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Sleep health and asynchronization
Brain & Development 33 (2011) 252–259 www.elsevier.com/locate/braindev
Review article
Sleep health and asynchronization Jun Kohyama ⇑ Tokyo Bay Urayasu/Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001, Japan
Abstract Recent surveys in Japan reported that more than half of children interviewed complained of daytime sleepiness, approximately one quarter reported insomnia, and some complained of both nocturnal insomnia and daytime sleepiness. To explain the pathophysiology of this type of sleep disturbance, a novel clinical concept of asynchronization has been proposed. Asynchronization involves disturbances in various aspects of biological rhythms that normally exhibit circadian oscillations. The putative major triggers for asynchronization include a combination of nighttime light exposure, which can disturb the biological clock and decrease melatonin secretion, and a lack of morning light exposure, which can prohibit normal synchronization of the biological clock to a 24-h cycle and decrease activity in the serotonergic system. The early phase of asynchronization may be caused by inadequate sleep hygiene, is likely to be functional, and to be relatively easily resolved by establishing a regular sleep–wakefulness cycle. However, without adequate intervention, these disturbances may gradually worsen, resulting into the chronic phase. No single symptom appears to be specific for the clinical phases, and the chronic phase is defined in terms of the response to interventions. The factors causing the transition from the early to chronic phase of asynchronization and those producing the difficulties of recovering patients with the chronic phase of asynchronization are currently unclear. Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Melatonin; Serotonin; Circadian singularity; Social jet lag
1. Introduction This mini-review first describes the neurological systems involved in circadian disruptions, then discusses the recently developed clinical concept of asynchronization of circadian function [1–4]. Because of space limitations, citations are restricted to recent studies. Please refer to other reviews by the author [2–4] for a more detailed list of references. The key features of adequate sleep hygiene are summarized in Table 1. These features are often used in addition to the diagnostic criteria for insomnia due to inadequate sleep hygiene [5], characteristics of the biological clock [2–4], and food-anticipatory rhythms. Many individuals living in modern societies do not achieve adequate sleep health. The term ‘social jet lag’ has been used to describe ⇑ Tel.: +81 47 351 3101; fax: +81 47 352 6237.
E-mail address: [email protected].
cases where an individual’s circadian rhythms are out of phase with their daily schedule, a condition characterized by delayed wake-up times, delayed bedtimes, and an irregular lifestyle [6,7]. Approximately one quarter of the world’s population is subjected to a 1-h time change twice a year (daylight savings time; DST). DST is known to disturb the typical seasonal changes observed in sleep timing, as assessed by the duration of mid-sleep times. In addition, the beginning of DST (i.e. spring) is associated with an increase in rates of traffic accidents and myocardial infarctions. DST thus appears to produce social jet lag in a huge number of people. In addition, more than 2.1 billion people used air travel in 2006, meaning that a substantial proportion of the population also suffers from travel-related jet lag. Because circadian rhythm problems are so common, there is an urgent need for the development of effective treatment strategies. A survey in Japan revealed that more than half of the preschoolers/students interviewed
0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.09.006
J. Kohyama / Brain & Development 33 (2011) 252–259 Table 1 Healthy sleep habits (Sleep Health Practice/Treatment; SHP/T). 1 2 3 4 5 6
Increase exposure to morning light Engage in physical activity during daytime Sleep in the dark during the night (i.e. turn off all artificial lighting) Eat regular meals Avoid substances that disturb sleep (e.g. caffeine, alcohol, nicotine) Avoid excessive media exposure (e.g. video games, computers, television)
complained of daytime sleepiness, while approximately one quarter of junior high school students reported suffering from insomnia [8–12], most likely resulting from inadequate sleep hygiene. However, the provision of adequate sleep hygiene is often ineffective as a therapeutic approach. This suggests that unknown factors or neuronal mechanisms may prevent recovery from insomnia and daytime sleepiness. In the 2nd edition of the international classification of sleep disorders [5], inadequate sleep hygiene is listed as a cause of insomnia. However, this classification does not describe any disorders involving insomnia, hypersomnia and circadian rhythm disruptions due to inadequate sleep health [5]. In addition, rhythm disruptions resulting from delayed wake-up times and bedtimes and irregular lifestyles are reported to be associated with problematic behaviors [2–4,8] regardless of sleep duration [13]. Asynchronization was thus developed as a novel clinical concept to explain the pathogenesis/pathophysiology of a condition involving insomnia, hypersomnia and circadian rhythm disruptions [2–4], and includes the concept of social jet lag. 2. Neurological systems involved in circadian disruptions 2.1. Biological clock Light stimuli are conveyed to the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract, and activate the N-methyl-D-aspartate (NMDA)/nonNMDA receptors of the SCN. Signals from the SCN regulate various circadian rhythms, including feeding, locomotion, sleep–wake alternation, corticosterone secretion [14], and the autonomic nervous system. Morning exposure to sunlight leads individuals to become accustomed to a 24-h light–dark cycle. Conversely, light exposure at night can delay or retard the circadian clock phase and disrupt its functioning [15]. Nevertheless, people commonly continue to live under conditions of widespread, nocturnal, bright, artificial light. Nonphotic cues, such as physical activity, social factors, and eating time also serve to synchronize the circadian system to a 24-h day. A self-assessment questionnaire has been developed to classify individuals as morning-type or evening-type (i.e. lark or owl chronotypes) [16]. Endogenous phasing of the circadian biological clock in morning-type individuals
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varies from that of evening-type individuals [17], who experience a temperature rise later in the morning and later waking times [18]. Moreover, individuals who are alert in the morning experience earlier circadian rhythm temperature peaks than individuals who are alert in the evening [19]. A recent study examining the molecular rhythms of people classified as ‘larks’ or ‘owls’, as assessed by the Bmal1 expression of skin cells, reported that cells taken from larks exhibited shorter molecular periods than those taken from owls [20]. However, approximately half of the lark and owl cells exhibited ‘normal’ circadian period lengths, and the cellular clocks of owls were generally more difficult to reset than those of individuals with more typical schedules, whereas the larks’ cellular clocks were more easily reset. These findings suggest that individual differences in chronotype can result from innate differences in circadian period length and the ease with which an individual’s rhythms can be synchronized to the night/day cycle. 2.2. Melatonergic system Melatonin acts as a hypnotic and an effective freeradical scavenger and antioxidant. It has been found to regulate the circadian phase, and is implicated in inhibiting cancer development and growth. Exposure to bright light during the night has been found to decrease melatonin secretion. The onset of melatonin secretion typically begins 14–16 h after waking, around dusk. Exposure to bright, midday light has been shown to increase melatonin secretion during the night, without a circadian phase shift. Preliminary results from a study of 3-year-old children suggest that early sleepers tend to exhibit higher levels of urinary 6-sulfatoxymelatonin (6SM, assessed by the 6SM/creatinine ratio), the primary melatonin metabolite, compared with late sleepers. In accord with this result, decreased melatonin levels in aged zebrafish have been shown to correlate with altered circadian rhythms. In contrast, alterations in melatonin rhythms were reported to have no effect on the circadian rhythms of locomotor activity and body temperature in rats. Synthesized melatonin receptor agonists may have clinical value for the treatment of insomnia. Ramelteon, one of the melatonin agonists available in Japan, has been found to exert sleep-inducing effects in humans [21]. This compound stimulates both MT1 and MT2 receptors [22]. Activation of MT1 receptors in the SCN [23] inhibits the activity of SCN in rats [24], and that of MT2 receptors exerts phase-advancing effects on SCN cell activity in rats [23]. In humans, melatonin exerts phase-advancing effects when administered in the evening [25]. Ramelteon may thus be expected to exert phase-altering effects in humans, but the sleep inducing effects of this drug in humans remain to be fully characterized.
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2.3. Serotonergic system Exposure to morning light can activate the serotonergic system, whereas nocturnal lifestyles lacking morning light exposure are unlikely to cause activation. The serotonergic system is activated through rhythmic movements, such as gait, chewing and respiration. Thus, adequate physical activity may be important for serotonin activation. Exercise-derived benefits for brain function have been demonstrated at the molecular level, and physical activity has been reported to decrease the risk of Alzheimer’s disease. A study by Kennaway et al. reported that activation of 5-HT2C, similarly to a light pulse, produced long-lasting phase shifts in the melatonin rhythm, but his effect was blocked by a 5-HT2C antagonist [26]. There is also evidence that serotonin is capable of phase-advancing the master pacemaker oscillation when applied during the subjective day, and inhibiting light-induced phase shifts during the subjective night [27]. Low serotonin syndrome, involving aggressiveness, impulsivity, and suicidal behavior, has been proposed as a clinical condition. In male adult vervet monkeys, an association was found between decreased serotonergic activity and a disadvantage in attaining high social status, while enhanced activity was related to a status advantage. Based on animal experiments and post-mortem human anatomical and neurochemical data, disturbances of the lateral orbito-prefrontal circuit have been found to induce aggressive behavior and a loss of sociability, and the serotonergic system has been shown to activate this circuit. Serotonin levels have also been shown to enhance learning abilities. Serotonergic activity is profoundly affected by the sleep–wakefulness cycle, exhibiting maximal activity while waking and the lowest activity during rapid eye movement sleep. Taken together, these findings suggest that an irregular sleep–wakefulness rhythm disturbs emotional control and sociability due to decreased serotonergic activity in the lateral orbito-prefrontal circuit. 2.4. Other systems Glycine ingestion before bedtime has been found to significantly improve subjective sleep quality among individuals with insomniac tendencies [28]. Oral administration of glycine in rats was found to induce a significant increase in the glycine concentration in the plasma and cerebrospinal fluid, and a significant decrease in core body temperature, associated with an increase in cutaneous blood flow. The NMDA receptor in the SCN is thought to be involved in sensing increases in CSF glycine concentration [29]. In addition, other compounds are also likely to be involved in the control of insomnia, hypersomnia and circadian oscillations, including the wakeand sleep-promoting/inhibiting systems [3], dopamine, neuropeptide Y, ghrelin [30], and opioid peptides.
Describing the details of these systems is beyond the scope of the current review. 3. Desynchronization In the absence of time cues, daily rhythms can become altered and develop their own rhythm. After living under unusual sleep conditions for a considerable period of time, reciprocal phase interactions within the circadian rhythm, such as sleep–wakefulness and temperature, tend to become disturbed. Humans typically wake in the morning when their body temperature begins to rise from its lowest level and fall asleep at night when their body temperature begins to decline from its highest level. However, if this reciprocal interaction is impaired, the phase relationship between body temperature and sleep–wake circadian rhythms can become disrupted. This phenomenon has been termed ‘circadian desynchronization’ on the basis of basic science studies, but this term is not used clinically. This type of disruption is proposed to produce various physical and mood disturbances, such as disturbed nighttime sleep, impaired daytime alertness and performance, disorientation, gastrointestinal problems, loss of appetite, inappropriate timing of defecation, and excessive need to urinate during the night. Similar complaints and mood alterations have been observed in patients with jet lag or seasonal affective disorder, as well as in most astronauts during space travel. It should also note that evening-type individuals are suggested to be more likely to suffer from circadian desynchronization [31,32]. External and internal desynchronization are described as two of the three major components involved in jet lag, in addition to sleep deprivation. External desynchronization refers to conflict between the internal clock and external time cues. As an individual is exposed to new external time cues following travel, their internal clock can adjust to a time zone, sometimes over the course of several days. Internal desynchronization (i.e. a loss of phase-coupling between phenomena that act as circadian oscillation cues) takes place during the readjustment of internal clocks, with each system adjusting itself independently. That is, in a state of internal desynchronization, peripheral clocks function without synchrony. Internal desynchronization can also be induced by acute manipulation resulting in phase alteration, as in the case of jet lag. Sleep loss can occur as a result of internal and external desynchronization, decreasing the prevalence and performance of physical and mental activities. This can ultimately result in a decrease in serotonergic activity, presumably due to a lack of rhythmic activity. Interestingly, the rate of recovery from jet lag varies between individuals, as well as with the direction of time zone change. For transmeridian travelers, both physical cues, such as daylight and darkness, and social cues such as mealtimes and noise, encourage realignment of the circadian
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system. In contrast, for shift workers, physical cues (and most social cues) are often opposed to nocturnal alignment in day-oriented societies. Therefore, circadian realignment for shift workers often takes longer than realignment from jet lag. A World Health Organization report concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” [33]. Reduced activity of the melatonergic system is a hypothesized causative factor involved in the association between circadian disruption and cancer. In addition, a forced, abnormal schedule can induce desynchronization. Based on the findings discussed above, modern lifestyles involving widespread exposure to artificial bright light may thus be expected to produce effects similar to shift-work related disorders or social jet lag. 4. Asynchronization 4.1. Requirement for categorization of asynchronization as a novel clinical entity In Japan, several surveys [8–12] have revealed that more than half of the preschoolers/students questioned complained of daytime sleepiness, while approximately one quarter of junior high and high school students reported suffering from insomnia. These results suggest that many young people in Japan are persistently tired and inactive. The common complaints of these subjects included the desire to sleep, a persistent need to yawn, a desire to lie down, eyestrain, memory difficulties, and neck stiffness, among others. These symptoms are similar to the associated features of behaviorally-induced insufficient sleep syndrome [5], suggesting that insomnia due to inadequate sleep hygiene may produce this type of hypersomnia. Features related to inadequate sleep hygiene include low levels of physical activity (sedentary behavior), excessive media exposure, and excessive caffeine use. If inadequate sleep hygiene causes asynchronization, providing the conditions of adequate sleep hygiene/health would be expected to ameliorate the symptoms (Table 1). However, such therapeutic approaches have commonly been found to fail. Although delayed wake-up and bed times can be symptomatic of a delayed sleep phase form of circadian rhythm sleep disorder, it should be noted that there is confusion between the categorization of this disorder and the biological and lifestyle-related sleep phase delays that are especially common during adolescence. According to the diagnostic criteria, patients with circadian sleep disorders of the delayed sleep phase type or the irregular sleep–wakefulness type should both exhibit normal sleep duration for their age [5]. However, the sleep duration of many young people in Japan who exhibit intractable circadian rhythm disruptions is decreased (or varies day by day), resulting in complaints of both insomnia and hypersomnia. It is possible that unknown
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factors in addition to simple sleep loss and inadequate sleep health are involved in many cases of young people in Japan that exhibit intractable circadian rhythm disruptions and complain of both insomnia and hypersomnia. These findings suggest that the concept of circadian desynchronization is insufficient to explain such disease conditions in these young people, and that decreased activity in the melatonergic and serotonergic systems is likely to be involved. Categorization of this condition as a novel clinical entity is thus required to develop a greater understanding of the pathogenesis/pathophysiology of this disease [2–4]. In an early study, Winfree reported that a specific, dim, pulsed, blue light stimulus with a unique timing and duration resulted in unusual broadening of the daily eclosion peaks of the fruit fly, Drosophila pseudoobscura, completely obscuring the circadian rhythm in some cases [34]. This phenomenon has been termed ‘circadian singularity behavior’ and has since been described in a range of organisms including algae, plants, and mammals. In humans, circadian rhythms of rectal temperature and plasma cortisol were reported to be abolished by a single, long duration, bright-light pulse administered during one or two successive circadian cycles [35]. In addition, a critical light pulse (3-h light pulses delivered near subjective midnight) was shown to drive cellular clocks toward singularity behavior in mammals [15]. Interestingly, this phenomenon appears to be transient [36], although the removal of the stimulus is required. The novel clinical concept termed ‘asynchronization’ proposed here is based on these findings and the basic concept of circadian singularity. 4.2. Clinical phases and symptoms of asynchronization Asynchronization results from disturbed aspects (e.g. cycle, amplitude, phase, and interrelationship) of biological rhythms that normally exhibit circadian oscillation. These disruptions presumably involve decreased serotonergic and/or melatonergic activity. The major trigger of asynchronization is hypothesized to be a combination of light exposure during nighttime, which reduces melatonin secretion, and a lack of morning light exposure, which decreases serotonergic activity. Both triggers are known to disturb biological clock function in the SCN. In addition, similar to the components of jet lag, sleep deprivation may constitute part of the symptomatology of asynchronization. Sleep shortage can exert a negative effect on daytime functioning, general wellbeing, metabolic and endocrine function, body weight, susceptibility to viral infection, psychomotor skills and mood. The proposed symptoms of asynchronization include disturbances of the autonomic nervous system (i.e. sleepiness, insomnia, disturbed hormonal excretion, gastrointestinal problems, and sympathetic nervous system
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predominance), as well as higher brain function disruption (i.e. disorientation, loss of sociability, loss of will or motivation, and impaired alertness and performance). Additional putative symptoms of asynchronization include neurological (attention deficits, aggression, impulsiveness, and hyperactivity), psychiatric (depressive disorders, personality disorders, and anxiety disorders), and somatic (tiredness, fatigue, neck and/or back stiffness, and headache) disruption. The early phase of asynchronization is easily induced by delayed wake-up and bedtimes, and an irregular lifestyle, producing unsatisfactory physical, mental, and/or emotional conditions that can lead to a decreased level of physical activity. It should be noted that the symptoms of this state could be induced by inadequate sleep health. This condition is likely to be functional, and to be relatively easily resolved by establishing a regular sleep–wakefulness cycle. However, without adequate intervention, these disturbances may gradually worsen, resulting in a further decrease in physical activity and also serotonergic and/or melatonergic activity, and can be difficult to resolve. Some patients classified as suffering from the chronic phase of asynchronization have been found to exhibit a long sleep duration of more than 10 h, while some complained of insomnia due to hyperarousal conditions resulting from the presumable predominance of the sympathetic nervous system activity. These results suggest the involvement of both wakefulness- and sleep-promoting/inhibiting systems in the chronic phase of asynchronization. No single symptom appears to be specific for the clinical phases, and the chronic phase is defined in terms of the response to interventions in the novel classification proposed here. Patients with the early phase of asynchronization are likely to recover without difficulty, but those with the chronic phase are unlikely to recover easily. Pro-
viding the conditions of adequate sleep health listed in Table 1 is not an adequate therapeutic treatment for this condition. The blue lines in Fig. 1 represent vicious cycles, and the enhancement of these cycles is proposed to induce the transition into the chronic phase of asynchronization. The development of the clinical phases of asynchronization might also be affected by individual differences in how easily an individual’s rhythms can be synchronized to the night/day cycle [20]. An additional parallel assumption is that certain unknown factors (represented by the red line) act as promoters for the progression into the chronic phase of asynchronization. Most preschoolers do not progress to the chronic phase of asynchronization, and a recently examined patient suffering from asynchronization was found to have conflict with her mother, indicating that age and family context may be factors involved in the transition from the early to the chronic phase of the disorder. 4.3. Potential therapeutic approaches for treatment of asynchronization 4.3.1. Basic principles For synchronization of the biological clock to a 24-h cycle, morning light and avoidance of nocturnal light are essential. Therefore, the absence of these two elements can be considered risk factors for developing asynchronization. Steroid secretion is maximal in the morning under normal conditions, and light-induced adrenal gene expression and corticosterone release have been demonstrated experimentally. As described earlier, physical activity, social factors, and eating times are known to affect the circadian clock. Adequate physical activity (exercise), participation in social activities, and regular mealtimes are likely to prevent asynchronization. Taken together, these findings suggest that the Late bedtime (Light exposure at night)
Waking late in the morning (Lack of morning light exposure)
Inadequate sleep health (caffeine, extreme media exposure, etc)
Early phase of asynchronization Unfavorable physical & mental conditions (fatigue, pain, depressive mood, etc)
(Symptoms due to inadequate sleep health) Unknown factors? e.g. Wake/Sleeppromoting/ inhibiting systems?
Insomnia an enhancement of vicious cycles?
Sleep deficiency Daytime sleepiness
Chronic phase of asynchronization Melatonin reduction Low serotonin activity
Low physical activity
Fig. 1. Schematic diagram of the development of asynchronization. The broad blue lines constitute vicious cycles, and enhancement of these cycles is involved in the transition to the chronic phase of asynchronization. Certain unknown factors (broad red line) might act as promoters for the progression from the early to chronic phase of asynchronization.
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Saikokeishi-to (10)
Kami- shouyousan (24)
Zyuzen-taiho-to (48) and/or Ninjin-yoei-to (108)
Zyuzen-taiho-to (48) and/or Ninjin-yoei-to (108)
With insomnia Kihi-to (65) with fatigue Hochu-ekkito (41) With insomnia Kihi-to (65) Hochu-ekkito (41)
GI disturbance Anemia Depressive tendency
Saiko-karyukotuborei-to (12)
Aggressiveness or impulsiveness
Hachimiziou-gan (7)
Child patients refusing to attend school
Chronic fatigue syndrome
Rokumi-gan (88), Hochu-ekki-to (41), and Sho-Saiko-to (9) Ninjin-yoei-to (108) Fatigue syndrome
Numbers in parentheses are the standardized numbers for each prescription in Japan.
Rokumigan (87) Sinbu-to (30) or Ougiken-chu-to (98) and Ninzin-to (32)
Rokumigun (87)
Seishoekki-to (136)
Apathy Glowing (or heat sensation in the palm or foot) Systemic hypofunction and/or coldness Weakness in the lower extremities
Table 2 Examples of typical Kampo prescriptions for similar disease conditions to asynchronization.
4.3.2. Conventional and alternative approaches Light therapy, medication, physical activity and chronotherapy are conventional approaches used to treat asynchronization. Possibly useful medications include hypnotics, antidepressants, vitamin B12, melatonin and its agonists. But their actions are targeted against each symptom triggering the onset of asynchronization. Kampo medicine is a traditional Japanese herbal medicine originating from traditional Chinese medicine. Since Kampo prescription includes several components with a special distribution considering the personal characters into mind, the way of actions of Kampo is difficult to determine from the current way of analysis. However, from this not analytic but integral view point, I feel therapeutic possibilities of Kampo against patients with the chronic phase of asynchronization. Examples of Kampo prescriptions are listed in Table 2 [4]. In addition to these prescriptions, Kanbaku-taisou-to (72) (numbers in parentheses indicate standardized numbers for prescription in Japan) and Yoku-kan-san (54) are the author’s preference for patients suffering from the early phase of asynchronization and for those with presumed elevated sympathetic nervous system activity. Dai-saikoto (8) is also used to treat insomnia due to hypertension or tinnitus. Other potential alternative approaches include direct contact, autonomic nervous system control, pulsed light, and rhythmic movements such as qigong, tanden breathing, and rhythmic physical activity such as locomotion [2–4]. Maletic and Raison [37] discussed the high rates of comorbidity observed between major depression, fibromyalgia, and neuropathic pain, highlighting the role of dysregulation of stress/inflammatory pathways. In addition, patients with chronic fatigue syndrome have been found to exhibit sleep difficulties, pain, fatigue, and depressive mood alteration. Each of these disease conditions possesses a specific origin, major symptoms, and course, but circadian disruptions of various variables that normally show diurnal fluctuations are also reported in each of these disorders. It should be noted that serotonergic and melatonergic agents as well as physical activity and bright light/darkness [38] are known to exert favorable effects on some patients with these disease conditions. Although the relationship between these disease conditions and asynchronization remains to be determined, the therapeutic approaches discussed above may extend current methods for treating patients with asynchronization. For example, favorable effects of acupuncture or shiatsu (acupressure) have been reported for alleviating depression, fibromyalgia, insomnia, chronic fatigue syndrome, and sleep disturbance [2–4].
Fatigue after acute infection
social promotion of favorable sleep health, including health education beginning in the early elementary school years, may be an appropriate measure to prevent the development of asynchronization.
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These may be promising therapeutic tools for treatment of asynchronization, but appropriate diagnostic standards and methodologies as part of treatment strategies remain to be developed.
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5. Conclusions This review described the symptoms exhibited by patients suffering from an early phase of asynchronization. These symptoms overlap with the symptomatology of inadequate sleep health. The poor therapeutic responses of patients in the chronic phase of asynchronization were then discussed. Factors that induce the transition from the early to the chronic phase of asynchronization remain to be solved. Age and family context may also be factors involved in this transition. Unfortunately, the current social trend of non-stop activity may produce unfavorable effects on SCN function, in accord with the unfavorable effects of nocturnal light on humans [15]. Future studies will be required to fully elucidate the properties of the human biological clock, in the hope of developing effective treatment for patients suffering from asynchronization. Acknowledgments A part of this study was presented at the 10th Asian & Oceanian Congress of Child Neurology in Daegu, Korea, June 12, 2009. This study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan (19231001). References [1] Kohyama J. A novel proposal explaining sleep disturbance of children in Japan – asynchronization (in Japanese). No To Hattatsu 2008;40:277–83. [2] Kohyama J. A newly proposed disease condition produced by light exposure during night: asynchronization. Brain Dev 2009;31:255–73. [3] Kohyama J. Neurochemical and neuropharmacological aspects of circadian disruptions: an introduction to asynchronization. Curr Neuropharmacol; in press. [4] Kohyama J. A novel disease condition presenting with insomnia and hypersomnia – asynchronization. In: Yolanda E Soriento, editors. Melatonin, sleep and insomnia. Nova Science Publisher; in press. [5] American Academy of Sleep Medicine. The International classification of sleep disorder. 2nd ed. American Academy of Sleep Medicine, Westchester; 2005. [6] Wittmann M, Dinich J, Merrow M, Roenneberg T. Social jet lag: misalignment of biological and social time. Chronobiol Int 2006;23:497–509. [7] Phillips ML. Circadian rhythms: of owls, larks and alarm clocks. Nature 2009;458:142–4. [8] Abe S. Differences in physical status of children (in Japanese). In: Mamorukai Nihon Kodomo Wo, editor. Kodomo Hakusho. Tokyo: Soudo Bunka; 2005. p. 108–10. [9] Suzuki M, Takahashi C, Nomura Y, Segawa M. What do care workers worry about in relationships between modern young
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Review article
Sleep health and asynchronization Jun Kohyama ⇑ Tokyo Bay Urayasu/Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001, Japan
Abstract Recent surveys in Japan reported that more than half of children interviewed complained of daytime sleepiness, approximately one quarter reported insomnia, and some complained of both nocturnal insomnia and daytime sleepiness. To explain the pathophysiology of this type of sleep disturbance, a novel clinical concept of asynchronization has been proposed. Asynchronization involves disturbances in various aspects of biological rhythms that normally exhibit circadian oscillations. The putative major triggers for asynchronization include a combination of nighttime light exposure, which can disturb the biological clock and decrease melatonin secretion, and a lack of morning light exposure, which can prohibit normal synchronization of the biological clock to a 24-h cycle and decrease activity in the serotonergic system. The early phase of asynchronization may be caused by inadequate sleep hygiene, is likely to be functional, and to be relatively easily resolved by establishing a regular sleep–wakefulness cycle. However, without adequate intervention, these disturbances may gradually worsen, resulting into the chronic phase. No single symptom appears to be specific for the clinical phases, and the chronic phase is defined in terms of the response to interventions. The factors causing the transition from the early to chronic phase of asynchronization and those producing the difficulties of recovering patients with the chronic phase of asynchronization are currently unclear. Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Melatonin; Serotonin; Circadian singularity; Social jet lag
1. Introduction This mini-review first describes the neurological systems involved in circadian disruptions, then discusses the recently developed clinical concept of asynchronization of circadian function [1–4]. Because of space limitations, citations are restricted to recent studies. Please refer to other reviews by the author [2–4] for a more detailed list of references. The key features of adequate sleep hygiene are summarized in Table 1. These features are often used in addition to the diagnostic criteria for insomnia due to inadequate sleep hygiene [5], characteristics of the biological clock [2–4], and food-anticipatory rhythms. Many individuals living in modern societies do not achieve adequate sleep health. The term ‘social jet lag’ has been used to describe ⇑ Tel.: +81 47 351 3101; fax: +81 47 352 6237.
E-mail address: [email protected].
cases where an individual’s circadian rhythms are out of phase with their daily schedule, a condition characterized by delayed wake-up times, delayed bedtimes, and an irregular lifestyle [6,7]. Approximately one quarter of the world’s population is subjected to a 1-h time change twice a year (daylight savings time; DST). DST is known to disturb the typical seasonal changes observed in sleep timing, as assessed by the duration of mid-sleep times. In addition, the beginning of DST (i.e. spring) is associated with an increase in rates of traffic accidents and myocardial infarctions. DST thus appears to produce social jet lag in a huge number of people. In addition, more than 2.1 billion people used air travel in 2006, meaning that a substantial proportion of the population also suffers from travel-related jet lag. Because circadian rhythm problems are so common, there is an urgent need for the development of effective treatment strategies. A survey in Japan revealed that more than half of the preschoolers/students interviewed
0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.09.006
J. Kohyama / Brain & Development 33 (2011) 252–259 Table 1 Healthy sleep habits (Sleep Health Practice/Treatment; SHP/T). 1 2 3 4 5 6
Increase exposure to morning light Engage in physical activity during daytime Sleep in the dark during the night (i.e. turn off all artificial lighting) Eat regular meals Avoid substances that disturb sleep (e.g. caffeine, alcohol, nicotine) Avoid excessive media exposure (e.g. video games, computers, television)
complained of daytime sleepiness, while approximately one quarter of junior high school students reported suffering from insomnia [8–12], most likely resulting from inadequate sleep hygiene. However, the provision of adequate sleep hygiene is often ineffective as a therapeutic approach. This suggests that unknown factors or neuronal mechanisms may prevent recovery from insomnia and daytime sleepiness. In the 2nd edition of the international classification of sleep disorders [5], inadequate sleep hygiene is listed as a cause of insomnia. However, this classification does not describe any disorders involving insomnia, hypersomnia and circadian rhythm disruptions due to inadequate sleep health [5]. In addition, rhythm disruptions resulting from delayed wake-up times and bedtimes and irregular lifestyles are reported to be associated with problematic behaviors [2–4,8] regardless of sleep duration [13]. Asynchronization was thus developed as a novel clinical concept to explain the pathogenesis/pathophysiology of a condition involving insomnia, hypersomnia and circadian rhythm disruptions [2–4], and includes the concept of social jet lag. 2. Neurological systems involved in circadian disruptions 2.1. Biological clock Light stimuli are conveyed to the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract, and activate the N-methyl-D-aspartate (NMDA)/nonNMDA receptors of the SCN. Signals from the SCN regulate various circadian rhythms, including feeding, locomotion, sleep–wake alternation, corticosterone secretion [14], and the autonomic nervous system. Morning exposure to sunlight leads individuals to become accustomed to a 24-h light–dark cycle. Conversely, light exposure at night can delay or retard the circadian clock phase and disrupt its functioning [15]. Nevertheless, people commonly continue to live under conditions of widespread, nocturnal, bright, artificial light. Nonphotic cues, such as physical activity, social factors, and eating time also serve to synchronize the circadian system to a 24-h day. A self-assessment questionnaire has been developed to classify individuals as morning-type or evening-type (i.e. lark or owl chronotypes) [16]. Endogenous phasing of the circadian biological clock in morning-type individuals
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varies from that of evening-type individuals [17], who experience a temperature rise later in the morning and later waking times [18]. Moreover, individuals who are alert in the morning experience earlier circadian rhythm temperature peaks than individuals who are alert in the evening [19]. A recent study examining the molecular rhythms of people classified as ‘larks’ or ‘owls’, as assessed by the Bmal1 expression of skin cells, reported that cells taken from larks exhibited shorter molecular periods than those taken from owls [20]. However, approximately half of the lark and owl cells exhibited ‘normal’ circadian period lengths, and the cellular clocks of owls were generally more difficult to reset than those of individuals with more typical schedules, whereas the larks’ cellular clocks were more easily reset. These findings suggest that individual differences in chronotype can result from innate differences in circadian period length and the ease with which an individual’s rhythms can be synchronized to the night/day cycle. 2.2. Melatonergic system Melatonin acts as a hypnotic and an effective freeradical scavenger and antioxidant. It has been found to regulate the circadian phase, and is implicated in inhibiting cancer development and growth. Exposure to bright light during the night has been found to decrease melatonin secretion. The onset of melatonin secretion typically begins 14–16 h after waking, around dusk. Exposure to bright, midday light has been shown to increase melatonin secretion during the night, without a circadian phase shift. Preliminary results from a study of 3-year-old children suggest that early sleepers tend to exhibit higher levels of urinary 6-sulfatoxymelatonin (6SM, assessed by the 6SM/creatinine ratio), the primary melatonin metabolite, compared with late sleepers. In accord with this result, decreased melatonin levels in aged zebrafish have been shown to correlate with altered circadian rhythms. In contrast, alterations in melatonin rhythms were reported to have no effect on the circadian rhythms of locomotor activity and body temperature in rats. Synthesized melatonin receptor agonists may have clinical value for the treatment of insomnia. Ramelteon, one of the melatonin agonists available in Japan, has been found to exert sleep-inducing effects in humans [21]. This compound stimulates both MT1 and MT2 receptors [22]. Activation of MT1 receptors in the SCN [23] inhibits the activity of SCN in rats [24], and that of MT2 receptors exerts phase-advancing effects on SCN cell activity in rats [23]. In humans, melatonin exerts phase-advancing effects when administered in the evening [25]. Ramelteon may thus be expected to exert phase-altering effects in humans, but the sleep inducing effects of this drug in humans remain to be fully characterized.
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2.3. Serotonergic system Exposure to morning light can activate the serotonergic system, whereas nocturnal lifestyles lacking morning light exposure are unlikely to cause activation. The serotonergic system is activated through rhythmic movements, such as gait, chewing and respiration. Thus, adequate physical activity may be important for serotonin activation. Exercise-derived benefits for brain function have been demonstrated at the molecular level, and physical activity has been reported to decrease the risk of Alzheimer’s disease. A study by Kennaway et al. reported that activation of 5-HT2C, similarly to a light pulse, produced long-lasting phase shifts in the melatonin rhythm, but his effect was blocked by a 5-HT2C antagonist [26]. There is also evidence that serotonin is capable of phase-advancing the master pacemaker oscillation when applied during the subjective day, and inhibiting light-induced phase shifts during the subjective night [27]. Low serotonin syndrome, involving aggressiveness, impulsivity, and suicidal behavior, has been proposed as a clinical condition. In male adult vervet monkeys, an association was found between decreased serotonergic activity and a disadvantage in attaining high social status, while enhanced activity was related to a status advantage. Based on animal experiments and post-mortem human anatomical and neurochemical data, disturbances of the lateral orbito-prefrontal circuit have been found to induce aggressive behavior and a loss of sociability, and the serotonergic system has been shown to activate this circuit. Serotonin levels have also been shown to enhance learning abilities. Serotonergic activity is profoundly affected by the sleep–wakefulness cycle, exhibiting maximal activity while waking and the lowest activity during rapid eye movement sleep. Taken together, these findings suggest that an irregular sleep–wakefulness rhythm disturbs emotional control and sociability due to decreased serotonergic activity in the lateral orbito-prefrontal circuit. 2.4. Other systems Glycine ingestion before bedtime has been found to significantly improve subjective sleep quality among individuals with insomniac tendencies [28]. Oral administration of glycine in rats was found to induce a significant increase in the glycine concentration in the plasma and cerebrospinal fluid, and a significant decrease in core body temperature, associated with an increase in cutaneous blood flow. The NMDA receptor in the SCN is thought to be involved in sensing increases in CSF glycine concentration [29]. In addition, other compounds are also likely to be involved in the control of insomnia, hypersomnia and circadian oscillations, including the wakeand sleep-promoting/inhibiting systems [3], dopamine, neuropeptide Y, ghrelin [30], and opioid peptides.
Describing the details of these systems is beyond the scope of the current review. 3. Desynchronization In the absence of time cues, daily rhythms can become altered and develop their own rhythm. After living under unusual sleep conditions for a considerable period of time, reciprocal phase interactions within the circadian rhythm, such as sleep–wakefulness and temperature, tend to become disturbed. Humans typically wake in the morning when their body temperature begins to rise from its lowest level and fall asleep at night when their body temperature begins to decline from its highest level. However, if this reciprocal interaction is impaired, the phase relationship between body temperature and sleep–wake circadian rhythms can become disrupted. This phenomenon has been termed ‘circadian desynchronization’ on the basis of basic science studies, but this term is not used clinically. This type of disruption is proposed to produce various physical and mood disturbances, such as disturbed nighttime sleep, impaired daytime alertness and performance, disorientation, gastrointestinal problems, loss of appetite, inappropriate timing of defecation, and excessive need to urinate during the night. Similar complaints and mood alterations have been observed in patients with jet lag or seasonal affective disorder, as well as in most astronauts during space travel. It should also note that evening-type individuals are suggested to be more likely to suffer from circadian desynchronization [31,32]. External and internal desynchronization are described as two of the three major components involved in jet lag, in addition to sleep deprivation. External desynchronization refers to conflict between the internal clock and external time cues. As an individual is exposed to new external time cues following travel, their internal clock can adjust to a time zone, sometimes over the course of several days. Internal desynchronization (i.e. a loss of phase-coupling between phenomena that act as circadian oscillation cues) takes place during the readjustment of internal clocks, with each system adjusting itself independently. That is, in a state of internal desynchronization, peripheral clocks function without synchrony. Internal desynchronization can also be induced by acute manipulation resulting in phase alteration, as in the case of jet lag. Sleep loss can occur as a result of internal and external desynchronization, decreasing the prevalence and performance of physical and mental activities. This can ultimately result in a decrease in serotonergic activity, presumably due to a lack of rhythmic activity. Interestingly, the rate of recovery from jet lag varies between individuals, as well as with the direction of time zone change. For transmeridian travelers, both physical cues, such as daylight and darkness, and social cues such as mealtimes and noise, encourage realignment of the circadian
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system. In contrast, for shift workers, physical cues (and most social cues) are often opposed to nocturnal alignment in day-oriented societies. Therefore, circadian realignment for shift workers often takes longer than realignment from jet lag. A World Health Organization report concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” [33]. Reduced activity of the melatonergic system is a hypothesized causative factor involved in the association between circadian disruption and cancer. In addition, a forced, abnormal schedule can induce desynchronization. Based on the findings discussed above, modern lifestyles involving widespread exposure to artificial bright light may thus be expected to produce effects similar to shift-work related disorders or social jet lag. 4. Asynchronization 4.1. Requirement for categorization of asynchronization as a novel clinical entity In Japan, several surveys [8–12] have revealed that more than half of the preschoolers/students questioned complained of daytime sleepiness, while approximately one quarter of junior high and high school students reported suffering from insomnia. These results suggest that many young people in Japan are persistently tired and inactive. The common complaints of these subjects included the desire to sleep, a persistent need to yawn, a desire to lie down, eyestrain, memory difficulties, and neck stiffness, among others. These symptoms are similar to the associated features of behaviorally-induced insufficient sleep syndrome [5], suggesting that insomnia due to inadequate sleep hygiene may produce this type of hypersomnia. Features related to inadequate sleep hygiene include low levels of physical activity (sedentary behavior), excessive media exposure, and excessive caffeine use. If inadequate sleep hygiene causes asynchronization, providing the conditions of adequate sleep hygiene/health would be expected to ameliorate the symptoms (Table 1). However, such therapeutic approaches have commonly been found to fail. Although delayed wake-up and bed times can be symptomatic of a delayed sleep phase form of circadian rhythm sleep disorder, it should be noted that there is confusion between the categorization of this disorder and the biological and lifestyle-related sleep phase delays that are especially common during adolescence. According to the diagnostic criteria, patients with circadian sleep disorders of the delayed sleep phase type or the irregular sleep–wakefulness type should both exhibit normal sleep duration for their age [5]. However, the sleep duration of many young people in Japan who exhibit intractable circadian rhythm disruptions is decreased (or varies day by day), resulting in complaints of both insomnia and hypersomnia. It is possible that unknown
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factors in addition to simple sleep loss and inadequate sleep health are involved in many cases of young people in Japan that exhibit intractable circadian rhythm disruptions and complain of both insomnia and hypersomnia. These findings suggest that the concept of circadian desynchronization is insufficient to explain such disease conditions in these young people, and that decreased activity in the melatonergic and serotonergic systems is likely to be involved. Categorization of this condition as a novel clinical entity is thus required to develop a greater understanding of the pathogenesis/pathophysiology of this disease [2–4]. In an early study, Winfree reported that a specific, dim, pulsed, blue light stimulus with a unique timing and duration resulted in unusual broadening of the daily eclosion peaks of the fruit fly, Drosophila pseudoobscura, completely obscuring the circadian rhythm in some cases [34]. This phenomenon has been termed ‘circadian singularity behavior’ and has since been described in a range of organisms including algae, plants, and mammals. In humans, circadian rhythms of rectal temperature and plasma cortisol were reported to be abolished by a single, long duration, bright-light pulse administered during one or two successive circadian cycles [35]. In addition, a critical light pulse (3-h light pulses delivered near subjective midnight) was shown to drive cellular clocks toward singularity behavior in mammals [15]. Interestingly, this phenomenon appears to be transient [36], although the removal of the stimulus is required. The novel clinical concept termed ‘asynchronization’ proposed here is based on these findings and the basic concept of circadian singularity. 4.2. Clinical phases and symptoms of asynchronization Asynchronization results from disturbed aspects (e.g. cycle, amplitude, phase, and interrelationship) of biological rhythms that normally exhibit circadian oscillation. These disruptions presumably involve decreased serotonergic and/or melatonergic activity. The major trigger of asynchronization is hypothesized to be a combination of light exposure during nighttime, which reduces melatonin secretion, and a lack of morning light exposure, which decreases serotonergic activity. Both triggers are known to disturb biological clock function in the SCN. In addition, similar to the components of jet lag, sleep deprivation may constitute part of the symptomatology of asynchronization. Sleep shortage can exert a negative effect on daytime functioning, general wellbeing, metabolic and endocrine function, body weight, susceptibility to viral infection, psychomotor skills and mood. The proposed symptoms of asynchronization include disturbances of the autonomic nervous system (i.e. sleepiness, insomnia, disturbed hormonal excretion, gastrointestinal problems, and sympathetic nervous system
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predominance), as well as higher brain function disruption (i.e. disorientation, loss of sociability, loss of will or motivation, and impaired alertness and performance). Additional putative symptoms of asynchronization include neurological (attention deficits, aggression, impulsiveness, and hyperactivity), psychiatric (depressive disorders, personality disorders, and anxiety disorders), and somatic (tiredness, fatigue, neck and/or back stiffness, and headache) disruption. The early phase of asynchronization is easily induced by delayed wake-up and bedtimes, and an irregular lifestyle, producing unsatisfactory physical, mental, and/or emotional conditions that can lead to a decreased level of physical activity. It should be noted that the symptoms of this state could be induced by inadequate sleep health. This condition is likely to be functional, and to be relatively easily resolved by establishing a regular sleep–wakefulness cycle. However, without adequate intervention, these disturbances may gradually worsen, resulting in a further decrease in physical activity and also serotonergic and/or melatonergic activity, and can be difficult to resolve. Some patients classified as suffering from the chronic phase of asynchronization have been found to exhibit a long sleep duration of more than 10 h, while some complained of insomnia due to hyperarousal conditions resulting from the presumable predominance of the sympathetic nervous system activity. These results suggest the involvement of both wakefulness- and sleep-promoting/inhibiting systems in the chronic phase of asynchronization. No single symptom appears to be specific for the clinical phases, and the chronic phase is defined in terms of the response to interventions in the novel classification proposed here. Patients with the early phase of asynchronization are likely to recover without difficulty, but those with the chronic phase are unlikely to recover easily. Pro-
viding the conditions of adequate sleep health listed in Table 1 is not an adequate therapeutic treatment for this condition. The blue lines in Fig. 1 represent vicious cycles, and the enhancement of these cycles is proposed to induce the transition into the chronic phase of asynchronization. The development of the clinical phases of asynchronization might also be affected by individual differences in how easily an individual’s rhythms can be synchronized to the night/day cycle [20]. An additional parallel assumption is that certain unknown factors (represented by the red line) act as promoters for the progression into the chronic phase of asynchronization. Most preschoolers do not progress to the chronic phase of asynchronization, and a recently examined patient suffering from asynchronization was found to have conflict with her mother, indicating that age and family context may be factors involved in the transition from the early to the chronic phase of the disorder. 4.3. Potential therapeutic approaches for treatment of asynchronization 4.3.1. Basic principles For synchronization of the biological clock to a 24-h cycle, morning light and avoidance of nocturnal light are essential. Therefore, the absence of these two elements can be considered risk factors for developing asynchronization. Steroid secretion is maximal in the morning under normal conditions, and light-induced adrenal gene expression and corticosterone release have been demonstrated experimentally. As described earlier, physical activity, social factors, and eating times are known to affect the circadian clock. Adequate physical activity (exercise), participation in social activities, and regular mealtimes are likely to prevent asynchronization. Taken together, these findings suggest that the Late bedtime (Light exposure at night)
Waking late in the morning (Lack of morning light exposure)
Inadequate sleep health (caffeine, extreme media exposure, etc)
Early phase of asynchronization Unfavorable physical & mental conditions (fatigue, pain, depressive mood, etc)
(Symptoms due to inadequate sleep health) Unknown factors? e.g. Wake/Sleeppromoting/ inhibiting systems?
Insomnia an enhancement of vicious cycles?
Sleep deficiency Daytime sleepiness
Chronic phase of asynchronization Melatonin reduction Low serotonin activity
Low physical activity
Fig. 1. Schematic diagram of the development of asynchronization. The broad blue lines constitute vicious cycles, and enhancement of these cycles is involved in the transition to the chronic phase of asynchronization. Certain unknown factors (broad red line) might act as promoters for the progression from the early to chronic phase of asynchronization.
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Saikokeishi-to (10)
Kami- shouyousan (24)
Zyuzen-taiho-to (48) and/or Ninjin-yoei-to (108)
Zyuzen-taiho-to (48) and/or Ninjin-yoei-to (108)
With insomnia Kihi-to (65) with fatigue Hochu-ekkito (41) With insomnia Kihi-to (65) Hochu-ekkito (41)
GI disturbance Anemia Depressive tendency
Saiko-karyukotuborei-to (12)
Aggressiveness or impulsiveness
Hachimiziou-gan (7)
Child patients refusing to attend school
Chronic fatigue syndrome
Rokumi-gan (88), Hochu-ekki-to (41), and Sho-Saiko-to (9) Ninjin-yoei-to (108) Fatigue syndrome
Numbers in parentheses are the standardized numbers for each prescription in Japan.
Rokumigan (87) Sinbu-to (30) or Ougiken-chu-to (98) and Ninzin-to (32)
Rokumigun (87)
Seishoekki-to (136)
Apathy Glowing (or heat sensation in the palm or foot) Systemic hypofunction and/or coldness Weakness in the lower extremities
Table 2 Examples of typical Kampo prescriptions for similar disease conditions to asynchronization.
4.3.2. Conventional and alternative approaches Light therapy, medication, physical activity and chronotherapy are conventional approaches used to treat asynchronization. Possibly useful medications include hypnotics, antidepressants, vitamin B12, melatonin and its agonists. But their actions are targeted against each symptom triggering the onset of asynchronization. Kampo medicine is a traditional Japanese herbal medicine originating from traditional Chinese medicine. Since Kampo prescription includes several components with a special distribution considering the personal characters into mind, the way of actions of Kampo is difficult to determine from the current way of analysis. However, from this not analytic but integral view point, I feel therapeutic possibilities of Kampo against patients with the chronic phase of asynchronization. Examples of Kampo prescriptions are listed in Table 2 [4]. In addition to these prescriptions, Kanbaku-taisou-to (72) (numbers in parentheses indicate standardized numbers for prescription in Japan) and Yoku-kan-san (54) are the author’s preference for patients suffering from the early phase of asynchronization and for those with presumed elevated sympathetic nervous system activity. Dai-saikoto (8) is also used to treat insomnia due to hypertension or tinnitus. Other potential alternative approaches include direct contact, autonomic nervous system control, pulsed light, and rhythmic movements such as qigong, tanden breathing, and rhythmic physical activity such as locomotion [2–4]. Maletic and Raison [37] discussed the high rates of comorbidity observed between major depression, fibromyalgia, and neuropathic pain, highlighting the role of dysregulation of stress/inflammatory pathways. In addition, patients with chronic fatigue syndrome have been found to exhibit sleep difficulties, pain, fatigue, and depressive mood alteration. Each of these disease conditions possesses a specific origin, major symptoms, and course, but circadian disruptions of various variables that normally show diurnal fluctuations are also reported in each of these disorders. It should be noted that serotonergic and melatonergic agents as well as physical activity and bright light/darkness [38] are known to exert favorable effects on some patients with these disease conditions. Although the relationship between these disease conditions and asynchronization remains to be determined, the therapeutic approaches discussed above may extend current methods for treating patients with asynchronization. For example, favorable effects of acupuncture or shiatsu (acupressure) have been reported for alleviating depression, fibromyalgia, insomnia, chronic fatigue syndrome, and sleep disturbance [2–4].
Fatigue after acute infection
social promotion of favorable sleep health, including health education beginning in the early elementary school years, may be an appropriate measure to prevent the development of asynchronization.
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These may be promising therapeutic tools for treatment of asynchronization, but appropriate diagnostic standards and methodologies as part of treatment strategies remain to be developed.
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5. Conclusions This review described the symptoms exhibited by patients suffering from an early phase of asynchronization. These symptoms overlap with the symptomatology of inadequate sleep health. The poor therapeutic responses of patients in the chronic phase of asynchronization were then discussed. Factors that induce the transition from the early to the chronic phase of asynchronization remain to be solved. Age and family context may also be factors involved in this transition. Unfortunately, the current social trend of non-stop activity may produce unfavorable effects on SCN function, in accord with the unfavorable effects of nocturnal light on humans [15]. Future studies will be required to fully elucidate the properties of the human biological clock, in the hope of developing effective treatment for patients suffering from asynchronization. Acknowledgments A part of this study was presented at the 10th Asian & Oceanian Congress of Child Neurology in Daegu, Korea, June 12, 2009. This study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan (19231001). References [1] Kohyama J. A novel proposal explaining sleep disturbance of children in Japan – asynchronization (in Japanese). No To Hattatsu 2008;40:277–83. [2] Kohyama J. A newly proposed disease condition produced by light exposure during night: asynchronization. Brain Dev 2009;31:255–73. [3] Kohyama J. Neurochemical and neuropharmacological aspects of circadian disruptions: an introduction to asynchronization. Curr Neuropharmacol; in press. [4] Kohyama J. A novel disease condition presenting with insomnia and hypersomnia – asynchronization. In: Yolanda E Soriento, editors. Melatonin, sleep and insomnia. Nova Science Publisher; in press. [5] American Academy of Sleep Medicine. The International classification of sleep disorder. 2nd ed. American Academy of Sleep Medicine, Westchester; 2005. [6] Wittmann M, Dinich J, Merrow M, Roenneberg T. Social jet lag: misalignment of biological and social time. Chronobiol Int 2006;23:497–509. [7] Phillips ML. Circadian rhythms: of owls, larks and alarm clocks. Nature 2009;458:142–4. [8] Abe S. Differences in physical status of children (in Japanese). In: Mamorukai Nihon Kodomo Wo, editor. Kodomo Hakusho. Tokyo: Soudo Bunka; 2005. p. 108–10. [9] Suzuki M, Takahashi C, Nomura Y, Segawa M. What do care workers worry about in relationships between modern young
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