Phase response curve

A phase response curve (PRC) illustrates the transient

change 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 elds; examples of biological oscillations are the heartbeat, circadian rhythms,
and the regular, repetitive ring observed in some neurons in the absence of noise.[1]

tive circadian time is plotted vs. phase shift magnitude.

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. Each of these treatments
has its own PRC which will vary according to the species
being studied; its shape may also vary individually, just
slightly. The magnitude is dose-dependent.[2] The discussions below are restricted to the human PRCs for the
chronobiotics light and melatonin.

PRCs in circadian rhythms

1.1 Light PRC

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 specic clock times. Each individual has her/his own circadian
clock and chronotype, and dawn in the illustration refers to a
persons time of spontaneous awakening when well-rested and
sleeping regularly. The PRC shows when a stimulus, in this case
light to the eyes, will eect a change, an advance or a delay.
The curves highest point coincides with the subjects lowest body
temperature.

Phase response curves for light and for melatonin administration

In circadian rhythm research, a PRC illustrates the relationship between a treatments time of administration
and the treatments eect on a circadian rhythm. Normally, the bodys various physiological rhythms will be
synchronized within an individual organism (human or
animal). The sleepwake cycle is the most familiar of
these rhythms; for humans, a treatment designed to affect circadian rhythms will most often be intended to
adjust sleep timing, by either delaying it to later in the
day (night), or advancing it. Extreme morning people
may want to delay their sleep timing; extreme evening
chronotypes may wish to advance it.

Starting about two hours before an individuals regular

bedtime, exposure of the eyes to light will delay the
circadian phase, causing later wake-up time and later
sleep onset. The delaying eect gets stronger as evening
progresses; it is also dependent on the wavelength and
illuminance (brightness) of the light. The eect is small
in dim indoor lighting.
About ve hours after usual bedtime, coinciding with the
body temperature nadir (the lowest point of the core body
temperature during sleep) the PRC peaks and the eect
changes abruptly from phase delay to phase advance. Immediately after this peak, light exposure has its greatest phase-advancing eect, causing earlier wake-up and
sleep onset. Again, illuminance greatly aects results;

A PRC is a graph showing, by convention, time of the

subjects endogenous day along the x-axis and the amount
of the phase shift (in hours) along the y-axis. The curve
has one peak and one nadir in each 24-hour cycle. Rela1

2 PRC IN NEURONS

indoor light may be less than 500 lux while light therapy uses up to 10,000 lux. The eect diminishes until
about two hours after spontaneous wake-up time, when it
reaches approximately zero.

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.[10] This stimulates the phase-advance porDuring the period between two hours after usual wake-up tion of the PRC and helps keep the body on a regular
time and two hours before usual bedtime, light exposure sleep-wake schedule. It also helps prepare the body for
has little or no eect on circadian phase (slight eects sleep.
generally cancelling each other out).
Administration of melatonin at any time may have a mild
Another image of the PRC for light is here (Figure 1). hypnotic (sleep-inducing) eect. The expected eect on
sleep phase timing, if any, is predicted by the PRC.
Within that image, the explanatory text is
Delay region: evening light shifts sleepiness later and 1.3

Additive eects

Advance region: morning light shifts sleepiness earlier.[3]

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 reLight therapy, typically with a light box producing 10,000 spective PRCs, produce a larger phase advance shift than
lux at a prescribed distance, can be used in the evening to bright light alone,[11] for a total of up to 21 hours.
2
delay or in the morning to advance a persons sleep timing. Because losing sleep to obtain bright light exposure All times are approximate and vary from one person to
is considered undesirable by most people, and because another. In particular, there is no convenient way to accuit is very dicult to estimate exactly when the greatest rately determine the times of the peaks and zero-crossings
eect (the PRC peak) will occur in an individual, the of these curves in an individual. Administration of light
treatment is usually applied daily just prior to bedtime or melatonin close to the time at which the eect is ex(to achieve phase delay), or just after spontaneous awak- pected to change sense abruptly may, if the changeover
time is not accurately known, produce an opposite eect
ening (to achieve phase advance).
to that desired.
In addition to its use in the adjustment of circadian
rhythms, light therapy is used as treatment for several
aective disorders including seasonal aective disorder 1.4 Origin of the PRC
(SAD).[4]
In 2002 Brown University researchers led by David The rst published usage of the term phase response
Berson announced the discovery of special cells in the curve was in 1960 by Patricia DeCoursey. The daily
human eye, ipRGCs (intrinsically photosensitive retinal activity rhythms of her ying squirrels, kept in constant
ganglion cells),[5] which many researchers now believe darkness, responded to pulses of light exposure. The recontrol the light entrainment eect of the phase response sponse varied according to the time of daythat is, the
curve. In the human eye, the ipRGCs have the greatest animals subjective daywhen light was administered.
response to light in the 460480 nm (blue) range. In one When DeCoursey plotted all her data relating the quantity
experiment, 400 lux of blue light produced the same ef- and direction (advance or delay) of phase-shift on a single
fects as 10,000 lux of white light.[6] A theory of spectral curve, she created the PRC. It has since been a standard
[12]
opponency, in which the addition of other spectral colors tool in the study of biological rhythms.
renders blue light less eective for circadian phototransduction, was supported by research reported in 2005.[7]

2 PRC in neurons

1.2

Melatonin PRC

Phase response curve analysis can be used to understand the intrinsic properties and oscillatory behavior of
regular-spiking neurons.[13] The neuronal PRCs can be
classied 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.[14]

The phase response curve for melatonin is roughly twelve

hours out of phase with the phase response curve for
light.[8] At spontaneous wake-up time, exogenous (externally administered) melatonin has a slight phase-delaying
eect. The amount of phase-delay increases until about
eight hours after wake-up time, when the eect swings
abruptly from strong phase delay to strong phase advance.
The phase-advance eect diminishes as the day goes on
until it reaches zero about bedtime. From usual bedtime
until wake-up time, exogenous melatonin has no eect on Experimental estimation of PRC in living, regularspiking neurons involves measuring the changes in intercircadian phase.[9]

3
spike interval in response to a small perturbation, such as
a transient pulse of current. Notably, the PRC of a neuron is not xed but may change when ring frequency[15]
or neuromodulatory state of the neuron[16] is changed.

References

[1] Carmen C. Canavier (2006).

sponse curve.
Scholarpedia.
doi:10.4249/scholarpedia.1332.

Phase re1 (12): 1332.

[2] Burgess HJ, Revell VL, Eastman CI (January 2008).

A three pulse phase response curve to three milligrams
of melatonin in humans. J. Physiol. (Lond.). 586
(2): 639647. doi:10.1113/jphysiol.2007.143180. PMC
2375577 . PMID 18006583.
[3] Kripke, DF; Loving, RT (2001). Bringing Therapy to
Light. Sleep Review (01).
[4] Walsh, JM; Atkinson, LA; Corlett, SA; Lall, GS
(2014). An insight into light as a chronobiological
therapy. ChronoPhysiology and Therapy. 4: 7985.
doi:10.2147/CPT.S56589. Retrieved 31 May 2015.
[5] Brown Scientists Uncover Inner Workings of Rare Eye
Cells
[6] Glickman G, Byrne B, Pineda C, Hauck WW, Brainard
GC (March 2006). Light therapy for seasonal affective disorder with blue narrow-band light-emitting
diodes (LEDs)". Biol. Psychiatry. 59 (6): 502507.
doi:10.1016/j.biopsych.2005.07.006. PMID 16165105.
[7] Figueiro MG, Bullough JD, Bierman A, Rea MS (October 2005). Demonstration of additivity failure in human
circadian phototransduction. Neuro Endocrinol. Lett. 26
(5): 4938. PMID 16264413.
[8] Lewy, Alfred J; Bauer, Vance K; Ahmed, Saeeduddin;
Thomas, Katherine H; Cutler, Neil L; Singer, Cliord
M; Mott, Mary T; Sack, Robert L (1992). Melatonin
shifts human circadian rhythms according to a phaseresponse curve. Chronobiology International. 9 (5):
380392. doi:10.3109/07420529209064550. PMID
1394610. Retrieved 23 June 2015.
[9] Burgess, Helen J.; Revell, Victoria L.; Eastman, Charmane I. (15 January 2008). A three pulse phase response curve to three milligrams of melatonin in humans. The Journal of Physiology. 586 (2): 639647.
doi:10.1113/jphysiol.2007.143180. PMC 2375577 .
PMID 18006583. Retrieved 23 June 2015.
[10] Sletten, Tracey L.; Vincenzi, Simon; Redman, Jennifer
R.; Lockley, Steven W.; Rajaratnam, Shantha M. W.
(2010). Timing of Sleep and Its Relationship with the
Endogenous Melatonin Rhythm. Frontiers in Neurology.
1. doi:10.3389/fneur.2010.00137. Retrieved 23 June
2015.
[11] Revell VL, Burgess HJ, Gazda CJ, Smith MR, Fogg LF,
Eastman CI (January 2006). Advancing human circadian

rhythms with afternoon melatonin and morning intermittent bright light. J. Clin. Endocrinol. Metab. 91 (1):
5459. doi:10.1210/jc.2005-1009. PMID 16263827.
[12] Zivkovic, Bora; aka Coturnix (2007). Clock Tutorial
#3c - Darwin On Time. A Blog Around the Clock. ScienceBlogs LLC. Archived from the original on 2005-0106. Retrieved 2007-11-03. [The PRC is] the single most
important methodological tool in the study of all biological rhythms. Cite uses deprecated parameter |coauthors=
(help)
[13] Gutkin BS, Ermentrout GB, Reyes AD (August 2005).
Phase-response curves give the responses of neurons to
transient inputs. J. Neurophysiol. 94 (2): 16231635.
doi:10.1152/jn.00359.2004. PMID 15829595.
[14] Ermentrout B (July 1996). Type I membranes, phase
resetting curves, and synchrony. Neural Comput. 8
(5): 9791001. doi:10.1162/neco.1996.8.5.979. PMID
8697231.
[15] Tsubo Y, Takada M, Reyes AD, Fukai T (June 2007).
Layer and frequency dependencies of phase response
properties of pyramidal neurons in rat motor cortex. Eur.
J. Neurosci. 25 (11): 34293441. doi:10.1111/j.14609568.2007.05579.x. PMID 17553012.
[16] Stiefel KM, Gutkin BS, Sejnowski TJ (2008). Ermentrout, Bard, ed.
Cholinergic neuromodulation
changes phase response curve shape and type in cortical pyramidal neurons. PLoS ONE. 3 (12): e3947.
doi:10.1371/journal.pone.0003947. PMC 2596483 .
PMID 19079601.

4 Further reading
Rosenthal NE, Joseph-Vanderpool JR, Levendosky
AA, et al. (August 1990). Phase-shifting eects of
bright morning light as treatment for delayed sleep
phase syndrome. Sleep. 13 (4): 35461. PMID
2267478.
Lewy A, Sack R, Fredrickson R (1983). The use of
bright light in the treatment of chronobiologic sleep
and mood disorders: The phase-response curve.
Psychopharmacol Bull. 19: 5235.
Lewy AJ, Ahmed S, Latham JM, et al. (1992).
Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int. 9
(5): 380392. doi:10.3109/07420529209064550.
PMID 1394610.
Figueiro MG, Rea MS (2010). Lack of shortwavelength light during the school day delays dim
light melatonin onset (DLMO) in middle school students. Neuro Endocrinol. Lett. 31 (1): 926.
PMID 20150866.

5 SEE ALSO

See also
Circadian rhythm sleep disorders
Delayed sleep phase syndrome
Chronobiology

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