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Melatonin Rhythm Observed throughout a Three-Cycle Bright-Light Stimulus Designed to Reset the Human Circadian Pacemaker

Circadian, Neuroendocrine, and Sleep Disorders Section, Division of Endocrinology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115

Richard E. Kronauer

Division of Applied Sciences, Harvard University, Cambridge, MA 02138

Jeanne F. Duffy

Circadian, Neuroendocrine, and Sleep Disorders Section, Division of Endocrinology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115

Gordon H. Williams

Division of Endocrinology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115

Charles A. Czeisler

Circadian, Neuroendocrine, and Sleep Disorders Section, Division of Endocrinology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115

Exposure to light and darkness can rapidly induce phase shifts of the human circadian pacemaker. A type 0 phase response curve (PRC) to light that has been reported for humans was based on circadian phase data collected from constant routines performed before and after a three-cycle light stimulus, but resetting data observed throughout the entire resetting protocol have not been previously reported. Pineal melatonin secretion is governed by the hypothalamic circadian pacemaker via a well-defined neural pathway and is reportedly less subject to the masking effects of sleep and activity than body temperature. The authors reasoned that observation of the melatonin rhythm throughout the three-cycle light resetting trials could provide daily phase-resetting information, allowing a dynamic view of the resetting response of the circadian pacemaker to light. Subjects (n = 12) living in otherwise dim light (~10-15 lux) were exposed to a noncritical stimulus of three cycles of bright light (~9500 lux for 5 h per day) timed to phase advance or phase delay the human circadian pacemaker; control subjects (n = 11) were scheduled to the same protocols but exposed to three 5-h darkness cycles instead of light. Subjects underwent initial and final constant routine phase assessments; hourly melatonin samples and body temperature data were collected throughout the protocol. Average daily phase shifts of 1 to 3 h were observed in 11 of 12 subjects receiving the bright light, supporting predictions obtained using Kronauer’s phase-amplitude model of the resetting response of the human circadian pacemaker. The melatonin rhythm in the 12th subject progressively attenuated in amplitude throughout the resetting trial, becoming undetectable for > 32 hours preceding an abrupt reappearance of the rhythm at a shifted phase with a recovered amplitude. The data from control subjects who remained in dim lighting and darkness delayed on average – 0.2 h per day, consistent with the daily delay expected due to the longer than 24-h intrinsic period of the human circadian pacemaker. Both temperature and melatonin rhythms shifted by equivalent amounts in both bright light-treated and control subjects (R = 0.968; p < 0.0001; n = 23). Observation of the melatonin rhythm throughout a three-cycle resetting trial has provided a dynamic view of the daily phase-resetting response of the human circadian pacemaker. Taken together with the observation of strong type 0 resetting in humans in response to the same three-cycle stimulus applied at a critical phase, these data confirm the importance of considering both phase and amplitude when describing the resetting of the human circadian pacemaker by light.

Key Words: melatonin • phase shifts • light • suprachiasmatic nucleus • phase response curve • circadian rhythms • human • body temperature • circadian period

Journal of Biological Rhythms, Vol. 14, No. 3, 237-253 (1999)
DOI: 10.1177/074873099129000560


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