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.

Tryptophan

From Wikipedia, the free encyclopedia

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

 

l-Tryptophan

Names
IUPAC name Tryptophan or (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid
Other names 2-Amino-3-(1H-indol-3-yl)propanoic acid
Identifiers
CAS Number	73-22-3
3D model (JSmol)	Interactive image Zwitterion: Interactive image
ChEBI	CHEBI:16828
ChEMBL	ChEMBL54976
ChemSpider	6066
DrugBank	DB00150
ECHA InfoCard	100.000.723
IUPHAR/BPS	717
KEGG	D00020
PubChem CID	6305
UNII	8DUH1N11BX
CompTox Dashboard (EPA)	DTXSID5021419
Properties
Chemical formula	C11H12N2O2
Molar mass	204.229 g·mol−1
Solubility in water	Soluble: 0.23 g/L at 0 °C, 11.4 g/L at 25 °C, 17.1 g/L at 50 °C, 27.95 g/L at 75 °C
Solubility	Soluble in hot alcohol, alkali hydroxides; insoluble in chloroform.
Acidity (pKa)	2.38 (carboxyl), 9.39 (amino)
Magnetic susceptibility (χ)	-132.0·10−6 cm3/mol
Pharmacology
ATC code	N06AX02 (WHO)
Supplementary data page
Structure and properties	Refractive index (n), Dielectric constant (εr), etc.
Thermodynamic data	Phase behaviour solid–liquid–gas
Spectral data	UV, IR, NMR, MS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a non-polar aromatic amino acid. It is essential in humans, meaning the body cannot synthesize it; it must be obtained from the diet. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin and vitamin B3. It is encoded by the codon UGG.

Like other amino acids, tryptophan is a zwitterion at physiological pH where the amino group is protonated (–NH₃⁺; pK_a = 9.39) and the carboxylic acid is deprotonated ( –COO⁻; pK_a = 2.38).

Function

Metabolism of l-tryptophan into serotonin and melatonin (left) and niacin (right). Transformed functional groups after each chemical reaction are highlighted in red.

Amino acids, including tryptophan, are used as building blocks in protein biosynthesis, and proteins are required to sustain life. Many animals (including humans) cannot synthesize tryptophan: they need to obtain it through their diet, making it an essential amino acid. Tryptophan is among the less common amino acids found in proteins, but it plays important structural or functional roles whenever it occurs. For instance, tryptophan and tyrosine residues play special roles in "anchoring" membrane proteins within the cell membrane. In addition, tryptophan functions as a biochemical precursor for the following compounds:

• Serotonin (a neurotransmitter), synthesized by tryptophan hydroxylase.
• Melatonin (a neurohormone) is in turn synthesized from serotonin, via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase enzymes.
• Niacin, also known as vitamin B₃, is synthesized from tryptophan via kynurenine and quinolinic acids.
• Auxins (a class of phytohormones) are synthesized from tryptophan.

The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood, and depression.

In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. Binding of this repressor to the tryptophan operon prevents transcription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop, and when the cell's tryptophan levels go down again, transcription from the trp operon resumes. This permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels. 

Tryptophan metabolism by human gastrointestinal microbiota Tryptophan Clostridium sporogenes Lacto- bacilli Tryptophanase- expressing bacteria IPA I3A Indole Liver Brain IPA I3A Indole Indoxyl sulfate AST-120 AhR Intestinal immune cells Intestinal epithelium PXR Mucosal homeostasis: ↓TNF-α ↑Junction protein- coding mRNAs L cell GLP-1 T J Neuroprotectant: ↓Activation of glial cells and astrocytes ↓4-Hydroxy-2-nonenal levels ↓DNA damage –Antioxidant –Inhibits β-amyloid fibril formation Maintains mucosal reactivity: ↑IL-22 production Associated with vascular disease: ↑Oxidative stress ↑Smooth muscle cell proliferation ↑Aortic wall thickness and calcification Associated with chronic kidney disease: ↑Renal dysfunction –Uremic toxin Kidneys This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut. Indole is produced from tryptophan by bacteria that express tryptophanase. Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. Lactobacillus species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production. Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction. AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.

Recommended dietary allowance

In 2002, the U.S. Institute of Medicine set a Recommended Dietary Allowance (RDA) of 5 mg/kg body weight/day of Tryptophan for adults 19 years and over.

Dietary sources

Tryptophan is present in most protein-based foods or dietary proteins. It is particularly plentiful in chocolate, oats, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, buckwheat, spirulina, and peanuts. Contrary to the popular belief that cooked turkey contains an abundance of tryptophan (with this being used as an explanation for sleepiness following consumption of the meat), the tryptophan content in turkey is typical of poultry.

Use as an antidepressant

Because tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is then converted into the neurotransmitter serotonin, it has been proposed that consumption of tryptophan or 5-HTP may improve depression symptoms by increasing the level of serotonin in the brain. Tryptophan is sold over the counter in the United States (after being banned to varying extents between 1989 and 2005) and the United Kingdom as a dietary supplement for use as an antidepressant, anxiolytic, and sleep aid. It is also marketed as a prescription drug in some European countries for the treatment of major depression. There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet, but consuming purified tryptophan increases the serotonin level in the brain, whereas eating foods containing tryptophan does not. This is because the transport system that brings tryptophan across the blood–brain barrier also transports other amino acids which are contained in protein food sources. High blood plasma levels of other large neutral amino acids prevent the plasma concentration of tryptophan from increasing brain concentration levels.

In 2001 a Cochrane review of the effect of 5-HTP and tryptophan on depression was published. The authors included only studies of a high rigor and included both 5-HTP and tryptophan in their review because of the limited data on either. Of 108 studies of 5-HTP and tryptophan on depression published between 1966 and 2000, only two met the authors' quality standards for inclusion, totaling 64 study participants. The substances were more effective than placebo in the two studies included but the authors state that "the evidence was of insufficient quality to be conclusive" and note that "because alternative antidepressants exist which have been proven to be effective and safe, the clinical usefulness of 5-HTP and tryptophan is limited at present". The use of tryptophan as an adjunctive therapy in addition to standard treatment for mood and anxiety disorders is not supported by the scientific evidence.

Side effects

Potential side effects of tryptophan supplementation include nausea, diarrhea, drowsiness, lightheadedness, headache, dry mouth, blurred vision, sedation, euphoria, and nystagmus (involuntary eye movements).

Interactions

Tryptophan taken as a dietary supplement (such as in tablet form) has the potential to cause serotonin syndrome when combined with antidepressants of the MAOI or SSRI class or other strongly serotonergic drugs. Because tryptophan supplementation has not been thoroughly studied in a clinical setting, its interactions with other drugs are not well known.

Isolation

The isolation of tryptophan was first reported by Frederick Hopkins in 1901. Hopkins recovered tryptophan from hydrolysed casein, recovering 4–8 g of tryptophan from 600 g of crude casein.

Biosynthesis and industrial production

As an essential amino acid, tryptophan is not synthesized from simpler substances in humans and other animals, so it needs to be present in the diet in the form of tryptophan-containing proteins. Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate: anthranilate condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. The ring of the ribose moiety is opened and subjected to reductive decarboxylation, producing indole-3-glycerol phosphate; this, in turn, is transformed into indole. In the last step, tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid serine.

The industrial production of tryptophan is also biosynthetic and is based on the fermentation of serine and indole using either wild-type or genetically modified bacteria such as B. amyloliquefaciens, B. subtilis, C. glutamicum or E. coli. These strains carry mutations that prevent the reuptake of aromatic amino acids or multiple/overexpressed trp operons. The conversion is catalyzed by the enzyme tryptophan synthase.

Society and culture

Eosinophilia–myalgia syndrome

There was a large outbreak of eosinophilia-myalgia syndrome (EMS) in the U.S. in 1989, with more than 1,500 cases reported to the CDC and at least 37 deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990, with other countries following suit.

Subsequent studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. It eventually became clear that recent batches of Showa Denko's L-tryptophan were contaminated by trace impurities, which were subsequently thought to be responsible for the 1989 EMS outbreak. However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS.

The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, but continued to limit the importation of tryptophan not intended for an exempted use until 2005.

The fact that the Showa Denko facility used genetically engineered bacteria to produce the contaminated batches of L-tryptophan later found to have caused the outbreak of eosinophilia-myalgia syndrome has been cited as evidence of a need for "close monitoring of the chemical purity of biotechnology-derived products". Those calling for purity monitoring have, in turn, been criticized as anti-GMO activists who overlook possible non-GMO causes of contamination and threaten the development of biotech.

Turkey meat and drowsiness

A common assertion in the US is that heavy consumption of turkey meat results in drowsiness, due to high levels of tryptophan contained in turkey. However, the amount of tryptophan in turkey is comparable to that contained in other meats. Drowsiness after eating may be caused by other foods eaten with the turkey, particularly carbohydrates. Ingestion of a meal rich in carbohydrates triggers the release of insulin. Insulin in turn stimulates the uptake of large neutral branched-chain amino acids (BCAA), but not tryptophan, into muscle, increasing the ratio of tryptophan to BCAA in the blood stream. The resulting increased tryptophan ratio reduces competition at the large neutral amino acid transporter (which transports both BCAA and aromatic amino acids), resulting in more uptake of tryptophan across the blood–brain barrier into the cerebrospinal fluid (CSF). Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. The resultant serotonin is further metabolised into melatonin by the pineal gland. Hence, these data suggest that "feast-induced drowsiness"—or postprandial somnolence—may be the result of a heavy meal rich in carbohydrates, which indirectly increases the production of melatonin in the brain, and thereby promotes sleep.

Research

In 1912 Felix Ehrlich demonstrated that yeast attacks the natural amino acids essentially by splitting off carbon dioxide and replacing the amino group with hydroxyl. By this reaction, tryptophan gives rise to tryptophol.

Tryptophan affects brain serotonin synthesis when given orally in a purified form and is used to modify serotonin levels for research. Low brain serotonin level is induced by administration of tryptophan-poor protein in a technique called "acute tryptophan depletion". Studies using this method have evaluated the effect of serotonin on mood and social behavior, finding that serotonin reduces aggression and increases agreeableness.

Fluorescence

Tryptophan is an important intrinsic fluorescent probe (amino acid), which can be used to estimate the nature of the microenvironment around the tryptophan residue. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues.