Advanced Sleep Phase Syndrome Research Articles

Impact of an Individually Tailored Light Mask on Sleep Parameters in Older Adults With Advanced Phase Sleep Disorder

ABSTRACTObjective: This study investigated whether light delivered through the eyelids of sleeping persons might create phase delay in older adults who are adversely affected by advanced sleep phase disorder. Participants: Thirty-two cognitively intact, community-dwelling participants aged ≥ 50 years (20 females, 12 males) with Pittsburgh Sleep Quality Index scores ≥ 5 (poor sleep) completed the study. Methods: This within-subjects, randomized, two-treatment crossover design study exposed participants to an active “blue” (λmax = 480 nm) lighting intervention or a placebo “red” (λmax = 640 nm) control through closed eyelids during sleep for 8 weeks. Conditions were administered 1 hr after bedtime using custom-built light masks delivering a train of 2-s duration light pulses presented every 30 s for ≤ 2 hr (approximately 240 pulses/night). Dependent variables were subjective measures of sleep and depression (questionnaires) and objective measures of sleep (wrist actigraphy), analyzed using linear mixed models with treatment, period, and carryover as fixed effects. Results: The actigraphy analysis found no effect of the intervention or the control condition on sleep start time, total sleep time, number of sleep bouts, or sleep efficiency, either compared to baseline or to one another. Subjective responses of study participants, however, indicated statistically significant (p < 0.05) improvement in seven of eight reported measures of sleep quality with both the intervention and the control condition, but no difference between the two conditions. Conclusions: The participants reported improvement in sleep quality, but the intervention did not confer additional advantages after adjusting for period and carryover effects.

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.

Le traitement par la lumière des troubles circadiens du rythme veille-sommeil

Phototherapy is one treatment of circadian sleep-wake disorders, which is based on consensual and numerous scientific and clinical evidences. Phototherapy efficiency depends on several light characteristics based on intensity, length of exposure, time of exposure and wavelength. Phototherapy is potentially indicated in the following circadian disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), jet-lag and night-shift work sleep-wake disorders (NSSWD). Phototherapy, acting via the retina, may be avoided in patients with retina disorders, an ophthalmologist should be consulted.

Sleep problems in adults with autism spectrum disorder and intellectual disability

Sleep problems (SP) are recognized as a common comorbid condition in autism spectrum disorder (ASD) and can influence core autism symptoms and mental and physical health. SPs can be lifelong and have been reported that adults on the autistic spectrum with and without intellectual disability (ID) present SPs (longer sleep latency, frequent night awakenings, and circadian rhythm sleep-wake disorders). A prospective, objective sleep study was conducted in 41 adults with ASD (33 ± 6 years old) and ID and 51 typically developing adults (33 ± 5 years old) using ambulatory circadian monitoring (ACM) recording wrist temperature, motor activity, body position, sleep, and light intensity. The findings indicated that individuals with ASD presented sleep difficulties including low sleep efficiency, prolonged sleep latency and increased number and length of night awakenings, together with daily sedentary behavior, and increased nocturnal activity. Furthermore, indications of an advanced sleep-wake phase disorder were found in these autistic adults. Examining sleep and markers of the circadian system showed significant differences between adults with ASD and ID and an age-matched, healthy adult population. The sleep disturbances described for this sample of adults with ASD and ID are similar to those of already described for adults with ASD without ID; their relationship with intellectual ability should be further studied. Improving knowledge of sleep patterns in ASD adults with ID might help to designed targeted interventions to improve their functioning and reduce family stress. Autism Research 2019, 12: 66-79. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: SPs are very frequent in autism from childhood to adulthood. We recorded sleep with a watch-like device in adults with autism and ID and compared sleep patterns with nonautistic volunteers. Results showed poorer sleep conditions in adults with autism (increased sleep latency and number/length of night awakenings) that resulted in decreased sleep efficiency. Increasing knowledge of the SPs in adults on the autism spectrum will allow to improve their and their families' quality of life.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Circadian Rhythm Sleep-Wake Disorders.

The endogenous circadian rhythms are one of the cardinal processes that control sleep. They are self-sustaining biological rhythms with a periodicity of approximately 24 hours that may be entrained by external zeitgebers (German for time givers), such as light, exercise, and meal times. This article discusses the physiology of the circadian rhythms, their relationship to neurologic disease, and the presentation and treatment of circadian rhythm sleep-wake disorders. Classic examples of circadian rhythms include cortisol and melatonin secretion, body temperature, and urine volume. More recently, the impact of circadian rhythm on several neurologic disorders has been investigated, such as the timing of occurrence of epileptic seizures as well as neurobehavioral functioning in dementia. Further updates include a more in-depth understanding of the symptoms, consequences, and treatment of circadian sleep-wake disorders, which may occur because of extrinsic misalignment with clock time or because of intrinsic dysfunction of the brain. An example of extrinsic misalignment occurs with jet lag during transmeridian travel or with intrinsic circadian rhythm sleep-wake disorders such as advanced or delayed sleep-wake phase disorders. In advanced sleep-wake phase disorder, which is most common in elderly individuals, sleep onset and morning arousal are undesirably early, leading to impaired evening function with excessive sleepiness and sleep-maintenance insomnia with early morning awakening. By contrast, delayed sleep-wake phase disorder is characterized by an inability to initiate sleep before the early morning hours, with subsequent delayed rise time, leading to clinical symptoms of severe sleep-onset insomnia coupled with excessive daytime sleepiness in the morning hours, as patients are unable to "sleep in" to attain sufficient sleep quantity. Irregular sleep-wake rhythm disorder is misentrainment with patches of brief sleep and wakefulness spread throughout the day, leading to unstable sleep and waking behavioral patterns and an entirely idiosyncratic sleep-wake schedule. Familiarity with these major circadian rhythm sleep-wake disorder phenotypes and their overlap with other neurologic disorders is essential for the neurologist so that clinicians may intervene and improve patient functioning and quality of life.

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK.

The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α.

Can dim light melatonin onset be predicted by the timing of sleep in patients with possible circadian sleep-wake rhythm disorders?

Dim Light Melatonin Onset (DLMO) is a reliable marker of the endogenous circadian rhythm. To determine if sleep timing can predict DLMO, we investigated the relationship between sleep timing and DLMO in patients in various circadian sleep-wake rhythm disorders (CSWRDs), ages and genders. We found that correlations were only moderate between DLMO and sleep-onset in the complete data-set, but they increased in patients with delayed sleep-wake phase disorder (DSWPD), DSWPD patients with a regular sleep pattern and patients with advanced sleep-wake phase disorder (ASWPD); the levels of correlation were r = 0.542, 0.657, 0.728 and 0.814, respectively. In DSWPD patients with a regular sleep pattern, mid-sleep strongly correlated (r = 0.839) with DLMO. Correlation in other CSRWDs was not significant. DLMO, sleep-onset and age were most discriminated factors between the various CSRWDs. Estimation of DLMO is only possible in patients with ASWPD and in DSWPD patients with a regular sleep pattern.

Natural Variation in Human Clocks.

Our own species has a diurnal activity pattern and an average circadian period of 24.2h. Exact determination of circadian period requires expensive and intrusive protocols, and investigators are therefore using chronotype questionnaires as a proxy quantitative measure. Both measures show a normal distribution suggestive of a polygenic trait. The genetic components of the 24-h feedback loop that generates circadian rhythms within our cells have been mapped in detail, identifying a number of candidate genes which have been investigated for genetic polymorphisms relating to the phenotypic variance. Key in this mechanism is the inhibitory complex containing period and cryptochrome proteins and interacting protein kinases and ubiquitin ligases, and the stability of this complex is recognized as the major determinant of circadian periodicity. The identification of the causative mutations in familial circadian rhythms sleep disorders has shed additional light into this mechanism. Mutations in the negative feedback protein-encoding genes PER2 and CRY2 as well as the CSNK1D gene encoding casein kinase I delta have been shown to cause advanced sleep phase disorder, and a mutation in the CRY1 gene delayed sleep phase disorder. The candidate gene approach has also yielded a number of genetic associations with chronotype as determined by questionnaires. More recently, genome-wide association studies of chronotype have both confirmed associations with the candidate clock gene PER2 and identified a serious of novel genes associated with variability in circadian rhythmicity, which have yet to be explored. While considerable progress has thus been made with mapping the phenotypic diversity in human circadian rhythms and the genomic variability that causes it, studies to date have been mostly focused on individuals of European descent, and there is a strong need for research on other populations.

Rigid Cooperation of Per1 and Per2 proteins.

Period circadian clock (Per) genes Per1 and Per2 have essential roles in circadian oscillation. In this study, we identified a new role of Per1-Per2 cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of Per1 and Per2 knockout mice depended on the copy number ratio of Per1:Per2. We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both Per1(−/−) and Per2(−/−) mice were entrained to a broader range of period length than wild-type mice. To analyse Per1-Per2 cooperative roles at the cell culture level, we established a Per2 knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the Per1 coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to “circa” 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium.

Pathophysiology and strategic treatment of sighted non-24-h sleep–wake rhythm disorders

Non-24-h sleep–wake rhythm disorder (N24SWD) is one type of circadian rhythm sleep–wake disorder. Once developed, N24SWD causes occupational and social dysfunction due to its early onset, long-term morbidity, and intractable nature, imposing a huge burden on individuals with the disorder. N24SWD is highly prevalent in blind individuals who have had no photic entrainment. The pathophysiology of sighted N24SWD in individuals with no visual impairment is unclear, but as a concept, impaired entrainment to the 24-h day–night cycle or abnormality in the free-running period (τ) was thought to be the cause of N24SWD. A recent study using a strict forced desynchrony protocol revealed prolonged τ in sighted N24SWD patients. In contrast, some evening chronotypes are able to entrain to the 24-h-day cycle despite having similarly prolonged τ. Therefore, the onset of N24SWD could be reasonably explained by the multiple-hit hypothesis, which proposes that disease onset requires the coexistence of multiple vulnerabilities, such as prolonged τ, abnormal photosensitivity, overexposure to ambient light in the delay zone of the phase response curve, and psychiatric problems. The application of a molecular genetic approach similar to that used in the study of advanced sleep–wake phase disorder is difficult because of the absence of familial occurrence in most sighted N24SWD patients. However, a different experimental approach such as whole-exome analysis of individual cases may be useful for clarifying the molecular basis underlying the onset of sighted N24SWD.

Sleeping Laboratory: Intelligent Glass And Sensor Technology In Real Time Medical Environment.

Sleep studies are used to evaluate and diagnose a variety of sleep problems. A sleep study is very potential in controlling neurological, breathing and movement disorders. Some of the problems that may lead doctor to order a sleep study are snoring, sleep apnea, sleep walking, bedwetting, sleep talking, the feeling of being tired all day, sleeping during a day. A sleeping laboratory can detect these interruptions, analyse and record detailed information to help doctor diagnose problem and determine the best treatment. Light therapies and simulation of day-night environment have been recognized that can stabilize the patterns of delayed sleep phase syndrome and advanced sleep phase syndrome. In this paper we present sleeping laboratory based on smart glass controlled automatically by sensors, ccd camera and real-time pattern recognition environment. We present sensor network and real-time multiparametric algorithms sending signals to intelligent glass controller. For classification we used fast SVM classifier with new kernel method. Historical medical database is used as training set for automated classifier.

Migraine genetics: New opportunities, new challenges

As migraine runs in families and has a strong genetic component, many investigations have aimed to identify the genetic factors that confer susceptibility to this disease. Initial studies of rare monogenic migraine disorders led to the identification of the first migraine genes (1). Specific mutations in the genes CACNA1A, ATP1A2 and SCN1A, which all encode subunits of ion transporters that play a part in neurotransmission, have been identified for familial hemiplegic migraine, an autosomal dominant subtype of migraine with aura characterized by a transient hemiparesis during the aura. Genes with an apparent vascular function were identified by studying monogenic diseases in which migraine is prominent, such as NOTCH3 in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and CSNK1D in familial advanced sleep phase syndrome. As a result of a recent technical revolution in the way DNA analyses are performed, which allows costeffective massive genotyping in large cohorts of many thousands of patients, it is now feasible to identify causal genetic variants for common polygenic disorders. This technical breakthrough has led to what is often referred to as the genome-wide association study (GWAS) era. As a consequence, in the last decade, numerous GWASs have been performed, which have led to the discovery of thousands of genes and gene variants for hundreds of traits, including various common neurological diseases (2). An essential factor for a GWAS to be successful in migraine was the fact that clinicians and geneticists with an interest in migraine organized themselves in the International Headache Genetics Consortium (IHGC) (http:// www.headachegenetics.org/). The IHGC connects no less than 34 research groups from 12 countries from Europe, the USA and Australia and brings together an ever-increasing wealth of well-characterized genetic information and high-quality diagnostic data, as well as analysis expertise, to discover the basis for future treatments of migraine and other headache disorders. The success of IHGC’s gene discovery efforts is evident from four GWASs that investigated over 23,000 patients and hundreds of thousands of control subjects. Migraine-associated single nucleotide polymorphisms (SNPs) were identified in 13 loci and the assigned genes suggest the involvement of vascular (C7orf10, PHACTR1, TGFBR2) and neuronal (ASTN2, FHL5, LRP1, MEF2D, MMP16, MTDH, PHACTR1, PRDM16) pathways, as well as metalloproteinases (AJAP1, MMP16, TSPAN2) and a pain nociceptor (TRPM8) in migraine pathophysiology (3–6). As the identified gene variants, without exception, have small effect sizes (odds ratio< 1.2), a legitimate question is whether they will really further our understanding of migraine pathophysiology and have practical clinical applications. This special issue of Cephalalgia contains reviews that present recent findings and viewpoints on how genetic data can be used in research and the clinic. In addition, it contains several studies with original data, most of which were initiated by the IHGC, which address issues related to, for example, the genetic architecture of migraine subtypes, gene variants in relation to drug response and disease pathophysiology. The review by Chasman et al. (7) discusses the importance of the appropriate ascertainment of the migraine status of individual patients enrolled in genetic studies. Challenges and solutions in diagnosing patients in very large population-based cohorts and how this is different from clinic-based cohorts, where clinical information is, in general, more detailed, are extensively discussed. Because an increase in sample

Animal models of monogenic migraine.

Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine.

Researchers Uncover Genetic Link Between Sleep, Seasonal Depression

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessResearchers Uncover Genetic Link Between Sleep, Seasonal DepressionNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:15 Apr 2016https://doi.org/10.1176/appi.pn.2016.4a17AbstractAnalysis of a family with a history of advanced sleep phase disorder and seasonal affective disorder points to the role of the gene PER3 in both conditions.Researchers have long recognized that sleep and mood go hand in hand; patients with depression often experience too much or too little sleep, and sleep deprivation can alter mood. Yet, the molecular basis of this connection has remained unknown.iStock/spfdigitalA research team at the University of California, San Francisco (UCSF), recently identified a gene that they believe could provide a link between sleep and mood regulation. The researchers found a mutation in a critical circadian gene called PERIOD3 (PER3) when analyzing the genomes of several members of an extended family with high rates of seasonal affective disorder (SAD) and familial advanced sleep phase disorder (FASP)—a condition in which people have an accelerated biological clock (that is, slightly less than 24 hours).“People with this disorder would naturally drift in time, going to bed and waking up a little earlier each day,” explained study coauthor Louis Ptáček, M.D., a professor of neurology at the UCSF School of Medicince. “Obviously, the constraints of human society do not allow for that, and that leads to poor sleep behaviors.” In turn, noted Ptáček, the lack of quality sleep can lead to many physical and mental problems. To understand how PER3 affects circadian rhythm and mood, the researchers engineered a strain of mice with the PER3 mutation. When exposed to a normal light-dark cycle (12 hours of light, 12 hours of darkness), the mice with the PER3 mutation behaved similarly to mice without the mutation. However, when the mice were exposed to light for only four hours and darkness for 20 hours, the mice started showing delays in their regular routines of activity and rest compared with control animals under the same conditions. The PER3 mutant mice also showed more depression-like symptoms than mice without the mutation during the periods of extended darkness, as observed in the tail suspension test (the mice with the PER3 mutation spent more time immobile). Treating the animals with the antidepressant imipramine led to a decrease in the depressive-like symptoms.Ying-Hui Fu, Ph.D., a neurology professor at UCSF and coauthor of the study, told Psychiatric News that the role of the period gene family in circadian disorders has been studied for a while, but few paid much attention to PER3.“Evolutionarily, PER3 is just a little different from PER1 and PER2, which are the key components of the 24-hour clock. When PER3 is knocked out in mice, the circadian disruptions are not as strong as with those other two genes, so it has been somewhat ignored,” she said.“But this discovery suggests that while PER3 may not be as critical on the sleep side, it might be a nexus connecting sleep and mood,” she continued. Their findings were published February 22 in the Proceedings of the National Academy of Sciences.While the PER3 mutation has been identified in only one family to date, Ptáček believes that this work holds broader significance; he pointed out that genomewide studies looking for depression risk factors among the general population have repeatedly identified genetic polymorphisms, or variants, near the PER3 region. “No one has been able to prove that these variants specifically affected PER3, but with our new data, the findings from these genomewide studies suddenly become more believable,” he said.This work was supported by multiple grants from the National Institutes of Health. ■An abstract of “A PERIOD3 Variant Causes a Circadian Phenotype and Is Associated With a Seasonal Mood Trait” can be accessed here. ISSUES NewArchived

The Diagnosis and Treatment of Circadian Rhythm Disorders

Event Abstract Back to Event The Diagnosis and Treatment of Circadian Rhythm Disorders Leon C. Lack1* 1 Flinders University, Australia Sleepiness is determined biologically by two comparable but independent factors: homeostatic sleep drive and circadian rhythm sleep drive. The circadian sleepiness varies with a host of synchronised endogenous physiological and hormonal rhythms across the 24-hour period. Normal entrainment of this circadian system favours sleep at night (aprox. 2300-0700h) and alertness/productivity during the day. However, abnormalities of the circadian system in timing or amplitude can cause chronic or short term difficulties sleeping when desired and being alert when necessary. Delayed sleep phase disorder (DSPD) results from a 2-6 hour delay from normal of the circadian system making it impossible to initiate sleep before 0100h. Advanced sleep phase disorder (ASPD) results from an abnormally early timed circadian system making it impossible to maintain sleep past 0300h. Free-running rhythms do not remain stable in the 24-hour period but tend to drift later making night-time sleep and daytime alertness difficult for periods of days or weeks. Jet-lag and shiftwork usually produce short-lived sleep/wake problems. Since the most common disorders are from abnormal timing of the circadian system, tools to re-time circadian rhythms such as retinal light stimulation and exogenous melatonin administration can be used to treat these disorders. Light intensity, duration, and wavelength are important dimensions for treatment effect. However, the timing of light is critical for the effectiveness of these treatments. Bright light stimulation pushes the endogenous sleep period away from it like similar poles on a bar magnet (e.g. south/south) while the time of melatonin administration pulls the endogenous sleep period towards it like two opposite magnetic poles (e.g. north/south). The ‘push’ and ‘pull’ effects can be combined to shepherd the endogenous sleep period into the desired time (e.g. 2300-0700h). Other behavioural procedures and cognitive therapies can also be helpful in the treatment of these problematic circadian rhythm disorders. Keywords: Circadian Rhythm, Sleep, Sleep Disorders, delayed sleep phase syndrome, advanced sleep phase disorder, Circadian rhythm disorder Conference: ASP2016 - The 26th Annual Meeting of the Australasian Society for Psychophysiology, Adelaide Australia, Adelaide,SA, Australia, 12 Dec - 14 Dec, 2016. Presentation Type: Oral Presentation Topic: Abstract (general) Citation: Lack LC (2016). The Diagnosis and Treatment of Circadian Rhythm Disorders. Conference Abstract: ASP2016 - The 26th Annual Meeting of the Australasian Society for Psychophysiology, Adelaide Australia. doi: 10.3389/conf.fnhum.2016.221.00001 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Nov 2016; Published Online: 05 Dec 2016. * Correspondence: Prof. Leon C Lack, Flinders University, Adelaide, Australia, leon.lack@flinders.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Leon C Lack Google Leon C Lack Google Scholar Leon C Lack PubMed Leon C Lack Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

From migraine genes to mechanisms.

Migraine is a common multifactorial episodic brain disorder with strong genetic basis. Monogenic subtypes include rare familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, familial advanced sleep-phase syndrome (FASPS), and retinal vasculopathy with cerebral leukodystrophy. Functional studies of disease-causing mutations in cellular and/or transgenic models revealed enhanced (glutamatergic) neurotransmission and abnormal vascular function as key migraine mechanisms. Common forms of migraine (both with and without an aura), instead, are thought to have a polygenic makeup. Genome-wide association studies have already identified over a dozen genes involved in neuronal and vascular mechanisms. Here, we review the current state of molecular genetic research in migraine, also with respect to functional and pathway analyses. We will also discuss how novel experimental approaches for the identification and functional characterization of migraine genes, such as next-generation sequencing, induced pluripotent stem cell, and optogenetic technologies will further our understanding of the molecular pathways involved in migraine pathogenesis.

PER1 Phosphorylation Specifies Feeding Rhythm in Mice

Organization of circadian behavior, physiology, and metabolism is important for human health. An S662G mutation in hPER2 has been linked to familial advanced sleep-phase syndrome (FASPS). Although the paralogous phosphorylation site S714 in PER1 is conserved in mice, its specific function in circadian organization remains unknown. Here, we find that the PER1S714G mutation accelerates the molecular feedback loop. Furthermore, hPER1S714G mice, but not hPER2S662G mice, exhibit peak time of food intake that is several hours before daily energy expenditure peaks. Both the advanced feeding behavior and the accelerated clock disrupt the phase of expression of several key metabolic regulators in the liver and adipose tissue. Consequently, hPER1S714G mice rapidly develop obesity on a high-fat diet. Our studies demonstrate that PER1 and PER2 are linked to different downstream pathways and that PER1 maintains coherence between the circadian clock and energy metabolism.

Circadian Rhythms in Health and Disease

Circadian rhythms refer to the regulation of physiology in a 24-hour cycle and are involved in our sleep-wake cycle, core body temperature, hormone secretion, hunger, mood, and more. Circadian rhythm disorders arise from a misalignment of the timing of our circadian rhythms regulated by the suprachiastmatic nucleus (SCN) and the normal sleep-wake times required to meet the demands of our daily routines. The biological markers of circadian rhythm are melatonin levels and core body temperature, although diagnosing circadian rhythm disorders is done mainly by clinical history, sleep logs, and actigraphy. Delayed sleep phase syndrome, non-24-hour sleep wake disorder, advanced sleep phase syndrome, shift work sleep disorder, and jet lag are the circadian rhythms disorders discussed in this review. Treatments for these including melatonin, light therapy, chronotherapy, and pharmacotherapy are reviewed for each. Additional studies are needed to better determine the optimal timing and dosing for melatonin for circadian rhythm disorders and for insomnia.

Genetic and Immunologic Aspects of Sleep and Sleep Disorders

The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis.