phase-adjustment of human circadian rhythms by light and

J Phys Fitness Sports Med, 5 (4): 287-299 (2016)DOI: 10.7600/jpfsm.5.287

JPFSM: Review Article

Phase-adjustment of human circadian rhythms by light andphysical exercise

Yujiro Yamanaka1* and Jim Waterhouse2

Received: August 23, 2016 / Accepted: September 8, 2016

Abstract The human circadian system derives from two distinct circadian oscillators that separately regulate circadian rhythms of body temperature and plasma melatonin, and of the sleep-wake cycle. The oscillator for body temperature and melatonin is the central circadian pacemaker, located in the hypothalamic suprachiasmatic nucleus (SCN), and the oscillator for sleep-wake cycle is another oscillator, located in the brain but outside the SCN. Although bright light is a primary zeitgeber for circadian rhythms, non-photic time cues such as a strict sleep schedule and timed physical exercise act as a non-photic zeitgeber for the sleep-wake cycle under dim light conditions, independent on the SCN circadian pacemaker. Recently, timed physical exercise under bright light has been shown to accelerate re-entrainment of circadian rhythms to an advanced sleep schedule. Physical exercise may enhance the phase-shift of circa-dian rhythm caused by bright light by changing light perception. In the field of sports medicine and exercise science, adjustment of the circadian rhythm is important to enable elite athletes to take a good sleep and enhance exercise performance, especially after inter-continental travel and jet lag. Keywords : circadian rhythm, internal desynchronization, bright light, physical exercise, jet lag

Introduction

Circadian rhythms are defined as those which show ap-proximately 24-h fluctuations (period range of 20 h to 28 h) in physiology, behavior, performance, etc. In the real world, however, the circadian rhythms of the sleep-wake cycle and plasma melatonin show stable rhythmicity with a period of 24 h, equal to that of the solar day1) (Fig. 1). However, such rhythms persist and show a stable free-running rhythm with a period of about 25 h under con-stant conditions and in the absence of time cues2). This observation of a free-running circadian rhythm implies that it is generated by an internal oscillator, the circadian pacemaker. The circadian pacemaker is part of an important physio-logical system which enables living organisms to adapt to the daily day-night cycles caused by the Earth’s rotation period of 24 h; it is normally entrained to these natural light-dark (LD) cycles (see below). In humans, the natu-ral LD cycle (particularly its bright light component) is a predominant zeitgeber for the circadian pacemaker, but non-photic time cues, such as a strict sleep schedule, have been reported to affect circadian rhythms in totally blind

persons3) and in sighted persons living under conditions of constant darkness4). However, whether or not the photic and non-photic time cues specifically interact with each other in causing entrainment of circadian rhythms under natural circumstances remains an unanswered question. In this review, we discuss underlying mechanisms re-lating to phase adjustment of the human circadian pace-maker by bright light and physical exercise. In addition, we address a strategy to prevent or minimize the disorder of jet lag, based on current chronobiological knowledge.

Formal properties of the circadian system in humans

Internal synchronization. Physiological and behavioral (sleep-wake cycle) rhythms in most organisms, including humans, show a period of ca. 24 h (circadian rhythm), generated by the circadian pacemaker in the SCN. Most importantly, the circadian pacemaker regulates and main-tains internal temporal order of physiological function in the organism. In the presence of a 24-h LD cycle, the circadian pacemaker entrains to (synchronizes with) it through the action of zeitgebers. The time of sleep onset is approximately 6 h before the trough of core tempera-ture, and the time of waking up is approximately 3 h after this trough. The secretion of the pineal hormone, melato-*Correspondence: [email protected]

1 Laboratory of Life and Health Sciences, Hokkaido University, Graduate School of Education, N-11, W-7, Kita-ku, Sapporo, Hokkaido 060-0811, Japan

2 School of Sport and Exercise Sciences, Tom Reilly Building, Byrom Street Campus, Liverpool John Moores University, Liverpool, L3 3AF, UK

288 JPFSM : Yamanaka Y and Waterhouse J

nin, starts approximately 3 h before sleep onset, and peak melatonin secretion is located at around the midpoint of sleep5).

Free-running rhythm. If subjects remain in conditions where there are no cues indicating the passage of time – that is, without externally-imposed light-dark, tempera-ture and humidity cycles, and in the absence of interac-tions with people who know the time of the solar day - their rhythms exhibit a period slightly different in length from 24 h (“circadian”, about a day). This is called a free-

running rhythm. The body clock tends to run slow, the free-running period of rectal temperature being reported to average 25.0 h in 147 subjects who stayed in a tem-poral isolation facility under various conditions of light intensity, workload and room temperature2). In agreement with this, in a similar study upon Japanese subjects, the free-running periods of core body temperature from 20 healthy subjects averaged 25.2 h under dim light condi-tions of 300 lux6). In addition, there is a sex difference, the free-running period in males being significantly lon-ger than in females6). How closely such values reflect the exact free-running period of the SCN, tau, is unclear, since it is influenced by the light intensity during waking2). Since, during free-run-ning conditions, individuals tend to go to sleep closer to the time of the temperature trough than normal, this will expose them more than usual to the phase-delaying por-tion of the light PRC (see below) and so might increase the value of tau. Three solutions to this problem have been suggested: 1. Perform free-running experiments with light intensities as low as possible; 2. Estimate tau in blind individuals. (Indeed, the mean value for tau in to-tally blind subjects has been found to average 24.5 h2)); 3. Estimate tau during a forced desynchronization protocol, during which light when awake falls on all portions of the light PRC, with the result that any phase-shifting effects of light will cancel out7). The main issue is that, when the free-running period of humans is being estimated, careful attention should be paid to the exact experimental condi-tions. Nevertheless, the general view is that free-running tau is slightly greater than 24 h, and this requires entrain-ment of the body clock under normal (nyctohemeral) cir-cumstances.

Internal desynchronization of human circadian rhythms. When subjects stay in an isolation facility under free-running conditions, even though the free-running period of the sleep-wake cycle and the circadian rhythm of core body temperature have the same period (of approximately 25.0 h) for the first days, it is sometimes observed that the period of the sleep-wake cycle then desynchronizes from that of the circadian rhythm of core body temperature - a phenomenon known as spontaneous internal desynchro-nization8). Under this form of desynchronization, the free-running period of circadian rhythm of core body tempera-ture remains with a period of about 25.0 h, whereas that of the sleep-wake cycle becomes longer than 30 h or shorter than 20 h2) (Fig. 2). In more detail, if the sleep-wake cycle lengthens then the temperature rhythm shortens slightly (and vice versa). This form of desynchronization is also observed between the sleep-wake cycle and circadian rhythm of plasma melatonin1). Interestingly, when the rhythm of core body temperature and the sleep-wake cy-cle free-run with different periods, the duration of sleep is dependent on the phase-angle difference between the two rhythms10,11). The duration of sleep is longer when sleep

Fig. 1 Stable 24-h rhythms in plasma melatonin and the sleep-wake cycle.

(Panel A) Circadian plasma melatonin rhythm measured repeatedly 4 times from one subject who was studied in an isolation facility at weekly intervals1). The rising phase of melatonin rhythm shows a small deviation, whereas the falling phase was very stable, and the circa-dian profile as a whole was also stable under entrained conditions. (Panel B) Double-plotted actogram of wrist activity collected into 10-min bins from one subject mea-sured for 4 weeks under entrained conditions. Black ar-eas indicate the times of wrist activity. The small panel in the actogram shows the chi-square periodogram, which indicates a significant periodicity at 24.0 h (Yamanaka et al. unpublished).

289JPFSM : Photic and non-photic entrainment of human circadian system

starts before the minimum of temperature, whereas the duration is shorter when sleep starts after the minimum. Also, when exhibiting spontaneous internal desynchroni-zation, subjects periodically complain of various physi-ological and psychological dysfunctions. These problems arise because the phase-angle difference between the two rhythms changes each cycle, and they are most marked when the two rhythms are phased approximately 12 h dif-ferent from their normal relationship. The phenomenon of spontaneous internal desynchroni-zation supports the idea that the sleep-wake cycle and the circadian rhythms of core body temperature and plasma melatonin are regulated by two distinct oscillators that are normally coupled9,12) (Fig. 3). Why uncoupling should occur spontaneously in some cases (see above) remains unclear, but it has been speculated that, in due course, all subjects performing a free-running experiment would, eventually, show spontaneous internal desynchronization.

Photic entrainment and the phase-response curve to light. The free-running period of the human circadian clock is normally longer than 24 h, and so a phase advance is needed every day to entrain the clock to the 24-h environ-mental LD cycle. Bright light (natural sunlight) is a pri-mary zeitgeber (entraining agent) for the circadian clock in humans. Fig. 4 demonstrates a so-called light phase-response curve (PRC) produced by a single 3-h pulse of bright light at about 5,000 lux13,14). The PRC was obtained from subjects staying in an isolation facility under free-running (time-free) conditions. The subjects received a pulse of bright light at different circadian phases. In this PRC, the phase-advance portion coincides with late sub-

jective night and early subjective morning, the phase-delay portion with early subjective night, and the middle of sub-jective day is a dead-zone when bright light does not pro-duce a significant phase shift (dead-zone). Under normal circumstances, therefore, our circadian clock is entrained to a 24-h LD cycle by a phase advance caused by exposure to natural sunlight in the morning after waking up. The phase-shifting effect by light on the circadian clock is influenced by its wavelength. The human circadian clock is more sensitive to light of a short wavelength than light of a longer wavelength15). In mammals, the light information is transmitted from the eye to the circa-dian pacemaker in the SCN via the retino-hypothalamic tract16). It has been reported that the retinal photopigment

Fig. 2 Spontaneous internal desynchronization of human circadian rhythms under constant conditions in temporal isolation2). Representative recordings of spontaneous internal desynchronization between the sleep-wake cycle and rectal temperature

rhythm under constant conditions. Arrows indicate the day when internal desynchronization started. Open and closed horizontal bars indicate the wake and sleep periods. Upward and downward triangles indicate the times of maximum and minimum rectal temperature, respectively.

Fig. 3 Two-oscillator model of human circadian rhythms. In this model, Oscillator I drives the circadian rhythms of

body temperature and melatonin; it is located in the SCN and entrained by light-dark cycle. Oscillator II drives the sleep-wake cycle; it is probably located in extra-SCN brain regions and entrained by non-photic time cues12).


melanopsin plays this important role of transducing the light information and transmitting it to the circadian pace-maker17). The spectral peak of melanopsin absorption is approximately 480 nm – light of short wavelength18). As for seasonal changes in the environmental LD cycle, the duration of the light period is longer in summer (long photoperiod) than winter (short photoperiod). In addition, the incident light energy is stronger in summer. Conse-quently, the phase of entrainment is expected to change with the seasons. In support of this view, the circadian rhythms of plasma melatonin were found to be phase ad-vanced in summer compared to winter19).

Non-photic entrainment. Although bright light is a pri-mary zeitgeber for the human circadian clock, approxi-mately half of totally blind persons who do not exhibit light-induced melatonin suppression show normal entrain-ment of their circadian rhythms20). In addition, Aschoff et al. reported that circadian rhythms in sighted subjects living in constant darkness entrained to a 24-h period when undertaking a strict sleep-wake schedule of 24 h for 4 days4). These observations imply that a strict social/behavioral schedule might be a candidate for a non-photic zeitgeber of the circadian clock in humans. There are also compelling case studies for non-photic entrainment in totally blind persons3). In this study, the circadian rhythms of core body temperature and plasma melatonin entrained to 23.8-h sleep-wake schedule in a temporal isolation facility, even though the free-running periods, estimated by a forced desynchrony protocol, were different from this value - 24.1 h on average. However, it was not clear in this study that the sleep-wake cycle actually entrained to the 23.8 h sleep-wake schedule (rather than merely re-flected the adherence of the subjects to the imposed pro-tocol). In addition, it remains unknown whether the cir-cadian rhythm of plasma melatonin showed entrainment

due to the strict sleep-wake schedule acting as a non-photic zeitgeber rather than reflected other effects due to the imposed sleep-wake cycle. With regard to this issue, Hashimoto et al. examined the non-photic entrainment of the sleep-wake cycle and the circadian rhythm of plasma melatonin to a strict sleep-wake schedule in sighted subjects who stayed in a tem-poral isolation unit in constant dim light conditions (less than 10 lux)21). In this study, the subjects slept at their ha-bitual sleep time on the first day, and then the sleep time was phase-advanced by 8 h. The advanced sleep schedule was continued for 8 days and the subjects were then re-leased into free-running conditions for a period of 6 days. At the end of the advanced schedule, the sleep-wake cycle had almost completely adjusted to the advanced schedule, and then free-ran from this advanced phase. By contrast, the circadian rhythm of plasma melatonin failed to ad-vance during the 8 days when the sleep-wake cycle was advanced (showing, instead, only marginal phase shifts), and then phase delayed during the free-running condi-tions. As a result, the rhythms of the sleep-wake cycle and melatonin became desynchronized (Fig. 5). This phenom-enon is termed “partial entrainment” or “entrainment by partition” and is another type of internal desynchroniza-tion between the sleep-wake cycle and circadian rhythm of plasma melatonin. The partial entrainment of the sleep-wake cycle clearly indicates that photic and non-photic time cues differen-tially affect the sleep-wake cycle and circadian rhythm of plasma melatonin. In addition, the same authors reported that the desynchronized rhythms gradually became re-synchronized by advances (Fig. 5, top) or delays (Fig. 5, bottom) of the sleep-wake cycles during the free-running phase of the experiment. This process of resynchroniza-tion suggested that the oscillator for sleep-wake cycle is under the control of the oscillator responsible for the cir-

Fig. 4 Phase response curve (PRC) to a single pulse of bright light measured from subjects under free-running conditions.

The data were taken from the results of 2 labo-ratories13,14). Subjects were exposed to bright light pulses (3 h of 5000 lux). The x-axis shows the circadian time of the mid-point of the 3-h bright light pulse. Circadian time 0 is defined as the minimum of core body temperature. A clock time axis, for an entrained subject with a 7-h sleep period from 23.00 to 07.00 h (open square) and typical time of temperature minimum at 04.00 h (black triangle), has been added.


cadian rhythm of plasma melatonin. In other words, the effect of (the coupling force between) the oscillator con-trolling the circadian rhythm of plasma melatonin upon the oscillator controlling the sleep-wake cycle seems to be stronger than that in the opposite direction.

Physical exercise as a non-photic zeitgeber for human circadian rhythms

Effect of physical exercise on the circadian rhythm un-der dim light conditions. Effects of timed physical ex-ercise on the circadian rhythm of plasma melatonin have been examined under dim light conditions22,23). Buxton et al. reported a phase-response curve for a single trial of high intensity exercise (75% V・O2max)24). In this PRC, physical exercise at midnight produced phase-delays, whereas it induced phase-advances when exercise was taken in the early evening. The amount of phase-shift elicited by the single bout exercise was smaller than that produced by bright light13,14). Since other evidence indi-cates that a single bout of physical exercise has no effects on the circadian rhythms of plasma melatonin25) and core body temperature26), it seems that a single bout exercise

might be, at best, only a weak zeitgeber for the circadian pacemaker in humans. As for the effect of regular physical exercise on the circadian rhythm, there is good evidence that the circa-dian rhythm of plasma melatonin in totally blind persons entrained to a strict sleep-wake schedule of 23.8 h period, which included a daily bout of exercise on a bicycle er-gometer for 10 min taken 6 h after waking up3). In addi-tion, Miyazaki et al. reported that daily physical exercise for 2 h twice a day was accompanied by entrainment of the circadian rhythm of plasma melatonin to a strict sleep-wake schedule of 23.6 h under dim light conditions (<10 lux), whereas control subjects, who did not take exercise, showed phase delays of the melatonin rhythm25). Further-more, Barger et al. reported that daily physical exercise at night accelerated re-entrainment of the circadian rhythm of plasma melatonin to 9-h phase delay of the sleep-wake schedule27). Taken together, these observations suggest that daily physical exercise affects the human circadian pacemaker whereas, somewhat paradoxically, studies us-ing a strict sleep-wake schedule (where normal physical activities will show rhythmicity) did not provide support for phase-shifting effects and/or entrainment caused by the sleep-wake cycle. With regard to an attempt to resolve this paradox, Yamanaka et al. had previously examined the effect of regular physical exercise on re-entrainment of the sleep-wake cycle and the circadian rhythm of plasma melato-nin to an 8-h phase advance of the sleep-wake schedule under dim light conditions28). In this study, the subjects’ sleep-wake schedule was phase-advanced by 8 h from its habitual value for 4 days. The exercise group performed interval exercise (15 min of running alternating with 15 min of rest) for 2 h upon a cycle ergometer twice a day after the wake period had been advanced. The control group sat quietly on a chair during the same period. At the end of the 4 days, the subjects were released into free-running conditions. By measuring the phase position of sleep-wake cycle and circadian rhythm of plasma mela-tonin on the first day of the free-running conditions, the re-entrainment of these rhythms to the advanced sleep schedule could be evaluated. It was demonstrated that daily physical exercise facilitated the re-entrainment of the sleep-wake cycle but not of the circadian rhythm of plasma melatonin. Although the circadian rhythm of plasma melatonin was phase delayed on the last day of the advanced sleep schedule, the amount of this delay shift was smaller in the exercise group than in the no-exercise control group (Fig. 6). In this study, the subjects performed physical exercise at midnight and in the early morning, times when a single bout exercise had previ-ously been reported to elicit a phase delay of the circadian rhythm of plasma melatonin24). Thus, it was expected that the circadian rhythm of plasma melatonin would be more phase delayed in the exercise group than in the control (no-exercise) group, a prediction which was not supported

Fig. 5 Partial entrainment of the sleep-wake cycle. The subjects stayed in an isolation facility under dim-

light conditions. After the 8-h advanced sleep schedule for 8 days (open square), the subjects were released into free-running conditions. Arrows indicate the onset of the spontaneous sleep period on the first day of the free-running phase of the experiment21).


bright light facilitated the re-entrainment of circadian rhythms to an 8-h advance of the sleep schedule, using a similar experimental protocol to that used previously28). In this newer study, the exercise group performed 15 min of exercise/15 min of rest on a bicycle ergometer for a peri-od of 2 h, twice a day, under bright light conditions (>5000 lux)29). This protocol showed that physical exercise under bright light significantly accelerated re-entrainment to the 8-h advance of the sleep-wake schedule of not only the sleep-wake cycle but also the circadian rhythm of plasma melatonin (Fig. 7). By contrast, the control subjects (who did not perform physical exercise), even though they also showed re-entrainment of sleep-wake cycle, did not show a significant phase shift from baseline values in their circadian rhythm of plasma melatonin when they started the free-running part of the protocol. That is, internal desynchronization between the sleep-wake cycle and the circadian rhythm of plasma melatonin had occurred in the control group. In this study, sleep polysomnography was also recorded during the baseline and advanced sleep por-tions of the protocol. During the advanced sleep portion, the control subjects (no exercise) showed significantly decreased sleep efficiency, with increasing wakefulness after sleep onset, whereas the exercise group maintained sleep efficiency at baseline values during the advanced

by our findings. Also, Barger et al. reported that regular physical exercise at midnight produced a greater phase delay and facilitated re-entrainment to a 9-h phase-delay in the sleep-wake schedule under dim light conditions27). These findings suggest that the direction of the phase shift of melatonin produced by exercise is different from that produced by the change of sleep-wake schedule. In other words, daily physical exercise might affect the circadian rhythm of plasma melatonin only indirectly – physical exercise acting upon the oscillator controlling the sleep-wake cycle, this oscillator then acting upon the oscillator that is responsible for the circadian rhythm of melatonin.

Effect of physical exercise under bright light on circadian rhythms. As noted above, daily physical exercise acts as a non-photic zeitgeber for the sleep-wake cycle rather than the circadian rhythm of plasma melatonin, whereas bright light acts as a zeitgeber for circadian rhythms in general. In the normal world, however, the combined ef-fects of bright light (natural sunlight and artificial light) and non-photic cues (such as social schedule and physical exercise) on circadian rhythms should be considered. To identify possible mechanisms by which physical exercise under bright light conditions might phase shift circadian rhythms, it was investigated if physical exercise under

Fig. 6 Partial entrainment. Physical exercise facilitates the entrainment of the sleep-wake cycle, but not the melatonin rhythm, under dim light conditions.

Black horizontal bars indicate the sleep periods. Open circles indicate the peaks of the plasma melatonin rhythm measured at baseline, on the last day of shift schedule, and on the last day of the free-running period, respectively. The rectal temperature rhythm is expressed in a raster plot, the shaded area indicating times when the temperature was below the mean value for all val-ues obtained during the experiment. Open rectangles in the two right panels indicate the 2-h periods of intermittent exercise28). For more details, see text.


Circadian rhythm in sports performance

There is much evidence to indicate that sports perfor-mance shows a clear 24-h variation in elite athletes living normally and entrained to the solar light/dark cycle30,31). In general, the rhythms of different aspects of sports perfor-mance are associated with that of core body temperature. Peak performance occurs in the early evening, around the time of maximum core body temperature, whereas worst performance is in the early morning around the time of the minimum temperature32,33). Body temperature is af-fected not only by the circadian pacemaker in the SCN but also by external factors such as environmental tem-perature, the individual’s health and sleep, which factors directly moderate body temperature (masking factors). In addition, time awake influences mental fatigue and physi-cal fatigue (due to muscle activity), these issues having been reviewed by Reilly and Waterhouse (2009)34). Kline et al. have investigated the circadian rhythm of swimming performance in subjects following a 3-h ultra-short sleep-wake cycle (120 min of waking and 60 min of sleep) under dim light35). Experienced swimmers lived on an ultra-short sleep-wake cycle for a period of 50-55h.

sleep period. These two studies28,29) indicate that the effect of physi-cal exercise on the human circadian system is dependent on the light conditions when the exercise is performed. As indicated as Fig. 7, physical exercise was performed at midnight and early morning, these times covering both the phase-delay and phase-advance portions of the light PRC (Fig. 4). One possible explanation of the greater phase advance is that physical exercise enhances light perception of the circadian pacemaker and so, in bright light, induces a greater phase advance shift. Fig. 8 sum-marizes the results of the two studies28,29), showing the ef-fects of physical exercise under the two different lighting conditions. There are limitations in an experiment performed in an isolation facility with only a small number of subjects and strictly controlled environmental conditions (e.g. light intensity, temperature and humidity). Further studies are needed to assess whether timed physical exercise under bright light is really beneficial for promoting adjustment of the circadian pacemaker in humans in normal circum-stances.

Fig. 7 Physical exercise under bright light accelerates the re-entrainment of human circadian rhythms to an 8-h advance in sleep schedule.

Representative recording of sleep-wake cycle, time of peak of plasma melatonin rhythm, and body temperatures below the overall average (left), and of the circadian profile of plasma melatonin measured on days 1 and 6 (right), are illustrated. All data come from the same individual who participated: without exercise (upper panels) and with exercise (lower panels)29).


reported that jet lag negatively affects sports perfor-mance37) and cognitive function38). Performance time for a 270-m sprint was increased for the first 4 days after an eastward flight across 6 time zones37), and back and leg strength and reaction time were impaired after a westward flight across 5 time zones39). These studies indicate that jet lag negatively influences athletic, physical and mental performance. Therefore, it becomes important to mini-mize jet-lag disorder in elite athletes, to ensure mainte-nance of their sports performance levels in competitions.

The process of re-entrainment of circadian rhythms to a new environmental light-dark cycle after transmerid-ian travel

Several studies in the field have examined in the field the re-entrainment process of circadian rhythms after transmeridian flights40-44). Klein and Wegmann examined the time-course of re-entrainment of the circadian rhythm in body temperature and psychomotor performance af-ter flights between Germany and the U.S.A (in both the eastward and westward directions) across 6 time zones40). They reported that the speed of re-entrainment was faster after the westward than the eastward flights, and this dif-ference was attributed to the fact that the free-running pe-riod in humans is longer than 24 h (see above). Takahashi et al. measured re-entrainment of the circadian rhythm of plasma melatonin in 6 males after an eastward flight (across 8 time zones) between Tokyo (TYO) and Los An-geles (LAX)42). They carried out 24-h blood sampling to assess the circadian rhythm of plasma melatonin at TYO before the flight and on the first and fifth day after the

Swimming performance showed a circadian rhythm with peak performance 5-7 h before the temperature minimum and a trough from 1 h before to 1 h after the temperature minimum. Kline’s study provides compelling evidence that the circadian rhythm in sports performance is inde-pendent of many environmental and behavioral masking factors but it could not exclude an effect of muscle fatigue due to repeated exercise tests. Further studies are needed to evaluate in more detail the circadian rhythm of sport performance using an experimental protocol that mini-mizes effects of time awake and also reduces the amount of muscle fatigue due to repeated testing. As a consequence of the role of the circadian pacemaker in athletic performance, appropriate phase adjustment of it is important for the athletes, especially immediately af-ter they have travelled across time zones.

Sports performance in athletes after crossing time zones; effects of jet lag

After rapid flights across time zones, most people tem-porarily suffer various psychological and physiological symptoms such as insomnia, daytime sleepiness, gastroin-testinal disruption, etc. These symptoms, caused by rapid transmeridian travel, are known as jet-lag disorder (“jet lag”). The American Academy of Sleep Medicine defines this disorder as the symptoms generated by circadian misalignment, an inevitable consequence of crossing time zones too rapidly for the circadian system to keep pace36). In professional athletes, there are many occasions when they are required to participate in international matches after travel across time zones. At least two studies have

Fig. 8 Two-oscillator model of the human circadian system and underlying mechanisms causing phase adjustment of the two oscillators by photic (light) and non-photic time cues.

Based on previous studies by one of the authors28,29). The lower two lines summarize the results of mean phase-shift of melatonin peak and sleep onset after the last day of advanced schedule in the control (no-exercise) and exercise groups.


pacemaker in the SCN50), non-photic time cues such as timed feeding51) and exercise52-55) also affect circadian rhythms in the peripheral clocks independently of the out-put of the SCN. For example, restricted feeding strongly affects the peripheral clock in the liver51), and timed ex-ercise affects those in the lung and skeletal muscle52-55). There is also evidence that exercise affects the SCN in some species. For example, in hamsters, daytime wheel-running activity suppressed the expression of the clock gene Period1 and Period2 in the SCN56), and the free-run-ning period under DD was shortened by daily wheel-run-ning activity in mice57) and rats58). Also, under LD cycles, timed exposure to wheel-running activity enhanced the amplitude of PERIOD2::LUCIFERASE expression in the SCN of VPAC2KO mice, suggesting that increased physi-cal activity strengthens the coupling intensity between SCN cells59). Previous studies in nocturnal rodents have documented that the rhythm in the SCN re-entrains more rapidly than that of the peripheral clocks and behavior after a large shift of the light-dark cycle49,60). On the other hand, in humans, the behavioral sleep-wake cycle re-entrains more rapidly than the circadian rhythms of body temperature and plasma melatonin which are regulated by the SCN pacemaker. Thus, the major coping strategy cop-ing for jet lag seems to be to facilitate re-entrainment of SCN-based circadian pacemaker. From the features of circadian system in humans de-scribed above, a basic strategy for coping with the jet lag is to facilitate re-entrainment of the circadian pacemaker by timed exposure to bright light (or bright light with physical exercise) and, equally important, timed avoid-ance of bright light and exercise. Timed exposure to bright light has proved to accelerate the re-entrainment of the circadian rhythms of both body temperature61) and plasma melatonin45). Fig. 9 illustrates the best and worst times of exposure to bright light by new local time at the destination if phase adjustment of the body clock is re-quired. As noted above, travelers should coordinate the time of exposure to bright light at their destination, especially after an eastward flight. Alternatively, a simple and ef-fective strategy to prevent or reduce the jet lag is at least partial adjustment of circadian rhythms and the sleep-wake cycle prior to travel. The time taken to alleviate the effects of jet-lag disorder depends on the number of time zones crossed, and so there is advantage in trying to pre-adapt if the flight is across several time zones. Burgess et al. examined whether a gradual phase-advance shift of subject’s habitual sleep schedule by 1h/day for 3 days could phase-advance the circadian rhythm of saliva mela-tonin62). In their study, three groups were studied after 3 different regimens of morning light exposure given during the first 3.5 h after waking up. The light regimens were: continuous bright light (>3000 lux), intermittent bright light (>3000 lux, 0.5 h on, 0.5 h off, etc), or dim light (<60 lux). The continuous light group showed a greater phase

flight at LAX. In LAX, the subjects were exposed to natu-ral sunlight during the waking period except on the blood sampling days. Four of six subjects showed orthodromic reentrainment (re-entrainment in the predicted direction, a phase advance), another subject showed antidromic re-entrainment (re-entrainment in the direction opposite to that predicted, a phase delay), and the other subject did not show a meaningful phase-shift. In a later experiment, Takahashi et al. studied the re-entrainment of the circa-dian rhythm of plasma melatonin in 8 males after an east-ward flight between TYO and New York (11 time zones to the east)43). Seven of eight subjects showed antidromic re-entrainment (phase delays) and only one showed or-thodromic re-entrainment (phase advance). These two field studies demonstrated that the speed of orthodromic re-entrainment after a flight to the east was about 55 min per day and that the speed after antidromic re-entrainment (a delay of the body clock) was about 65 min per day. In other words, the body clock seems able to delay more rapidly than it can advance. Furthermore, the direction of re-entrainment (orthodromic vs. antidromic) after an east-ward flight seems to depend on the timing of exposure to bright light. It has also been proposed that antidromic re-entrainment after a flight to the east occurs when the daylight in the new time zone falls upon the phase-delay portion of an unadjusted light PRC (that is, 20.00-04.00 h by “old” time, which corresponds to 04.00-12.00 h on new local time after a flight across 8 time zones to the east). This hypothesis was supported by results from a simulated eastward flight across 8 time zones performed in the isolation facility45).

Practical strategies for coping with jet lag in athletes

How to minimize the effect of jet lag on sports perfor-mance in travelers and athletes? Reilly et al. (2009)46) and Waterhouse et al. (1997 and 2007)47,48) previously reviewed general strategies to minimize jet lag. As already noted in the present review, the human circadian pacemaker consists of two distinct oscillators that separately regulate the circadian rhythms of body temperature and melatonin and that of the sleep-wake cycle. These two oscillators differentially respond to photic and non-photic time cues such as social sched-ule and physical exercise. The central oscillator is located in the SCN, which mainly entrains to the environmental LD cycle, whereas another subservient (slave) oscillator is thought to be located in the brain outside of the SCN and entrains to non-photic time cues. Moreover, the non-photic time cues may feed back to the central oscillator via their actions upon the slave oscillator and the sleep-wake cycle. Furthermore, recent advances in molecular biology reveal that most peripheral organs also have self-sustained circadian clocks, so-called “peripheral clocks”49). Although the peripheral clocks are generally regulated by a circadian signal from the central circadian


temperature by vasodilation65,66), this effect is believed to contribute to the soporific effect of melatonin. As noted above, sports performance is associated with body tem-perature, and so ingestion of melatonin at some times would lead to an undesirable decrease in body tempera-ture and increase sleepiness, which might negatively affect sports performance. More practically, melatonin ingestion in the evening after an eastward flight is a use-ful strategy because both the soporific and chronobiotic effects require ingestion at this time and any negative ef-fects will have worn off by the next day.

Conclusions

Bright light and physical exercise affect circadian rhythms and the sleep-wake cycle differently. Effects of physical exercise on the human circadian system depend upon the lighting conditions, a bout of exercise being less effective in dim light. Physical exercise under dim light mainly affects the sleep-wake cycle but also acts as a weak zeitgeber for the circadian rhythm of plasma mela-tonin. By contrast, physical exercise under bright light can produce a larger phase shift of the circadian rhythm of plasma melatonin when compared with the effects of bright light alone. Strategies to minimize jet lag are now known, but further integrative studies are needed to assess if such strategies help athletes in practice and enable them to maintain sports performance in competition.

advance (2.0 h) than the dim light group (0.6 h), the inter-mittent light group showing intermediate phase advances (1.5 h). This same group then examined the effect of dif-ferent rates of daily advance of the habitual sleep sched-ule (1 h/day or 2 h/day) for 3 days, the bright light being given in the morning after waking63). The mean of phase advances were not significantly different between the two groups, but the sleep quality in the group whose schedule was advanced by 2h/day was significantly impaired over the 3 days in comparison with the group whose schedule had been advanced less each day. Thus, in order to main-tain sleep quality, the rate of shifting the sleep schedule before the flight must be considered. Taken together, this evidence indicates that a gradual shift of the sleep schedule, using bright light given im-mediately after waking, can be used to reduce jet lag after arriving in the new time zone, since the circadian rhythms will have already have adjusted to some extent, so decreasing the amount of adjustment required after the flight. Ingestion of exogenous melatonin (or a melatonin re-ceptor agonist) has the ability to phase-shift circadian rhythms. The direction of phase shift depends on the time of ingestion. Melatonin produces phase advances when taken in the evening (before bedtime) and phase delays when taken in the morning (after waking up)64). That is, it acts as a chronobiotic. The phase-shifting effect of mela-tonin ingestion results because the circadian pacemaker in the SCN has type1 and type 2 melatonin receptors. Mela-tonin ingestion also has a direct effect to decrease body

Fig. 9 Recommendations for the use of bright light to facilitate the re-entrainment of circadian rhythms by exposure to bright light after time-zone transitions.

Fig. 9 assumes a core body temperature minimum (and cross-over of the light PRC) at 04.00 h “body time”, the main time for light exposure to produce a phase delay being 21.00-03.00 h “body time”, and the main time for light exposure to produce a phase advance being 05.00-11.00 h “body time”. Note that, due to the tendency for antidromic re-entrainment following flights to the east across more than 9 time zones, it is recommended that these be treated as flights to the west (eastward across X time zones = westward across [24-X] time zones) and light used to promote a phase delay. (Modified from Waterhouse et al. 2007)48)


Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this article.

Acknowledgments

Due to space limitations, we were, unfortunately, unable to com-ment on all of the relevant studies and thus apologize for not citing all pertinent references. This work was supported by Grants-in-Aid for Scientific Research (C) (No.16K01723) (to Y.Y.) from the Ministry of Education, Culture, Sports, Science and Technology.

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phase-adjustment of human circadian rhythms by light and

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