Grandner M, Mullington JM, Hashmi SD, Redeker NS, Watson NF, Morgenthaler TI. Sleep Duration and Hypertension: Analysis of > 700,000 Adults by Age and Sex. J Clin Sleep Med. 2018;14 (6) :1031-1039.Abstract
STUDY OBJECTIVES: The objective of this study was to evaluate the cross-sectional relationship between sleep duration and hypertension in a large, nationally-representative dataset that spans 10 years. This analysis may provide detailed information with high resolution about how sleep duration is related to hypertension and how this differs by demographic group. METHODS: Data were aggregated from the 2013 Behavioral Risk Factor Surveillance System (n = 433,386) and the combined 2007-2016 National Health Interview Surveys (n = 295,331). These data were collected by the Centers for Disease Control and Prevention from nationally-representative samples. Surveys were combined, and survey-specific weights were used in all analyses. Sleep duration was assessed with the item, "On average, how many hours of sleep do you get in a 24-hour period?" in both surveys. Hypertension was assessed as self-reported history. Covariates were assessed identically in both datasets and included, age (in 5-year groupings), sex, race/ethnicity, and employment status. RESULTS: In adjusted analyses, compared to 7 hours, increased risk of hypertension was seen among those sleeping ≤ 4 hours (odds ratio [OR] = 1.86, < .0005), 5 hours (OR = 1.56, < .0005), 6 hours (OR = 1.27, < .0005), 9 hours (OR = 1.19, < .0005), and ≥ 10 hours (OR = 1.41, < .0005). When stratified by age, sex, and race/ethnicity groups, short sleep was associated with increased risk for all age groups < 70 years, and long sleep (≥ 10 hours only) was associated with risk for all except < 24 years and > 74 years. Findings for short sleep were relatively consistent across all race/ethnicities, although findings for long sleep were less pronounced among Black/African-American and Other/Multiracial groups. A significant sleep by 3-way sleep × age × sex interaction ( < .0005) suggests that the relationship depends on both age and sex. For both men and women, the OR of having hypertension associated with short sleep decreases with increasing age, but there is a higher association between short sleep and hypertension for women, throughout the adult lifespan. CONCLUSIONS: Both short and long sleep duration are associated with increased hypertension risk across most age groups. The influence of covariates is stronger upon long sleep relationships. Relationships with short sleep were stronger among younger adults and women.
Alkozei A, Haack M, Skalamera J, Smith R, Satterfield BC, Raikes AC, Killgore WD. Chronic sleep restriction affects the association between implicit bias and explicit social decision making. Sleep Health. 2018;4 (5) :456-462.Abstract
OBJECTIVES: Previous work suggests that sleep restriction (SR) reduces cognitive control and may increase negative implicit biases. Here we investigated whether SR might influence decision making on a social-evaluative task where individuals had to make judgments of threat based on facial photographs. Furthermore, we investigated the effect of changes in negative implicit biases as a result of sleep restriction on this decision-making task. DESIGN: Fourteen healthy adults underwent two 3-week counterbalanced in-laboratory stays (chronic SR and control sleep [CS] conditions). Participants completed the Arab Muslim Names implicit association test (a measure of implicit bias/attitudes toward Arab Muslims) and the Karolinska Airport Task (a measure of explicit decision making). The Karolinska Airport Task requires participants to judge the potential dangerousness of individuals based on facial photographs. RESULTS: After SR, participants were more likely to deem individuals with less positive and more negative facial features as dangerous than after CS. In addition, after SR, those participants showing higher negative implicit bias toward Arab Muslims tended to consider as more dangerous individuals with more quintessentially untrustworthy facial features (r = 0.76, P = .007), whereas this relationship was nonsignificant after CS (r = 0.33, P = .28). CONCLUSIONS: These findings show not only that SR may increase implicit biases against a particular minority group but that SR also modifies how individuals make explicit decisions about another's trustworthiness based on facial features. These findings may have important implications for many occupations where workers who are routinely restricted of sleep are also responsible for making judgments about other people's trustworthiness (eg, police, security, military personnel).
Alkozei A, Killgore WD, Smith R, Dailey NS, Bajaj S, Raikes AC, Haack M. Chronic sleep restriction differentially affects implicit biases toward food among men and women: preliminary evidence. J Sleep Res. 2018;27 (4) :e12629.Abstract
Chronic sleep restriction and obesity are two major public health concerns. This study investigated how chronic sleep restriction changes implicit attitudes towards low- and high-calorie foods. In a randomized, counterbalanced cross-over design, 17 participants (eight females, nine males) underwent two laboratory testing sessions where they were either sleep-restricted for 3 weeks (i.e. underwent three weekly cycles of 5 nights of 4 h of sleep followed by 2 nights of 8 h of sleep opportunity) or received 3 weeks of control sleep (i.e. 8 h of sleep opportunity per night for 3 weeks). There was evidence for a significant sleep condition x sex interaction (F  = 4.60, P = 0.04). After chronic sleep restriction, men showed a trend towards a significant decrease in their implicit attitudes favouring low-calorie foods (P = 0.08), whereas women did not show a significant change (P = 0.16). Men may be at increased risk of weight gain when sleep-deprived due to a reduced bias towards low-calorie foods.
Simpson NS, Scott-Sutherland J, Gautam S, Sethna N, Haack M. Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization. Pain. 2018;159 :33-40. Publisher's VersionAbstract
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Simpson N, Haack M, Mullington JM. Sleep and immune regulation. In: Chokroverty S Sleep Disorders Medicine: Basic Science, Technical Considerations and Clinical Aspects. 4th ed. New York, NY, USA: Springer ; 2017. pp. 195–203.
Morgenthaler TI, Dort L, Mullington J. Transparency and Partnership. J Clin Sleep Med. 2017;13 (5) :763.
Alkozei A, Killgore WD, Smith R, Dailey NS, Bajaj S, Haack M. Chronic Sleep Restriction Increases Negative Implicit Attitudes Toward Arab Muslims. Scientific Reports. 2017;7 :4285.Abstract
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.
Yang H, Haack M, Gautam S, Meier-Ewert HK, Mullington J. Repetitive exposure to shortened sleep leads to blunted sleep-associated blood pressure dipping. Journal of Hypertension. 2017.Abstract

Background: Blood pressure (BP) dips at night during sleep in healthy individuals but in disturbed sleep, dipping is blunted. However, the impact of chronic insufficient sleep duration, with limited intermittent recovery sleep, on BP dipping is not known. The objective of this study was to examine, in a controlled experimental model, the influence of chronic sleep restriction on BP patterns at night and during the day.
Method: In a highly controlled 22-day in-hospital protocol, 45 healthy participants (age 322 years; BMI 241kg/m2; 22 men and 23 women) were randomly assigned to one of two conditions: repeated sleep restriction (4 h of sleep/night from 0300 to 0700 h for three nights followed by recovery sleep of 8 h, repeated four times in succession) or a sleep control group (8 h/night from 2300 to 0700 h).
Results: Beat-to-beat BP and polysomnography were recorded and revealed that sleep-associated DBP dipping was significantly blunted during all four blocks of sleep restriction (P¼0.002). Further, DBP was significantly increased for the whole day during the first, second, and fourth block of sleep restriction (all P<0.01), and SBP was significantly increased for the whole day during the first block of sleep restriction.
Conclusion: Repeated exposure to significantly shortened sleep blunts sleep-associated BP dipping, despite intermittent catch-up sleep. Individuals frequently experiencing insufficient sleep may be at increased risk for hypertension due to repetitive blunting of sleep-associated BP dipping, and resultant elevations in average circadian BP.
Keywords: autonomic nervous system, blood pressure, circadian, blood pressure dipping, diurnal, heart rate, sleep deprivation, sodium excretion
Abbreviations: BL, baseline; BP, blood pressure; CRC, clinical research center; CVD, cardiovascular disease; HR, heart rate; N1, N2, N3, stages 1–3 in nonrapid eye movement sleep; Rec, recovery; REM, rapid eye movement; SE, sleep efficiency; TST, total sleep time

Morgenthaler TI, Hashmi S, Croft JB, Dort L, Heald JL, Mullington J. High School Start Times and the Impact on High School Students: What We Know, and What We Hope to Learn. J Clin Sleep Med. 2016;12 (12) :1681-1689.Abstract
STUDY OBJECTIVES: Several organizations have provided recommendations to ensure high school starts no sooner than 08:30. However, although there are plausible biological reasons to support such recommendations, published recommendations have been based largely on expert opinion and a few observational studies. We sought to perform a critical review of published evidence regarding the effect of high school start times on sleep and other relevant outcomes. METHODS: We performed a broad literature search to identify 287 candidate publications for inclusion in our review, which focused on studies offering direct comparison of sleep time, academic or physical performance, behavioral health measures, or motor vehicular accidents in high school students. Where possible, outcomes were combined for meta-analysis. RESULTS: After application of study criteria, only 18 studies were suitable for review. Eight studies were amenable to meta-analysis for some outcomes. We found that later school start times, particularly when compared with start times more than 60 min earlier, are associated with longer weekday sleep durations, lower weekday-weekend sleep duration differences, reduced vehicular accident rates, and reduced subjective daytime sleepiness. Improvement in academic performance and behavioral issues is less established. CONCLUSIONS: The literature regarding effect of school start time delays on important aspects of high school life suggests some salutary effects, but often the evidence is indirect, imprecise, or derived from cohorts of convenience, making the overall quality of evidence weak or very weak. This review highlights a need for higher-quality data upon which to base important and complex public health decisions.
Simpson NS, Diolombi M, Scott-Sutherland J, Yang H, Bhatt V, Gautam S, Mullington JM, Haack M. Repeating patterns of sleep restriction and recovery: Do we get used to it?. Brain, Behavior, and Immunity. 2016;58 :142-151.Abstract

Despite its prevalence in modern society, little is known about the long-term impact of restricting sleep during the week and ‘catching up’ on weekends. This common sleep pattern was experimentally modeled with three weeks of 5 nights of sleep restricted to 4 h followed by two nights of 8-h recovery sleep. In an
intra-individual design, 14 healthy adults completed both the sleep restriction and an 8-h control condition, and the subjective impact and the effects on physiological markers of stress (cortisol, the inflammatory marker IL-6, glucocorticoid receptor sensitivity) were assessed. Sleep restriction was not perceived to be subjectively stressful and some degree of resilience or resistance to the effects of sleep restriction was observed in subjective domains. In contrast, physiological stress response systems remain activated with repeated exposures to sleep restriction and limited recovery opportunity. Morning IL-6 expression in monocytes was significantly increased during week 2 and 3 of sleep restriction, and remained
increased after recovery sleep in week 2 (p < 0.05) and week 3 (p < 0.09). Serum cortisol showed a significantly dysregulated 24 h-rhythm during weeks 1, 2, and 3 of sleep restriction, with elevated morning cortisol, and decreased cortisol in the second half of the night. Glucocorticoid sensitivity of monocytes
was increased, rather than decreased, during the sleep restriction and sleep recovery portion of each week. These results suggest a disrupted interplay between the hypothalamic-pituitary-adrenal and inflammatory systems in the context of repeated exposure to sleep restriction and recovery. The observed
dissociation between subjective and physiological responses may help explain why many individuals continue with the behavior pattern of restricting and recovering sleep over long time periods, despite a cumulative deleterious physiological effect.

Mullington JM, Abbott SM, Carroll JE, Davis CJ, Dijk D-J, Dinges DF, Gehrman PR, Ginsburg GS, Gozal D, Haack M, et al. Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health. Sleep. 2016;39 (4) :727-36.
Morgenthaler TI, Croft JB, Dort LC, Loeding LD, Mullington JM, Thomas SM. Development of the National Healthy Sleep Awareness Project Sleep Health Surveillance Questions. J Clin Sleep Med. 2015;11 (9) :1057-62.Abstract
OBJECTIVES: For the first time ever, as emphasized by inclusion in the Healthy People 2020 goals, sleep health is an emphasis of national health aims. The National Healthy Sleep Awareness Project (NHSAP) was tasked to propose questions for inclusion in the next Behavioral Risk Factor Surveillance System (BRFSS), a survey that includes a number of questions that target behaviors thought to impact health, as a means to measure community sleep health. The total number of questions could not exceed five, and had to include an assessment of the risk for obstructive sleep apnea (OSA). METHODS: An appointed workgroup met via teleconference and face-to-face venues to develop an inventory of published survey questions being used to identify sleep health, to develop a framework on which to analyze the strengths and weaknesses of current survey questions concerning sleep, and to develop recommendations for sleep health and disease surveillance questions going forward. RESULTS: The recommendation was to focus on certain existing BRFSS questions pertaining to sleep duration, quality, satisfaction, daytime alertness, and to add to these other BRFSS existing questions to make a modified STOP-BANG questionnaire (minus the N for neck circumference) to assess for risk of OSA. CONCLUSIONS: Sleep health is an important dimension of health that has previously received less attention in national health surveys. We believe that 5 questions recommended for the upcoming BRFSS question banks will assist as important measures of sleep health, and may help to evaluate the effectiveness of interventions to improve sleep health in our nation.
Mullington J, Pack AI, Ginsburg GS. In Pursuit of Sleep-Circadian Biomarkers. Sleep. 2015;38 (11) :1665-6.
Floam S, Simpson N, Nemeth E, Scott-Sutherland J, Gautam S, Haack M. Sleep characteristics as predictor variables of stress systems markers in insomnia disorder. J Sleep Res. 2015;24 (3) :296-304.Abstract
This study investigates the extent to which sleep characteristics serve as predictor variables for inflammatory, hypothalamic-pituitary-adrenal and autonomic systems markers. Twenty-nine participants with a diagnosis of insomnia disorder based on the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (age 25.3 ± 1.6 years, insomnia duration 6.6 ± 0.8 years) and 19 healthy control sleepers (age 25.4 ± 1.4 years) underwent a 2-week at-home evaluation keeping a sleep diary and wearing an actigraph, followed by a visit to the Research Center to measure blood pressure, and collect blood and urine samples. The actigraphy- and diary-based variables of sleep duration, sleep-onset latency, wake after sleep onset and sleep fragmentation/number of night-time awakenings were averaged and entered as dependent variables in regression analyses. Composite scores were calculated for the autonomic (blood pressure, norepinephrine), inflammatory (monocyte counts, interleukin-6, C-reactive protein) and hypothalamic-pituitary-adrenal systems (cortisol), and used as predictor variables in regression models. Compared with controls, individuals with insomnia had a shorter sleep duration (P < 0.05), and a higher hypothalamic-pituitary-adrenal and inflammatory composite score (P < 0.05). The higher inflammatory score was mainly due to higher circulating monocytes (P < 0.05), rather than differences in interleukin-6 or C-reactive protein. In persistent insomnia disorder, cortisol is upregulated and associated with actigraphy- and diary-based wake after sleep onset, suggesting that wake after sleep onset may serve as a marker to identify individuals at increased risks for disorders associated with a hyperactive hypothalamic-pituitary-adrenal system. The absence of autonomic and pro-inflammatory changes (interleukin-6, C-reactive protein), despite a substantial decrease in actigraphic sleep duration, may relate to a higher resilience to the adverse biological consequences of insomnia in this young age group.
Zee PC, Badr SM, Kushida C, Mullington JM, Pack AI, Parthasarathy S, Redline S, Szymusiak RS, Walsh JK, Watson NF. Strategic opportunities in sleep and circadian research: report of the Joint Task Force of the Sleep Research Society and American Academy of Sleep Medicine. Sleep. 2014;37 (2) :219-27.
Chesson AL, Chervin RD, Benca RM, Greenough GP, O'Hearn DJ, Auckley DH, Littner M, Mullington JM, Malhotra A, Berry RB, et al. Organization and structure for sleep medicine programs at academic institutions: Part 2--goals and strategies to optimize patient care, education, and discovery. Sleep. 2013;36 (6) :803-11.
Chervin RD, Chesson AL, Benca RM, Greenough GP, O'Hearn DJ, Auckley DH, Littner M, Mullington JM, Malhotra A, Berry RB, et al. Organization and structure for sleep medicine programs at academic institutions: Part 1--current challenges. Sleep. 2013;36 (6) :795-801.
Haack M, Serrador J, Cohen D, Simpson N, Meier-Ewert H, Mullington JM. Increasing sleep duration to lower beat-to-beat blood pressure: a pilot study. J Sleep Res. 2013;22 (3) :295-304.Abstract
Strong evidence has accumulated over the last several years, showing that low sleep quantity and/or quality plays an important role in the elevation of blood pressure. We hypothesized that increasing sleep duration serves as an effective behavioral strategy to reduce blood pressure in prehypertension or type 1 hypertension. Twenty-two participants with prehypertension or stage 1 hypertension, and habitual sleep durations of 7 h or less, participated in a 6-week intervention study. Subjects were randomized to a sleep extension group (48 ± 12 years, N = 13) aiming to increase bedtime by 1 h daily over a 6-week intervention period, or to a sleep maintenance group (47 ± 12 years, N = 9) aiming to maintain habitual bedtimes. Both groups received sleep hygiene instructions. Beat-to-beat blood pressure was monitored over 24 h, and 24-h urine and a fasting blood sample were collected pre- and post-intervention. Subjects in the sleep extension group increased their actigraphy-assessed daily sleep duration by 35 ± 9 min, while subjects in the sleep maintenance condition increased slightly by 4 ± 9 min (P = 0.03 for group effect). Systolic and diastolic beat-to-beat blood pressure averaged across the 24-h recording period significantly decreased from pre- to post-intervention visit in the sleep extension group by 14 ± 3 and 8 ± 3 mmHg, respectively (P < 0.05). Though the reduction of 7 ± 5 and 3 ± 4 mmHg in the sleep maintenance group was not significant, it did not differ from the blood pressure reduction in the sleep extension group (P = 0.15 for interaction effect). These changes were not paralleled by pre- to post-intervention changes in inflammatory or sympatho-adrenal markers, nor by changes in caloric intake. While these preliminary findings have to be interpreted with caution due to the small sample size, they encourage future investigations to test whether behavioral interventions designed to increase sleep duration serve as an effective strategy in the treatment of hypertension.
Dushay J, Gao C, Gopalakrishnan GS, Crawley M, Mitten EK, Wilker E, Mullington J, Maratos-Flier E. Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes. Diabetes Care. 2012;35 (1) :4-11.Abstract
OBJECTIVE: To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women. RESEARCH DESIGN AND METHODS: Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m(2)) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight. RESULTS: Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (-7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (-2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss. CONCLUSIONS: Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.
Haack M, Scott-Sutherland J, Santangelo G, Simpson NS, Sethna N, Mullington JM. Pain sensitivity and modulation in primary insomnia. Eur J Pain. 2012;16 (4) :522-33.Abstract
Sleep of good quantity and quality is considered a biologically important resource necessary to maintain homeostasis of pain-regulatory processes. To assess the role of chronic sleep disturbances in pain processing, we conducted laboratory pain testing in subjects with primary insomnia. Seventeen participants with primary insomnia (mean ± SEM 22.6 ± 0.9 yrs, 11 women) were individually matched with 17 healthy participants. All participants wore an actigraph device over a 2-week period and completed daily sleep and pain diaries. Laboratory pain testing was conducted in a controlled environment and included (1) warmth detection threshold testing, (2) pain sensitivity testing (threshold detection for heat and pressure pain), and (3) tests to access pain modulatory mechanisms (pain facilitation and inhibition). Primary insomnia subjects reported experiencing spontaneous pain on twice as many days as healthy controls during the at-home recording phase (p < 0.05). During laboratory testing, primary insomnia subjects had lower pain thresholds than healthy controls (p < 0.05 for heat pain detection threshold, p < 0.08 for pressure pain detection threshold). Unexpectedly, pain facilitation, as assessed with temporal summation of pain responses, was reduced in primary insomnia compared to healthy controls (p < 0.05). Pain inhibition, as assessed with the diffuse noxious inhibitory control paradigm (DNIC), was attenuated in insomnia subjects when compared to controls (p < 0.05). Based on these findings, we propose that pain-inhibitory circuits in patients with insomnia are in a state of constant activation to compensate for ongoing subclinical pain. This constant activation ultimately may result in a ceiling effect of pain-inhibitory efforts, as indicated by the inability of the system to adequately function during challenge.