Desynchronizing the sleep–wake cycle from circadian timing to assess their separate contributions to physiology and behaviour and to estimate intrinsic circadian period

Wei Wang, Robin K. Yuan, Jude F. Mitchell, Kirsi-Marja Zitting, Melissa A. St. Hilaire, James K. Wyatt, Frank A. J. L. Scheer, Kenneth P. Wright, Emery N. Brown, Joseph M. Ronda, Elizabeth B. Klerman, Jeanne F. Duffy, Derk-Jan Dijk, Charles A. Czeisler

Published: 2022-11-13 DOI: 10.1038/s41596-022-00746-y

Circadian Rhythms

Forced Desynchrony

Intrinsic Period

Sleep-Wake Cycle

AI 解读

Efficient and safe single-cell cloning of human pluripotent stem cells using the CEPT cocktail

Profiling native pulmonary basement membrane stiffness using atomic force microscopy

Genetic circuit design automation with Cello 2.0

Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages

Scalable dual-omics profiling with single-nucleus chromatin accessibility and mRNA expression sequencing 2 (SNARE-seq2)

A practical guide to scanning light-field microscopy with digital adaptive optics

Effective high-throughput isolation of fully human antibodies targeting infectious pathogens

Improved sampling and DNA extraction procedures for microbiome analysis in food-processing environments

MOF-derived nanoporous carbons with diverse tunable nanoarchitectures

Tutorial: a statistical genetics guide to identifying HLA alleles driving complex disease

查看全部

Sections

Figures

References

Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep–nobreakwake state and associated behaviors, such as changes in posture, light levels, fast
Introduction
Materials
Procedure 1: the standard procedure
Procedure 2: the real-life case study procedure
Troubleshooting
Timing
Anticipated results
References
ACKNOWLEDGMENTS
ACKNOWLEDGMENTS

Mills, J. N., Minors, D. S. & Waterhouse, J. M. Proceedings: Urinary and temperature rhythms on days of abnormal length. J. Physiol. 257, 54P–55P (1976).
Hunter, J. Of the heat of animals and vegetables. Philos. Trans. R. Soc. Lond. 68, 7–49 (1778).
Ogle, W. in St. George’s Hospital Reports (eds. Ogle, J. W. & Holmes, T.) 220–245 (John Churchill and Sons, 1866).
Benedict, F. G. Studies in body-temperature. I. Influence of the inversion of the daily routine; the temperature of night-workers. Am. J. Physiol. 11, 145–169 (1904).
Gibson, R. B. The effects of transposition of the daily routine on the rhythm of temperature variation. Am. J. Med. Sci. 129, 1048–1059 (1905).
Kleitman, N. Sleep and Wakefulness. (University of Chicago Press, 1939).
Aschoff, J., Gerecke, U. & Wever, R. Phasenbeziehungen zwischen den circadianen perioden der aktivitaet und der kerntemperatur beim menschen. Eur. J. Physiol. 295, 173–183 (1967).
Aschoff, J. Desynchronization and resynchronization of human circadian rhythms. Aerosp. Med. 40, 844–849 (1969).
Mills, J. N., Minors, D. S. & Waterhouse, J. M. The physiological rhythms of subjects living on a day of abnormal length. J. Physiol. 268, 803–826 (1977).
Czeisler, C. A. Human circadian physiology: internal organization of temperature, sleep-wake, and neuroendocrine rhythms monitored in an environment free of time cues. Ph.D. thesis, Stanford University (1978).
Schulz, H., Bes, E. & Jobert, M. in Sleep–Wake Disorders (eds. Meier-Ewert, K. & Okawa, M.) (Springer, 1997).
Klerman, E. B., Dijk, D. J., Kronauer, R. E. & Czeisler, C. A. Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period. Am. J. Physiol. 270, R271–R282 (1996).
Aschoff, J. & Wever, R. Spontanperiodik des menschen bei ausschluss aller zeitgeber. Die Naturwissenschaften 49, 337–342 (1962).
Aschoff, J., Gerecke, U. & Wever, R. Desynchronization of human circadian rhythms. Jpn. J. Physiol. 17, 450–457 (1967).
Sulzman, F. M., Fuller, C. A. & Moore-Ede, M. C. Spontaneous internal desynchronization of circadian rythms in the squirrel monkey. Comp. Biochem. Physiol. A Physiol. 58, 63–67 (1977).
Czeisler, C. A. & Jewett, M. E. in Handbook of Sleep Disorders (ed. Thorpy, M. J.) 117–137 (Marcel Dekker, 1990).
Pittendrigh, C. S. & Daan, S. A functional analysis of circadian pacemakers in nocturnal rodents. IV. Entrainment: pacemaker as clock. J. Comp. Physiol. A 106, 291–331 (1976).
Carskadon, M. A. & Dement, W. C. Sleep studies on a 90-minute day. Electroencephalogr. Clin. Neurophysiol. 39, 145–155 (1975).
Lavie, P. & Scherson, A. Ultrashort sleep-waking schedule. I. Evidence of ultradian rhythmicity in ‘sleep ability’. Electroencephalogr. Clin. Neurophysiol. 52, 163–174 (1981).
Lavie, P. Ultrashort sleep-waking schedule III. “Gates” and “forbidden zones” for sleep. Electroencephalogr. Clin. Neurophysiol. 63, 414–425 (1986).
Haimov, I. & Lavie, P. Circadian characteristics of sleep propensity function in healthy elderly: a comparison with young adults. Sleep 20, 294–300 (1997).
Åkerstedt, T., Hume, K., Minors, D. & Waterhouse, J. Experimental separation of time of day and homeostatic influences on sleep. Am. J. Physiol. 274, R1162–R1168 (1998).
Kripke, D. F. et al. Circadian phase in adults of contrasting ages. Chronobiol. Int. 22, 695–709 (2005).
Eastman, C. I., Suh, C., Tomaka, V. A. & Crowley, S. J. Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans. Sci. Rep. 5, 8381 (2015).
Boivin, D. B. et al. Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects. Arch. Gen. Psychiatry 54, 145–152 (1997).
Waterhouse, J. et al. Light of domestic intensity produces phase shifts of the circadian oscillator in humans. Neurosci. Lett. 245, 97–100 (1998).
Cajochen, C., Wyatt, J. K., Czeisler, C. A. & Dijk, D. J. Separation of circadian and wake duration-dependent modulation of EEG activation during wakefulness. Neuroscience 114, 1047–1060 (2002).
Cohen, D. A. et al. Uncovering residual effects of chronic sleep loss on human performance. Sci. Transl. Med. 2, 14ra13 (2010).
Czeisler, C. A. et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284, 2177–2181 (1999).
Duffy, J. F. et al. Sex difference in the near-24-hour intrinsic period of the human circadian timing system. Proc. Natl Acad. Sci. USA 108, 15602–15608 (2011).
Hull, J. T., Klerman, E. B., Dijk, D. J., Czeisler, C. A. & Lockley, S. W. Human circadian period of NLP blind individual with no conscious light perception assessed under field and forced desynchrony conditions. In 72nd Cold Spring Harbor Laboratory Symposium: Clocks & Rhythms (eds. Stillman, B., Stewart D., & Grodzicker, T.) 65 (Cold Spring Harbor Laboratory, 2007).
Dijk, D. J. & Czeisler, C. A. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J. Neurosci. 15, 3526–3538 (1995).
Wyatt, J. K., Ritz-De Cecco, A., Czeisler, C. A. & Dijk, D. J. Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am. J. Physiol. Regul. Integr. Comp. Physiol. 277, R1152–R1163 (1999).
Dijk, D.-J., Duffy, J. F. & Czeisler, C. A. Age-related increase in awakenings: impaired consolidation of nonREM sleep at all circadian phases. Sleep 24, 565–577 (2001).
Dijk, D.-J., Duffy, J. F., Riel, E., Shanahan, T. L. & Czeisler, C. A. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J. Physiol. 516, 611–627 (1999).
Dijk, D.-J., Duffy, J. F. & Czeisler, C. A. Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep. Chronobiol. Int. 17, 285–311 (2000).
Duffy, J. F., Rimmer, D. W. & Czeisler, C. A. Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase. Behav. Neurosci. 115, 895–899 (2001).
Wright, K. P. Jr., Hull, J. T. & Czeisler, C. A. Relationship between alertness, performance, and body temperature in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R1370–R1377 (2002).
Münch, M. et al. Age-related attenuation of the evening circadian arousal signal in humans. Neurobiol. Aging 26, 1307–1319 (2005).
Wyatt, J. K., Dijk, D.-J., Cecco, A. R.-D., Ronda, J. M. & Czeisler, C. A. Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep 29, 609–618 (2006).
Cain, S. W., Rimmer, D. W., Duffy, J. F. & Czeisler, C. A. Exercise distributed across day and night does not alter circadian period in humans. J. Biol. Rhythms 22, 534–541 (2007).
O’Donnell, D. et al. Comparison of subjective and objective assessments of sleep in healthy older subjects without sleep complaints. J. Sleep. Res. 18, 254–263 (2009).
Lee, J. H. et al. Neurobehavioral performance in young adults living on a 28-h day for 6 weeks. Sleep 32, 905–913 (2009).
Silva, E. J., Wang, W., Ronda, J. M., Wyatt, J. K. & Duffy, J. F. Circadian and wake-dependent influences on subjective sleepiness, cognitive throughput, and reaction time performance in older and young adults. Sleep 33, 481–490 (2010).
Munch, M., Silva, E. J., Ronda, J. M., Czeisler, C. A. & Duffy, J. F. EEG sleep spectra in older adults across all circadian phases during NREM sleep. Sleep 33, 389–401 (2010).
Duffy, J. F., Lowe, A. S., Silva, E. J. & Winkelman, J. W. Periodic limb movements in sleep exhibit a circadian rhythm that is maximal in the late evening/early night. Sleep. Med. 12, 83–88 (2011).
Santhi, N. et al. Sex differences in the circadian regulation of sleep and waking cognition in humans. Proc. Natl Acad. Sci. USA 113, E2730–E2739 (2016).
Lee, M. L. et al. Fragmentation of rapid eye movement and nonrapid eye movement sleep without total sleep loss impairs hippocampus-dependent fear memory consolidation. Sleep 39, 2021–2031 (2016).
McHill, A. W., Hull, J. T., Wang, W., Czeisler, C. A. & Klerman, E. B. Chronic sleep curtailment, even without extended (>16-h) wakefulness, degrades human vigilance performance. Proc. Natl Acad. Sci. USA 115, 6070–6075 (2018).
Zitting, K. M. et al. Young adults are more vulnerable to chronic sleep deficiency and recurrent circadian disruption than older adults. Sci. Rep. 8, 11052 (2018).
Zitting, K. M. et al. Human resting energy expenditure varies with circadian phase. Curr. Biol. 28, 3685–3690.e3 (2018).
Grady, S., Aeschbach, D., Wright, K. P. Jr. & Czeisler, C. A. Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment. Neuropsychopharmacology 35, 1910–1920 (2010).
Wyatt, J. K., Cajochen, C., Ritz-De Cecco, A., Czeisler, C. A. & Dijk, D. J. Low-dose repeated caffeine administration for circadian-phase-dependent performance degradation during extended wakefulness. Sleep 27, 374–381 (2004).
Weaver, D. R. The suprachiasmatic nucleus: a 25-year retrospective. J. Biol. Rhythms 13, 100–112 (1998).
Shanahan, T. L. Circadian physiology and the plasma melatonin rhythm in humans. M.D. thesis, Harvard Medical School (1995).
Scheer, F. A., Wright, K. P. Jr., Kronauer, R. E. & Czeisler, C. A. Plasticity of the intrinsic period of the human circadian timing system. PLoS One 2, e721 (2007).
Czeisler, C. A. et al. Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle. Science 233, 667–671 (1986).
Duffy, J. F. & Dijk, D. J. Getting through to circadian oscillators: why use constant routines? J. Biol. Rhythms 17, 4–13 (2002).
Dijk, D. J. & Duffy, J. F. Novel approaches for assessing circadian rhythmicity in humans: a review. J. Biol. Rhythms 35, 421–438 (2020).
Wright, K. P. Jr., Hughes, R., Kronauer, R. E., Dijk, D. J. & Czeisler, C. A. Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc. Natl Acad. Sci. USA 98, 14027–14032 (2001).
Banich, M. T. et al. fMri studies of Stroop tasks reveal unique roles of anterior and posterior brain systems in attentional selection. J. Cogn. Neurosci. 12, 988–1000 (2000).
Wright, K. P. Jr., Gronfier, C., Duffy, J. F. & Czeisler, C. A. Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans. J. Biol. Rhythms 20, 168–177 (2005).
Gronfier, C., Wright, K. P. Jr., Kronauer, R. E. & Czeisler, C. A. Entrainment of the human circadian pacemaker to longer-than-24-h days. Proc. Natl Acad. Sci. USA 104, 9081–9086 (2007).
Kronauer, R. E., Czeisler, C. A., Pilato, S. F., Moore-Ede, M. C. & Weitzman, E. D. Mathematical model of the human circadian system with two interacting oscillators. Am. J. Physiol. 242, R3–R17 (1982).
Borbély, A. A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982).
Daan, S., Beersma, D. G. M. & Borbély, A. A. Timing of human sleep: recovery process gated by a circadian pacemaker. Am. J. Physiol. 246, R161–R183 (1984).
Dijk, D. J. & Czeisler, C. A. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci. Lett. 166, 63–68 (1994).
Duffy, J. F., Zitting, K. M. & Czeisler, C. A. The case for addressing operator fatigue. Rev. Hum. Factors Ergon. 10, 29–78 (2015).
Muto, V. et al. Local modulation of human brain responses by circadian rhythmicity and sleep debt. Science 353, 687–690 (2016).
Stepanski, E. J. & Wyatt, J. K. Use of sleep hygiene in the treatment of insomnia. Sleep. Med. Rev. 7, 215–225 (2003).
Eastman, C. I., Norwood, A. A., Velez, S. L., Paech, G. M. & Crowley, S. J. 0713 SEX AND THE FORBIDDEN ZONE. Sleep 40, A264 (2017).
Crowley, S. J. & Eastman, C. I. 0248 Sleep and the Forbidden Zone: Trouble for Teens. Sleep 41, A96 (2018).
Johnson, M. P. et al. Short-term memory, alertness and performance: a reappraisal of their relationship to body temperature. J. Sleep. Res. 1, 24–29 (1992).
Edgar, D. M., Dement, W. C. & Fuller, C. A. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J. Neurosci. 13, 1065–1079 (1993).
Franken, P. & Dijk, D. J. Circadian clock genes and sleep homeostasis. Eur. J. Neurosci. 29, 1820–1829 (2009).
Klerman, E. B. in Zeitgebers, Entrainment and Masking of the Circadian System Sapporo Symposium (eds. Honma, K. & Honma, S.) 155–169 (Hokkaido Univ. Press, 2001).
Kitamura, S. et al. Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type. Biol. Psychiatry 73, 63–69 (2013).
Carskadon, M. A., Labyak, S. E., Acebo, C. & Seifer, R. Intrinsic circadian period of adolescent humans measured in conditions of forced desynchrony. Neurosci. Lett. 260, 129–132 (1999).
Crowley, S. J. & Eastman, C. I. Free-running circadian period in adolescents and adults. J. Sleep. Res. 27, e12678 (2018).
Kantermann, T. & Eastman, C. I. Circadian phase, circadian period and chronotype are reproducible over months. Chronobiol. Int. 35, 280–288 (2018).
Eastman, C. I., Tomaka, V. A. & Crowley, S. J. Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work. Sci. Rep. 6, 36716 (2016).
Eastman, C. I., Tomaka, V. A. & Crowley, S. J. Sex and ancestry determine the free-running circadian period. J. Sleep. Res. 26, 547–550 (2017).
Eastman, C. I., Molina, T. A., Dziepak, M. E. & Smith, M. R. Blacks (African Americans) have shorter free-running circadian periods than whites (Caucasian Americans). Chronobiol. Int. 29, 1072–1077 (2012).
Hiddinga, A. E., Beersma & Van Den Hoofdakker, R. H. Endogenous and exogenous components in the circadian variation of core body temperature in humans. J. Sleep. Res. 6, 156–163 (1997).
Hasan, S. et al. Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin. FASEB J. 26, 2414–2423 (2012).
Hida, A. et al. In vitro circadian period is associated with circadian/sleep preference. Sci. Rep. 3, 2074 (2013).
Silva, E. J. & Duffy, J. F. Sleep inertia varies with circadian phase and sleep stage in older adults. Behav. Neurosci. 122, 928–935 (2008).
Scheer, F. A., Shea, T. J., Hilton, M. F. & Shea, S. A. An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night. J. Biol. Rhythms 23, 353–361 (2008).
Burke, T. M., Scheer, F. A., Ronda, J. M., Czeisler, C. A. & Wright, K. P. Jr. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions. J. Sleep. Res. 24, 364–371 (2015).
McHill, A. W. et al. Chronic sleep restriction greatly magnifies performance decrements immediately after awakening. Sleep 42, zsz032 (2019).
Lazar, A. S. et al. Circadian period and the timing of melatonin onset in men and women: predictors of sleep during the weekend and in the laboratory. J. Sleep. Res. 22, 155–159 (2013).
Weitzman, E. D. et al. Effects of a prolonged 3-hour sleep-wake cycle on sleep stages, plasma cortisol, growth hormone, and body temperature in man. J. Clin. Endocrinol. Metab. 38, 1018–1030 (1974).
Strijkstra, A. M., Meerlo, P. & Beersma, D. G. M. Forced desynchrony of circadian rhythms of body temperature and activity in rats. Chronobiol. Int. 16, 431–440 (1999).
Koorengevel, K. M., Beersma, D. G., den Boer, J. A. & van den Hoofdakker, R. H. Mood regulation in seasonal affective disorder patients and healthy controls studied in forced desynchrony. Psychiatry Res. 117, 57–74 (2003).
Yasenkov, R. & Deboer, T. Circadian regulation of sleep and the sleep EEG under constant sleep pressure in the rat. Sleep 33, 631–641 (2010).
Pomplun, M. et al. The effects of circadian phase, time awake, and imposed sleep restriction on performing complex visual tasks: evidence from comparative visual search. J. Vis. 12, 14 (2012).
Wotus, C. et al. Forced desynchrony reveals independent contributions of suprachiasmatic oscillators to the daily plasma corticosterone rhythm in male rats. PLoS One 8, e68793 (2013).
Wu, L. J., Acebo, C., Seifer, R. & Carskadon, M. A. Sleepiness and cognitive performance among younger and older adolescents across a 28-hour forced desynchrony protocol. Sleep 38, 1965–1972 (2015).
Walsh, L., McLoone, S., Ronda, J., Duffy, J. F. & Czeisler, C. A. Non-contact pressure-based sleep/wake discrimination. IEEE Trans. Biomed. Eng. 64, 1750–1760 (2017).
Qian, J., Scheer, F. A., Hu, K. & Shea, S. A. The circadian system modulates the rate of recovery of systolic blood pressure after exercise in humans. Sleep 43, zsz253 (2020).
Morgan, L. et al. Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism. J. Endocrinol. 157, 443–451 (1998).
Scheer, F. A., Hilton, M. F., Mantzoros, C. S. & Shea, S. A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl Acad. Sci. USA 106, 4453–4458 (2009).
Scheer, F. A. et al. Impact of the human circadian system, exercise, and their interaction on cardiovascular function. Proc. Natl Acad. Sci. USA 107, 20541–20546 (2010).
Buxton, O. M. et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci. Transl. Med. 4, 129ra143 (2012).
Swanson, C. M. et al. Bone turnover markers after sleep restriction and circadian disruption: a mechanism for sleep-related bone loss in humans. J. Clin. l Endocrinol. Metab. 102, 3722–3730 (2017).
Yuan, R. K. et al. Fasting blood triglycerides vary with circadian phase in both young and older people. Physiol. Rep. 8, e14453 (2020).
Scheer, F. et al. The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles. Proc. Natl Acad. Sci. USA 118, e2018486118 (2021).
Chellappa, S. L. et al. Daytime eating prevents internal circadian misalignment and glucose intolerance in night work. Sci. Adv. 7, eabg9910 (2021).
Chellappa, S. L. et al. Proof-of-principle demonstration of endogenous circadian system and circadian misalignment effects on human oral microbiota. FASEB J. 36, e22043 (2022).
Zitting, K. M. et al. Chronic circadian disruption on a high-fat diet impairs glucose tolerance. Metabolism 130, 155158 (2022).
Archer, S. N. et al. Mistimed sleep disrupts circadian regulation of the human transcriptome. Proc. Natl Acad. Sci. USA 111, E682–E691 (2014).
Chang, A. M., Buch, A. M., Bradstreet, D. S., Klements, D. J. & Duffy, J. F. Human diurnal preference and circadian rhythmicity are not associated with the CLOCK 3111C/T gene polymorphism. J. Biol. Rhythms 26, 276–280 (2011).
Chang, A. M. et al. Chronotype genetic variant in PER2 is associated with intrinsic circadian period in humans. Sci. Rep. 9, 5350 (2019).
Micic, G., Lovato, N., Ferguson, S. A., Burgess, H. J. & Lack, L. Circadian tau differences and rhythm associations in delayed sleep-wake phase disorder and sighted non-24-hour sleep-wake rhythm disorder. Sleep 44, zsaa132 (2021).
Ben-Hamo, M. et al. Circadian forced desynchrony of the master clock leads to phenotypic manifestation of depression in rats. eNeuro 3, ENEURO.0237-16.2016 (2016).
Laing, E. E. et al. Blood transcriptome based biomarkers for human circadian phase. Elife 6, e20214 (2017).
Moses, J., Naitoh, P. & Johnson, L. C. The REM cycle in altered sleep/wake schedules. Psychophysioly 15, 569–575 (1978).
Micic, G. et al. Circadian melatonin and temperature taus in delayed sleep-wake phase disorder and non-24-hour sleep-wake rhythm disorder patients: an ultradian constant routine study. J. Biol. Rhythms 31, 387–405 (2016).
Czeisler, C. A. & Dijk, D. J. in Handbook of Behavioral Neurobiology: Circadian Clocks (eds. Takahashi, J. S., Turek, F. W., & Moore, R. Y.) 531–569 (Plenum, 2001).
Aschoff, J. Circadian rhythms in man: a self-sustained oscillator with an inherent frequency underlies human 24-hour periodicity. Science 148, 1427–1432 (1965).
Czeisler, C. A., Weitzman, E. D., Moore-Ede, M. C., Zimmerman, J. C. & Knauer, R. S. Human sleep: its duration and organization depend on its circadian phase. Science 210, 1264–1267 (1980).
Brown, E. N. & Czeisler, C. A. The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data. J. Biol. Rhythms 7, 177–202 (1992).
Weitzman, E. D., Czeisler, C. A., Zimmerman, J. C., Ronda, J. M. & Knauer, R. S. in Disorders of Sleeping and Waking: Indications and Techniques (ed. Guilleminault, C.) 297–329 (Addison-Wesley, 1982).
Dinges, D. F. & Powell, J. W. Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations. Behav. Res. Methods Instrum. Comput. 17, 652–655 (1985).
Enright, J. T. in Circadian Clocks (ed. Aschoff, J.) 112–124 (North-Holland, 1965).
Brown, E. N., Solo, V. & Zhang, Z. in Methods in Enzymology, Numerical Computer Methods Vol. 383 (eds. Brand, L. & Johnson, M. L.) 383–405 (Academic, 2004).
Sargent, C., Darwent, D., Ferguson, S. A., Kennaway, D. J. & Roach, G. D. Sleep restriction masks the influence of the circadian process on sleep propensity. Chronobiol. Int. 29, 565–571 (2012).
Buxton, O. M., Lee, C. W., L’Hermite-Balériaux, M., Turek, F. W. & Van Cauter, E. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R714–R724 (2003).
Dijk, D. J., Duffy, J. F. & Czeisler, C. A. Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J. Sleep. Res. 1, 112–117 (1992).
Jewett, M. E. Models of Circadian and Homeostatic Regulation of Human Performance and Alertness. Ph.D. thesis, Harvard University (1997).
Krahn, L. E. et al. Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine. J. Clin. Sleep. Med. 17, 2489–2498 (2021).
Fraser, S., Cowen, P., Franklin, M., Franey, C. & Arendt, J. Direct radioimmunoassay for melatonin in plasma. Clin. Chem. 29, 396–397 (1983).
Yie, S. M., Johansson, E. & Brown, G. M. Competitive solid-phase enzyme immunoassay for melatonin in human and rat serum and rat pineal gland. Clin. Chem. 39, 2322–2325 (1993).
de Almeida, E. A. et al. Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv. Syst. 27, 879–891 (2011).
Kennaway, D. J. A critical review of melatonin assays: past and present. J. Pineal Res. 67, e12572 (2019).
Laird, N. M. & Ware, J. H. Random-effects models for longitudinal data. Biometrics 38, 963–974 (1982).
Brown, E. N., Choe, Y., Luithardt, H. & Czeisler, C. A. A statistical model of the human core-temperature circadian rhythm. Am. J. Physiol. Endocrinol. Metab. 279, E669–E683 (2000).
Rechtschaffen, A. & Kales, A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects (US Government Printing Office, 1968).
Cajochen, C., Wyatt, J. K., Czeisler, C. A., Bonikowska, M. & Dijk, D. J. Non-linear interaction between the circadian and homeostatic modulation of slow eye movements during wakefulness in humans. J. Sleep. Res. 9, 58 (2000).
Wyatt, R. J., Fram, D. H., Kupfer, D. J. & Snyder, F. Total prolonged drug-induced REM sleep suppression in anxious- depressed patients. Arch. Gen. Psychiatry 24, 145–155 (1971).
Aeschbach, D. et al. Two circadian rhythms in the human electroencephalogram during wakefulness. Am. J. Physiol. 277, R1771–R1779 (1999).
Smith, M. E., McEvoy, L. K. & Gevins, A. The impact of moderate sleep loss on neurophysiologic signals during working-memory task performance. Sleep 25, 784–794 (2002).
Gillberg, M., Kecklund, G. & Åkerstedt, T. Relations between performance and subjective ratings of sleepiness during a night awake. Sleep 17, 236–241 (1994).
Kennaway, D. J. Measuring melatonin by immunoassay. J. Pineal Res. 69, e12657 (2020).

Desynchronizing the sleep­­–wake cycle from circadian timing to assess their separate contributions to physiology and behaviour and to estimate intrinsic circadian period

Supplementary information

Supplementary Information

Reporting Summary

推荐阅读

Desynchronizing the sleep–wake cycle from circadian timing to assess their separate contributions to physiology and behaviour and to estimate intrinsic circadian period