Human Sleep and Inflammatory Systems Laboratory

Engert LC, Haack M. Immune, neuroendocrine, and metabolic functions in insomnia disorder. In: Kushida CA Encyclopedia of Sleep and Circadian Rhythms. 2nd ed. Elsevier ; In Press.Abstract

Substantial evidence supports that insomnia prospectively increases risks for developing a wide range of diseases, including cardiovascular, metabolic, neurodegenerative, autoimmune, carcinogenic diseases, and pain disorders. The mechanisms underlying increased disease risks in individuals suffering from insomnia are an active area of research and involve dysregulations of multiple biological systems, including immune, neuroendocrine, and metabolic processes. Dysregulations in these physiological domains as they have been observed in insomnia disorder will be reviewed and their potential in mediating increased disease risk will be discussed.

Besedovsky L, Dang R, Engert LC, Goldstein MR, Devine JK, Bertisch SM, Mullington JM, Simpson N, Haack M. Differential effects of an experimental model of prolonged sleep disturbance on inflammation in healthy females and males. PNAS Nexus. 2022;1 (1) :pgac004. Publisher's Version 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.

Mazzotti DR, Haendel MA, McMurry JA, Smith CJ, Buysse DJ, Roenneberg T, Penzel T, Purcell S, Redline S, Zhang Y, et al. Sleep and circadian informatics data harmonization: a workshop report from the Sleep Research Society and Sleep Research Network. Sleep. 2022;45 (6) :zsac002. Publisher's Version

Yang H, Goldstein MR, Vazquez M, Williams JP, Mullington JM. Effects of sleep and sleep deficiency on autonomic function in humans. Current Opinion in Endocrine and Metabolic Research. 2021;18 :268-274. Publisher's Version

Ma Y, Goldstein MR, Davis RB, Yeh GY. Profile of subjective-objective sleep discrepancy in patients with insomnia and sleep apnea. Journal of Clinical Sleep Medicine. 2021. Publisher's Version

Khalsa SBS, Goldstein MR. Treatment of chronic primary sleep onset insomnia with Kundalini Yoga: a randomized controlled trial with active sleep hygiene comparison. J Clin Sleep Med. 2021.Abstract

STUDY OBJECTIVES: Prior studies have suggested a benefit of yoga for alleviating sleep disturbance; however, many studies have had methodological limitations. This trial study aimed to extend that literature by including an active sleep hygiene (SH) comparison. METHODS: Participants aged 25-59 with a primary complaint of sleep onset insomnia lasting at least six months were block randomized to 8-week Kundalini Yoga or SH intervention, both consisting of initial 60-minute instruction and weekly check-ins. Daily sleep diaries and questionnaires were collected at baseline, throughout intervention, and at 6-month follow-up. Data were analyzed using linear mixed models (N=20 in each group). RESULTS: Participant ratings of the interventions did not significantly differ. SH improved several diary and questionnaire outcomes, however, yoga resulted in even greater improvements corresponding to medium-to-large between-group effect sizes. Total sleep time increased progressively across yoga treatment (d=0.95, p=.002), concurrent with increased sleep efficiency (SE; d=1.36, p<.001) and decreased sleep onset latency (SOL; d=-1.16, p<.001), but without changes in pre-sleep arousal (d=-0.30, p=.59). Remission rates were also higher for yoga compared to SH, with ≥80% of yoga participants reporting average SOL<30 minutes and SE>80% at 6-month follow-up. For over 50% of yoga participants, the insomnia severity index decreased by at least 8 points at end of treatment and follow-up. CONCLUSIONS: Yoga, taught in a self-care framework with minimal instructor burden, was associated with self-reported improvements above and beyond an active sleep hygiene comparison, sustained at 6-month follow-up. Follow-up studies are needed to assess actigraphy and polysomnography outcomes, as well as possible mechanisms of change. CLINICAL TRIAL REGISTRATION: Yoga as a Treatment for Insomnia (ClinicalTrials.gov, NCT00033865).

Yang H, Baltzis D, Bhatt V, Haack M, Meier-Ewert HK, Gautam S, Veves A, Mullington JM. Macro- and microvascular reactivity during repetitive exposure to shortened sleep: sex differences. Sleep. 2021;44 (5).Abstract

Epidemiological studies have reported strong association between sleep loss and hypertension with unknown mechanisms. This study investigated macrovascular and microcirculation changes and inflammatory markers during repetitive sleep restriction. Sex differences were also explored. Forty-five participants completed a 22-day in-hospital protocol. Participants were assigned to, (1) eight-hour sleep per night (control), or (2) sleep restriction (SR) condition: participants slept from 0300 to 0700 h for three nights followed by a recovery night of 8-h sleep, repeated four times. Macrocirculation assessed by flow mediated dilation (FMD) and microcirculation reactivity tests were performed at baseline, last day of each experimental block and during recovery at the end. Cell adhesion molecules and inflammatory marker levels were measured in blood samples. No duration of deprivation (SR block) by condition interaction effects were found for FMD, microcirculation, norepinephrine, cell adhesion molecules, IL-6 or IL-8. However, when men and women were analyzed separately, there was a statistical trend (p = 0.08) for increased IL-6 across SR blocks in women, but not in men. Interestingly, men showed a significant progressive (dose dependent) increase in skin vasodilatation (p = 0.02). A novel and unexpected finding was that during the recovery period, men that had been exposed to repeated SR blocks had elevated IL-8 and decreased norepinephrine. Macrocirculation, microcirculation, cell adhesion molecules, and markers of inflammation appeared to be resistant to this model of short-term repetitive exposures to the blocks of shortened sleep in healthy sleepers. However, men and women responded differently, with women showing mild inflammatory response and men showing more vascular system sensitivity to the repetitive SR.

References for data slides:

1. Haack et al. (2020), Neuropsychopharmacology

2. Besedovsky et al. (2019), Physiological Reviews

3. Yang et al. (2019), Sleep

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