mise à jour du
19 avril 2009
Brain &
A newly proposed disease condition produced by light
exposure during night: Asynchronization
Jun Kohyama


1. Introduction
The suprachismatic nucleus (SCN) is the site where circadian rhythms are generated. The SCN develops throughout the course of gestation, but is still immature for some time after birth. The SCN is suggested to be vulnerable to maternal influences [1]. Since disturbances of circadian rhythms in the young can impact the function of the SCN in the subsequent lifespan, techniques
to deal with them are much needed. However, we have little knowledge about the pathophysiology of the disruption of circadian rhythms in the clinical setting, making it difficult to find an appropriate clinical approach to treat these patients. It is very difficult at present to take adequate measures against circadian disruptions in patients.
This review article introduces the recent phenomenon of a nocturnal lifestyle among preschoolers/pupils/students in Japan, and the association between this nocturnal lifestyle and behavior. Then, the presumed involvement of the biological clock and the serotonergic
system in those who prefer a nocturnal lifestyle are reviewed. Finally, a new clinical entity - asynchronization - is proposed, in an attempt to elucidate the pathophysiology of circadian disruptions from which many preschoolers/pupils/students in Japan are evidently suffering, and to provide new clinical therapeutic approaches.
2. The recent phenomenon of a nocturnal lifestyle among preschoolers/pupils/students in Japan
2.2. Complaints of preschoolers/pupils/students in Japan in recent years
In 1979, 8.1% of children attending day nurseries in Japan were reported as yawning frequently in the morning, and 10.5% as becoming easily tired, while these numbers increased remarkably in 2000 to 53.2% and 76.6%, respectively [14]. Accordingly, approximately 80% of kindergarten and nursery school teachers reported that many children are sleep deprived [15].
"Yougokyouyukennkyuukai" (an association of nurse teachers in Tokyo) [16] reported that the rates of pupils and students who complained of sleepiness during the third and fourth lesson periods in the school (approximately from 10:00 to 12:00) were 50% for fifth and sixth grade elementary school boys, 60% for fifth and sixth grade elementary school girls, 70% for junior high school student boys, and 80% for junior high school student girls. In contrast to the early morning (around 4:00) and afternoon (around 14:00) periods, the late morning is the period when humans generally tend to be most alert and active [17].
In addition, according to "Zenkokuyougokyouinkai" [8], sleep insufficiency was reportedly felt by 47.3%, 60.8%, and 68.3% of fifth grade elementary school pupils, second grade junior high school students, and second grade senior high school students, respectively. The reasons given for the state of sleep insufficiency indicated by these pupils and students are shown in Table 1. Among these reasons, "hard to fall asleep" was listed among the top three reasons in all three age groups.
Kaneita et al. [18] conducted a nationwide study to ascertain the prevalence of insomnia, its symptoms, and associated factors among students in junior and senior high schools in Japan. A total of 103,650 adolescents responded, and 102,451 questionnaires were analyzed. The prevalence of a difficulty in initiating sleep, difficulty maintaining sleep, and early morning awakening was 14.8%, 11.3%, and 5.5%, respectively. Insomnia was defined as the presence of one or more of these three symptoms. The prevalence of insomnia was found to be 23.5%.
Taking these facts together, preschoolers/pupils/students in Japan are likely to be suffering from both daytime sleepiness and nocturnal insomnia. In a study of 9261 junior high school students (mean age of 12.8 years) in Toyama prefecture, Japan, Gaina et al. [19] found that (1) a total of 2328 students (25.2%) reported sleepiness almost always and 4401 (47.6%) reported sleepiness often, (2) reduced sleep time was significantly associated with sleepiness, and (3) a dose response relation was found between sleepiness and sleep disturbances, physical activity, and media contact time. They concluded that sleep insufficiency is the main cause of daytime sleepiness in junior high school students in Japan, and that proper sleep habits, a high physical activity level, and limited TV viewing time should be promoted among junior high school students.
Exercise is one of the issues cited as important for good sleep hygiene [20], and an association between the duration of television viewing and the irregularity of sleep habits in young children has been described [21]. Television viewing in childhood and adolescence is reported to be associated with being overweight, poor fitness, smoking, and raised cholesterol in adulthood [22]. According to Gaina et al. [23], watching television along with playing videogames for a long period of time were significantly associated with prolonged sleep onset latency, which is associated with poor sleep hygiene and insufficient sleep time. Lack of sleep increases body weight [24]; being overweight tends to reduce physical activity, and a low physical activity level in turn tends to exacerbate being overweight. Low physical activity and excessive media exposure are likely to be factors that increase inadequate sleep hygiene, which can result in insomnia. In addition, lack of discipline in the home and in the public education system, and the prevalence of shopping centers that are open 24h per day may stimulate the increase in insomnia. The insomnia induced by inadequate sleep hygiene can then lead to the reported sleep
insufficiency and daytime sleepiness of pupils/students in Japan. This might be the reason why pupils/students in Japan are suffering from both daytime sleepiness and nocturnal insomnia.
According to research in March 2001 in Tokyo [6], three major complaints of elementary school pupils were "persistent need to yawn" (62%), "desire to sleep" (58%), and "desire to lie down" (47%). Complaints of junior high school students were "desire to sleep" (boys/girls; 73.8%/80.8%), "persistent need to yawn" (43.6%/ 69.1%), and "desire to lie down" (43.2%/47.2%). The other complaints raised by more than 20% ofjunior high school students were "hard to remember" (35.2%/ 33.6%), "hard to be active" (21.3%/28.0%), "hard to concentrate" (21.0%/23.8%), "irritated" (20.5%/24.2%), "hypersensitive" (20.0%/27.0%), "neck stiffness" (29.30/o/35.1%), and "lumbago" (26.50/o/23.2%). Irritability, concentration and attention deficits, reduced vigilance, distractibility, reduced motivation, anergia, dysphoria, fatigue, restlessness, incoordination, and malaise were issues that the International Classification of Sleep Disorders-2 (ICSD-2) [25] has described as associated features of behaviorally induced insufficient sleep syndrome. It should be noted that a not insignificant number of pupils/students in Japan complain about precisely these issues. Are these complaints explained only by sleep insufficiency? As mentioned previously, bedtime delay in youngsters reduces total daily sleep duration [4], and approximately 80% of kindergarten and nursery school teachers reported that many children are sleep deprived [15]. In fact, sleep deprivation has been demonstrated to exert a negative effect on daytime functioning [26-28], general well-being [29], metabolic and endocrine function [30,31], and body weight [24].
However, the required sleep duration of an individual person is very difficult to determine, because the need for sleep is variable and depends on several factors [32]. In adults there are people who normally sleep for both long and short periods, and such habits are considered to develop at a young age [25]. However, such individual differences should not be taken to say that people do not need to take care of their sleep duration. In general, the late morning is the period when humans tend to be most alert and active [17]. If people are alert and active during the late morning, their sleep duration, sleep quality, and life rhythms are likely healthy.
3. Nocturnal lifestyles and behaviors
A shortage of sleep, and delayed bedtimes and wakeup times are known to produce physical, mental, and/or emotional problems.
3.2. Studies on preschooler
3.2.1. Child behavior checklist (CBCL) and sleep habits
3.2.2. The ability to copy a triangle and sleep habits
3.2.3. Physical activity and sleep habits
4.1. Biological clock and desynchronization
Circadian signals from the SCN come to the dorsomedial nucleus of the hypothalamus via the subparaventricular zone. The dorsomedial nucleus of the hypothalamus combines inputs from the SCN with those from other areas, allowing for flexible control, and sends signals to structures that regulate various circadian rhythms such as feeding, locomotion, sleep wake alternation, corticosterone secretion [49], and the autonomic nervous system [50]. The endogenous period of the circadian clock of most people is longer than 24 h, and it is through exposure to sunlight in the morning people are entrained to the Earth 24 h cycle [51]. Conversely, light exposure at night delays the phase of the circadian clock [51] or disrupts its function [52]. In addition, bright light during night decreases the secretion of melatonin [53], which shifts circadian phase, acts as a hypnotic, is an effective free radical scavenger and antioxidant, and induces the expression of gonadotropininhibitory hormone. Non-photic cues, e.g., the timing of feeding [54], activity [55], etc. also serve to synchronize the circadian system to the 24 h day. In the absence of such time cues, our daily rhythms are apt to become altered, and show their own rhythm. After spending life under such conditions for a considerable period of time, the staging of various biological rhythms, such as sleep-wakefulness and temperature, has been shown to change [56]. Under such conditions, reciprocal phase interactions within the circadian rhythms are disturbed. In general, most people spontaneously wake-up in the morning when body temperature begins to rise from its lowest level, and fall asleep in the evening when body temperature begins to decline from its highest level. However, once the reciprocal interaction is impaired, the phase relationship between body temperature and sleep wake circadian rhythms is disrupted [56]. This condition, which is known as circadian desynchronization [57,58], may produce various physical and mood disturbances (disturbed nighttime sleep, impaired daytime alertness and performance, disorientation, gastrointestinal problems, loss of appetite, inappropriate timing of defecation, excessive need to urinate during the night). Similar complaints and mood alterations are observed in patients with jet lag [59], seasonal affective disorder [60] and in astronauts [61].
Kerkhof and Van Dongen [62] have reported that the endogenous phasing of the circadian biological clock of morning-type individuals differs from that of eveningtype individuals. According to Bailey and Heitkemper [63], evening-type individuals have a later morning temperature rise, and later wake-up time than morning types. Moreover, individuals who are at their most alert in the morning have an earlier peak in their temperature circadian rhythm than individuals who are most alert in the evening [64]. These reports suggested that eveningtype individuals suffer from circadian desynchronization [57,58]. Taking these reports into consideration, those with delayed wake-up times, delayed bedtimes, and an irregular lifestyle (an evening preference) are hypothesized to suffer from circadian desynchronization.
Arendt et al. [59] showed that the rate of recovery from jet lag, whose symptoms may be ascribed in large part to temporary circadian desynchronization, varies with individuals, as well as with the direction of time zone change. The susceptibility for manifesting symptoms, presumably due to desynchronization, is likely to be different in different individuals. In this regard, the following reports suggest that susceptibility to desynchronization is affected by biological background.
Nilssen et al. [65] compared the prevalence of sleep problems in two ethnically different populations living under the same extreme arctic climate. A total of 453 Norwegians (319 males and 134 females) were compared with 450 Russians (317 males and 133 females), all aged 18 years or older, living in Svalbard, the northernmost regular settlement in the world. In Russians, 81% of the male subjects and 77% of the female subjects reported sleeping problems lasting for at least 2 weeks. The corresponding figures for the Norwegians were 22% (for males) and 25% (for females). Whereas sleeping problems among Norwegians were approximately equally frequent throughout the year, Russians reported more problems during the polar night. The 1 year prevalence of self-reported depression in the same two ethnically different populations was also compared [66]. Among Russians, the 1 year prevalence of self-reported depression lasting for at least 2 weeks was 26.8% for men and 44.7% for women. The corresponding figures
for Norwegians were 10.7% and 15.6%. For the period with the polar night the figures were 5.5% and 6.7% for Norwegian men and women, respectively, and 21.7% and 37.1% for Russian men and women, respectively. More than 50% of the Norwegian population in these studies [65,66] came from the northern part of Norway, whereas the Russian subjects were mostly recruited from the southern part of Russia and from the Ukraine. Nilssen et al. [65,66] postulated that insufficient acclimatization after migration to the north is essential for understanding these results. The susceptibility to manifesting symptoms that are presumably due to desynchronization is likely to be affected in part by unknown biological background factors, including acclimatization that cannot be altered at least within one generation.
4.2. Serotonergic system
5.2. Proposal of asynchronization
Aschoff and Wever described in 1976 [105] that the activity rhythm (wakefulness and sleep) and other rhythmic variables (e.g., temperature) often have the same circadian period of approximately 25 h, but on occasions the activity period may become substantially longer (e.g., 33 h), while the other rhythms continue with a period of about 25 h. Such a state is termed internal desynchronization. Thus, circadian desynchronization is the term used to indicate a loss of the coupling of phases between phenomena leading to circadian oscillation. It should be noted that this term came from basic studies and was not originally a clinical-oriented term.
Many preschoolers/pupils/students in Japan who exhibit delayed wake-up times, delayed bedtimes, and an irregular lifestyle may have a loss of the coupling of phases between phenomena that lead to circadian oscillation, and a decrease in amplitudes of certain other phenomena, although no concrete evidence has been as yet obtained. Desynchronization by itself is not an adequate term to describe the conditions from which many preschoolers/pupils/students in Japan are suffering. In addition, reduced serotonergic activity or serotonindepleting condition is likely to be present in some of them. A novel clinical notion is needed to improve the understanding of the pathophysiology of the disturbances of these preschoolers/pupils/students. This new entity should contribute to both increased understanding and help ameliorate the problems of many preschoolers/pupils/students in Japan. The term "asynchronization" is meant to designate the conditions that many preschoolers/pupils/students in Japan with delayed wake-up times, delayed bedtimes, and an irregular lifestyle have displayed. Although asynchronization is a clinical-oriented term, this term was chosen in consideration of the recent discovery of a "singularity behavior" in mammalian circadian clocks [52].
In 1970, Winfree [106] reported that a specific dim blue light pulse stimulus with a unique stimulus time and duration resulted in unusual broadening of the daily eclosion peaks of the fruitfly, Drosophila pseudoobscura, even to the extreme of obscuring the circadian rhythm. This phenomenon is called "circadian singularity behavior", and has been shown in a range of organisms such as algae, plants, and mammals [107-112], suggesting that it is a shared phenomenon among all circadian clocks. In humans, Jewett et al. [109] reported that circadian rhythms in rectal temperature and plasma cortisol were abolished by a single, long duration, bright light pulse given during one or two successive circadian cycles. At the molecular level, Huang et al. [113] demonstrated that both temperature increase and light pulses can trigger singularity behavior in Neurospora circadian clock gene frequency. Ukai et al. [52] reported that a critical light pulse (3 h light pulses delivered at an approximately specific circadian time (CT) 17 (near subjective midnight (=CT 18))) drives cellular clocks into singularity behavior in mammals. Interestingly, this phenomenon is transient [113], although the removal of the stimulus is needed.
The essence of asynchronization is the disturbance of various aspects (e.g., cycle, amplitude, phase and interrelationship) of the biological rhythms that normally exhibit circadian oscillation, presumably involving decreased serotonergic system activity. The major trigger of asynchronization is hypothesized to be a combination of light exposure during the night and a lack of light exposure in the morning. Asynchronization results in the disturbance of variable systems. Thus, symptoms of asynchronization (Table 6) include disturbances of the autonomic nervous system (sleepiness, insomnia, disturbance of hormonal excretion, gastrointestinal problems, sympathetic nervous system predominance, etc.) and higher brain function (disorientation, loss of sociality, loss of will or motivation, impaired alertness and performance, etc.). Neurological (attention deficit, aggression, impulsiveness, hyperactivity, etc.), psychiatric (depressive disorders, personality disorders, anxiety disorders, etc.) and somatic (tiredness, fatigue, neck and/or back stiffness, headache, etc.) disturbances are also putative symptoms of asynchronization. The complaints introduced in this article (disturbances of higher brain function; memory problems, concentration problems, neurological disturbances; irritation, hypersensitivity, somatic disturbances; persistent yawn, desire for sleep, wish to lie down, inactivity, neck stiffness, lumbago) could be symptoms of asynchronization.
To detect the disturbance of the biological rhythms, actigraphic recordings [114] as well as the diurnal measuring of body temperature, corticosteroids and melatonm must be useful. Takimoto et al. monitored human clock genes in whole blood cells to evaluate internal synchronization [115].
The early phase of asynchronization is hypothesized to be very similar to desynchronization. During this phase, disturbances are functional and can be resolved relatively easily by the establishment of a regular sleep wakefulness cycle; however, without adequate intervention disturbances can gradually worsen, involving a decrease in serotonergic activity, and can become difficult to resolve. In Fig. 1, red lines, especially the broad ones, are hypothesized to be involved in asynchronization. A portion of the patients with chronic fatigue syndrome, orthostatic dysregulation, burnout, vital exhaustion, fibromyalgia, and depression are suggested to be suffering from asynchronization.
Circadian singularity behaviors are similar to the concept put forward here, asynchronization. The early phase of asynchronization is hypothesized to be a very similar condition to desynchronization. Ukai et al. [52] also demonstrated that desynchronization of individual
cellular clocks underlies singularity behavior. Although it is hypothesized that asynchronization is difficult to resolve, circadian singularity behavior has been shown to be reversible. According to Ukai et al. [52], a light pulse at CT 9-15 (transition from subjective day to night) reversed circadian singularity behavior. In addition to removing stimuli that induce circadian singularity behavior, an investigation to identify adequate stimuli to reverse circadian singularity behavior in the clinical setting should be undertaken. Respiration. Qigong is an ancient oriental mindful exercise [159], also described as a mind-body integrative exercise or intervention from traditional Chinese medicine which is used to prevent and cure ailments, as well as to improve health and energy levels [160]. According to Wikipedia [161], Qigong (or ch'i kung) refers to a wide variety of traditional "cultivation" practices that involve movement and/or regulated breathing designed to be therapeutic. Qigong is practiced for health maintenance purposes, as a therapeutic intervention, as a medical profession, a spiritual path and/or component of Chinese martial arts. The 'qi' in 'qigong' means breath or gaseous vapor in Chinese, and, by extension, 'life force', 'energy' or even 'cosmic breath'. 'Gong' means work applied to a discipline or the resultant level of skill, so 'qigong' is thus 'breath work' or 'energy work'. Qigong recently can be considered as an alternative therapy to help meet the increasing demand of non-pharmacologic modalities in achieving biopsychosocial health for those suffering from anxiety [159] or for treating pain [162]. Although thus far obtained from meta-analyses based on low-quality studies and small numbers of hypertensive participants, Qigong and Zen practitioners meditation have been shown to significantly reduce blood pressure [163].
Zen practitioners conduct "tanden breathing" that involves slow breathing (range of 0.05-0. 15 Hz) into the lower abdomen [164]. Tanden breathing was found to affect the cardiac variability which is controlled by the autonomic nervous system. Although rhythmical respiration is reported to activate serotonergic activity [68], Arita and Takahashi [165] preliminarily found that tanden respiration elevates serotonergic activity. Other rhythmic movements. Chewing is reported to activate serotonergic activity [68,166]. This behavior could potentially be applied in managing asynchronization through deliberately activating serotonergic activity.
Segawa reported [167] that failure in locomotion (crawling) during infancy (=failure in interlimb coordination between the upper and the lower extremities) is caused by the hypofunction of the serotonergic and/ or noradrenergic neurons that resulted in postural atonia by disfacilitating the postural augmentation pathways and/or disinhibiting the postural suppression pathway and preventing locomotion [168]. Segawa also described that forced crawl training could relief symptoms resulted from low serotonergic activity [169].
6. Conclusions
Many children in Japan, from youngsters to senior high school students, suffer from both daytime sleepiness and nocturnal insomnia, and are persistently tired and inactive. Are these complaints explained only by sleep insufficiency? This article focused on the association between nocturnal lifestyle and the problems of these preschoolers/pupils/students with special reference to the biological clock and the serotonergic system, although involvements of dopamine [170], opioid peptide [89] and so on are also possible. A novel clinical concept - asynchronization - is proposed and a similar basic concept - singularity - is introduced.
For adolescents, Gaina et al. [23] and Gau et al. [40] have recommended morning-type behavior for reducing behavioral/emotional problems. Yokomaku et al. [44] suggest that this recommendation should extend to preschoolers. Ayurveda, an ancient system of health care that is native to the Indian subcontinent, tells us that in addition to good conduct, thought, diet, interpersonal dealings and physical activity, early awakening, and going to bed early are good for a healthy life [171]. Ekken Haibara wrote in his essay that one should wake-up early in the morning and should avoid a late bedtime to live a healthy life [172]. Byoukesuchi, a book describing medical practices needed at home, said that one should go to bed early at night and wake-up before dawn to spend a healthy life [173]. Although the authors of these texts did not know about biological clocks or the serotonergic system, they all recommended early awakening and going to bed early, probably because they observed people felt and performed better when they followed these habits. Thus, both traditional wisdom and recent research recommend morning-type behavior. However, the advantages of evening-type behavior should be mentioned. For example, those with a preference for evening-type behavior are known to find it easier to adjust to conditions with a disturbed circadian rhythm such as jet lag than those with a preference for morning-type behavior [174] although the life span of hamsters with frequent phase shifting is reported to be shortened.
Senior high school students in Korea are reported to go to bed (0:54 on school nights) [176] later than those in Japan (0:06 [7] or 23:50 [8]). Although Chinese senior high school students in Hong Kong went to bed earlier (23:24) than those in Japan, it was concluded that they did not get enough sleep [177]. In addition, some of those who are called NEET (Not in Employment, Education, or Training) [178] might be suffering from asynchronization. The introduction of asynchronization is expected to help advance the understanding of the pathophysiology of an evening-type behavior preference that affects many children/pupils/students in Japan and other countries, and to provide methods for both investigating and treating it. The author hopes that such progress will contribute to both the protection from and treatment of those suffering from asynchronization, and also help prevent the next generation from developing circadian disruptions at an early stage of life.