A phase response curve (PRC) illustrates the transient change (phase response) in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received. PRCs are used in various fields; examples of biological oscillations are the heartbeat, circadian rhythms, and the regular, repetitive firing observed in some neurons in the absence of noise.
In circadian rhythms
Phase response curves for light and for melatonin administration
In humans and animals, there is a regulatory system that governs the phase relationship of an organism's internal circadian clock
to a regular periodicity in the external environment (usually governed
by the solar day). In most organisms, a stable phase relationship is
desired, though in some cases the desired phase will vary by season,
especially among mammals with seasonal mating habits.
In circadian rhythm research, a PRC illustrates the relationship between a chronobiotic's
time of administration (relative to the internal circadian clock) and
the magnitude of the treatment's effect on circadian phase.
Specifically, a PRC is a graph showing, by convention, time of the
subject's endogenous day along the x-axis and the amount of the phase shift (in hours) along the y-axis.
Each curve has one peak and one trough in each 24-hour cycle. Relative
circadian time is plotted against phase-shift magnitude. The treatment
is usually narrowly specified as a set intensity and colour and duration
of light exposure to the retina and skin, or a set dose and formulation
of melatonin.
These curves are often consulted in the therapeutic setting.
Normally, the body's various physiological rhythms will be synchronized
within an individual organism (human or animal), usually with respect to
a master biological clock. Of particular importance is the sleep–wake
cycle. Various sleep disorders and externals stresses (such as jet lag) can interfere with this. People with non-24-hour sleep–wake disorder often experience an inability to maintain a consistent internal clock. Extreme chronotypes
usually maintain a consistent clock, but find that their natural clock
does not align with the expectations of their social environment. PRC
curves provide a starting point for therapeutic intervention. The two
common treatments used to shift the timing of sleep are light therapy, directed at the eyes, and administration of the hormone melatonin,
usually taken orally. Either or both can be used daily. The phase
adjustment is generally cumulative with consecutive daily
administrations, and — at least partially — additive with concurrent
administrations of distinct treatments. If the underlying disturbance is
stable in nature, ongoing daily intervention is usually required. For
jet lag, the intervention serves mainly to accelerate natural alignment,
and ceases once desired alignment is achieved.
Note that phase response curves from the experimental setting are
usually aggregates of the test population, that there can be mild or
significant variation within the test population, that individuals with
sleep disorders often respond atypically, and that the formulation of
the chronobiotic might be specific to the experimental setting and not
generally available in clinical practice (e.g. for melatonin, one
sustained-release formulation might differ in its release rate as
compared to another); also, while the magnitude is dose-dependent,
not all PRC graphs cover a range of doses. The discussions below are
restricted to the PRCs for the light and melatonin in humans.
Light
The time shown on the x-axis
is vague: dawn – mid-day – dusk – night – dawn. These times do not
refer to actual sun-up etc. nor to specific clock times. Each individual
has her/his own circadian "clock" and chronotype, and dawn in the
illustration refers to a person's time of spontaneous awakening when
well-rested and sleeping regularly. The PRC shows when a stimulus, in
this case light to the eyes, will effect a change, an advance or a
delay. The curve's highest point coincides with the subject's lowest
body temperature.
Starting about two hours before an individual's regular bedtime,
exposure of the eyes to light will delay the circadian phase, causing
later wake-up time and later sleep onset. The delaying effect gets
stronger as evening progresses; it is also dependent on the wavelength
and illuminance ("brightness") of the light. The effect is small if indoor lighting is dim (< 3 Lux).
About five hours after usual bedtime, coinciding with the body
temperature trough (the lowest point of the core body temperature during
sleep) the PRC peaks and the effect changes abruptly from phase delay
to phase advance. Immediately after this peak, light exposure has its
greatest phase-advancing effect, causing earlier wake-up and sleep
onset. Again, illuminance greatly affects results; indoor light may be
less than 500 lux while light therapy
uses up to 10,000 lux. The effect diminishes until about two hours
after spontaneous wake-up time, when it reaches approximately zero.
During the period between two hours after usual wake-up time and
two hours before usual bedtime, light exposure has little or no effect
on circadian phase (slight effects generally cancelling each other out).
Another image of the PRC for light is here (Figure 1). Within that image, the explanatory text is
Delay region: evening light shifts sleepiness later and
Light therapy, typically with a light box producing 10,000 lux at a
prescribed distance, can be used in the evening to delay or in the
morning to advance a person's sleep timing. Because losing sleep to
obtain bright light exposure is considered undesirable by most people,
and because it is very difficult to estimate exactly when the greatest
effect (the PRC peak) will occur in an individual, the treatment is
usually applied daily just prior to bedtime (to achieve phase delay), or
just after spontaneous awakening (to achieve phase advance).
In 2002 Brown University researchers led by David Berson announced the discovery of special cells in the human eye, ipRGCs (intrinsically photosensitive retinal ganglion cells),
which many researchers now believe control the light entrainment effect
of the phase response curve. In the human eye, the ipRGCs have the
greatest response to light in the 460–480 nm (blue) range. In one
experiment, 400 lux of blue light produced the same effects as
10,000 lux of white light from a fluorescent source.
A theory of spectral opponency, in which the addition of other spectral
colors renders blue light less effective for circadian
phototransduction, was supported by research reported in 2005.
Melatonin
The phase response curve for melatonin is roughly twelve hours out of phase with the phase response curve for light. At spontaneous wake-up time, exogenous
(externally administered) melatonin has a slight phase-delaying effect.
The amount of phase-delay increases until about eight hours after
wake-up time, when the effect swings abruptly from strong phase delay to
strong phase advance. The phase-advance effect diminishes as the day
goes on until it reaches zero about bedtime. From usual bedtime until
wake-up time, exogenous melatonin has no effect on circadian phase.
The human body produces its own (endogenous) melatonin starting about two hours before bedtime, provided the lighting is dim. This is known as dim-light melatonin onset, DLMO.
This stimulates the phase-advance portion of the PRC and helps keep the
body on a regular sleep-wake schedule. It also helps prepare the body
for sleep.
Administration of melatonin at any time may have a mild hypnotic (sleep-inducing) effect. The expected effect on sleep phase timing, if any, is predicted by the PRC.
Additive effects
In a 2006 study Victoria L. Revell et al.
showed that a combination of morning bright light and afternoon
melatonin, both timed to phase advance according to the respective PRCs,
produce a larger phase advance shift than bright light alone, for a
total of up to 21⁄2
hours. All times are approximate and vary from one person to another.
In particular, there is no convenient way to accurately determine the
times of the peaks and zero-crossings of these curves in an individual.
Administration of light or melatonin close to the time at which the
effect is expected to change sense abruptly may, if the changeover time
is not accurately known, produce an opposite effect to that desired.
Exercise
In a 2019 study Shawn D. Youngstedt et al.,
showed that in humans "Exercise elicits circadian phase‐shifting
effects, but additional information is needed. [...] Significant
phase–response curves were established for aMT6(melatonin derivative)
onset and acrophase with large phase delays from 7:00 pm to 10:00 pm
and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm"
Origin
The first
published usage of the term "phase response curve" was in 1960 by
Patricia DeCoursey. The "daily" activity rhythms of her flying squirrels,
kept in constant darkness, responded to pulses of light exposure. The
response varied according to the time of day – that is, the animals'
subjective "day" – when light was administered. When DeCoursey plotted
all her data relating the quantity and direction (advance or delay) of
phase-shift on a single curve, she created the PRC. It has since been a
standard tool in the study of biological rhythms.
Phase response curve analysis can be used to understand the intrinsic properties and oscillatory behavior of regular-spiking neurons.
The neuronal PRCs can be classified as being purely positive (PRC type
I) or as having negative parts (PRC type II). Importantly, the PRC type
exhibited by a neuron is indicative of its input–output function
(excitability) as well as synchronization behavior: networks of PRC type
II neurons can synchronize their activity via mutual excitatory
connections, but those of PRC type I can not.
Experimental estimation of PRC in living, regular-spiking neurons
involves measuring the changes in inter-spike interval in response to a
small perturbation, such as a transient pulse of current. Notably, the
PRC of a neuron is not fixed but may change when firing frequency or neuromodulatory state of the neuron is changed.
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders
which affect the timing of sleep. CRSDs arise from a persistent pattern
of sleep/wake disturbances that can be caused either by dysfunction in
one's biological clock
system, or by misalignment between one's endogenous oscillator and
externally imposed cues. As a result of this mismatch, those affected by
circadian rhythm sleep disorders have a tendency to fall asleep at
unconventional time points in the day. These occurrences often lead to
recurring instances of disturbed rest, where individuals affected by the
disorder are unable to go to sleep and awaken at "normal" times for
work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.
Overview
Humans,
like most living organisms, have various biological rhythms. These
biological clocks control processes that fluctuate daily (e.g., body
temperature, alertness, hormone secretion), generating circadian rhythms.
Among these physiological characteristics, the sleep-wake propensity
can also be considered one of the daily rhythms regulated by the
biological clock system. Human's sleeping cycles are tightly regulated
by a series of circadian processes working in tandem, allowing for the
experience of moments of consolidated sleep during the night and a long
wakeful moment during the day. Conversely, disruptions to these
processes and the communication pathways between them can lead to
problems in sleeping patterns, which are collectively referred to as
circadian rhythm sleep disorders.
Normal rhythm
A circadian rhythm
is an entrainable, endogenous, biological activity that has a period of
roughly twenty-four hours. This internal time-keeping mechanism is
centralized in the suprachiasmatic nucleus
(SCN) of humans, and allows for the internal physiological mechanisms
underlying sleep and alertness to become synchronized to external
environmental cues, like the light-dark cycle.
The SCN also sends signals to peripheral clocks in other organs, like
the liver, to control processes such as glucose metabolism. Although these rhythms will persist in constant light or dark conditions, different Zeitgebers
(time givers such as the light-dark cycle) give context to the clock
and allow it to entrain and regulate expression of physiological
processes to adjust to the changing environment. Genes that help control
light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY.
A full circadian cycle can be described as a twenty-four hour circadian
day, where circadian time zero (CT 0) marks the beginning of a
subjective day for an organism and CT 12 marks the start of subjective
night.
Humans with regular circadian function have been shown to
maintain regular sleep schedules, regulate daily rhythms in hormone
secretion, and sustain oscillations in core body temperature.
Even in the absence of Zeitgebers, humans will continue to maintain a
roughly 24-hour rhythm in these biological activities. Regarding sleep,
normal circadian function allows people to maintain balance rest and
wakefulness that allows people to work and maintain alertness during the
day's activities, and rest at night.
Some misconceptions regarding circadian rhythms and sleep
commonly mislabel irregular sleep as a circadian rhythm sleep disorder.
In order to be diagnosed with CRSD, there must be either a misalignment
between the timing of the circadian oscillator and the surrounding
environment, or failure in the clock entrainment pathway. Among people with typical circadian clock function, there is variation in chronotypes,
or preferred wake and sleep times, of individuals. Although chronotype
varies from individual to individual, as determined by rhythmic
expression of clock genes,
people with typical circadian clock function will be able to entrain to
environmental cues. For example, if a person wishes to shift the onset
of a biological activity, like waking time, light exposure during the
late subjective night or early subjective morning can help advance one's
circadian cycle earlier in the day, leading to an earlier wake time.
Diagnosis
The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population suffers from a CRSD, many people are often misdiagnosed with insomnia
instead of a CRSD. Of adults diagnosed with sleep disorders, an
estimated 10% have a CRSD and of adolescents with sleep disorders, an
estimated 16% may have a CRSD.
Patients diagnosed with circadian rhythm sleep disorders typically
express a pattern of disturbed sleep, whether that be excessive sleep
that intrudes on working schedules and daily functions, or insomnia at
desired times of sleep. Note that having a preference for extreme early
or late wake times are not related to a circadian rhythm sleep disorder
diagnosis. There must be distinct impairment of biological rhythms that
affects the person's desired work and daily behavior. For a CRSD
diagnosis, a sleep specialist gathers the history of a patient's sleep
and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO).
Gathering this data gives insight into the patient's current schedule,
as well as the physiological phase markers of the patient's biological
clock.
The start of the CRSD diagnostic process is a thorough sleep
history assessment. A standard questionnaire is used to record the sleep
habits of the patient, including typical bedtime, sleep duration, sleep latency,
and instances of waking up. The professional will further inquire about
other external factors that may impact sleep. Prescription drugs that
treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors
and other antidepressants are associated with abnormal sleep behaviors.
Other daily habits like work schedule and timing of exercise are also
recorded—because they may impact an individual's sleep and wake
patterns. To measure sleep variables candidly, patients wear actigraphy
watches that record sleep onset, wake time, and many other
physiological variables. Patients are similarly asked to self-report
their sleep habits with a week-long sleep diary to document when they go
to bed, when they wake up, etc. to supplement the actigraphy data.
Collecting this data allows sleep professionals to carefully document
and measure patient's sleep habits and confirm patterns described in
their sleep history.
Other additional ways to classify the nature of a patient's sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep. Questionnaires like the Pittsburgh Sleep Quality Index
(PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of
sleep disruption. Specifically, these questionnaires can help the
professional assess the patient's problems with sleep latency, undesired
early-morning wakefulness, and problems with falling or staying asleep.
Tayside children's sleep questionnaire is a ten-item questionnaire for sleep disorders in children aged between one and five years old.
Types
Currently,
the International Classification of Sleep Disorders (ICSD-3) lists 6
disorders under the category of circadian rhythm sleep disorders.
CRSDs can be categorized into two groups based on their
underlying mechanisms: The first category is composed of disorders where
the endogenous oscillator has been altered, known as intrinsic type
disorders. The second category consists of disorders in which the
external environment and the endogenous circadian clock are misaligned,
called extrinsic type CRSDs.
Intrinsic
Delayed sleep phase disorder
(DSPD): Individuals who have been diagnosed with delayed sleep phase
disorder have sleep-wake times which are delayed when compared to normal
functioning individuals. People with DSPD typically have very long
periods of sleep latency when they attempt to go to sleep during
conventional sleeping times. Similarly, they also have trouble waking up
at conventional times.
Advanced sleep phase disorder
(ASPD): People with advanced sleep phase disorder exhibit
characteristics opposite to those with delayed sleep phase disorder.
These individuals have advanced sleep wake times, so they tend to go to
bed and wake up much earlier as compared to normal individuals. ASPD is
less common than DSPD, and is most prevalent within older populations.
Familial Advanced Sleep Phase Syndrome (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G).
Families that have this mutation in PER2 experience extreme phase
advances in sleep, waking up around 2 AM and going to bed around 7 PM.
Irregular sleep–wake rhythm disorder
(ISWRD) is characterized by a normal 24-hr sleeping period. However,
individuals with this disorder experience fragmented and highly
disorganized sleep that can manifest in the form of waking frequently
during the night and taking naps during the day, yet still maintaining
sufficient total time asleep. People with ISWRD often experience a range
of symptoms from insomnia to excessive daytime sleepiness.
Non-24-hour sleep–wake disorder
(N24SWD): Most common in individuals that are blind and unable to
detect light, is characterized by chronic patterns of sleep/wake cycles
which are not entrained to the 24-hr light-dark environmental cycle. As a
result of this, individuals with this disorder will usually experience a
gradual yet predictable delay of sleep onset and waking times. Patients
with DSPD may develop this disorder if their condition is untreated.
Extrinsic
Shift work sleep disorder
(SWSD): Approximately 9% of Americans who work night or irregular work
shifts are believed to experience Shift work sleep disorder. Night shift work directly opposes the environmental cues that entrain our biological clock,
so this disorder arises when an individual's clock is unable to adjust
to the socially imposed work schedule. Shift work sleep disorder can
lead to severe cases of insomnia as well as excessive daytime
sleepiness.
Jet lag:
Jet lag is best characterized by difficulty falling asleep or staying
asleep as a result of misalignment between one's internal circadian
system and external, or environmental cues. It is typically associated
with rapid travel across multiple time zones.
Alzheimer's disease
CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimer's disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments. On one hand, it has been stated that people with AD have melatonin
alteration and high irregularity in their circadian rhythm that lead to
a disrupted sleep-wake cycle, probably due to damage on hypothalamic
SCN regions typically observed in AD.
On the other hand, disturbed sleep and wakefulness states have been
related to worsening of an AD patient's cognitive abilities, emotional
state and quality of life.
Moreover, the abnormal behavioural symptoms of the disease negatively
contribute to overwhelming patient's relatives and caregivers as well.
However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood.
Therefore, further studies exploring this field have been highly
recommended, mainly considering the increasing life expectancy and
significance of neurodegenerative diseases in clinical practices.
Treatment
Possible treatments for circadian rhythm sleep disorders include:
Chronotherapy,
best shown to effectively treat delayed sleep phase disorder, acts by
systematically delaying an individual's bedtime until their sleep-wake
times coincide with the conventional 24-hr day.
Light therapy
utilizes bright light exposure to induce phase advances and delays in
sleep and wake times. This therapy requires 30–60 minutes of exposure to
a bright (5,000–10,000 lux) white, blue, or natural light at a set time
until the circadian clock is aligned with the desired schedule.
Treatment is initially administered either upon awakening or before
sleeping, and if successful may be continued indefinitely or performed
less frequently.
Though proven very effective in the treatment of individuals with DSPD
and ASPD, the benefits of light therapy on N24SWD, shift work disorder,
and jet lag have not been studied as extensively.
Hypnotics have also been used clinically alongside bright light exposure therapy and pharmacotherapy for the treatment of CRSDs such as Advanced Sleep Phase Disorder.
Additionally, in conjunction with cognitive behavioral therapy,
short-acting hypnotics also present an avenue for treating co-morbid
insomnia in patients suffering from circadian sleep disorders.
Melatonin,
a naturally occurring biological hormone with circadian rhythmicity,
has been shown to promote sleep and entrainment to external cues when
administered in drug form (0.5–5.0 mg). Melatonin administered in the
evening causes phase advances in sleep-wake times while maintaining
duration and quality of sleep. Similarly, when administered in the early
morning, melatonin can cause phase delays. It has been shown most
effective in cases of shift work sleep disorder and delayed phase sleep
disorder, but has not been proven particularly useful in cases of jet
lag.
Dark therapy,
for example, the use of blue-blocking goggles, is used to block blue
and blue-green wavelength light from reaching the eye during evening
hours so as not to hinder melatonin production.
A circadian rhythm (/sərˈkeɪdiən/), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to the environment (entrained by the environment). These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi and cyanobacteria.
The term circadian comes from the Latincirca, meaning "around" (or "approximately"), and diēm, meaning "day". Processes with 24-hour cycles are more generally called diurnal rhythms; diurnal rhythms should not be called circadian rhythms unless they can be confirmed as endogenous, and not environmental.
Although circadian rhythms are endogenous, they are adjusted to the local environment by external cues called zeitgebers (German for "time givers"), which include light, temperature and redox cycles. In clinical settings, an abnormal circadian rhythm in humans is known as a circadian rhythm sleep disorder.
History
While
there are multiple mentions of "natural body cycle" in Eastern and
Native American cultures, the earliest recorded Western accounts of a
circadian process date from the 4th century BC, when Androsthenes, a ship's captain serving under Alexander the Great, described diurnal leaf movements of the tamarind tree. The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic
Rhyme to Aid in the Selection of Acu-points According to the Diurnal
Cycle, the Day of the Month and the Season of the Year.
In 1729, French scientist Jean-Jacques d'Ortous de Mairan
conducted the first experiment designed to distinguish an endogenous
clock from responses to daily stimuli. He noted that 24-hour patterns in
the movement of the leaves of the plant Mimosa pudica persisted, even when the plants were kept in constant darkness.
In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski
showed that animals are capable of maintaining 24-hour activity
patterns in the absence of external cues such as light and changes in
temperature.
In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Auguste Forel, Ingeborg Beling, and Oskar Wahl conducted numerous experiments to determine whether this rhythm was attributable to an endogenous clock. The existence of circadian rhythm was independently discovered in fruit flies in 1935 by two German zoologists, Hans Kalmus and Erwin Bünning.
In 1954, an important experiment reported by Colin Pittendrigh demonstrated that eclosion (the process of pupa turning into adult) in Drosophila pseudoobscura
was a circadian behaviour. He demonstrated that while temperature
played a vital role in eclosion rhythm, the period of eclosion was
delayed but not stopped when temperature was decreased.
The term circadian was coined by Franz Halberg in 1959. According to Halberg's original definition:
The term "circadian" was derived from circa (about) and dies
(day); it may serve to imply that certain physiologic periods are close
to 24 hours, if not exactly that length. Herein, "circadian" might be
applied to all "24-hour" rhythms, whether or not their periods,
individually or on the average, are different from 24 hours, longer or
shorter, by a few minutes or hours.
Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 ± 4 h; circa (about, approximately) and dies
(day or 24 h). Note: term describes rhythms with an about 24-h cycle
length, whether they are frequency-synchronized with (acceptable) or are
desynchronized or free-running from the local environmental time scale,
with periods of slightly yet consistently different from 24-h.
Ron Konopka and Seymour Benzer identified the first clock mutation in Drosophila in 1971, naming the gene "period" (per) gene, the first discovered genetic determinant of behavioral rhythmicity. per gene was isolated in 1984 by two teams of researchers. Konopka, Jeffrey Hall, Michael Roshbash and their team showed that per locus is the centre of the circadian rhythm, and that loss of per stops circadian activity. At the same time, Michael W. Young's team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017.
Joseph Takahashi discovered the first mammalian circadian clock mutation (clockΔ19) using mice in 1994. However, recent studies show that deletion of clock
does not lead to a behavioral phenotype (the animals still have normal
circadian rhythms), which questions its importance in rhythm generation.
The first human clock mutation was identified in an extended Utah
family by Chris Jones, and genetically characterized by Ying-Hui Fu and
Louis Ptacek. Affected individuals are extreme 'morning larks' with 4 hour advanced sleep and other rhythms. This form of familial advanced sleep phase syndrome is caused by a single amino acid change, S662➔G, in the human PER2 protein.
Criteria
To be called circadian, a biological rhythm must meet these three general criteria:
The rhythm has an endogenous free-running period that lasts approximately 24 hours.
The rhythm persists in constant conditions, (i.e., constant darkness)
with a period of about 24 hours. The period of the rhythm in constant
conditions is called the free-running period and is denoted by the Greek
letter τ (tau). The rationale for this criterion is to distinguish
circadian rhythms from simple responses to daily external cues. A rhythm
cannot be said to be endogenous
unless it has been tested and persists in conditions without external
periodic input. In diurnal animals (active during daylight hours), in
general τ is slightly greater than 24 hours, whereas, in nocturnal
animals (active at night), in general τ is shorter than 24 hours.
The rhythms are entrainable. The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment. The external stimulus used to entrain a rhythm is called the Zeitgeber, or "time giver". Travel across time zones illustrates the ability of the human biological clock to adjust to the local time; a person will usually experience jet lag before entrainment of their circadian clock has brought it into sync with local time.
The rhythms exhibit temperature compensation. In other words,
they maintain circadian periodicity over a range of physiological
temperatures. Many organisms live at a broad range of temperatures, and
differences in thermal energy will affect the kinetics
of all molecular processes in their cell(s). In order to keep track of
time, the organism's circadian clock must maintain roughly a 24-hour
periodicity despite the changing kinetics, a property known as
temperature compensation. The Q10 temperature coefficient is a measure of this compensating effect. If the Q10 coefficient remains approximately 1 as temperature increases, the rhythm is considered to be temperature-compensated.
Origin
Circadian rhythms allow organisms to anticipate and prepare for
precise and regular environmental changes. They thus enable organisms to
better capitalize on environmental resources (e.g. light and food)
compared to those that cannot predict such availability. It has
therefore been suggested that circadian rhythms put organisms at a
selective advantage in evolutionary terms. However, rhythmicity appears
to be as important in regulating and coordinating internal metabolic processes, as in coordinating with the environment.
This is suggested by the maintenance (heritability) of circadian
rhythms in fruit flies after several hundred generations in constant
laboratory conditions,
as well as in creatures in constant darkness in the wild, and by the
experimental elimination of behavioral—but not physiological—circadian
rhythms in quail.
What drove circadian rhythms to evolve has been an enigmatic
question. Previous hypotheses emphasized that photosensitive proteins
and circadian rhythms may have originated together in the earliest
cells, with the purpose of protecting replicating DNA from high levels
of damaging ultraviolet
radiation during the daytime. As a result, replication was relegated to
the dark. However, evidence for this is lacking, since the simplest
organisms with a circadian rhythm, the cyanobacteria, do the opposite of
this - they divide more in the daytime.
Recent studies instead highlight the importance of co-evolution of
redox proteins with circadian oscillators in all three domains of life
following the Great Oxidation Event approximately 2.3 billion years ago. The current view is that circadian changes in environmental oxygen levels and the production of reactive oxygen species
(ROS) in the presence of daylight are likely to have driven a need to
evolve circadian rhythms to preempt, and therefore counteract, damaging
redox reactions on a daily basis.
The simplest known circadian clocks are bacterial circadian rhythms, exemplified by the prokaryote cyanobacteria. Recent research has demonstrated that the circadian clock of Synechococcus elongatus can be reconstituted in vitro with just the three proteins (KaiA, KaiB, KaiC) of their central oscillator. This clock has been shown to sustain a 22-hour rhythm over several days upon the addition of ATP. Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription/translation feedback mechanism.
A defect in the human homologue of the Drosophila "period" gene was identified as a cause of the sleep disorder FASPS (Familial advanced sleep phase syndrome),
underscoring the conserved nature of the molecular circadian clock
through evolution. Many more genetic components of the biological clock
are now known. Their interactions result in an interlocked feedback loop
of gene products resulting in periodic fluctuations that the cells of
the body interpret as a specific time of the day.
It is now known that the molecular circadian clock can function within a single cell. That is, it is cell-autonomous. This was shown by Gene Block in isolated mollusk basal retinal neurons (BRNs).
At the same time, different cells may communicate with each other
resulting in a synchronised output of electrical signaling. These may
interface with endocrine glands
of the brain to result in periodic release of hormones. The receptors
for these hormones may be located far across the body and synchronise
the peripheral clocks of various organs. Thus, the information of the
time of the day as relayed by the eyes
travels to the clock in the brain, and, through that, clocks in the
rest of the body may be synchronised. This is how the timing of, for
example, sleep/wake, body temperature, thirst, and appetite are
coordinately controlled by the biological clock.
Importance in animals
Circadian
rhythmicity is present in the sleeping and feeding patterns of animals,
including human beings. There are also clear patterns of core body
temperature, brain wave activity, hormone production, cell regeneration, and other biological activities. In addition, photoperiodism,
the physiological reaction of organisms to the length of day or night,
is vital to both plants and animals, and the circadian system plays a
role in the measurement and interpretation of day length. Timely
prediction of seasonal periods of weather conditions, food availability,
or predator activity is crucial for survival of many species. Although
not the only parameter, the changing length of the photoperiod
('daylength') is the most predictive environmental cue for the seasonal
timing of physiology and behavior, most notably for timing of migration,
hibernation, and reproduction.
Effect of circadian disruption
Mutations
or deletions of clock gene in mice have demonstrated the importance of
body clocks to ensure the proper timing of cellular/metabolic events;
clock-mutant mice are hyperphagic and obese, and have altered glucose metabolism. In mice, deletion of the Rev-ErbA alpha
clock gene facilitates diet-induced obesity and changes the balance
between glucose and lipid utilization predisposing to diabetes.
However, it is not clear whether there is a strong association between
clock gene polymorphisms in humans and the susceptibility to develop the
metabolic syndrome.
Effect of light–dark cycle
The
rhythm is linked to the light–dark cycle. Animals, including humans,
kept in total darkness for extended periods eventually function with a free-running rhythm. Their sleep cycle is pushed back or forward each "day", depending on whether their "day", their endogenous
period, is shorter or longer than 24 hours. The environmental cues that
reset the rhythms each day are called zeitgebers (from the German,
"time-givers"). Totally blind subterranean mammals (e.g., blind mole ratSpalax
sp.) are able to maintain their endogenous clocks in the apparent
absence of external stimuli. Although they lack image-forming eyes,
their photoreceptors (which detect light) are still functional; they do
surface periodically as well.
Free-running organisms that normally have one or two consolidated
sleep episodes will still have them when in an environment shielded
from external cues, but the rhythm is not entrained to the 24-hour
light–dark cycle in nature. The sleep–wake rhythm may, in these
circumstances, become out of phase with other circadian or ultradian rhythms such as metabolic, hormonal, CNS electrical, or neurotransmitter rhythms.
Recent research has influenced the design of spacecraft environments, as systems that mimic the light–dark cycle have been found to be highly beneficial to astronauts. Light therapy has been trialed as a treatment for sleep disorders.
Arctic animals
Norwegian researchers at the University of Tromsø have shown that some Arctic animals (e.g., ptarmigan, reindeer)
show circadian rhythms only in the parts of the year that have daily
sunrises and sunsets. In one study of reindeer, animals at 70 degrees North showed circadian rhythms in the autumn, winter and spring, but not in the summer. Reindeer on Svalbard at 78 degrees North
showed such rhythms only in autumn and spring. The researchers suspect
that other Arctic animals as well may not show circadian rhythms in the
constant light of summer and the constant dark of winter.
A 2006 study in northern Alaska found that day-living ground squirrels and nocturnal porcupines
strictly maintain their circadian rhythms through 82 days and nights of
sunshine. The researchers speculate that these two rodents notice that
the apparent distance between the sun and the horizon is shortest once a
day, and thus have a sufficient signal to entrain (adjust) by.
Butterfly and moth
The navigation of the fall migration of the Eastern North American monarch butterfly (Danaus plexippus)
to their overwintering grounds in central Mexico uses a
time-compensated sun compass that depends upon a circadian clock in
their antennae. Circadian rhythm is also known to control mating behavior in certain moth species such as Spodoptera littoralis, where females produce specific pheromone that attracts and resets the male circadian rhythm to induce mating at night.
In plants
Sleeping tree by day and night
Plant circadian rhythms tell the plant what season it is and when to
flower for the best chance of attracting pollinators. Behaviors showing
rhythms include leaf movement, growth, germination, stomatal/gas
exchange, enzyme activity, photosynthetic activity, and fragrance
emission, among others.
Circadian rhythms occur as a plant entrains to synchronize with the
light cycle of its surrounding environment. These rhythms are
endogenously generated, self-sustaining and are relatively constant over
a range of ambient temperatures. Important features include two
interacting transcription-translation feedback loops: proteins
containing PAS domains, which facilitate protein-protein interactions;
and several photoreceptors that fine-tune the clock to different light
conditions. Anticipation of changes in the environment allows
appropriate changes in a plant's physiological state, conferring an
adaptive advantage.
A better understanding of plant circadian rhythms has applications in
agriculture, such as helping farmers stagger crop harvests to extend
crop availability and securing against massive losses due to weather.
Light is the signal by which plants synchronize their internal
clocks to their environment and is sensed by a wide variety of
photoreceptors. Red and blue light are absorbed through several
phytochromes and cryptochromes.
One phytochrome, phyA, is the main phytochrome in seedlings grown in
the dark but rapidly degrades in light to produce Cry1. Phytochromes B–E
are more stable with phyB, the main phytochrome in seedlings grown in
the light. The cryptochrome (cry) gene is also a light-sensitive
component of the circadian clock and is thought to be involved both as a
photoreceptor and as part of the clock's endogenous pacemaker
mechanism. Cryptochromes 1–2 (involved in blue–UVA) help to maintain the
period length in the clock through a whole range of light conditions.
The central oscillator generates a self-sustaining rhythm and is
driven by two interacting feedback loops that are active at different
times of day. The morning loop consists of CCA1 (Circadian and
Clock-Associated 1) and LHY (Late Elongated Hypocotyl), which encode
closely related MYB transcription factors that regulate circadian
rhythms in Arabidopsis, as well as PRR 7 and 9 (Pseudo-Response
Regulators.) The evening loop consists of GI (Gigantea) and ELF4, both
involved in regulation of flowering time genes.
When CCA1 and LHY are overexpressed (under constant light or dark
conditions), plants become arrhythmic, and mRNA signals reduce,
contributing to a negative feedback loop. Gene expression of CCA1 and
LHY oscillates and peaks in the early morning, whereas TOC1 gene
expression oscillates and peaks in the early evening. While it was
previously hypothesised that these three genes model a negative feedback
loop in which over-expressed CCA1 and LHY repress TOC1 and
over-expressed TOC1 is a positive regulator of CCA1 and LHY,
it was shown in 2012 by Andrew Millar and others that TOC1, in fact,
serves as a repressor not only of CCA1, LHY, and PRR7 and 9 in the
morning loop but also of GI and ELF4 in the evening loop. This finding
and further computational modeling of TOC1 gene functions and interactions suggest a reframing of the plant circadian clock as a triple negative-component repressilator model rather than the positive/negative-element feedback loop characterizing the clock in mammals.
In 2018, researchers found that the expression of PRR5 and TOC1
hnRNA nascent transcripts follows the same oscillatory pattern as
processed mRNA transcripts rhythmically in A.thaliana.LNKs binds to the
5'region of PRR5 and TOC1 and interacts with RNAP II and other
transcription factors. Moreover, RVE8-LNKs interaction enables a
permissive histone-methylation pattern (H3K4me3) to be modified and the
histone-modification itself parallels the oscillation of clock gene
expression.
It has previously been found that matching a plant’s circadian
rhythm to its external environment’s light and dark cycles has the
potential to positively affect the plant. Researchers came to this conclusion by performing experiments on three different varieties of Arabidopsis thaliana. One of these varieties had a normal 24-hour circadian cycle.
The other two varieties were mutated, one to have a circadian cycle of
more than 27 hours, and one to have a shorter than normal circadian
cycle of 20 hours.
The Arabidopsis with the 24-hour circadian cycle was grown in three different environments.
One of these environments had a 20-hour light and dark cycle (10 hours
of light and 10 hours of dark), the other had a 24-hour light and dark
cycle (12 hours of light and 12 hours of dark),and the final environment
had a 28-hour light and dark cycle (14 hours of light and 14 hours of
dark).
The two mutated plants were grown in both an environment that had a
20-hour light and dark cycle and in an environment that had a 28-hour
light and dark cycle. It was found that the variety of Arabidopsis with a 24-hour circadian rhythm cycle grew best in an environment that also had a 24-hour light and dark cycle. Overall, it was found that all the varieties of Arabidopsis thaliana had greater levels of chlorophyll and increased growth in environments whose light and dark cycles matched their circadian rhythm.
Researchers suggested that a reason for this could be that matching an Arabidopsis’s
circadian rhythm to its environment could allow the plant to be better
prepared for dawn and dusk, and thus be able to better synchronize its
processes. In this study, it was also found that the genes that help to control chlorophyll peaked a few hours after dawn. This appears to be consistent with the proposed phenomenon known as metabolic dawn.
According to the metabolic dawn hypothesis, sugars produced by
photosynthesis have potential to help regulate the circadian rhythm and
certain photosynthetic and metabolic pathways. As the sun rises, more light becomes available, which normally allows more photosynthesis to occur. The sugars produced by photosynthesis repress PRR7. This repression of PRR7 then leads to the increased expression of CCA1. On the other hand, decreased photosynthetic sugar levels increase PRR7 expression and decrease CCA1 expression. This feedback loop between CCA1 and PRR7 is what is proposed to cause metabolic dawn.
Key centers of the mammalian and Drosophila brains (A) and the circadian system in Drosophila (B).
The molecular mechanism of circadian rhythm and light perception are best understood in Drosophila. Clock genes are discovered from Drosophila, and they act together with the clock neurones. There are two unique rhythms, one during the process of hatching (called eclosion) from the pupa, and the other during mating.
The clock neurones are located in distinct clusters in the central
brain. The best-understood clock neurones are the large and small
lateral ventral neurons (l-LNvs and s-LNvs) of the optic lobe.
These neurones produce pigment dispersing factor (PDF), a neuropeptide
that acts as a circadian neuromodulator between different clock
neurones.
Molecular interactions of clock genes and proteins during Drosophila circadian rhythm.
Drosophila circadian rhythm is through a
transcription-translation feedback loop. The core clock mechanism
consists of two interdependent feedback loops, namely the PER/TIM loop
and the CLK/CYC loop. The CLK/CYC loop occurs during the day and initiates the transcription of the per and tim genes. But their proteins levels remain low until dusk, because during daylight also activates the doubletime (dbt) gene. DBT protein causes phosphorylation and turnover of monomeric PER proteins.
TIM is also phosphorylated by shaggy until sunset. After sunset, DBT
disappears, so that PER molecules stably bind to TIM. PER/TIM dimer
enters the nucleus several at night, and binds to CLK/CYC dimers. Bound
PER completely stops the transcriptional activity of CLK and CYC.
In the early morning, light activates the cry gene and its
protein CRY causes the breakdown of TIM. Thus PER/TIM dimer
dissociates, and the unbound PER becomes unstable. PER undergoes
progressive phosphorylation and ultimately degradation. Absence of PER
and TIM allows activation of clk and cyc genes. Thus, the clock is reset to start the next circadian cycle.
PER-TIM Model
This protein model was developed bases on the oscillations of the PER and TIM proteins in the Drosophila.
It is based on its predecessor, the PER model where it was explained
how the per gene and its protein influence the biological clock.
The model includes the formation of a nuclear PER-TIM complex which
influences the transcription of the per and the tim genes (by providing
negative feedback) and the multiple phosphorylation of these two
proteins. The circadian oscillations of these two proteins seem to
synchronise with the light-dark cycle even if they are not necessarily
dependent on it.
Both PER and TIM proteins are phosphorylated and after they form the
PER-TIM nuclear complex they return inside the nucleus to stop the
expression of the per and tim mRNA. This inhibition lasts as long as the
protein, or the mRNA is not degraded.
When this happens, the complex releases the inhibition. Here can also
be mentioned that the degradation of the TIM protein is sped up by
light.
In mammals
A variation of an eskinogram illustrating the influence of light and darkness on circadian rhythms and related physiology and behavior through the suprachiasmatic nucleus in humans
The primary circadian clock in mammals is located in the suprachiasmatic nucleus (or nuclei) (SCN), a pair of distinct groups of cells located in the hypothalamus.
Destruction of the SCN results in the complete absence of a regular
sleep–wake rhythm. The SCN receives information about illumination
through the eyes. The retina of the eye contains "classical" photoreceptors ("rods" and "cones"), which are used for conventional vision. But the retina also contains specialized ganglion cells
that are directly photosensitive, and project directly to the SCN,
where they help in the entrainment (synchronization) of this master
circadian clock. The proteins involved in the SCN clock are homologous
to those found in the fruit fly.
These cells contain the photopigment melanopsin and their signals follow a pathway called the retinohypothalamic tract,
leading to the SCN. If cells from the SCN are removed and cultured,
they maintain their own rhythm in the absence of external cues.
The SCN takes the information on the lengths of the day and night from the retina, interprets it, and passes it on to the pineal gland, a tiny structure shaped like a pine cone and located on the epithalamus. In response, the pineal secretes the hormone melatonin. Secretion of melatonin peaks at night and ebbs during the day and its presence provides information about night-length.
Several studies have indicated that pineal melatonin feeds back
on SCN rhythmicity to modulate circadian patterns of activity and other
processes. However, the nature and system-level significance of this
feedback are unknown.
The circadian rhythms of humans can be entrained to slightly
shorter and longer periods than the Earth's 24 hours. Researchers at
Harvard have shown that human subjects can at least be entrained to a
23.5-hour cycle and a 24.65-hour cycle (the latter being the natural
solar day-night cycle on the planet Mars).
Humans
When
eyes receive light from the sun, the pineal gland's production of
melatonin is inhibited and the hormones produced keep the human awake.
When the eyes do not receive light, melatonin is produced in the pineal
gland and the human becomes tired.
Early research into circadian rhythms suggested that most people
preferred a day closer to 25 hours when isolated from external stimuli
like daylight and timekeeping. However, this research was faulty because
it failed to shield the participants from artificial light. Although
subjects were shielded from time cues (like clocks) and daylight, the
researchers were not aware of the phase-delaying effects of indoor
electric lights.
The subjects were allowed to turn on light when they were awake and to
turn it off when they wanted to sleep. Electric light in the evening
delayed their circadian phase. A more stringent study conducted in 1999 by Harvard University estimated the natural human rhythm to be closer to 24 hours and 11 minutes: much closer to the solar day.
Consistent with this research was a more recent study from 2010, which
also identified sex differences with the circadian period for women
being slightly shorter (24.09 hours) than for men (24.19 hours).
In this study, women tended to wake up earlier than men and exhibit a
greater preference for morning activities than men, although the
underlying biological mechanisms for these differences are unknown.
Biological markers and effects
The classic phase markers for measuring the timing of a mammal's circadian rhythm are:
For temperature studies, subjects must remain awake but calm and
semi-reclined in near darkness while their rectal temperatures are taken
continuously. Though variation is great among normal chronotypes,
the average human adult's temperature reaches its minimum at about
5:00 a.m., about two hours before habitual wake time. Baehr et al.
found that, in young adults, the daily body temperature minimum
occurred at about 04:00 (4 a.m.) for morning types, but at about 06:00
(6 a.m.) for evening types. This minimum occurred at approximately the
middle of the eight-hour sleep period for morning types, but closer to
waking in evening types.
Melatonin is absent from the system or undetectably low during daytime. Its onset in dim light, dim-light melatonin onset (DLMO), at roughly 21:00 (9 p.m.) can be measured in the blood or the saliva. Its major metabolite
can also be measured in morning urine. Both DLMO and the midpoint (in
time) of the presence of the hormone in the blood or saliva have been
used as circadian markers. However, newer research indicates that the
melatonin offset may be the more reliable marker. Benloucif et al.
found that melatonin phase markers were more stable and more highly
correlated with the timing of sleep than the core temperature minimum.
They found that both sleep offset and melatonin offset are more strongly
correlated with phase markers than the onset of sleep. In addition, the
declining phase of the melatonin levels is more reliable and stable
than the termination of melatonin synthesis.
Other physiological changes that occur according to a circadian rhythm include heart rate and many cellular processes "including oxidative stress, cell metabolism, immune and inflammatory responses, epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment."
In a study of young men, it was found that the heart rate reaches its
lowest average rate during sleep, and its highest average rate shortly
after waking.
In contradiction to previous studies, it has been found that
there is no effect of body temperature on performance on psychological
tests. This is likely due to evolutionary pressures for higher cognitive
function compared to the other areas of function examined in previous
studies.
Outside the "master clock"
More-or-less
independent circadian rhythms are found in many organs and cells in the
body outside the suprachiasmatic nuclei (SCN), the "master clock".
Indeed, neuroscientist Joseph Takahashi and colleagues stated in a 2013
article that "almost every cell in the body contains a circadian clock." For example, these clocks, called peripheral oscillators, have been found in the adrenal gland, oesophagus, lungs, liver, pancreas, spleen, thymus, and skin. There is also some evidence that the olfactory bulb and prostate may experience oscillations, at least when cultured.
Though oscillators in the skin respond to light, a systemic influence has not been proven. In addition, many oscillators, such as liver cells, for example, have been shown to respond to inputs other than light, such as feeding.
Light resets the biological clock in accordance with the phase response curve (PRC). Depending on the timing, light can advance or delay the circadian rhythm. Both the PRC and the required illuminance vary from species to species, and lower light levels are required to reset the clocks in nocturnal rodents than in humans.
Enforced longer or shorter cycles
Various
studies on humans have made use of enforced sleep/wake cycles strongly
different from 24 hours, such as those conducted by Nathaniel Kleitman in 1938 (28 hours) and Derk-Jan Dijk and Charles Czeisler in the 1990s (20 hours). Because people with a normal (typical) circadian clock cannot entrain to such abnormal day/night rhythms,
this is referred to as a forced desynchrony protocol. Under such a
protocol, sleep and wake episodes are uncoupled from the body's
endogenous circadian period, which allows researchers to assess the
effects of circadian phase (i.e., the relative timing of the circadian
cycle) on aspects of sleep and wakefulness including sleep latency and other functions - both physiological, behavioral, and cognitive.
Studies also show that Cyclosa turbinata
is unique in that its locomotor and web-building activity cause it to
have an exceptionally short-period circadian clock, about 19 hours. When
C. turbinata spiders are placed into chambers with periods of
19, 24, or 29 hours of evenly split light and dark, none of the spiders
exhibited decreased longevity in their own circadian clock. These
findings suggest that C. turbinata do not suffer the same costs of extreme desynchronization as do other species of animals.
How humans can optimize their circadian rhythm in terms of ability to achieve proper sleep
Human health
A short nap during the day does not affect circadian rhythms.
Pioneering the New Field of Circadian Medicine
The leading edge of circadian biology research is translation of
basic body clock mechanisms into clinical tools, and this is especially
relevant to the treatment of cardiovascular disease.
This is leading to the development of an entirely new field of
medicine, termed Circadian Medicine. Pioneering research reveals that
Circadian Medicine can lead to longer and healthier lives. For example:
1) "Circadian Lighting" or reducing adverse light at night in hospitals
may improve patient outcomes post-myocardial infarction (heart attack). 2) "Circadian Chronotherapy" or timing of medications can reduce adverse cardiac remodeling in patients with heart disease. Timing of medical treatment in coordination with the body clock, chronotherapeutics,
may also benefit patients with hypertension (high blood pressure) by
significantly increasing efficacy and reduce drug toxicity or adverse
reactions.
3) "Circadian Pharmacology" or drugs targeting the circadian clock
mechanism have been shown experimentally in rodent models to
significantly reduce the damage due to heart attacks and prevent heart
failure.
Importantly, for rational translation of the most promising Circadian
Medicine therapies to clinical practice, it is imperative that we
understand how it helps treats disease in both biological sexes.
One of the first studies to determine how disruption of circadian
rhythms causes cardiovascular disease was performed in the Tau
hamsters, which have a genetic defect in their circadian clock
mechanism. When maintained in a 24 hour light-dark cycle that was "out
of sync" with their normal 22 circadian mechanism they developed
profound cardiovascular and renal disease; however, when the Tau animals
were raised for their entire lifespan on a 22 hour daily light-dark
cycle they had a healthy cardiovascular system.
The adverse effects of circadian misalignment on human physiology has
been studied in the laboratory using a misalignment protocol, and by studying shift workers.
Circadian Desynchrony and other Health Conditions
Subsequent studies have shown that maintaining normal sleep and
circadian rhythms is important for many aspects of brain and health. A number of studies have also indicated that a power-nap,
a short period of sleep during the day, can reduce stress and may
improve productivity without any measurable effect on normal circadian
rhythms. Circadian rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness. A reversal in the sleep–wake cycle may be a sign or complication of uremia, azotemia or acute kidney injury. Studies have also helped elucidate how light has a direct effect on human health through it's influence on the circadian biology.
Indoor lighting
Lighting
requirements for circadian regulation are not simply the same as those
for vision; planning of indoor lighting in offices and institutions is
beginning to take this into account. Animal studies on the effects of light in laboratory conditions have until recently considered light intensity (irradiance) but not color, which can be shown to "act as an essential regulator of biological timing in more natural settings".
Obesity and diabetes
Obesity and diabetes
are associated with lifestyle and genetic factors. Among those factors,
disruption of the circadian clockwork and/or misalignment of the
circadian timing system with the external environment (e.g., light–dark
cycle) might play a role in the development of metabolic disorders.
Shift work or chronic jet lag
have profound consequences for circadian and metabolic events in the
body. Animals that are forced to eat during their resting period show
increased body mass and altered expression of clock and metabolic genes.
In humans, shift work that favors irregular eating times is associated
with altered insulin sensitivity and higher body mass. Shift work also
leads to increased metabolic risks for cardio-metabolic syndrome, hypertension, and inflammation.
Airline pilots and cabin crew
Due
to the work nature of airline pilots, who often cross several time
zones and regions of sunlight and darkness in one day, and spend many
hours awake both day and night, they are often unable to maintain sleep
patterns that correspond to the natural human circadian rhythm; this
situation can easily lead to fatigue. The NTSB cites this as contributing to many accidents, and has conducted several research studies in order to find methods of combating fatigue in pilots.
Disruption to rhythms usually has a negative effect. Many travelers have experienced the condition known as jet lag, with its associated symptoms of fatigue, disorientation and insomnia.
Disruption to rhythms in the longer term is believed to have
significant adverse health consequences for peripheral organs outside
the brain, in particular in the development or exacerbation of
cardiovascular disease. Blue LED lighting suppresses melatonin production five times more than the orange-yellow high-pressure sodium (HPS) light; a metal halide lamp, which is white light, suppresses melatonin at a rate more than three times greater than HPS. Depression symptoms from long term nighttime light exposure can be undone by returning to a normal cycle.
Effect of drugs
Studies
conducted on both animals and humans show major bidirectional
relationships between the circadian system and abusive drugs. It is
indicated that these abusive drugs affect the central circadian
pacemaker. Individuals suffering from substance abuse display disrupted
rhythms. These disrupted rhythms can increase the risk for substance
abuse and relapse. It is possible that genetic and/or environmental
disturbances to the normal sleep and wake cycle can increase the
susceptibility to addiction.
It is difficult to determine if a disturbance in the circadian
rhythm is at fault for an increase in prevalence for substance abuse—or
if other environmental factors such as stress are to blame.
Changes to the circadian rhythm and sleep occur once an individual
begins abusing drugs and alcohol. Once an individual chooses to stop
using drugs and alcohol, the circadian rhythm continues to be disrupted.
The stabilization of sleep and the circadian rhythm might
possibly help to reduce the vulnerability to addiction and reduce the
chances of relapse.
Circadian rhythms and clock genes expressed in brain regions outside the suprachiasmatic nucleus may significantly influence the effects produced by drugs such as cocaine. Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.
Circadian rhythms was taken as an example of scientific knowledge
being transferred into the public sphere, together with the Wikipedia
article for circadian clocks.
Shifts in scientific understanding were documented over time on these
articles, reflected in the editing history and the reference list.
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