A biomathematical model of a human operator’s falling asleep

Quantitative analysis of the transition from wakefulness to sleep and prediction of the moment when errors in professional activity appear because of a decrease in the arousal level require microinterval monitoring of falling asleep. A psychomotor test was developed that rapidly decreased the arousal level, which made it possible to record as many as 10–20 episodes of correct and erroneous activity within 40 min and isolate the periods electrophysiologically corresponding to wakefulness and brief sleep. Seventy subjects were tested, and 6700 fragments of recordings with correct and erroneous performance were analyzed. Analysis of the experimental data showed that the transition from wakefulness to sleep includes intermediate short and relatively long periods of wakefulness and sleep, whose durations are distributed according to the double exponential law. A mathematical model describing the time course of alternation of these four states of wakefulness and sleep predicts the probability of prolonged, potentially dangerous disturbances in operator activity because of microsleep as dependent on the initial state and individual characteristics of subjects. The results will be useful both for the development of devices monitoring and predicting changes in the physiological arousal level and for analysis of traffic and industrial accidents.     

Sleep deprivation in a quantitative physiologically based model of the ascending arousal system

A physiologically based quantitative model of the human ascending arousal system is used to study sleep deprivation after being calibrated on a small set of experimentally based criteria. The model includes the sleep-wake switch of mutual inhibition between nuclei which use monoaminergic neuromodulators, and the ventrolateral preoptic area. The system is driven by the circadian rhythm and sleep homeostasis. We use a small number of experimentally derived criteria to calibrate the model for sleep deprivation, then investigate model predictions for other experiments, demonstrating the scope of application. Calibration gives an improved parameter set, in which the form of the homeostatic drive is better constrained, and its weighting relative to the circadian drive is increased. Within the newly constrained parameter ranges, the model predicts repayment of sleep debt consistent with experiment in both quantity and distribution, asymptoting to a maximum repayment for very long deprivations. Recovery is found to depend on circadian phase, and the model predicts that it is most efficient to recover during normal sleeping phases of the circadian cycle, in terms of the amount of recovery sleep required. The form of the homeostatic drive suggests that periods of wake during recovery from sleep deprivation are phases of relative recovery, in the sense that the homeostatic drive continues to converge toward baseline levels. This undermines the concept of sleep debt, and is in agreement with experimentally restricted recovery protocols. Finally, we compare our model to the two-process model, and demonstrate the power of physiologically based modeling by correctly predicting sleep latency times following deprivation from experimental data.     

Cardiac and respiratory activity at arousal from sleep under controlled ventilation conditions.

Arousal from sleep is associated with elevated cardiac and respiratory activity. It is unclear whether this occurs because of homeostatic mechanisms or a reflex activation response associated with arousal. Cardiorespiratory activity was measured during spontaneous arousals from sleep in subjects breathing passively on a ventilator. Under such conditions, homeostatic mechanisms are eliminated. Ventilation, end-tidal PCO2, mask pressure, diaphragmatic electromyograph, heart rate, and blood pressure were measured in four normal subjects under two conditions: assisted ventilation and a normal ventilation control condition. In the control condition, there was a normal, sleep-related fall in ventilation and rise in end-tidal PCO2. Subsequently, at an arousal, there was an increase in respiratory and cardiac activity. In the ventilator condition, a vigorous cardiorespiratory response to a spontaneous arousal from sleep remained. These results indicate that sleep-related respiratory stimuli are not necessary for the occurrence of elevated cardiorespiratory activity at an arousal from sleep and are consistent with the hypothesis that such activity is at least in part due to a reflex activation response.     

Inspiratory-resistive loading increases the ventilatory response to arousal but does not reduce genioglossus muscle activity on the return to sleep

Arousals from sleep are thought to predispose to obstructive sleep apnea by causing hyperventilation and hypocapnia, which reduce airway dilator muscle activity on the return to sleep. However, prior studies of auditory arousals have not resulted in reduced genioglossus muscle activity [GG-electromyogram (EMG)], potentially because airway resistance prior to arousal was low, leading to a small ventilatory response to arousal and minimal hypocapnia. Thus we aimed to increase the ventilatory response to arousal by resistive loading prior to auditory arousal and determine whether reduced GG-EMG occurred on the return to sleep. Eighteen healthy young men and women were recruited. Subjects were instrumented with a nasal mask with a pneumotachograph, an epiglottic pressure catheter, and intramuscular GG-EMG electrodes. Mask CO(2) levels were monitored. Three- to 15-s arousals from sleep were induced with auditory tones after resting breathing (No-Load) or inspiratory-resistive loading (Load; average 8.4 cmH(2)O·l(-1)·s(-1)). Peak minute ventilation following arousal was greater after Load than No-Load (mean ± SE; 8.0 ± 0.6 vs. 7.4 ± 0.6 l/min, respectively). However, the nadir end tidal partial pressure of CO(2) did not differ between Load conditions (43.1 ± 0.6 and 42.8 ± 0.5 mmHg, respectively), and no period of reduced GG activity occurred following the return to sleep (GG-EMG baseline, minimum after Load and No-Load = 2.9 ± 1.2%, 3.1 ± 1.3%, and 3.0 ± 1.3% max, respectively). These findings indicate that the hyperventilation, which occurs following tone-induced arousal, is appropriate for the prevailing level of respiratory drive, because loading did not induce marked hypocapnia or lower GG muscle activity on the return to sleep. Whether similar findings occur following obstructive events in patients remains to be determined.     

Dietary Modulation of Drosophila Sleep-Wake Behaviour

Background

A complex relationship exists between diet and sleep but despite its impact on human health, this relationship remains uncharacterized and poorly understood. Drosophila melanogaster is an important model for the study of metabolism and behaviour, however the effect of diet upon Drosophila sleep remains largely unaddressed.

Methodology/Principal Findings

Using automated behavioural monitoring, a capillary feeding assay and pharmacological treatments, we examined the effect of dietary yeast and sucrose upon Drosophila sleep-wake behaviour for three consecutive days. We found that dietary yeast deconsolidated the sleep-wake behaviour of flies by promoting arousal from sleep in males and shortening periods of locomotor activity in females. We also demonstrate that arousal from nocturnal sleep exhibits a significant ultradian rhythmicity with a periodicity of 85 minutes. Increasing the dietary sucrose concentration from 5% to 35% had no effect on total sucrose ingestion per day nor any affect on arousal, however it did lengthen the time that males and females remained active. Higher dietary sucrose led to reduced total sleep by male but not female flies. Locomotor activity was reduced by feeding flies Metformin, a drug that inhibits oxidative phosphorylation, however Metformin did not affect any aspects of sleep.

Conclusions

We conclude that arousal from sleep is under ultradian control and regulated in a sex-dependent manner by dietary yeast and that dietary sucrose regulates the length of time that flies sustain periods of wakefulness. These findings highlight Drosophila as an important model with which to understand how diet impacts upon sleep and wakefulness in mammals and humans.     

注意缺陷多动障碍低觉醒模型的新证据

注意缺陷多动障碍（Attention Deficit Hyperactivity Disorder,ADHD）是儿童期常见的一种发展性的异常,其病因及发生机理至今未明。低觉醒模型是ADHD成因的一种假设。本文从睡眠障碍导致的低觉醒探讨ADHD发生机理。通过对ADHD儿童的睡眠障碍进行分析以及将ADHD外在表现与睡眠剥夺后的表现进行对比分析,得出ADHD儿童存在的低觉醒是由于外显的或内隐的睡眠障碍引起的,一方面间接证明了低觉醒模型,另一方面为ADHD的成因研究开拓了新的思路。     

Re-patterning sleep architecture in Drosophila through gustatory perception and nutritional quality

Organisms perceive changes in their dietary environment and enact a suite of behavioral and metabolic adaptations that can impact motivational behavior, disease resistance, and longevity. However, the precise nature and mechanism of these dietary responses is not known. We have uncovered a novel link between dietary factors and sleep behavior in Drosophila melanogaster. Dietary sugar rapidly altered sleep behavior by modulating the number of sleep episodes during both the light and dark phase of the circadian period, independent of an intact circadian rhythm and without affecting total sleep, latency to sleep, or waking activity. The effect of sugar on sleep episode number was consistent with a change in arousal threshold for waking. Dietary protein had no significant effect on sleep or wakefulness. Gustatory perception of sugar was necessary and sufficient to increase the number of sleep episodes, and this effect was blocked by activation of bitter-sensing neurons. Further addition of sugar to the diet blocked the effects of sweet gustatory perception through a gustatory-independent mechanism. However, gustatory perception was not required for diet-induced fat accumulation, indicating that sleep and energy storage are mechanistically separable. We propose a two-component model where gustatory and metabolic cues interact to regulate sleep architecture in response to the quantity of sugar available from dietary sources. Reduced arousal threshold in response to low dietary availability may have evolved to provide increased responsiveness to cues associated with alternative nutrient-dense feeding sites. These results provide evidence that gustatory perception can alter arousal thresholds for sleep behavior in response to dietary cues and provide a mechanism by which organisms tune their behavior and physiology to environmental cues.     

Arousal in Drosophila

Arousal can be described as an endogenously generated or exogenously induced change in behavioral responsiveness. Changes in levels of arousal, such as occur during sleep or attention, most likely accomplish adaptive functions common to most animals. Recent evidence demonstrating changing arousal states in Drosophila melanogaster complements other behavioral research in this model organism. Herein we review the methodology related to the study of circadian rhythms, sleep and anesthesia where arousal, or lack of it, plays an essential role. We end this review by discussing a new method that allows for the first time to correlate changes in brain electrophysiology to changes in behavioral arousal in the fruit fly.     

Mathematical Models for Sleep-Wake Dynamics: Comparison of the Two-Process Model and a Mutual Inhibition Neuronal Model

Sleep is essential for the maintenance of the brain and the body, yet many features of sleep are poorly understood and mathematical models are an important tool for probing proposed biological mechanisms. The most well-known mathematical model of sleep regulation, the two-process model, models the sleep-wake cycle by two oscillators: a circadian oscillator and a homeostatic oscillator. An alternative, more recent, model considers the mutual inhibition of sleep promoting neurons and the ascending arousal system regulated by homeostatic and circadian processes. Here we show there are fundamental similarities between these two models. The implications are illustrated with two important sleep-wake phenomena. Firstly, we show that in the two-process model, transitions between different numbers of daily sleep episodes can be classified as grazing bifurcations. This provides the theoretical underpinning for numerical results showing that the sleep patterns of many mammals can be explained by the mutual inhibition model. Secondly, we show that when sleep deprivation disrupts the sleep-wake cycle, ostensibly different measures of sleepiness in the two models are closely related. The demonstration of the mathematical similarities of the two models is valuable because not only does it allow some features of the two-process model to be interpreted physiologically but it also means that knowledge gained from study of the two-process model can be used to inform understanding of the behaviour of the mutual inhibition model. This is important because the mutual inhibition model and its extensions are increasingly being used as a tool to understand a diverse range of sleep-wake phenomena such as the design of optimal shift-patterns, yet the values it uses for parameters associated with the circadian and homeostatic processes are very different from those that have been experimentally measured in the context of the two-process model.     

A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system

A quantitative, physiology-based model of the ascending arousal system is developed, using continuum neuronal population modeling, which involves averaging properties such as firing rates across neurons in each population. The model includes the ventrolateral preoptic area (VLPO), where circadian and homeostatic drives enter the system, the monoaminergic and cholinergic nuclei of the ascending arousal system, and their interconnections. The human sleep-wake cycle is governed by the activities of these nuclei, which modulate the behavioral state of the brain via diffuse neuromodulatory projections. The model parameters are not free since they correspond to physiological observables. Approximate parameter bounds are obtained by requiring consistency with physiological and behavioral measures, and the model replicates the human sleep-wake cycle, with physiologically reasonable voltages and firing rates. Mutual inhibition between the wake-promoting monoaminergic group and sleep-promoting VLPO causes ;;flip-flop' behavior, with most time spent in 2 stable steady states corresponding to wake and sleep, with transitions between them on a timescale of a few minutes. The model predicts hysteresis in the sleep-wake cycle, with a region of bistability of the wake and sleep states. Reducing the monoaminergic-VLPO mutual inhibition results in a smaller hysteresis loop. This makes the model more prone to wake-sleep transitions in both directions and makes the states less distinguishable, as in narcolepsy. The model behavior is robust across the constrained parameter ranges, but with sufficient flexibility to describe a wide range of observed phenomena.     

Bruxism and nocturnal groaning

Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated.     

A network model for activity-dependent sleep regulation

We develop and characterize a dynamical network model for activity-dependent sleep regulation. Specifically, in accordance with the activity-dependent theory for sleep, we view organism sleep as emerging from the local sleep states of functional units known as cortical columns; these local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g. by the circadian clock). We model these cortical columns as coupled or networked activity-integrators that transition between sleep and waking states based on thresholds on the total activity. The model dynamics for three canonical experiments (which we have studied both through simulation and system-theoretic analysis) match with experimentally observed characteristics of the cortical-column network. Most notably, assuming connectedness of the network graph, our model predicts the recovery of the columns to a synchronized state upon temporary overstimulation of a single column and/or randomization of the initial sleep and activity-integration states. In analogy with other models for networked oscillators, our model also predicts the possibility for such phenomena as mode-locking.     

Influence of repeated exposure to rapidly developing hypoxaemia on the arousal and cardiopulmonary response to rapidly developing hypoxaemia in lambs

Experiments were done on four lambs to determine if repeated exposure to rapidly developing hypoxaemia influences the cardiopulmonary and arousal response from sleep. Each lamb was anaesthetized and instrumented for sleep staging and measurements of arterial haemoglobin oxygen saturation. No sooner than three days after surgery, measurements were made in quiet sleep and active sleep during control periods when the animal was breathing 21% oxygen and during experimental periods of rapidly developing hypoxaemia when the animal was breathing 5% oxygen for approximately 100 epochs of sleep. Arousal occurred from both sleep states during rapidly developing hypoxaemia but was delayed in active sleep compared to quiet sleep. The time to arousal and the decrease in arterial haemoglobin oxygen saturation were significantly increased with repeated exposure to rapidly developing hypoxaemia during both quiet sleep and active sleep. Thus, our data provide evidence that repeated exposure to rapidly developing hypoxaemia produces an arousal response decrement in lambs. Since it is possible that alterations in the arousal response to respiratory stimuli play a role in sudden infant death, studies to investigate the mechanism of the arousal response decrement following repeated exposure to rapidly developing hypoxaemia are warranted.     

Sleep and arousal patterns of co-sleeping human mother/infant pairs: a preliminary physiological study with implications for the study of sudden infant death syndrome (SIDS)

The prevailing research design for studying infant sleep erroneously assumes the species-wide normalcy of solitary nocturnal sleep rather than a social sleeping environment. In fact, current clinical perspectives on infant sleep, which are based exclusively on studies of solitary sleeping infants, may partly reflect culturally induced rather than species-typical infant sleep patterns which can only be gleaned, we contend here, from infants sleeping with their parents--the context within which, and for well over 4 million years, the hominid infant's sleep, breathing, and arousal patterns evolved. Our physiological study of five co-sleeping mother-infant pairs in a sleep lab is the first study of its kind to document the unfolding sleep patterns of mothers and infants sleeping in physical contact. Our data show that co-sleeping mothers and infants exhibit synchronous arousals, which, because of the suspected relationship between arousal and breathing stability in infants, have important implications for how we study environmental factors possibly related to some forms of the sudden infant death syndrome (SIDS). While our data show that co-sleeping mothers and infants also experience many moments of physiological independence from each other, it is clear that the temporal unfolding of particular sleep stages and awake periods of the mother and infant become entwined and that on a minute-to-minute basis, throughout the night, much sensory communication is occurring between them. Our research acknowledges the human infant's evolutionary past and considers the implications that nocturnal separation (a historically novel and alien experience for them) has for maternal and infant well-being in general and SIDS research strategies in particular.     

Tone induction of ocular activity and dream imagery from stage 2 sleep.

Currently, there is debate as to whether ponto-geniculo-occipital (PGO) waves or the resulting cortical arousal associated with such neural activity constitute the biological substrate of dreaming. The present study aimed to induce PGO activity in humans using an external stimulation technique. Participants (N = 15) were presented with tones (1,000 Hz) of increasing intensity during Stage II and rapid eye movement (REM) sleep. A peizosensor fixed to the eyelid captured ocular activity (OA) as an indicator of PGO activity in response to the tone. Compared to the stimulation, the Stage II control condition with no Stage II tone-induced ocular activity (OA) condition showed: a) more imagery reports that were rated as more vivid, and b) more electroencephalogram (EEG) arousal time. EEG arousal was correlated with the average Stage II imagery across participants. None of these findings were observed from REM sleep. It was concluded that investigation of PGO analogues, or even PGO activity itself, and dreaming might be inherently flawed due to the confounding presence of EEG arousal, as the two may be intimately linked. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology

Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.     

Effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnea.

During obstructive sleep apnea (OSA), systemic (Psa) and pulmonary (Ppa) arterial pressures acutely increase after apnea termination, whereas left and right ventricular stroke volumes (SV) reach a nadir. In a canine model (n = 6), we examined the effects of arousal, parasympathetic blockade (atropine 1 mg/kg iv), and sleep state on cardiovascular responses to OSA. In the absence of arousal, SV remained constant after apnea termination, compared with a 4.4 +/- 1.7% decrease after apnea with arousal (P < 0.025). The rise in transmural Ppa was independent of arousal (4.5 +/- 1.0 vs. 4.1 +/- 1.2 mmHg with and without arousal, respectively), whereas Psa increased more after apnea termination in apneas with arousal compared with apneas without arousal. Parasympathetic blockade abolished the arousal-induced increase in Psa, indicating that arousal is associated with a vagal withdrawal of the parasympathetic tone to the heart. Rapid-eye-movement (REM) sleep blunted the increase in Psa (pre- to end-apnea: 5.6 +/- 2.3 mmHg vs. 10.3 +/- 1.6 mmHg, REM vs. non-REM, respectively, P < 0.025), but not transmural Ppa, during an obstructive apnea. We conclude that arousal and sleep state both have differential effects on the systemic and pulmonary circulation in OSA, indicating that, in patients with underlying cardiovascular disease, the hemodynamic consequences of OSA may be different for the right or the left side of the circulation.     

Arousal responses to airway occlusion in sleeping dogs: comparison of nasal and tracheal occlusions

Previous studies have shown that the arousal threshold to hypoxia, hypercapnia, and tracheal occlusions is greatly depressed in rapid-eye-movement (REM) sleep compared with slow-wave sleep (SWS). The aim of this study was to compare the arousal thresholds in SWS and REM sleep in response to an upper airway pressure stimulus. We compared the waking responses to tracheal (T) vs. nasal (N) occlusion in four unanesthetized, naturally sleeping dogs. The dogs either breathed through a tracheal fistula or through the snout using a fiberglass mask. A total of 295 T and 160 N occlusion tests were performed in SWS and REM sleep. The mean time to arousal during N and T tests was variable in the same dog and among the dogs. The mean time to arousal in SWS-tracheal occlusion was longer than that in N tests in only two of the four dogs. The total number of tests inducing arousal within the first 15 s of SWS-nasal occlusion tests was significantly more than that of T tests (N: 47%; T: 27%). There was a marked depression of arousal within the initial 15 s of REM sleep in T tests compared with N tests (N: 21%; T: 0%). The frequency of early arousals in REM tests was less than that of SWS for both N and T tests. The early arousal in N occlusion is in sharp contrast to the well-described depressed arousal responses to hypoxia, hypercapnia, and asphyxia. This pattern of arousal suggests that the upper airway mechanoreceptors may play an important role in the induction of an early arousal from nasal occlusion.