Non-24-hour sleep–wake disorder

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Non-24-hour sleep–wake disorder
Other names Hypernychthemeral syndrome, free-running disorder
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Progressively shifting nighttime
Complications None if sleeping according to biological clock, sleep deprivation otherwise
DurationLifetime
CausesBlindness for the blind, unknown cause for the sighted
Diagnostic method Sleep diary, actigraphy
Treatment Medication
Medication Tasimelteon, melatonin
Frequency50–70% of totally (without light perception) blind people, less prevalent in sighted

Non-24-hour sleep–wake disorder (non-24, [1] N24SWD, [2] or N24) is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising daily delays in sleep onset and wake times in an individual living in a society". [3] Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although, this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, [4] it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. [2] The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015. [2] [5]

Contents

People with non-24 experience daily shifts in the circadian rhythm such as peak time of alertness, body temperature minimum, metabolism and hormone secretion. These shifts do not align with the natural light–dark cycle. Non-24-hour sleep–wake disorder causes a person's sleep–wake cycle to move around the clock every day, to a degree dependent on the length of the cycle. This is known as free-running sleep. [6]

People with the disorder may have an especially hard time adjusting to changes in "regular" sleep–wake cycles, such as vacations, stress, evening activities, time changes like daylight saving time, travel to different time zones, illness, medications (especially stimulants or sedatives), changes in daylight hours in different seasons, and growth spurts, which are typically known to cause fatigue. They also show lower sleep propensity after total sleep deprivation than do normal sleepers. [7]

Non-24 can begin at any age, not uncommonly in childhood. It is sometimes preceded by delayed sleep phase disorder. [8]

Most people with this disorder find that it severely impairs their ability to function in school, in employment, and in their social lives. Typically, they are "partially or totally unable to function in scheduled activities on a daily basis, and most cannot work at conventional jobs". [3] Attempts to keep conventional hours by people with the disorder generally result in insomnia (which is not a normal feature of the disorder itself) and excessive sleepiness, [3] to the point of falling into microsleeps, as well as myriad effects associated with acute and chronic sleep deprivation. People with non-24 who force themselves to live to a normal workday "are not often successful and may develop physical and psychological complaints during waking hours, i.e. sleepiness, fatigue, headache, decreased appetite, or depressed mood. Patients often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school." [7]

In blind people

It has been estimated that non-24 occurs in more than half of all people who are totally blind. [2] [9] [10] The disorder can occur at any age, from birth onwards. It generally follows shortly after loss or removal of a person's eyes, [11] as the photosensitive ganglion cells in the retina are also removed. [12]

Without light to the retina, the suprachiasmatic nucleus (SCN), located in the hypothalamus, is not cued each day to synchronize the circadian rhythm to the 24-hour social day, resulting in non-24 for many totally blind individuals. [9] Non-24 is rare among visually impaired patients who retain at least some light perception. Researchers have found that even minimal light exposure at night can affect the body clock. [13]

Symptoms

People with this disorder might find it difficult to follow a regular clock scheme, as their biological clock can shift so much that they are sleepy during the day and experience insomnia during night. [2] Another common diagnostic feature is the cyclical nature of non-24: people will experience certain periods, whether they be weeks or months, of sleeping during the day (symptomatic periods) that alternate with periods of sleeping during normal nighttime hours (asymptomatic periods).

Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include: [14]

Causes

The possible causes of non-24-hour sleep-wake disorder are 2-fold: (1), extrinsic: isolation from daily light cycles (such as working in an environment completely devoid of natural lighting); and (2), intrinsic: where some condition, such as blindness or malfunctioning biochemical response to light in the subject, prevent normal levels of light-activated melatonin release. [19] Melatonin is responsible for sleep regulation, and its release is controlled by the amount of light entering the eyes. [20]

Sighted

Sighted people with non-24 appear to be more rare than blind people with the disorder, and the etiology of their circadian disorder is less well understood. [21] At least, one case of a sighted person developing non-24 was preceded by head injury; [22] another patient diagnosed with the disorder was later found to have a "large pituitary adenoma that involved the optic chiasma". [3] Thus, the problem appears to be neurological. Specifically, it is thought to involve abnormal functioning of the suprachiasmatic nucleus (SCN) in the hypothalamus. [23] Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder. [21] "Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy". [8] According to the American Academy of Sleep Medicine (AASM), "patients with free-running (FRD) rhythms are thought to reflect a failure of entrainment". [24]

There have been several experimental studies of sighted people with the disorder. McArthur et al. reported treating a sighted patient who "appeared to be subsensitive to bright light". [25] In other words, the brain (or the retina) does not react normally to light (people with the disorder may or may not, however, be unusually subjectively sensitive to light; one study found that they were more sensitive than the control group [7] ). In 2002 Uchiyama et al. examined five sighted non-24 patients who showed, during the study, a sleep–wake cycle averaging 25.12 hours. [26] That is appreciably longer than the 24.02-hour average shown by the control subjects in that study, which was near the average innate cycle for healthy adults of all ages: the 24.18 hours found by Charles Czeisler. [27] The literature usually refers to a "one- to two-hour" delay per 24-hour day (i.e. a 25- to 26-hour cycle). [28]

Uchiyama et al. had earlier determined that sighted non-24 patients' minimum core body temperature occurs much earlier in the sleep episode than the normal two hours before awakening. They suggest that the long interval between the temperature trough and awakening makes illumination upon awakening virtually ineffective, [29] as per the phase response curve (PRC) for light.

In their clinical review in 2007, Okawa and Uchiyama reported that people with non-24 have a mean habitual sleep duration of nine to ten hours and that their circadian periods average 24.8 hours. [7]

Blind

As stated above, the majority of patients with non-24 are totally blind. The failure of entrainment is explained by the loss of photic input to the circadian clock. Non-24 is rare among visually impaired patients who retain at least some light perception; even minimal light exposure can synchronize the body clock. [13] A few cases have been described in which patients are subjectively blind, but are normally entrained and have an intact response to the suppressing effects of light on melatonin secretion, indicating preserved neural pathways between the retina and hypothalamus. [30] [31]

Circadian rhythm

All living animals have an internal clock, the circadian rhythm, which is close to 24 hours' duration. For humans, the average duration is 24 hours and 20 minutes, and individually some people have more or less than 24 hours. Everyday exposure to the morning light resets the circadian rhythm to 24 hours, so that there is no drifting. [32]

However, people with non-24 have a circadian rhythm significantly longer (or, rarely, shorter) than 24 hours. [3] This makes it difficult to reset to 24 hours daily, just like it is difficult for people with a rhythm close to 24 hours to try to reset to 25 hours daily. [33] [34] The majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of light (photic) input to reset the circadian clock. Their brains may have normal circadian clocks that do not receive input from the eyes about environmental light levels, as the clocks require a functioning retina, optic nerve, and visual processing center. This makes the sleep pattern variable from one day to the next, with different wake-up time and bedtime every day. [3] [32]

People with a circadian rhythm that is quite near to 24 hours may be able to sleep on a conventional, socially acceptable schedule, that is, at night. Others, with a "daily" cycle upwards of 25 hours or more, may need to adopt a sleep pattern that is congruent with their free-running circadian clock, by daily shifts in their sleep times, which often results in satisfactory sleep but with negative social and occupational consequences. [35]

The disorder also occurs in sighted people for reasons that are not well understood. Their circadian rhythms are not normal, often running to more than 25 hours. Their visual systems may function normally but their brains are incapable of making the large adjustment to a 24-hour schedule.[ citation needed ]

Though often referred to as non-24, for example by the FDA, [36] the disorder is also known as non-24-hour sleep–wake syndrome or disorder, [3] free-running disorder (FRD), [37] hypernychthemeral syndrome, [38] [37] hypernychthemeral sleep-wake cycle disturbance, [39] circadian rhythm sleep disorder—free-running type or nonentrained type, [37] non-24-hour circadian rhythm disorder. or just N24 for short in everyday speech.

The disorder is an invisible disability that can be "extremely debilitating in that it is incompatible with most social and professional obligations". [8]

Mechanisms

The internal circadian clock, located in the hypothalamus of the brain, generates a signal that normally is slightly longer (occasionally shorter) than 24 hours, on average 24 hours and 11 minutes. [27] This slight deviation is, in almost everyone, corrected by exposure to environmental time cues, especially the light–dark cycle, which reset the clock and synchronize (entrain) it to the 24-hour day. Morning light exposure resets the clock earlier, and evening exposure resets it later, thereby bracketing the rhythm to an average 24-hour period. If people who do not have non-24-hour sleep-wake disorder are deprived of external time cues (living in a cave or artificial time-isolated environment with no light), their circadian rhythms will "free-run" with a cycle of a little more (occasionally less) than 24 hours, expressing the intrinsic period of each individual's circadian clock. The circadian rhythms of individuals with non-24 can resemble those of experimental subjects living in a time-isolated environment even though they are living in normal society.[ citation needed ]

The circadian clock modulates many physiological rhythms. [15] The most easily observed of these is the propensity for sleep and wake; thus, people with non-24 experience symptoms of insomnia and daytime sleepiness (similar to "jet lag") when their endogenous circadian rhythms drift out of synchrony with the social/solar 24-hour day, but they conform to a conventional schedule. Eventually, their circadian rhythms will drift back into normal alignment, when symptoms temporarily resolve. Thus the overall pattern involves periodic symptoms on a weekly or monthly basis, depending on the length of the internal circadian cycle. For example, an individual with a circadian period of 24.5 hours would drift 30 minutes later each day and would be maximally misaligned every 48 days. If patients set their own schedule for sleep and wake, aligned to their endogenous non-24 period (as is the case for most sighted patients with this disorder), symptoms of insomnia and wake-time sleepiness are much reduced. However, such a schedule is incompatible with most occupations and social relationships.[ citation needed ]

The AASM suggests that non-24 might be different disorders in sighted and blind people, with different internal and external contributing factors—as these can affect treatment response, different treatments could be needed. [Notes 1] Future studies should therefore try to identify and assess these factors. [2]

Diagnosis

This disorder can have symptomatic periods, where "the time of high sleep propensity gradually shifts, such that patients experience daytime hypersomnolence and nighttime insomnia". [2]

In sighted people, the diagnosis is typically made based on a history of persistently delayed sleep onset that follows a non-24-hour pattern. Hayakawa et al. (2005) reported on the basis of 57 cases of sighted patients that the average day length was 24.9 ± 0.4 hours (with the range of 24.4–26.5). [40] [41]

Medical classification

International Classification of Sleep Disorders (ICSD)

NameCodeSourceYearCitation
Non-24-Hour Sleep–Wake Rhythm DisorderICSD-32014 [42]
Non-24-Hour Sleep–Wake Syndrome (alternatively, Non-24-Hour Sleep–Wake Disorder)780.55-2ICSD-22005 [43]
Non-24-Hour Sleep–Wake Syndrome (or Non-24-Hour Sleep–Wake Disorder)780.55-2ICSD Revised1997 [44]
Non-24-Hour Sleep–Wake Syndrome (or Non-24-Hour Sleep–Wake Disorder)780.55-2ICSD1990
Non-24-Hour Sleep–Wake SyndromeC.2.dDCSAD1979 [45]

Since 2005, the disorder has been recognized by name in the U.S. National Center for Health Statistics and the U.S. Centers for Medicare and Medicaid Services in their adaptation and extension of the WHO's International Statistical Classification of Diseases and Related Health Problems (ICD):

Since 2013, the disorder has been recognized by the American Psychiatric Association:

Treatment

Tasimelteon

The Food and Drug Administration (FDA) approved in January 2014 the melatonin agonist tasimelteon for the treatment of non-24 for blind people. This is the first FDA-approved drug for any circadian rhythm sleep disorder, since melatonin is unregulated. In the largest treatment study with non-24 patients, it was demonstrated that tasimelteon safely and effectively treated totally blind patients; entrainment occurred in 20% (8 of 40) of patients receiving the drug compared with 3% (1 of 38) receiving placebo. In a separate meta-analysis, melatonin supplementation achieved a 67% (12 of 18) entrainment rate. Studies directly comparing tasimelteon and melatonin have yet to be performed. Study authors noted that the lower rates of entrainment with tasimelteon may have been due to short duration of treatment. [2] [47]

Melatonin, light therapy and dark therapy

Phase response curves for light and for melatonin administration PRC-Light+Mel.png
Phase response curves for light and for melatonin administration

Melatonin administration 1 hour before bedtime is considered another treatment for non-24. However, it is important to note that melatonin may only treat the inability to sleep and may not help to improve the daytime sleepiness.

Light therapy, which involves a bright light exposure of thousands of lux of white light or about 400 lux of blue light on awakening to counteract the tendency for circadian rhythms to delay (similar to treatment for delayed sleep phase disorder [7] and seasonal affective disorder), is not currently recommended until more studies appear, although it has been found to be effective in some cases. [2] [48] [49] [50] This can be combined with dark therapy (or scototherapy), which involves filtering blue light (using software, screen filters or (amber-color) glasses) and preferring red-colored lights with a low amount of lux in the few hours before bedtime to avoid melatonin suppression. [51]

Both melatonin administration and light therapy work by shifting circadian rhythms according to a phase response curve (PRC), with the melatonin PRC being essentially the inverse of the light PRC. Furthermore, light can suppress melatonin secretion. [2] Both have a duration of approximately 12 hours, in opposite phase: light PRC spikes at the beginning of the day and lowers throughout the day with a depression after 8 hours for the last 4 hours, whereas natural melatonin spikes at the start of the biological night and drops around the time of waking up or light perception. The first 8 hours are called the "advance zone" whereas the last few hours the "delay zone". The change from advancement to delay zones is progressive, passing through a long area of no effect (a "dead zone"), but the change from delay to advancement is abrupt, occurring a few hours before wake-up time or bedtime for light or melatonin respectively. When melatonin supplementation is taken in the melatonin PRC advance zone (i.e., the last few hours before bedtime), it resets the clock earlier; when taken in the melatonin PRC delay zone (i.e., few hours before and after wake-up time), it shifts the clock later. In other words, melatonin has most effect when it is taken at times when natural melatonin is not normally present, thus during the day: when taken in the morning, melatonin causes phase delays (shifts to a later time), and when taken in the afternoon/evening it causes phase advances (shifts to an earlier time). However, for a sleep phase delayed person, the time of biological morning and biological afternoon/evening might differ depending on the circadian clock shift in the affected person. This means that if melatonin is taken during the usual bedtime and wake-up time (i.e., usual nighttime), it may have no effect. Therefore, successful entrainment depends on both the melatonin dosage and the appropriate timing of melatonin administration. The accuracy needed for successfully timing the administration of melatonin might require a period of trial and error, as does the dosage. However, entrainment was also observed when giving a dose of melatonin as low as 0.05 mg and without any timing, by just continuing melatonin administration at the same time every day until their circadian rhythm shifted enough to coincide with melatonin administration (which took from 1 to 2 months). [2] [52]

In addition to natural fluctuations within the circadian rhythm, seasonal changes including temperature, hours of daylight, light intensity and diet are likely to affect the efficacy of melatonin and light therapies since these exogenous zeitgebers would compete for hormonal homeostasis. Further to this, there are unforeseen disruptions to contend with even when a stabilized cycle is achieved, such as travel, exercise, stress, alcohol, or even the use of light-emitting technology close to a subjective evening/night.[ medical citation needed ]

Prevalence

There are an estimated 140,000 people with non-24—both sighted and blind—in the European Union, a total prevalence of approximately 3 per 10,000, or 0.03%. [53] It is unknown how many individuals with this disorder do not seek medical attention, so incidence may be higher. The European portal for rare diseases, Orphanet, lists non-24 as a rare disease by their definition: fewer than 1 affected person for every 2000 population. [38] The US National Organization for Rare Disorders (NORD) lists non-24 as a rare disease by its definition. [54]

Blind

While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect up to 70% of totally blind individuals. [2] It is estimated by researchers that of the 1.3 million blind people in the U.S., [55] 10% have no light perception at all. [30] Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, have non-24. [10]

History

In the 1980s and 1990s, several trials of melatonin administration to totally blind individuals without light perception produced improvement in sleep patterns, but it was unclear at that time if the benefits were due to entrainment from light cues. [56] [57] [58] [59] The ability of melatonin administration to entrain free-running rhythms was first demonstrated by Redman, et al. in 1983 in rats who were maintained in a time-free environment. [60] Then, using endogenous melatonin as a marker for circadian rhythms, several research groups showed that appropriately timed melatonin administration could entrain free-running rhythms in the totally blind: they found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained, and when the dose was gradually reduced to 0.5 mg in three of the subjects, entrainment persisted. [61] [62] Subsequently, it was observed that treatment initiated with the 0.5 mg dose could produce entrainment on some patients. [63] [64] Interestingly, one subject who failed to entrain at a higher dose was successfully entrained at a lower dose. [65] A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion. [7]

There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s. [66] In 2005, ramelteon (trade name Rozerem) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia treatment in adults. [67] Melatonin in the form of prolonged release (trade name Circadin) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years and older, for primary insomnia. [68] Tasimelteon (trade name Hetlioz) received FDA approval in January 2014 for blind persons diagnosed with non-24. [69] TIK-301 (Tikvah Therapeutics, Atlanta, USA) has been in phase II clinical trial in the United States since 2002 and the FDA granted it orphan drug designation in May 2004, for use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception as well as individuals with tardive dyskinesia. [70]

The first report and description of a case of non-24, a man living on 26-hour days, who happened to be sighted, was "A man with too long a day" by Ann L. Eliott et al. in November 1970. [71] The related and more common delayed sleep phase disorder was not described until 1981.

The first detailed study of non-24 in a blind subject was by Miles Le and his colleagues in 1977. The researchers reported on a 28-year-old male who had a 24.9-hour rhythm in sleep, plasma cortisol, and other parameters. Even while adhering to a typical 24-hour schedule for bedtime, rise time, work, and meals, the man's body rhythms continued to shift. [72] [73]

Research

Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing. [74] It has been suggested[ by whom? ] that there are non-photic time cues that are important for maintaining entrainment, but these cues are yet to be characterized.

Very preliminary research on light sensitivity suggest that not only insensitivity but also circadian hypersensitivity to light might be at play for patients with a delayed sleep phase disorder. [75] [76]

Society

NASA explored the potential impact on circadian rhythm and possible development of a sleep–wake disorder by human astronauts who would go on a mission to Mars, by assessing mission personnel who worked remotely on the Phoenix Mars Lander project and were asked to follow a Mars day of 24.65 hours for 78 days. [33] [34]

See also

Notes

  1. ↑ This assumes that multiple treatments exist.

Related Research Articles

Free-running sleep is a rare sleep pattern whereby the sleep schedule of a person shifts later every day. It occurs as the sleep disorder non-24-hour sleep–wake disorder or artificially as part of experiments used in the study of circadian and other rhythms in biology. Study subjects are shielded from all time cues, often by a constant light protocol, by a constant dark protocol or by the use of light/dark conditions to which the organism cannot entrain such as the ultrashort protocol of one hour dark and two hours light. Also, limited amounts of food may be made available at short intervals so as to avoid entrainment to mealtimes. Subjects are thus forced to live by their internal circadian "clocks".

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximize the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Delayed sleep phase disorder</span> Chronic sleep disorder

Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is the delaying of a person's circadian rhythm compared to those of societal norms. The disorder affects the timing of biological rhythms including sleep, peak period of alertness, core body temperature, and hormonal cycles. People with this disorder are often called night owls.

Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening sleepiness and very early morning awakening. This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

Chronotherapy is a behavioural treatment that attempts to move bedtime and rising time later and later each day, around the clock, until a person is sleeping on a normal schedule. This treatment can be used by people with delayed sleep phase disorder (DSPD), who generally cannot reset their circadian rhythm by moving their bedtime and rising time earlier. DSPD is a circadian rhythm sleep disorder, characterised by a mismatch between a person's internal biological clock and societal norms. Chronotherapy uses the human phase response to light or melatonin. The American Academy of Sleep Medicine has recommended chronotherapy for the treatment of circadian rhythm and sleep disorders.

A phase response curve (PRC) illustrates the transient change in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received. PRCs are used in various fields; examples of biological oscillations are the heartbeat, circadian rhythms, and the regular, repetitive firing observed in some neurons in the absence of noise.

<span class="mw-page-title-main">Circadian rhythm sleep disorder</span> Family of sleep disorders which affect the timing of sleep

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this misalignment, those affected by circadian rhythm sleep disorders can fall asleep at unconventional time points in the day, or experience excessive daytime sleepiness if they resist. These occurrences often lead to recurring instances of disrupted rest and wakefulness, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.

Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT1 and MT2 control this process. Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported.

In the study of chronobiology, entrainment refers to the synchronization of a biological clock to an environmental cycle. An example is the interaction between circadian rhythms and environmental cues, such as light and temperature. Entrainment helps organisms adapt their bodily processes with the timing of a changing environment. For example, entrainment is manifested during travel between time zones, hence why humans experience jet lag.

Light effects on circadian rhythm are the response of circadian rhythms to light.

<span class="mw-page-title-main">Tasimelteon</span> Wakefulness medication

Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder. In June 2014, the European Medicines Agency (EMA) accepted an EU filing application for tasimelteon and in July 2015, the drug was approved in the European Union for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults, but not in the case of non-24 in sighted people.

Irregular sleep–wake rhythm disorder (ISWRD) is a rare form of circadian rhythm sleep disorder. It is characterized by numerous naps throughout the 24-hour period, no main nighttime sleep episode, and irregularity from day to day. Affected individuals have no pattern of when they are awake or asleep, may have poor quality sleep, and often may be very sleepy while they are awake. The total time asleep per 24 hours is normal for the person's age. The disorder is serious—an invisible disability. It can create social, familial, and work problems, making it hard for a person to maintain relationships and responsibilities, and may make a person home-bound and isolated.

Robert Leroy Sack is an American physician and researcher specializing in sleep medicine. He is certified by the American Board of Psychiatry and Neurology and the American Board of Sleep Disorders Medicine. On the faculty of the Oregon Health & Science University since 1977, he is the medical director of its Clinical Sleep Disorders Medicine Program which he developed parallel with his research on circadian rhythms.

<span class="mw-page-title-main">Charles Czeisler</span> American physician and sleep researcher

Charles Andrew Czeisler is a Hungarian-American physician and sleep and circadian researcher. He is a leading researcher and author in the fields of the effects of light on human physiology, circadian rhythms and sleep medicine.

Michael Terman is an American psychologist best known for his work in applying the biological principles of the circadian timing system to psychiatric treatments for depression and sleep disorders. This subspecialty is known as Chronotherapeutics.

Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.

Dr. Debra J. Skene is a chronobiologist with specific interest in the mammalian circadian rhythm and the consequences of disturbing the circadian system. She is also interested in finding their potential treatments for people who suffer from circadian misalignment. Skene and her team of researchers tackle these questions using animal models, clinical trials, and most recently, liquid chromatography-mass spectrometry. Most notably, Skene is credited for her evidence of a novel photopigment in humans, later discovered to be melanopsin. She was also involved in discovering links between human PER3 genotype and an extremely shifted sleep schedules categorized as extreme diurnal preference. Skene received her Bachelor of Pharmacy, Master of Science, and Ph.D. in South Africa.

<span class="mw-page-title-main">Charmane Eastman</span> American academic research scientist in chronobiology

Charmane Eastman is an American academic research scientist whose career has focused on studying circadian rhythms and their relationships to sleep, jet lag, and shift work. She has also studied winter depression, more properly known as seasonal affective disorder (SAD). Of special focus are the effects of bright light and melatonin on circadian rhythms.

In chronobiology, photoentrainment refers to the process by which an organism's biological clock, or circadian rhythm, synchronizes to daily cycles of light and dark in the environment. The mechanisms of photoentrainment differ from organism to organism. Photoentrainment plays a major role in maintaining proper timing of physiological processes and coordinating behavior within the natural environment. Studying organisms’ different photoentrainment mechanisms sheds light on how organisms may adapt to anthropogenic changes to the environment.

Elizabeth Klerman is a professor of neurology at Harvard Medical School. Her research focuses on applying circadian and sleep research principles to human physiology and pathophysiology. She also uses mathematical analysis and modeling to study human circadian, sleep, and objective neurobehavioral performance and subjective (self-reported) mood and alertness rhythms.

References

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