Phase response curve

A phase response curve (PRC) illustrates the relationship between the timing of administration of a sleep phase affecting drug or treatment, and the effect on the sleep phase (a/k/a sleep timing). It has a  sigmoidal ('S') shape when plotted as relative circadian time vs. phase shift magnitude. Such a curve has one peak and, the opposite, one nadir in each 24 hours.

An image of the PRC for light is here.

Light PRC
Light therapy, typically with a light box producing 10,000 lux at a prescribed distance, has its greatest effect about five hours after usual bedtime. Starting about two hours before bedtime, exposure to bright light will delay the circadian phase, causing later wake-up time and later sleep onset. The closer to the middle of the night (relative to the individual's normal sleep-wake schedule), the greater the effect on circadian phase. This continues until the PRC's peak about five hours after usual bedtime, when the effect changes abruptly from phase delay to phase advance. Immediately after this peak, bright light exposure has its greatest phase advancing effect, causing earlier wake-up and sleep onset. The effect diminishes until about two hours after usual wake-up time, when it reaches zero. During the period between two hours after usual wake-up time to two hours before usual bedtime, bright light exposure has little or no effect on circadian phase (slight effects generally cancelling each other out).

Because losing sleep to obtain bright light exposure is considered undesirable by most people, the treatment is usually applied just prior to bedtime (to achieve phase delay), or just after awakening (to achieve phase advance).



In 2002, Brown 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 light in the 460-480nm (blue) range. In one experiment, 400 lux of blue light produced the same effects as 10,000 lux of white light. Furthermore, there is now evidence for a theory of spectral opponency, in which the addition of other spectral colors renders blue light less effective for circadian phototransduction.

Melatonin PRC
The phase-response curve for melatonin is roughly twelve hours out of phase with the phase-response curve for light. At usual 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 natural action 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 resultant effect on sleep phase is governed by the PRC.

Effects are additive
In a newer study (2006), Victoria L. Revell et al have shown 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.

N.B. All times are approximate and vary among individuals. In particular, there is no convenient way of determining the exact timing of the peaks of these curves in an individual. For this reason, administration of light and/or melatonin should generally be avoided for at least an hour on either side of the expected time of the abrupt change of effect. This provides a safety margin to avoid producing the opposite effect of the desired one.