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a) b)
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Glycine
and GABA
c)
C
1–C8
T1–T
L1–L
S1–S
GABA
5HT
Noradrenaline
ACh
Glu
Motor pools
Groups of respiratory neurons
12
5
5
Inspiratory neurons
Inspiratory projections
Excitation
Inhibition
VRG
Glycine
and GABA
C
1–C8
T1–T
L1–L
S1–S
12
5
5
Hypoglossal (XII)
Figure 2. The main neuronal groups and their role in generating the brain state of REM
sleep. a) Traditionally, interactions of cholinergic and aminergic cell clusters has been used to
explain the defining features of REM sleep: 1) ascending cortical activation and 2) descending
spinal motor inhibition. b) Recent advances suggest that REM sleep is due to the interaction of
glutamatergic and GABAergic cell clusters; for more details, see the main text. The inhibition
of spinal motor activity in REM sleep is mediated by descending projections to the medial and
ventral horn of the spinal cord, and increased release of the inhibitory amino acids glycine
(predominantly) and GABA onto spinal motoneurons. c) The mechanism of upper airway
motor suppression in REM sleep appears dierent. For the hypoglossal motor pool, for example,
which innervates the musculature of the tongue via cranial nerve XII, a cholinergic mechanism
mediates the strong motor inhibition of REM sleep. This inhibition counteracts the inspiratory
drive to motor pool that originates from the ventral respiratory group via the pre-Bötzinger
complex (PBC) and premotoneurons in the lateral reticular formation (the latter two indicated
as inspiratory neurons, in blue). The hypoglossal motor pool also receives tonic state-dependent
drive from the reticular formation (in grey). C: cervical vertebra; T: thoracic vertebra; L: lumbar
vertebra; S: sacral vertebra; 5HT: serotonin; ACh: acetylcholine; Glu: glutamate. Reproduced and
modified from Horner et al. (2016) with permission from the publisher.
The molecular mechanisms that control sleep rhythms are highly phylogenetically
conserved. The characteristic EEG of NREM sleep comprises prominent oscillatory
thalamocortical rhythms that include the delta and spindle rhythms, as well
as a recently described slow (<1 Hz) oscillation. Slow oscillation influences the
Tongue
PBC
DRG
XII
4
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W
R
N1
N2
N3
23:00 00:00 01:00 02:00 03:00 04:00 05:00
Figure 3. Hypnogram of a healthy young adult showing five sleep cycles. W: wake; R: REM
sleep; N1–3: respective stages of NREM sleep.
timing of delta and spindle rhythms, and it likely eects memory integration and
consolidation. The characteristic EEG of REM sleep, conversely, reflects a distributed
neuronal network activated through a net tonic increase in reticular, thalamocortical
and cortical neuronal firing rates. REM muscular atonia results from tonic
postsynaptic inhibition of spinal anterior horn cells by the pontomedullary reticular
formation (figure 2).
Both the sleep–wake and REM–NREM oscillators give rise to regularly recurring
changes in neuromodulation of the forebrain structures that mediate behaviour and
cognitive processes.
Sleep and ageing
The amount of time we spend asleep fluctuates across the lifespan according to
neurodevelopmental changes, health and life events. Newborn infants commonly
require between 10 and 18 h of sleep per day for optimal neurodevelopment. This
need reduces to 9–12 h by the end of the first year of life. Some clinicians, however,
recommend that >12 h per night may be required for preschoolers. This equates to
∼12 h per night for primary school children in order to achieve optimal cognitive
functioning and development. Paediatric daytime somnolence is known to be
associated with slower improvement in verbal comprehension. Notably, daytime
naps have been shown to help consolidate learning in preschool children and the
memory loss associated with nap deprivation in this age group was not reversed
with an overnight sleep. This may be of particular relevance for children with a
learning delay.
Adults need around 7–8 h sleep per night. Ageing negatively aects total sleep
quantity, sleep eciency and SWS. The incidence of waking aer sleep onset tends
to increase with ageing process. Ageing also aects sleep architecture so that time
spent in SWS and REM sleep diminishes, whilst the time spent in stages N1 and N2
of NREM sleep increases.
Thus, normal ageing appears to be associated with reduced ability to initiate and
maintain sleep. Physiological later age-dependent changes in sleep include changes
in sleep architecture, increased sleep fragmentation and increased susceptibility to
certain sleep disorders, such as OSA, insomnia and REM behaviour disorder.
Moreover, PSG findings, such as significant reductions in SWS associated with
ageing, are linked to poorer episodic memory scores. In addition, spectral power
in the frequency range of sleep spindles is also reduced in middle-aged and older
adults, with maximal reductions observed over frontal regions. However, the largest
age-related impairments appear in the final sleep cycles of the night, with significant
reduction of faster frequency spindles. Conversely, the duration of REM sleep remains
relatively constant throughout adulthood.
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In summary, sleep beyond the fih decade of age is associated with several wellcharacterised changes in sleep architecture that include advanced sleep timing (i.e.
earlier bedtimes and rise times), longer sleep-onset latency, shorter overall sleep
duration, increased sleep fragmentation, more fragile sleep (i.e. greater likelihood of
being woken by external sensory stimuli), reduced SWS, increased time spent in lighter
N1 and N2 sleep, shorter and fewer NREM–REM cycles, and finally, an increased time
spent awake throughout the night. The increased number of arousals per night may
be consequent to the decline in neural systems that regulate sleep or an age-related
change in arousal thresholds to external stimuli.
Of note is, however, that whilst older adults experience more awakening during sleep,
they do not seem to report extensive middle insomnia. In addition, there are some
remarkable sex dierences. For instance, majority of sleep ageing changes have been
reported as more prominent in men. Nonetheless, this changes in women in the
perimenopausal or postmenopausal period, who then appear to show similar decline
in quality and quantity of sleep.
Sex dierences in sleep
Sleep is known to be modulated by sex hormones, although the exact mechanisms
underlying this interplay remain to be fully mapped out. For instance, sleep is known to
be aected by the ovarian hormones in women across the adult lifespan. Development
of sleep disorder following menopause contributes to accelerated cognitive decline
and dementia in older women. Disturbed sleep architecture during perimenopausal
changes is associated with the presence of vasomotor symptoms (hot flushes) and
lower sleep eciency. Higher cortisol levels or greater cortisol reactivity has been
suggested as one mechanism that links hot flashes, sleep and depressive or anxiety
symptoms to decrements in cognitive performance.
Sleep disturbances and insomnia are reported by 40–60% of perimenopausal
women. Moreover, the perimenopausal transition is linked with increased frequency
of self-reported problems, such as falling and staying asleep, and reduced total sleep
time. (Peri)menopausal sleep disruption can exacerbate other pre-existing sleep
disorders, including restless leg syndrome and circadian disorders, as well as lead to
increased prevalence of new ones, such as OSA. OSA prevalence increases partly due
to weight gain, and probably also due to hormone changes and other mechanisms.
Similarly, higher risk of insomnia, and depressive and anxiety disorders are reported.
Of note is that postmenopausal women who receive timely hormone replacement
therapy have a reduced latency to fall asleep, and fewer night-time awakenings and
less wakefulness. In addition, the timing of oestrogen exposure in relation to the
menopausal transition and age are increasingly seen as clinically important. In the
case of cognitive outcomes, some evidence supports the ‘critical window hypothesis’
that suggests that exposure early in the menopausal transition or postmenopausal
period may confer cognitive benefit, with exposure later in the menopausal transition
having no, or even detrimental eects.
Sleep complaints are also known to increase during other periods of large
fluctuations of ovarian hormones, including during puberty, pregnancy and the
menopausal transition. Moreover, there is also evidence for sleep changes across
the menstrual cycle. Poorest quality of sleep is traditionally reported during the
mid-to-late luteal phase. This phase is associated with increased reports of nighttime awakenings and arousals, and with decreased SWS. In addition, sleep spindles
have been reported as more frequent and longer in duration, and to occur in higher
EEG spectral frequency during the luteal, than the follicular, phase. Interestingly,
6
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dierences in objective sleep measures have been demonstrated in women taking
oral contraceptives, with increased N2 and REM, and reduced SWS, relative to
naturally cycling women.
Moreover, women and men appear to dier in the eect of sleep on the hypoxic
ventilatory response (HVR). It is known that the ventilatory response to hypoxia falls
during sleep in healthy adults. In men, the HVR has been shown to be lower during
NREM sleep than during wakefulness. However, in women, the responses were
shown to be similar in wakefulness and NREM sleep. Previous investigations have
demonstrated that progesterone may be a ventilatory stimulant and, correspondingly,
women have been shown to have higher ventilatory responses in the luteal, than in
the follicular, menstrual phase.
Taken together, past studies suggest that women, with relatively higher resting
ventilation, have lower responses to hypoxia and hypercapnia. The major sex/gender
dierence appears in the levels of ventilatory response during wakefulness, which is
much higher in men than in women. However, the ventilatory responses in NREM
sleep, to hypocapnic hypoxia and to the posthypoxic ventilatory decline, appear
similar in both sexes/genders. During REM sleep, both sexes have been reported to
have lower HVRs than in NREM sleep.
Control of breathing during sleep and wakefulness
Problems with breathing are present in most common sleep disorders and are
associated with a wide range of poor health outcomes.
Continuous breathing movements only become apparent around the 11th week of
gestation. They are initially present during periods of low-amplitude electrocortical
activity, eye movement and no neck EMG activity, corresponding to the REM sleep
state. During NREM sleep, a potent inhibition (from the lateral pons) leads to a
complete cessation of breathing movements. At birth, the newborn establishes
gas exchange through the lungs. Thereaer, during the first year of life, respiratory
control and the chemical drives are subjected to significant maturation during which
irregularities of the breathing pattern become less frequent.
The brainstem respiratory network includes:
• Respiratory neurons that generate respiratory rhythm and drive the expression of
rhythmic activity in other components of the respiratory network.
• Respiratory motor pools that activate the primary and secondary muscles of
breathing.
• Chemosensors that detect alterations in blood gases and elicit a physiological
response.
The primary respiratory muscles are those that generate airflow, such as the
diaphragm. Conversely, the secondary accessory muscles, such as the pharyngeal
muscles, significantly modulate airflow passage. They can also support the act of
breathing, for example, the intercostal muscles, which contribute to the maintenance
of lung volume. The level of respiratory-related and tonic activities varies for dierent
muscle groups, with some muscles expressing mainly tonic activity and others (e.g.
intercostals) expressing both tonic and respiratory activity. Tonic activity is commonly
suppressed in sleep.
The main components of the respiratory network (figure 2c) are traditionally divided
into the ventral (VRG) and dorsal respiratory groups (DRG). The VRG group includes
Bötzinger expiratory complex neurons, pre-Bötzinger inspiratory complex neurons,
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rostral VRG (predominantly inspiratory) neurons and caudal VRG (predominantly
expiratory) neurons. The DRG consists of primarily inspiratory neurons that, together
with the nucleus of the solitary tract, receive projections and aerents important
to the reflex control of breathing. These aerents include the carotid and aortic
chemoreceptors and baroreceptors, and lung vagal aerents. Importantly, in the
case of hypoventilation during sleep, the physiological response includes both an
attempted chemoreceptor-mediated increase in ventilation and arousal from sleep.
In summary, the brain functions as a gain-setting device for breathing by altering the
neurochemistry of the key elements of respiratory control, including the respiratory
neurons, the motoneurons and the sites involved in the reflex modulation of breathing.
Moreover, the respiratory network is moderated by the same state-dependent arousal
and sleep systems shown in figures 1 and 2. During sleep, there is an increase in
the GABAergic inhibitory system tone and a corresponding decrease in excitatory
influences from the brain arousal systems. The overall result may be decreased brain
arousability, including alteration of drives to the respiratory network. These statedependent changes aect the musculature, especially that of the upper airways,
potentially leading to OSAs and hypopnoeas in susceptible individuals (figure 2c).
The automatic rhythm of breathing is generated by the intrinsic pacemaker cell
membrane properties and the sum eects of their interconnectivity within the
respiratory network. Essential to expression of this rhythmicity is a sucient level
of underlying tonic excitation, which is regulated by the wakefulness-dependent
neural systems (figure 1) as well as the peripheral and central chemoreceptors
(figures 4 and 5). Thus, the brain arousal systems provide a major source of such
5HT
Noradrenaline
Retrotrapezoid nucleus
Nucleus tractus solitarius
Figure 4. The key brain regions of interest of chemoception/responsivity to changes in CO 2 and
protons (H+). The retrotrapezoid nucleus located near the ventral surface of the medulla is a
key region that is intrinsically sensitive to alterations in CO2/H+. Dendrites from retrotrapezoid
neurons are in contact with the cerebrospinal fluid at the medullary surface and are activated by
increased CO2 (decreased H+). The graph demonstrates the response of a brainstem serotonergic
neuron to increases in inspired CO2. Of note is: 1) baseline activity (i.e. at zero inspired CO2) is
higher in wakefulness than in sleep; 2) the neuronal activity at any given inspired CO2 is greater
in wakefulness than in sleep; 3) the slope (gain) of response is also greater in wakefulness than
in sleep. These are three main features that comprise the overall respiratory responses to CO2,
as measured by changes in ventilation. 5HT: serotonin. Reproduced and modified from Horner
et al. (2016) with permission from the publisher.
8
Awake
Cell activity
Inspired CO
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‘behavioural’ excitation to modulate breathing volitionally or nonvolitionally. During
the transition to NREM sleep, such behavioural influences on respiratory network
activity are reduced and as a result, the respiratory system becomes dependent
upon feedback regulation in NREM sleep to sustain sucient activity. In NREM
sleep, tonic activity of the peripheral and central chemoreceptors maintains
eective breathing. However, any pathological process that may aect feedback
chemoreceptor control will thus cause severe respiratory disturbance. Conversely,
in REM sleep, the heightened state of brain arousal (figure 2) restores adequate
behavioural drives to the respiratory network.
Under physiological conditions, the levels of oxygen (O2) and carbon dioxide (CO2)
in the blood remain remarkably consistent under disparate physiological states,
ranging from SWS to exercise. The stable modus operandi is maintained through the
concerted actions of central and peripheral chemosensing mechanisms, of which
chemoreception of CO2 (figure 4) is, in humans, more sensitive than that of O2 (figure
5). It has been shown that relatively small (∼1.3 kPa (∼10 mmHg)) increases in P
from normal circulating levels (6.0 kPa (45 mmHg)) are sucient to promote a marked
change in V′E. However, a much greater P
from physiological levels is required to markedly change basal V′E. Sensitivity of the
decrease (2.7–5.3 kPa (20–40 mmHg))
aO
2
aCO
2
peripheral chemoreceptors to oxygen increases dramatically only when the O2 tension
of the blood flowing through the carotid body (CB) falls from between 10.7 kPa
(80 mmHg) and 13.3 kPa (100 mmHg) to 8.0 kPa (60 mmHg).
Ventilatory response to hypercapnia and hypoxia
The ventilatory responses to hypoxia and hypercapnia are fundamental to the
homeostatic regulation of arterial blood gases. These ventilatory responses are reduced
in NREM sleep, compared to wakefulness, and are further reduced in REM sleep.
Mammals respond to hypercapnia and hypoxia by increasing V′E to maintain a neutral
balance of acid and base (figure 4). Hypercapnia is the main driver of the ventilatory
response and is likely mediated by the retrotrapezoid nucleus, located on the ventral
medullary surface with aerents to the respiratory rhythm generator (figure 4). The
consequent hypercapnic ventilatory response (HCVR) is expressed as the change
Glomus cell output
Neurotransmitter
P
O
2
Blood Chemoreceptor cell CSN Respiratory sytem
Figure 5. Ventilatory response to hypoxaemia. Decreased P
(CB), the major peripheral chemoreceptor involved in hypoxic response. In the CB, hypoxia
activates the release of neurotransmitters from CB glomus cells that increase the activity of the
CSN, which is integrated in the brainstem to produce the HVR. The HVR aims to restore normal
blood O2 levels. Also note the inverse exponential relationship between hypoxaemia and HVR,
with the HVR being higher at lower P
release
Action potential
. P
aO
O
2
CSN output
2
frequency
: oxygen tension.
Systemic output
Ventilation
(HVR)
is sensed by the carotid body
aO
2
S
60 100
50
)
–1
(L·min
E
V
0
20 100
P
aO
aO
2
(mmHg)
2
(%)
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in V′E per change in CO2 at the end of exhalation. In contrast, the HVR arises from
peripheral chemoreceptors that sense P
of the common carotid arteries, the so-called CB (figure 5). It is expressed as the
change in V′E per change in S
responses, which may be genetic.
. There is inter-individual variation in these ventilatory
aO
2
and are located mainly at the bifurcation
aO
2
The threshold level of hypercapnia to provoke arousal from sleep is similar, on
average, between NREM and REM sleep in humans, whereas the level of asphyxial
hypoxia (e.g. hypoxia of the type experienced in OSA) oen elicits arousal at lower S
aO
in REM than NREM sleep. However, isocapnic hypoxia is generally a weak stimulus
of arousal from sleep and the threshold is similar between NREM and REM sleep.
Moreover, the normal decrease in V′E from wakefulness to sleep commonly results
in minimal changes in S
portion of the oxyhaemoglobin dissociation curve. However, if an individual is initially
, predominantly because the starting P
aO
2
is on the flat
aO
2
hypoxaemic, therefore initially positioned on the steep portion of the dissociation
curve, the eects can be significant. This can happen in individuals at altitude, or
with depressed ventilation or impairments in breathing for any reason. The core
physiological principle is that any state that lowers P
predispose to worsening hypoxaemia in sleep, especially in REM sleep.
in wakefulness will similarly
aO
2
The arterial chemoreceptors, aortic bodies and, in particular, the CB are activators of
regulatory mechanisms that act to minimise hypoxia and to prevent its deleterious
eects. The CBs are polymodal chemoreceptors, that sense P
other stimuli. They are responsible for the greatest part of the hyperventilation
, P
aO
and pH, among
aCO
2
2
observed during hypoxaemia and they contribute to the hyperventilation that
accompanies respiratory or metabolic acidosis. The remaining respiratory drive is due
to aortic bodies in the case of hypoxaemia and to central chemoreceptors in the case
of acidosis. The chemosensory unit of the CB are the glomus cells that, in response to
hypoxia, hypercapnia and acidosis, release neurotransmitters that modify (increasing
or inhibiting) the frequency of carotid sinus nerve (CSN) sensory fibres. Central CSN
projections terminate in the brainstem, where the firing frequency is integrated by the
respiratory central control system, generating a compensatory ventilatory response
(figure 5). This response is defined as HVR.
The HVR is characterised by an increase in V′E that allows the body to restore normal
blood O2 levels. The HVR depends on the intensity of hypoxia and on its duration. The
isocapnic HVR is divided into two phases:
2
• a first phase (0–5 min) of immediate ventilation increase (acute HVR (AHVR))
• a second phase (5–20 min) of slow decline (hypoxic ventilatory decline)
The CSN P
and below this, the slope between P
threshold to hypoxia corresponds to 9.3–10.0 kPa (70–75 mmHg)
aO
2
linear to exponential until 1.3–2.0 kPa (10–15 mmHg). At very low P
(<10 mmHg)), the discharges may tend to level o or decrease. At P
(∼75 mmHg), the O2 content of the blood is ∼95% normal, which implies that the CB
triggers hyperventilation before real tissue hypoxia appears. The relationship between
P
and ventilation is similar to that described for P
aO
2
being as high as the drop in P
Of note is that HVR may also depend on several other factors, including sex, age,
previous hypoxic exposures and sustained CO2 tension. In addition, it can be modified
in the presence of sustained or intermittent hypoxic episodes that can increase or
decrease breathing. If chronic and sustained, hypoxia (hours to months) promotes
10
(figure 5).
aO
2
and CSN discharges changes abruptly from
aO
2
and CSN activity, with the HVR
aO
2
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(<1.3 kPa
aO
2
∼10.0 kPa
aO
2
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an increase in V′E greater than that found during acute exposure (minutes) to the
same degree of hypoxia. This process is called ventilatory acclimatisation to hypoxia.
However, if the exposure is intermittent, it is believed to aggravate OSA severity by
enhancing AHVR, thereby promoting ventilatory overshoot when apnoea ends and
perpetuating apnoea during sleep, although this remains controversial. The reported
discrepancies may reflect individual variability, disease severity and the time of the
day at which the AHVR was evaluated. For example, it has been observed that HVR
is higher in the morning in the OSA patients, compared to the evening values, with
the response further augmented by repeated daily exposure to intermittent hypoxia
independent of the time of day.
In summary, interactions between the ventilatory responses to hypercapnia and
hypoxia, and arousal from sleep, can provoke unstable breathing and central apnoeas.
The same predisposition to unstable breathing during arousal from sleep will be also
relevant to the ventilatory responses to hypoxia or to combined hypercapnia and
hypoxia, i.e. asphyxia, as seen in SDB. For example, the equilibrium point for waking
ventilation could shi to the le in situations of acute or chronic hyperventilation
caused by anxiety, CHF, etc. Likewise, the equilibrium point for sleeping ventilation
could shi to the right with drug-induced respiratory depression.
Cardiovascular function during sleep
Recent evidence suggested that cardiovascular control during sleep plays a
substantial – possibly causal – role in overall cardiovascular risk. Myocardial infarction
and ischaemic stroke are more frequent during early morning hours, when REM sleep
predominates. This timing of events may be explained by both specific alterations in
autonomic regulation during sleep and circadian rhythm molecular clocks present in
each cardiovascular cells, as summarised in figure 6. However, a complete physiological
understanding of sleep-related cardiovascular control in men remains elusive.
Sleep and cardiovascular autonomic regulation
A physiological fall in sympathetic activity occurs during NREM sleep, particularly in
the deepest stage of NREM sleep, which is at stage N3 or SWS. Heart rate slows by
5% to 10%, and BP drops by ∼10%. This decline has been referred as the dipping
phenomenon. In studies where the circadian rhythm and sleep–wake cycle are
dissociated, the BP dipping eect is primarily related to the sleep–wake cycle rather
than to the endogenous circadian rhythm. Central commands during NREM may
involve the hypothalamic ventrolateral preoptic area, central thermoregulatory and
central baroreflex pathways, and command neurons in the pons and midbrain. The
baroreflex control is reset to lower levels of renal sympathetic nerve activity and BP,
compared with wakefulness. During NREM sleep, parasympathetic activity becomes
dominant and therefore, there is an increase in the high-frequency component of
heart rate variability compared with wakefulness and quite a marked reduction in the
low-frequency component.
During REM sleep, opposing changes in vascular resistance in dierent regional beds
have the net eect of increasing BP compared with that of NREM sleep, approaching
wakefulness BP levels. Renal sympathetic activity remains low in both REM and
NREM phases. REM sleep is characterised by autonomic instability with bursts of
sympathetic activity associated with baroreflex suppression and increased tone of
muscle vascular beds. Therefore, transitions from NREM to REM sleep are associated
with physiological increases in BP and significant heart rate variability, with further
links to a higher cardiovascular morbidity.
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+
Heart
REM
–
NTS
Baroreceptor input
Hypothalamus
Medulla
Spinal cord
NREM
Platelet and PAI
activation
Figure 6. The mechanisms underlying cardiovascular changes during REM sleep (green) and
NREM sleep (orange). The master molecular clock located in the suprachiasmatic nucleus
(SCN) synchronises peripheral clocks via various neurohumoral signals (blue). During sleep, the
vasculature and heart are regulated by the autonomic nervous system and by local cellular
clocks that control tone and metabolism. Dashed lines represent inhibitory pathways. VLPO:
ventrolateral preoptic nucleus; MPO: median preoptic nucleus; PVN: paraventricular nucleus;
RVLM/RVMM: rostral ventrolateral and ventromedial medulla; NTS: nucleus tractus solitarius;
PAI: plasminogen activator inhibitor; SNA: sympathetic nerve activation.
Vessels
+
VLPO
Autonomic premotor neurons
Increased SNA/return to wakefulness
PVN
MPO
SCN
–
RVLM/RVMM
Dipping phenomenon
(rate and metabolism)
These eects are primarily a consequence of central autonomic commands, which
may involve the midbrain periaqueductal grey, the sublaterodorsal and peduncular
pontine nuclei, and the vestibular and raphe obscurus medullary nuclei. A role in
permitting physiological changes in BP during sleep may be additionally played by
orexin peptides released by hypothalamic neurons, which target the postulated
neural pathways of central autonomic commands during NREM and REM sleep
stages. The recent pharmaceutical development of dual orexin receptor antagonists
for use in clinical insomnia oer an exciting opportunity to examine which central
neural pathways and mechanisms are essential for sleep-related changes in
cardiovascular function.
Traditionally, changes in cardiovascular function during sleep have been understood
to be primarily due to the altered balance of parasympathetic and sympathetic activity.
More recently, advances in knowledge on circadian rhythms and their molecular clocks
have brought new important players into cardiovascular regulation during sleep.
The circadian clocks in cardiovascular cell types
Several circadian rhythm molecular clocks are thought to be directly involved in cardiovascular function. The master molecular clock, located in the suprachiasmatic nucleus
of the hypothalamus, synchronises peripheral clocks via various neurohumoral
signals. Peripheral clocks are present in each of the cardiovascular cell types. They
12
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respond to the central circadian pacemaker, and to tissue-specific synchronisers such
as food intake and exercise. Within the vasculature, the circadian clock is involved in
signalling of residing cells, thrombus formation, and vascular function and tone. BP
rises before waking early in the morning. This is linked not only to sleep and wake
cycles but also to daily fluctuations in intrinsic blood vessel properties. Prothrombotic
plasminogen activator inhibitor-1 levels and platelet activation increase between
01:00 and 06:00 h, the eects which are attributed to the endogenous circadian
system. In the heart, circadian rhythms regulate heart rate, cardiac metabolism,
responsiveness to various extracellular signals, contractility, signalling, and heart
growth and regeneration, contributing to peaks in the incidence of cardiovascular
events during sleep and, particularly, in the early morning.
Cardiovascular functional aspects of peripheral clocks are currently far from being fully
understood. Nonetheless, it has been demonstrated that misalignment of external
stimuli (day–night cycle) and the intrinsic circadian clock is associated with impaired
cardiovascular function in humans. Artificial light and screen exposure in the evening
are just two examples of the external modifiers that can desynchronise intrinsic clocks.
In summary, cardiovascular function during normal sleep is associated with reductions
in BP and heart rate during NREM sleep phase (dipping phenomenon), and with
peaks in BP and heart rate variability in the transitions to REM sleep. Peripheral clocks
present in peripheral cell types and their synchronisation with the day–night cycle are
associated with prothrombotic features during sleep in humans (figure 6).
Further reading
• Bigalke JA, et al. (2022). Orexin, sleep, sympathetic neural activity, and cardiovascular function.
Hypertension; 79: 2643–2655.
• Chellappa SL, et al. (2019). Impact of circadian disruption on cardiovascular function and
disease. Trends Endocrinol Metab; 30: 767–779.
• Crnko S, et al. (2019). Circadian rhythms and the molecular clock in cardiovascular biology and
disease. Nat Rev Cardiol; 16: 437–447.
• Douglas NJ (2011). Respiratory physiology: understanding the control of ventilation. In:
Kryger MH, et al., eds. Principles and Practice of Sleep Medicine. 5th Edn. Philadelphia,
Saunders; pp. 250–258.
• Duy JF, et al. (2009). Eect of light on human circadian physiology. Sleep Med Clin; 4: 165–177.
• Fink AM, et al. (2018). Autonomic regulation during sleep and wakefulness: a review with
implications for defining the pathophysiology of neurological disorders. Clin Auton Res; 28:
509–518.
• Goldberg S, et al. (2017). Analysis of hypoxic and hypercapnic ventilatory response in healthy
volunteers. PLoS One; 12: e0168930.
• Horner RL, et al. (2016). Control of breathing and upper airways during sleep. In: Broaddus VC,
et al., eds. Murray & Nadel’s Textbook of Respiratory Medicine. 6th Edn. Philadelphia, Elsevier
Saunders; pp. 1511–1526.e1.
• Joseph V, et al. (2021). Control of breathing during sleep and wakefulness in the fetus, newborn,
and child. In: Gozal D, et al., eds. Pediatric Sleep Medicine: Mechanisms and Comprehensive Guide
to Clinical Evaluation and Management. Cham, Springer International Publishing; pp. 19–31.
• Mason RJ, et al. (2016). Control of breathing and upper airways during sleep. In: Broaddus VC,
et al., eds. Murray & Nadel’s Textbook of Respiratory Medicine. 6th Edn. Philadelphia, Elsevier
Saunders; pp. 1511–1526.
13ERS Handbook: Respiratory Sleep Medicine
Соседние файлы в папке Библиотека им академика М.И. Перельмана