From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach.

We present ten insights that can be gained from computational models based on molecular mechanisms for the mammalian circadian clock. These insights range from the conditions in which circadian rhythms occur spontaneously to their entrainment by the light-dark (LD) cycle and to clock-related disorders of the sleep-wake cycle. Endogenous oscillations originate spontaneously from transcription-translation feedback loops involving clock proteins such as PER, CRY, CLOCK and BMAL1. Circadian oscillations occur in a parameter domain bounded by critical values. Outside this domain the circadian network ceases to oscillate and evolves to a stable steady state. This conclusion bears on the nature of arrhythmic behavior of the circadian clock, which may not necessarily be due to mutations in clock genes. Entrainment by the LD cycle occurs in a certain range of parameter values, with a phase that depends on the endogenous period of the circadian clock. A decrease in PER phosphorylation is accompanied by a decrease in endogenous period and a phase advance of the clock; this situation accounts for the familial, advanced sleep phase syndrome (FASPS). The mirror delayed sleep phase syndrome (DSPS) can be accounted for, similarly, by an increase in PER phosphorylation and a rise in autonomous period. Failure of entrainment by the LD cycle in the model corresponds to the non-24 h sleep-wake cycle syndrome, in which the phase of the circadian clock drifts in the course of time. Quasi-periodic oscillations that develop in these conditions sometimes correspond to long-period patterns in which the circadian clock is nearly entrained for long bouts of time before its phase rapidly drifts until a new regime of quasi-entrainment is re-established. In regard to jet lag, the computational approach accounts for the two modes of re-entrainment observed after an advance or delay which correspond, respectively, to an eastward or westward flight: the clock adjusts in a direction similar (orthodromic) or opposite (antidromic) to that of the shift in the LD cycle. Computational modeling predicts that in the vicinity of the switch between orthodromic and antidromic re-entrainment the circadian clock may take a very long time to resynchronize with the LD cycle. Repetitive perturbations of the circadian clock due, for example, to chronic jet lag -a situation somewhat reminiscent of shift work- may lead to quasi-periodic or chaotic oscillations. The latter irregular oscillations can sometimes be observed in normal LD cycles, raising the question of their possible relevance to fragmented sleep patterns observed in narcolepsy. The latter condition, however, appears to originate from disorders in the orexin neural circuit, which promotes wakefulness, rather than from an irregular operation of the circadian clock.

Accelerometry-assessed sleep duration and timing in late childhood and adolescence in Scottish schoolchildren: A feasibility study.

Children and adolescents commonly suffer from sleep and circadian rhythm disturbances, which may contribute to poorer mental health and wellbeing during this critical developmental phase. Many studies however rely on self-reported sleep measures. This study assessed whether accelerometry data collection was feasible within the school setting as a method for investigating the extent of sleep and circadian disruption, and associations with subjective wellbeing, in Scotland. Fourteen days of wrist-worn accelerometry data were collected from 69 pupils, aged 10-14 years. Objective measures of sleep timing, sleep duration and circadian rest-activity patterns were derived. Questionnaires assessed subjective sleep timing, depressive symptoms, and experiences of wearing the accelerometer. Pupils slept on average less than 8 hours per night, failing to meet standard age-specific recommendations. Sleep timing was later and duration longer on weekends compared to weekdays (B = 0.87, 95% confidence interval (CI) 0.70, 1.04; B = 0.49, 95% CI 0.29, 0.69), indicating social jetlag. Lower daytime activity was correlated with higher depressive symptoms (r = -0.84, p = 0.008). Compared to primary school pupils, secondary pupils had shorter sleep window duration and lower circadian relative amplitude. Over half of participants reported some discomfort/inconvenience wearing the accelerometer. These data highlight that inadequate sleep is prevalent in this sample of schoolchildren. Future, larger scale investigations will examine in more detail the associations between sleep, circadian function and physical activity with mental health and wellbeing.

[Diagnosis and comorbidities of Circadian Rhythm Sleep Disorders]. / Diagnostic et comorbidités des troubles du rythme veille-sommeil.

Circadian rhythm sleep disorders (CRSD) result from a disturbed endogenous clock (intrinsic CRSD) or from a misalignment between the biological clock and an imposed environment (extrinsic CRSD). Among intrinsic CRSD, one distinguishes the delayed sleep-wake phase disorder, the advanced sleep-wake phase disorder, the irregular sleep-wake rhythm disorder and the non-24-hour sleep-wake rhythm disorder. Shift work disorder, jet lag disorder and circadian sleep-wake disorder not otherwise specified are extrinsic CRSD. Prevalences of the different CRSD remain largely unknown. Some CRSD are particularly frequent such as sleep delayed phase syndrome in adolescents. Overall, CRSD are probably under-diagnosed. CRSD generate insomnia and excessive daytime somnolence. A biological clock dysfunction has to be evoked in case of insomnia or sleepiness. Furthermore, as CRSD can overlap with other sleep disorders, their diagnosis and treatment are essential. CRSD cause significant mental, physical or socio-professional sufferings. They are frequently associated with comorbidities, mainly neurodevelopmental, psychiatric and neurodegenerative disorders. Regarding neurodevelopmental comorbidities, therapy using a chronobiological approach is complementary to the usual clinical care. It helps to limit the significant impact of CRSD on quality of live, daytime functioning, social interactions and neurocognitive difficulties in the children. In psychiatry, sleep disorders and circadian rhythms sleep-wake disorders are a factor of vulnerability, of suicidal risk, of relapse and pharmacoresistance. Thus, diagnosis of CRSD associated with a psychiatric disorder is of major importance. Treatment using a chronobiological approach reinforcing the entrainment of the sleep-wake cycle is complementary to usual treatments. Sleep disorders and circadian sleep-wake rhythm disorders can be a preclinical sign of Alzheimer's and Parkinson's disease. In the elderly, a beginning neurodegenerative disorder can be associated with a CRSD and complaints of sleepiness, nocturnal awakenings and/or irregular sleep-wake cycles. Patients affected by neurogenerative disorders are particularly vulnerable for having CRSD. Data from different studies suggest that CRSD participate in pathophysiology of Alzheimer's disease. Even though treatment of CRSD associated with neurodegenerative disorders is entirely part of the treatment strategy, it remains uncertain to which extend this treatment may impact disease progression.

[CME: Jet Lag Jetlag]. / CME: Jetlag CME-Fragen.

CME: Jet Lag Jetlag Abstract. Crossing several time zones by air travel leads to a temporary desynchronization of the internal clock with the external light/dark cycle. In the following jet lag occurs typically including difficulties falling asleep or waking up early as well as day-time sleepiness and significant reduction of wellbeing and fitness. To provide optimal medical advice, it is necessary to understand the human circadian rhythm and sleep-wake regulation. In consideration with additional information on travel plans, an approach to alleviate jet lag symptoms can be developed. This article addresses different supportive measures and advice on how to adjust to a new time zone and reduce jet lag symptoms.

Circadian Rhythm Sleep-Wake Disorders in Older Adults.

The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows wakefulness throughout the day and a long consolidated sleep episode at night. Mismatch between the desired timing of sleep and the ability to fall and remain asleep is a hallmark of the circadian rhythm sleep-wake disorders. This article discusses changes in circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep-wake disorders; and how neurologic diseases in older patients affect circadian rhythms and sleep.

Computing sleep deficiency.

Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints.

Effects of Long-Haul Transmeridian Travel on Subjective Jet-Lag and Self-Reported Sleep and Upper Respiratory Symptoms in Professional Rugby League Players.

PURPOSE: To examine the effects of 24-h travel west across 11 time zones on subjective jet-lag and wellness responses together with self-reported sleep and upper respiratory symptoms in 18 professional rugby league players. METHODS: Measures were obtained 1 or 2 d before (pretravel) and 2, 6, and 8 d after travel (post-2, post-6, and post-8) from Australia to the United Kingdom (UK) for the 2015 World Club Series. RESULTS: Compared with pretravel, subjective jet-lag remained significantly elevated on post-8 (3.1 ± 2.3, P < .05, d > 0.90), although it was greatest on post-2 (4.1 ± 1.4). Self-reported sleep-onset times were significantly earlier on post-2 than at all other time points (P < .05, d > 0.90), and large effect sizes suggested that wake times were earlier on post-2 than on post-6 and post-8 (d > 0.90). Although significantly more upper respiratory symptoms were reported on post-6 than at pretravel (P < .05, d ˃ 0.90), no incidence of injury and negligible changes in wellness and muscle strength and range of motion (P > .05, d < 0.90) were evident after travel. CONCLUSIONS: Results suggest that westward long-haul travel between Australia and the UK exacerbates subjective jet-lag and sleep responses, along with upper respiratory symptoms, in professional rugby league players. Of note, the increase in self-reported upper respiratory symptoms is a reminder that the demands of long-haul travel may be an additional concern in jet-lag for traveling athletes. However, due to the lack of sport-specific performance measures, it is still unclear whether international travel interferes with training to the extent that subsequent competition performance is impaired.

A 30-Minute, but Not a 10-Minute Nighttime Nap is Associated with Sleep Inertia.

STUDY OBJECTIVES: To assess sleep inertia following 10-min and 30-min naps during a simulated night shift. METHODS: Thirty-one healthy adults (aged 21-35 y; 18 females) participated in a 3-day laboratory study that included one baseline (BL) sleep (22:00-07:00) and one experimental night involving randomization to either: total sleep deprivation (NO-NAP), a 10-min nap (10-NAP) or a 30-min nap (30-NAP). Nap opportunities ended at 04:00. A 3-min psychomotor vigilance task (PVT-B), digit-symbol substitution task (DSST), fatigue scale, sleepiness scale, and self-rated performance scale were undertaken pre-nap (03:00) and at 2, 17, 32, and 47 min post-nap. RESULTS: The 30-NAP (14.7 ± 5.7 min) had more slow wave sleep than the 10-NAP (0.8 ± 1.5 min; P < 0.001) condition. In the NO-NAP condition, PVT-B performance was worse than pre-nap (4.6 ± 0.3 1/sec) at 47 min post-nap (4.1 ± 0.4 1/sec; P < 0.001). There was no change across time in the 10-NAP condition. In the 30-NAP condition, performance immediately deteriorated from pre-nap (4.3 ± 0.3 1/sec) and was still worse at 47 min post-nap (4.0 ± 0.5 1/sec; P < 0.015). DSST performance deteriorated in the NO-NAP (worse than pre-nap from 17 to 47 min; P < 0.008), did not change in the 10-NAP, and was impaired 2 min post-nap in the 30-NAP condition (P = 0.028). All conditions self-rated performance as better than pre-nap for all post-nap test points (P < 0.001). CONCLUSIONS: This study is the first to show that a 10-min (but not a 30-min) nighttime nap had minimal sleep inertia and helped to mitigate short-term performance impairment during a simulated night shift. Self-rated performance did not reflect objective performance following a nap.

Jet lag modification.

Athletes often are required to travel for sports participation, both for practice and competition. A number of those crossing multiple time zones will develop jet lag disorder with possible negative consequences on their performance. This review will discuss the etiology of jet lag disorder and the techniques that are available to shorten or minimize its effects. This includes both pharmacological and nonpharmacological approaches.

Chronotype predicts positive affect rhythms measured by ecological momentary assessment.

Evening chronotype, a correlate of delayed circadian rhythms, is associated with depression. Altered positive affect (PA) rhythms may mediate the association between evening chronotype and depression severity. Consequently, a better understanding of the relationship between chronotype and PA may aid in understanding the etiology of depression. Recent studies have found that individuals with evening chronotype show delayed and blunted PA rhythms, although these studies are relatively limited in sample size, representativeness and number of daily affect measures. Further, published studies have not included how sleep timing changes on workday and non-workdays, or social jet lag (SJL) may contribute to the chronotype-PA rhythm link. Healthy non-depressed adults (n = 408) completed self-report affect and chronotype questionnaires. Subsequently, positive and negative affects were measured hourly while awake for at least two workdays and one non-workday by ecological momentary assessment (EMA). Sleep variables were collected via actigraphy and compared across chronotype groups. A cosinor variant of multilevel modeling was used to model individual and chronotype group rhythms and to calculate two variables: (1) amplitude of PA, or the absolute amount of daily variation from peak to trough during one period of the rhythm and (2) acrophase, or the time at which the peak amplitude of affect rhythms occurred. On workdays, individuals with evening chronotype had significantly lower PA amplitudes and later workday acrophase times than their morning type counterparts. In contrast to predictions, SJL was not found to be a mediator in the relationship between chronotype and PA rhythms. The association of chronotype and PA rhythms in healthy adults may suggest the importance of daily measurement of PA in depressed individuals and would be consistent with the hypothesis that evening chronotype may create vulnerability to depression via delayed and blunted PA rhythms.

A new German Charité Jet Lag Scale for jet lag symptoms and application.

Travelling across multiple time zones provokes adaptation of endogenous circadian rhythm to the new time zone. Within the context of previous studies, an English-language state-of-health questionnaire, the Columbia Jet Lag Scale, is the only sufficiently validated scale for jet lag and its symptoms. This study presents a new state-of-health questionnaire in German, one intended to achieve standardisation of surveys on jet lag. The questionnaire was applied to define the baseline for the prevalence of jet lag symptoms based on a reference group (n = 36). The jet lag score ascertained was subsequently applied to determine the frequency of jet lag in a group of 53 subjects. Systematic investigation of the frequency of jet lag symptoms had not been previously presented. Among the group of 53 travelling test subjects, 60% demonstrated moderate jet lag symptoms. Practitioner Summary: This introduction of the Charité Jet Lag Scale, the first German jet lag questionnaire, calls attention to this topic for the first time since a 2000 publication in Ergonomics. Our systematic investigation of jet lag frequency, with the new scale, determined moderate jet lag symptoms among 60% of subjects.

Differential activation of the default mode network in jet lagged individuals.

Long-term exposure to transmeridian flights has been shown to impact cognitive functioning. Nevertheless, the immediate effects of jet lag in the activation of specific brain networks have not been investigated. We analyzed the impact of short-term jet lag on the activation of the default mode network (DMN). A group of individuals who were on a transmeridian flight and a control group went through a functional magnetic resonance imaging acquisition. Statistical analysis was performed to test for differences in the DMN activation between groups. Participants from the jet lag group presented decreased activation in the anterior nodes of the DMN, specifically in bilateral medial prefrontal and anterior cingulate cortex. No areas of increased activation were observed for the jet lag group. These results may be suggestive of a negative impact of jet lag on important cognitive functions such as introspection, emotional regulation and decision making in a few days after individuals arrive at their destination.

[Biological rhythm, sleep and jet lag]. / Biologische Rhythmen, Schlaf und Jet Lag.

Sleep is an active recovery process, which is governed by biological rhythms. This rhythmic variation influences almost all bodily functions and dictates the optimal time for sleep. Sleep itself is an inconsistent state mainly characterized by the alteration between REM and NREM sleep. Vital regenerative processes occur during sleep. Sleep is a basic prerequisite for wellbeing, health and performance. If the synchronization between sleep and the biological rhythms is disturbed, malfunctions of the organism have to be expected. Such a state can be found by a sudden shift of local time by travelling across time zones (jet lag). Therapeutic strategies can reduce the symptoms associated with the state of jet lag.

Adolescent sleep misalignment: a chronic jet lag and a matter of public health.

Sleep is a key element, both physiologically and psychologically, in adolescent development. The prevalence of sleep disorders in western countries is important, as with age the sleep-wake cycle of adolescents becomes irregular and delayed in relation with later sleep onset and waking time resulting in rhythm desynchronization. A large number of adolescents sleep for 7-8h instead of 9-10h per night, which can lead to a cumulative sleep debt with fatigue, behavioral problems and poor academic achievement. The effect of electronic media use (such as television, mobile phone, computer, and electronic gaming) on sleep has been the object of several international studies, though pubertal changes may also impact adolescent sleep. Adolescents and their parents should be educated by professionals, including physicians and nurses, on the key role of sleep in adolescent well being and quality of life. A number of basic rules are proposed to improve sleep in adolescents. The permanent social jet lag experienced by a number of adolescents should be considered as a matter of public health.

A phase 3, double-blind, randomized, placebo-controlled study of armodafinil for excessive sleepiness associated with jet lag disorder.

OBJECTIVE: To assess the effect of armodafinil, the longer-lasting isomer of modafinil, on jet lag disorder. PARTICIPANTS AND METHODS: This double-blind, randomized, parallel-group, multicenter study was conducted between September 18, 2008, and February 9, 2009. Adults with a history of jet lag symptoms on previous flights through multiple time zones flew from the United States to France (a 6-hour time zone change) for a 3-day laboratory-based study period. Participants received armodafinil (50 or 150 mg/d) or placebo each morning. Wakefulness was assessed by the coprimary outcomes, mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of all MSLT sessions across days 1 and 2) and Patient Global Impression of Severity in relation to jet lag symptoms (averaged across days 1 and 2). RESULTS: A total of 427 participants received armodafinil at 50 mg/d (n=142), armodafinil at 150 mg/d (n=143), or placebo (n=142). Armodafinil at 150 mg/d provided a significant benefit in sleep latency on the MSLT (days 1-2: mean, 11.7 minutes vs 4.8 minutes for placebo; P<.001) and participants' perception of their overall condition in relation to jet lag symptoms (Patient Global Impression of Severity, days 1-2: mean, 1.6 vs 1.9 for placebo; P<.05). The most frequently reported adverse events for armodafinil at 150 mg/d were headache (27%), nausea (13%), diarrhea (5%), circadian rhythm sleep disorder (5%), and palpitations (5%). CONCLUSION: Armodafinil increased wakefulness after eastward travel through 6 time zones. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00758498.

Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel.

OBJECTIVE: Ramelteon, an MT(1)/MT(2) melatonin receptor agonist, was evaluated for its ability to reduce sleep-onset difficulties associated with eastward jet travel. METHODS: Healthy adults (n=110) with a history of jet lag sleep disturbances were flown eastward across five time zones from Hawaii to the east coast of the US. Ramelteon 1, 4, or 8 mg or placebo was administered 5 min before bedtime (local time) for four nights. Sleep parameters were measured using polysomnography (PSG) on Nights 2, 3, and 4. Next-day residual effects were assessed using psychomotor and memory function tests. RESULTS: Compared to placebo, there was a significant decrease in mean latency to persistent sleep (LPS) on Nights 2-4 with ramelteon 1mg (-10.64 min, P=0.030). No consistent significant differences were observed with ramelteon vs. placebo on measures of next-day residual effects except on Day 4 where participants in all ramelteon groups performed significantly worse on the immediate memory recall test compared with placebo (P < or = 0.05). The incidence of adverse events was similar for ramelteon and placebo. CONCLUSION: After a 5-h phase advance due to eastward jet travel, ramelteon 1mg taken before bedtime for four nights reduced mean LPS relative to placebo in healthy adults.