Rütger Wever

The Circadian System of Man

As in other vertebrates, the human circadian system is characterized by a distinct temporal order of its components. This order is maintained by the coupling forces between various oscillators as well as by the entraining signals from the Zeitgebers (see Chapter 12). There is hardly a tissue or function that has not been shown to have some 24-hr variation. As an example, Figure 1 presents results of an experiment in which six subjects were held in groups of two on the same rigorous schedule. Although there were considerable interindi-vidual differences and also day-to-day variations, patterns like those shown in Figure 1 are satisfactorily reproducible. This reproducibility is again illustrated in Figure 2, which summarizes data on plasma Cortisol collected in six laboratories. To account for possible phase-controlling effects of sleep (see below), the curves are normalized with regard to the various sleep times of the subjects. Despite the fact that Cortisol, like many other hormones, is secreted in a highly variable sequence of episodes (see Chapter 12, Figure 1), a clear circadian pattern emerges in each curve, averaged from the data on n subjects, and there is perfect correspondence in phase and relative amplitude between the curves. It is noteworthy that two submaxima appear in all curves at about the same circadian phases. Presumably, they are not consequences of the usual meal timing but may represent a rhythm component interposed between the circadian domain and the episodes (cf. the discussion in Aschoff, 1979).

The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature

The sleep-wake cycle and the circadian rhythm of rectal temperature were recorded in subjects who lived singly in an isolation unit. In 10 subjects, the freerunning rhythms remained internally synchronized, 10 other subjects showed internal desynchronization. Times of onset and end of bedrest (“sleep”) were determined in each cycle and referred to the phase of the temperature rhythm. In the synchronized subjects, onset of sleep occurred, on the average, 1.34 h before the minimum of temperature, and end of sleep 6.94 h thereafter, with narrow distributions. The desynchronized subjects had a broad bimodal distribution of sleep onsets (peaks 6.3 and 1.3 h before the minimum); the duration of sleep varied between more than 15 h when sleep began about 10 h before the temperature minimum, and less than 4 h when sleep began several hours after the minimum. The dependence of sleep duration on body temperature is interpreted as a continuing action of the coupling forces between the two rhythms after mutual synchronization is lost.

Bright light affects human circadian rhythms

The relative effectiveness of external zeitgebers synchronizing circadian rhythms can be evaluated by mesuring the size of the range of entrainment. The experimental approach to measure entrainment limits is the application of an artificial zeitgeber with slowly and steadily changing period. In human circadian rhythms, an absolute light-dark (LD) cycle with a light intensity during L of 100 lux or less, results in an upper entrainment limit of 26.91±0.24 hours. The same limit is reached in constant illumination when only informations are given to the subjects. Consequently, the LD cycle is effective mainly with its behavioral component characterized by the request of the light-dark alternation to go to rest. In experiments with the same experimental protocol but higher intensity of illumination during L (∼400 lux, i.e., exceeding the threshold beyond which melatonin excretion is suppressed in humans), human circadian rhythms can be synchronized within a much larger range; the upper entrainment limit is, with all overt rhythms measured, beyond 29 hours. This means that bright light has an effect on the human circadian system which is qualitatively different from that of dim light, and which is similar to the effect of light in most animal experiments. This finding has theoretical and practical implications.

Light Effects on Human Circadian Rhythms: A Review of Recent Andechs Experiments

a continuously operating stimulus may affect the period and other parameters of endogenous, free-running rhythms, and, second, a periodically operating stimulus may act as a zeitgeber to synchronize the endogenous rhythm. In human circadian rhythms, it has been shown that these two aspects of the stimulus are always combined ; no stimulus is known that exerts an influence on only one of the two modes (Wever, 1979a). In the following review, responses of human free-running rhythms to external stimuli, continuous and periodic, are described. As light is the primary stimulus, much of the review is devoted to the effects of light. Since the hormone melatonin is often assumed to be involved in the generation and control of circadian rhythmicity, changes in melatonin secretion are discussed. Finally, preliminary results from experiments with administration of melatonin to humans are presented.

Beginn und Ende der täglichen Aktivität freilebender Vögel

Zahlreiche ornithologische Arbeiten enthalten Angaben fiber Erwachen odor ersten Gesang von VSgeln am Morgen und ihr Zuruhegehen am Abend. Meist sind dreJ Fragen bevorzugt behandelt: a) ~n~dert s:ich ,ira Verl~auf des Jahres die Hdligkeit, bei der eine Art morgen, s maffliegt ader zu sir~gen beginnt? b) Wie verhalten s~ich die Flugo,der Singhelligk~iten verschi,edeaer Art~a zu~inma,der? c) Welche UnterscMede be,stehen zwischen tier morgenc[lichen und abendlichen Flughelligkeit? Antwortea auf alle drei Fragen sind fiir die Kemntnis alex Arten und einer Reihe 5kologischer Besonderheiten wertvoll. Weit mehr gedeutung habea sbie im Zusammenhang mit Gesetzm//Bi,gkeiten der Tagesperio:dik. D.~,e bislang mitgeteilten Befunde gew~nnen allerdings erst dann ihr volles Gewieht, wenn es gelingt, aus ihnen mit ausr~ieher~de,r Sieherheit atlgeraein giilfige Regdn .xbzuleiten. Dazu ist e,s wiinschens,wert, dab ~ie Beobachtungen ~ber Flugodor S~r~ghelligkeiten kfinffig unter bestimmten Gesiehgspunkten a.s,gedehnt werd~n. Dot folgende Versueh, einige der teils ge,sicherten, tells n~r vermute~ten Regeln fiir Beginn und Ende des Vogeltages kurz zu umr~iBen, ha~ unter anderem den S~nn, zu weiterea Messangen auf die,sere Gebiet anzuregen.

Zum Mechanismus der biologischen 24-Stunden-Periodik

SummaryUsing the physical and mathematical basis given in two foregoing papers, a differential equation is proposed for a model of the biological 24-hour-periodicity. This oscillation equation contains two characteristic non-linearities describing the self-sustaining property and the “circadian rule”. The right side of the equation (“external force”) represents the controlling environmental conditions, mainly the intensity of illumination. Solutions were obtained for different environmental conditions using a digital computer.Under “constant conditions” the solution of the equation describes oscillations self-sustained within a certain range of environmental conditions. In this range the oscillations fulfil the circadian rule, e.g. for light-active organisms: The frequency and the mean value of the oscillation increase with increasing light intensity; with an additional (arbitrary) threshold separating activity time and rest time for describing an activity rhythm, the α∶ρ (activity time ∶ rest time) ratio and the total amount of activity also increase.Under periodically changing environmental conditions five properties of the “Zeitgeber” used (two distinct intensities with twilight transitions) are variable and varied: The range of oscillation of the Zeitgeber, its frequency, its mean value, its L ∶ D ratio (time relation of light time and dark time), and the duration of the twilights. The most important of the examined properties was the phase angle difference between the (forced) oscillation and the (forcing) Zeitgeber. The general result for light-active organisms was: The phase of the oscillation advances relative to the Zeitgeber (in sofar as the oscillation is synchronized) if the period of the Zeitgeber, or its mean value, or its L∶D ratio, or the duration of the twilights increase. In dark-active organisms, the relation between phase angle difference and the mean value or the L∶D ratio is reversed. Exceptions to this general rule exist in the relation between phase angle difference and L ∶ D ratio if the “free running” period of the oscillation deviates too much from the period of a “weak” Zeitgeber (mainly in dark-active organisms) or if the duration of the twilights is too short (especially if the transitions are rectangular).Single exposures to light (or darkness) during constant conditions result in phase shifts depending in direction and amount on the phase of the oscillation at which the disturbance occured. The resulting response curves depend in range and form on the one hand on the time of measuring the phase shifts (either immediately or after several periods — in the steady state — following the disturbance) and, on the other hand, on the intensity of the initial illumination, on the duration, and on the intensity of the exposures, each in a different manner. Moreover, response curves effective in LD conditions deviate from those measured under constant conditions; the reason being the difference in the energy state of the oscillations in the two conditions. Therefore, it is impossible to derive the phase angle difference between the oscillation and a Zeitgeber in self-sustained oscillations from the measurement of response curves alone.The oscillation equation used contains only one free parameter, the frequency coefficient. If this coefficient is changed, the equation describes other biological rhythms. For instance, with a high value it describes the behaviour of single nerve cells, and that not only in cases of spontaneous rhythmicity (e.g. receptor cells) but also in cases of reactions to single or rhythmic stimuli. Moreover, the derived characteristics of the equation — especially the non-linearities — seem to be significant for other biological problems such as control mechanisms.

Zur Zeitgeber-Stärke eines Licht-Dunkel-Wechsels für die circadiane Periodik des Menschen

SummaryCircadian rhythms of 8 human subjects were studied in strong isolation, under the influence of an artificial light-dark cycle with a period of 24 hours. None of the subjects was synchronized to this Zeitgeber, but all subjects showed autonomous (free-running) rhythms. In contrast to this, 16 subjects living under the influence of a same light-dark cycle but completed by sounds of a gong at regular intervals, were all synchronized to the Zeitgeber; at each sound of the gong, the subjects were instructed to give an urine sample, and to do some tests.The highly significant difference in the results obtained under these different conditions shows that an artificial light-dark cycle is a very weak Zeitgeber; it becomes effective when completed by regular acoustic signals. The reason may be that all the subjects had perceived the signals as social contacts. From this it is concluded that, in man, “social” Zeitgebers are more effective than “physical” Zeitgebers.ZusammenfassungDie circadiane Periodik von 8 Versuchspersonen wurde in strenger Isolation unter dem Einfluß eines künstlichen Licht-Dunkel-Wechsels mit einer Periode von 24 Std untersucht. Keine der Versuchspersonen war mit dem Zeitgeber synchronisiert, vielmehr zeigten alle eine autonome (freilaufende) Periodik. Im Gegensatz hierzu waren alle 16 Versuchspersonen, die unter dem Einfluß eines gleichen Licht-Dunkel-Wechsels lebten, der aber durch Gong-Signale in regelmäßigen Abständen ergänzt wurde, mit dem Zeitgeber synchronisiert; die Versuchspersonen waren dabei angewiesen, bei jedem Gong-Signal eine Urinprobe zu liefern und einige Tests zu absolvieren.Der hoch signifikante Unterschied in den unter den beiden verschiedenen Bedingungen gewonnenen Ergebnissen zeigt, daß ein künstlicher Licht-Dunkel-Wechsel auf Menschen nur eine sehr schwache Zeitgeber-Wirkung ausübt; erst die Ergänzung durch regelmäßige akustische Signale verleiht ihm Wirksamkeit. Als Ursache hierfür wird diskutiert, daß alle Versuchspersonen die Gong-Signale als sozialen Kontakt empfunden haben. Das bedeutet, daß für Menschen “soziale” Zeitgeber wirksamer sind als “physikalische”.

Use of light to treat jet lag: differential effects of normal and bright artificial light on human circadian rhythms.

The endogenously generated circadian rhythmicity is modified by special exogenous stimuli. Such an external modification can be manifested in two different modes. First, under constant conditions when the rhythms free-run, the period and many other rhythm parameters depend on the magnitude of the continuously operating effective stimulus; only within a limited range of external conditions (oscillatory range) does the rhythm persist in self-sustaining. Second, under the influence of a periodically operating effective stimulus (zeitgeber), the rhythm is synchronized, but only within a limited range of periods (range of entrainment). It is an experimental result in human circadian rhythms (but not a theoretical necessity) that every stimulus that is effective in one of the two modes mentioned is also effective in the other mode.’ The existence of a phase response curve is not an independent mode of effectiveness of a stimulus, but is an equivalent to the zeitgeber effectiveness of the same stimulus. This means that every stimulus that is effective as a zeitgeber when operating periodically releases a phase shift of the rhythm when given singly in an otherwise constant environment, and that is a phase shift, the amount and direction of which depend on the phase of the rhythm hit by the stimulus. Whereas phase relations under a defined zeitgeber, however, can be measured unambiguously and, hence, the respective phase response curve can be deduced indirectly and unambiguously, the direct measurement of a phase response curve meets with fundamental problems: every stimulus necessary for the measurement of one point within the phase response curve simultaneously alters the phase response curve. All parameters of the phase curve vary with the external conditions; for example, they are different in autonomous and heteronomous rhythms, and they differ even among heteronomous rhythms under the influence of zeitgebers with equal strength but with different periods.” The relative strength of a zeitgeber and, hence, the effectiveness of the stimulus under consideration with regard to circadian rhythms can be measured in two different ways. A first relative measure of the strength of a zeitgeber is the width of the range of entrainment: the larger this range the stronger the zeitgeber (or the weaker is the self-sustainment capacity of the underlying oscillator). Another relative measure of the relative zeitgeber strength is the duration of reentrainment after a phase shift of the zeitgeber: the faster this reentrainment the stronger is the zeitgeber. A phase shift of a synchronizing zeitgeber corresponds to a time shift accompanying a transmeridian flight. Consequently, experiments in which an artificial 24-hour zeitgeber is shifted for several hours simulate long-distance flights over a corresponding number of time zones. With such experiments, therefore, jet lag phenomena can be evaluated.’ In most animal circadian rhythms, light is the most effective external stimulus.

Circadian period and phase-angle difference in chaffinches (Fringilla coelebs L.).

Abstract 1. 1. Chaffinches were kept for 8 months alternatively in either constant conditions (with two different intensities of illumination) or in light-dark cycles (with two different ranges of light-intensity). 2. 2. The birds showed a clear circadian rhythm of activity in constant conditions with a relatively large interindividual variability of period values. 3. 3. The shorter the period, the longer was the activity-time and the greater the amount of activity per hour of activity-time. 4. 4. During entrainment, the phase-angle difference was strongly related to the spontaneous period as measured in constant conditions. 5. 5. The shorter the period, the more positive was the phase-angle difference and the greater the amount of activity per hour of activity-time. 6. 6. The results are discussed in view of a special circadian model. It operates with a variable level of the oscillation and a fixed threshold which separates the states of activity and rest.

Zum Einfluß der Dämmerung auf die circadiane Periodik

SummaryTheoretical considerations of circadian rhythms have shown that, under conditions of a light-dark cycle, the duration of twilight has a twofold influence on phase-angle difference between an activity cycle and the Zeitgeber: 1. The longer the twilight periods, the earlier occurs the activity relative to the Zeitgeber, and 2. the longer the twilight periods, the stronger changes the phase-angle difference with changing L∶D-ratio. In former biological experiments, these predictions are confirmed only with very long twilight periods and only with light-active birds. In experiments described here, phase-angle difference between activity cycle and Zeitgeber are examined in light-active birds (finches) and in dark-active mammals (hamsters) under the influence of short twilight periods with varying duration. All results show a clear agreement between theory and experiment.These results confirm the validity of the theory with stronger significance than any other biological experiment up to now, because the theoretical derivation of the twilight influence covers more essential aspects of the theory than the derivation of any other influence (e.g.: influence of L∶D-ratio). Furthermore, these results have consequences with regard to the seasonal change in phase-angle differences, because in nature not only the L∶D-ratio changes seasonally but also the duration of twilight. Especially in dark-active organisms, the twilight influence changes remarkably the seasonal course of phase-angle difference in comparison to that course derived only from the seasonal change in L∶D-ratio. Because of the prevailing twilight influence these phase-angle differences, as relevant for photoperiodic phenomena, take a similar course in light-active and in dark-active organisms.ZusammenfassungTheoretische Untersuchungen der circadianen Periodik mit Hilfe eines mathematischen Modells hatten zu der Voraussage geführt, daß die Phasenwinkel-Differenz zwischen einer Aktivitäts-Periodik und einem Licht-Dunkel-Zeitgeber in zweifacher Weise von der Dämmerungs-Dauer abhängt: 1. Je länger die Dämmerung, desto früher liegt die Aktivitäts-Periodik relativ zum Zeitgeber; 2. je länger die Dämmerung, desto stärker ändert sich die Phasenwinkel-Differenz zum Zeitgeber bei Variation des L∶D-Verhältnisses. In einer ersten Versuchsreihe waren diese Voraussagen für lange Dämmerungen und für licht-aktive Vögel bestätigt. In den hier beschriebenen Experimenten ist der Einfluß kurzer Dämmerungen verschiedener Dauer untersucht, und zwar bei licht-aktiven Finken-Vögeln und bei dunkel-aktiven Goldhamstern. Alle Ergebnisse stimmen mit den theoretischen Voraussagen überein.Die Ergebnisse dieser Versuche sind für die Bestätigung der Theorie von besonderer Bedeutung, da in die Ableitung des Dämmerungs-Einflusses mehr wesentliche Eigenschaften der Theorie eingehen als in die Ableitung aller anderen bisher untersuchten Einflüsse (z.B. des Einflusses variabler L∶D-Verhältnisse). Die hier beschriebenen Ergebnisse sind außerdem von Bedeutung für die jahreszeitliche Änderung der Phasenlage, die die natürliche Grundlage für photoperiodische Prozesse bildet: In der Natur wechselt im Verlaufe der Jahreszeiten nicht nur das L∶D-Verhältnis, sondern auch die Dämmerungs-Dauer. Besonders bei dunkelaktiven Organismen ändert die Mit-Berücksichtigung des Dämmerungs-Einflusses entscheidend den alleine unter Berücksichtigung des L∶D-Verhältnisses abgeleiteten Jahresgang der Phasenlage und gleicht ihn dem für licht-aktive Organismen gültigen an.