Data-driven mathematical modeling of sleep consolidation in early childhood.

Across early childhood development, sleep behavior transitions from a biphasic pattern (a daytime nap and nighttime sleep) to a monophasic pattern (only nighttime sleep). The transition to consolidated nighttime sleep, which occurs in most children between 2- and 5-years-old, is a major developmental milestone and reflects interactions between the developing homeostatic sleep drive and circadian system. Using a physiologically-based mathematical model of the sleep-wake regulatory network constrained by observational and experimental data from preschool-aged participants, we analyze how developmentally-mediated changes in the homeostatic sleep drive may contribute to the transition from napping to non-napping sleep patterns. We establish baseline behavior by identifying parameter sets that model typical 2-year-old napping behavior and 5-year-old non-napping behavior. Then we vary six model parameters associated with the dynamics of and sensitivity to the homeostatic sleep drive between the 2-year-old and 5-year-old parameter values to induce the transition from biphasic to monophasic sleep. We analyze the individual contributions of these parameters to sleep patterning by independently varying their age-dependent developmental trajectories. Parameters vary according to distinct evolution curves and produce bifurcation sequences representing various ages of transition onset, transition durations, and transitional sleep patterns. Finally, we consider the ability of napping and non-napping light schedules to reinforce napping or promote a transition to consolidated sleep, respectively. These modeling results provide insight into the role of the homeostatic sleep drive in promoting interindividual variability in developmentally-mediated transitions in sleep behavior and lay foundations for the identification of light- or behavior-based interventions that promote healthy sleep consolidation in early childhood.

A genetic variation in the adenosine A2A receptor gene contributes to variability in oscillatory alpha power in wake and sleep EEG and A1 adenosine receptor availability in the human brain.

The EEG alpha rhythm (∼ 8-13 Hz) is one of the most salient human brain activity rhythms, modulated by the level of attention and vigilance and related to cerebral energy metabolism. Spectral power in the alpha range in wakefulness and sleep strongly varies among individuals based on genetic predisposition. Knowledge about the underlying genes is scarce, yet small studies indicated that the variant rs5751876 of the gene encoding A2A adenosine receptors (ADORA2A) may contribute to the inter-individual variation. The neuromodulator adenosine is directly linked to energy metabolism as product of adenosine tri-phosphate breakdown and acts as a sleep promoting molecule by activating A1 and A2A adenosine receptors. We performed sleep and positron emission tomography studies in 59 healthy carriers of different rs5751876 alleles, and quantified EEG oscillatory alpha power in wakefulness and sleep, as well as A1 adenosine receptor availability with 18F-CPFPX. Oscillatory alpha power was higher in homozygous C-allele carriers (n = 27, 11 females) compared to heterozygous and homozygous carriers of the T-allele (n(C/T) = 23, n(T/T) = 5, 13 females) (F(18,37) = 2.35, p = 0.014, Wilk's Λ = 0.487). Furthermore, a modulatory effect of ADORA2A genotype on A1 adenosine receptor binding potential was found across all considered brain regions (F(18,40) = 2.62, p = 0.006, Wilk's Λ = 0.459), which remained significant for circumscribed occipital region of calcarine fissures after correction for multiple comparisons. In female participants, a correlation between individual differences in oscillatory alpha power and A1 receptor availability was observed. In conclusion, we confirmed that a genetic variant of ADORA2A affects individual alpha power, while a direct modulatory effect via A1 adenosine receptors in females is suggested.

CaMKIIa Neurons of the Ventromedial Hypothalamus Mediate Wakefulness and Anxiety-like Behavior.

Insomnia and anxiety are two common and closely related clinical problems that pose a threat to individuals' physical and mental well-being. There is a possibility that some nuclei and neural circuits in the brain are shared by both insomnia and anxiety. In the present study, using a combination of chemogenetics, optogenetics, polysomnographic recordings and the classic tests of anxiety-like behaviors, we verified that the calmodulin-dependent protein kinase II alpha (CaMKIIa) neurons of the ventromedial hypothalamus (VMH) are involved in the regulation of both wakefulness and anxiety. Chemogenetic manipulation of the VMH CaMKIIa neurons elicited an apparent increase in wakefulness during activation, whereas inhibition decreased wakefulness mildly. It substantiated that the VMH CaMKIIa neurons contribute to wakefulness. Then in millisecond-scale control of neuronal activity, short-term and long-term optogenetic activation induced the initiation and maintenance of wakefulness, respectively. We also observed that mice reduced exploratory behaviors in classic anxiety tests while activating the VMH CaMKIIa neurons and were anxiolytic while inhibiting. Additionally, photostimulation of the VMH CaMKIIa axons in the paraventricular hypothalamus (PVH) mediated wakefulness and triggered anxiety-like behaviors as well. In conclusion, our results demonstrate that the VMH participates in the control of wakefulness and anxiety, and offer a neurological explanation for insomnia and anxiety, which may be valuable for therapeutic interventions such as medication and transcranial magnetic stimulation.

Activation of Ventral Pallidum CaMKIIa-Expressing Neurons Promotes Wakefulness.

The ventral pallidum (VP) is involved in the regulation of a variety of behaviors such as motor, reward, and behavioral motivation, and the ability to perform these functions properly is dependent on a high degree of wakefulness. It is unknown whether VP CaMKIIa-expression (VPCaMKIIa) neurons also have a role in sleep-wake regulation and related neuronal circuit mechanisms. In the present experiment, we first used in vivo fiber photometry to find the population activity of VPCaMKIIa neurons which increased during the transitions from non-rapid-eye movement (NREM) sleep to wakefulness and NREM sleep to rapid-eye-movement (REM) sleep, with decreased during the transitions from wakefulness to NREM sleep. Then chemogenetic activation of VPCaMKIIa neurons induced an increase in wakefulness that lasted for 2 h. Mice that were exposed to short-term optogenetic stimulation woke up quickly from stable NREM sleep, and long-term optogenetic stimulation maintained wakefulness. In addition, optogenetic activation of the axons of VPCaMKIIa neurons in the lateral habenula (LHb) also facilitated the initiation and maintenance of wakefulness and mediated anxiety-like behavior. Finally, the method of chemogenetic inhibition was employed to suppress VPCaMKIIa neurons, and yet, inhibition of VPCaMKIIa neuronal activity did not result in an increase in NREM sleep and a decrease in wakefulness. Overall, our data illustrate that the activation of VPCaMKIIa neurons is of great importance for promoting wakefulness.

Weekend sleep after early and later school start times confirmed a model-predicted failure to catch up sleep missed on weekdays.

BACKGROUND: Many people believe they sleep for longer time on weekend nights to make up for sleep lost on weekdays. However, results of simulations of risetimes and bedtimes on weekdays and weekends with a sleep-wake regulating model revealed their inability to prolong weekend sleep. In particular, they predicted identical durations of weekend sleep after weeks with relatively earlier and relatively later risetime on weekdays. In the present study, this paradoxical prediction was empirically confirmed. METHODS: Times in bed were calculated from weekday and weekend risetimes and bedtimes in pairs of samples of students with early and later school start time and in subsets of samples from 7 age groups with weekday risetime earlier and later than 7:00 a.m. RESULTS: Among 35 pairs of students, mean age ± standard deviation was 14.5 ± 2.9 years and among the age group samples, 21.6 ± 14.6 years. As predicted by the simulations, times in bed on weekends were practically identical in the samples with early and later school start time and in two subsets with earlier and later weekday risetime. CONCLUSIONS: The model-based simulations of sleep times can inform an individual about an amount of irrecoverable loss of sleep caused by an advance shift of wakeups on weekdays.

Function and dysfunction of hypocretin/orexin: an energetics point of view.

The basic elements of animal behavior that are critical to survival include energy, arousal, and motivation: Energy intake and expenditure are fundamental to all organisms for the performance of any type of function; according to the Yerkes-Dodson law, an optimal level of arousal is required for animals to perform normal functions; and motivation is critical to goal-oriented behaviors in higher animals. The brain is the primary organ that controls these elements and, through evolution, has developed specialized structures to accomplish this task. The orexin/hypocretin system in the perifornical/lateral hypothalamus, which was discovered 15 years ago, is one such specialized area. This review summarizes a fast-growing body of evidence discerning how the orexin/hypocretin system integrates internal and external cues to regulate energy intake that can then be used to generate sufficient arousal for animals to perform innate and goal-oriented behaviors.

Sleep during "lockdown" highlighted the need to rethink the concept of weekend catch-up sleep.

PURPOSE: Many people believe in their ability to sleep for longer time on weekends to make up for sleep lost due to early wakeups on weekdays. This widely held belief was not supported by the simulations of rise- and bedtimes on weekdays and weekends with a sleep-wake regulating model. The simulations suggested the inability to extend sleep on any of two weekend nights and they predicted identical weekend sleep durations for weeks with relatively earlier and relatively later weekday risetimes. By April 2020, about half of the world's population was under some form of "lockdown" due to the COVID-19 pandemic. This "lockdown" provided a new opportunity to demonstrate the predictive power of the sleep-wake regulating models. Therefore, the purpose of this report was to support the prediction of identity of weekend sleep durations after weeks with earlier and later weekday wakeups. METHODS: Weekend and weekday rise- and bedtimes before and during "lockdown" for 31 samples were taken from recent journal publications. Time in bed on weekends and 12 other measures of sleep duration and timing were calculated and simulated. RESULTS: For only one of 13 measures, weekend time in bed, statistical analysis did not yield a statistically significant difference between the estimates obtained before and during "lockdown". The model-based simulations pointed to the 0.3-h delay of the sleep-wake cycle in response to the 1-h delay of weekday risetime during "lockdown". CONCLUSION: The model-based prediction was confirmed, thus, highlighting again the necessity to rethink the concept of weekend catch-up sleep.

Linking stages of non-rapid eye movement sleep to the spectral EEG markers of the drives for sleep and wake.

The conventional staging classification reduces all patterns of sleep polysomnogram signals to a small number of yes-or-no variables labeled wake or a stage of sleep (e.g., W, N1, N2, N3, and R for wake, the first, second, and third stages of non-rapid eye movement sleep and rapid eye movement sleep, respectively). However, the neurobiological underpinnings of such stages remained to be elucidated. We tried to evaluate their link to scores on the first and second principal components of the EEG spectrum (1PCS and 2PCS), the markers of two major groups of promoters/inhibitors of sleep/wakefulness delineated as the drives for sleep and wake, respectively. On two occasions, polysomnographic records were obtained from 69 university students during 50-min afternoon naps and 30-s stage epochs were assigned to 1PCS and 2PCS. Results suggested two dimensionality of the structure of individual differences in amounts of stages. Amount of N1 loaded exclusively on one of two dimensions associated with 1PCS, amounts of W and N2 loaded exclusively on another dimension associated with 2PCS, and amount of N3 was equally loaded on both dimensions. Scores demonstrated stability within each stage, but a drastic change in just one of two scores occurred during transitions from one stage to another on the way from wakefulness to deeper sleep (e.g., 2PCS changed from >0 to <0 during transition W→N1, 1PCS changed from <0 to >0 during transition N1→N2). Therefore, the transitions between stages observed during short naps might be linked to rapid changes in the reciprocal interactions between the promoters/inhibitors of sleep/wakefulness.NEW & NOTEWORTHY In the present nap study, two dimensionality of the structure of individual differences in sleep stages was revealed. These results also suggested that individual variation in the sleep and wake drives associated with the first and second principal components of the EEG spectrum might underlie this structure. It seemed that each stage might be related to a certain, stage-specific combination of wake-sleep promoting/inhibiting influences associated with these drives for sleep and wake.

Functional connectivity of the human hypothalamus during wakefulness and nonrapid eye movement sleep.

Animal experiments indicate that the hypothalamus plays an essential role in regulating the sleep-wake cycle. A recent neuroimaging study conducted under resting wakefulness conditions suggested the presence of a wake-promoting region and a sleep-promoting region in the human posterior hypothalamus and anterior hypothalamus, respectively, and interpreted their anticorrelated organization in resting-state functional networks as evidence for their opposing roles in sleep-wake regulation. However, whether and how the functional networks of the two hypothalamic regions reorganize according to their wake- or sleep-promoting roles during sleep are unclear. Here, we constructed functional networks of the posterior and anterior hypothalamus during wakefulness and nonrapid eye movement (NREM) sleep using simultaneous electroencephalography and functional magnetic resonance imaging data collected from 62 healthy participants. The functional networks of the posterior and anterior hypothalamus exhibited inversely correlated organizations during both wakefulness and NREM sleep. The connectivity strength of the posterior hypothalamic functional network was stronger during wakefulness than during stable sleep. From wakefulness to sleep, the anterior cingulate gyrus, paracingulate gyrus, insular cortex, and fontal operculum cortex showed decreased positive connectivity, while the precentral gyrus and postcentral gyrus showed decreased negative connectivity with the posterior hypothalamus. Additionally, the insular cortex and frontal operculum cortex showed negative connectivity during wakefulness and positive connectivity during sleep with the anterior hypothalamus, exhibiting an increasing trend. These findings provide insights into the correspondence between the functional network organizations and hypothalamic sleep-wake regulation in humans.

The psycho-sensory wake drive-a power source for power naps and other common sleep-wake phenomena: a hypothesis.

Power naps are extensively practiced worldwide and there exists ample documentation of their efficacy in reversing daytime sleepiness. The source of their efficacy, however, as well as the cause and manifestation of many other common sleep-wake phenomena, cannot be entirely explained by the most commonly accepted model of sleep-wake regulation, the two-process model of Borbély, which considers the drives of the circadian and homeostatic sleep processes only. When considering the causes and manifestations of these unexplained phenomena, there appears to be evidence of a wake-promoting drive that is independent of the circadian oscillator indicated in the two-process model of sleep-wake regulation. Although this posited secondary wake drive, herein referred to as the psycho-sensory wake drive, is always active during the awake state, its strength unpredictably varies during a normal day and, therefore, cannot be incorporated into the prevalent two-process model by any current mathematical formula. However, a supplemental graphic model superimposing it on the drives of Process S and Process C can provides plausible and parsimonious explanations for many otherwise unexplainable sleep-wake phenomena and enables rational guidelines for their effective practical management.

Interindividual differences in the dynamics of the homeostatic process are trait-like and distinct for sleep versus wakefulness.

The sleep homeostatic Process S reflects the build-up of sleep pressure during waking and its dissipation during sleep. Process S is modelled as a saturating exponential function during waking and a decreasing exponential function during sleep. Slow wave activity is a physiological marker for non-rapid eye movement (non-REM) sleep intensity and serves as an index of Process S. There is considerable interindividual variability in the sleep homeostatic responses to sleep and sleep deprivation. The aim of this study was to investigate whether interindividual differences in Process S are trait-like. Polysomnographic recordings of 8 nights (12-h sleep opportunities, 22:00-10:00 hours) interspersed with three 36-h periods of sustained wakefulness were performed in 11 healthy young adults. Empirical mean slow wave activity per non-REM sleep episode at episode mid-points were used for parameter estimation. Parameters of Process S were estimated using different combinations of consecutive sleep recordings, resulting in two to three sets of parameters per subject. Intraclass correlation coefficients were calculated to assess whether the parameters were stable across the study protocol and they showed trait-like variability among individuals. We found that the group-average time constants of the build-up and dissipation of Process S were 19.2 and 2.7 h, respectively. Intraclass correlation coefficients ranged from 0.48 to 0.56, which reflects moderate trait variability. The time constants of the build-up and dissipation varied independently among subjects, indicating two distinct traits. We conclude that interindividual differences in the parameters of the dynamics of the sleep homeostatic Process S are trait-like.

Role of the Histamine H3 Receptor in the Central Nervous System.

The Gi/o protein-coupled histamine H3 receptor is distributed throughout the central nervous system including areas like cerebral cortex, hippocampus and striatum with the density being highest in the posterior hypothalamus, i.e. the area in which the histaminergic cell bodies are located. In contrast to the other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located presynaptically and shows a constitutive activity. In detail, H3 receptors are involved in the inhibition of histamine release (presynaptic autoreceptor), impulse flow along the histaminergic neurones (somadendritic autoreceptor) and histamine synthesis. Moreover, they occur as inhibitory presynaptic heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic, GABAergic and perhaps cholinergic neurones. This review shows for four functions of the brain that the H3 receptor represents a brake against the wake-promoting, anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors) and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1 agonists and H3 inverse agonists elicit essentially the same effects, at least in rodents; these effects are opposite in direction to those elicited by brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3 inverse agonists for the symptomatic treatment of dementias is inconclusive, several members of this group have shown a marked potential for the treatment of disorders associated with excessive daytime sleepiness. In March 2016, the European Commission granted a marketing authorisation for pitolisant (WakixR) (as the first representative of the H3 inverse agonists) for the treatment of narcolepsy.

Objective markers for sleep propensity: comparison between the Multiple Sleep Latency Test and the Vigilance Algorithm Leipzig.

The regulation of wakefulness is important for high-order organisms. Its dysregulation is involved in the pathomechanism of several psychiatric disorders. Thus, a tool for its objective but little time-consuming assessment would be of importance. The Vigilance Algorithm Leipzig allows the objective measurement of sleep propensity, based on a single resting state electroencephalogram. To compare the Vigilance Algorithm Leipzig with the standard for objective assessment of excessive daytime sleepiness, a four-trial Multiple Sleep Latency Test in 25 healthy subjects was conducted. Between the first two trials, a 15-min, 25-channel resting electroencephalogram was recorded, and Vigilance Algorithm Leipzig was used to classify the sleep propensity (i.e., type of vigilance regulation) of each subject. The results of both methods showed significant correlations with the Epworth Sleepiness Scale (ρ = -0.70; ρ = 0.45, respectively) and correlated with each other (ρ = -0.54). Subjects with a stable electroencephalogram-vigilance regulation yielded significant increased sleep latencies compared with an unstable regulation (multiple sleep latency 898.5 s versus 549.9 s; P = 0.03). Further, Vigilance Algorithm Leipzig classifications allowed the identification of subjects with average sleep latencies <6 min with a sensitivity of 100% and a specificity of 77%. Thus, Vigilance Algorithm Leipzig provides similar information on wakefulness regulation in comparison to the much more cost- and time-consuming Multiple Sleep Latency Test. Due to its high sensitivity and specificity for large sleep propensity, Vigilance Algorithm Leipzig could be an effective and reliable alternative to the Multiple Sleep Latency Test, for example for screening purposes in large cohorts, where objective information about wakefulness regulation is needed.

Can the Brain's Thermostatic Mechanism Generate Sleep-Wake and NREM-REM Sleep Cycles? A Nested Doll Model of Sleep-Regulating Processes.

Evidence is gradually accumulating in support of the hypothesis that a process of thermostatic brain cooling and warming underlies sleep cycles, i.e., the alternations between non-rapid-eye-movement and rapid-eye-movement sleep throughout the sleep phase of the sleep-wake cycle. A mathematical thermostat model predicts an exponential shape of fluctuations in temperature above and below the desired temperature setpoint. If the thermostatic process underlies sleep cycles, can this model explain the mechanisms governing the sleep cyclicities in humans? The proposed nested doll model incorporates Process s generating sleep cycles into Process S generating sleep-wake cycles of the two-process model of sleep-wake regulation. Process s produces ultradian fluctuations around the setpoint, while Process S turns this setpoint up and down in accord with the durations of the preceding wake phase and the following sleep phase of the sleep-wake cycle, respectively. Predictions of the model were obtained in an in silico study and confirmed by simulations of oscillations of spectral electroencephalographic indexes of sleep regulation obtained from night sleep and multiple napping attempts. Only simple-inverse exponential and exponential-functions from the thermostatic model were used for predictions and simulations of rather complex and varying shapes of sleep cycles during an all-night sleep episode. To further test the proposed model, experiments on mammal species with monophasic sleep are required. If supported, this model can provide a valuable framework for understanding the involvement of sleep-wake regulatory processes in the mechanism of thermostatic brain cooling/warming.

Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice.

BACKGROUND: Sleep disturbances are a common comorbidity to most neurodevelopmental disorders and tend to worsen disease symptomatology. It is thus crucial to understand mechanisms underlying sleep disturbances to improve patients' quality of life. Neuroligin-2 (NLGN2) is a synaptic adhesion protein regulating GABAergic transmission. It has been linked to autism spectrum disorders and schizophrenia in humans, and deregulations of its expression were shown to cause epileptic-like hypersynchronized cerebral activity in rodents. Importantly, the absence of Nlgn2 (knockout: KO) was previously shown to alter sleep-wake duration and quality in mice, notably increasing slow-wave sleep (SWS) delta activity (1-4 Hz) and altering its 24-h dynamics. This type of brain oscillation is involved in memory consolidation, and is also a marker of homeostatic sleep pressure. Sleep deprivation (SD) is notably known to impair cognition and the physiological response to sleep loss involves GABAergic transmission. METHODS: Using electrocorticographic (ECoG) recordings, we here first aimed to verify how individual slow wave (SW; 0.5-4 Hz) density and properties (e.g., amplitude, slope, frequency) contribute to the higher SWS delta activity and altered 24-h dynamics observed in Nlgn2 KO mice. We further investigated the response of these animals to SD. Finally, we tested whether sleep loss affects the gene expression of Nlgn2 and related GABAergic transcripts in the cerebral cortex of wild-type mice using RNA sequencing. RESULTS: Our results show that Nlgn2 KO mice have both greater SW amplitude and density, and that SW density is the main property contributing to the altered 24-h dynamics. We also found the absence of Nlgn2 to accelerate paradoxical sleep recovery following SD, together with profound alterations in ECoG activity across vigilance states. Sleep loss, however, did not modify the 24-h distribution of the hypersynchronized ECoG events observed in these mice. Finally, RNA sequencing confirmed an overall decrease in cortical expression of Nlgn2 and related GABAergic transcripts following SD in wild-type mice. CONCLUSIONS: This work brings further insight into potential mechanisms of sleep duration and quality deregulation in neurodevelopmental disorders, notably involving NLGN2 and GABAergic neurotransmission.

The yin and yang of two opponent processes of sleep-wake regulation: Sex-associated differences in the spectral EEG markers of the drives for sleep and wake.

Although objectively measured characteristics of sleep efficiency and quality were found to be better in women than men, women more frequently than men suffer from poor or insufficient or non-restorative sleep. We explored this apparent paradox by testing the sex-associated differences in electroencephalographic (EEG) indicators of two opponent processes of sleep-wake regulation, the drives for sleep and wake. We tried to provide empirical support for the hypothesis that a stronger women's sleep drive can explain better objective characteristics of sleep quality in women than men, while a stronger women's wake drive can be an explanation of a higher frequency of sleep-related complaints in women than men. To our knowledge, this was the first attempt to examine the associations of sex with scores on the 1st and 2nd principal components of the EEG spectrum that can serve as objective spectral EEG markers of the opponent drives for sleep and wake, respectively. The particular prediction was that, in women compared to men, not only the 1st principal component score but also the 2nd principal component score could be higher (i.e. both drives could be stronger). In a sample of 80 university students (40 females), the EEG signals were recorded during 160 afternoon napping attempts (50 min or longer). The difference between male and female students in sleep latencies did not reach a statistically significant level. In accordance with our prediction, both principal component scores were found to be higher in female than in male students irrespective of sleep stage. It is likely that the influence of the wake drive is entirely overlooked in the polysomnographic studies due to the predominant contribution of the indicators of the sleep drive to the conventional objective characteristics of sleep quality. Therefore, a stronger women's sleep drive can be an explanation of women's better sleep quality in the results of polysomnographic studies. On the other hand, if a stronger women's wake drive can influence the perception of their sleep quality, this can explain their more frequent sleep-related complaints.

Exercise therapy in the application of sleep disorders.

Sleep disorders often accompany neurological injuries, significantly impacting patient recovery and quality of life.The efficacy and adherence of traditional treatment methods have certain limitations. Exercise has been found to be a highly beneficial treatment method, capable of preventing and alleviating neurological injuries and sleep disorders. This article reviews relevant research findings from both domestic and international sources over the past few decades, systematically summarizing and analyzing the application of exercise therapy in sleep disorders,strategy of exercise intervention program and the potential molecular mechanisms by which exercise therapy improves sleep disorders. Shortcomings in current research and suggestions are presented, providing a reference for future in-depth studies on exercise interventions for sleep disorders.

Napping and circadian sleep-wake regulation during healthy aging.

STUDY OBJECTIVES: Daytime napping is frequently reported among the older population and has attracted increasing attention due to its association with multiple health conditions. Here, we tested whether napping in the aged is associated with altered circadian regulation of sleep, sleepiness and vigilance performance. METHODS: Sixty healthy older individuals (mean age: 69y., 39 women) were recruited with respect to their napping habits (30 nappers, 30 non-nappers). All participants underwent an in-lab 40-h multiple nap protocol (10 cycles of 80 mins of sleep opportunity alternating with 160 mins of wakefulness), preceded and followed by a baseline and recovery sleep period. Saliva samples for melatonin assessment, sleepiness and vigilance performance were collected during wakefulness and electrophysiological data were recorded to derive sleep parameters during scheduled sleep opportunities. RESULTS: The circadian amplitude of melatonin secretion was reduced in nappers, compared to non-nappers. Furthermore, nappers were characterized by higher sleep efficiencies and REM sleep proportion during day- compared to night-time naps. The nap group also presented altered modulation in sleepiness and vigilance performance at specific circadian phases. DISCUSSION: Our data indicate that napping is associated with an altered circadian sleep-wake propensity rhythm and thereby contribute to the understanding of the biological correlates underlying napping and/or sleep-wake cycle fragmentation during healthy aging. Altered circadian sleep-wake promotion can lead to a less distinct allocation of sleep into night-time and/or a reduced wakefulness drive during the day, thereby potentially triggering the need to sleep at adverse circadian phase.

Reaction of the endogenous regulatory mechanisms to early weekday wakeups: a review of its popular explanations in light of model-based simulations.

Introduction: Several widely held explanations of the mechanisms underlying the responses of endogenous sleep-wake-regulating processes to early weekday wakeups have been proposed. Here, they were briefly reviewed and validated against simulations based on the rhythmostatic version of a two-process model of sleep-wake regulation. Methods: Simulated sleep times on weekdays and weekends were compared with the times averaged over 1,048 samples with either earlier or later weekday risetimes. In total, 74 paired samples were collected before and during lockdown, and 93 paired samples were collected during early and later school start times. Results: The counterintuitive predictions of the simulations included the following: 1) only one night of ad lib sleep is sufficient to restore the endogenously determined sleep times after 1 day/5 days of larger/smaller reduction/extension of the sleep/wake phase of the circadian sleep-wake cycle; 2) sleep loss on weekdays is irrecoverable; 3) irrespective of the amount of such deadweight loss, sleep on weekends is not prolonged; and 4) the control of the circadian clocks over the sleep-wake cyclicity is not disrupted throughout the week. Discussion: The following popular explanations of the gaps between weekends and weekdays in sleep timing and duration were not supported by these simulations: 1) early weekday wakeups cause "social jetlag," viewed as the weekend and weekday (back and forth) shifts of the sleep phase relative to the unchanged phase of the circadian clocks, and 2) early weekday wakeups cause an accumulation of "sleep debt paid back" on weekends, or, in other terms, people can "catch-up" or "compensate" sleep on weekends.

Aging, Sleep and Sleepiness Self-Assessment, and the Underlying Drives for Sleep and Wake.

In 2016, a mini-issue of Current Aging Science (CAS) entitled "Effects of Aging on Circadian and Sleep Timing" has been published to report the state of the art in the studies of the effects of aging on the circadian and sleep regulating processes. The emphasis has been given to the regulatory processes involved in age-specific problems with sleep timing, continuity, and duration. Such problems can serve as targets for novel treatments for geriatric and sleep disorders. In the following 6 years, some new findings provided further insight into the previously recognized age-specific problems and highlighted new questions of research on the relation of aging to the regulatory mechanisms underlying circadian rhythmicity, sleep, and sleepiness. The theoretic framework of one of the directions of this research regards the interaction between the competing drives for sleep and wake as one of the basic features of regulatory processes underlying circadian rhythms, including such rhythms as the sleep-wake cycle and the diurnal variation in alertnesssleepiness levels. Here, earlier and more recently highlighted questions of the research in this framework were briefly reviewed.