Phase response curve

Last updated December 29, 2024

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.^[1]^{[ better source needed ]}

In circadian rhythms

Phase response curves for light and for melatonin administration PRC-Light+Mel.png — 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. Humans 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,^[2] 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

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).^[3] Within that image, the explanatory text is

Delay region: evening light shifts sleepiness later and
Advance region: morning light shifts sleepiness earlier.^[4]

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 an individual'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 addition to its use in the adjustment of circadian rhythms, light therapy is used as treatment for several affective disorders including seasonal affective disorder (SAD).^[5]

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),^[6] 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.^[7] 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.^[8]

Melatonin

The phase response curve for melatonin is roughly twelve hours out of phase with the phase response curve for light.^[9] 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.^[10]^[11]

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.^[12] 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 individual 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.^[13]

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"^[14]

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.^[15]

In neurons

Phase response curve analysis can be used to understand the intrinsic properties and oscillatory behavior of regular-spiking neurons.^[16] 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.^[17]

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^[18] or neuromodulatory state of the neuron^[19] is changed.

Related Research Articles

Free-running sleep is a rare sleep pattern whereby the sleep schedule of a person shifts later every day. It occurs as the sleep disorder non-24-hour sleep–wake disorder or artificially as part of experiments used in the study of circadian and other rhythms in biology. Study subjects are shielded from all time cues, often by a constant light protocol, by a constant dark protocol or by the use of light/dark conditions to which the organism cannot entrain such as the ultrashort protocol of one hour dark and two hours light. Also, limited amounts of food may be made available at short intervals so as to avoid entrainment to mealtimes. Subjects are thus forced to live by their internal circadian "clocks".

Jet lag is a temporary physiological condition that occurs when a person's circadian rhythm is out of sync with the time zone they are in, and is a typical result from travelling rapidly across multiple time zones. For example, someone travelling from New York to London, i.e. from west to east, feels as if the time were five hours earlier than local time, and someone travelling from London to New York, i.e. from east to west, feels as if the time were five hours later than local time. The phase shift when travelling from east to west is referred to as phase-delay of the circadian cycle, whereas going west to east is phase-advance of the cycle. Most travellers find that it is harder to adjust time zones when travelling east. Jet lag was previously classified as a circadian rhythm sleep disorder.

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximize the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is the delaying of a person's circadian rhythm compared to those of societal norms. The disorder affects the timing of biological rhythms including sleep, peak period of alertness, core body temperature, and hormonal cycles. People with this disorder are often called night owls.

Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening sleepiness and very early morning awakening. This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive retinal ganglion cells allow it to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

Chronotherapy is a behavioural treatment that attempts to move bedtime and rising time later and later each day, around the clock, until a person is sleeping on a normal schedule. This treatment can be used by people with delayed sleep phase disorder (DSPD), who generally cannot reset their circadian rhythm by moving their bedtime and rising time earlier. DSPD is a circadian rhythm sleep disorder, characterised by a mismatch between a person's internal biological clock and societal norms. Chronotherapy uses the human phase response to light or melatonin. The American Academy of Sleep Medicine has recommended chronotherapy for the treatment of circadian rhythm and sleep disorders.

Non-24-hour sleep–wake disorder is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in a society". Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.

Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep–wake disorders (CRSWD), are a family of sleep disorders that affect the timing of sleep. CRSDs cause a persistent pattern of sleep/wake disturbances that arise 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 misalignment, those affected by circadian rhythm sleep disorders can fall asleep at unconventional time points in the day, or experience excessive daytime sleepiness if they resist. These occurrences often lead to recurring instances of disrupted rest and wakefulness, 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 represent the four main types of CRSD.

Shift work sleep disorder (SWSD) is a circadian rhythm sleep disorder characterized by insomnia, excessive sleepiness, or both affecting people whose work hours overlap with the typical sleep period. Insomnia can be the difficulty to fall asleep or to wake up before the individual has slept enough. About 20% of the working population participates in shift work. SWSD commonly goes undiagnosed, and it is estimated that 10–40% of shift workers have SWSD. The excessive sleepiness appears when the individual has to be productive, awake and alert. Both symptoms are predominant in SWSD. There are numerous shift work schedules, and they may be permanent, intermittent, or rotating; consequently, the manifestations of SWSD are quite variable. Most people with different schedules than the ordinary one might have these symptoms but the difference is that SWSD is continual, long-term, and starts to interfere with the individual's life.

Dawn simulation is a technique that involves timing a light, often called a wake-up light, sunrise alarm clock, or natural light alarm clock, in the bedroom to come on gradually, over a period of 30 minutes to 2 hours, before awakening to simulate dawn.

Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT₁ (or Mel_1A or MTNR1A) and MT₂ (or Mel_1B or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT₃ (or Mel_1C or MTNR1C) has been identified in amphibia and birds. The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT₁ and MT₂ control this process. Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. In 2019, X-ray crystal and cryo-EM structures of MT₁ and MT₂ were reported.

In the study of chronobiology, entrainment refers to the synchronization of a biological clock to an environmental cycle. An example is the interaction between circadian rhythms and environmental cues, such as light and temperature. Entrainment helps organisms adapt their bodily processes with the timing of a changing environment. For example, entrainment is manifested during travel between time zones, hence why humans experience jet lag.

Light effects on circadian rhythm are the response of circadian rhythms to light.

Michael Terman is an American psychologist best known for his work in applying the biological principles of the circadian timing system to psychiatric treatments for depression and sleep disorders. This subspecialty is known as Chronotherapeutics.

In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.

Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.

Dr. Debra J. Skene is a chronobiologist with specific interest in the mammalian circadian rhythm and the consequences of disturbing the circadian system. She is also interested in finding their potential treatments for people who suffer from circadian misalignment. Skene and her team of researchers tackle these questions using animal models, clinical trials, and most recently, liquid chromatography-mass spectrometry. Most notably, Skene is credited for her evidence of a novel photopigment in humans, later discovered to be melanopsin. She was also involved in discovering links between human PER3 genotype and an extremely shifted sleep schedules categorized as extreme diurnal preference. Skene received her Bachelor of Pharmacy, Master of Science, and Ph.D. in South Africa.

Charmane Eastman is an American academic research scientist whose career has focused on studying circadian rhythms and their relationships to sleep, jet lag, and shift work. She has also studied winter depression, more properly known as seasonal affective disorder (SAD). Of special focus are the effects of bright light and melatonin on circadian rhythms.

In chronobiology, photoentrainment refers to the process by which an organism's biological clock, or circadian rhythm, synchronizes to daily cycles of light and dark in the environment. The mechanisms of photoentrainment differ from organism to organism. Photoentrainment plays a major role in maintaining proper timing of physiological processes and coordinating behavior within the natural environment. Studying organisms’ different photoentrainment mechanisms sheds light on how organisms may adapt to anthropogenic changes to the environment.

References

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