Entrainment of the human circadian pacemaker to longer-than-24-h days

*Division of Sleep Medicine, Department of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
^¶Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115;
^‖Department of Integrative Physiology, Sleep and Chronobiology Laboratory, Center for Neuroscience, University of Colorado, Boulder, CO 80309;
**Division of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
^†Department of Chronobiology, Stem Cell and Brain Research, Institut National de la Santé et de la Recherche Médicale, Unité 846, Bron F-69500, France; and
^‡Université Lyon 1, Lyon F-69000, France

Communicated by J. Woodland Hastings, Harvard University, Cambridge, MA, March 28, 2007 (received for review January 17, 2007)

Abstract

Entrainment of the circadian pacemaker to the light:dark cycle is necessary for rhythmic physiological functions to be appropriately timed over the 24-h day. Nonentrainment results in sleep, endocrine, and neurobehavioral impairments. Exposures to intermittent bright light pulses have been reported to phase shift the circadian pacemaker with great efficacy. Therefore, we tested the hypothesis that a modulated light exposure (MLE) with bright light pulses in the evening would entrain subjects to a light:dark cycle 1 h longer than their own circadian period (τ). Twelve subjects underwent a 65-day inpatient study. Individual subject's circadian period was determined in a forced desynchrony protocol. Subsequently, subjects were released into 30 longer-than-24-h days (daylength of τ + 1 h) in one of three light:dark conditions: (i) ≈25 lux; (ii) ≈100 lux; and (iii) MLE: ≈25 lux followed by ≈100 lux, plus two 45-min bright light pulses of ≈9,500 lux near the end of scheduled wakefulness. We found that lighting levels of ≈25 lux were insufficient to entrain all subjects tested. Exposure to ≈100 lux was sufficient to entrain subjects, although at a significantly wider phase angle compared with baseline. Exposure to MLE was able to entrain the subjects to the imposed sleep–wake cycles but at a phase angle comparable to baseline. These results suggest that MLE can be used to entrain the circadian pacemaker to non-24-h days. The implications of these findings are important because they could be used to treat circadian misalignment associated with space flight and circadian rhythm sleep disorders such as shift-work disorder.

Footnotes

^§To whom correspondence should be addressed at:
Department of Chronobiology, Institut National de la Santé et de la Recherche Médicale, Unité 846, 18 Avenue du Doyen Lépine, F-69500 Bron, France.
E-mail: gronfier{at}lyon.inserm.fr
Author contributions: C.G., K.P.W., R.E.K., and C.A.C. designed research; C.G. performed research; C.G. analyzed data; and C.G., K.P.W., R.E.K., and C.A.C. wrote the paper.
Conflict of interest statement: C.A.C. has received consulting fees from or served as a paid member of scientific advisory boards for Actelion, Inc.; Aventis; Avera Pharmaceuticals, Inc.; Cephalon, Inc.; Coca-Cola Co.; Fedex Kinko's; Hypnion, Inc.; Morgan Stanley; Pfizer, Inc.; Respironics; Sleep Research Society; Takeda Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; and Warburg-Pincus. He owns an equity interest in Hypnion, Inc., Lifetrac; and Vanda Pharmaceuticals, Inc. He has received lecture fees from Alfresa; Cephalon, Inc., and Takeda, Inc.; Tanabe Seiyaku Co., Ltd.; Tokyo Electric Power Company; clinical trial research contracts from Cephalon, Inc., Merck, Sanofi-Aventis; and Pfizer, Inc.; an investigator-initiated research grant from Cephalon, Inc.; and unrestricted research and education funds from Cephalon, Inc., Philips Lighting; Sanofi Aventis; Sepracor; Takeda; and Resmed. He is the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc. Since 1985, Dr. Czeisler has served as an expert witness on various legal cases related to sleep and/or circadian rhythms. K.P.W. has received consulting fees, speaker fees, and clinical research grants from Cephalon, Inc.; received consulting fees, an investigator-initiated research grant, and educational grants from Takeda, Inc.; received consulting fees from Novartis, Inc.; and served as an equity paid member of a scientific advisory board for Axon Sleep Research Laboratories, Inc.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702835104/DC1.
Abbreviations:

AG,

angle of gaze;

MLE,

modulated light exposure;

ψ,

phase angle;

τ,

circadian period;

MELon,

melatonin onset;

MELoff,

melatonin offset;

PRC,

phase response curve;

FD,

forced desynchrony;

Dn,

day n;

CR,

constant routine.