Neuroscience of sleep

The neuroscience of sleep is the study of the neuroscientific and physiological basis of the nature of sleep and its functions. Traditionally, sleep has been studied as part of psychology and medicine. The study of sleep from a neuroscience perspective grew to prominence with advances in technology and the proliferation of neuroscience research from the second half of the twentieth century. The importance of sleep is demonstrated by the fact that organisms daily spend hours of their time in sleep, and that sleep deprivation can have disastrous effects ultimately leading to death in animals. For a phenomenon so important, the purposes and mechanisms of sleep are only partially understood, so much so that as recently as the late 1990s it was quipped: "The only known function of sleep is to cure sleepiness". However, the development of improved imaging techniques like EEG, PET and fMRI, along with faster computers have led to an increasingly greater understanding of the mechanisms underlying sleep. The fundamental questions in the neuroscientific study of sleep are:

What are the correlates of sleep i.e. what are the minimal set of events that could confirm that the organism is sleeping? How is sleep triggered and regulated by the brain and the nervous system? What happens in the brain during sleep? How can we understand sleep function based on physiological changes in the brain? What causes various sleep disorders and how can they be treated? Other areas of modern neuroscience sleep research include the evolution of sleep, sleep during development and aging, animal sleep, mechanism of effects of drugs on sleep, dreams and nightmares, and stages of arousal between sleep and wakefulness.

== Introduction ==

Rapid eye movement sleep (REM), non-rapid eye movement sleep (NREM or non-REM), and waking represent the three major modes of consciousness, neural activity, and physiological regulation. NREM sleep itself is divided into multiple stages: N1, N2 and N3. Sleep proceeds in 90-minute cycles of REM and NREM, the order normally being N1 → N2 → N3 → N2 → REM. As humans fall asleep, body activity slows down. Body temperature, heart rate, breathing rate, and energy use all decrease. Brain waves slow down. The excitatory neurotransmitter acetylcholine becomes less available in the brain. Humans often maneuver to create a thermally friendly environment—for example, by curling up into a ball if cold. Reflexes remain fairly active. REM sleep is considered closer to wakefulness and is characterized by rapid eye movement and muscle atonia. NREM is considered to be deep sleep (the deepest part of NREM is called slow wave sleep), and is characterized by lack of prominent eye movement, or muscle paralysis. Especially during non-REM sleep, the brain uses significantly less energy during sleep than it does in waking. In areas with reduced activity, the brain restores its supply of adenosine triphosphate (ATP), the molecule used for short-term storage and transport of energy. (Since in quiet waking the brain is responsible for 20% of the body's energy use, this reduction has an independently noticeable impact on overall energy consumption.) During slow-wave sleep, humans secrete bursts of growth hormone. All sleep, even during the day, is associated with the secretion of prolactin. According to the Hobson & McCarley activation-synthesis hypothesis, proposed in 1975–1977, the alternation between REM and non-REM can be explained in terms of cycling, reciprocally influential neurotransmitter systems. Sleep timing is controlled by the circadian clock, and in humans, to some extent by willed behavior. The term circadian comes from the Latin circa, meaning "around" (or "approximately"), and diem or dies, meaning "day". The circadian clock refers to a biological mechanism that governs multiple biological processes causing them to display an endogenous, entrainable oscillation of about 24 hours. These rhythms have been widely observed in plants, animals, fungi and cyanobacteria.

== Correlates of sleep ==

One of the important questions in sleep research is clearly defining the sleep state. This problem arises because sleep was traditionally defined as a state of consciousness and not as a physiological state, thus there was no clear definition of what minimum set of events constitute sleep and distinguish it from other states of partial or no consciousness. The problem of making such a definition is complicated because it needs to include a variety of modes of sleep found across different species. At a symptomatic level, sleep is characterized by lack of reactivity to sensory inputs, low motor output, diminished conscious awareness and rapid reversibility to wakefulness. However, to translate these into a biological definition is difficult because no single pathway in the brain is responsible for the generation and regulation of sleep. One of the earliest proposals was to define sleep as the deactivation of the cerebral cortex and the thalamus because of near lack of response to sensory inputs during sleep. However, this was invalidated because both regions are active in some phases of sleep. In fact, it appears that the thalamus is only deactivated in the sense of transmitting sensory information to the cortex. Some of the other observations about sleep included decrease of sympathetic activity and increase of parasympathetic activity in non-REM sleep, and increase of heart rate and blood pressure accompanied by decrease in homeostatic response and muscle tone during REM sleep. However, these symptoms are not limited to sleep situations and do not map to specific physiological definitions. More recently, the problem of definition has been addressed by observing overall brain activity in the form of characteristic EEG patterns. Each stage of sleep and wakefulness has a characteristic pattern of EEG which can be used to identify the stage of sleep. Waking is usually characterized by beta (12–30 Hz) and gamma (25–100 Hz) depending on whether there was a peaceful or stressful activity. The onset of sleep involves slowing down of this frequency to the drowsiness of alpha (8–12 Hz) and finally to theta (4–10 Hz) of Stage 1 NREM sleep. This frequency further decreases progressively through the higher stages of NREM and REM sleep. On the other hand, the amplitude of sleep waves is lowest during wakefulness (10–30μV) and shows a progressive increase through the various stages of sleep. Stage 2 is characterized by sleep spindles (intermittent clusters of waves at sigma frequency i.e. 12–14 Hz) and K complexes (sharp upward deflection followed by slower downward deflection). Stage 3 sleep has more sleep spindles. Stage 3 has very high amplitude delta waves (0–4 Hz) and is known as slow wave sleep. REM sleep is characterized by low amplitude, mixed frequency waves. A sawtooth wave pattern is often present.

== Ontogeny and phylogeny of sleep ==

The questions of how sleep evolved in the animal kingdom and how it developed in humans are especially important because they might provide a clue to the functions and mechanisms of sleep respectively.

=== Sleep evolution ===

The evolution of different types of sleep patterns is influenced by a number of selective pressures, including body size, relative metabolic rate, predation, type and location of food sources, and immune function. Sleep (especially deep SWS and REM) is tricky behavior because it steeply increases predation risk. This means that, for sleep to have evolved, the functions of sleep should have provided a substantial advantage over the risk it entails. In fact, studying sleep in different organisms shows how they have balanced this risk by evolving partial sleep mechanisms or by having protective habitats. Thus, studying the evolution of sleep might give a clue not only to the developmental aspects and mechanisms, but also to an adaptive justification for sleep. One challenge studying sleep evolution is that adequate sleep information is known only for two phyla of animals- chordata and arthropoda. With the available data, comparative studies have been used to determine how sleep might have evolved. One question that scientists try to answer through these studies is whether sleep evolved only once or multiple times. To understand this, they look at sleep patterns in different classes of animals whose evolutionary histories are fairly well-known and study their similarities and differences. Humans possess both slow wave and REM sleep, in both phases both eyes are closed and both hemispheres of the brain involved. Sleep has also been recorded in mammals other than humans. One study showed that echidnas possess only slow wave sleep (non-REM). This seems to indicate that REM sleep appeared in evolution only after therians. But this has later been contested by studies that claim that sleep in echidna combines both modes into a single sleeping state. Other studies have shown a peculiar form of sleep in odontocetes (like dolphins and porpoises). This is called the unihemispherical slow wave sleep (USWS). At any time during this sleep mode, the EEG of one brain hemisphere indicates sleep while that of the other is equivalent to wakefulness. In some cases, the corresponding eye is open. This might allow the animal to reduce predator risk and sleep while swimming in water, though the animal may also be capable of sleeping at rest. The correlates of sleep found for mammals are valid for birds as well i.e. bird sleep is very similar to mammals and involves both SWS and REM sleep with similar features, including closure of both eyes, lowered muscle tone, etc. However, the proportion of REM sleep in birds is much lower. Also, some birds can sleep with one eye open if there is high predation risk in the environment. This gives rise to the possibility of sleep in flight; considering that sleep is very important and some bird species can fly for weeks continuously, this seems to be the obvious result. However, sleep in flight has not been recorded, and is so far unsupported by EEG data. Further research may explain whether birds sleep during flight or if there are other mechanisms which ensure their remaining healthy during long flights in the absence of sleep. Unlike in birds, very few consistent features of sleep have been found among reptile species. The only common observation is that reptiles do not have REM sleep. Sleep in some invertebrates has also been extensively studied, e.g., sleep in fruitflies (Drosophila) and honeybees. Some of the mechanisms of sleep in these animals have been discovered while others remain quite obscure. The features defining sleep have been identified for the most part, and like mammals, this includes reduced reaction to sensory input, lack of motor response in the form of antennal immobility, etc. The fact that both the forms of sleep are found in mammals and birds, but not in reptiles (which are considered to be an intermediate stage) indicates that sleep might have evolved separately in both. Substantiating this might be followed by further research on whether the EEG correlates of sleep are involved in its functions or if they are merely a feature. This might further help in understanding the role of sleep in long term plasticity. According to Tsoukalas (2012), REM sleep is an evolutionary transformation of a well-known defensive mechanism, the tonic immobility reflex. This reflex, also known as animal hypnosis or death feigning, functions as the last line of defense against an attacking predator and consists of the total immobilization of the animal: the animal appears dead (cf. "playing possum"). The neurophysiology and phenomenology of this reaction show striking similarities to REM sleep, a fact which betrays a deep evolutionary kinship. For example, both reactions exhibit brainstem control, paralysis, sympathetic activation, and thermoregulatory changes. This theory integrates many earlier findings into a unified, and evolutionary well informed, framework.

=== Sleep development and aging === The ontogeny of sleep is the study of sleep across different age groups of a species, particularly during development and aging. Among mammals, infants sleep the longest. Human babies have 8 hours of REM sleep and 8 hours of NREM sleep on an average. The percentage of time spent on each mode of sleep varies greatly in the first few weeks of development and some studies have correlated this to the degree of precociality of the child. Within a few months of postnatal development, there is a marked reduction in percentage of hours spent in REM sleep. By the time the child becomes an adult, she or he spends about 6–7 hours in NREM sleep and only about an hour in REM sleep. This is true not only of humans, but of many animals dependent on their parents for food. The observation that the percentage of REM sleep is very high in the first stages of development has led to the hypothesis that REM sleep might facilitate early brain development. However, this theory has been contested by other studies. Sleep behavior undergoes substantial changes during adolescence. Some of these changes may be societal in humans, but other changes are hormonal. Another important change is the decrease in the number of hours of sleep, as compared to childhood, which gradually becomes identical to an adult. It is also being speculated that homeostatic regulation mechanisms may be altered during adolescence. Apart from this, the effect of changing routines of adolescents on other behavior such as cognition and attention is yet to be studied. Ohayon et al., for example, have stated that the decline in total sleep time from childhood to adolescence seems to be more associated with environmental factors rather than biological feature. In adulthood, the sleep architecture has been showing that the sleep latency and the time spent in NREM stages 1 and 2 may increase with aging, while the time spent in REM and SWS sleep seem to decrease. These changes have been frequently associated with brain atrophy, cognitive impairment and neurodegenerative disorders in old age. For instance, Backhaus et al. have pointed out that a decline in declarative memory consolidation in midlife (in their experiment: 48 to 55 years old) is due to a lower amount of SWS, which might already start to decrease around age of 30 years old. According to Mander et al., atrophy in the medial prefrontal cortex (mPFC) gray matter is a predictor of disruption in slow activity during NREM sleep that may impair memory consolidation in older adults. And sleep disturbances, such as excessive daytime sleepiness and nighttime insomnia, have been often referred as factor risk of progressive functional impairment in Alzheimer's disease (AD) or Parkinson's disease (PD). Therefore, sleep in aging is another equally important area of research. A common observation is that many older adults spend time awake in bed after sleep onset in an inability to fall asleep and experience marked decrease in sleep efficiency. There may also be some changes in circadian rhythms. Studies are ongoing about what causes these changes and how they may be reduced to ensure comfortable sleep of old adults.

== Brain activity during sleep ==

Understanding the activity of different parts of the brain during sleep can give a clue to the functions of sleep. It has been observed that mental activity is present during all stages of sleep, though from different regions in the brain. So, contrary to popular understanding, the brain never completely shuts down during sleep. Also, sleep intensity of a particular region is homeostatically related to the corresponding amount of activity before sleeping. The use of imaging modalities like PET, fMRI and MEG, combined with EEG recordings, gives a clue to which brain regions participate in creating the characteristic wave signals and what their functions might be.

=== Historical development of the stages model === The stages of sleep were first described in 1937 by Alfred Lee Loomis and his coworkers, who separated the different electroencephalography (EEG) features of sleep into five levels (A to E), representing the spectrum from wakefulness to deep sleep. In 1953, REM sleep was discovered as distinct, and thus William C. Dement and Nathaniel Kleitman reclassified sleep into four NREM stages and REM. The staging criteria were standardized in 1968 by Allan Rechtschaffen and Anthony Kales in the "R&K sleep scoring manual." In the R&K standard, NREM sleep was divided into four stages, with slow-wave sleep comprising stages 3 and 4. In stage 3, delta waves made up less than 50% of the total wave patterns, while they made up more than 50% in stage 4. Furthermore, REM sleep was sometimes referred to as stage 5. In 2004, the AASM commissioned the AASM Visual Scoring Task Force to review the R&K scoring system. The review resulted in several changes, the most significant being the combination of stages 3 and 4 into Stage N3. The revised scoring was published in 2007 as The AASM Manual for the Scoring of Sleep and Associated Events. Arousals, respiratory, cardiac, and movement events were also added.

=== NREM sleep activity === NREM sleep is characterized by decreased global and regional cerebral blood flow. It constitutes ~80% of all sleep in adult humans. Initially, it was expected that the brainstem, which was implicated in arousal would be inactive, but this was later on found to have been due to low resolution of PET studies and it was shown that there is some slow wave activity in the brainstem as well. However, other parts of the brain, including the precuneus, basal forebrain and basal ganglia are deactivated during sleep. Many areas of the cortex are also inactive, but to different levels. For example, the ventromedial prefrontal cortex is considered the least active area while the primary cortex, the least deactivated. NREM sleep is characterized by slow oscillations, spindles and delta waves. The slow oscillations have been shown to be from the cortex, as lesions in other parts of the brain do not affect them, but lesions in the cortex do. The delta waves have been shown to be generated by recurrent connections within the cerebral cortex. During slow wave sleep, the cortex generates brief periods of activity and inactivity at 0.5–4 Hz, resulting in the generation of the delta waves of slow wave sleep. During this period, the thalamus stops relaying sensory information to the brain, however it continues to produce signals, such as spindle waves, that are sent to its cortical projections. Sleep spindles of slow wave sleep are generated as an interaction of the thalamic reticular nucleus with thalamic relay neurons. The sleep spindles have been predicted to play a role in disconnecting the cortex from sensory input and allowing entry of calcium ions into cells, thus potentially playing a role in plasticity.

==== NREM 1 ==== NREM Stage 1 (N1 – light sleep, somnolence, drowsy sleep – 5–10% of total sleep in adults): This is a stage of sleep that usually occurs between sleep and wakefulness, and sometimes occurs between periods of deeper sleep and periods of REM. The muscles are active, and the eyes roll slowly, opening and closing moderately. The brain transitions from alpha waves having a frequency of 8–13 Hz (common in the awake state) to theta waves having a frequency of 4–7 Hz. Sudden twitches and hypnic jerks, also known as positive myoclonus, may be associated with the onset of sleep during N1. Some people may also experience hypnagogic hallucinations during this stage. During Non-REM1, humans lose some muscle tone and most conscious awareness of the external environment.

==== NREM 2 ==== NREM Stage 2 (N2 – 45–55% of total sleep in adults): In this stage, theta activity is observed and sleepers become gradually harder to awaken; the alpha waves of the previous stage are interrupted by abrupt activity called sleep spindl...

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Neuroscience - Neuroscience