200:), 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.
128:-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 their own circadian "clock" and chronotype, and dawn in the illustration refers to an individual'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.
108:, 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.
212:(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.
282:, 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.
300:. 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.
112:
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.
83:-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.
173:
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
140:
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
111:
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
86:
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
253:
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
303:
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
132:
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
99:
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
63:
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.
174:
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).
121:
52:
75:'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
242:
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
148:
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).
1103:
Rosenthal NE, Joseph-Vanderpool JR, Levendosky AA, Johnston SH, Allen R, Kelly KA, et al. (August 1990). "Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome".
197:
266:, showed that in humans "Exercise elicits circadian phase‐shifting effects, but additional information is needed. Significant phase–response curves were established for
223:, 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.
1125:
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".
864:
208:
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,
141:
effect, causing earlier wake-up and sleep onset. Again, illuminance greatly affects results; indoor light may be less than 500 lux while
145:
uses up to 10,000 lux. The effect diminishes until about two hours after spontaneous wake-up time, when it reaches approximately zero.
270:
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"
92:
554:
Figueiro MG, Bullough JD, Bierman A, Rea MS (October 2005). "Demonstration of additivity failure in human circadian phototransduction".
1138:
Lewy AJ, Ahmed S, Jackson JM, Sack RL (October 1992). "Melatonin shifts human circadian rhythms according to a phase-response curve".
581:
Lewy AJ, Ahmed S, Jackson JM, Sack RL (October 1992). "Melatonin shifts human circadian rhythms according to a phase-response curve".
989:
278:
The first published usage of the term "phase response curve" was in 1960 by
Patricia DeCoursey. The "daily" activity rhythms of her
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expected to change sense abruptly may, if the changeover time is not accurately known, produce an opposite effect to that desired.
322:
1227:
900:
Gutkin BS, Ermentrout GB, Reyes AD (August 2005). "Phase-response curves give the responses of neurons to transient inputs".
1169:"Lack of short-wavelength light during the school day delays dim light melatonin onset (DLMO) in middle school students"
327:
182:
296:
Phase response curve analysis can be used to understand the intrinsic properties and oscillatory behavior of regular-
508:
59:
In humans and animals, there is a regulatory system that governs the phase relationship of an organism's internal
39:
at which it is received. PRCs are used in various fields; examples of biological oscillations are the heartbeat,
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1217:
305:
177:
In addition to its use in the adjustment of circadian rhythms, light therapy is used as treatment for several
872:
1222:
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909:
32:
990:"Layer and frequency dependencies of phase response properties of pyramidal neurons in rat motor cortex"
1041:"Cholinergic neuromodulation changes phase response curve shape and type in cortical pyramidal neurons"
495:
1052:
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230:(sleep-inducing) effect. The expected effect on sleep phase timing, if any, is predicted by the PRC.
914:
219:) melatonin starting about two hours before bedtime, provided the lighting is dim. This is known as
438:
153:
767:"Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light"
509:"Light therapy for seasonal affective disorder with blue narrow-band light-emitting diodes (LEDs)"
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137:("brightness") of the light. The effect is small if indoor lighting is dim (< 3 Lux).
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43:, and the regular, repetitive firing observed in some neurons in the absence of noise.
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945:
Ermentrout B (July 1996). "Type I membranes, phase resetting curves, and synchrony".
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36:
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researchers led by David Berson announced the discovery of special cells in the
134:
765:
Revell VL, Burgess HJ, Gazda CJ, Smith MR, Fogg LF, Eastman CI (January 2006).
618:"A three pulse phase response curve to three milligrams of melatonin in humans"
390:"A three pulse phase response curve to three milligrams of melatonin in humans"
95:
often experience an inability to maintain a consistent internal clock. Extreme
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716:"Timing of sleep and its relationship with the endogenous melatonin rhythm"
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Sletten TL, Vincenzi S, Redman JR, Lockley SW, Rajaratnam SM (2010).
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Glickman G, Byrne B, Pineda C, Hauck WW, Brainard GC (March 2006).
884:
the single most important methodological tool in the study of all
119:
50:
1039:
Stiefel KM, Gutkin BS, Sejnowski TJ (2008). Ermentrout B (ed.).
55:
Phase response curves for light and for melatonin administration
667:"Clinical implications of the melatonin phase response curve"
79:-axis and the amount of the phase shift (in hours) along the
104:, directed at the eyes, and administration of the hormone
496:
Brown
Scientists Uncover Inner Workings of Rare Eye Cells
226:
Administration of melatonin at any time may have a mild
167:
Advance region: morning light shifts sleepiness earlier
71:
research, a PRC illustrates the relationship between a
458:"An insight into light as a chronobiological therapy"
816:"Human circadian phase-response curves for exercise"
771:
The
Journal of Clinical Endocrinology and Metabolism
671:
The
Journal of Clinical Endocrinology and Metabolism
814:Youngstedt SD, Elliott JA, Kripke DF (April 2019).
198:
intrinsically photosensitive retinal ganglion cells
161:
Delay region: evening light shifts sleepiness later
988:Tsubo Y, Takada M, Reyes AD, Fukai T (June 2007).
616:Burgess HJ, Revell VL, Eastman CI (January 2008).
456:Walsh J, Atkinson LA, Corlett SA, Lall GS (2014).
388:Burgess HJ, Revell VL, Eastman CI (January 2008).
35:induced by a perturbation as a function of the
156:. Within that image, the explanatory text is
8:
87:disorders and externals stresses (such as
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91:) can interfere with this. Humans with
152:Another image of the PRC for light is
865:"Clock Tutorial #3c - Darwin On Time"
7:
994:The European Journal of Neuroscience
262:In a 2019 study Shawn D. Youngstedt
27:) illustrates the transient change (
238:In a 2006 study Victoria L. Revell
871:. ScienceBlogs LLC. Archived from
14:
215:The human body produces its own (
1006:10.1111/j.1460-9568.2007.05579.x
308:state of the neuron is changed.
323:Circadian rhythm sleep disorder
93:non-24-hour sleep–wake disorder
525:10.1016/j.biopsych.2005.07.006
1:
437:Kripke DF, Loving RT (2001).
1167:Figueiro MG, Rea MS (2010).
1066:10.1371/journal.pone.0003947
634:10.1113/jphysiol.2007.143180
462:ChronoPhysiology and Therapy
406:10.1113/jphysiol.2007.143180
328:Delayed sleep phase disorder
31:) in the cycle period of an
1173:Neuro Endocrinology Letters
1140:Chronobiology International
583:Chronobiology International
556:Neuro Endocrinology Letters
439:"Bringing Therapy to Light"
183:seasonal affective disorder
1249:
902:Journal of Neurophysiology
289:
268:aMT6(melatonin derivative)
1152:10.3109/07420529209064550
959:10.1162/neco.1996.8.5.979
820:The Journal of Physiology
622:The Journal of Physiology
595:10.3109/07420529209064550
394:The Journal of Physiology
374:10.4249/scholarpedia.1332
221:dim-light melatonin onset
733:10.3389/fneur.2010.00137
869:A Blog Around the Clock
16:Graph of phase response
720:Frontiers in Neurology
349:"Phase response curve"
129:
124:The time shown on the
56:
1228:Neuroscience of sleep
924:10.1152/jn.00359.2004
513:Biological Psychiatry
290:Further information:
123:
54:
1127:Psychopharmacol Bull
783:10.1210/jc.2005-1009
683:10.1210/jc.2010-1031
665:Lewy A (July 2010).
347:Canavier CC (2006).
47:In circadian rhythms
21:phase response curve
1057:2008PLoSO...3.3947S
863:Zivkovic B (2007).
365:2006SchpJ...1.1332C
179:affective disorders
947:Neural Computation
886:biological rhythms
475:10.2147/CPT.S56589
130:
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41:circadian rhythms
1240:
1233:Sleep physiology
1218:Circadian rhythm
1198:
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234:Additive effects
190:Brown University
69:circadian rhythm
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298:spiking neurons
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154:here (Figure 1)
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1028:on 2013-01-05.
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479:. Retrieved
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443:Sleep Review
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73:chronobiotic
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1179:(1): 92–6.
777:(1): 54–9.
135:illuminance
97:chronotypes
33:oscillation
1207:Categories
879:2007-11-03
334:References
286:In neurons
217:endogenous
196:, ipRGCs (
181:including
910:CiteSeerX
468:: 79–85.
210:exogenous
204:Melatonin
194:human eye
106:melatonin
1195:20150866
1133:: 523–5.
1085:19079601
1045:PLOS ONE
1014:17553012
975:17168880
932:15829595
850:30784068
801:16263827
752:21188265
701:20610608
652:18006583
568:16264413
541:42586876
533:16165105
424:18006583
312:See also
258:Exercise
228:hypnotic
188:In 2002
1186:3349218
1160:1394610
1118:2267478
1076:2596483
1053:Bibcode
1022:1232793
967:8697231
841:6462487
792:3841985
743:3008942
726:: 137.
692:2928905
643:2375577
603:1394610
415:2375577
361:Bibcode
248:⁄
185:(SAD).
89:jet lag
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481:31 May
422:
412:
274:Origin
264:et al.
240:et al.
1106:Sleep
1018:S2CID
971:S2CID
537:S2CID
116:Light
37:phase
1191:PMID
1156:PMID
1114:PMID
1081:PMID
1010:PMID
963:PMID
928:PMID
846:PMID
797:PMID
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