Advanced Sleep Phase Research Articles

Sex Difference in Sleep‐Time Preference and Sleep Need: A Cross‐Sectional Survey among Italian Pre‐Adolescents, Adolescents, and Adults

The aim of this study was to examine sex differences in sleep‐time preference by age among Italian pre‐adolescents, adolescents, and adults. The final sample consisted of 8,972 participants (5,367 females and 3,605 males) from 10 to 87 yrs of age. To assess preferred sleep habits, we considered the answers to the open‐ended questions of the Morningness‐Eveningness Questionnaire (MEQ). In agreement with previous studies, we found that sleep‐time preference started to shift toward eveningness from the age of 13 yrs. Females reached their peak in eveningness earlier (about 17 yrs of age) than males (about 21 yrs of age). Thereafter, the ideal sleep‐time preference advanced in men and women with increasing age. Females presented a more significant advanced sleep phase than males only during the years when sexual hormones are typically active. Moreover, females reported a longer ideal sleep duration than males across all age groups examined, except in over 55 yrs one. (Author correspondence: vincenzo.natale@unibo.it)

Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop

Regulation of circadian clock components by phosphorylation plays essential roles in clock functions and is conserved from fungi to mammals. In the Neurospora circadian negative feedback loop, FREQUENCY (FRQ) protein inhibits WHITE COLLAR (WC) complex activity by recruiting the casein kinases CKI and CKII to phosphorylate the WC proteins, resulting in the repression of frq transcription. On the other hand, CKI and CKII progressively phosphorylate FRQ to promote FRQ degradation, a process that is a major determinant of circadian period length. Here, by using whole-cell isotope labeling and quantitative mass spectrometry methods, we show that the WC-1 phosphorylation events critical for the negative feedback process occur sequentially-first by a priming kinase, then by the FRQ-recruited casein kinases. We further show that the cyclic AMP-dependent protein kinase A (PKA) is essential for clock function and inhibits WC activity by serving as a priming kinase for the casein kinases. In addition, PKA also regulates FRQ phosphorylation, but unlike CKI and CKII, PKA stabilizes FRQ, similar to the stabilization of human PERIOD2 (hPER2) due to the phosphorylation at the familial advanced sleep phase syndrome (FASPS) site. Thus, PKA is a key clock component that regulates several critical processes in the circadian negative feedback loop.

Circadian rhythmicity and the pharmacologic management of insomnia.

The circadian clock modulates timing of sleep and wakefulness. In certain situations, the circadian potentiation of wakefulness may interfere with desired sleep-scheduling, particularly in the elderly and shift workers. Known abnormalities of circadian regulation are defined by their impact on sleep-wake state expression. In delayed sleep phase syndrome, patients have trouble going to sleep and arising at reasonable hours and are alert in the evening and sleepy in the morning. Patients with advanced sleep phase syndrome are sleepy in the evening and awaken very early and alert in the morning. In shift-work sleep disorder, individuals attempt to wake and sleep out of phase with the circadian clock. As with jet lag, the clock is functioning normally, but the requirements on the clock are abnormal. Typical insomnia can also be associated with circadian rhythm alterations. Practice guidelines and clinical studies data are needed to lead appropriate therapy selection and effective management.

Circadian Rhythm Sleep Disorders: Part II, Advanced Sleep Phase Disorder, Delayed Sleep Phase Disorder, Free-Running Disorder, and Irregular Sleep-Wake Rhythm

This the second of two articles reviewing the scientific literature on the evaluation and treatment of circadian rhythm sleep disorders (CRSDs), employing the methodology of evidence-based medicine. We herein report on the accumulated evidence regarding the evaluation and treatment of Advamced Sleep Phase Disorder (ASPD), Delayed Sleep Phase Disorder (DSPD), Free-Running Disorder (FRD) and Irregular Sleep-Wake Rhythm ISWR). A set of specific questions relevant to clinical practice were formulated, a systematic literature search was performed, and relevant articles were abstracted and graded. A substantial body of literature has accumulated that provides a rational basis the evaluation and treatment of CRSDs. Physiological assessment has involved determination of circadian phase using core body temperature and the timing of melatonin secretion. Behavioral assessment has involved sleep logs, actigraphy and the Morningness-Eveningness Questionnaire (MEQ). Treatment interventions fall into three broad categories: 1) prescribed sleep scheduling, 2) circadian phase shifting ("resetting the clock"), and 3) symptomatic treatment using hypnotic and stimulant medications. Circadian rhythm science has also pointed the way to rational interventions for CRSDs and these treatments have been introduced into the practice of sleep medicine with varying degrees of success. More translational research is needed using subjects who meet current diagnostic criteria.

Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders

The expanding science of circadian rhythm biology and a growing literature in human clinical research on circadian rhythm sleep disorders (CRSDs) prompted the American Academy of Sleep Medicine (AASM) to convene a task force of experts to write a review of this important topic. Due to the extensive nature of the disorders covered, the review was written in two sections. The first review paper, in addition to providing a general introduction to circadian biology, addresses "exogenous" circadian rhythm sleep disorders, including shift work disorder (SWD) and jet lag disorder (JLD). The second review paper addresses the "endogenous" circadian rhythm sleep disorders, including advanced sleep phase disorder (ASPD), delayed sleep phase disorder (DSPD), irregular sleep-wake rhythm (ISWR), and the non-24-hour sleep-wake syndrome (nonentrained type) or free-running disorder (FRD). These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the AASM to present recommendations for the assessment and treatment of CRSDs based on the two accompanying comprehensive reviews. The main diagnostic tools considered include sleep logs, actigraphy, the Morningness-Eveningness Questionnaire (MEQ), circadian phase markers, and polysomnography. Use of a sleep log or diary is indicated in the assessment of patients with a suspected circadian rhythm sleep disorder (Guideline). Actigraphy is indicated to assist in evaluation of patients suspected of circadian rhythm disorders (strength of recommendation varies from "Option" to "Guideline," depending on the suspected CRSD). Polysomnography is not routinely indicated for the diagnosis of CRSDs, but may be indicated to rule out another primary sleep disorder (Standard). There is insufficient evidence to justify the use of MEQ for the routine clinical evaluation of CRSDs (Option). Circadian phase markers are useful to determine circadian phase and confirm the diagnosis of FRD in sighted and unsighted patients but there is insufficient evidence to recommend their routine use in the diagnosis of SWD, JLD, ASPD, DSPD, or ISWR (Option). Additionally, actigraphy is useful as an outcome measure in evaluating the response to treatment for CRSDs (Guideline). A range of therapeutic interventions were considered including planned sleep schedules, timed light exposure, timed melatonin doses, hypnotics, stimulants, and alerting agents. Planned or prescribed sleep schedules are indicated in SWD (Standard) and in JLD, DSPD, ASPD, ISWR (excluding elderly-demented/nursing home residents), and FRD (Option). Specifically dosed and timed light exposure is indicated for each of the circadian disorders with variable success (Option). Timed melatonin administration is indicated for JLD (Standard); SWD, DSPD, and FRD in unsighted persons (Guideline); and for ASPD, FRD in sighted individuals, and for ISWR in children with moderate to severe psychomotor retardation (Option). Hypnotic medications may be indicated to promote or improve daytime sleep among night shift workers (Guideline) and to treat jet lag-induced insomnia (Option). Stimulants may be indicated to improve alertness in JLD and SWD (Option) but may have risks that must be weighed prior to use. Modafinil may be indicated to improve alertness during the night shift for patients with SWD (Guideline).

Sleep Quality in Young Adults with Very Low Birth Weight--the Helsinki Study of Very Low Birth Weight Adults

To assess the relationship between very low birth weight (VLBW; <1,500 g) and quality and amount of sleep in young adults. We compared 89 VLBW and 78 term-born 19- to 26-year-old adults, by actigraphy and the Basic Nordic Sleep Questionnaire. There were no group differences in sleep quality or amount (p's >.15), although VLBW adults went to bed on average 36 min earlier (95% confidence interval 6-66 min). Shorter gestational age was related to longer sleep latency both within VLBW (standardized regression coefficient beta = -.36, p =.040) and term-born adults (beta = -.25, p =.029). Adults with VLBW had similar quality and amount of sleep as those born at term, although VLBW adults went to bed earlier, suggesting an advanced sleep phase. Within each group, a lower gestational age was related to a longer sleep onset.

Plasticity of the Intrinsic Period of the Human Circadian Timing System

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light (∼450 lux; ∼1.2 W/m2) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.

Beyond Intuitive Modeling: Combining Biophysical Models with Innovative Experiments to Move the Circadian Clock Field Forward

Two major approaches have been used to model circadian clocks. Qualitative modeling, used prior to the recent wealth of detailed molecular knowledge, makes general predictions but cannot provide detailed mechanistic insights. The more recent biophysical approach, on the other hand, incorporates the biochemical events that drive the clock and can make detailed and testable molecular predictions. These predictions are being tested using new experimental techniques that measure reaction kinetics and the behavior of individual cells. A joint modeling and experimental approach has recently been used to understand how mutations affecting phosphorylation can lead to a short circadian period in tau mutant hamsters and in humans with familial advanced sleep phase syndrome (FASPS). Another recent study has revealed novel single-cell phenotypes of clock gene mutations, demanding revision of current biophysical models yet validating certain model predictions that were previously overlooked. A new paradigm for clock research is emerging in which modeling inspires new experimental efforts, experimental data inspire new modeling efforts, and joint modeling/experimental studies lead to a deeper understanding of mammalian circadian rhythms.

Practice Parameters for the Use of Actigraphy in the Assessment of Sleep and Sleep Disorders: An Update for 2007

Actigraphy is increasingly used in sleep research and the clinical care of patients with sleep and circadian rhythm abnormalities. The following practice parameters update the previous practice parameters published in 2003 for the use of actigraphy in the study of sleep and circadian rhythms. Based upon a systematic grading of evidence, members of the Standards of Practice Committee, including those with expertise in the use of actigraphy, developed these practice parameters as a guide to the appropriate use of actigraphy, both as a diagnostic tool in the evaluation of sleep disorders and as an outcome measure of treatment efficacy in clinical settings with appropriate patient populations. Actigraphy provides an acceptably accurate estimate of sleep patterns in normal, healthy adult populations and inpatients suspected of certain sleep disorders. More specifically, actigraphy is indicated to assist in the evaluation of patients with advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), and shift work disorder. Additionally, there is some evidence to support the use of actigraphy in the evaluation of patients suspected of jet lag disorder and non-24hr sleep/wake syndrome (including that associated with blindness). When polysomnography is not available, actigraphy is indicated to estimate total sleep time in patients with obstructive sleep apnea. In patients with insomnia and hypersomnia, there is evidence to support the use of actigraphy in the characterization of circadian rhythms and sleep patterns/disturbances. In assessing response to therapy, actigraphy has proven useful as an outcome measure in patients with circadian rhythm disorders and insomnia. In older adults (including older nursing home residents), in whom traditional sleep monitoring can be difficult, actigraphy is indicated for characterizing sleep and circadian patterns and to document treatment responses. Similarly, in normal infants and children, as well as special pediatric populations, actigraphy has proven useful for delineating sleep patterns and documenting treatment responses. Recent research utilizing actigraphy in the assessment and management of sleep disorders has allowed the development of evidence-based recommendations for the use of actigraphy in the clinical setting. Additional research is warranted to further refine and broaden its clinical value.

A clinical approach to circadian rhythm sleep disorders

Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-h social and physical environment. In addition to physiological and environmental factors, maladaptive behaviors often play an important role in the development of many of the circadian rhythm sleep disorders. This review will focus on the clinical approach to the diagnosis and management of the various circadian rhythm sleep disorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type, irregular sleep–wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleep diaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral and environmental factors often are involved in the development of these conditions, a multimodal approach is usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as well as avoidance of bright light at the wrong time of the day and pharmacologic approaches, such as melatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication for the treatment of circadian rhythm sleep disorders.

A novel SNP inhPer2associates with diurnal preference in a healthy population

Several studies have shown that polymorphisms of clock genes are associated with diurnal preferences. We investigated whether other polymorphisms also are related to diurnal preference. Our examination targeted the region around the phosphorylation site of hPer2, as a previous report has shown that one single nucleotide polymorphism (SNP) at this site causes familial advanced sleep phase syndrome. We found three other SNPs in this region, with one synonymous SNP significantly correlated to diurnal preference in a healthy population. Although no functional relevance was predicted, this result indicates that diurnal preference in a healthy population is associated with this synonymous SNP of the hPer2 gene.

Novel Insights from Genetic and Molecular Characterization of the Human Clock

Biological rhythms govern the ebb and flow of life on planet Earth. Animals have an internal timekeeping mechanism that precisely regulates 24-hour rhythms of body function and behavior and synchronizes them to the day/night cycle. Circadian pacemakers trigger behavioral and physiological processes that dictate our daily rhythms. Despite the importance of the circadian clock to all aspects of our physiology and behavior, the opportunity to probe the human circadian clock only recently became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep phase syndrome, FASPS). We have now cloned several genes and identified mutations causing FASPS. Study of these genes and the proteins they encode and engineering of the human mutations into mouse models are allowing study of this fascinating phenotype and yielding novel insights into circadian regulation in humans. Ultimately, such work will allow us to understand the similarities and differences between the human clock and those of model organisms. In addition, recent studies have also linked disruption of the circadian clock with numerous ailments, including cancer, cardiovascular diseases, asthma, and learning disorders. Thus, studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health and disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet lag, various clock-related sleep and psychiatric disorders, and other human diseases.

Role of Phosphorylation in the Mammalian Circadian Clock

Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

Circadian Rhythms in the CNS and Peripheral Clock Disorders: Human Sleep Disorders and Clock Genes

Genetic analyses of circadian rhythm sleep disorders (CRSD), such as familial advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS), and morningness-eveningness revealed the relationship between variations in clock genes and diurnal change in human behaviors. Variations such as T3111C in the Clock gene are reportedly associated with morningness-eveningness. Two of the pedigrees of familial ASPS (FASPS) are caused by mutations in clock genes: the S662G mutation in the Per2 gene or the T44A mutation in the casein kinase 1 delta (CK1δ) gene, although these mutations are not found in other pedigrees of FASPS. As for DSPS, a missense variation in the Per3 gene is identified as a risk factor, while the one in the CK1ε gene is thought to be protective. These findings suggest that further, as yet unidentified, gene variations are involved in human circadian activity. Many of the CRSD-relevant variations reported to date seem to affect the phosphorylation status of the clock proteins. A recent study using mathematical models of circadian rhythm generation has provided a new insight into the role of phosphorylation in the molecular mechanisms of these disorders.

Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2

Circadian rhythms are endogenous oscillations of physiological and behavioral phenomena with period length of approximately 24 hr. A mutation in human Period 2 (hPER2), a gene crucial for resetting the central clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times. The FASPS hPER2 S662G mutation resulted in PER2 being hypophosphorylated by casein kinase I (CKI) in vitro. We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. Altering CKIdelta dosage modulates the S662 phenotype demonstrating that CKIdelta can regulate period through PER2 in vivo. Modeling a naturally occurring human variant in mice has yielded novel insights into PER2 regulation.

A Circadian Sleep Disorder Reveals a Complex Clock

Circadian rhythms are established by transcription of clock genes and autoregulatory transcriptional feedback loops. In this issue, Xu et al. (2007) characterize mice expressing a human Per2 mutation identified in patients with familial advanced sleep phase syndrome. Their results reveal that PER2 phosphorylation, by CK1delta and other kinases, is surprisingly complex and has opposite effects on PER2 levels and period length.

Genetic Basis for Sleep Regulation and Sleep Disorders

Sleep disorders arise by an interaction between the environment and the genetic makeup of the individual but the relative contribution of nature and nurture varies with diseases. At one extreme are the disorders with simple Mendelian patterns of inheritance such as familial advanced sleep phase syndrome, and at the other extreme are diseases such as insomnia, which can be associated with a multitude of medical and psychiatric conditions. In this article, we review data on the relative contribution of genetic and environmental factors in the pathogenesis of various sleep disorders. The understanding of many of these disorders has been advanced by the study of sleep and circadian rhythms in model laboratory organisms. We summarize this model system research and how it relates to human sleep disorders. The current challenge in this field is the identification of susceptibility genetic loci for complex diseases such as obstructive sleep apnea. We anticipate such identification will increase our ability to assess risk for disease before symptom onset and by doing so will shift the focus from treatment to prevention of disease.

Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)

PERIOD (PER) proteins are central components within the mammalian circadian oscillator, and are believed to form a negative feedback complex that inhibits their own transcription at a particular circadian phase. Phosphorylation of PER proteins regulates their stability as well as their subcellular localization. In a systematic screen, we have identified 21 phosphorylated residues of mPER2 including Ser 659, which is mutated in patients suffering from familial advanced sleep phase syndrome (FASPS). When expressing FASPS-mutated mPER2 in oscillating fibroblasts, we can phenocopy the short period and advanced phase of FASPS patients' behavior. We show that phosphorylation at Ser 659 results in nuclear retention and stabilization of mPER2, whereas phosphorylation at other sites leads to mPER2 degradation. To conceptualize our findings, we use mathematical modeling and predict that differential PER phosphorylation events can result in opposite period phenotypes. Indeed, interference with specific aspects of mPER2 phosphorylation leads to either short or long periods in oscillating fibroblasts. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster as well as the doubletime mutants (dbtS and dbtL ) in Drosophila.

睡眠障害の理解

The most frequent sleep problems are sleep-related breathing disorders, insomnia, excessive daytime sleepiness, and circadian rhythm disorder. In 2004, we treated 468 sleep disorder patients, at the Sleep Disorder Center, Shiga University of Medical Science Hospital. Forty-nine percent of the subjects were diagnosed as having sleep related breathing disorders, 22% as insomnia, 10% as rhythm disorders and 5% as having excessive daytime sleepiness. Insomnia is a common sleep-wake-related complaint, and sleeping pills are among the most commonly prescribed drugs in clinical practice. However, insomnia is a symptom that can be caused by various disorder's, many of which require specific therapies. One specific cause of insomnia in older adults is restless legs syndrome. This condition, characterized by an urge to move the legs, which is usually accompanied by sensations of discomfort and aggravations of symptoms by rest. Daytime sleepiness is a common complaint. Snoring, the use of hypnotic agents, sleep difficulties, irregular sleep-wake schedule and sleep deprivation are related to daytime sleepiness. Circadian rhythm sleep disorders have intrinsic and extrinsic subtypes: delayed sleep phase syndrome, advanced sleep phase syndrome and non-24-h sleep-wake syndrome. The underlying problem of circadian rhythm sleep disorders is that the patient cannot sleep when sleep is desired. Waking episodes may occur at inappropriate times; therefore, the patient may complain of insomnia or excessive sleepiness.

Treatment of sleep disorders in elderly patients

Sleep disorders are common among the elderly and are associated with diminished quality of life, increased risk for development of psychiatric disorders, inappropriate use of sleep aids, and decreased daytime functioning. The most common and important sleep disorders in the elderly include insomnia, obstructive sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, and the advanced sleep phase syndrome. In this article, we summarize the current treatment strategies for each of these sleep-related disorders. Before contemplating specific treatments, the authors recommend that more conservative and nonpharmacologic therapies be attempted first because the elderly are more likely to have medication side effects or complications related to surgery. Many sleep problems can be treated by simple sleep hygiene modifications that can be implemented and adopted easily. For others, therapies that specifically consider older adults may be required. For each of the sleep disorders we provide an updated discussion of therapies beginning with diet and lifestyle, pharmacologic treatment, interventional procedures, surgery, assistive devices, physical and speech therapy, exercise, and emerging therapies with specific considerations for older adults.