Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans

Abstract

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.

Figures

Figure 1

A) Phase angle of entrainment for subjects in study 1 (n=19). Following two days of exposure to a light-dark schedule with light levels equivalent to normal daytime indoor light, melatonin onset was delayed but the range of phase angles was similar when comparing day 1 to the CR. B) Phase angle of entrainment for subjects in study 2 (n=15). Following five days of exposure to a moderately bright light-dark schedule, melatonin onset was delayed and inter-individual differences in phase angle were reduced when comparing day 1 to the CR. Symbols represent individual subjects. Solid line represents habitual sleep time. Values in square brackets represent light level exposure in the angle of gaze.

Figure 2

Association between intrinsic circadian period during forced desynchrony (T-Cycle= 28.0) and the phase angle of entrainment on A) day 1 of entry to the laboratory, B) day 7, the first cycle of the constant routine (CRa), and C) day 8, the second cycle of the constant routine (CRb) for subjects in study 2. Symbols represent individual subjects for whom melatonin onset and intrinsic period data were available. The dashed line represents a linear fit of the data. The phase angle of entrainment, as determined by the relationship between melatonin onset and habitual sleep time, is positively and robustly related to intrinsic circadian period (τm) with slopes ranging from 2.42 to 5.25.

Figure 3

Association between the drift in melatonin onset time during CR and intrinsic circadian period during forced desynchrony (T-Cycle=28.0) of study 2. Symbols represent individual subjects for whom two melatonin onsets and intrinsic period data were available. The solid black line represents the change in melatonin onset that would have occurred had subjects drifted at a rate equal to the intrinsic period of their internal clock. The dashed line represents a linear fit of the data.