Vol. 92, Issue 2, 852-862, February 2002
HIGHLIGHTED TOPICS
Functional Genomics of Sleep and Circadian Rhythm
Invited Review: Integration of human sleep-wake regulation and
circadian rhythmicity
Derk-Jan
Dijk1 and
Steven W.
Lockley2
1 Centre for Chronobiology, School of Biomedical and Life
Sciences, University of Surrey, Guildford GU27XH, United Kingdom;
and 2 Division of Sleep Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115
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ABSTRACT |
The
human sleep-wake cycle is generated by a circadian process, originating
from the suprachiasmatic nuclei, in interaction with a separate
oscillatory process: the sleep homeostat. The sleep-wake cycle is
normally timed to occur at a specific phase relative to the external
cycle of light-dark exposure. It is also timed at a specific phase
relative to internal circadian rhythms, such as the pineal melatonin
rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of
responsiveness of the circadian pacemaker to light. Variations in these
internal and external phase relationships, such as those that occur in
blindness, aging, morning and evening, and advanced and delayed
sleep-phase syndrome, lead to sleep disruptions and complaints. Changes
in ocular circadian photoreception, interindividual variation in the
near-24-h intrinsic period of the circadian pacemaker, and sleep
homeostasis can contribute to variations in external and internal
phase. Recent findings on the physiological and molecular-genetic
correlates of circadian sleep disorders suggest that the timing of the
sleep-wake cycle and circadian rhythms is closely integrated but is, in
part, regulated differentially.
sleep homeostasis; entrainment; clock genes; blindness; aging
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INTRODUCTION |
WE ARE ALL CONSCIOUS OF BEDTIME and
wake time and the subjective quality of sleep. Our appreciation of the
importance of the sleep-wake cycle is further enhanced when confronted
with the consequences of its disruption. Disturbance in the timing of
sleep cycles occurs, for example, in response to shift work, jet lag, long work hours, and social and family demands and leads to decrements in quality of life, performance, and health. Disorders of daily sleep
patterns are also observed in blind individuals, in older people, and
in sighted young individuals suffering from circadian sleep disorders.
Such disorders often lead to the use of sleep aids; hypnotics are among the most commonly prescribed medications.
Biological (circadian) clocks are thought to play an important
role in the regulation of sleep-wake cycles and their disorders. Recently, remarkable progress has been made in the understanding of
functions and mechanisms of circadian clocks in various model systems
and at levels of description ranging from the intact organism to clock
gene expression in vitro. Progress has also been made in our
understanding of regulation of the timing of the human sleep-wake cycle
and its integration with the timing of some endogenous circadian
rhythms in endocrinology and physiology. The human sleep-wake cycle is not simply driven by the circadian pacemaker located in the
suprachiasmatic nuclei (SCN) but instead is generated through interactions of circadian rhythmicity, a sleep-wake oscillatory process
(sleep homeostasis), circadian photoreception, as well as feedback from
the sleep-wake cycle onto these processes (see Fig.
1). Alterations in these processes and
their interactions may lead to sleep and wakefulness occurring at
abnormal clock times (altered external timing) and/or out of phase with
endogenous circadian rhythms (altered internal timing). Here we
describe some recent developments related to the circadian sleep
propensity rhythm, sleep homeostasis, and circadian photoreception.
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Fig. 1.
A circadian pacemaker (clock), presumably located in the
suprachiasmatic nuclei (SCN), and a sleep homeostat, presumably located
outside the SCN, are two major determinants of the timing of the human
sleep-wake cycle and sleep structure. The oscillation of the sleep
homeostat is strongly, and maybe exclusively, determined by the
sleep-wake cycle (arrow 1). Light input to the circadian
clock is mediated by circadian photoreception. The sleep-wake cycle is
a major determinant of light input to the clock (arrow 2).
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SEPARATION OF CIRCADIAN AND SLEEP HOMEOSTATIC PROCESSES |
It has long been recognized that, for an adequate description of
the phenomenology of sleep-wake timing on an approximate daily time
basis, two separate but interacting oscillatory processes need to be
postulated: a strong circadian oscillator and a sleep-wake oscillatory
process or sleep homeostat (for reviews, see Refs. 12,
14, and 15). Early key evidence for the existence of these two processes included the observation of spontaneous desynchrony between the sleep-wake cycle and the circadian rhythm of body temperature during classical temporal isolation studies (6, 30) and the circadian variation of sleep duration during
experimentally displaced sleep (8). These data have been
summarized in mathematical and conceptual models of the sleep-wake
cycle in which the contribution of the two oscillatory processes to
sleep timing was defined (13, 32, 63). Experimental human
and animal work during the past two decades has confirmed such dual
regulation of sleep timing by a circadian process and a relaxation-type
sleep-wake oscillatory process. The latter process is also referred to
as a sleep homeostat because, from a functional perspective, this
oscillatory process regulates the average level of sleep debt. Sleep
debt increases during wakefulness and dissipates during sleep. More
recently, quantification of the relative contribution of these
processes, by forced desynchrony of the sleep-wake cycle from the
circadian process, has shown that these processes contribute about
equally to sleep consolidation and waking performance (36,
98). The relative contribution of these two processes to sleep
structure and aspects of the electroencephalogram (EEG) during
non-rapid eye movement (NREM) and rapid eye movement (REM)
sleep varies widely (37, 41).
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CIRCADIAN SLEEP-WAKE PROPENSITY SIGNAL |
Lesions of the SCN in animals and a few clinical cases in
which hypothalamic areas close to the SCN were damaged have
demonstrated that the strong circadian process affecting sleep timing
and sleep structure is generated by the SCN (27, 46,
87).1 In humans, the
SCN is thought to generate a wake or arousal signal that increases in
strength throughout the biological day (i.e., during the habitual wake
episode), peaking in the evening hours, at ~2200 h. The strength of
this signal declines during the biological night [i.e., during the
habitual sleep episode (36, 48)], to reach a minimum at
~0600 h, which coincides with the temperature nadir
(36). In the absence of this circadian arousal signal, sleep-wake consolidation is lost and the monophasic sleep-wake cycle is
replaced by a polyphasic sleep-wake cycle, presumably dictated
primarily by sleep homeostasis. Thus the circadian pacemaker maintains
timing of the sleep-wake cycle and consolidation of sleep-wake behavior
by opposing the increase in (homeostatic) sleep need associated with
sustained wakefulness. Experiments in which sleep was scheduled to
occur at many circadian phases have demonstrated that a consolidated
8-h episode of sleep can only be obtained at one specific phase
relationship between the sleep-wake cycle and endogenous circadian
rhythmicity. Only when sleep is initiated ~6 h before the temperature
nadir, i.e., shortly after the crest of the wake propensity rhythm,
will sleep remain virtually uninterrupted for 8 h (see Fig.
2).
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Fig. 2.
Wakefulness in scheduled sleep episodes as a simultaneous
function of time since start of sleep episode and circadian phase of
the core body temperature rhythm. Consolidation of sleep for 8 h
or more is only observed when sleep is initiated ~6-8 h before
the temperature nadir (dashed line). [From Ref. 36 with
permission.]
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The circadian sleep-wake propensity rhythm could be generated by a
circadian modulation of wake propensity, a circadian modulation of
sleep propensity, or a circadian modulation of both. Evidence that the
circadian pacemaker primarily affects wake propensity has been derived
from studies in squirrel monkeys. SCN lesions lead to an increase in
total sleep time per 24 h, in conjunction with the loss of
circadian sleep timing (48). Such an increase in total
sleep time suggests that promotion of wakefulness is absent in the
absence of the SCN. On the other hand, both SCN lesion studies in
animals and forced desynchrony studies in young and older healthy
people support the view that the SCN also actively promotes sleep, in
particular in the second half of the normal sleep episode (40,
97). Thus, in the intact squirrel monkey, wakefulness in the
second half of the subjective night is at its lowest levels and well
below the percentage of wakefulness observed in the SCN-lesioned animal
(48). Comparisons of the REM sleep rebound after REM sleep
deprivation in control and SCN-lesioned rats have demonstrated that,
during the major rest phase, the SCN actively promotes entry into REM
sleep (97). In humans, sleep spindle activity is highest
during the biological night. Furthermore, sleep latencies in older
people are longer than in young people at around the temperature nadir
but not at other circadian phases, suggesting that the active promotion
of sleep by the SCN is diminished at this circadian phase in older
people (40).
The waveform of the endogenously generated circadian sleep-wake
propensity rhythm may change in response to variations in day length
(photoperiod), such that after prolonged exposure to long dark episodes
the internal biological night is extended (94, 95).
The circadian arousal and/or circadian hypnotic signal(s) could be
humoral and/or neural. The circadian variation in sleep propensity is
closely associated with the circadian rhythm of plasma melatonin
(35, 68). Recent functional neuroanatomic studies have
identified some of the pathways by which the SCN may transmit circadian
information to sleep and arousal centers in the rat. Efferents from the
SCN can modulate numerous systems, including the adrenergic,
serotonergic, histaminergic, and the orexin systems (1, 7, 73,
75, 79). Deficiencies in the orexin system have been implicated
in the sleep disorder narcolepsy (81, 82). Narcoleptic
patients experience excessive daytime sleepiness and multiple sleep
attacks during the day as though they were unable to maintain
wakefulness. Edgar and colleagues (33) demonstrated that,
whereas the timing of the circadian modulation of sleep propensity is
normal, the strength of this signal, i.e., the promotion of
wakefulness, appears to be markedly attenuated in narcoleptics. The
recent insights derived from studies of the orexin system in
narcoleptic patients suggest that orexin may be a part of this
circadian effector system.
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MEDIATORS AND MARKERS OF SLEEP HOMEOSTASIS |
Slow-wave sleep (SWS) and EEG slow-wave activity (SWA) during NREM
sleep are the classical markers of the sleep homeostatic process.
Increases in SWA and visually scored SWS after sleep deprivation are
not obliterated in SCN-lesioned rodents (90). In humans,
SWS and SWA decline during sleep independent of the circadian phase at
which sleep occurs. Furthermore, the duration of wakefulness predicts
how much SWS and SWA occur during sleep at all circadian phases
(9, 34). Thus the localization of the sleep homeostat is
likely to be distinct from the SCN and could be diffuse. There is now
convincing evidence that the time course of the sleep homeostatic
process can also be monitored during wakefulness in humans.
Low-frequency components in the EEG increase as the duration of
wakefulness progresses at all circadian phases (3, 19, 21,
49). Scheduling multiple naps during the day attenuates this
increase in low-frequency activity during wakefulness
(22). This is similar to the previously observed reduction
of SWA during sleep following daytime naps (96). It thus
appears that low-frequency components of EEG during wakefulness are
closely associated with sleep homeostasis. Interestingly, the effects
of wakefulness on both the sleep and wake EEG are most pronounced in
frontal cortical areas of the brain (20, 21, 49, 50).
Whether and how these local changes in the EEG are related to the
circadian and sleep-wake-dependent modulation of performance remains to
be established.
A number of hypotheses on the neurochemical basis of sleep homeostasis
have been put forward (for review, see Ref. 16). There is
now substantial evidence for a role of the neuromodulator adenosine in
mediating sleep homeostatic signals. Levels of adenosine in basal
forebrain areas increase during sustained wakefulness, and
administration of adenosine to these brain areas leads to sleep
(11). Such a role for adenosine would be consistent with the popular use of the adenosine antagonist caffeine to combat sleepiness. The kinetics of the sleep homeostatic process in mice, as
indexed by EEG SWA, has been shown to be under strong genetic control.
Quantitative trait loci analysis has identified genomic regions that
contribute to this genetic control and that contain genes that regulate
adenosine levels (52).
The concept that circadian and sleep homeostatic processes are
functionally and anatomically distinct can be further investigated by
studying sleep timing and structure and responses to challenges of the
sleep homeostat in mammals with altered clock genes
(99). The first of such studies indicated that sleep
duration and the response to sleep loss may be affected by mutations of
the murine Clock gene. Interestingly, REM sleep, the sleep
stage most strongly regulated by circadian processes, is most modified
in Clock-mutant mice (80). Some people
suffering from a human familial form of advanced sleep-phase syndrome
(ASPS) have been shown to carry an altered hPer2 gene
(91), one of the key clock genes. It appears that in
patients suffering from this disorder sleep structure is within the
normal range (55, 84).
Clock genes may be involved in the generation of sleep-wake oscillatory
processes. During pharmacologically induced desynchrony between
rest-activity cycles and circadian rhythms in rats entrained to 24-h
light-dark cycles, some clock genes (rPer1,
rPer2, and rBmal1, but not rClock)
in the parietal cortex and caudate putamen oscillate in synchrony with
the rest-activity cycle. In contrast, clock gene expression in the SCN
remained phase locked to the light-dark cycle and the rhythm of pineal
melatonin (78). Alternatively, these extra-SCN rhythms in
clock gene expression could be driven by the rest-activity cycle.
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CIRCADIAN PHOTORECEPTION IN HUMANS |
Although it was once thought that light was not a major
synchronizer of human circadian rhythms, it has now been shown that multiple rhythms driven by the SCN, including the rhythms of sleep propensity and pineal melatonin, can be shifted by scheduled ocular light exposure (31). Current estimates of the sensitivity
of the human circadian pacemaker to light indicate that ordinary room
light exerts an effect that is 50% of the maximal effect induced by
very bright indoor light (100). Similar high sensitivities have been obtained in dose-response studies of the direct effects of
light on melatonin suppression, subjective alertness, and EEG and
electrooculogram correlates of alertness (23). Such
studies indicate that the range of illuminances (expressed in lux) over which light exerts a differential effect spans two to three log units.
Such a small dynamic range has previously been observed for circadian
responses in animal studies and is in accordance with the hypothesis
that the effects of light on the circadian timing system are mediated
by a photoreceptive system distinct from the system mediating vision
(77).
Quantitative aspects of circadian photoreception such as the
relationship between duration and intensity of light and the phase
shifting effects are under intense investigation and have shown that
the first minutes of light exposure are most effective (85). In mice, circadian phase shifting and neuroendocrine
and pupillary responses to light can be elicited in the absence of rods
and cones, suggesting that another ocular photoreceptor is involved in
mediating these effects (53, 76). In humans, the spectral
sensitivity of the circadian photoreceptive system has been
investigated using light-induced melatonin suppression as the dependent
variable. The assessment of the relative efficacy of different
wavelengths of light varying from 420 to 600 nm on suppression of
melatonin has now demonstrated that short wavelengths (blue light) are
most effective in suppressing melatonin (18). A detailed
analysis of these data suggested that neither rods nor cones primarily
mediate the light-induced neuroendocrine response (17,
89). This neuroendocrine response is often used as a proxy for
the circadian phase shifting effects of light, but it remains to be
established whether the spectral sensitivity for phase shifting is
similar to that observed for melatonin suppression. Nevertheless, these
data are the first compelling evidence that the human circadian
photoreceptive system is distinct from the photoreceptive system
involved in image formation. It has been hypothesized that melanopsin
located in the ganglion cells of the human inner retina is the
photopigment mediating these circadian light responses
(83). The question of how this spectral sensitivity of the
human circadian system is related to its entrainment to the natural
light-dark cycle remains to be investigated.
Phase shifts of endogenous circadian rhythms, including the sleep
propensity rhythm, can be induced by broad-spectrum light exposure even
when the sleep-wake cycle is kept constant (31). Thus most
of the effects of light on the circadian pacemaker are not necessarily
mediated through the sleep-wake oscillator and are most likely mediated
by the direct projection from the retinal ganglion cells to the SCN,
the retinohypothalamic tract. The sleep-wake cycle nevertheless plays
an important role in regulating light input to the pacemaker because we
close our eyes to sleep and open our eyes when awake (see Fig. 1).
Consideration of the interaction between sleep-wake behavior and light
input to the light-sensitive pacemaker may be important for the
understanding of synchronization of the human circadian system.
Previously, it was postulated that effects of light on the circadian
pacemaker were in part mediated through a sleep-wake oscillator, which
in turn would affect the circadian oscillator. Currently, the
mechanisms by which light could exert such direct effects on the
sleep-wake oscillatory process are unknown. Direct projections from the
retina to extra-SCN hypothalamic areas, such as the ventrolateral
preoptic area, which is known to contain sleep-active neurons
(74), may play a role in mediating such effects of light.
This view of entrainment by light via the sleep-wake oscillator also
implies that the sleep-wake cycle exerts an influence on the circadian
pacemaker. Experiments in which the sleep-wake cycle was inverted have
shown that under these conditions the feedback effects are small
(44). However, there is now growing evidence from both
animal and human studies that such feedback from the sleep-wake cycle
onto the SCN could nevertheless be significant, in particular for the
maintenance of entrainment (5, 54, 62, 96a).
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DETERMINANTS OF PHASE RELATIONSHIPS BETWEEN THE SLEEP-WAKE CYCLE,
ENDOGENOUS CIRCADIAN RHYTHMS, AND THE ENVIRONMENT |
In young healthy individuals without abnormalities in their sleep
timing, sleep occurs during melatonin secretion and the trough of the
endogenous circadian component of the temperature cycle. Sleep begins
just after maximal circadian wake propensity and ends just after
maximal circadian sleep propensity. Sleep also occurs at a specific
phase relative to the circadian rhythm in response to light; the
largest shifts of circadian rhythmicity in response to ocular light
exposure can be induced near the transition of wakefulness to sleep and
vice versa (see Fig. 3). Determinants of
the internal and external phase relationships between circadian rhythms, the sleep-wake cycle, and the external world include exposure
and the responsiveness to light, the intrinsic period of the human
circadian pacemaker, and the rate at which homeostatic sleep need
builds up during wakefulness and dissipates during sleep.
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Fig. 3.
Schematic representation of the timing of the habitual sleep
episode in young adults relative to the circadian rhythm of core body
temperature, plasma melatonin, wake propensity, and the responsiveness
to light. The circadian variation in the responsiveness to light is a
schematic representation (see Refs. 31 and 60
for review). Note that the maximum of the melatonin rhythm is located
~2 h before the nadir of the circadian temperature rhythm. Sleep
disruption (wakefulness within scheduled sleep episodes) is maximal
when sleep is scheduled just before the rise of melatonin. [Based on
data published in Ref. 40.]
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Can the variation in the phenomenology of sleep-wake timing be
explained by variations in the intrinsic period of the circadian pacemaker, circadian photoreception and responsiveness of the circadian
pacemaker to light, or changes in the sleep-homeostatic process?
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INTRINSIC PERIOD OF THE HUMAN CIRCADIAN PACEMAKER: ASSOCIATION WITH
INTERNAL AND EXTERNAL PHASE RELATIONSHIPS |
The notion that the intrinsic period of the human circadian
pacemaker is near 25 h has been recently challenged. It was
recognized that the exquisite sensitivity of the human circadian
pacemaker to room levels of light may have affected the period estimate in the classical free running experiments from which the estimate of
25 h was derived (60). During the past decade, a
number of laboratories have investigated this aspect of human circadian rhythmicity by assessing intrinsic periodicity under conditions in
which the confounding effects of room light exposure were controlled. Such experiments in sighted subjects (young, older, or adolescent) and
in blind adult subjects in whom the circadian system is not entrained
yielded estimates of intrinsic period that are close to 24 h (see
Refs. 26, 28, 38,
57, 69, and references therein).
Relatively minor discrepancies between these estimates in populations
of sighted and blind subjects may be related to selection of subjects
included in the population average, aftereffects of entrainment to
light on the observed period, study methodology, or differential
control of potential nonphotic time cues (28). Experiments
in which the confounding effects of light were carefully controlled
have now shown that, in young subjects, phase angle of entrainment is
correlated with the intrinsic period of the circadian pacemaker. One
estimate of the intrinsic period of the human circadian pacemaker under
such conditions is 24 h and 11 min, with a remarkably small
variation (SD of 8 min) (28). This small variation is
nevertheless associated with entrained phase, such that a 6-min
difference in intrinsic period leads to an approximately 1-h difference
in entrained phase (45).
In healthy older people without sleep complaints and without sleep
disorders, circadian rhythms of melatonin, core body temperature, and
cortisol occur at an earlier clock time than that in young adults
(25, 43, 45a). In older people, habitual wake time has been shown to also occur earlier relative to the core body temperature and plasma melatonin rhythms. This internal circadian phase advance of
wake time has also been observed during forced desynchrony of the
sleep-wake cycle and the endogenous circadian rhythm of plasma
melatonin and core body temperature (40, 43, 45a).
Therefore, the age-related change in the interaction of the sleep-wake
oscillator and endogenous circadian rhythmicity is such that wake time
is not only advanced with respect to clock time (altered external timing) but also advanced relative to internal circadian rhythms (altered internal timing). Although the advance of entrained phase (external timing) could theoretically be explained by an age-related reduction of the intrinsic period, the simultaneous advance of wake
time relative to endogenous circadian rhythms could not. (A plot of the
internal and external phase relationships in these two categories,
compared with the theoretical changes in internal phase relationships
due to changes in period, illustrates this point; see Fig.
4.) In addition, empirical assessments of
the intrinsic period in young and older people have yielded identical estimates (28). Thus the age-related 1-h difference in the
timing of the core body temperature and melatonin rhythm
between young and older people cannot currently be accounted for by an
age-related reduction in intrinsic period (28, 57),
suggesting that changes in the period of the circadian system are not
primarily responsible for the age-related changes in sleep timing.
However, it may be worthwhile to point out that, according to the
observed association between entrained phase and intrinsic period in
young subjects, an age-related difference in intrinsic period of only
~6 min would be required to account for the age-related difference in
entrained phase (45).
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Fig. 4.
Schematic representation of the differences in internal
phase relationship between wake time and circadian rhythm of core body
temperature between owls and larks and between young and older people,
compared with theoretical phase relationships that could be expected in
individuals with relatively longer or shorter intrinsic periods ( )
of the circadian pacemaker. Tmin, circadian phase marker core body
temperature minimum. Note that the relationship between Tmin and wake
time is not constant (i.e., parallel) in owls vs. larks, young vs.
older age, and long vs. short , thus demonstrating changes in
internal phase relationships between circadian and sleep rhythms.
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DIURNAL PREFERENCE |
People vary in their diurnal preference for the timing of
activity and sleep, and this preference is paralleled in their
physiology. In morning types, wake time, the temperature nadir, and the
plasma melatonin rhythm occur at earlier clock times than in evening types (10, 42, 58, 59). Sleep deprivation studies have indicated that the homeostatic aspect of sleep regulation is not markedly different between morning and evening types (64).
Furthermore, differences in the timing of circadian melatonin and core
body temperature rhythms persist under constant routine conditions (in
the absence of a sleep-wake cycle), demonstrating that such differences
are not a direct consequence of altered sleep-wake timing. Examinations
of the internal phase relationships between the sleep-wake cycle and
endogenous circadian rhythms have led to the somewhat paradoxical
conclusion that morning types, who wake up at an earlier clock time,
wake later relative to the circadian cycle of temperature and melatonin
(42). The opposite is true for evening types. As
previously discussed, in young subjects, small variations in intrinsic
period are correlated with variations in diurnal preference. A 6-min
difference in intrinsic period is correlated with a change in
Horne-Östberg rating (a measure of diurnal preference) by
5-10 points (out of 70-point range) (45). These data
indicate that differences in intrinsic period of a magnitude smaller
than those associated with clock mutants in rodents have significant
consequences for sleep-wake timing and diurnal preference in humans. In
fact, an association between diurnal preference and a polymorphism in
the human Clock gene has been described (56).
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ADVANCED AND DELAYED SLEEP PHASE SYNDROMES |
ASPS and delayed sleep-phase syndromes (DSPS) are often thought to
be associated with advanced and delayed timing of endogenous circadian
rhythms, such as temperature and melatonin. Surprisingly, few studies
have carefully characterized the circadian physiology in such sleep disorders.
In an examination of the internal and external phase relationships in
DSPS patients, delayed bedtime, delayed wake time, and a later clock
time for the onset and peak of the melatonin rhythm were reported
(88, 92). In addition, bedtime and wake time were
reportedly delayed relative to the melatonin rhythm. Therefore, DSPS
patients appear not only to wake up at a later clock time but also at a
later phase of the endogenous rhythm of melatonin and temperature. The
observation is in contrast to evening types who wake up earlier in the
endogenous circadian cycle. An association between DSPS and
polymorphisms in the clock gene hPer3 has been reported,
suggesting that circadian processes may contribute to this condition
(47).
The timing of sleep and circadian rhythms of temperature and melatonin
in individuals suffering from familial forms of ASPS has been
described. As may be expected, the timing of both sleep and endogenous
circadian rhythms was advanced by as much as 4 h (55,
84). The internal phase relationships between sleep and the
circadian rhythms of melatonin and temperature appeared normal in these
patients. Sleep structure (i.e., SWS and REM sleep expressed as a
percentage of total sleep time) also appeared normal, suggesting that
the primary change in these patients is not associated with the sleep
homeostatic facet of sleep-wake regulation but rather in the circadian
aspect. So far, assessments of intrinsic period in the absence of the
confounding effects of light are not available for such patients. The
free-running period, assessed in a classical free-running paradigm, has
been reported to be rather short in one patient (55). This
may be related to the change in a hPer2 phosphorylation
site, which has been reported in a separate study for some but not all
ASPS patients (91).
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CHANGES IN CIRCADIAN PHOTORECEPTION IN AGING AND IN BLIND
INDIVIDUALS? |
Changes in circadian photoreception or changes in the
responsiveness of the circadian pacemaker to light due to changes
downstream from the circadian photoreceptors may contribute to
variations in the entrained phase. Initial comparisons of the
responsiveness to light in young and older healthy volunteers suggested
that older people were somewhat less sensitive to light in the
phase-advance portion of the phase response curve (PRC). The
responsiveness to light in the phase-delay portion of the PRC was not
significantly different (61). These findings are
inconsistent with the hypothesis that changes in responsiveness of the
pacemaker to light underlie the observed phase advance. The phase
advance in older people may be mediated by the observed internal phase
advance of wake time. As a result, this would increase light exposure
in the phase-advance region of the PRC and would thereby contribute to
the advance of endogenous circadian rhythms (43). This
hypothesis highlights the potential role of sleep-wake behavior and
changes in internal phase relationship between sleep and circadian
rhythms in the determination of entrained phase.
Alteration of light input and the responsiveness of the oscillator to
light have been indirectly examined in studies of circadian rhythms in
blind subjects. Despite massive loss of visual function, the majority
of blind individuals with some degree of light perception maintain
normal circadian rhythmicity (29, 69, 72). Similar observations were reported for rodless mice (51). No
significant associations have been observed between circadian rhythm
abnormalities and specific retinal abnormalities. In fact, within
totally blind subjects, the best predictor of circadian rhythm
disorders appears to be the lack of intact eyes (69), an
observation which is consistent with the distinct nature of the
circadian photoreceptive system. The report of several blind
individuals who, despite having no conscious light perception, are
sensitive to light-induced suppression of melatonin (29)
is consistent with a functional circadian photoreceptive system. These
subjects reported no cyclic sleep disorders and presumably have
photically entrained circadian rhythms despite no visual function.
Alternatively, the lack of association between retinal abnormalities
and entrainment may be explained by the effects of nonphotic time cues
(regular sleep-wake cycle, societal constraints, etc), exerting
sufficient drive onto the pacemaker to maintain entrainment
(62).
A variety of abnormal sleep-wake patterns, as well as internal and
external phase relationships have been reported in totally blind
subjects. Approximately 25% have normally timed hormonal rhythms
relative to the light-dark cycle, clock time, and the sleep-wake cycle.
A further 25% have hormonal rhythms entrained to an abnormal clock
time but maintain more or less normal sleep timing. The remainder have
nonentrained (non-24-h) hormonal rhythms and non-24-h sleep-wake
cycles. These subjects attempt to maintain a normal internal phase
relationship but are often unsuccessful because of the conflict between
internal circadian timing and external 24-h time cues
(70). Thus, in these totally blind subjects, not only do
we observe abnormal phase relationships of endogenous circadian rhythms
relative to clock time (altered external timing) but also highly
abnormal internal and external phase relationships with respect to
sleep timing (altered internal timing). Such observations represent the
most extreme example of the consequences of altering the phase angle
between sleep and the internal circadian system. Exogenous melatonin
administration (5 or 10 mg/day) can be used to successfully treat
non-24-h sleep-wake disorder (71, 86) and, if
appropriately timed, can realign both abnormal internal phase
relationships and the relationship between the circadian system and the
external 24-h social day.
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ALTERATIONS IN SLEEP HOMEOSTASIS |
Self-reported sleep need and sleep duration are found to vary
between individuals. First, sleep regulation in habitual short and long
sleepers has been studied in the context of the circadian and
homeostatic regulation of sleep. Analyses of both the sleep EEG and
waking EEG indicate that short sleepers live under a higher homeostatic
sleep pressure (2, 4). Second, sleep duration declines
across the life span. It has been well documented that SWS and SWA
decline with age (24, 93). These findings suggest that
sleep need may decline with age. The age-related reduction in SWS and
sleep duration is observed at all circadian phases, even when older
subjects are scheduled to a rest-activity cycle similar to young
subjects (40) (see Fig. 5).
Thus major differences in activity or daytime napping cannot be the
primary cause of such changes. Analyses of awakenings in young and
older subjects have further shown that it is primarily the
consolidation of NREM sleep that is impaired in older subjects
(39). Quantitative analyses of the EEG in young and older
subjects have demonstrated that the age-related changes in the spectral
composition of the EEG are a near-mirror image of the changes induced
by an increase in homeostatic sleep pressure after sleep deprivation
(24, 67) and opposite to the effects of the major
inhibitory neurotransmitter GABA on the EEG (65). In
addition, the age-related changes in the EEG appear most prominent in
frontal cortical areas (66). These data are consistent
with the hypothesis that the major aspect of age-related changes in
human sleep are related to the extra-SCN sleep process. Whether this
change reflects an age-related reduction in sleep need or age-related
changes in the ability to maintain sleep remains unclear. Age-related
changes in the circadian aspect of sleep regulation appear limited to a
reduction of the active promotion of sleep in the early morning
(40).
View larger version (42K):
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|
Fig. 5.
Comparison of the time course of slow-wave sleep (SWS;
top) and wakefulness (bottom) in sleep episodes
scheduled at many circadian phases in young (left) and older
(right) people. Note that in older people more wakefulness
and less SWS within scheduled sleep episodes is present at all
circadian phases. [From Ref. 38 with permission, based on
data published in Ref. 40.]
|
|
| |
CONCLUSION AND PERSPECTIVES |
Human sleep-wake timing and circadian rhythmicity are closely
interrelated but are, in part, separable and mediated by distinct processes. Consideration of both external and internal sleep timing may
provide new parameters to quantify the phenomenology of normal and
abnormal sleep regulation. Detailed description and controlled examination of both internal and external phase relationships and
comprehensive description of sleep and circadian physiology could
clarify the contribution of circadian processes, sleep homeostasis, and
circadian photoreception and their molecular-genetic basis to the
phenomenology of sleep timing. Examination of the impact of specific
genotypes affecting sleep phenomenology on sleep physiology, circadian
physiology, as well as circadian photoreception will undoubtedly lead
to the discovery of new postgenomic physiology. This in turn may lead
us to revise or abandon current concepts and necessitate the design of
new conceptual frameworks and therapeutic approaches for human sleep
timing and its disorders.
| |
ACKNOWLEDGEMENTS |
We are grateful to Dr. Shantha Rajaratnam for constructive comments
on the manuscript. We also thank Drs. Josephine Arendt and Debra J. Skene at the University of Surrey and Dr. Charles A. Czeisler at
Brigham and Women's Hospital for continued support.
| |
FOOTNOTES |
S. W. Lockley is supported by the Wellcome Trust (Grant
060018/Z/99/Z).
Address for reprint requests and other correspondence: D.-J.
Dijk, Centre for Chronobiology, School of Biomedical and Life Sciences,
Univ. of Surrey, Guildford GU2 7XH UK (E-mail:
d.j.dijk{at}surrey.ac.uk).
1
We will use the term circadian process in the
general context of this paper to mean the signal(s) that affect sleep
propensity and sleep structure and originate from the circadian
pacemaker, presumably located in the SCN.
10.1152/japplphysiol.00924.2001
| |
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TOP
ABSTRACT
INTRODUCTION
