Solving the mystery of human sleep schedules one mutation at a time

Abstract

Sleep behavior remains one of the most enigmatic areas of life. The unanswered questions range from “why do we sleep?” to “how we can improve sleep in today’s society?” Identification of mutations responsible for altered circadian regulation of human sleep lead to unique opportunities for probing these territories. In this review, we summarize causative circadian mutations found from familial genetic studies to date. We also describe how these mutations mechanistically affect circadian function and lead to altered sleep behaviors, including shifted or shortening of sleep patterns. In addition, we discuss how the investigation of mutations can not only expand our understanding of the molecular mechanisms regulating the circadian clock and sleep duration, but also bridge the pathways between clock/sleep and other human physiological conditions and ailments such as metabolic regulation and migraine headaches.     

No first night shift effect observed following a nocturnal main sleep and a prophylactic 1-h afternoon nap

ABSTRACT

Neurobehavioural impairment on the first night shift is often greater than on subsequent night shifts due to extended wakefulness. The aim of the study was to determine whether a 1-h afternoon nap prior to the first night shift is sufficient to produce neurobehavioural performance at levels comparable to the second night shift. Twelve male volunteers (mean age 22.9 years) participated in a laboratory protocol that simulated two 12-h night shifts. A nap preceded the first shift and a 7-h daytime sleep was scheduled between shifts. Neurobehavioural performance and subjective sleepiness measured across each night did not significantly differ between first and second shifts.     

Nitric oxide production in the basal forebrain is required for recovery sleep

Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. Here, we assessed the role of the intercellular gaseous signaling agent NO in sleep homeostasis. We measured the concentration of nitrite and nitrate, indicative of NO production, in the basal forebrain (BF) of rats during sleep deprivation (SD), and found the level increased by 100 +/- 51%. To test whether an increase in NO production might play a causal role in recovery sleep, we administered compounds into the BF that increase or decrease concentrations of NO. Infusion of either a NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, or a NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), completely abolished non-rapid eye movement (NREM) recovery sleep. Infusion of a NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2diolate (DETA/NO), produced an increase in NREM that closely resembled NREM recovery after prolonged wakefulness. The effects of inhibition of NO synthesis and the pharmacological induction of sleep were effective only in the BF area. Indicators of energy metabolism, adenosine, lactate and pyruvate increased during prolonged wakefulness and DETA/NO infusion, whereas L-NAME infusion during SD prevented the increases. We conclude that an increase in NO production in the BF is a causal event in the induction of recovery sleep.     

An ameliorative effect of recovery sleep on total sleep deprivation-induced neurodegeneration

Neurodegenerative changes following sleep deprivation (SD) result in debilitating behavioral and cognitive dysfunction. SD causes gradual cognitive impairment and later results in neurodegeneration. These changes are thought to be the consequences of cellular disorganization and degeneration in selected brain areas – the hippocampus, prefrontal cortex, amygdala, and hypothalamus. We investigated the histological changes in mice exposed to 6 days SD and to the effects of 2 days of recovery sleep in the brain regions listed above. Cytological changes, total viable cell count in hippocampal subregions, Bcl-2 expression, and degenerative changes like cell morphology and membrane integrity of neurons were evaluated. Results demonstrated that prolonged SD decreased the count of viable and healthy cells and caused a decrease in Bcl-2 positive cells and an increase in degenerated cells with pyknotic morphology, chromatolysis and darkly stained cytoplasm. Degenerative changes were ameliorated by 2 days of recovery sleep or rehabilitation after SD. Data suggest that chronic SD constitutes a severe threat to the brain and leads to neurodegeneration, while rehabilitation or recovery sleep ameliorates or protects the brain from neurodegenerative challenges.     

The impact of training schedules on the sleep and fatigue of elite athletes

In any sport, successful performance requires a planned approach to training and recovery. While sleep is recognized as an essential component of this approach, the amount and quality of sleep routinely obtained by elite athletes has not been systematically evaluated. Data were collected from 70 nationally ranked athletes from seven different sports. Athletes wore wrist activity monitors and completed self-report sleep/training diaries for 2 weeks during normal training. The athletes also recorded their fatigue level prior to each training session using a 7-point scale. On average, the athletes spent 08:18?±?01:12?h in bed, fell asleep at 23:06?±?01:12?h, woke at 6:48?±?01:30?h and obtained 06:30?±?01:24?h of sleep per night. There was a marked difference in the athletes’ sleep/wake behaviour on training days and rest days. Linear mixed model analyses revealed that on nights prior to training days, time spent in bed was significantly shorter (p?=?0.001), sleep onset and offset times were significantly earlier (p?<?0.001) and the amount of sleep obtained was significantly less (p?=?0.001), than on nights prior to rest days. Moreover, there was a significant effect of sleep duration on pre-training fatigue levels (p?≤?0.01). Specifically, shorter sleep durations were associated with higher levels of pre-training fatigue. Taken together, these findings suggest that the amount of sleep an elite athlete obtains is dictated by their training schedule. In particular, early morning starts reduce sleep duration and increase pre-training fatigue levels. When designing schedules, coaches should be aware of the implications of the timing of training sessions for sleep and fatigue. In cases where early morning starts are unavoidable, countermeasures for minimizing sleep loss – such as strategic napping during the day and correct sleep hygiene practices at night – should be considered.     

Athletes underestimate sleep quantity during daytime nap opportunities

ABSTRACT

This study examined the difference between athletes’ self-reported and objective sleep durations during two nap opportunities. Twelve well-trained male soccer players’ sleep durations were assessed using polysomnography and a self-report question during a 60- and 120-min nap opportunity. Participants underestimated sleep compared to objective sleep assessments for both the 60-min nap opportunity (p = 0.004) and 120-min nap opportunity (p = 0.001). Soccer players underestimated their sleep duration by approximately 10 min per hour of nap opportunity. It is yet to be determined if athletes are likely to underestimate sleep duration during their main nighttime sleep period.     

Restricted and unrestricted sleep schedules of Asian adolescent,high-level student athletes: effects on sleep durations,marksmanship and cognitive performance

The present study sought to compare the effects of a restricted and unrestricted sleep schedule on shooting, cognitive performance and measures of sleepiness and fatigue of Asian, adolescent high-level student athletes. Twenty-four (12 female; 14.1 ± 1.4 years) athletes performed assessments of shooting and cognitive performance (psychomotor vigilance and working memory) at the start and end of five-day restricted or unrestricted sleep (two conditions). Restricted sleep during a five-day training week resulted in no significant performance changes in cognitive or shooting performance compared with unrestricted sleep during a five-day training week, despite there being moderate-to-strong associations between increases in total sleep time and certain aspects of shooting performance. Daytime fatigue levels during the unrestricted sleep period were significantly lower than during sleep restriction. These findings highlight the relationships between nocturnal sleep extension and shooting performance amongst high-level athletes.     

Shift work and sleep disorder comorbidity tend to go hand in hand

Taking into consideration that shift work has a wide-ranging impact on circadian and sleep functioning, it seems likely that shift work increases the risk of a general sleep disturbance, spread out over a multitude of comorbid sleep disorders. The aim of the present study is to analyze and present the sleep disorder data of 250 shift workers and 971 permanent day workers, taken from a nationally representative sample. Additional data concerning duration, timing, and quality of sleep, daytime functioning and social/family variables were added to the analyses. The results showed that the shift workers experienced significantly more difficulties with the variability of their sleep times, reported more napping and considered themselves more as poor sleepers than the day workers. Most importantly, shift work, in comparison with day work, appeared associated with a significantly higher prevalence of the clinical, International Classification of Sleep Disorders’ defined symptoms of nearly all main sleep disorders (including shift work disorder). For shift workers, the prevalence of a general sleep disturbance was 39.0% (95%CI 33.2 – 45.2), significantly higher than for day workers (24.6%, 95%CI 22.0 – 27.4). Moreover, shift workers were characterized by high levels of sleep disorder comorbidity. In addition, exclusively for shift workers, the prevalence of disordered sleep systematically decreased across decades of life and was considerably higher for single versus partnered shift workers. This study adds to the insight into the interacting factors that determine shift work coping and may play a role in occupational health interventions aimed at reducing sleep problems and thus improving the resilience and tolerance of the shift worker.     

Correlations between sleep patterns and cardiovascular diseases in a Chinese middle-aged population

Epidemiological and animal studies have suggested an association between habitual sleep patterns and cardiovascular (CV) disease, but the results are still controversial. Therefore, the aims of this study are to investigate the relationships between habitual sleep patterns and CV disease based on Prospective Urban Rural Epidemiology (PURE) China study. PURE China study recruited 46 285 participants, aged 35–70, from 12 provinces and 115 communities in China. Habitual sleep patterns and CV disease were self-reported. Multilevel logistic regression was used in our analysis. In this study, 39 515 participants were eligible in our analysis, including 23 345 (59.1%) women and 16 170 (40.9%) men. Sleeping ≥9 h per day was associated with increased odds of CV disease (OR = 1.16, 95% CI: 1.01–1.32, p = 0.033) compared with sleeping 7–8 h per day. Taking daytime naps was also associated with an increased odds of CV disease, and the CV odds increased with increasing napping duration (p for trend < 0.001). For the sleeping < 6 h per day, we only found an association with coronary artery disease (CAD) (OR = 1.58, 95% CI: 1.01–2.48, p = 0.046). Participants with only 7–8 h sleep per night had lowest prevalence of CV disease (OR = 0.77, 95% CI: 0.65–0.90, p = 0.001) compared with other sleep patterns. Napping, long and short duration of habitual sleep may increase the odds of CV disease. Only participants sleeping 7–8 hours at night are recommended in this study, and large longitudinal studies are needed to confirm these results.     

Making errors at work due to sleepiness or sleep problems is not confined to non-standard work hours: results of the 2016 Sleep Health Foundation national survey

Almost one-third of Australians report having made errors at work that are related to sleep issues. While there is significant literature investigating the role of sleep in workplace health and safety in shiftworking and nightwork operations, long working hours, work-family conflict, and commute times getting longer also impact day workers’ sleep behaviors and opportunities. The aim of this study was to examine the relationship between sleep duration and disorders, sleep health and hygiene factors, work-related factors and errors at work in Australian workers. From a sample of 1011 Australian adults, age-adjusted binary logistic regression analyses were conducted in 512 workers who provided responses to the question “Thinking about the past three months, how many days did you make errors at work because you were too sleepy or you had a sleep problem?” A number of sleep behaviors and poor sleep hygiene factors were linked with work errors related to sleepiness or sleep problems, with age-adjusted odds of errors (confidence intervals) up to 11.6 times higher (5.4–25.1, p < 0.001) in those that snored, 7.7 (4.6–12.9) times higher in those reporting more than three sleep issues (p < 0.001), 7.0 times higher (3.4–14.8) in short (≤5 hours/night) sleepers (p < 0.021), 6.1 times higher (2.9–12.7) in those staying up later than planned most nights of the week (p< 0.001) and 2.4 times higher (1.6–3.7) in those drinking alcohol ≥3 nights/week before bed (p < 0.001). More than 40% of participants working non-standard hours reported making errors at work, and they were more likely to be young (compared to the main sample of workers) and more likely to engage in work activities in the hour before bed. Sleep factors (other than clinical sleep disorders) were associated with an increased likelihood of sleep-related work errors. Both day workers and those working non-standard hours engage in work, sleep and health behaviors that do not support good sleep health, which may be impacting safety and productivity in the workplace through increased sleepiness-related errors.     

Shift work and inter-individual differences in sleep and sleepiness

Inter-individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter-individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter-individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter-individual differences were shown to constitute a trait. Interestingly, self-evaluations of sleepiness did not correspond well with the trait inter-individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter-individual differences in vulnerability to sleep loss do not appear to be limited due to self-selection mechanisms. Indeed, even among a highly select group of active-duty jet fighter pilots flying a series of simulated night missions, systematic inter-individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter-individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.     

The impact of shift starting time on sleep duration,sleep quality,and alertness prior to injury in the People’s Republic of China

Early shift start time and night shifts are associated with reduced sleep duration and poor sleep quality that often lead to increased fatigue levels, performance decrements and adverse safety and health outcomes. This study investigates the impact of shift starting time on sleep patterns, including the duration and quality of sleep and alertness/sleepiness at the time of injury, in a large epidemiological field study of hospitalized adults with severe work-related hand injury in the People’s Republic of China (PRC) from multiple industries with severe work-related traumatic hand injury were recruited from 11 hospitals in three industrially-developed cities in the PRC: Ningbo, Liuzhou and Wuxi. Analysis of covariance (ANCOVA) was used to compare sleep duration, sleep quality and alertness/sleepiness across 3?h increments of shift start time, while adjusting for age, gender, work hours, shift duration, day of injury and several transient work-related factors. Effect modification by gender was also evaluated. Seven-hundred and three hospitalized adults (96.4%) completed a face-to-face interview within 4 days of injury; 527 (75.0%) were male, with a mean (±SEM) age of 31.8?±?0.4 years. Overall, these adults worked relatively long weekly (55.7?±?0.6?h) and daily hours (8.6?±?0.07?h). Average sleep duration prior to injury was 8.5?h (±0.07), and showed significant variations (p value <0.05) across shift starting time increments. Overall mean prior sleep duration was shortest for individuals starting shifts from “21:00–23:59” (5.6±0.8?h) followed by midnight “00:00–02:59” (6.1?±?0.6?h). However, a statistically significant interaction (p?<?0.05) was observed between gender and shift starting time on mean sleep duration. For males the shortest sleep duration was 5.6?h (“21:00–23:59”) and for females the shortest was 4.3?h (“24:00–02:59” and “15:00–17:59”). Sleep quality (generally quite well) and alertness/sleepiness based on the KSS (generally alert) did not vary significantly across shift starting time. Results suggest that sleep duration is shortest among injured PRC adults starting shifts late night and early morning. However, with more than 8.5?h of sleep on average work days, Chinese slept much longer than typical US day workers (Sleep in America Poll, 2012, 6:44 on workdays, 7:35 on free days), and this may help to explain higher than expected alertness/sleepiness scores at the time of injury.     

Importance of sleep for avian vocal communication

Sleep is one of the few truly ubiquitous animal behaviours, and though many animals spend enormous periods of time asleep, we have only begun to understand the consequences of sleep disturbances. In humans, sleep is crucial for effective communication. Birds are classic models for understanding the evolution and mechanisms of human language and speech. Bird vocalizations are remarkably diverse, critical, fitness-related behaviours, and the way sleep affects vocalizations is likely similarly varied. However, research on the effects of sleep disturbances on avian vocalizations is shockingly scarce. Consequently, there is a critical gap in our understanding of the extent to which sleep disturbances disrupt communication. Here, we argue that sleep disturbances are likely to affect all birds'' vocal performance by interfering with motivation, memory consolidation and vocal maintenance. Further, we suggest that quality sleep is likely essential when learning new vocalizations and that sleep disturbances will have especially strong effects on learned vocalizations. Finally, we advocate for future research to address gaps in our understanding of how sleep influences vocal learning and performance in birds.     

Shift work tolerance and the importance of sleep quality: a study of police officers

The aim of this study was to examine how subjective shift work tolerance was related to general health variables, with the expectation of inter-individual differences in the nature of this relation. A total of 740 employees of the Dutch Police force completed a questionnaire, covering seven health-related domains: sleep quality, sleep duration, need for recovery, fatigue, physical health, mental health, and work–life balance. Based on subjective reports of shift work tolerance, participants were classified as intolerant, medium-tolerant, or tolerant workers. Analysis involved group comparisons, regression, and cluster analysis. Eighteen percentage of the shift workers were classified as intolerant. The intolerant and medium-tolerant workers expressed more severe complaints than the tolerant workers, for all seven health-related domains. Shift work tolerance was primarily related to sleep quality and subsequently to need for recovery, fatigue, and work–life balance. No indications were found for systematic inter-individual differences in the nature of this relationship. For all participants equally, the degree of shift work tolerance was related to the severity of health-related complaints. This study highlights the central role of sleep for tolerance to shift work and underlines the need for occupational medicine to take explicit account of sleep.     

Shift work and depressive symptoms: the mediating effect of vitamin D and sleep quality

Shift work is associated with vitamin D level, sleep quality, and depressive symptoms. Vitamin D and sleep quality are also associated with depressive symptoms. The purpose of this study was to compare vitamin D level, sleep quality, and depressive symptoms between shift workers and daytime workers and analyze the mediating effect of vitamin D and sleep quality between shift work and depressive symptoms. Among those who participated in the Kangbuk Samsung Health Study in 2012 and 2014, 82,078 cases of full-time workers were analyzed. We evaluated their shift work, vitamin D level, sleep quality, and depressive symptoms with blood samples and questionnaires. Chi-square tests, t-tests, and path statistical analysis were performed. More depressive symptoms, lower vitamin D levels, and poorer sleep quality were associated with shift work. According to a path analysis, shift work had both a direct effect and an indirect effect on depressive symptoms, each mediated by sleep quality and vitamin D level. When a multigroup analysis was conducted for each sex, paths containing sleep quality were more significant in female shift workers than male shift workers; paths involving vitamin D did not differ between sexes. To assess depression risk in shift workers, evaluating vitamin D level and sleep quality is essential. Also, sleep problems are more prevalent in female compared to male shift workers with respect depression prevalence.     

The effect of consecutive transmeridian flights on alertness,sleep–wake cycles and sleepiness: A case study

ABSTRACT

Travel across time zones disrupts circadian rhythms causing increased daytime sleepiness, impaired alertness and sleep disturbance. However, the effect of repeated consecutive transmeridian travel on sleep–wake cycles and circadian dynamics is unknown. The aim of this study was to investigate changes in alertness, sleep–wake schedule and sleepiness and predict circadian and sleep dynamics of an individual undergoing demanding transmeridian travel. A 47-year-old healthy male flew 16 international flights over 12 consecutive days. He maintained a sleep–wake schedule based on Sydney, Australia time (GMT + 10?h). The participant completed a sleep diary and wore an Actiwatch before, during and after the flights. Subjective alertness, fatigue and sleepiness were rated 4 hourly (08:00–00:00), if awake during the flights. A validated physiologically based mathematical model of arousal dynamics was used to further explore the dynamics and compare sleep time predictions with observational data and to estimate circadian phase changes. The participant completed 191?h and 159 736?km of flying and traversed a total of 144 time-zones. Total sleep time during the flights decreased (357.5?min actigraphy; 292.4?min diary) compared to baseline (430.8?min actigraphy; 472.1?min diary), predominately due to restricted sleep opportunities. The daily range of alertness, sleepiness and fatigue increased compared to baseline, with heightened fatigue towards the end of the flight schedule. The arousal dynamics model predicted sleep/wake states during and post travel with 88% and 95% agreement with sleep diary data. The circadian phase predicted a delay of only 34?min over the 16 transmeridian flights. Despite repeated changes in transmeridian travel direction and flight duration, the participant was able to maintain a stable sleep schedule aligned with the Sydney night. Modelling revealed only minor circadian misalignment during the flying period. This was likely due to the transitory time spent in the overseas airports that did not allow for resynchronisation to the new time zone. The robustness of the arousal model in the real-world was demonstrated for the first time using unique transmeridian travel.     

Circadian gene variants influence sleep and the sleep electroencephalogram in humans

The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25–1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75–4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.     

Circadian rhythms in healthy aging--effects downstream from the pacemaker

Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms “downstream” from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24h routine, sleeping at night) and unmasking (36h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men). (Chronobiology International, 17(3), 355-368, 2000)