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HOW TO MEASURE CIRCADIAN RHYTHMS IN HUMANS

by A. Wirz-Justice, Switzerland

he scientific study of human circadian rhythms of research, they laid the basis for the formal began when a curious researcher asked properties of the human circadian system analo- Tclever questions and went ahead to test them gous to that developed by Pittendrigh and Daan for on himself. Nathaniel Kleitman spent a month in a rodents.3 dark underground cave in 1938, having developed The timing and structure of sleep and waking is an “apparatus for determining and for recording considered to arise from interactions between the motility and rectal temperature during sleep.”1 biological or circadian pacemaker (designat- Kleitman’s monitoring of bed movements by means ed “process C”) and a sleep homeostatic process of a primitive polygraph to produce a continuous Anna WIRZ-JUSTICE, PhD dependent on duration of prior awake (“pro- Centre for 4 readout of motor activity anticipated measurement Psychiatric University Clinics cess S”) (Figure 1). This 2-process model is appli- techniques that have only recently become prac- Basel, SWITZERLAND cable not only to the sleep-wake , but also to tical thanks to advances in microelectronics. He the understanding of the temporal patterns of near- clearly demonstrated that under constant dim en- ly every neuroendocrine, physiological, and psycho- vironmental conditions sleep did not retain its 24- logical function. The model has proved extremely pattern, but shifted later by day. He also useful for understanding a variety of sleep distur- tried to live on a “28-hour day,” as a test of whether bances, and can be used to interpret apparent rhyth- the usual 24-hour cycle might simply be a reaction mic abnormalities in depression, as well as provid- to the outside world. The “28-hour day” is a tech- ing a framework for specific therapeutic approaches. nique now used to separate the sleep-wake cycle (which can more or less follow this long day) from Characteristics of the the endogenous circadian cycle (which cannot). Two decades later, Jürgen Aschoff and Rütger Biological help us keep time on this rotating Wever created a more comfortable underground planet. The advantage of an internal clock to regu- “bunker” for human temporal isolation experiments, late sleep and wakefulness within the appropriate measured motility (by means of sensors in the bed and floors), rectal temperature, urine output, and SELECTED ABBREVIATIONS AND ACRONYMS many other physiological and behavioral variables, and concluded that humans have endogenous cir- DLMO dim light onset cadian cycles like and mice and flies.2 They MCTQ Munich Questionnaire also placed subjects on days of varying lengths, and MEQ Morning-Eveningness Questionnaire tested to what extent the biological clock could syn- SCN suprachiasmatic nuclei chronize to the given periodicity. In more than 25

he biological clock drives all circadian rhythms in humans, provide a reasonable estimate of circadian phase. Chronobiology whether relative to neurobehavioral function, , requires long-term measurement over at least one 24-hour cycle, T , or behavior. The most obvious rhythm is the and new microchip technologies permit noninvasive and contin- sleep-wake cycle, which differs in timing across individuals uous data collection over many days and (eg, actimetry). (“chronotype”—from early-morning larks to late-night owls). The next decade of research will surely yield further insights into However, not all changes in sleep-wake cycle behavior are a con- human circadian clock function and its pathologies. sequence of abnormal clock function. Knowledge of the formal Medicographia. 2007;29:84-90. (see French abstract on page 90) properties of the circadian system, the role of for ad- equate synchronization to the 24-hour day, and how sleep is reg- Keywords: human circadian system; sleep regulation; forced ulated, has led to the development of stringent protocols to in- desynchrony; constant routine; ambulatory monitoring; vestigate the characteristics of circadian rhythms and sleep. These melatonin studies have provided gold standards for estimating circadian amplitude and phase, and have identified the most useful phys- Address for correspondence: Professor Anna Wirz-Justice, Centre for Chronobiology, iological or hormonal markers. We are now at the second stage Psychiatric University Clinics Basel, Wilhelm Klein Strasse 27, CH-4025 Basel, of trying to develop simpler markers for ambulatory use, which Switzerland (e-mail: [email protected])

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phases is that physiology and behavior can antic- er can entrain, and where endogenous rhythmicity ipate transitions between day and night and not retains its freerunning (as originally shown merely react to them. A circadian clock not only by Kleitman, Aschoff, and Wever). generates a cycle to match the solar day, it must It should be noted that this natural periodicity, τ, also maintain an appropriate phase relation to it. is not only a genetically determined characteristic: This process of optimal synchronization with the τ is subject to “after-effects,” ie, is changed by what- environment is called entrainment, and is mediat- ever environmental light pattern and intensity the ed by periodic stimuli (“zeitgebers”) acting on the subject was exposed to prior to the study,2 such as clock. The endogenous period of the circadian pace- maker under time-free conditions (as in a cave or a bunker) is known as τ, and the phase relation be- Zeitgebers tween rhythm and during stable entrain- ment is defined as ψ (eg, the difference between the phase of a given such as sleep Circadian onset and the phase of a zeitgeber such as dusk or sleep-wake cycle, 2 3 dawn) (Figure 2). LIGHT 1 2 neurobehavioral Individual differences in τ may lead to different 4 Output performance, mood, ψ—the best known example is a person with short , melatonin, τ being a “” chronotype, and someone with long temperature, , etc. τ being an “owl” chronotype.5 However, τ is not the only factor that influences phase: sensitivity to light or zeitgeber strength (when and how long a person is exposed to what wavelengths and intensities of Figure 1. Circadian and homeostatic regulation of sleep. Two major pro- light), and amplitude of the circadian pacemaker, cesses are involved in driving the circadian sleep-wake cycle as well as are also determinants. all other behavioral and neuroendocrine outputs: their known anatomical The most important zeitgeber is light, providing correlates are schematically represented: (1) ; (2) suprachiasmatic the photic signal for day and night as well as the nuclei (SCN); (3) : anterior (ventrolateral preoptic nucle- . The master circadian clock in the suprachi- us—sleep-promoting); posterior (tuberomammillar nucleus—; orexin [A/B]-producing neurons [wake-promoting]); (4) midbrain and asmatic nuclei (SCN) consists of two coupled os- pons ( [NE]; raphe nuclei [5-HT]; pedonculopontine cillatory systems that respond to dawn and dusk.6 tegmentum and laterodorsal tegmentum [ACh]). The change in daylength with seasons is mimicked Abbreviations: 5-HT, ; ACh, acetylcholine; NE, norepinephrine. in many species by changes in the duration of ac- tivity and rest (α:ρ). Three main steps are impor- tant for biological clock function (Figure 1): input Light Dark Sleep (zeitgebers, retina) ==> SCN circadian pacemaker α ρ (eg, clock genes, /peptides) ==> α:ρ (activity:rest duration) output (pineal melatonin synthesis, thermoregu- lation, etc). These factors then interact with the sleep-wake homeostat to regulate, continuously in time, sleep propensity and sleep architecture, and ψ (entrained) influence phenomena as different as mood and per- Successive days formance or hormonal output.

Which circadian clock characteristics do we want to measure? τ (free run)

A graphic representation of the various character- istics of the circadian system is shown in Figure 2. First, under entrained conditions, the sleep period Phase angle sleep midpoint to the remains at a stable phase angle with respect to the LD cycle light-dark cycle (ψ), with a given activity-rest ratio DLMO (α:ρ); and, second, in the absence of time cues (zeit- gebers), the sleep period shifts later and later each Phase angle DLMO day following the of the endogenous to the LD cycle pacemaker (τ). Phase angle DLMO Freerunning period (τ) to sleep midpoint The freerunning period ( ) is a characteristic of the τ 12 15 18 21 24 03 06 09 12 circadian pacemaker that can only be measured in humans using very elaborate protocols: either in a Time of day (h) time-isolation environment in dim light,2 whereby the endogenous rhythmicity reveals itself in a “free Figure 2. Schematic characteristics of the sleep-wake cycle. The sleep 7 period (green bars) is plotted on consecutive days with respect to external run,” or in a “forced desynchrony” protocol where time (the light:dark [LD] cycle) and internal time (the circadian phase the given sleep-wake cycle is much longer or short- marker dim light melatonin onset [DLMO], green circles). See text for er than the range to which the circadian pacemak- details.

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the duration of the photoperiod (τ is longer in win- urine) are collected under dim light and controlled ter than in summer8). Thus, a measured τ could re- posture conditions, the melatonin rhythm provides flect behavioral differences with respect to light ex- an optimal marker of circadian phase in humans. posure, rather than just a genetic difference. “Dim light melatonin onset” (DLMO) is the easiest Novel techniques now in development can mea- marker of body clock time we have, because it can sure the τ of clock gene expression in tissue cultures be feasibly measured in saliva before a person goes from skin biopsies (this yields a τ for “peripheral” to sleep.12 If an entire 24-hour rhythm is measured, clocks, whose exact relationship to the τ expressed phase can be defined as required—at the peak, the by the central clock in the SCN is not yet known).9 midline crossing point, offset of secretion, etc. How- ever, many studies measure only part of the rhythm, Phase angle (ψ) taking evening samples under controlled conditions The simplest way to find out about anyone’s pre- before sleep to measure when melatonin synthesis ferred phase position is to ask their preferred sleep begins (DLMO). To understand putative abnormal- on free days. Habitual bedtime and wake-up ities, one can measure the phase angle of the sleep midpoint to external time (in Figure 2, dusk; but dawn is equally valid), or the phase angle of inter- 80 nal time as measured by DLMO to the LD cycle or to sleep midpoint. 70 However, melatonin assays are not (yet) a rapid Morning chronotype or an easily available method for everyday diagnos- 60 tic use. A large, carefully controlled study of mela- tonin rhythms and sleep timing in the same sub- 50 Intermediate chronotype jects has found a close phase-relationship of this

MEQ score 40 marker of internal time to the sleep midpoint (Fig- 13 Evening chronotype ure 3). An algorithm was developed that is of great 30 clinical utility, since sleep midpoint can be used as a reasonable (indirect) estimate of circadian phase 20 (this is valid only if sleep is not too disturbed14). In 19 2021 22 2324 1 addition, the algorithm allows calculation of when DLMO time (h) bright should be applied with respect to internal (ie, circadian) and not external (clock) Figure 3. Correlation of internal circadian time with chronotype in winter time. This is the first example of applying circadi- depression. The timing of dim light melatonin onset (DLMO, threshold an principles to determine individual timing of a of 3 pg/mL) is strongly correlated with the morningness-eveningness score treatment: the important therapeutic consequences on the Morning-Eveningness Questionnaire (MEQ) in patients with winter are higher remission rates to light therapy than depression (r=--0.81, N=35, P<0.001). The wide spread of chronotype is when prescribing the same clock time for everyone. similar to that found in the general population. Redrawn from unpub- lished data related to reference 13 with permission from M. Terman. We thus can use an everyday, straightforward de- termination of sleep midpoint (calculated from the time on free days are obviously chosen because this MEQ, MCTQ, or a of sleep logs) to provide a is the comfortable ψ for that individual. The sleep rough estimate of an individual’s internal clock time. pattern gives a first simple estimate of a person’s There are provocative indications that the same phase, commonly known as chronotype, which phase-advancing strategy with early morning light, ranges from extreme early birds to extreme late- known to be beneficial for treatment of winter de- night owls. The most reliable phase marker with pression is key to sustained improvement in non- respect to sleep timing is the sleep midpoint (sleep seasonal depression. Intriguing data from a pre- onset time -- wakeup time / 2). Questionnaires about liminary study in depressed bipolar patients (on sleep preferences have long been used to better lithium) treated by , indicates that quantify this characteristic. The classic Horne-Ost- morning light therapy individually timed to max- berg Morning-Eveningness Questionnaire (MEQ)10 imize a circadian rhythm phase advance not only is now available as an online self-assessment (Au- sustained the rapid sleep deprivation response, but toMEQ) with personalized feedback (www.cet.org). patients continued to improve (not found with light Recently, the Munich Chronotype Questionnaire given at 11 AM to all) (F. Benedetti, personal com- (MCTQ) has been developed,5 validated against sleep munication). logs, and also automated (www.imp-muenchen.de); it is available so far in English, German, Spanish, Amplitude Italian, French, and Dutch. Objective measurement The amplitude of a circadian oscillation is an im- of rest-activity cycle timing can be made with ac- portant characteristic. When amplitude is low, a timetry.11 zeitgeber can theoretically elicit larger phase shifts To go a step further, beyond sleep phase to inter- than when amplitude is high. Measuring amplitude nal clock phase, we need a good output of the circa- of clock function is, however, rather difficult in dian clock that can be reliably measured. The pineal practice, and there is only indirect evidence from melatonin fulfils this role admirably.12 All circadian rhythms of melatonin or temperature that species that secrete melatonin do so at night; light amplitude can be diminished (by very specific tim- immediately suppresses its synthesis. It has been ing of a light pulse) or augmented (by increasing well established that if samples (saliva or blood or light intensity/duration).

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wakefulness. Thus, actimetry may be used to doc- ument changes in entrainment state related to ef- ficacy of a given treatment (whether pharmaceuti- cal or not). Indeed, a recent study in patients with seasonal affective disorder showed a delayed rest- activity cycle and low activity when depressed, with increased activity and better synchronization fol- lowing clinical improvement with light therapy.15 There has not yet been very much long-term activ- ity monitoring in major depression. These patients may not show a single or consistent abnormality, but rather, large interindividual differences in their rest-activity cycle patterns. This is what we are see- ing in an ongoing study of 6 weeks actimetry in ma- Figure 4. Long-term activity jor depression during pregnancy (Figure 4). This

Successive days monitoring in depression. An unstable rest-activity cycle is indicative of poor cir- example of an activity moni- cadian entrainment, and may contribute to some tor, the size of a wristwatch aspects of the illness. (Cambridge Neurotechnolo- gy®), is shown being worn Over the years, validation of actimetry by sleep on the nondominant hand. EEG in healthy subjects led to the development of Movements are collected at analysis programs for actimetric “sleep” that pro- 1- to 2-minute intervals and vide an estimate of a number of classic parameters stored until readout. The circadian rest-activity cycle (, wake-up time, wake bouts, sleep effi- is double plotted, ie, day 1 ciency, etc). Analysis programs for circadian vari- and 2 on one line, day 2 and ables (of which there are a variety) can provide an 3 on the next line, etc. This estimate of, eg, relative amplitude (maximum-min- double plot makes visualiza- imum), intradaily stability (estimates of strength of tion of shifted and irregular rhythms easier. On the ver- coupling to zeitgebers), and interdaily variability tical axis of each line is the (degree of fragmentation).16 amount of activity per unit In conclusion, actimetry is an easy, noninvasive, time: the higher the bar the and relatively inexpensive tool that deserves more greater the activity (blacker). Upper panel: 6 weeks’ record- use in the clinic. It provides objective verification of ing of a control pregnant chronotype (time of going to bed and waking up), woman with regular sleep and documents changes in sleep-wake patterns dur- patterns. Middle and lower ing illness and following treatment. A minimum panels: examples of irregular of 1 week’s recording is recommended to compare rest-activity cycles and dis- 24 1224 12 24 turbed nights in pregnant the pattern of work and free days and to reduce vari- women suffering from major ability. Time of day (h) depression (Wirz-Justice, un- published data). Why circadian clock characteristics are not easy to see How can we measure the circadian rest-activity cycle? Measuring the rest-activity cycle is a first step in looking at 24-h patterns of behavior. However, to Actimetry is a noninvasive technique for ambula- dig deeper and look at endogenous circadian pace- tory monitoring of rest-activity (which is not neces- maker characteristics requires special techniques sarily always congruous with sleep-wake) cycles.11 and validated markers. It has long been recognized It is the equivalent of the running wheel for ham- that the overtly measured rhythm of a given vari- sters and mice in human circadian biology, with the able over 24 is not only determined by the same advantages of measurement over longer pe- biological clock and sleep homeostat, but also by riods of time than in sleep research (1 to 2 nights’ zeitgebers such as light, or behavior, which can polysomnography). Additionally, 24-hour monitor- have direct or indirect effects on many functions, ing can reveal unusual patterns of rest and activi- so-called “masking.”17 Some examples are shown in ty that provide information quite different from the Figure 5 (next page).18-20 sleep EEG (eg, timing and duration of daytime naps). Masking modifies the pattern of daily rhythms Familiarity with the literature on abnormal that are measured in naturalistic environments. As rest-activity cycles and the formal properties of the shown in Figure 5, postural changes rapidly affect mammalian circadian system (eg, τ , ψ, see above)3 ,18 as does sleep,19 thus giving a can help interpret the observed phenomena. How- false estimate of amplitude and phase when look- ever, it must be clearly recognized that actimetry ing at the complete 24-hour measured curves. Light does not necessarily reflect the underlying circadi- in the evening can suppress melatonin or delay its an clock characteristics. onset, even at lower intensities (>100 lux).20 Thus, in A tenet of human chronobiology is that adequate order to elucidate the characteristics of the endoge- entrainment means better sleep and higher alert- nous circadian pacemaker, it has been necessary to ness, and better cognitive state and mood during develop protocols that control for masking effects.

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Forced desynchrony protocol: Under time-free conditions subjects are asked to sleep on a very A Lying down Standing up short or very long cycle (eg, a 20-hour or 28-hour day).21 The circadian system can no longer entrain 36.6 to these extremes, and remains at its endogenous 37.0 period (usually longer than 24 hours); this means 36.9 that over the entire protocol, sleep occurs at every 36.5 circadian phase. Post hoc analysis allows a “pure”

CBT (°C) 36.8 circadian and a “pure” sleep homeostatic compo- nent to be educed from any variable measured (psy- 36.7 chomotor vigilance to sleep EEG parameters21 to 36.4 subjective mood state (eg, see Figure 3 in refer- N=8 N=9 36.6 ence 22). 10 11 12 13 13 14 15 Constant routine protocol: Under time-free con- Time of day (h) ditions, subjects are kept in a constant semirecum- B bent posture in bed, under dim light, controlled temperature, and humidity, and given small iso- 37.0 With sleep Without sleep caloric snacks and water every 1 to 2 hours during a period of 40 hours of total sleep deprivation.23 This 36.8 protocol minimizes masking and provides valid es- timates of circadian rhythm amplitude and phase 36.6 (eg, core body temperature, melatonin).24 CBT (°C) 36.4 Modifications of the above have been developed N=36 N=7 that are easier for patients and still reveal circadian 36.2 16 18 20 22 24 02 04 06 08 16 18 20 22 24 02 04 06 08 information: Constant bed rest protocol: Ad libitum sleep al- Time of day (h) lowed instead of sleep deprivation (easier for pa- C 10 tients). Certain circadian rhythms can be measured under these conditions (eg, sleep propensity, rapid- Without light 8 movement [REM] sleep; see, for example, Fig- ure 3 in reference 25) Multiple nap protocol: By scheduling longer naps 6 over the 24-hour day (eg, 150 minutes awake: 75 minutes asleep) sleep pressure (process S) does not 4 accumulate and the circadian rhythms of many pa- N=7 rameters thereby usually masked emerge very clear- 2 With light ly (eg, subjective sleepiness; see Figure 3 in refer- Salivary melatonin (pg/mL) ence 26). 5000 lux 0 The forced desynchrony protocol in particular has 19 20 21 22 23 24 dissected out the relative contributions of the sleep- Time of day (h) wake homeostat and circadian pacemaker to a large number of neurobehavioral and physiologic func- Figure 5. Examples of behavioral and environmental masking effects. Three tions, which provide the basis for suggested mea- examples of masking effects on circadian rhythms are shown: (A) posture and sures in Table I. These are exhaustive and long pro- (B) sleep modify core body temperature (CBT); evening light suppresses mela- tocols, and thus expensive in terms of recruitment tonin secretion (C). Redrawn from reference 18 (Panel A): Kräuchi K, Cajochen C, Wirz-Justice A. Thermophysiolog- effort, time in the laboratory, and 24-hour contin- ic aspects of the three-process-model of sleepiness regulation. Clin Sports Med. 2005;24:287-300. uous monitoring. Each has its respective advan- Copyright © 2005, Elsevier; reference 19 (Panel B): Kräuchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. . 2001;25(5 suppl):S92-S96. Copyright © tages, and elegant studies over the last decade have 2001, Nature Publishing Group; and reference 20 (Panel C): Wirz-Justice A, Kräuchi K, Cajochen consolidated the database, established standard val- C, Danilenko KV, Renz C, Weber J. Evening melatonin and bright light administration induce ad- ues, and led to a qualitative hierarchy of “which ditive phase shifts in dim light melatonin onset. J Pineal Res. 2002;36:192-194. Copyright © 2002, Munksgaard International Publishers. measures are suitable for which question.” The ma- jor questions of what changes in ψ , phase relation- To measure endogenous circadian ships between dawn and dusk (α:ρ), or circadian rhythms—back to the lab! amplitude occur in major depression require labo- ratory studies that will help elucidate whether clock When attempting to document circadian rhythm dysfunction is a core feature of the illness. disturbances, there is always the question of how much sleep “interferes” with what one measures. Markers of the clock And often, one wants to measure sleep disturbances as well, because of their obviously important role in In summary, Table I provides a short list of puta- the illness. The 2-process model4 is useful here in tive clock markers for researchers and clinicians. selecting the appropriate markers that reflect either The list additionally contains external zeitgebers, the more circadian or more sleep-related homeo- since these impact on the structure of sleep and static factors. The accepted “gold-standard” proto- wake—from the important role of social zeitgebers cols are the: to putative conflicting zeitgebers as found in shift

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CIRCADIAN CHARACTERISTICS Ideal lab protocol Shorter (less perfect) alternatives

τ Temporal isolation (free running) DLMO over 3 consecutive weeks Forced desynchrony ψ (chronotype) Sleep midpoint (MEQ, MCTQ, sleep logs, actimetry) ψ Constant routine (circadian rhythms DLMO of core body temperature, melatonin, cortisol, heart rate, etc) Amplitude Constant routine (circadian rhythm Actimetry (relative amplitude of core body temperature?) highest-lowest activity) α:ρ Actimetry Sleep logs Stability of entrainment DLMO over successive days or weeks Actimetry for at least 7 days (intradaily stability) Retinal function Melatonin suppression test Ophthalmology checkup: (does not necessarily test circadian photo- receptor function) Measured light input Ambulatory light monitoring Light logs (time outdoors) (zeitgeber strength) Social zeitgebers Social Rhythm Metric Questionnaire

SLEEP HOMEOSTAT EEG characteristics Table I. Markers of circadian rhythms and Decline in process S during Slow-wave activity (eg, 0.75-4.5 Hz) the sleep homeostat. sleep in NREM sleep Abbreviations: DLMO, dim light melatonin onset; Rise in process S during wake / activity in wake EEG MCTQ, Munich Chrono- θ α type Questionnaire; MEQ, (particularly frontal) Morning-Eveningness Questionnaire; NREM, Slow eye movements in wake EEG nonrapid eye movement (sleep). workers. Zeitgeber strength (eg, how much light valid data about the best markers of the clock. To- does an individual receive and at what time of day) gether with the development of new technologies is an important factor for entrainment. Retinal in- that allow noninvasive measurement of physiology put is a further factor; since light is the major zeit- and behavior over many days (eg, i-buttons for skin geber, eye problems may diminish photic input to temperatures,27 actimetry), we have reached the the clock. Blind persons, for whom this signal is ab- stage where chronobiology theory meets ambula- sent, cannot usually synchronize well: they show tory research practice. The next decade will surely phase-delayed or even free-running sleep-wake cy- bring insights into the complexity of temporal or- cles, indicating that social zeitgebers are not always ganization in humans and examples of pathophys- sufficient for entrainment. iology of clock function. Thanks to more than a decade of elegant studies carried out in healthy humans in forced desyn- Many of these approaches are being developed within the chrony and constant routine protocols, we have EU 6th Framework Project EUCLOCK (#018741).

REFERENCES 1. Kleitman N. Sleep and Wakefulness.Revised and 7. Dijk DJ, Edgar DM. Circadian and homeostatic melatonin profile as a marker for circadian phase po- enlarged edition. Chicago, Ill; The University of Chica- control of wakefulness and sleep. In: Turek FW, Zee sition. J Biol Rhythms.1999;14:227-237. go Press; 1987. PC, eds. Regulation of Sleep and Circadian Rhythms. 13. Terman M, Terman JS. Light therapy for - 2. Wever RA. The Circadian System of Man: Results New York, NY: Marcel Dekker, Inc; 1999:111-147. al and nonseasonal depression: efficacy, protocol, of Experiments Under Temporal Isolation. New York, 8. Wirz-Justice A, Wever RA, Aschoff J. Seasonality in safety, and side effects. CNS Spectr. 2005;10:647- NY: Springer Verlag; 1979. freerunning circadian rhythms in man. Naturwis- 663. 3. Pittendrigh CS, Daan S. A functional analysis of senschaften.1984;71:316-319. 14. Wright H, Lack L, Bootzin R. Relationship be- circadian pacemakers in nocturnal rodents. J Comp 9. Brown SA, Fleury-Olela F, Nagoshi E, et al. The pe- tween dim light melatonin onset and the timing of Physiol (A).1976;106:233-355. riod length of fibroblast circadian gene expression sleep in sleep onset insomniacs. Sleep Biol Rhythms. 4. Borbély AA, Achermann P. Sleep and varies widely among human individuals. PLoS Biol. 2006;4:78-80. models of sleep regulation. In: Kryger MH, Roth T, 2005;3:e338. 15. Winkler D, Pjrek E, Praschak-Rieder N, et al. Dement WC, eds. Principles and Practice of Sleep 10. Horne JA, Östberg O. A self-assessment question- in patients with seasonal affective disorder Medicine. Philadelphia, Pa: WB Saunders Company; naire to determine morningness-eveningness in hu- and healthy control subjects treated with light thera- 2000:377-390. man circadian rhythms. Int J Chronobiol. 1976;4: py. Biol Psychiatry. 2005;58:331-336. 5. Roenneberg T, Wirz-Justice A, Merrow M. Life be- 97-110. 16. Van Someren EJ. Actigraphic monitoring of move- tween clocks: daily temporal patterns of human chro- 11. Ancoli-Israel S, Cole R, Alessi C, Chambers M, ment and rest-activity rhythms in aging, Alzheimer’s notypes. J Biol Rhythms. 2003;18:80-90. Moorcroft W, Pollak CP. The role of actigraphy in the disease, and Parkinson’s disease. IEEE Trans Rehabil 6. Moore RY. Circadian rhythms: basic neurobiology study of sleep and circadian rhythms. Sleep. 2003;26: Eng.1997;5:394-398. and clinical applications. Ann Rev Med.1997;48:253- 342-392. 17. Mrosovsky N. Masking: , definitions, and 266. 12. Lewy AJ, Cutler NL, Sack RL. The endogenous measurement. Chronobiol Int.1999;16:415-429.

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18. Kräuchi K, Cajochen C, Wirz-Justice A. Thermo- CA. Ageing and the circadian and homeostatic regu- cillators: why use constant routines? J Biol Rhythms. physiologic aspects of the three-process-model of lation of human sleep during forced desynchrony of 2002;17:4-13. sleepiness regulation. Clin Sports Med. 2005;24:287- rest, melatonin and temperature rhythms. J Physiol. 25. Wirz-Justice A, Cajochen C, Nussbaum P. A schizo- 300. 1999;516:611-627. phrenic patient with an arrhythmic circadian rest- 19. Kräuchi K, Wirz-Justice A. Circadian clues to sleep 22. Boivin DB, Czeisler CA, Dijk DJ, et al. Complex in- activity cycle. Psychiatry Res.1997;73:83-90. onset mechanisms. Neuropsychopharmacology. 2001; teraction of the sleep-wake cycle and circadian phase 26. Cajochen C, Knoblauch V, Kräuchi K, Renz C, 25(5 suppl):S92-S96. modulates mood in healthy subjects. Arch Gen Psy- Wirz-Justice A. Dynamics of frontal EEG activity, 20. Wirz-Justice A, Kräuchi K, Cajochen C, Danilenko chiatry.1997;54:145-152. sleepiness and body temperature under high and low KV, Renz C, Weber J. Evening melatonin and bright 23. Czeisler CA, Kronauer RE, Allan JS, et al. Bright sleep pressure. NeuroReport. 2001;12:2277-2281. light administration induce additive phase shifts in light induction of strong (Type 0) resetting of the 27. van Marken Lichtenbelt WD, Daanen HA, Wouters dim light melatonin onset. J Pineal Res. 2002;36: human circadian pacemaker. Science. 1989;244: L, et al. Evaluation of wireless determination of skin 192-194. 1328-1333. temperature using iButtons. Physiol Behav. 2006;88: 21. Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler 24. Duffy JF, Dijk DJ. Getting through to circadian os- 489-497.

COMMENT MESURER LES RYTHMES CIRCADIENS CHEZ L’HOMME

horloge biologique contrôle tous les rythmes circadiens ont fourni des critères de référence pour l’estimation de l’ampli- ’ chez l’homme, que ce soit pour les fonctions neurocom- tude et de la phase circadiennes et ont permis l’identification des L portementales, les sécrétions hormonales, la physiologie marqueurs physiologiques et hormonaux les plus utiles. Nous en ou le comportement. Le rythme le plus évident est celui du cycle sommes maintenant à la deuxième étape, celle du développement veille-sommeil dont la synchronisation diffère selon les individus de marqueurs plus simples à usage ambulatoire pour une esti- (« chronotype » – du lève-tôt « au chant du coq », au couche-tard mation raisonnablement exacte de la phase circadienne. La chro- « au cri du hibou »). Cependant, les altérations du cycle veille- nobiologie nécessite des mesures à long terme sur au moins un sommeil ne sont pas tous une conséquence d’un fonctionnement cycle de 24 heures et les nouvelles technologies à micropuce per- anormal de l’horloge circadienne. La connaissance des proprié- mettent le recueil continu de données, de façon non invasive et tés formelles du système circadien, du rôle des synchroniseurs sur de nombreux jours et semaines (par ex., l’actimétrie). Au (zeitgebers) pour la bonne synchronisation des 24 heures de la cours des prochaines dix années, la recherche permettra sûrement journée et de la façon dont le sommeil est régulé, a permis le dé- une compréhension plus approfondie du fonctionnement de l’hor- veloppement de protocoles rigoureux pour la recherche des ca- loge circadienne humaine et de sa pathologie. ractéristiques des rythmes circadiens et du sommeil. Ces études

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