The new science of sleep: From cells to large-scale societies.

In the past 20 years, more remarkable revelations about sleep and its varied functions have arguably been made than in the previous 200. Building on this swell of recent findings, this essay provides a broad sampling of selected research highlights across genetic, molecular, cellular, and physiological systems within the body, networks within the brain, and large-scale social dynamics. Based on this raft of exciting new discoveries, we have come to realize that sleep, in this moment of its evolution, is very much polyfunctional (rather than monofunctional), yet polyfunctional for reasons we had never previously considered. Moreover, these new polyfunctional insights powerfully reaffirm sleep as a critical biological, and thus health-sustaining, requisite. Indeed, perhaps the only thing more impressive than the unanticipated nature of these newly emerging sleep functions is their striking divergence, from operations of molecular mechanisms inside cells to entire group societal dynamics.

The Negative Effects of Travel on Student Athletes Through Sleep and Circadian Disruption.

Collegiate athletes must satisfy the academic obligations common to all undergraduates, but they have the additional structural and social stressors of extensive practice time, competition schedules, and frequent travel away from their home campus. Clearly such stressors can have negative impacts on both their academic and athletic performances as well as on their health. These concerns are made more acute by recent proposals and decisions to reorganize major collegiate athletic conferences. These rearrangements will require more multi-day travel that interferes with the academic work and personal schedules of athletes. Of particular concern is additional east-west travel that results in circadian rhythm disruptions commonly called jet lag that contribute to the loss of amount as well as quality of sleep. Circadian misalignment and sleep deprivation and/or sleep disturbances have profound effects on physical and mental health and performance. We, as concerned scientists and physicians with relevant expertise, developed this white paper to raise awareness of these challenges to the wellbeing of our student-athletes and their co-travelers. We also offer practical steps to mitigate the negative consequences of collegiate travel schedules. We discuss the importance of bedtime protocols, the availability of early afternoon naps, and adherence to scheduled lighting exposure protocols before, during, and after travel, with support from wearables and apps. We call upon departments of athletics to engage with sleep and circadian experts to advise and help design tailored implementation of these mitigating practices that could contribute to the current and long-term health and wellbeing of their students and their staff members.

Correction: Sleep loss leads to the withdrawal of human helping across individuals, groups, and large-scale societies.

[This corrects the article DOI: 10.1371/journal.pbio.3001733.].

Sleep, alcohol, and caffeine in financial traders.

Alcohol and caffeine are two of the most commonly used substances for altering human consciousness. While their adverse effects on sleep have been separately examined in the laboratory and epidemiological levels, how they impact real-world night-to-night sleep, in isolation or together, remains unclear. This is especially true in occupations wherein the use of alcohol and caffeine is high (e.g., financial services sector). Using a six-week micro-longitudinal study, here we examined the real-world impact of alcohol, caffeine, and their combined consumption in a cohort of financial traders. We demonstrate that alcohol consumption significantly degrades the subjective quality of sleep (p < 0.001). Caffeine consumption led to a different phenotype of sleep impairment, resulting in a detrimental reduction in sleep quantity (p = 0.019), rather than a marked alteration in sleep quality. Contrary to our hypothesis, when consumed in combination, evening alcohol consumption interacted with ongoing caffeine consumption such that alcohol partially mitigated the impairments in sleep quantity associated with caffeine (p = 0.032). This finding suggests the sedating effects of alcohol and the psychoactive stimulant effects of caffeine obscure each other's impact on sleep quantity and sleep quality, respectively-potentially explaining their interdependent use in this cohort (i.e., "self-medication" of evening sedation with alcohol to combat the prior daytime ingestion of caffeine and vice versa). More generally, these results contribute to a unique understanding of the singular and combinatory impacts of two of the most commonly used substances for augmenting human consciousness under free-living, real-world conditions, the performance-impairing (and thus economic-cost) consequences of which may be important to the business sector and the society.

Human REM sleep recalibrates neural activity in support of memory formation.

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.

Coordinated human sleeping brainwaves map peripheral body glucose homeostasis.

Insufficient sleep impairs glucose regulation, increasing the risk of diabetes. However, what it is about the human sleeping brain that regulates blood sugar remains unknown. In an examination of over 600 humans, we demonstrate that the coupling of non-rapid eye movement (NREM) sleep spindles and slow oscillations the night before is associated with improved next-day peripheral glucose control. We further show that this sleep-associated glucose pathway may influence glycemic status through altered insulin sensitivity, rather than through altered pancreatic beta cell function. Moreover, we replicate these associations in an independent dataset of over 1,900 adults. Of therapeutic significance, the coupling between slow oscillations and spindles was the most significant sleep predictor of next-day fasting glucose, even more so than traditional sleep markers, relevant to the possibility of an electroencephalogram (EEG) index of hyperglycemia. Taken together, these findings describe a sleeping-brain-body framework of optimal human glucose homeostasis, offering a potential prognostic sleep signature of glycemic control.

NREM sleep as a novel protective cognitive reserve factor in the face of Alzheimer's disease pathology.

BACKGROUND: Alzheimer's disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. METHODS: Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of ß-amyloid (Aß) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. RESULTS: We demonstrated that NREM SWA significantly moderates the effect of Aß status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aß burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aß pathological burden, and thus without the same  need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aß status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). CONCLUSIONS: These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.

Sleep Loss Influences the Interconnected Brain-Body Regulation of Cardiovascular Function in Humans.

OBJECTIVE: Poor sleep is associated with hypertension, a major risk factor for cardiovascular disease. However, the mechanism(s) through which sleep loss affects cardiovascular health remains largely unknown, including the brain and body systems that regulate vascular function. METHODS: Sixty-six healthy adults participated in a repeated-measures, crossover, experimental study involving assessments of cardiovascular function and brain connectivity after a night of sleep and a night of sleep deprivation. RESULTS: First, sleep deprivation significantly increased blood pressure-both systolic and diastolic. Interestingly, this change was independent of any increase in heart rate, inferring a vasculature-specific rather than direct cardiac pathway. Second, sleep loss compromised functional brain connectivity within the vascular control network, specifically the insula, anterior cingulate, amygdala, and ventral and medial prefrontal cortices. Third, sleep loss-related changes in brain connectivity and vascular tone were not independent, but significantly interdependent, with changes within the vascular control brain network predicting the sleep-loss shift toward hypertension. CONCLUSIONS: These findings establish an embodied framework in which sleep loss confers increased risk of cardiovascular disease through an impact upon central brain control of vascular tone, rather than a direct impact on accelerated heart rate itself.

How people wake up is associated with previous night's sleep together with physical activity and food intake.

How people wake up and regain alertness in the hours after sleep is related to how they are sleeping, eating, and exercising. Here, in a prospective longitudinal study of 833 twins and genetically unrelated adults, we demonstrate that how effectively an individual awakens in the hours following sleep is not associated with their genetics, but instead, four independent factors: sleep quantity/quality the night before, physical activity the day prior, a breakfast rich in carbohydrate, and a lower blood glucose response following breakfast. Furthermore, an individual's set-point of daily alertness is related to the quality of their sleep, their positive emotional state, and their age. Together, these findings reveal a set of non-genetic (i.e., not fixed) factors associated with daily alertness that are modifiable.

Sleep loss leads to the withdrawal of human helping across individuals, groups, and large-scale societies.

Humans help each other. This fundamental feature of homo sapiens has been one of the most powerful forces sculpting the advent of modern civilizations. But what determines whether humans choose to help one another? Across 3 replicating studies, here, we demonstrate that sleep loss represents one previously unrecognized factor dictating whether humans choose to help each other, observed at 3 different scales (within individuals, across individuals, and across societies). First, at an individual level, 1 night of sleep loss triggers the withdrawal of help from one individual to another. Moreover, fMRI findings revealed that the withdrawal of human helping is associated with deactivation of key nodes within the social cognition brain network that facilitates prosociality. Second, at a group level, ecological night-to-night reductions in sleep across several nights predict corresponding next-day reductions in the choice to help others during day-to-day interactions. Third, at a large-scale national level, we demonstrate that 1 h of lost sleep opportunity, inflicted by the transition to Daylight Saving Time, reduces real-world altruistic helping through the act of donation giving, established through the analysis of over 3 million charitable donations. Therefore, inadequate sleep represents a significant influential force determining whether humans choose to help one another, observable across micro- and macroscopic levels of civilized interaction. The implications of this effect may be non-trivial when considering the essentiality of human helping in the maintenance of cooperative, civil society, combined with the reported decline in sufficient sleep in many first-world nations.

A Nationally Representative Survey Assessing Restorative Sleep in US Adults.

Restorative sleep is a commonly used term but a poorly defined construct. Few studies have assessed restorative sleep in nationally representative samples. We convened a panel of 7 expert physicians and researchers to evaluate and enhance available measures of restorative sleep. We then developed the revised Restorative Sleep Questionnaire (REST-Q), which comprises 9 items assessing feelings resulting from the prior sleep episode, each with 5-point Likert response scales. Finally, we assessed the prevalence of high, somewhat, and low REST-Q scores in a nationally representative sample of US adults (n= 1,055) and examined the relationship of REST-Q scores with other sleep and demographic characteristics. Pairwise correlations were performed between the REST-Q scores and other self-reported sleep measures. Weighted logistic regression analyses were conducted to compare scores on the REST-Q with demographic variables. The prevalence of higher REST-Q scores (4 or 5 on the Likert scale) was 28.1% in the nationally representative sample. REST-Q scores positively correlated with sleep quality (r=0.61) and sleep duration (r=0.32), and negatively correlated with both difficulty falling asleep (r=-0.40) and falling back asleep after waking (r=-0.41). Higher restorative sleep scores (indicating more feelings of restoration upon waking) were more common among those who were: ≥60 years of age (OR=4.20, 95%CI: 1.92-9.17); widowed (OR=2.35, 95%CI:1.01-5.42), and retired (OR=2.02, 95%CI:1.30-3.14). Higher restorative sleep scores were less frequent among those who were not working (OR=0.36, 95%CI: 0.10-1.00) and living in a household with two or more persons (OR=0.51,95%CI:0.29-0.87). Our findings suggest that the REST-Q may be useful for assessing restorative sleep.

Impact of insufficient sleep on dysregulated blood glucose control under standardised meal conditions.

AIMS/HYPOTHESIS: Sleep, diet and exercise are fundamental to metabolic homeostasis. In this secondary analysis of a repeated measures, nutritional intervention study, we tested whether an individual's sleep quality, duration and timing impact glycaemic response to a breakfast meal the following morning. METHODS: Healthy adults' data (N = 953 [41% twins]) were analysed from the PREDICT dietary intervention trial. Participants consumed isoenergetic standardised meals over 2 weeks in the clinic and at home. Actigraphy was used to assess sleep variables (duration, efficiency, timing) and continuous glucose monitors were used to measure glycaemic variation (>8000 meals). RESULTS: Sleep variables were significantly associated with postprandial glycaemic control (2 h incremental AUC), at both between- and within-person levels. Sleep period time interacted with meal type, with a smaller effect of poor sleep on postprandial blood glucose levels when high-carbohydrate (low fat/protein) (pinteraction = 0.02) and high-fat (pinteraction = 0.03) breakfasts were consumed compared with a reference 75 g OGTT. Within-person sleep period time had a similar interaction (high carbohydrate: pinteraction = 0.001, high fat: pinteraction = 0.02). Within- and between-person sleep efficiency were significantly associated with lower postprandial blood glucose levels irrespective of meal type (both p < 0.03). Later sleep midpoint (time deviation from midnight) was found to be significantly associated with higher postprandial glucose, in both between-person and within-person comparisons (p = 0.035 and p = 0.051, respectively). CONCLUSIONS/INTERPRETATION: Poor sleep efficiency and later bedtime routines are associated with more pronounced postprandial glycaemic responses to breakfast the following morning. A person's deviation from their usual sleep pattern was also associated with poorer postprandial glycaemic control. These findings underscore sleep as a modifiable, non-pharmacological therapeutic target for the optimal regulation of human metabolic health. Trial registration ClinicalTrials.gov NCT03479866.

An open-source, high-performance tool for automated sleep staging.

The clinical and societal measurement of human sleep has increased exponentially in recent years. However, unlike other fields of medical analysis that have become highly automated, basic and clinical sleep research still relies on human visual scoring. Such human-based evaluations are time-consuming, tedious, and can be prone to subjective bias. Here, we describe a novel algorithm trained and validated on +30,000 hr of polysomnographic sleep recordings across heterogeneous populations around the world. This tool offers high sleep-staging accuracy that matches human scoring accuracy and interscorer agreement no matter the population kind. The software is designed to be especially easy to use, computationally low-demanding, open source, and free. Our hope is that this software facilitates the broad adoption of an industry-standard automated sleep staging software package.

Tau and ß-Amyloid Burden Predict Actigraphy-Measured and Self-Reported Impairment and Misperception of Human Sleep.

Alzheimer's disease is associated with poor sleep, but the impact of tau and ß-amyloid (Aß) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aß predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aß PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aß, was associated with markedly worse objective sleep. In contrast, Aß and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aß burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aß deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.SIGNIFICANCE STATEMENT Alzheimer's disease is associated with sleep disruption, often before significant memory decline. Thus, real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and ß-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater ß-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer's disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer's disease-related behavioral changes.

Sleep Disturbance Forecasts ß-Amyloid Accumulation across Subsequent Years.

Experimental sleep-wake disruption in rodents and humans causally modulates ß-amyloid (Aß) dynamics (e.g., [1-3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aß accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aß accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aß accumulation with [11C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aß deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aß deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aß pathological progression, prior to cognitive symptoms of Alzheimer's disease (AD).

An electrophysiological marker of arousal level in humans.

Deep non-rapid eye movement sleep (NREM) and general anesthesia with propofol are prominent states of reduced arousal linked to the occurrence of synchronized oscillations in the electroencephalogram (EEG). Although rapid eye movement (REM) sleep is also associated with diminished arousal levels, it is characterized by a desynchronized, 'wake-like' EEG. This observation implies that reduced arousal states are not necessarily only defined by synchronous oscillatory activity. Using intracranial and surface EEG recordings in four independent data sets, we demonstrate that the 1/f spectral slope of the electrophysiological power spectrum, which reflects the non-oscillatory, scale-free component of neural activity, delineates wakefulness from propofol anesthesia, NREM and REM sleep. Critically, the spectral slope discriminates wakefulness from REM sleep solely based on the neurophysiological brain state. Taken together, our findings describe a common electrophysiological marker that tracks states of reduced arousal, including different sleep stages as well as anesthesia in humans.

Electroencephalogram (EEG for short) is a widespread technique that helps to monitor the electrical activity of the brain. In particular, it can be used to examine, recognize and compare different states of brain consciousness such as sleep, wakefulness or general anesthesia. Yet, during rapid eye movement sleep (the sleep phase in which dreaming occurs), the electrical activity of the brain is similar to the one recorded during wakefulness, making it difficult to distinguish these states based on EEG alone. EEG records brain activity in the shape of rhythmic waves whose frequency, shape and amplitude vary depending on the state of consciousness. In the EEG signal from the human brain, the higher frequency waves are weaker than the low-frequency waves: a measure known as spectral slope reflects the degree of this difference in the signal strength. Previous research suggests that spectral slope can be used to distinguish wakefulness from anesthesia and non-REM sleep. Here, Lendner et al. explored whether certain elements of the spectral slope could also discern wakefulness from all states of reduced arousal. EEG readings were taken from patients and volunteers who were awake, asleep or under anesthesia, using electrodes placed either on the scalp or into the brain. Lendner et al. found that the spectral slope could distinguish wakefulness from anesthesia, deep non-REM and REM sleep. The changes in the spectral slope during sleep could accurately track the degree of arousal with great temporal precision and across a wide range of time scales. This method means that states of consciousness can be spotted just from a scalp EEG. In the future, this approach could be embedded into the techniques used for monitoring sleep or anesthesia during operations; it could also be harnessed to monitor other low-response states, such as comas.

Broken sleep predicts hardened blood vessels.

Why does poor-quality sleep lead to atherosclerosis? In a diverse sample of over 1,600 individuals, we describe a pathway wherein sleep fragmentation raises inflammatory-related white blood cell counts (neutrophils and monocytes), thereby increasing atherosclerosis severity, even when other common risk factors have been accounted for. Improving sleep quality may thus represent one preventive strategy for lowering inflammatory status and thus atherosclerosis risk, reinforcing public health policies focused on sleep health.