Intrinsic Period and Light Intensity Determine the Phase Relationship between Melatonin and Sleep in Humans

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 (ψ)—is strongly determined by the intrinsic period (τ) 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 (~450 lux)–dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (~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.

[1]  M. Uchiyama,et al.  Melatonin Rhythms in Delayed Sleep Phase Syndrome , 1999, Journal of biological rhythms.

[2]  S. Honma,et al.  Period and Phase Adjustments of Human Circadian Rhythms in the Real World , 2003, Journal of biological rhythms.

[3]  R. Wever,et al.  Re-entrainment of circadian rhythms after phase-shifts of the Zeitgeber. , 1975, Chronobiologia.

[4]  D. P. King,et al.  A CLOCK polymorphism associated with human diurnal preference. , 1998, Sleep.

[5]  Christian Cajochen,et al.  A Phase Response Curve to Single Bright Light Pulses in Human Subjects , 2003, The Journal of physiology.

[6]  A. Kalsbeek,et al.  Suprachiasmatic control of melatonin synthesis in rats: inhibitory and stimulatory mechanisms , 2003, The European journal of neuroscience.

[7]  A. Muzet,et al.  A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves. , 1996, Sleep.

[8]  T. Åkerstedt,et al.  Validation of the S and C components of the three-process model of alertness regulation. , 1995, Sleep.

[9]  Josephine Arendt,et al.  A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. , 2003, Sleep.

[10]  S. A. Smith,et al.  A circadian pacemaker in free-living chipmunks: essential for survival? , 2000, Journal of Comparative Physiology A.

[11]  M. Smolensky,et al.  Circadian rhythmic aspects of human cardiovascular function: a review by chronobiologic statistical methods. , 1976, Chronobiologia.

[12]  R. Wever,et al.  The Circadian System of Man: Results of Experiments Under Temporal Isolation , 1979 .

[13]  S. Reppert,et al.  Melatonin receptors in human hypothalamus and pituitary: implications for circadian and reproductive responses to melatonin. , 1993, The Journal of clinical endocrinology and metabolism.

[14]  Derk-Jan Dijk,et al.  Entrained phase of the circadian pacemaker serves to stabilize alertness and performance throughout the habitual waking day. , 1994 .

[15]  C A Czeisler,et al.  Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  C A Czeisler,et al.  Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase. , 2001, Behavioral neuroscience.

[17]  Richard E Kronauer,et al.  Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients. , 1997, The American journal of physiology.

[18]  D. Skene,et al.  Melatonin administration can entrain the free-running circadian system of blind subjects. , 2000, The Journal of endocrinology.

[19]  C. Pittendrigh,et al.  ON THE SIGNIFICANCE OF TRANSIENTS IN DAILY RHYTHMS. , 1958, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Trevor R. Norman,et al.  The effect of gender on the melatonin suppression by light: a dose response relationship , 2000, Journal of Neural Transmission.

[21]  A. Kalsbeek,et al.  Glutamatergic clock output stimulates melatonin synthesis at night , 2004, The European journal of neuroscience.

[22]  M. Hastings,et al.  Effect of asymmetrical reductions of photoperiod on pineal melatonin, locomotor activity and gonadal condition of male Syrian hamsters. , 1987, The Journal of endocrinology.

[23]  H. Illnerová,et al.  Exposure to long summer days affects the human melatonin and cortisol rhythms , 1997, Brain Research.

[24]  D.G.M. Dijk,et al.  Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  D B Boivin,et al.  Dynamic resetting of the human circadian pacemaker by intermittent bright light. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[26]  Charles A. Czeisler,et al.  INFLUENCE OF LIGHT ON CIRCADIAN RHYTHMICITY IN HUMANS , 1999 .

[27]  D. Skene,et al.  Suppression of Nocturnal Plasma Melatonin and 6-Sulphatoxymelatonin by Bright and Dim Light in Man , 1987, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[28]  C. Eastman,et al.  Combinations of Bright Light, Scheduled Dark, Sunglasses, and Melatonin to Facilitate Circadian Entrainment to Night Shift Work , 2003, Journal of biological rhythms.

[29]  A. Lewy,et al.  Entrainment of free-running circadian rhythms by melatonin in blind people. , 2000, The New England journal of medicine.

[30]  DM Edgar,et al.  Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  G. Barbato,et al.  Conservation of photoperiod-responsive mechanisms in humans. , 1993, The American journal of physiology.

[32]  R. Kronauer,et al.  Efficacy of a single sequence of intermittent bright light pulses for delaying circadian phase in humans. , 2004, American journal of physiology. Endocrinology and metabolism.

[33]  P. Achermann,et al.  Sleep Homeostasis and Models of Sleep Regulation , 1999 .

[34]  J. Paquet,et al.  Natural bright light exposure in the summer and winter in subjects with and without complaints of seasonal mood variations , 1998, Biological Psychiatry.

[35]  C. Czeisler,et al.  Relationship between alertness, performance, and body temperature in humans. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[36]  Daniel Aeschbach,et al.  A longer biological night in long sleepers than in short sleepers. , 2003, The Journal of clinical endocrinology and metabolism.

[37]  A. Lewy,et al.  Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? , 1997, Sleep.

[38]  J. Arendt Melatonin assays in body fluids. , 1978, Journal of neural transmission. Supplementum.

[39]  A. Lewy,et al.  Melatonin as a Hormone and as a Marker for Circadian Phase Position in Humans , 2002 .

[40]  M. Uchiyama,et al.  Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep–wake syndrome in humans , 2000, Neuroscience Letters.

[41]  S. Daan,et al.  Timing of human sleep: recovery process gated by a circadian pacemaker. , 1984, The American journal of physiology.

[42]  R. Kronauer,et al.  Stability, precision, and near-24-hour period of the human circadian pacemaker. , 1999, Science.

[43]  Leslie G. Ungerleider,et al.  Effects of damage to the suprachiasmatic area of the anterior hypothalamus on the daily melatonin and cortisol rhythms in the rhesus monkey , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[44]  Fred W. Turek,et al.  Regulation of sleep and circadian rhythms , 1999 .

[45]  D. Edgar,et al.  Circadian and Homeostatic Control of Rapid Eye Movement (REM) Sleep: Promotion of REM Tendency by the Suprachiasmatic Nucleus , 2000, The Journal of Neuroscience.

[46]  R. Kronauer,et al.  Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression , 2000, The Journal of physiology.

[47]  Sun-Ok Gwon University of Texas at Austin의 연구 현황 , 2002 .

[48]  Han S Lee,et al.  The Suprachiasmatic Nucleus: A Clock of Multiple Components , 2003, Journal of biological rhythms.

[49]  J. Paquet,et al.  Phase Relationships between Sleep-Wake Cycle and Underlying Circadian Rhythms in Morningness-Eveningness , 2004, Journal of biological rhythms.

[50]  Yoshiyuki Sakaki,et al.  Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons , 2004, Journal of biological rhythms.

[51]  R. Ogilvie,et al.  Sleep onset: Normal and abnormal processes. , 1994 .

[52]  G. Daily,et al.  Nocturnality and species survival. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Christopher R. Jones,et al.  Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans , 1999, Nature Medicine.

[54]  A. Lewy,et al.  The Endogenous Melatonin Profile as a Marker for Circadian Phase Position , 1999, Journal of biological rhythms.

[55]  D. Skene,et al.  Use of melatonin in circadian rhythm disorders and following phase shifts. , 1996, Acta neurobiologiae experimentalis.

[56]  Laura K Barger,et al.  Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[57]  R. Wurtman,et al.  Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C. Eastman,et al.  The effects of prior light history on the suppression of melatonin by light in humans , 2002, Journal of pineal research.

[59]  C. Czeisler,et al.  Absence of Circadian Phase Resetting in Response to Bright Light Behind the Knees , 2002, Science.

[60]  J. Emens,et al.  Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin , 2001, Neuroscience Letters.

[61]  R. Moore,et al.  Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. , 1972, Brain research.

[62]  C. Czeisler,et al.  Circadian and sleep-dependent regulation of hormone release in humans. , 1999, Recent progress in hormone research.

[63]  W. Revelle,et al.  Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness–eveningness , 2000, Journal of sleep research.

[64]  C. Czeisler,et al.  Adaptation of human pineal melatonin suppression by recent photic history. , 2004, The Journal of clinical endocrinology and metabolism.

[65]  D. Dijk,et al.  Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. , 1999, The American journal of physiology.

[66]  C S Pittendrigh,et al.  Temporal organization: reflections of a Darwinian clock-watcher. , 1993, Annual review of physiology.

[67]  K. Hoffmann Zur Beziehung zwischen Phasenlage und Spontanfrequenz bei der endogenen Tagesperiodik , 1963 .

[68]  D. Dawson,et al.  The Relationship Between the Dim Light Melatonin Onset and Sleep on a Regular Schedule in Young Healthy Adults , 2003, Behavioral sleep medicine.

[69]  K. Spiegel,et al.  Impact of sleep debt on metabolic and endocrine function , 1999, The Lancet.

[70]  Charles A Czeisler,et al.  The Influence of Subjective Alertness and Motivation on Human Performance Independent of Circadian and Homeostatic Regulation , 2003, Journal of biological rhythms.

[71]  D. Klein,et al.  Pineal N-acetyltransferase and hydroxyindole-O-methyl-transferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus , 1979, Brain Research.

[72]  C A Czeisler,et al.  Variation of electroencephalographic activity during non‐rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans , 1997, The Journal of physiology.

[73]  Serge Daan,et al.  A functional analysis of circadian pacemakers in nocturnal rodents , 2005, Journal of comparative physiology.

[74]  C. Eastman,et al.  SLEEP LOGS OF YOUNG ADULTS WITH SELF-SELECTED SLEEP TIMES PREDICT THE DIM LIGHT MELATONIN ONSET , 2002, Chronobiology international.

[75]  P. Badia,et al.  Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. , 1997, Sleep.

[76]  Anna Wirz-Justice,et al.  Is Sleep per se a Zeitgeber in Humans? , 2003, Journal of biological rhythms.

[77]  M. Dubocovich,et al.  Familial advanced sleep phase syndrome. , 2001, Archives of neurology.