Melatonin (updated)

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Melatonin

Melatonin

Clinical data
Pronunciation	/ˌmɛləˈtoʊnɪn/
Trade names	Many
Other names	N-acetyl-5-methoxy tryptamine
AHFS/Drugs.com	Consumer Drug Information
License data	EU EMA: by INN
Routes of administration	By mouth, sublingual, transdermal
ATC code	N05CH01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: OTC UK: POM (Prescription only) US: Dietary supplement
Pharmacokinetic data
Bioavailability	30–50%
Metabolism	Liver via CYP1A2 mediated 6-hydroxylation
Metabolites	6-hydroxymelatonin, N-acetyl-5lhydroxytryptamine, 5-methoxytryptamine
Elimination half-life	30–50 minutes
Excretion	Kidney
Identifiers
IUPAC name[show]
CAS Number	73-31-4
PubChem CID	896
IUPHAR/BPS	224
DrugBank	DB01065
ChemSpider	872
UNII	JL5DK93RCL
KEGG	D08170
ChEBI	CHEBI:16796
ChEMBL	ChEMBL45
CompTox Dashboard (EPA)	DTXSID1022421
ECHA InfoCard	100.000.725
Chemical and physical data
Formula	C13H16N2O2
Molar mass	232.283 g·mol−1
3D model (JSmol)	Interactive image
Melting point	117 °C (243 °F)

Melatonin is a hormone that regulates the sleep–wake cycle. It is primarily released by the pineal gland. As a supplement, it is often used for the short-term treatment of trouble sleeping such as from jet lag or shift work. Evidence of benefit, however, is unclear. One review found onset of sleep occurred 6 minutes faster with use but found no change in total time asleep. It may work as well as the medication ramelteon. It is typically taken by mouth.

Side effects from supplements are minimal at low doses for short durations. Side effects may include sleepiness, headaches, nausea, diarrhea, and abnormal dreams. Use is not recommended during pregnancy or breastfeeding. Use is also not recommended in those with liver problems.

In animals (including humans), melatonin is involved in synchronizing the circadian rhythm including sleep–wake timing, blood pressure regulation, and seasonal reproduction. Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant. In plants it functions to defend against oxidative stress. Melatonin is also present in various foods.

Melatonin was discovered in 1958. It is sold over the counter in Canada and the United States. In the United Kingdom it is a prescription-only medication. A month's supply costs about US $1 to 4 in the United States. In the United Kingdom a month's supply costs the NHS about 15 pounds. It is not FDA-approved for any use. In Australia and Europe, it is approved for trouble sleeping in people over the age of 54.

Medical use

 

Sleep disorders

Positions on the benefits of melatonin for insomnia are mixed. An Agency for Healthcare Research and Quality (AHRQ) review from 2015 stated that evidence of benefit in the general population was unclear. A review from 2017 found a modest effect on time until onset of sleep. Another review from 2017 put this decrease at 6 minutes to sleep onset but found no difference in total sleep time. Melatonin may also be useful in delayed sleep phase syndrome. Melatonin appears to work as well as ramelteon but costs less.

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies. In Europe it is used for short-term treatment of insomnia in people who are 55 years old or older. It is deemed to be a first line agent in this group.

Melatonin reduces the time until onset of sleep and increases sleep duration in children with neurodevelopmental disorders.

Dementia

A 2016 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's it has little to no effect. Melatonin may, however, help with sundowning.

Jet lag and shift work

Melatonin is known to reduce jet lag, especially in eastward travel. If the time it is taken is not correct, however, it can instead delay adaption.

Melatonin appears to have limited use against the sleep problems of people who work shift work. Tentative evidence suggests that it increases the length of time people are able to sleep.

Adverse effects

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses. Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo. Prolonged-release melatonin is safe with long-term use of up to 12 months. Although not recommended for long term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over the counter sleep aids if a sleeping medication must be used for an extended period of time. Low-doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect, but instead appear to cause drowsiness for a longer period of time.

Melatonin can cause nausea, next-day grogginess, and irritability. In the elderly, it can cause reduced blood flow and hypothermia. In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.

Melatonin can lower follicle-stimulating hormone levels. Melatonin's effects on human reproduction remain unclear.

In those taking warfarin, some evidence suggests there may exist a potentiating drug interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.

Functions

When eyes receive light from the sun, the pineal gland's production of melatonin is inhibited and the hormones produced keep the human awake. When the eyes do not receive light, melatonin is produced in the pineal gland and the human becomes tired.

Circadian rhythm

In animals, melatonin plays an important role in the regulation of sleep–wake cycles. Human infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am. Human melatonin production decreases as a person ages. Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.

Antioxidant

Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993. In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH^•, O₂^−•, and NO^•. In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.

Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin. Due to its capacity for free radical scavenging, indirect effects on the expression of antioxidant enzymes, and its significant concentrations within mitochondria, a number of authors have indicated that melatonin has an important physiological function as a mitochondrial antioxidant.

The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals. Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).

Immune system

While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

Biosynthesis

Overview of melatonin biosynthesis

In animals, biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan. L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase to produce 5-hydroxytryptophan. This intermediate (5-HTP) is decarboxylated by pyridoxal phosphate and 5-hydroxytryptophan decarboxylase to produce serotonin. Serotonin is itself an important neurotransmitter, but is also converted into N-acetylserotonin by serotonin N-acetyltransferase with acetyl-CoA. Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the synthesising reactions are similar, but with slight variations in the last two enzymes.

It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.

Mechanism

Mechanism of melatonin biosynthesis

In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the THB to O₂ could produce a superoxide which could recombine with the THB radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O₂ could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan.

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO₂ from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine. PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO₂. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.

It has been proposed that histidine residue His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetylserotonin.

N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.

Regulation

In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis. Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.

Blue light, principally around 460–480 nm, suppresses melatonin biosynthesis, proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. The incandescent light bulb widely used in the 20th century produced relatively little blue light. Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions. Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.

Pharmacology

 

Pharmacodynamics

In humans, melatonin is a full agonist of melatonin receptor 1 (picomolar binding affinity) and melatonin receptor 2 (nanomolar binding affinity), both of which belong to the class of G-protein coupled receptors (GPCRs). Melatonin receptors 1 and 2 are both G_i/o-coupled GPCRs, although melatonin receptor 1 is also G_q-coupled. Melatonin also acts as a high-capacity free radical scavenger within mitochondria which also promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase via signal transduction through melatonin receptors.

Pharmacokinetics

When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening. Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated. Melatonin has a half life of 35–50 minutes. In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva. The bioavalibility of melatonin is between 10 and 50%.

Melatonin is metabolised in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. 5% of melatonin is excreted in the urine as the unchanged drug.

Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).

The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.

History

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin. As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.

In 1958, dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin. In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.

The discovery that melatonin is an antioxidant was made in 1993. The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995. Around the same time, the hormone got a lot of press as a possible treatment for many illnesses. The New England Journal of Medicine editorialized in 2000: "With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear."

Other animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.

Many animals use the variation in duration of melatonin production each day as a seasonal clock. In animals including humans, the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals. In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds and hamsters. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering its levels.

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors. This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.

Plants

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions. Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram. Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats. In some common foods and beverages, including coffee and walnuts, the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.

Occurrence

 

Dietary supplement

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada. The FDA regulations applying to medications are not applicable to melatonin. As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin. In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.

Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g, bananas and grapes, rice and cereals, herbs, plums, olive oil, wine and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.

As reported in the New York Times in May 2011, beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs. The FDA considered whether these food products could continue to be sold with the label "dietary supplements". On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive. A different company selling a melatonin-containing beverage received a warning letter in 2015.

Commercial availability

Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication. It is available in doses from less than half a milligram to 5 mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic and does not carry a risk of contamination or the means of transmitting infectious material.

Melatonin is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US $400 million during 2017.

Research

A bottle of melatonin tablets. Melatonin is available in timed-release and in liquid forms.

Various uses and effects of melatonin have been studied. A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.

Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.

Cancer

A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive. A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.

Protection from radiation

Both animal and human studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure. Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without major known side effects.

Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.

Secondary dysmenorrhoea

A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.

Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.

Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.

Psychiatry

Melatonin might improve sleep in people with autism. Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin. Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings. However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed.

While the packaging of melatonin often warns against use in people under 18 years of age, available studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD. However, larger and longer studies are needed to establish long-term safety and optimal dosing.

Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy. Some evidence supports an antidepressant effect.

Effects of sleep deprivation on cognitive performance

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Effects_of_sleep_deprivation_on_cognitive_performance

It has been estimated that over 20% of adults suffer from some form of sleep deprivation. Insomnia and sleep deprivation are common symptoms of depression and can be an indication of other mental disorders. The consequences of not getting enough sleep could have dire results; not only to the health of the individual, but those around them as sleep deprivation increases the risk of human-error related accidents, especially with vigilance-based tasks involving technology.

Attention

Neural substrates

The parietal lobes of the brain are largely involved in attention. Lesions to this region of the brain in humans result in difficulty or inability to attend to events that are contralateral to the lesioned hemisphere. Those with lesions to the posterior parietal lobe have little to no difficulty shifting attention to and from stimuli appearing in the space ipsilateral to the lesioned hemisphere. However, they do display a slowed response in shifting their focus of current attention to events and stimuli appearing contralateral to the lesioned hemisphere.

Studies involving single-unit recordings from the parietal lobes of monkeys have indicated that there are neurons solely involved in integrating visual spatial information with postural information. Without this apparent combining of spatial information, it would be difficult or impossible to locate objects in external space, as information provided solely by the retina is insufficient. The position of the eyes, head and body must also be taken into consideration.

In addition, studies involving transcranial magnetic stimulation application over the parietal lobes as well as positron emission tomography (PET) analysis of the parietal lobes suggest that this region is involved in conjunction searches, but not in single-feature searches.

Auditory attention

The Primary auditory cortex is highlighted in magenta, and has been known to interact with all areas highlighted on this neural map.

 

Auditory attention has been examined following sleep deprivation. Researchers examined the auditory attention of twelve non-sleep-deprived subjects and twelve sleep-deprived subjects at various time intervals. Subjects were involved in an auditory attention task, which required the reproduction of the spatial relationships between four letters, using a graph composed of six squares, immediately following the presentation of an item from a tape recorder. It was found that auditory attention of sleep-deprived individuals is affected as the total amount of sleep-deprivation increases, possibly due to lowered perceptual vigilance.

Divided attention

Functional magnetic resonance imaging (fMRI) scans of the brains of subjects exposed to thirty-five hours of sleep deprivation indicate that sleep deprivation is related to increases in prefrontal cortex and parietal lobe activation during tasks that combine verbal learning and arithmetic. This is particularly apparent in the right hemisphere. In non sleep-deprived individuals involved in verbal learning and arithmetic tasks the anterior cingulate cortex and the right prefrontal cortex are active. Following sleep deprivation there is increased activation of the left inferior frontal gyrus and the bilateral parietal lobes. This information suggests that divided attention tasks require more attentional resources than normally required by a non sleep-deprived individual.

Exogenous and endogenous attention

Studies using event-related potential (ERP) recordings have found that twenty-four hours of sleep deprivation decreases ERP response to signal inputs from endogenous, but not exogenous, sources. Therefore, it is suggested that sleep deprivation affects endogenously driven selective attention to a greater extent than exogenously driven selected attention.

Selective attention

Twenty-four hours of sleep deprivation has been found to affect the functional connectivity between the inferior frontal parietal region (IPS) and the parahippocampal place area (PPA). However, sleep deprivation does not affect the attention modulation index of the PPA. With this information, researchers have concluded that the psychophysiological interaction (PPI) is more involved in selective attention than the IPS and PPA.

Research has found that together, attention and sleep deprivation modulate the parahippocampal place area (PPA) activation and scene processing. Specifically, sleep deprivation was related to significant decreases in PPA activation while attending to scenes and when ignoring scenes. This is explained by the absence of change in the Attention Modulation Index (AMI). Face recognition is not affected by sleep deprivation.

Sleep deprivation has been shown to negatively affect picture classification speed and accuracy, as well as recognition memory. It results in an inability to avoid attending to irrelevant information displayed during attention-related tasks. (Norton) It also decreases activation in the ventral visual area and the frontal parietal control regions.

Supervisory attention

Studies involving sleep deprived subjects’ performance on choice reaction time tests, in which response inhibition, task shifting skill and task strategy were involved, have been conducted and analyzed. These three cognitive processes are involved and critical in tasks involving supervisory attention, which is defined as behaviour that arises through the selection and implementation of schemas. Following one night of total sleep deprivation, subjects showed no decline in task shifting or response inhibition performance. However, sleep deprivation does affect the ability to use preparatory bias to increase performance speed. It is suggested that the brain’s cognitive resources make an active effort to succeed in a challenging task when subjected to sleep deprivation, and that this deficit becomes apparent in tasks involving preparatory bias.

Visuospatial attention

Deficits in cognitive performance due to continuous sleep restriction are not well understood. However, there have been studies looking into physiological arousal of the sleep-deprived brain. Participants, whose total amount of sleep had been restricted by 33% throughout one week, were subjected to reaction time tests. The results of these tests were analyzed using quantitative EEG analysis. The results indicate that the frontal regions of the brain are first to be affected, whereas the parietal regions remain active until the effects of sleep deprivation become more severe, which occurred towards the end of the week. In addition, EEG and ERP analysis reveals that activation deficits are more apparent in the non-dominant hemisphere than in the dominant hemisphere.

Thalamus.

 

The effects of sleep deprivation on cognitive performance have been studied through the use of parametric visual attention tasks. Functional magnetic resonance imaging of participants' brains who were involved in ball-tracking tasks of various difficulty levels were obtained. These images were taken during rested wakefulness and again after one night of sleep deprivation. The thalamus is more highly activated when accompanied by sleep deprivation than when the subject is in a state of rested wakefulness. Contrarily, the thalamus is more highly activated during difficult tasks accompanied by rested wakefulness, but not during a state of sleep deprivation. Researchers propose that the thalamic resources, which are normally activated during difficult tasks, are being activated in an attempt to maintain alertness during states of sleep deprivation. In addition, an increase in thalamic activation is related to a decrease in the parietal, prefrontal and cingulate cortex activation, resulting in the overall impairment of attentional networks, which are necessary for visuospatial attention performance.

Functional Magnetic Resonance Imaging (fMRI) studies indicate that the posterior cingulate (PCC) and medial prefrontal cortex are involved in the anticipatory allocation of spatial attention. When sleep-deprived, PCC activity decreases, impairing selective attention. Subjects were exposed to an attention-shifting task involving spatially informative, misleading and uninformative cues preceding the stimuli. When sleep-deprived, subjects showed increased activation in the left intraparietal sulcus. This region is activated when exposed to stimuli in unexpected locations. These findings suggest that sleep-deprived individuals may be impaired in their ability to anticipate the locations of upcoming events. In addition, inability to avoid attending to irrelevant events may also be induced by sleep-deprivation.

By contrast, other studies have indicated that the effects of sleep deprivation on cognitive performance, specifically, sustained visual attention, are more global and bilateral in nature, as opposed to more lateralized deficit explanations. In a study using the Choice Visual Perception Task, subjects were exposed to stimuli appearing in various locations in visual space. Results indicate that sleep deprivation results in a general decline in visual attention. It is also suggested that the sleep-deprived brain is able to maintain a certain level of cognitive performance during tasks requiring divided attention by recruiting additional cortical regions that are not normally used for such tasks.

Executive function

Prefrontal cortex

 

Anterior cingulate cortex

 

Executive functioning is "the ability to plan and coordinate a willful action in the face of alternatives, to monitor and update action as necessary and suppress distracting material by focusing attention on the task at hand". The prefrontal cortex has been identified as the most important region involved in executive functioning.

Researchers believe that three of the most 'basic' executive functions are: shifting, updating, and inhibition. Shifting back and forth between different tasks is considered a very important mental behavior involved in executive functioning as it involves active disengagement from the present task and engaging in a new task. Updating is believed to be involved in working memory (closely associated with the function of the prefrontal cortex), where the information that is active needs to be updated by replacing old, now irrelevant information with new, relevant information based on the objective. Inhibition involves controlled and deliberate impedance of automatic, predominant responses.

The anterior cingulate cortex has been implemented in the process of inhibiting a habitual response or detecting possible conflicts in responses; this is shown by the Stroop test. Studies have found that as little as 36 hours of sleep deprivation cause a performance reduction in tasks requiring these executive functions.

The processes above illustrate a model of controlled versus automatic behavior that was hypothesized by Shallice et al. (1989), called the supervisory attentional system. This system is believed to come into play when intervention of habitual response is necessary. Damage to the prefrontal cortex will cause a breakdown in this system, resulting in utilization behaviors. These behaviors would include spontaneous sequences of action on irrelevant objects in the surroundings with no clear goal in mind. This theory has helped to extend the knowledge we now have on executive functions.

Decision making

Decision making involves a range of executive functions that need to be combined and organized in order to respond in the most appropriate manner, i.e. respond with the most advantageous decision. There are many aspects to the process of decision making, including those discussed above. Other processes involved that correlate to executive function will be discussed below.

Complexity

While most important decisions are made over a longer period of time involving more in-depth cognitive analysis, usually we have limited time in which to assimilate a large amount of information into an informed decision. Lack of sleep appears to negatively affect our ability to appreciate and respond to increasing complexity, as was found in performance deficits after 1 night of sleep deprivation on a simulated marketing game.

The game involved subjects promoting a fictional product while getting feedback on the financial effects of their decisions. They would continuously have to take into account new variables to succeed which would increase the game's complexity.

Other examples of inability to process complex information includes a decrease in ability to assess facial expressions, an increase in resolving to the use of stereotypes and racial biases in evaluations, and an increase in taking the easier solution to solving interpersonal problems.

Innovation

Intuitively, because sleep deprivation had a negative effect on handling the complexity of the simulated marketing game, it also affected innovative processes as subjects failed to adopt a more innovative (and rewarding) style of play. Innovative thinking involves the construction of new behaviors based on the assimilation of continuously changing or novel information. In a study of military personnel who had undergone two nights of sleep deprivation, results showed marked reductions in the ability to generate ideas about a given topic (categories test); this is known as ideational fluency.

Approximate Location of the Orbitofrontal cortex.

Risk

Risk versus reward analysis is an important part of decision making. Attempting to create a representation and response to a risky situation highly involves the orbitofrontal cortex. In a study that involved risk taking analysis of drivers who had been driving for 12 hours straight, it was found that they were more willing to make hazardous maneuvers and were reluctant to adopt any form of a cautious driving style.

Some studies shed further light on this phenomenon. One study used real life decision making scenarios involving choosing cards from 1 of 4 decks of cards. Different cards were considered as a reward while the others were a penalty. The sleep deprived subjects failed to alter their selection methods, continuing to choose cards from decks that were producing a high amount of penalty cards, whereas the control subjects were able to change their choosing strategy by a cost-benefit analysis based on monitoring the outcomes they were getting as they went along.

Planning

The process of planning would be done congruently with decision making in determining the outcome behavior. As has been shown so far, sleep deprivation has many detrimental effects on executive functions and planning is not spared. One study involved cadets who were required to complete simulated military operations under sleep deprived conditions. Results showed a decrease in the subjects ability to 'plan on the fly' and overall outcomes were less than those for well rested cadets.

Another psychological test used to assess planning and decision making is the Tower of London test. This test has been widely used in the testing of executive functions as well as studies of sleep deprived subjects. In a study examining performance on this test after 45–50 hours of sleep deprivation, it was found that the sleep deprived subjects not only took longer, but required more moves to complete the task than did the controls.

Error correction

Being able to show insight into one's performance on different tasks and correct or modify those behaviors if they are incorrect is an important part of executive functioning. The problems that could be associated with being unable to learn from a mistake or adapt to a mistake could impair many behaviors.

A common test used to assess error correction and trouble shooting with regards to the frontal lobe is the Wisconsin Card Sorting Test. This test involves a change in the rules which requires a shift in strategy. In the same study discussed above, detriments were also found on this task in the sleep deprived individuals. 

Memory

Research evidence suggests that sleep is involved in the acquisition, maintenance and retrieval of memories as well as memory consolidation. Subsequently, sleep deprivation has been shown to affect both working memory and long-term memory processes.

Working memory

Sleep deprivation increases the number of errors made on working memory tasks. In one study, the working memory task involved illuminating a sequence of 3 or 4 coloured lights, then asking both sleep deprived and non-sleep deprived individuals to memorize and repeat back the sequence. The sleep deprived performed the task much faster than those in the control condition (i.e., not sleep deprived), which initially appeared to be a positive effect. However, there was a significant difference in the number of errors made, with the fatigued group performing much worse.

Evidence from imaging studies also demonstrates the influence of sleep deprivation on working memory. EEG studies have documented lower accuracy and slower reaction times among sleep deprived participants performing working memory tasks. Decreasing alertness and lack of focus triggered deficits in working memory that are accompanied by significant degradation of event-related potentials.

PET scans shows global decrease in glucose metabolism in response to sleep deprivation. As subjects become increasingly impaired on working memory tasks, a more specific decrease of glucose occurs in the thalamus, prefrontal cortex and posterior parietal cortex.

fMRI scans following brief sleep deprivation (24 hours or less) show increases in thalamic activation. Verbal working memory tasks normally cause increases in left temporal lobe activity. However, after 35 hours of deprivation, there are noted decreases in temporal lobe activation and increases in parietal lobe activation.

Working memory model.

The working memory span is also affected by sleep deprivation. When sleep deprived participants in a study were asked to remember a nonsense word and locate it among a number of similar words, the length of time they could hold it in their working memory decreased by 38% compared to rested individuals.

Long-term memory

One way sleep is involved in the creation of long-term memories is through memory consolidation, which is the process by which a new memory is changed into a more permanent form. This is believed to be accomplished by creating connections between the medial temporal lobes and neocortical areas. NREM (non-REM) and REM sleep are both believed to be implicated, with current theories suggesting NREM is most particularly involved in procedural memory and REM with declarative memory.

Animal studies have partly validated these claims. For instance, one study conducted with rats showed that REM sleep deprivation after learning a new task disrupted their ability to perform the task again later. This was especially true if the task was complex (i.e., involved using unusual information or developing novel adaptive behaviours).

There is similar evidence for the role of sleep in procedural memory in humans. Participants in one study were trained on a procedural memory skill involving perceptual-motor skills. Those who were NREM sleep deprived performed significantly worse on subsequent trials compared to those who were fully rested. Another study using a visuo-motor procedural memory task documented similar results. Participants who were sleep deprived following the initial training showed no improvement on trials the next day, while those who received sleep showed significant positive changes. Studies such as these clearly demonstrate the disruptive influence sleep deprivation has on memory consolidation of procedural and declarative memories.

Sleep deprivation also has a documented effect on the ability to acquire new memories for subsequent consolidation. A study done on mice that were sleep deprived before learning a new skill but allowed to rest afterward displayed a similar number of errors on later trials as the mice that were sleep deprived only after the initial learning. In this case, it is hypothesized that rather than preventing the memory from being consolidated, sleep deprivation interfered with the initial acquisition of the memory. Mice with pre-trial sleep deprivation also took significantly longer to learn a task than well-rested mice.

Sleep deprivation is also implicated in impaired ability to retrieve stored long-term memories. When an aversive stimulus was included in a trial (i.e., a blowdryer would blast hot air and noise at a mouse), mice that were sleep deprived were less anxious on subsequent trials. This suggests they had not retrieved all of the memory related to the unpleasant experience.

Explanations for the effect of sleep deprivation on memory

Several theories have been put forth to explain the effect sleep deprivation has on memory. 

One early study into neurochemical influences on sleep and memory was conducted with cats and demonstrated that sleep deprivation increased brain protein synthesis. There is evidence that these altered levels of proteins could increase the excitability of the central nervous system, thus increasing the susceptibility of the brain to other neurochemical agents that can cause amnesia. Further research has revealed that the protein kinase A (PKA) signalling pathway is crucial to long-term memory. If PKA or protein synthesis inhibition occurs at certain moments during sleep, memory consolidation can be disrupted. In addition, mice with genetic inhibition of PKA have been shown to have long-term memory deficits. Thus, sleep deprivation may act through the inhibition of these protein synthesis pathways. 

Acetylcholine (ACh) may also be involved in the effects of sleep deprivation, particularly with regards to spatial memory. Muscarinic antagonists, or chemicals that block ACh, impair spatial learning when administered prior to a training task among rats. ACh levels are also found to be lower when measured following a period of sleep deprivation. ACh has also been shown to increase the activity of the PKA pathway, which is needed for memory consolidation.

Serotonin levels (in the form of 5-HT) have been shown to decrease during REM and NREM sleep, leading some researchers to believe that it is also involved in memory consolidation during sleep. Mice lacking the receptor gene for 5-HT engage in more REM sleep and perform better on spatial memory tasks. Researchers have hypothesized that sleep deprivation interferes with the normal reduction in levels of 5-HT, impairing the process of memory consolidation.

Another theory suggests that the stress brought on by sleep deprivation affects memory consolidation by changing the concentration of corticosteroids in the body. This was simulated in one study by elevating the concentration of glucocorticoids during early sleep stages. The observed effects on memory retention the next day were similar to those obtained from individuals who had received no sleep.

Sleep deprivation may affect memory by interfering with neuroplasticity as measured by long-term potentiation in the hippocampus. This reduced plasticity may be the root cause of impairments in both working memory among humans and spatial memory among rats. Sleep deprivation may additionally affect memory by reducing the proliferation of cells in the hippocampus.

Sleep deprivation has also been associated with decreased overall membrane excitability of neurons in the brain. Activation of these membranes is critical for the formation of memories. Mitochondria play an essential role in modulating neuron excitability, and research has shown that sleep deprivation is involved in inhibiting mitochondrial metabolism.

Practical effects

Risk of traffic collisions

Reduced duration of sleep, as well as an increase in time spent awake, are factors that highly contribute to the risk of traffic collisions, the severity and fatality rates of which are on the same level as driving under the influence of alcohol, with 19 hours of wakefulness corresponding to a BAC of 0.05%, and 24 hours of wakefulness corresponding to a BAC of 0.10%. Compounding this issue is the proven dissociation between objective performance and subjective alertness; individuals vastly underestimate the effect that sleep deprivation has on their cognitive performance, particularly during the circadian night. Much of the effect of acute sleep deprivation can be countered by napping, with longer naps giving more benefit than shorter naps. Some industries, particularly the Fire Service, have traditionally allowed workers to sleep while on duty, between calls for service. In one study of EMS providers, 24-hour shifts were not associated with a higher frequency of negative safety outcomes when compared to shorter shifts.

This is especially relevant for young adults as they require 8–9 hours of sleep at night to overcome excessive daytime sleepiness and are among the highest risk group for driving while feeling tired and sleep deprivation related crashes.

Sleep in space

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Sleep_in_space

 

An astronaut asleep in the microgravity of Earth orbit-continual free-fall around the earth, inside the pressurized module Harmony node of the International Space Station in 2007

Sleeping in space is an important part of space medicine and mission planning, with impacts on the health, capabilities and morale of astronauts.

Human spaceflight often requires astronaut crews to endure long periods without rest. Studies have shown that lack of sleep can cause fatigue that leads to errors while performing critical tasks. Also, individuals who are fatigued often cannot determine the degree of their impairment. Astronauts and ground crews frequently suffer from the effects of sleep deprivation and circadian rhythm disruption. Fatigue due to sleep loss, sleep shifting and work overload could cause performance errors that put space flight participants at risk of compromising mission objectives as well as the health and safety of those on board.

Mission Specialist Margaret Rhea Seddon, wearing a blindfold, sleeps in SLS-1 module (STS-40)

 

Overview

Sleeping in space requires that astronauts sleep in a crew cabin, a small room about the size of a shower stall. They lie in a sleeping bag which is strapped to the wall. Astronauts have reported having nightmares, dreams, and snoring while sleeping in space.

Sleeping and crew accommodations need to be well ventilated; otherwise, astronauts can wake up oxygen-deprived and gasping for air, because a bubble of their own exhaled carbon dioxide had formed around their heads. Brain cells are extremely sensitive to a lack of oxygen and brain cells can start dying less than 5 minutes after their oxygen supply disappears; the result is that brain hypoxia can rapidly cause severe brain damage or even death. A decrease of oxygen to the brain can cause dementia and brain damage, as well as a host of other symptoms.

In the early 21st century, crew on the ISS were said to average about six hours of sleep per day.

On the ground

Chronic sleep loss can impact performance similarly to total sleep loss and recent studies have shown that cognitive impairment after 17 hours of wakefulness is similar to impairment from an elevated blood alcohol level.

It has been suggested that work overload and circadian desynchronization may cause performance impairment. Those who perform shift work suffer from increased fatigue because the timing of their sleep/wake schedule is out of sync with natural daylight. They are more prone to auto and industrial accidents as well as a decreased quality of work and productivity on the job.

Ground crews at NASA are also affected by slam shifting (sleep shifting) while supporting critical International Space Station operations during overnight shifts. 

In space

Flight engineer Nikolai Budarin, uses a computer in a sleep station in the Zvezda Service Module on the International Space Station (ISS).

 

Cosmonaut Yury Usachov in his sleeping compartment on Mir, called a Kayutka

 

During the Apollo program, it was discovered that adequate sleep in the small volumes available in the command module and Lunar Module was most easily achieved if (1) there was minimum disruption to the pre-flight circadian rhythm of the crew members; (2) all crew members in the spacecraft slept at the same time; (3) crew members were able to doff their suits before sleeping; (4) work schedules were organized – and revised as needed – to provide an undisturbed (radio quiet) 6-8 hour rest period during each 24-hour period; (5) in zero-gravity, loose restraints were provided to keep the crewmen from drifting; (6) on the lunar surface, a hammock or other form of bed was provided; (7) there was an adequate combination of cabin temperature and sleepwear for comfort; (8) the crew could dim instrument lights and either cover their eyes or exclude sunlight from the cabin; and (9) equipment such as pumps were adequately muffled.

NASA management currently has limits in place to restrict the number of hours in which astronauts are to complete tasks and events. This is known as the "Fitness for Duty Standards". Space crews' current nominal number of work hours is 6.5 hours per day, and weekly work time should not exceed 48 hours. NASA defines critical workload overload for a space flight crew as 10-hour work days for 3 days per work week, or more than 60 hours per week (NASA STD-3001, Vol. 1). Astronauts have reported that periods of high-intensity workload can result in mental and physical fatigue. Studies from the medical and aviation industries have shown that increased and intense workloads combined with disturbed sleep and fatigue can lead to significant health issues and performance errors.

Research suggests that astronauts' quality and quantity of sleep while in space is markedly reduced than while on Earth. The use of sleep-inducing medication could be indicative of poor sleep due to disturbances. A study in 1997 showed that sleep structure as well as the restorative component of sleep may be disrupted while in space. These disturbances could increase the occurrence of performance errors.

Current space flight data shows that accuracy, response time and recall tasks are all affected by sleep loss, work overload, fatigue and circadian desynchronization. 

Factors that contribute to sleep loss and fatigue

The most common factors that can affect the length and quality of sleep while in space include:

• noise
• physical discomfort
• voids
• disturbances caused by other crew members
• temperature

An evidence gathering effort is currently underway to evaluate the impact of these individual, physiological and environmental factors on sleep and fatigue. The effects of work-rest schedules, environmental conditions and flight rules and requirements on sleep, fatigue and performance are also being evaluated.

Factors that contribute to circadian desynchronization

Exposure to light is the largest contributor to circadian desynchronization on board the ISS. Since the ISS orbits the Earth every 1.5 hours, the flight crew experiences 16 sunrises and sunsets per day. Slam shifting (sleep shifting) is also a considerable external factor that causes circadian desynchronization in the current space flight environment.

Other factors that may cause circadian desynchronization in space:

• shift work
• extended work hours
• timeline changes
• slam shifting (sleep shifting)
• prolonged light of lunar day
• Mars sol on Earth
• Mars sol on Mars
• abnormal environmental cues (i.e.: unnatural light exposure)

Sleep loss, genetics, and space

Both acute and chronic partial sleep loss occur frequently in space flight due to operational demands and for physiological reasons not yet entirely understood. Some astronauts are affected more than others. Earth-based research has demonstrated that sleep loss poses risks to astronaut performance, and that there are large, highly reliable individual differences in the magnitude of cognitive performance, fatigue and sleepiness, and sleep homeostatic vulnerability to acute total sleep deprivation and to chronic sleep restriction in healthy adults. The stable, trait-like (phenotypic) inter-individual differences observed in response to sleep loss point to an underlying genetic component. Indeed, data suggest that common genetic variations (polymorphisms) involved in sleep-wake, circadian, and cognitive regulation may serve as markers for prediction of inter-individual differences in sleep homeostatic and neurobehavioral vulnerability to sleep restriction in healthy adults. Identification of genetic predictors of differential vulnerability to sleep restriction will help identify astronauts most in need of fatigue countermeasures in space flight and inform medical standards for obtaining adequate sleep in space.

Computer-based simulation information

Biomathematical models are being developed to instantiate the biological dynamics of sleep need and circadian timing. These models could predict astronaut performance relative to fatigue and circadian desynchronization.