June C. Lo

PER3 Polymorphism Predicts Sleep Structure and Waking Performance

Circadian rhythmicity and sleep homeostasis interact to regulate sleep-wake cycles [1-4], but the genetic basis of individual differences in sleep-wake regulation remains largely unknown [5]. PERIOD genes are thought to contribute to individual differences in sleep timing by affecting circadian rhythmicity [6], but not sleep homeostasis [7, 8]. We quantified the contribution of a variable-number tandem-repeat polymorphism in the coding region of the circadian clock gene PERIOD3 (PER3) [9, 10] to sleep-wake regulation in a prospective study, in which 24 healthy participants were selected only on the basis of their PER3 genotype. Homozygosity for the longer allele (PER3(5/5)) had a considerable effect on sleep structure, including several markers of sleep homeostasis: slow-wave sleep (SWS) and electroencephalogram (EEG) slow-wave activity in non-rapid eye movement (non-REM) sleep and theta and alpha activity during wakefulness and REM sleep were all increased in PER3(5/5) compared to PER3(4/4) individuals. In addition, the decrement of cognitive performance in response to sleep loss was significantly greater in the PER3(5/5) individuals. By contrast, the circadian rhythms of melatonin, cortisol, and peripheral PER3 mRNA expression were not affected. The data show that this polymorphism in PER3 predicts individual differences in the sleep-loss-induced decrement in performance and that this differential susceptibility may be mediated by its effects on sleep homeostasis.

Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome

Significance Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, but the mechanisms involved remain largely unexplored. We show that one wk of insufficient sleep alters gene expression in human blood cells, reduces the amplitude of circadian rhythms in gene expression, and intensifies the effects of subsequent acute total sleep loss on gene expression. The affected genes are involved in chromatin remodeling, regulation of gene expression, and immune and stress responses. The data imply molecular mechanisms mediating the effects of sleep loss on health and highlight the interrelationships between sleep homeostasis, circadian rhythmicity, and metabolism. Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved remain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis, circadian rhythmicity, and metabolism.

Effects of partial and acute total sleep deprivation on performance across cognitive domains, individuals and circadian phase.

Background Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. Methodology/Principal Findings We conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6±4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load. Conclusions/Significance Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity interact to determine waking performance across cognitive domains and individuals.

Sleep, diurnal preference, health, and psychological well-being: a prospective single-allelic-variation study.

Individual differences in sleep and diurnal preference associate with physical and mental health characteristics, but few genetic determinants of these differences have been identified. A variable number tandem repeat (VNTR) polymorphism in the PERIOD3 (PER3) gene (rs57875989) has been reported to associate with diurnal preference, i.e., preferred timing of waking and sleep. Here, the authors investigate in a prospective single-candidate genetic variant study whether allelic variation for this polymorphism associates also with reported actual sleep timing and sleep duration, as well as psychological and health measures. Six hundred and seventy-five subjects, aged 20 to 35 yrs, completed questionnaires to assess sleep and psychological and health characteristics and were genotyped for the PER3 VNTR. Homozygosity for the longer allele (PER35/5) of the VNTR was associated with increased morning preference, earlier wake time and bedtime, and reduced daytime sleepiness. Separate analyses of work and rest days demonstrated that the increase in time in bed during rest days was greatest in PER35/5 homozygotes. PER3 genotype modified the effects of sleep timing and duration on fluid intelligence and body mass index. Genotype was not associated with physical or psychological characteristics as assessed by the SF-36 Health Questionnaire, the General Health Questionnaire, the Big Five Inventory, the Behavioral Inhibition System–Behavioral Activation System scales, and the Positive and Negative Affect Scale, even though these measures varied significantly with diurnal preference as assessed by the Morningness-Eveningness Questionnaire. Whereas diurnal preference also predicts mental health and psychological characteristics, as well as sleep timing, the PER3 VNTR specifically affects measures of sleep timing and may also modify the effects of sleep on health outcome measures. (Author correspondence: a.lazar@surrey.ac.uk)

Cognitive Performance, Sleepiness, and Mood in Partially Sleep Deprived Adolescents: The Need for Sleep Study

STUDY OBJECTIVES To investigate the effects of sleep restriction (7 nights of 5 h time in bed [TIB]) on cognitive performance, subjective sleepiness, and mood in adolescents. METHODS A parallel-group design was adopted in the Need for Sleep Study. Fifty-six healthy adolescents (25 males, age = 15-19 y) who studied in top high schools and were not habitual short sleepers were randomly assigned to Sleep Restriction (SR) or Control groups. Participants underwent a 2-w protocol consisting of 3 baseline nights (TIB = 9 h), 7 nights of sleep opportunity manipulation (TIB = 5 h for the SR and 9 h for the control groups), and 3 nights of recovery sleep (TIB = 9 h) at a boarding school. A cognitive test battery was administered three times each day. RESULTS During the manipulation period, the SR group demonstrated incremental deterioration in sustained attention, working memory and executive function, increase in subjective sleepiness, and decrease in positive mood. Subjective sleepiness and sustained attention did not return to baseline levels even after 2 recovery nights. In contrast, the control group maintained baseline levels of cognitive performance, subjective sleepiness, and mood throughout the study. Incremental improvement in speed of processing, as a result of repeated testing and learning, was observed in the control group but was attenuated in the sleep-restricted participants, who, despite two recovery sleep episodes, continued to perform worse than the control participants. CONCLUSIONS A week of partial sleep deprivation impairs a wide range of cognitive functions, subjective alertness, and mood even in high-performing high school adolescents. Some measures do not recover fully even after 2 nights of recovery sleep. COMMENTARY A commentary on this article appears in this issue on page 497.

Sex differences in the circadian regulation of sleep and waking cognition in humans

Significance Circadian rhythms affect our physiology and psychology, in health and disease. Most of our knowledge about the human circadian timing system is based on research in men. Some circadian characteristics, such as the intrinsic frequency of the circadian clock and the amplitude of the melatonin rhythm, have been shown to differ between men and women. Whether the circadian regulation of mental functions differs between men and women is unknown. Here we show that circadian rhythmicity in mental functions exhibits sex differences so that the night-time impairment in cognitive performance is greater in women than in men. These findings are significant in view of shift-work–related cognitive deficits and disturbances of mood, which are more prevalent in women. The sleep–wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep–wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.

Self-reported sleep duration and cognitive performance in older adults: a systematic review and meta-analysis

Sleep is important for optimal cognitive functioning across the lifespan. Among older adults (≥55 years), self-reported short and long sleep durations have been repeatedly, albeit inconsistently, reported to elevate the risk for poor cognitive function. This meta-analytic review quantitatively summarizes the risk for poorer cognitive function among short and long sleepers in older adults. Eligible publications were searched online and manually. A total of 35 independent samples (N = 97,264) from 11 cross-sectional and seven prospective cohort studies were included. Pooled odds ratios (OR) with 95% confidence intervals (CI) were derived using random-effects models. Self-reported short and long sleep increased the odds for poor cognitive function by 1.40 (CI = 1.27-1.56) and 1.58 times (CI = 1.43-1.74), respectively. Effect sizes varied across studies and may have been moderated by both study type (cross-sectional and prospective) and cognitive domain assessed. For cross-sectional studies, extreme sleep durations were significantly associated with poorer multiple-domain performance, executive functions, verbal memory, and working memory capacity. Prospective cohort studies revealed the significant long-term impact of short and long sleep on multiple-domain performance only. These findings establish self-reported extreme sleep duration as a risk factor for cognitive aging.

Reduced functional segregation between the default mode network and the executive control network in healthy older adults: A longitudinal study

The effects of age on functional connectivity (FC) of intrinsic connectivity networks (ICNs) have largely been derived from cross-sectional studies. Far less is known about longitudinal changes in FC and how they relate to ageing-related cognitive decline. We evaluated intra- and inter-network FC in 78 healthy older adults two or three times over a period of 4years. Using linear mixed modeling we found progressive loss of functional specialization with ageing, evidenced by a decline in intra-network FC within the executive control (ECN) and default mode networks (DMN). In contrast, longitudinal inter-network FC between ECN and DMN showed a u-shaped trajectory whereby functional segregation between these two networks initially increased over time and later decreased as participants aged. The rate of loss in functional segregation between ECN and DMN was associated with ageing-related decline in processing speed. The observed longitudinal FC changes and their associations with processing speed remained after correcting for longitudinal reduction in gray matter volume. These findings help connect ageing-related changes in FC with ageing-related decline in cognitive performance and underscore the value of collecting concurrent longitudinal imaging and behavioral data.

Sleep duration and age-related changes in brain structure and cognitive performance.

STUDY OBJECTIVES To investigate the contribution of sleep duration and quality to age-related changes in brain structure and cognitive performance in relatively healthy older adults. DESIGN Community-based longitudinal brain and cognitive aging study using a convenience sample. SETTING Participants were studied in a research laboratory. PARTICIPANTS Relatively healthy adults aged 55 y and older at study commencement. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Participants underwent magnetic resonance imaging and neuropsychological assessment every 2 y. Subjective assessments of sleep duration and quality and blood samples were obtained. Each hour of reduced sleep duration at baseline augmented the annual expansion rate of the ventricles by 0.59% (P = 0.007) and the annual decline rate in global cognitive performance by 0.67% (P = 0.050) in the subsequent 2 y after controlling for the effects of age, sex, education, and body mass index. In contrast, global sleep quality at baseline did not modulate either brain or cognitive aging. High-sensitivity C-reactive protein, a marker of systemic inflammation, showed no correlation with baseline sleep duration, brain structure, or cognitive performance. CONCLUSIONS In healthy older adults, short sleep duration is associated with greater age-related brain atrophy and cognitive decline. These associations are not associated with elevated inflammatory responses among short sleepers. CITATION Lo JC, Loh KK, Zheng H, Sim SK, Chee MW. Sleep duration and age-related changes in brain structure and cognitive performance.

Circadian period and the timing of melatonin onset in men and women: predictors of sleep during the weekend and in the laboratory

Sleep complaints and irregular sleep patterns, such as curtailed sleep during workdays and longer and later sleep during weekends, are common. It is often implied that differences in circadian period and in entrained phase contribute to these patterns, but few data are available. We assessed parameters of the circadian rhythm of melatonin at baseline and in a forced desynchrony protocol in 35 participants (18 women) with no sleep disorders. Circadian period varied between 23 h 50 min and 24 h 31 min, and correlated positively (n = 31, rs = 0.43, P = 0.017) with the timing of the melatonin rhythm relative to habitual bedtime. The phase of the melatonin rhythm correlated with the Insomnia Severity Index (n = 35, rs = 0.47, P = 0.004). Self‐reported time in bed during free days also correlated with the timing of the melatonin rhythm (n = 35, rs = 0.43, P = 0.01) as well as with the circadian period (n = 31, rs = 0.47, P = 0.007), such that individuals with a more delayed melatonin rhythm or a longer circadian period reported longer sleep during the weekend. The increase in time in bed during the free days correlated positively with circadian period (n = 31, rs = 0.54, P = 0.002). Polysomnographically assessed latency to persistent sleep (n = 34, rs = 0.48, P = 0.004) correlated with the timing of the melatonin rhythm when participants were sleeping at their habitual bedtimes in the laboratory. This correlation was significantly stronger in women than in men (Z = 2.38, P = 0.017). The findings show that individual differences in circadian period and phase of the melatonin rhythm associate with differences in sleep, and suggest that individuals with a long circadian period may be at risk of developing sleep problems.