Elsevier

Sleep Medicine Reviews

Volume 11, Issue 6, December 2007, Pages 429-438
Sleep Medicine Reviews

Physiological review
Epidemiology of the human circadian clock

https://doi.org/10.1016/j.smrv.2007.07.005Get rights and content

Summary

Humans show large inter-individual differences in organising their behaviour within the 24-h day—this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. This distribution is predominantly based on differences in an individuals’ circadian clock. The relationship between the circadian system and different “chronotypes” is formally and genetically well established in experimental studies in organisms ranging from unicells to mammals. To investigate the epidemiology of the human circadian clock, we developed a simple questionnaire (Munich ChronoType Questionnaire, MCTQ) to assess chronotype. So far, more than 55,000 people have completed the MCTQ, which has been validated with respect to the Horne–Østberg morningness–eveningness questionnaire (MEQ), objective measures of activity and rest (sleep-logs and actimetry), and physiological parameters. As a result of this large survey, we established an algorithm which optimises chronotype assessment by incorporating the information on timing of sleep and wakefulness for both work and free days. The timing and duration of sleep are generally independent. However, when the two are analysed separately for work and free days, sleep duration strongly depends on chronotype. In addition, chronotype is both age- and sex-dependent.

Introduction

The days of all organisms are structured by an interaction of solar and biological cycles. Solar cycles are a consequence of the Earth's rotation, as its surface is periodically exposed to and shielded from light. Daily biological cycles are a product of an endogenous circadian clock that is present in organisms of all phyla. The alteration between light and darkness produces a host of signals (light, temperature, availability of resources, etc.) which can act as cues (zeitgebers) capable of synchronising endogenous timing systems. The introduction of technical clocks has added a third temporal dimension—social time—that influences the daily life of humans. Although time zones were introduced to accommodate the continuously changing solar times, they are only approximations. As a consequence, the sun rises and sets at different social times within each time zone. The most extreme example of this discrepancy exists in China where one sixth of the Earth's circumference officially lives on Peking time. The difference between solar and social time is so large in Western China that citizens do not adjust their lives according to official time.

In mammals, a clock centre (pacemaker) resides in the suprachiasmatic nucleus (SCN) located above the crossing of the optic nerves. The circadian clock controls physiology at numerous levels, from gene expression to complex behaviours (e.g., sleep and performance). When shielded from solar and social time (constant conditions), the biological clock “runs free” with an endogenous period close to 24 h. In real life, circadian clocks are usually synchronised to 24 h by zeitgebers.1 The most important zeitgeber is light (and darkness) which is also responsible for the daily rhythmicity of all other environmental signals. Unlike many other animals, the zeitgeber light is detected exclusively by the eyes in mammals, by a combination of rods, cones, and a recently discovered additional retinal photopigment, melanopsin, which is found to be dispersed in the ganglion cell layer.2, 3 The retinal signals are transduced to the SCN via collaterals of the optic nerves where they synchronise (as glutamatergic input) the circa-daily-rhythm produced by SCN neurons to exactly 24 h.4 Via its rhythmic outputs, the SCN coordinates all the cellular circadian clocks throughout the body's organs and tissues to adapt physiology to the Earth's rotation.

An active process called entrainment ensures that the biological clock is stably synchronised to its zeitgebers. Depending on its phase, the circadian clock responds differently to a zeitgeber stimulus1, 5: at some phases (e.g., late night to early morning), light advances the clock, at others, e.g., afternoon and evening), light delays. In the middle of the day, the circadian clock may respond little or not at all to light.

As with other genetic traits, circadian properties depend on specific genotypes. Different variants of “clock” genes6, 7 are associated, for example, with the period length of the circadian rhythm in constant conditions. In a given population, free-running periods are distributed around a species-specific mean which has been shown in both animal experimentation8 and human studies.9, 10, 11 Genetic variation is also, at least in part, responsible for the individual differences of the circadian clock under entrained conditions.12, 13, 14, 15, 16 Individuals adopt a specific temporal relationship to the zeitgeber (e.g., the time difference between dawn and wake-up, the core body temperature minimum, or the melatonin onset). This relationship between external and internal time is called phase of entrainment, and when people differ in this trait, they are referred to as different chronotypes.17

Daily human behaviour has mainly been assessed by questionnaires designed to associate individuals with temporal preferences called “morningness–eveningness” (ME18). The questions used are mostly subjective, relating sleep and activity times to a personal “feeling best rhythm”18 to the habits of others (e.g., “I get up later than most people”,19), or to hypothetical situations (e.g., “Approximately, what time would you get up if you were entirely free to plan your day?”20). The degree of “ME” is expressed as a score which correlates with the timing of individuals’ temperature, melatonin, or cortisol rhythms.21, 22, 23 The ME questionnaire (MEQ) does not explicitly assess free and workdays separately nor does it ask for actual sleep and activity times24 or exposure to outdoor light. These points, however, are essential questions for a quantitative determination of chronotype that could be of use for genetic or epidemiological analysis. The ME-score representing preferences (the higher the score the stronger the morningness preference; range: 16–86) is not a direct measurement of phase of entrainment and is, therefore, not strictly measuring chronotype. This approach likely reflects the fact that the MEQ was developed before the first clock gene had been identified, i.e., before a genetic approach was the norm.

We have, therefore, developed a new questionnaire, the Munich ChronoType Questionnaire (MCTQ) to assess individual chronotype with great precision.17, 25, 26, 27 The MCTQ asks people simple questions about their sleep and activity times such as: when do you go to bed, how long do you need to fall asleep, when do you wake up? All questions are asked separately for work and for free days. It has been validated with highly significant correlations by over 600 sleep-logs, by actimetry, and by correlations to biochemical rhythms such as melatonin and cortisol (unpublished data). The MCTQ has been also validated against the widely used MEQ,18 showing high correlations.28 The questionnaire has now been answered by more than 55,000 people and, thus, represents an excellent database for studying the epidemiology of human chronotypes.

Section snippets

Distribution of human chronotypes, based on the MCTQ

To quantify chronotype, a single phase marker ideally has to be extracted from the different times queried in the MCTQ. We started by assigning mid-sleep on free days (MSF; the half-way point between sleep-onset and sleep-end) as a definition of chronotype.28 The distribution of chronotypes within a population (judged by MSF, mainly assessed in Germany, Switzerland, the Netherlands, and Austria) is almost normal with a slight over-representation of later chronotypes (Figure 1 top). The most

Chronotype and sleep duration

In addition to sleeping at different times, people also sleep for different durations. This poses a difficulty for an unambiguous chronotype determination. Sleep duration is, as suggested above, often different between work and free days (Figure 2 top and middle, respectively). Analysing the length of sleep in half-hour-bins shows that 21% of the population, sleeps between 7 and 7.5 h on workdays. Forty-one percent sleep shorter and 38% sleep longer, resulting in an almost perfect normal

Conclusions

Dependencies of chronotype on age and sex as well as insights into how social schedules as experienced during the workweek may confound sleep/wake behaviour have not only made this accurate estimation possible, but also allow standardisation of the chronotype of an individual so that it becomes independent of age and sex. These adjustments are an important prerequisite for genetic and epidemiological studies. Our understanding of the complex genetics that underlie chronotype (which is the only

Acknowledgements

Our work is supported by the 6th European Framework Programme EUCLOCK (018741) and the Daimler-Benz-Stiftung project CLOCKWORK.

References (44)

  • M.S. Freedman et al.

    Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors

    Science

    (1999)
  • S. Panda et al.

    Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting

    Science

    (2002)
  • D.R. Weaver

    The suprachiasmatic nucleus: a 25-year retrospective

    J Biol Rhythms

    (1998)
  • T. Roenneberg et al.

    Demasking biological oscillators: properties and principles of entrainment exemplified by the Neurospora circadian clock

    Proc Natl Acad Sci USA

    (2005)
  • M.W. Young et al.

    Time zones: a comparative genetics of circadian clocks

    Nat Rev Genet

    (2001)
  • C.S. Pittendrigh et al.

    A functional analysis of circadian pacemakers in nocturnal rodents: V. Pacemaker structure: a clock for all seasons

    J Comp Physiol A

    (1976)
  • R. Wever

    The circadian system of man

    (1979)
  • E.B. Klerman

    Non-photic effects on the circadian system: results from experiments in blind and sighted individuals

  • J Appl Physiol

    (2002)
  • C.R. Jones et al.

    Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans

    Nat Med

    (1999)
  • T. Ebisawa et al.

    Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome

    EMBO Rep

    (2001)
  • K.L. Toh et al.

    An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome

    Science

    (2001)
  • Cited by (0)

    Dedicated to Anna Wirz-Justice in recognition of her contributions to the field made during her career at the Psychiatric University Clinics Basel.

    *

    The most important references are denoted by an asterisk.

    View full text