Biomathematical modeling of fatigue due to sleep inertia.

Biomathematical models of fatigue capture the physiology of sleep/wake regulation and circadian rhythmicity to predict changes in neurobehavioral functioning over time. We used a biomathematical model of fatigue linked to the adenosinergic neuromodulator/receptor system in the brain as a framework to predict sleep inertia, that is, the transient neurobehavioral impairment experienced immediately after awakening. Based on evidence of an adenosinergic basis for sleep inertia, we expanded the biomathematical model with novel differential equations to predict the propensity for sleep inertia during sleep and its manifestation after awakening. Using datasets from large laboratory studies of sleep loss and circadian misalignment, we calibrated the model by fitting just two new parameters and then validated the model's predictions against independent data. The expanded model was found to predict the magnitude and time course of sleep inertia with generally high accuracy. Analysis of the model's dynamics revealed a bifurcation in the predicted manifestation of sleep inertia in sustained sleep restriction paradigms, which reflects the observed escalation of the magnitude of sleep inertia in scenarios with sleep restriction to less than âˆ¼ 4 h per day. Another emergent property of the model involves a rapid increase in the predicted propensity for sleep inertia in the early part of sleep followed by a gradual decline in the later part of the sleep period, which matches what would be expected based on the adenosinergic regulation of non-rapid eye movement (NREM) sleep and its known influence on sleep inertia. These dynamic behaviors provide confidence in the validity of our approach and underscore the predictive potential of the model. The expanded model provides a useful tool for predicting sleep inertia and managing impairment in 24/7 settings where people may need to perform critical tasks immediately after awakening, such as on-demand operations in safety and security, emergency response, and health care.

Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men.

CONTEXT: Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance. OBJECTIVE: We clamped cortisol and testosterone and determined the effect on insulin resistance. METHODS: This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states. RESULTS: Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone. CONCLUSION: Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health.

Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans.

Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. We sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24-hour constant routine protocol following 3 days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.

Interleukin-6 (IL-6) response to a simulated night-shift schedule is modulated by brain-derived neurotrophic factor (BDNF) genotype.

The BDNF gene contains a polymorphism (Val66Met) that influences sleep and may be associated with more flexible adaptation to circadian misalignment. Fifteen adult men (10 Val/Val homozygotes, 5 Val/Met heterozygotes) participated in a laboratory study involving two 5 d cycles of simulated night shifts. Circulating interleukin-6 (IL-6) was measured from plasma, sleep was recorded polysomnographically, and performance was measured using a psychomotor vigilance test. Compared to Val/Val homozygotes, heterozygotes exhibited a blunted IL-6 temporal (diurnal) pattern, less daytime sleep restriction, and less nighttime performance impairment after the first simulated night-shift cycle. These observations suggest that heterozygotes experienced more flexible circadian adaptation.

Astrocyte expression of the Drosophila TNF-alpha homologue, Eiger, regulates sleep in flies.

Sleep contributes to cognitive functioning and is sufficient to alter brain morphology and function. However, mechanisms underlying sleep regulation remain poorly understood. In mammals, tumor necrosis factor-alpha (TNFα) is known to regulate sleep, and cytokine expression may represent an evolutionarily ancient mechanism in sleep regulation. Here we show that the Drosophila TNFα homologue, Eiger, mediates sleep in flies. We show that knockdown of Eiger in astrocytes, but not in neurons, significantly reduces sleep duration, and total loss-of-function reduces the homeostatic response to sleep loss. In addition, we show that neuronal, but not astrocyte, expression of the TNFα receptor superfamily member, Wengen, is necessary for sleep deprivation-induced homeostatic response and for mediating increases in sleep in response to human TNFα. These data identify a novel astrocyte-to-neuron signaling mechanism in the regulation of sleep homeostasis and show that the Drosophila cytokine, Eiger, represents an evolutionarily conserved mechanism of sleep regulation across phylogeny.

The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models.

Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2-/- mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2-/- clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2-/- mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.

Shift Work: Disrupted Circadian Rhythms and Sleep-Implications for Health and Well-Being.

PURPOSE OF REVIEW: Our 24/7 society is dependent on shift work, despite mounting evidence for negative health outcomes from sleep displacement due to shift work. This paper reviews short- and long-term health consequences of sleep displacement and circadian misalignment due to shift work. RECENT FINDINGS: We focus on four broad health domains: metabolic health; risk of cancer; cardiovascular health; and mental health. Circadian misalignment affects these domains by inducing sleep deficiency, sympathovagal and hormonal imbalance, inflammation, impaired glucose metabolism, and dysregulated cell cycles. This leads to a range of medical conditions, including obesity, metabolic syndrome, type II diabetes, gastrointestinal dysfunction, compromised immune function, cardiovascular disease, excessive sleepiness, mood and social disorders, and increased cancer risk. SUMMARY: Interactions of biological disturbances with behavioral and societal factors shape the effects of shift work on health and well-being. Research is needed to better understand the underlying mechanisms and drive the development of countermeasures.

Time-on-Task Effect During Sleep Deprivation in Healthy Young Adults Is Modulated by Dopamine Transporter Genotype.

Study Objectives: The time-on-task (TOT) effect and total sleep deprivation (TSD) have similar effects on neurobehavioral functioning, including increased performance instability during tasks requiring sustained attention. The TOT effect is exacerbated by TSD, suggesting potentially overlapping mechanisms. We probed these mechanisms by investigating genotype-phenotype relationships on psychomotor vigilance test (PVT) performance for 3 a-priori selected genes previously linked to the TOT effect and/or TSD: dopamine active transporter 1 (DAT1), catechol-O-methyltransferase (COMT), and tumor necrosis factor alpha (TNFα). Methods: N = 82 healthy adults participated in 1 of 3 laboratory studies. A 10-min PVT was administered repeatedly during 38 h of TSD. We assessed changes in response time (RT) across each minute of the PVT as a function of time awake and genotype. Additionally, cumulative relative RT frequency distributions were constructed to examine changes in performance from the first to the second 5 min of the PVT as a function of genotype. Results: DAT1, COMT, and TNFα were associated with differences in the build-up of the TOT effect across the 10-min PVT. DAT1 additionally modulated the interaction between TSD and the TOT effect. Subjects homozygous for the DAT1 10-repeat allele were relatively protected against TOT deficits on the PVT during TSD compared to carriers of the 9-repeat allele. Conclusions: DAT1 is known to regulate dopamine reuptake and is highly expressed in the striatum. Our results implicate striatal dopamine in mechanisms involved in performance instability that appear to be common to TSD and the TOT effect. Furthermore, DAT1 may be a candidate biomarker of resilience to the build-up of performance impairment across TOT due to TSD.

Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7.

Sleep is found widely in the animal kingdom. Despite this, few conserved molecular pathways that govern sleep across phyla have been described. The mammalian brain-type fatty acid binding protein (Fabp7) is expressed in astrocytes, and its mRNA oscillates in tandem with the sleep-wake cycle. However, the role of FABP7 in regulating sleep remains poorly understood. We found that the missense mutation FABP7.T61M is associated with fragmented sleep in humans. This phenotype was recapitulated in mice and fruitflies bearing similar mutations: Fabp7-deficient mice and transgenic flies that express the FABP7.T61M missense mutation in astrocytes also show fragmented sleep. These results provide novel evidence for a distinct molecular pathway linking lipid-signaling cascades within astrocytes in sleep regulation among phylogenetically disparate species.

TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults.

Cytokines such as TNFα play an integral role in sleep/wake regulation and have recently been hypothesized to be involved in cognitive impairment due to sleep deprivation. We examined the effect of a guanine to adenine substitution at position 308 in the TNFα gene (TNFα G308A) on psychomotor vigilance performance impairment during total sleep deprivation. A total of 88 healthy women and men (ages 22-40) participated in one of five laboratory total sleep deprivation experiments. Performance on a psychomotor vigilance test (PVT) was measured every 2-3h. The TNFα 308A allele, which is less common than the 308G allele, was associated with greater resilience to psychomotor vigilance performance impairment during total sleep deprivation (regardless of time of day), and also provided a small performance benefit at baseline. The effect of genotype on resilience persisted when controlling for between-subjects differences in age, gender, race/ethnicity, and baseline sleep duration. The TNFα G308A polymorphism predicted less than 10% of the overall between-subjects variance in performance impairment during sleep deprivation. Nonetheless, the differential effect of the polymorphism at the peak of performance impairment was more than 50% of median performance impairment at that time, which is sizeable compared to the effects of other genotypes reported in the literature. Our findings provided evidence for a role of TNFα in the effects of sleep deprivation on psychomotor vigilance performance. Furthermore, the TNFα G308A polymorphism may have predictive potential in a biomarker panel for the assessment of resilience to psychomotor vigilance performance impairment due to sleep deprivation.

Individual differences in vulnerability to sleep loss in the work environment.

There are considerable individual differences in cognitive performance deficits resulting from extended work hours and shift work schedules. Recent progress in sleep and performance research has yielded new insights into the causes and consequences of these individual differences. Neurobiological processes of sleep/wake regulation underlie trait individual variability in vulnerability to performance impairment due to sleep loss. Trait vulnerability to sleep loss is observed in the laboratory and in the work environment, even in occupational settings where (self-)selection pressures are high. In general, individuals do not seem to accurately assess the magnitude of their own vulnerability. Methods for identifying workers who are most at risk of sleep loss-related errors and accidents would therefore be helpful to target fatigue countermeasure interventions at those needing them most. As yet, no reliable predictors of vulnerability to sleep loss have been identified, although candidate genetic predictors have been proposed. However, a Bayesian forecasting technique based on closed-loop feedback of measured performance has been developed for individualized prediction of future performance impairment during ongoing operations. Judiciously selecting or monitoring individuals in specific tasks or occupations, within legally and ethically acceptable boundaries, has the potential to improve operational performance and productivity, reduce errors and accidents, and save lives. Trait individual variability in responses to sleep loss represents a major complication in the application of one-size-fits-all hours of service regulations--favoring instead modern fatigue risk management strategies, because these allow flexibility to account for individual vulnerability or resilience to the performance consequences of extended work hours and shift work schedules.

Performance impairment consequent to sleep loss: determinants of resistance and susceptibility.

PURPOSE OF REVIEW: Five years ago, it was first demonstrated that there are considerable, stable individual differences in performance impairment due to sleep deprivation. The discovery of this new phenotype, which has been labeled 'trototype', led to a surge of research activity aiming to identify predictors. RECENT FINDINGS: Genes involved in the adenosinergic and circadian regulation of sleep have been identified as candidate predictors of individuals' resistance or susceptibility to performance impairment resulting from sleep deprivation. Furthermore, brain regions potentially involved in the expression of individual differences in vulnerability to sleep loss have been found. This research has provided new insights into the mechanisms underlying sleep/wake regulation and responses to loss of sleep. To date, however, it remains unknown how much of the phenotypic variability is explained by any of the putative predictors of trototype. SUMMARY: The existence of substantial, phenotypic individual differences in performance impairment consequent to sleep loss has important implications for fatigue risk management in operational settings and for the symptomology and treatment of sleep disorders, putting a premium on the discovery of reliable predictors.

Circadian rhythm profiles in women with night eating syndrome.

Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings accompanied by food intake. Patients with NES display a delayed circadian pattern of food intake but retain a normal sleep-wake cycle. These characteristics initiated the current study, in which the phase and amplitude of behavioral and neuroendocrine circadian rhythms in patients with NES were evaluated. Fifteen women with NES (mean age +/- SD, 40.8 +/- 8.7 y) and 14 control subjects (38.6 +/- 9.5 y) were studied in the laboratory for 3 nights, with food intake measured daily. Blood also was collected for 25 h (every 2 h from 0800 to 2000 h, and then hourly from 2100 to 0900 h) and assayed for glucose and 7 hormones (insulin, ghrelin, leptin, melatonin, cortisol, thyroid-stimulating hormone [TSH] and prolactin). Statistical analyses utilized linear mixed-effects cosinor analysis. Control subjects displayed normal phases and amplitudes for all circadian rhythms. In contrast, patients with NES showed a phase delay in the timing of meals, and delayed circadian rhythms for total caloric, fat, and carbohydrate intake. In addition, phase delays of 1.0 to 2.8 h were found in 2 food-regulatory rhythms-leptin and insulin-and in the circadian melatonin rhythm (with a trend for a delay in the circadian cortisol rhythm). In contrast, circulating levels of ghrelin, the primary hormone that stimulates food intake, were phase advanced by 5.2 h. The glucose rhythm showed an inverted circadian pattern. Patients with NES also showed reduced amplitudes in the circadian rhythms of food intake, cortisol, ghrelin, and insulin, but increased TSH amplitude. Thus, patients with NES demonstrated significant changes in the timing and amplitude of various behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation. As such, NES may result from dissociations between central (suprachiasmatic nucleus) timing mechanisms and putative oscillators elsewhere in the central nervous system or periphery, such as the stomach or liver. Considering these results, chronobiologic treatments for NES such as bright light therapy may be useful. Indeed, bright light therapy has shown efficacy in reducing night eating in case studies and should be evaluated in controlled clinical trials.

A new mathematical model for the homeostatic effects of sleep loss on neurobehavioral performance.

The two-process model of sleep regulation makes accurate predictions of sleep timing and duration for a variety of experimental sleep deprivation and nap sleep scenarios. Upon extending its application to waking neurobehavioral performance, however, the model fails to predict the effects of chronic sleep restriction. Here we show that the two-process model belongs to a broader class of models formulated in terms of coupled non-homogeneous first-order ordinary differential equations, which have a dynamic repertoire capturing waking neurobehavioral functions across a wide range of wake/sleep schedules. We examine a specific case of this new model class, and demonstrate the existence of a bifurcation: for daily amounts of wakefulness less than a critical threshold, neurobehavioral performance is predicted to converge to an asymptotically stable state of equilibrium; whereas for daily wakefulness extended beyond the critical threshold, neurobehavioral performance is predicted to diverge from an unstable state of equilibrium. Comparison of model simulations to laboratory observations of lapses of attention on a psychomotor vigilance test (PVT), in experiments on the effects of chronic sleep restriction and acute total sleep deprivation, suggests that this bifurcation is an essential feature of performance impairment due to sleep loss. We present three new predictions that may be experimentally verified to validate the model. These predictions, if confirmed, challenge conventional notions about the effects of sleep and sleep loss on neurobehavioral performance. The new model class implicates a biological system analogous to two connected compartments containing interacting compounds with time-varying concentrations as being a key mechanism for the regulation of psychomotor vigilance as a function of sleep loss. We suggest that the adenosinergic neuromodulator/receptor system may provide the underlying neurobiology.