In Press
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 VersionAbstract
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 (, 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.
Mullington JM, Cunningham TJ, Haack M, Yang H. Causes and Consequences of Chronic Sleep Deficiency and the Role of Orexin. Front Neurol Neurosci. 2021;45 :128-138.Abstract
Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, and impaired neurobehavioral functioning. On a population level, insufficient sleep is associated with increased risk for hypertension and diabetes. Sleep disturbance is very common, and about half the population will report that they have experienced insomnia at some time in their lives. Approximately 10% of the population describe daytime impairment due to sleep disturbance at night, consistent with a diagnosis of insomnia disorder. The hypothalamic neuropeptides, orexin-A and orexin-B, act through G-protein-coupled receptors (orexin-1 and orexin-2 receptors). Dual and selective orexin-2 receptor antagonists have shown efficacy in inducing sleep in men and women with insomnia disorder by accelerating sleep onset and improving sleep efficiency and total sleep time. Further study comparing these medications, in short- and longer-term use models, is recommended. Greater understanding of comparative effects on mood, neurobehavioral, and physiological systems will help determine the extent of clinical utility of dual versus selective orexin receptor antagonists.
Rodriguez-Seijas C, Fields EC, Bottary R, Kark SM, Goldstein MR, Kensinger EA, Payne JD, Cunningham TJ. Comparing the Impact of COVID-19-Related Social Distancing on Mood and Psychiatric Indicators in Sexual and Gender Minority (SGM) and Non-SGM Individuals. Front Psychiatry. 2020;11 :590318.Abstract
Empirical evidence demonstrates mental health disparities between sexual and gender minority individuals (SGM) compared with cisgender heterosexual individuals. SGM individuals report elevated rates of emotional distress, symptoms related to mood and anxiety disorders, self-harm, and suicidal ideation and behavior. Social support is inversely related to psychiatric symptoms, regardless of SGM status. The COVID-19 pandemic-with its associated limited social interactions-represents an unprecedented period of acute distress with potential reductions in accessibility of social support, which might be of particular concern for SGM individuals' mental well-being. In the present study, we explored the extent to which potential changes in mental health outcomes (depressive symptoms, worry, perceived stress, positive and negative affect) throughout the duration of the pandemic were related to differences in perceptions of social support and engagement in virtual social activity, as a function of SGM status. Utilizing a large sample of US adults (N = 1,014; 18% reported SGM status), we assessed psychiatric symptoms, perceptions of social isolation, and amount of time spent socializing virtually at 3 time windows during the pandemic (between March 21 and May 21). Although SGM individuals reported greater levels of depression compared with non-SGM individuals at all 3 time points, there was no interaction between time and SGM status. Across all participants, mental health outcomes improved across time. Perceived social isolation was associated with poorer mental health outcomes. Further, time spent engaging in virtual socialization was associated with reduced depression, but only for those in self-reported quarantine. We discuss these results in terms of the nature of our sample and its impact on the generalizability of these findings to other SGM samples as well as directions for future research aimed at understanding potential health disparities in the face of the COVID-19 pandemic.
Goldstein MR, Lewin RK, Allen JJB. Improvements in well-being and cardiac metrics of stress following a yogic breathing workshop: Randomized controlled trial with active comparison. J Am Coll Health. 2020 :1-11.Abstract
Objective: Compare two distinct psychosocial stress-management workshops.Participants: Undergraduate and graduate students (n = 69 for analysis, completed April 2017).Methods: Participants were randomized to one of two workshops (Sudarshan Kriya Yoga, SKY; Wisdom On Wellness, WOW), matched in terms of duration, group size, etc. Outcomes were questionnaires and psychophysiological response to laboratory stress induction at pre, post, and 3-month follow-up.Results: SKY and WOW participants demonstrated similar workshop ratings and retention rates. SKY demonstrated greater improvements on a number of self-report measures relative to WOW, including perceived stress, sleep, social connectedness, distress, anxiety, depression, conscientiousness, self-esteem, and life satisfaction. Both groups improved in terms of heart rate measures of stress reactivity, however, these outcomes were partially related to changes in resting values at post-workshop and follow-up.Conclusions: These findings offer insight into unique patterns of change between yogic breathing, acceptance-based approaches to stress management versus cognitively based approaches.
Gaffey AE, Redeker NS, Rosman L, Mullington JM, Brandt CA, Haskell SG, Burg MM. The role of insomnia in the association between posttraumatic stress disorder and hypertension. J Hypertens. 2020;38 (4) :641-648.Abstract
OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with incident hypertension. Although this relationship is poorly understood, PTSD is also associated with insomnia symptoms, which increases the risk for hypertension. Whether insomnia contributes to PTSD-associated risk for hypertension is unknown. METHODS: We examined self-report survey and electronic health record data from 1109 participants in the Women Veterans Cohort Study (mean age: 43.8 ± 10.9 years; 52% women, 81% White) to assess the cross-sectional associations between PTSD symptom severity, recent symptoms of insomnia, and hypertension, defined as self-reported treatment for high blood pressure in the last year. Structural equation modeling was used to examine whether insomnia symptoms mediate the association between PTSD and hypertension. RESULTS: PTSD symptom severity was associated with hypertension (r = 0.09, P < 0.001). PTSD symptom severity and hypertension were each associated with the insomnia symptoms difficulty falling asleep, difficulty staying asleep, and worry/distress about sleep problems (PTSD: rs = 0.58--0.62, P <  0.001; hypertension: rs = 0.07--0.10, P <  0.001). A latent variable derived from those symptoms mediated 9% of the association between PTSD symptom severity and hypertension (P = 0.02). CONCLUSION: In this study of young and middle-aged Veterans, insomnia symptoms mediated the association between PTSD and hypertension. Difficulties falling asleep and maintaining sleep and related distress may be particularly deleterious for cardiovascular health in Veterans. Longitudinal data is required to further investigate the associations between PTSD, insomnia, and hypertension.
Haspel JA, Anafi R, Brown MK, Cermakian N, Depner C, Desplats P, Gelman AE, Haack M, Jelic S, Kim BS, et al. Perfect timing: circadian rhythms, sleep, and immunity - an NIH workshop summary. JCI Insight. 2020;5 (1).Abstract
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.
Haack M, Simpson N, Sethna N, Kaur S, Mullington J. Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications. Neuropsychopharmacology. 2020;45 (1) :205-216.Abstract
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.
Mullington JM. Please forgive our appearance while under biomarker construction. Sleep. 2019;42 (1).
Makarem N, Shechter A, Carnethon MR, Mullington JM, Hall MH, Abdalla M. Sleep Duration and Blood Pressure: Recent Advances and Future Directions. Curr Hypertens Rep. 2019;21 (5) :33.Abstract
PURPOSE OF REVIEW: This review discusses the recent literature on subjectively and objectively assessed sleep duration in relation to hypertension risk and out-of-clinic blood pressure (BP) measures and highlights critical areas for future research. RECENT FINDINGS: Sleep duration, particularly short sleep, may influence BP through disturbed autonomic balance, hormonal imbalances, increased adiposity and metabolic dysfunction, and disrupted circadian rhythms. Observational studies indicate that short and long sleep are associated with hypertension risk, reduced nocturnal dipping, and elevated morning BP, but evidence is stronger for short sleep. Experimental sleep restriction increases BP, while sleep extension may lower BP in prehypertensive individuals. Women and racial/ethnic minorities are more prone to the detrimental effects of short sleep on BP. Additional studies are warranted to clarify the association of objectively assessed sleep with BP level and diurnal pattern and to determine the sex- and race-specific effects of sleep restriction and extension on BP.
Redeker NS, Caruso CC, Hashmi SD, Mullington JM, Grandner M, Morgenthaler TI. Workplace Interventions to Promote Sleep Health and an Alert, Healthy Workforce. J Clin Sleep Med. 2019;15 (4) :649-657.Abstract
STUDY OBJECTIVES: The purpose of this review is to synthesize the published literature that addresses employer-initiated interventions to improve the sleep of workers and in turn improve health, productivity, absenteeism, and other outcomes that have been associated with sleep disorders or sleep deficiency. METHODS: We conducted a systematic search and a selective narrative review of publications in PubMed from 1966 to December 2017. We extracted study characteristics, including the workers' professions, workplace settings and shift work, and workplace interventions focused on worker sleep. Because of the high degree of heterogeneity in design and outcomes, we conducted a narrative review. RESULTS: We identified 219 publications. After restriction to publications with studies of workplace interventions that evaluated the outcomes of sleep duration or quality, we focused on 47 articles. An additional 13 articles were accepted in the pearling process. Most studies employed non-randomized or controlled pretest and posttest designs and self-reported measures of sleep. The most common workplace interventions were educational programs stressing sleep hygiene or fatigue management. Other interventions included timed napping before or after work, urging increased daytime activity levels, modifying workplace environmental characteristics such as lighting, and screening, and referral for sleep disorders treatment. Overall, most reports indicated that employer efforts to encourage improved sleep hygiene and healthier habits result in improvements in sleep duration, sleep quality, and self-reported sleepiness complaints. CONCLUSIONS: These studies suggest employer-sponsored efforts can improve sleep and sleep-related outcomes. The existing evidence, although weak, suggests efforts by employers to encourage better sleep habits and general fitness result in self-reported improvements in sleep-related outcomes, and may be associated with reduced absenteeism and better overall quality of life. Candidate workplace strategies to promote sleep health are provided.
Devine JK, Bertisch SM, Yang H, Scott-Sutherland J, Wilkins A, Molina V, Henrikson K, Haack M. Glucocorticoid and inflammatory reactivity to a repeated physiological stressor in insomnia disorder. Neurobiol Sleep Circadian Rhythms. 2019;6 :77-84.Abstract
Despite known associations of insomnia disorder with alterations in cytokine and glucocorticoid (GC) production, neither the sensitivity of immune cells to a GC signal nor the reactivity of the hypothalamus-pituitary-adrenal (HPA) axis and inflammatory system to stress, or adaptation of these systems to repeated stress have been assessed in patients with insomnia. To investigate potential dysregulation in stress reactivity and adaptation to repeated exposure, a physiological stressor (the cold pressor test; CPT) was repeatedly administered to N = 20 participants with insomnia disorder (based on DSM-V, 18 females, age 30 ± 2.5 years) and N = 20 sex-matched healthy controls following an at-home actigraphy and in-laboratory PSG. HPA and inflammatory markers (serum cortisol, plasma interleukin [IL]-6) were measured at baseline/resting levels and following each of the three CPTs. In addition, sensitivity of monocytes to the synthetic GC dexamethasone was assessed in-vitro at baseline levels in order to examine the cortisol-IL-6 interplay at the cell level. Compared to healthy controls, individuals with insomnia disorder exhibited shorter sleep duration as assessed by actigraphy and PSG (p ≤ 0.05). HPA, but not inflammatory reactivity to the repeated CPT challenge was greater in insomnia disorder (p ≤ 0.05 for group effect), due to greater cortisol responses to the initial CPT (p ≤ 0.05). There were no between-group differences in the ability of the HPA to adapt to stress repetition nor in basal/resting levels of cortisol, IL-6, and GC sensitivity. These findings suggest that insomnia disorder potentiates HPA axis reactivity to initial/novel stressors, which may constitute a pathway underlying adverse health consequences in the long term.
Yang H, Haack M, Dang R, Gautam S, Simpson NS, Mullington JM. Heart rate variability rebound following exposure to persistent and repetitive sleep restriction. Sleep. 2019;42 (2).Abstract
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.
Lazaridou A, Koulouris A, Devine JK, Haack M, Jamison RN, Edwards RR, Schreiber KL. Impact of daily yoga-based exercise on pain, catastrophizing, and sleep amongst individuals with fibromyalgia. J Pain Res. 2019;12 :2915-2923.Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiological Reviews. 2019;99 (3) :1325-1380. Publisher's VersionAbstract
Sleep and immunity are bidirectionally linked. Immune system activation
alters sleep, and sleep in turn affects the innate and adaptive arm of our body’s defense
system. Stimulation of the immune system by microbial challenges triggers an inflammatory
response, which, depending on its magnitude and time course, can induce an increase in sleep
duration and intensity, but also a disruption of sleep. Enhancement of sleep during an infection is
assumed to feedback to the immune system to promote host defense. Indeed, sleep affects various
immune parameters, is associated with a reduced infection risk, and can improve infection outcome
and vaccination responses. The induction of a hormonal constellation that supports immune functions
is one likely mechanism underlying the immune-supporting effects of sleep. In the absence of an
infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several
inflammatory mediators, such as cytokines. This notion is supported by findings that prolonged sleep
deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade
inflammation and is associated with various diseases that have an inflammatory component, like
diabetes, atherosclerosis, and neurodegeneration. Here, we review available data on this regulatory
sleep-immune crosstalk, point out methodological challenges, and suggest questions open for future