Oxidative stress mechanisms in tissue injury. Free radical toxicity induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination).
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O− 2 (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide).
Further, some reactive oxidative species act as cellular messengers in
redox signaling. Thus, oxidative stress can cause disruptions in normal
mechanisms of cellular signaling.
Chemically,
oxidative stress is associated with increased production of oxidizing
species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.
The effects of oxidative stress depend upon the size of these changes,
with a cell being able to overcome small perturbations and regain its
original state. However, more severe oxidative stress can cause cell
death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.
Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage. Most long-term effects are caused by damage to DNA. DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol,
have been extensively studied. Recently the focus has shifted to some
of the more complex lesions. Tandem DNA lesions are formed at
substantial frequency by ionizing radiation and metal-catalyzedH2O2 reactions. Under anoxic conditions,
the predominant double-base lesion is a species in which C8 of guanine
is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T). Most of these oxygen-derived species are produced by normal aerobic metabolism.
Normal cellular defense mechanisms destroy most of these. Repair of
oxidative damages to DNA is frequent and ongoing, largely keeping up
with newly induced damages. In rat urine, about 74,000 oxidative DNA
adducts per cell are excreted daily.
There is also a steady state level of oxidative damages in the DNA of a
cell. There are about 24,000 oxidative DNA adducts per cell in young
rats and 66,000 adducts per cell in old rats.
Likewise, any damage to cells is constantly repaired. However, under
the severe levels of oxidative stress that cause necrosis, the damage
causes ATP depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.
Polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid,
are primary targets for free radical and singlet oxygen oxidations. For
example, in tissues and cells, the free radical oxidation of linoleic
acid produces racemic mixtures of 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12-E-octadecadienoic acid (9-EE-HODE), and 11-hydroxy-9Z,12-Z-octadecadienoic acid as well as 4-Hydroxynonenal while singlet oxygen attacks linoleic acid to produce (presumed but not yet proven to be racemic mixtures of) 13-hydroxy-9Z,11E-octadecadienoic acid, 9-hydroxy-10E,12-Z-octadecadienoic acid, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic (see 13-Hydroxyoctadecadienoic acid and 9-Hydroxyoctadecadienoic acid). Similar attacks on arachidonic acid produce a far larger set of products including various isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals.
While many of these products are used as markers of oxidative stress,
the products derived from linoleic acid appear far more predominant than
arachidonic acid products and therefore easier to identify and quantify
in, for example, atheromatous plaques.
Certain linoleic acid products have also been proposed to be markers
for specific types of oxidative stress. For example, the presence of
racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of
linoleic acid whereas the presence of racemic 10-hydroxy-8E,12Z-octadecadienoic acid and 12-hydroxy-9Z-13-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid.
In addition to serving as markers, the linoleic and arachidonic acid
products can contribute to tissue and/or DNA damage but also act as
signals to stimulate pathways which function to combat oxidative stress.
One-electron reduction state of O2, formed in many autoxidation reactions and by the electron transport chain. Rather unreactive but can release Fe2+ from iron-sulfur proteins and ferritin. Undergoes dismutation to form H2O2 spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation.
Formed by radical reactions with cellular components such as lipids and nucleobases.
RO•, alkoxy and ROO•, peroxy radicals
Oxygen centred organic radicals. Lipid forms participate in lipid peroxidation reactions. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction.
Formed in a rapid reaction between •O− 2
and NO•. Lipid-soluble and similar in reactivity to hypochlorous acid.
Protonation forms peroxynitrous acid, which can undergo homolytic
cleavage to form hydroxyl radical and nitrogen dioxide.
Production and consumption of oxidants
One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from mitochondria during oxidative phosphorylation. E. coli mutants that lack an active electron transport chain produce as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms. One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.
Other enzymes capable of producing superoxide are xanthine oxidase, NADPH oxidases and cytochromes P450.
Hydrogen peroxide is produced by a wide variety of enzymes including
several oxidases. Reactive oxygen species play important roles in cell
signalling, a process termed redox signaling. Thus, to maintain proper cellular homeostasis, a balance must be struck between reactive oxygen production and consumption.
The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin.
Other enzymes that have antioxidant properties (though this is not
their primary role) include paraoxonase, glutathione-S transferases, and
aldehyde dehydrogenases.
The amino acid methionine is prone to oxidation, but oxidized
methionine can be reversible. Oxidation of methionine is shown to
inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins.
This gives a plausible mechanism for cells to couple oxidative stress
signals with cellular mainstream signaling such as phosphorylation.
Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome (ME/CFS). Oxidative stress also contributes to tissue injury following irradiation and hyperoxia,
as well as in diabetes. In hematological cancers, such as leukemia, the
impact of oxidative stress can be bilateral. Reactive oxygen species
can disrupt the function of immune cells, promoting immune evasion of leukemic cells. On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells.
Oxidative stress is likely to be involved in age-related
development of cancer. The reactive species produced in oxidative
stress can cause direct damage to the DNA and are therefore mutagenic, and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis. Infection by Helicobacter pylori
which increases the production of reactive oxygen and nitrogen species
in human stomach is also thought to be important in the development of gastric cancer.
Oxidative stress can cause DNA damage in neurons. In neuronal progenitor cells, DNA damage is associated with increased secretion of amyloid beta proteins Aβ40 and Aβ42.
This association supports the existence of a causal relationship
between oxidative DNA damage and Aβ accumulation and suggests that
oxidative DNA damage may contribute to Alzheimer's disease (AD) pathology.
AD is associated with an accumulation of DNA damage (double-strand
breaks) in vulnerable neuronal and glial cell populations from early
stages onward, and DNA double-strand breaks are increased in the hippocampus of AD brains compared to non-AD control brains.
The use of antioxidants to prevent some diseases is controversial. In a high-risk group like smokers, high doses of beta carotene increased the rate of lung cancer since high doses of beta-carotene in conjunction of high oxygen tension due to smoking results in a pro-oxidant effect and an antioxidant effect when oxygen tension is not high. In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease.
However, while consumption of food rich in vitamin E may reduce the
risk of coronary heart disease in middle-aged to older men and women,
using vitamin E supplements also appear to result in an increase in
total mortality, heart failure, and hemorrhagic stroke.
The American Heart Association therefore recommends the consumption of
food rich in antioxidant vitamins and other nutrients, but does not
recommend the use of vitamin E supplements to prevent cardiovascular
disease. In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is also mixed.Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.
Oxidative stress (as formulated in Denham Harman's free-radical theory of aging)
is also thought to contribute to the aging process. While there is good
evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans, recent evidence from Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species. The situation in mammals is even less clear. Recent epidemiological findings support the process of mitohormesis,
but a 2007 meta-analysis finds that in studies with a low risk of bias
(randomization, blinding, follow-up), some popular antioxidant
supplements (vitamin A, beta carotene, and vitamin E) may increase
mortality risk (although studies more prone to bias reported the
reverse).
The USDA removed the table showing the Oxygen Radical Absorbance Capacity
(ORAC) of Selected Foods Release 2 (2010) table due to the lack of
evidence that the antioxidant level present in a food translated into a
related antioxidant effect in the body.
Metal catalysts
Metals such as iron, copper, chromium, vanadium, and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes production of reactive radicals and reactive oxygen species.
The presence of such metals in biological systems in an uncomplexed
form (not in a protein or other protective metal complex) can
significantly increase the level of oxidative stress. These metals are
thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide. The hydroxyl radical then can modify amino acids. For example, meta-tyrosine and ortho-tyrosine form by hydroxylation of phenylalanine.
Other reactions include lipid peroxidation and oxidation of
nucleobases. Metal-catalyzed oxidations also lead to irreversible
modification of arginine, lysine, proline, and threonine. Excessive
oxidative-damage leads to protein degradation or aggregation.
The reaction of transition metals with proteins oxidated by
reactive oxygen or nitrogen species can yield reactive products that
accumulate and contribute to aging and disease. For example, in Alzheimer's patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.
Non-metal redox catalysts
Certain
organic compounds in addition to metal redox catalysts can also produce
reactive oxygen species. One of the most important classes of these is
the quinones. Quinones can redox cycle with their conjugate semiquinones and hydroquinones, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.
Immune defense
The
immune system uses the lethal effects of oxidants by making the
production of oxidizing species a central part of its mechanism of
killing pathogens; with activated phagocytes producing both reactive oxygen and nitrogen species. These include superoxide (•O− 2), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-).
Although the use of these highly reactive compounds in the cytotoxic
response of phagocytes causes damage to host tissues, the
non-specificity of these oxidants is an advantage since they will damage
almost every part of their target cell. This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.
Male infertility
SpermDNA fragmentation appears to be an important factor in the cause of male infertility, since men with high DNA fragmentation levels have significantly lower odds of conceiving. Oxidative stress is the major cause of DNA fragmentation in spermatozoa. A high level of the oxidative DNA damage 8-oxo-2'-deoxyguanosine is associated with abnormal spermatozoa and male infertility.
In a rat model of premature aging, oxidative stress induced DNA damage in the neocortex and hippocampus was substantially higher than in normally aging control rats.
Numerous studies have shown that the level of 8-oxo-2'-deoxyguanosine,
a product of oxidative stress, increases with age in the brain and
muscle DNA of the mouse, rat, gerbil and human. Further information on the association of oxidative DNA damage with aging is presented in the article DNA damage theory of aging. However, it was recently shown that the fluoroquinolone antibiotic Enoxacin can diminish aging signals and promote lifespan extension in nematodes C. elegans by inducing oxidative stress.
Origin of eukaryotes
The great oxygenation event began with the biologically induced appearance of oxygen in the Earth's atmosphere about 2.45 billion years ago. The rise of oxygen levels due to cyanobacterialphotosynthesis
in ancient microenvironments was probably highly toxic to the
surrounding biota. Under these conditions, the selective pressure of
oxidative stress is thought to have driven the evolutionary
transformation of an archaeal lineage into the first eukaryotes. Oxidative stress might have acted in synergy with other environmental stresses (such as ultraviolet radiation and/or desiccation)
to drive this selection. Selective pressure for efficient repair of
oxidative DNA damages may have promoted the evolution of eukaryotic sex
involving such features as cell-cell fusions, cytoskeleton-mediated chromosome movements and emergence of the nuclear membrane. Thus, the evolution of meiotic
sex and eukaryogenesis may have been inseparable processes that evolved
in large part to facilitate repair of oxidative DNA damages.
COVID-19 and cardiovascular injury
It has been proposed that oxidative stress may play a major role in determining cardiac complications in COVID-19.
Sleeping Princess: An early 20th-century painting by Victor Vasnetsov
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 high computational power 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 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.
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.
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
Animal Sleep: Sleeping white tiger
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.
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, 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
Slow Wave Sleep
REM Sleep
EEG waveforms of brain activity during sleep
Hypnogram
showing sleep architecture from midnight to 6:30 am, with deep sleep
early on. There is more REM (marked red) before waking. (Current
hypnograms reflect the recent decision to combine NREM stages 3 and 4
into a single stage 3.)
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.[68] 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 spindles (or thalamocortical spindles) and K-complexes.
Sleep spindles range from 11 to 16 Hz (most commonly 12–14 Hz). During
this stage, muscular activity as measured by EMG decreases, and
conscious awareness of the external environment disappears.
NREM Stage 3 (N3 – 15–25% of total sleep in adults): Formerly divided into stages 3 and 4, this stage is called slow-wave sleep (SWS) or deep sleep. SWS is initiated in the preoptic area and consists of delta activity,
high amplitude waves at less than 3.5 Hz. The sleeper is less
responsive to the environment; many environmental stimuli no longer
produce any reactions. Slow-wave sleep is thought to be the most restful
form of sleep, the phase which most relieves subjective feelings of
sleepiness and restores the body.
This stage is characterized by the presence of a minimum of 20% delta waves
ranging from 0.5–2 Hz and having a peak-to-peak amplitude >75 μV.
(EEG standards define delta waves to be from 0 to 4 Hz, but sleep
standards in both the original R&K model (Allan Rechtschaffen and Anthony Kales in the "R&K sleep scoring manual."), as well as the new 2007 AASM guidelines have a range of 0.5–2 Hz.) This is the stage in which parasomnias such as night terrors, nocturnal enuresis, sleepwalking, and somniloquy
occur. Many illustrations and descriptions still show a stage N3 with
20–50% delta waves and a stage N4 with greater than 50% delta waves;
these have been combined as stage N3.
30 seconds of REM sleep. Eye movements highlighted by red box.
REM Stage (REM Sleep – 20–25% of total sleep in adults):
REM sleep is where most muscles are paralyzed, and heart rate,
breathing and body temperature become unregulated. REM sleep is turned
on by acetylcholine secretion and is inhibited by neurons that secrete monoamines including serotonin. REM is also referred to as paradoxical sleep
because the sleeper, although exhibiting high-frequency EEG waves
similar to a waking state, is harder to arouse than at any other sleep
stage. Vital signs indicate arousal and oxygen consumption by the brain is higher than when the sleeper is awake. REM sleep is characterized by high global cerebral blood flow, comparable to wakefulness.
In fact, many areas in the cortex have been recorded to have more blood
flow during REM sleep than even wakefulness- this includes the hippocampus, temporal-occipital areas, some parts of the cortex, and basal forebrain. The limbic and paralimbic system including the amygdala are other active regions during REM sleep.
Though the brain activity during REM sleep appears very similar to
wakefulness, the main difference between REM and wakefulness is that, arousal in REM is more effectively inhibited. This, along with the virtual silence of monoaminergic neurons in the brain, may be said to characterize REM.
A newborn baby spends 8 to 9 hours a day just in REM sleep. By
the age of five or so, only slightly over two hours is spent in REM.
The function of REM sleep is uncertain but a lack of it impairs the
ability to learn complex tasks. Functional paralysis from muscular atonia
in REM may be necessary to protect organisms from self-damage through
physically acting out scenes from the often-vivid dreams that occur
during this stage.
In EEG recordings, REM sleep is characterized by high frequency, low amplitude activity and spontaneous occurrence of beta and gamma waves.
The best candidates for generation of these fast frequency waves are
fast rhythmic bursting neurons in corticothalamic circuits. Unlike in
slow wave sleep, the fast frequency rhythms are synchronized over
restricted areas in specific local circuits between thalamocortical and
neocortical areas. These are said to be generated by cholinergic processes from brainstem structures.
Apart from this, the amygdala plays a role in REM sleep
modulation, supporting the hypothesis that REM sleep allows internal
information processing. The high amygdalar activity may also cause the
emotional responses during dreams. Similarly, the bizarreness of dreams may be due to the decreased activity of prefrontal regions, which are involved in integrating information as well as episodic memory.
Ponto-geniculo-occipital waves
REM sleep is also related to the firing of ponto-geniculo-occipital
waves (also called phasic activity or PGO waves) and activity in the
cholinergic ascending arousal system. PGO waves have been recorded in
the lateral geniculate nucleus and occipital cortex
during the pre-REM period and are thought to represent dream content.
The greater signal-to-noise ratio in the LG cortical channel suggests
that visual imagery in dreams may appear before full development of REM
sleep, but this has not yet been confirmed. PGO waves may also play a
role in development and structural maturation of brain, as well as long term potentiation in immature animals, based on the fact that there is high PGO activity during sleep in the developmental brain.
Network reactivation
The
other form of activity during sleep is reactivation. Some
electrophysiological studies have shown that neuronal activity patterns
found during a learning task before sleep are reactivated in the brain
during sleep.
This, along with the coincidence of active areas with areas responsible
for memory have led to the theory that sleep might have some memory
consolidation functions. In this relation, some studies have shown that
after a sequential motor task, the pre-motor and visual cortex areas involved are most active during REM sleep, but not during NREM. Similarly, the hippocampal
areas involved in spatial learning tasks are reactivated in NREM sleep,
but not in REM. Such studies suggest a role of sleep in consolidation
of specific memory types. It is, however, still unclear whether other
types of memory are also consolidated by these mechanisms.
Hippocampal neocortical dialog
The hippocampal neocortical dialog refers to the very structured interactions during SWS between groups of neurons called ensembles in the hippocampus and neocortex.
Sharp wave patterns (SPW) dominate the hippocampus during SWS and
neuron populations in the hippocampus participate in organized bursts
during this phase. This is done in synchrony with state changes in the
cortex (DOWN/UP state) and coordinated by the slow oscillations in
cortex. These observations, coupled with the knowledge that the
hippocampus plays a role in short to medium term memory whereas the
cortex plays a role in long-term memory, have led to the hypothesis that
the hippocampal neocortical dialog might be a mechanism through which
the hippocampus transfers information to the cortex. Thus, the
hippocampal neocortical dialog is said to play a role in memory
consolidation.
Sleep regulation
Sleep regulation refers to the control of when an organism transitions between sleep and wakefulness.
The key questions here are to identify which parts of the brain are
involved in sleep onset and what their mechanisms of action are. In humans and most animals sleep and wakefulness seems to follow an electronic flip-flop model i.e. both states are stable, but the intermediate states are not.
Of course, unlike in the flip-flop, in the case of sleep, there seems
to be a timer ticking away from the minute of waking so that after a
certain period one must sleep, and in such a case even waking becomes an
unstable state. The reverse may also be true to a lesser extent.
Sleep onset can be negatively influenced from lesions in the preoptic area and anterior hypothalamus leading to insomnia while lesions in the posterior hypothalamus lead to sleepiness. This was further narrowed down to show that the central midbrain tegmentum
is the region that plays a role in cortical activation. Thus, sleep
onset seems to arise from activation of the anterior hypothalamus along
with inhibition of the posterior regions and the central midbrain
tegmentum. Further research has shown that the hypothalamic region
called ventrolateral preoptic nucleus produces the inhibitory neurotransmitter GABA that inhibits the arousal system during sleep onset.
Models of sleep regulation
Sleep is regulated by two parallel mechanisms, homeostatic regulation and circadian regulation, controlled by the hypothalamus and the suprachiasmatic nucleus (SCN),
respectively. Although the exact nature of sleep drive is unknown,
homeostatic pressure builds up during wakefulness and this continues
until the person goes to sleep. Adenosine
is thought to play a critical role in this and many people have
proposed that the pressure build-up is partially due to adenosine
accumulation. However, some researchers have shown that accumulation
alone does not explain this phenomenon completely. The circadian rhythm
is a 24-hour cycle in the body, which has been shown to continue even in
the absence of environmental cues. This is caused by projections from
the SCN to the brain stem.
This two process model was first proposed in 1982 by Borbely,
who called them Process S (homeostatic) and Process C (Circadian)
respectively. He showed how the slow wave density increases through the
night and then drops off at the beginning of the day while the circadian
rhythm is like a sinusoid. He proposed that the pressure to sleep was
the maximum when the difference between the two was highest.
In 1993, a different model called the opponent process model
was proposed. This model explained that these two processes opposed
each other to produce sleep, as against Borbely's model. According to
this model, the SCN, which is involved in the circadian rhythm, enhances
wakefulness and opposes the homeostatic rhythm. In opposition is the
homeostatic rhythm, regulated via a complex multisynaptic pathway in the
hypothalamus that acts like a switch and shuts off the arousal system.
Both effects together produce a see-saw like effect of sleep and
wakefulness.
More recently, it has been proposed that both models have some validity
to them, while new theories hold that inhibition of NREM sleep by REM
could also play a role.
In any case, the two process mechanism adds flexibility to the simple
circadian rhythm and could have evolved as an adaptive measure.
Thalamic regulation
Much of the brain activity in sleep has been attributed to the thalamus and it appears that the thalamus may play a critical role in SWS. The two primary oscillations in slow wave sleep,
delta and the slow oscillation, can be generated by both the thalamus
and the cortex. However, sleep spindles can only be generated by the
thalamus, making its role very important. The thalamic pacemaker
hypothesis
holds that these oscillations are generated by the thalamus but the
synchronization of several groups of thalamic neurons firing
simultaneously depends on the thalamic interaction with the cortex.
The thalamus also plays a critical role in sleep onset when it changes
from tonic to phasic mode, thus acting like a mirror for both central
and decentral elements and linking distant parts of the cortex to
co-ordinate their activity.
Ascending reticular activating system
The ascending reticular activating system consists of a set of neural subsystems that project from various thalamic nuclei and a number of dopaminergic, noradrenergic, serotonergic, histaminergic, cholinergic, and glutamatergic brain nuclei.
When awake, it receives all kinds of non-specific sensory information
and relays them to the cortex. It also modulates fight or flight
responses and is hence linked to the motor system. During sleep onset,
it acts via two pathways: a cholinergic pathway that projects to the
cortex via the thalamus and a set of monoaminergic pathways that
projects to the cortex via the hypothalamus. During NREM sleep this
system is inhibited by GABAergic neurons in the ventrolateral preoptic area and parafacial zone, as well as other sleep-promoting neurons in distinct brain regions.
Sleep function
Sleep deprivation studies show that sleep is particularly important to normal brain function. Sleep is needed to remove reactive oxygen species caused by oxidative stress (and generally autophagy) and to repair DNA. REM sleep also decrease concentration of noradrenaline, which when in excess amount causes the cell to undergo apoptosis.
It is likely that sleep evolved to fulfill some primeval function and took on multiple functions over time (analogous to the larynx, which controls the passage of food and air, but descended over time to develop speech capabilities).
The multiple hypotheses proposed to explain the function of sleep
reflect the incomplete understanding of the subject. While some
functions of sleep are known, others have been proposed but not
completely substantiated or understood. Some of the early ideas about
sleep function were based on the fact that most (if not all) external
activity is stopped during sleep. Initially, it was thought that sleep
was simply a mechanism for the body to "take a break" and reduce wear.
Later observations of the low metabolic rates in the brain during sleep seemed to indicate some metabolic functions of sleep. This theory is not fully adequate as sleep only decreases metabolism by about 5–10%.
With the development of EEG, it was found that the brain has almost
continuous internal activity during sleep, leading to the idea that the
function could be that of reorganization or specification of neuronal
circuits or strengthening of connections.
These hypotheses are still being explored. Other proposed functions of
sleep include- maintaining hormonal balance, temperature regulation and
maintaining heart rate.
According to a recent sleep disruption and insomnia review study,
there are short-term and long-term negative consequences on healthy
individuals. The short term consequences include increased stress
responsivity and psychosocial issues such as impaired cognitive or
academic performance and depression. Experiments indicated that, in
healthy children and adults, episodes of fragmented sleep or insomnia
increased sympathetic activation, which can disrupt mood and cognition.
The long term consequences include metabolic issues such as glucose
homeostasis disruption and even tumor formation and increased risks of
cancer.
Preservation
The
"Preservation and Protection" theory holds that sleep serves an
adaptive function. It protects the animal during that portion of the
24-hour day in which being awake, and hence roaming around, would place
the individual at greatest risk.
Organisms do not require 24 hours to feed themselves and meet other
necessities. From this perspective of adaptation, organisms are safer by
staying out of harm's way, where potentially they could be prey to
other, stronger organisms. They sleep at times that maximize their
safety, given their physical capacities and their habitats.
This theory fails to explain why the brain disengages from the
external environment during normal sleep. However, the brain consumes a
large proportion of the body's energy at any one time and preservation
of energy could only occur by limiting its sensory inputs. Another
argument against the theory is that sleep is not simply a passive
consequence of removing the animal from the environment, but is a
"drive"; animals alter their behaviors in order to obtain sleep.
Therefore, circadian regulation is more than sufficient to explain periods of activity and quiescence
that are adaptive to an organism, but the more peculiar specializations
of sleep probably serve different and unknown functions. Moreover, the
preservation theory needs to explain why carnivores like lions, which
are on top of the food chain
and thus have little to fear, sleep the most. It has been suggested
that they need to minimize energy expenditure when not hunting.
Waste clearance from the brain
During sleep, metabolic waste products, such as immunoglobulins, protein fragments or intact proteins like beta-amyloid, may be cleared from the interstitium via a glymphatic system of lymph-like channels coursing along perivascular spaces and the astrocyte network of the brain. According to this model, hollow tubes between the blood vessels and astrocytes act like a spillway allowing drainage of cerebrospinal fluid carrying wastes out of the brain into systemic blood. Such mechanisms, which remain under preliminary research as of 2017,
indicate potential ways in which sleep is a regulated maintenance period
for brain immune functions and clearance of beta-amyloid, a risk factor for Alzheimer's disease.
Restoration
Wound healing has been shown to be affected by sleep.
It has been shown that sleep deprivation affects the immune system.
It is now possible to state that "sleep loss impairs immune function
and immune challenge alters sleep," and it has been suggested that sleep
increases white blood cell counts.
A 2014 study found that depriving mice of sleep increased cancer growth
and dampened the immune system's ability to control cancers.
The effect of sleep duration on somatic
growth is not completely known. One study recorded growth, height, and
weight, as correlated to parent-reported time in bed in 305 children
over a period of nine years (age 1–10). It was found that "the variation
of sleep duration among children does not seem to have an effect on
growth." It is well established that slow-wave sleep affects growth hormone levels in adult men.
During eight hours' sleep, Van Cauter, Leproult, and Plat found that
the men with a high percentage of SWS (average 24%) also had high growth
hormone secretion, while subjects with a low percentage of SWS (average
9%) had low growth hormone secretion.
There is some supporting evidence of the restorative function of
sleep. The sleeping brain has been shown to remove metabolic waste
products at a faster rate than during an awake state.
While awake, metabolism generates reactive oxygen species, which are
damaging to cells. In sleep, metabolic rates decrease and reactive
oxygen species generation is reduced allowing restorative processes to
take over. It is theorized that sleep helps facilitate the synthesis of
molecules that help repair and protect the brain from these harmful
elements generated during waking.
The metabolic phase during sleep is anabolic; anabolic hormones such as
growth hormones (as mentioned above) are secreted preferentially during
sleep.
Energy conservation could as well have been accomplished by
resting quiescent without shutting off the organism from the
environment, potentially a dangerous situation. A sedentary nonsleeping
animal is more likely to survive predators, while still preserving
energy. Sleep, therefore, seems to serve another purpose, or other
purposes, than simply conserving energy. Another potential purpose for
sleep could be to restore signal strength in synapses that are activated
while awake to a "baseline" level, weakening unnecessary connections
that to better facilitate learning and memory functions again the next
day; this means the brain is forgetting some of the things we learn each
day.
Entropy reduction
This theory is related to the restorative role of sleep but distinct enough since it deals with a very specific quantify: entropy.
In a very simplified way, wakefulness can be associated with increased
disorder in the nervous system and this disorder can threaten the high
order that is needed for proper function of the nervous system. Entropy
is related to order and disorder, but it is not necessarily the same. Cortical activity gets progressively disrupted during wakefulness and sleep restores the levels of cortical activity close to criticality. Signal noise affects many aspect of the central nervous system. Understanding the relationship between wakefulness and entropy can be approached from the field of statistical mechanics. At a substratum level, interactions with the environment increase the number of possible micro states of the nervous system and this leads to an increase in entropy.
The reduction in entropy can also be approached from the perspective of classic and non-equilibrium thermodynamics. The central nervous system uses a disproportionate amount of the available energy supply. Most of the energy usage of the nervous system is devoted to electric neuronal activity and synaptic processes. Energy is used in large amounts by the Na+/K + -ATPase pump to move sodium and potassium in the generation of action potentials; this process is highly efficient but entropy is still generated.
Endocrine function
The secretion of many hormones is affected by sleep-wake cycles. For example, melatonin, a hormonal timekeeper, is considered a strongly circadian hormone, whose secretion increases at dim light and peaks during nocturnal sleep, diminishing with bright light to the eyes.
In some organisms melatonin secretion depends on sleep, but in humans
it is independent of sleep and depends only on light level. Of course,
in humans as well as other animals, such a hormone may facilitate
coordination of sleep onset. Similarly, cortisol and thyroid stimulating hormone (TSH) are strongly circadian and diurnal hormones, mostly independent of sleep. In contrast, other hormones like growth hormone (GH) & prolactin are critically sleep-dependent, and are suppressed in the absence of sleep.
GH has maximum increase during SWS while prolactin is secreted early
after sleep onset and rises through the night. In some hormones whose
secretion is controlled by light level, sleep seems to increase
secretion. Almost in all cases, sleep deprivation has detrimental
effects. For example, cortisol, which is essential for metabolism (it is
so important that animals can die within a week of its deficiency) and
affects the ability to withstand noxious stimuli, is increased by waking
and during REM sleep.
Similarly, TSH increases during nocturnal sleep and decreases with
prolonged periods of reduced sleep, but increases during total acute
sleep deprivation.
Because hormones play a major role in energy balance and metabolism, and
sleep plays a critical role in the timing and amplitude of their
secretion, sleep has a sizable effect on metabolism. This could explain
some of the early theories of sleep function that predicted that sleep
has a metabolic regulation role.
According to Plihal & Born, sleep generally increases recalling
of previous learning and experiences, and its benefit depends on the
phase of sleep and the type of memory. For example, studies based on declarative and procedural memory
tasks applied over early and late nocturnal sleep, as well as
wakefulness controlled conditions, have been shown that declarative
memory improves more during early sleep (dominated by SWS) while
procedural memory during late sleep (dominated by REM sleep).
Regarding to declarative memory, the functional role of SWS has
been associated with hippocampal replays of previously encoded neural
patterns that seem to facilitate long-term memories consolidation.
This assumption is based on the active system consolidation hypothesis,
which states that repeated reactivations of newly encoded information
in hippocampus during slow oscillations in NREM sleep mediate the
stabilization and gradually integration of declarative memory with
pre-existing knowledge networks on the cortical level.
It assumes the hippocampus might hold information only temporarily and
in fast-learning rate, whereas the neocortex is related to long-term
storage and slow-learning rate.This dialogue between hippocampus and neocortex occurs in parallel with hippocampal sharp-wave ripples and thalamo-cortical spindles,
synchrony that drives the formation of spindle-ripple event which seems
to be a prerequisite for the formation of long-term memories.
Reactivation of memory also occurs during wakefulness and its
function is associated with serving to update the reactivated memory
with new encoded information, whereas reactivations during SWS are
presented as crucial for memory stabilization.
Based on targeted memory reactivation (TMR) experiments that use
associated memory cues to triggering memory traces during sleep, several
studies have been reassuring the importance of nocturnal reactivations
for the formation of persistent memories in neocortical networks, as
well as highlighting the possibility of increasing people's memory
performance at declarative recalls.
Furthermore, nocturnal reactivation seems to share the same
neural oscillatory patterns as reactivation during wakefulness,
processes which might be coordinated by theta activity.
During wakefulness, theta oscillations have been often related to
successful performance in memory tasks, and cued memory reactivations
during sleep have been showing that theta activity is significantly
stronger in subsequent recognition of cued stimuli as compared to uncued
ones, possibly indicating a strengthening of memory traces and lexical
integration by cuing during sleep.
However, the beneficial effect of TMR for memory consolidation seems to
occur only if the cued memories can be related to prior knowledge.
Other studies have been also looking at the specific effects of
different stages of sleep on different types of memory. For example, it
has been found that sleep deprivation does not significantly affect
recognition of faces, but can produce a significant impairment of
temporal memory (discriminating which face belonged to which set shown).
Sleep deprivation was also found to increase beliefs of being correct,
especially if they were wrong. Another study reported that the
performance on free recall of a list of nouns is significantly worse
when sleep deprived (an average of 2.8 ± 2 words) compared to having a
normal night of sleep (4.7 ± 4 words). These results reinforce the role
of sleep on declarative memory formation. This has been further confirmed by observations of low metabolic activity in the prefrontal cortex and temporal and parietal lobes
for the temporal learning and verbal learning tasks respectively. Data
analysis has also shown that the neural assemblies during SWS correlated
significantly more with templates than during waking hours or REM
sleep. Also, post-learning, post-SWS reverberations lasted 48 hours,
much longer than the duration of novel object learning (1 hour),
indicating long term potentiation.
Moreover, observations include the importance of napping:
improved performance in some kinds of tasks after a 1-hour afternoon
nap; studies of performance of shift workers, showing that an equal
number of hours of sleep in the day is not the same as in the night.
Current research studies look at the molecular and physiological basis
of memory consolidation
during sleep. These, along with studies of genes that may play a role
in this phenomenon, together promise to give a more complete picture of
the role of sleep in memory.
Renormalizing the synaptic strength
Sleep
can also serve to weaken synaptic connections that were acquired over
the course of the day but which are not essential to optimal
functioning. In doing so, the resource demands can be lessened, since
the upkeep and strengthening of synaptic connections constitutes a large
portion of energy consumption by the brain and tax other cellular
mechanisms such as protein synthesis for new channels.Without a mechanism like this taking place during sleep, the metabolic
needs of the brain would increase over repeated exposure to daily
synaptic strengthening, up to a point where the strains become excessive
or untenable.
Behavior change with sleep deprivation
One approach to understanding the role of sleep is to study the deprivation of it. Sleep deprivation
is common and sometimes even necessary in modern societies because of
occupational and domestic reasons like round-the-clock service, security
or media coverage, cross-time-zone projects etc. This makes
understanding the effects of sleep deprivation very important.
Many studies have been done from the early 1900s to document the
effect of sleep deprivation. The study of REM deprivation began with William C. Dement
around 1960. He conducted a sleep and dream research project on eight
subjects, all male. For a span of up to 7 days, he deprived the
participants of REM sleep by waking them each time they started to enter
the stage. He monitored this with small electrodes attached to their
scalp and temples. As the study went on, he noticed that the more he
deprived the men of REM sleep, the more often he had to wake them.
Afterwards, they showed more REM sleep than usual, later named REM rebound.
The neurobehavioral
basis for these has been studied only recently. Sleep deprivation has
been strongly correlated with increased probability of accidents and
industrial errors. Many studies have shown the slowing of metabolic activity in the brain with many hours of sleep debt. Some studies have also shown that the attention network in the brain is particularly affected by lack of sleep,
and though some of the effects on attention may be masked by alternate
activities (like standing or walking) or caffeine consumption, attention deficit cannot be completely avoided.
Sleep deprivation has been shown to have a detrimental effect on
cognitive tasks, especially involving divergent functions or
multitasking.
It also has effects on mood and emotion, and there have been multiple
reports of increased tendency for rage, fear or depression with sleep
debt. However, some of the higher cognitive functions seem to remain unaffected albeit slower. Many of these effects vary from person to person
i.e. while some individuals have high degrees of cognitive impairment
with lack of sleep, in others, it has minimal effects. The exact
mechanisms for the above are still unknown and the exact neural pathways
and cellular mechanisms of sleep debt are still being researched.
A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Polysomnography is a test commonly used for diagnosing some sleep disorders. Sleep disorders are broadly classified into dyssomnias, parasomnias, circadian rhythm sleep disorders (CRSD), and other disorders including ones caused by medical or psychological conditions and sleeping sickness. Some common sleep disorders include insomnia (chronic inability to sleep), sleep apnea (abnormally low breathing during sleep), narcolepsy (excessive sleepiness at inappropriate times), cataplexy
(sudden and transient loss of muscle tone), and sleeping sickness
(disruption of sleep cycle due to infection). Other disorders that are
being studied include sleepwalking, sleep terror and bed wetting.
Studying sleep disorders is particularly useful as it gives some
clues as to which parts of the brain may be involved in the modified
function. This is done by comparing the imaging and histological
patterns in normal and affected subjects. Treatment of sleep disorders
typically involves behavioral and psychotherapeutic
methods though other techniques may also be used. The choice of
treatment methodology for a specific patient depends on the patient's
diagnosis, medical and psychiatric history, and preferences, as well as
the expertise of the treating clinician. Often, behavioral or
psychotherapeutic and pharmacological approaches are compatible and can effectively be combined to maximize therapeutic benefits.
Frequently, sleep disorders have been also associated with
neurodegenerative diseases, mainly when they are characterized by
abnormal accumulation of alpha-synuclein, such as multiple system atrophy (MSA), Parkinson's disease (PD) and Lewy body disease (LBD).For instance, people diagnosed with PD have often presented different kinds of sleep concerns, commonly regard to insomnia (around 70% of the PD population), hypersomnia (more than 50% of the PD population), and REM sleep behavior disorder (RBD) - that may affect around 40% of the PD population and it is associated with increased motor symptoms.
Furthermore, RBD has been also highlighted as a strong precursor of
future development of those neurodegenerative diseases over several
years in prior, which seems to be a great opportunity for improving
treatments.
Sleep disturbances have been also observed in Alzheimer's disease (AD), affecting about 45% of its population. Moreover, when it is based on caregiver reports this percentage is even higher, about 70%. As well as in PD population, insomnia and hypersomnia are frequently recognized in AD patients, which are associated with accumulation of Beta-amyloid, circadian rhythm sleep disorders (CRSD) and melatonin alteration. Additionally, changes in sleep architecture are observed in AD too.
Even though with ageing the sleep architecture seems to change
naturally, in AD patients it is aggravated. SWS is potentially decreased
(sometimes totally absent), spindles and the time spent in REM sleep
are also reduced, while its latency is increased.
The poorly sleep onset in AD has been also associated with
dream-related hallucination, increased restlessness, wandering and
agitation, that seem to be related with sundowning - a typical chronobiological phenomenon presented in the disease.
The neurodegenerative conditions are commonly related to brain
structures impairments, which might disrupt the states of sleep and
wakefulness, circadian rhythm, motor or non motor functioning.
On the other hand, sleep disturbances are also frequently related to
worsening patient's cognitive functioning, emotional state and quality
of life. Furthermore, these abnormal behavioural symptoms negatively contribute to overwhelming their relatives and caregivers.
Therefore, a deeper understanding of the relationship between sleep
disorders and neurodegenerative diseases seems to be extremely
important, mainly considering the limited research related to it and the
increasing expectancy of life.
A related field is that of sleep medicine
which involves the diagnosis and therapy of sleep disorders and sleep
deprivation, which is a major cause of accidents. This involves a
variety of diagnostic methods including polysomnography, sleep diary, multiple sleep latency test, etc. Similarly, treatment may be behavioral such as cognitive behavioral therapy or may include pharmacological medication or bright light therapy.
"The Knight's Dream", a 1655 painting by Antonio de Pereda
Dreams are successions of images, ideas, emotions, and sensations
that occur involuntarily in the mind during certain stages of sleep
(mainly the REM stage). The content and purpose of dreams are not yet
clearly understood though various theories have been proposed. The
scientific study of dreams is called oneirology.
There are many theories about the neurological basis of dreaming. This includes the activation synthesis theory—the
theory that dreams result from brain stem activation during REM sleep;
the continual activation theory—the theory that dreaming is a result of
activation and synthesis but dreams and REM sleep are controlled by
different structures in the brain; and dreams as excitations of
long-term memory—a theory which claims that long-term memory excitations
are prevalent during waking hours as well but are usually controlled
and become apparent only during sleep.
There are multiple theories about dream function as well. Some
studies claim that dreams strengthen semantic memories. This is based on
the role of hippocampal neocortical dialog and general connections between sleep and memory. One study surmises that dreams erase junk data in the brain. Emotional adaptation and mood regulation are other proposed functions of dreaming.
From an evolutionary
standpoint, dreams might simulate and rehearse threatening events, that
were common in the organism's ancestral environment, hence increasing a
person's ability to tackle everyday problems and challenges in the
present. For this reason these threatening events may have been passed
on in the form of genetic memories.
This theory accords well with the claim that REM sleep is an
evolutionary transformation of a well-known defensive mechanism, the
tonic immobility reflex.
Most theories of dream function appear to be conflicting, but it
is possible that many short-term dream functions could act together to
achieve a bigger long-term function. It may be noted that evidence for none of these theories is entirely conclusive.
The incorporation of waking memory events into dreams is another
area of active research and some researchers have tried to link it to
the declarative memory consolidation functions of dreaming.
A related area of research is the neuroscience basis of nightmares. Many studies have confirmed a high prevalence of nightmares and some have correlated them with high stress levels. Multiple models of nightmare production have been proposed including neo-Freudian models as well as other models such as image contextualization model, boundary thickness model, threat simulation model etc. Neurotransmitter
imbalance has been proposed as a cause of nightmares, as also affective
network dysfunction- a model which claims that nightmare is a product
of dysfunction of circuitry normally involved in dreaming. As with dreaming, none of the models have yielded conclusive results and studies continue about these questions.
