- 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.
-
-
- 5.3.3.5. 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.
-
-
- 5.3.3.6. 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.
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