of the entire scalp, TTFields coverage peaked near 1 S/m at the GTV or CTV for the head models. TTFields coverage in both the GTV and scalp increased up to 1 S/m for the head models but plateaued thereafter. Contouring under the scalp increased scalp hotspots by +316% in E at 1 S/m compared to altering the conductivity of the entire scalp. GTV hotspots decreased by +17% in E at 1 S/m. TTFields delivery can be modulated by the conductivity of hydrogel and scalp/skin at the transducer-scalp or transducer-skin interface. Optimizing this aspect of TTFields delivery may increase tumor control while minimizing toxicity at the scalp or skin.

Chronic sleep restriction is a common experience; and while it has negative physiological effects, little is known about how it affects human behavior. To date, no study has investigated whether chronic sleep restriction can influence implicit attitudes (e.g., towards a race). Here, in a randomized, counterbalanced crossover design, we subjected participants to 3 weeks of chronic sleep restriction in the lab (i.e., 3 weekly cycles of 5 nights of 4 hours of sleep per night followed by 2 nights of 8 hours of sleep) and found evidence for an increased negative implicit bias towards Arab Muslims. No indicators of an implicit bias were found in these same individuals when they were rested (during a counterbalanced 3-week period of 8 hours time in bed per night). These findings suggest that chronic sleep restriction may “unmask” implicit racial or ethnic biases that are otherwise inhibited when in a rested state. Because chronic sleep restriction is prevalent among many occupations that routinely interact with ethnic minorities in potentially high-conflict situations (e.g., police officers), it is critical to consider the role that restricted sleep may play in exacerbating negative implicit attitudes and their potential for provoking unintentional and potentially harmful behavioral consequences.

Introduction Prior research has reported NREM spectral EEG differences between individuals with insomnia and good-sleeper controls, including elevated high-frequency EEG power (beta/gamma bands, ~16-50Hz) and, to a lesser extent, elevations in sleep spindle parameters. However, the mechanisms driving these differences remain unclear. Harmonics have been observed in EEG data as spectral peaks at multiples of a fundamental frequency associated with an event (e.g., for a 14Hz spindle, the 2nd harmonic is expected to be a peak at 28Hz). Thus far, there has been very limited application of this idea of spectral harmonics to sleep spindles, even though these patterns can indeed be seen in some existing literature. We sought to build on this literature to apply spectral harmonic analysis to better understand differences between insomnia and good sleepers. Methods 15 individuals with insomnia disorder (DSM-5 criteria, 13 female, age 18–32 years) and 15 good-sleeper controls (matched for sex, age, and BMI) completed an overnight polysomnography recording in the laboratory and subsequent daytime testing. Insomnia diagnosis was determined by a board-certified sleep specialist, and exclusion criteria included psychiatric history within past 6 months, other sleep disorders, significant medical conditions, and medications with significant effects on inflammation, autonomic function, or other psychotropic effects. Results Consistent with prior studies, we found elevated sleep spindle density and fast sigma power (14-16Hz). Despite no difference in beta or gamma band power when averaged across NREM sleep, time-frequency analysis centered on the peaks of detected spindles revealed a phasic elevation in spectral power surrounding the 28Hz harmonic peak in the insomnia group, especially for spindles coupled with slow waves. We also observed an overall pattern of time-locked delay in the 28Hz harmonic peak, occurring approximately 40 msec after spindle peaks. Furthermore, we observed a 42Hz ‘3rd harmonic’ peak, not yet predicted by the existing modeling work, which was also elevated for insomnia. Conclusion In conjunction with existing mathematical modeling work that has linked sleep spindle harmonic peaks with thalamic relay nuclei as the primary generators of this EEG signature, these findings may enable novel insights into specific thalamocortical mechanisms of insomnia and non-restorative sleep. Support (if any) NIH 5T32HL007901-22

Introduction Insufficient sleep has been shown to increase the risk of a person developing hypertension. Impaired baroreflex sensitivity (BRS) is one of the known underlying mechanisms involved that is responsible for increasing blood pressure (BP). This project investigates the relationship between sleep, BRS, and BP during Valsalva’s Maneuver (VM). Methods Fifty participants (59.8 ± 1.5 years; 31 women) completed 3 overnight in-hospital stays. The first stay (S1) was a baseline control; the second stay (S2) followed a 4-week wait-list control condition; the third stay (S3) followed an 8-week randomly assigned intervention that used sleep hygiene approaches and scheduling to either A) stabilize sleep timing, or B) stabilize and extend the bed period. The study is still ongoing, and we are blind to whether participants were randomized to arm A or B of the study. A linear regression model analyzing the R-R Interval (RRI) and corresponding systolic BP was used to calculate the BRS function and the maximum change in SBP (BPMax) during Early Phase II (EPII) of VM. Results There was an increasing BRS trend across the three stays during EPII (p=.051). There was no significant increase between S1 and S2 (p=.876), but BRS significantly increased following 8 weeks of intervention at S3 compared to S1 (p=0.033) and S2 (p=0.037). There was also a significant decrease in BPMax across the three stays during EPII (p<.001). There was no significant decrease in EPII BPMax between S1 and S2 (p=.325), but BPMax significantly decreased in S3 compared to S1 (p<0.001) and S2 (p=0.002). Conclusion While we are still blind to condition, both conditions are considered active as they both involve stabilizing the sleep period using sleep hygiene. These preliminary data suggest that stabilization of sleep timing and possibly duration, has a positive impact on BP regulation. Support (if any) NIH (R01HL125379 to Dr. Janet Mullington), Harvard Catalyst, Harvard Clinical and Translational Science Center (UL1TR001102).

Introduction Insufficient sleep is associated with an increased risk of hypertension. It is well established that long-term BP regulation is modulated by the renin-angiotensin-aldosterone system (RAAS) and chronic kidney disease is a strong independent risk factor for development of cardiovascular disease. This study investigated the biomarkers of RAAS and renal function during repetitive exposures to controlled, experimental sleep restriction (SR). We hypothesized an upregulation of RAAS and increased markers of impaired renal function. Methods Twenty-one healthy participants (11 women, average age 31±2 years) completed the 22-day in-hospital SR protocol: permitted 4h of sleep/night from 0300-0700 for 3 nights followed by a recovery sleep, repeated 4 times. Blood samples were collected and plasma renin activity (PRA) was assessed in the morning (7:05am) and in the evening before bedtime (22:45pm) at baseline, experimental days (3rd day of each of the 4 blocks), and recovery. Urinary albumin to creatinine ratio (ACR) was measured from 24-h urinary collection at baseline, first and fourth SR blocks. Estimated glomerulus filtration rate (eGFR) was calculated based on the serum cystatin C levels at baseline and last block of SR. Results Percent change of evening PRA significantly increased during 4 blocks of SR and recovery (SR effect p=0.039), but not morning PRA (SR effect p=0.34). Specifically, evening PRA increased up to 98.4% in the first (p<0.01), 61.3% in the second (p=0.04) SR blocks, and 57.5% (p=0.05) in recovery. Urinary ACR showed no significant changes during first or fourth SR blocks (SR effect p=0.28). In addition, eGFR did not change in the fourth SR block compared to BL (paired t-test, p=0.27). Conclusion We did not see increased markers of impaired renal function (ACR or eGFR). Rather, short-term repetitive exposures to SR significantly increased percent change of PRA measured before bedtime, and evening PRA did not return to BL level during recovery. Our results suggested that sleep deficiency may contribute to hypertension through upregulation of RAAS during wake time. Support (if any) SRSF (CDA to Huan Yang), NIH (R01HL106782 to Dr. Janet Mullington), Harvard Catalyst, Harvard Clinical and Translational Science Center (UL1TR001102).

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.