Physiology and Neuroanatomy
of sleep
BY
AHMAD YOUNES
PROFESSOR OF THORACIC MEDICINE
Mansoura Faculty of Medicine
Behavioral Definition:
• Wakefulness: is a state in which the person is aware of and
responds to sensory input from the environment.
• Sleep: is a state of behavioral quiescence accompanied by an
elevated arousal threshold and a species-specific sleep
posture (recumbent sleep posture, closed eyes, diminished
responsiveness to external stimuli and decrease in or
absence of movements)
• Sleep is an ACTIVE process. It is a reversible state of
unresponsiveness to stimuli of the outside world and to responses
within the brain which underlie perception.
• Sleep is a state of reversible un-conciousness in which the brain is
relatively more responsive to internal than external stimuli
Sleep function
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Memory consolidation
Energy conservation
Body growth
Regulation of immune function
Protective behavioral adaptation
Sleep architecture
• Sleep architecture is a term used to describe the
division of sleep among the different sleep stages
using specific EEG, EOG, and chin EMG criteria. It
also involves the relationship of the individual sleep
stages to each other .
• Sleep can be differentiated into NREM sleep and
REM sleep. NREM sleep can be further subdivided
into stages 1, 2, 3, and 4 sleep. NREM stages 3
and 4 sleep are often collectively referred to as slow
wave or delta wave sleep.
Sleep Architecture
W
1
REM
2
3+4
(SWS)
1
2
3
75% SWS
4
5
6
7
8
75% REM
General information
• NREM and REM occur in alternating cycles, each lasting approximately
90-100 minutes, with a total of 4-5 cycles.
• In the healthy young adult, NREM sleep accounts for 75-90% of sleep
time (3-5% stage I, 50-60% stage II, and 10-20% stages III and IV). REM
sleep accounts for 10-25% of sleep time.
• Total sleep time in the healthy young adult approximates 6-8 hours.
• The newborn sleeps approximately 16-20 hours per day; these numbers
decline to a mean of 10 hours during childhood.
• In the full-term newborn, sleep cycles last approximately 60 minutes
(50% NREM, 50% REM, alternating through a 3-4 h inter-feeding period).
General information
• Pregnancy:
st trimester (increase in total sleep time ,daytime sleepiness
and nocturnal awakening )
2nd trimester (normal sleep )
3rd trimester (increased nocturnal awakening with subsequent
daytime sleepiness and decreased total sleep time)
• In elderly, SWS decrease and N2 compensatory increase,
increase in latency to fall asleep and the number and
duration of overnight arousal periods, time in bed increase
with subsequent complaint of insomnia .
Regulation of Sleep and Wakefulness:
• Two basic intrinsic components
1-Circadian rhythm (process C)
2-Sleep homeostasis (process S),
Sleep homeostasis is characterized by an increase in sleep pressure following
sleep deprivation that is related to the duration of prior wakefulness followed
by a decline in sleep need as sleep accumulates.
Circadian process There are two circadian peaks in wakefulness : one
occurring (early evening) and a second peak (late morning). Sleep propensity
is least during these peaks of circadian rhythms of arousal
Greatest sleep propensity during periods of (overnight between 3:00 and 5:00
am; early-mid afternoon between 3:00 and 5:00 pm).
3-Sleep inertia (process W), refers to the short-lived reduction of alertness that
occurs immediately following awakening from sleep and disappears within 2 to
4 hours.
Brain Mechanisms Controlling Sleep
• Sleep is promoted by a complex set of neural and
chemical mechanisms
• Daily rhythm of sleep and arousal
– Supra-chiasmatic nucleus of the hypothalamus (body clock)
– pineal gland’s secretion of melatonin
• Light is called a Zeitgeber, a German word meaning
time-giver because it set the supra-chiasmatic clock
• Altering light/dark cycles produces phase shift and
entrainment
Evidence for the SCN as biological clock
• Circadian = diurnal + nocturnal
• Zeitgebers and the SCN: Biological clock
– Altering light/dark cycles produces phase shift and
entrainment
– SCN lesions disrupt circadian rhythms
– Transplanted SCNs set rhythms of donor animal
Light and Melatonin
The pineal gland is a tiny endocrine gland situated at
the centre of the brain
• The major pineal hormone, however, is melatonin, a
derivative of the amino acid tryptophan.
• Melatonin secreted by pineal gland signals brain
that it is time to sleep
• Light suppresses melatonin secretion.
• Bright light very early in the morning can cause a
phase advance
• Bright lighting can reduce fatigue for workers forced
to work at night
Neuroanatomy of Wakefulness
The reticular activating system (RAS) is located in the brain stem. it is
believed to play a role in sleep and waking, behavioral motivation,
breathing, and the beating of the heart.
RF has two major ascending projections into the forebrain:
1. Dorsal pathway → thalamus → cerebral cortex (thalamocortical system)
2. Ventral pathway → subthalamus and posterior hypothalamus → basal
forebrain and septum → cerebral cortex
• The ascending reticular activating system also receives input from
visceral,somatic, and special sensory systems.
• The descending RAS connects to the cerebellum and to nerves
responsible for the various senses.
• Neurotransmitters
Acetylcholine , Dopamine ,Glutamate ,Histamine ,Hypocretin (orexin)
,Norepinephrine, Serotonin
Most wake circuits originate in the Brain stem arousal nuclei
(BAN), which stimulate the thalamus, hypothalamus (Hyp) and
basal forebrain. These projections also inhibit sleep centers
Neuroanatomy of NREM sleep
• NREM sleep
Forebrain (anterior hypothalamuspreoptic region, including ventrolateral preoptic
area [VLPO] and basal forebrain)
• Neurotransmitters
serotonin and gammaaminobutyric acid (GABA).
Other neurotransmitters include adenosine,
norepinephrine,
The ventrolateral preoptic nucleus (VLPO) in the hypothalamus inhibits the
BAN and the parts of the hypothalamus involved in wakefulness. This leads
to inhibition of other wake-centers including the thalamus, basal forebrain,
and the cortex, and thus the initiation and maintenance of sleep.
Neuroanatomy of REM sleep
• REM sleep Pons (pedunculopontine tegmental
nuclei and the laterodorsal tegmental nuclei)
Brainstem reticular formation, especially oral
pontine reticular formation ,Other brainstem (lower
medullary) and spinal cord neurons
• Neurotransmitters:
The main REM sleep neurotransmitter is
acetylcholine.
Other neurotransmitters include GABA and glycine.
The SCN is the circadian “pacemaker” and is influenced by light, activity,
and melatonin to promote either wake or sleep. Signals from the SCN are
amplified by the SPZ and the DMN, which project to the VLPO (promotes
sleep), the lateral hypothalamus (promotes wakefulness), and the PVN
(controls pineal melatonin release).
The PVN is stimulated by the SCN, in a circadian fashion, to produce corticotrophinreleasing factor (CRF). This acts on the pituitary gland (Pit), which in turn produces
adrenocorticotrophic hormone (ACTH). ACTH is then released into the bloodstream
where it initiates the release of cortisol from the adrenal glands. Cortisol is one of the
factors involved in the sleep/wake cycle through a feedback system whereby it can
then influence activity in the hypothalamus. Thus the HPA axis is important to
regulation of sleep and arousal.
Summary
• Circadian arousal is largely influenced by ocular exposure to light; thus it
rises in the morning, declines with a gradual slope throughout the day,
and then declines further beginning in the late evening.
• Body temperature is also at its lowest in the early morning, rising
throughout the morning and then staying fairly steady until it begins to
decline again in the late evening.
• Combined with this, a morning pulse of cortisol, which binds to circadian
hypothalamic receptors, stimulates arousal from sleep with levels
declining throughout the day.
• In addition, certain brain chemicals (e.g., adenosine, a byproduct of
energy metabolism), accumulate during waking time and decline during
sleep. The varying levels of these chemicals affect one’s wake
propensity, with wake propensity declining as they accumulate and then
increasing as the sleep debt is paid.
Hyperarousal is considered an underlying cause of insomnia and may
be related to dysfunction of the HPA axis.
With hypoarousal, there is thought to be reduced basal ACTH
secretion and a reduction of central CRF. Extreme hypoarousal
underlies excessive sleepiness present in numerous sleep/wake
disorders.
Autonomic nervous system physiology
• Parasympathetic tone increase and sympathetic tone decrease during
NREM sleep
• During arousals , sympathetic tone increase in bursts .
• During tonic REM sleep ,Parasympathetic tone increase even further
whereas sympathetic tone reaches its lowest level .
• During phasic REM sleep sympathetic tone transiently increases .
• Muscle tone is maximal during wakefulness but decrease during NREM
sleep and decrease even further during REM sleep
• During REM sleep , myotonic bursts (phasic twitches ) as evidenced by
intermittent surges in EMG .
• Overall decrease in upper airway dilator muscles during NREM sleep
,the reduction is even greater during REM sleep .
Respiratory physiology
• Minute ventilation falls by 0.5-1.5 liters during NREM sleep
due to a reduction in tidal volume rather than in respiratory
rate .
• During REM sleep the fall in minute ventilation is similar but
being irregular during phasic REM.
• Functional residual capacity decrease by 10% during sleep.
• Arterial Pao2 decrease by 3-10 mmHg and Sao2 decrease
by <2%.
• Arterial Paco2 increase by 2-8 mmHg during sleep .
Respiratory physiology
• Hypoxic ventillatory response and hyper-capnic
ventillatory response decrease during NREM sleep
and decrease further during REM sleep due to
decreased chemo-sensitivities.
• Cough reflex decrease during NREM and REM
sleep .
The Upper Airway as a Collapsible Cylinder
• Upper airway patency is influenced by several factors,
including its collapsibility, length, and caliber, and pressure
gradient against its wall.
• Intraluminal extrathoracic airway pressure decreases during
inspiration, leading to a narrowing of the airway. Narrowing
of the airway initially accelerates airflow, which further
promotes airway narrowing.
• The critical closing pressure (Pcrit) is the intraluminal
pressure at which the upper airway collapses and airflow
ceases. Pcrit is progressively less negative as one goes
from non-snorers, to snorers, to persons with predominantly
hypopnea, and, finally, to those with apnea whose Pcrit is
generally near atmospheric pressure.
The Upper Airway as a Collapsible Cylinder
• Activation of upper airway dilator muscles decreases Pcrit
(reduces airway collapsibility) and increases airflow.
• The activity of the upper airway dilator muscles is diminished
by sleep, alcohol ingestion, and the use of muscle relaxants.
• During wakefulness, reflex upper airway dilator muscle
activation is triggered by negative subatmospheric
intraluminal pressure. This Reflex is diminished as sleep
progresses from NREM to REM sleep.
• Upper airway dilator response to hypoxia and hypercapnia is
suppressed during NREM sleep and may be completely
abolished during REM sleep.
• Activation of upper airway muscles preceding activation of
the diaphragm
Cardio-vascular physiology
• Heart rate decrease during NREM sleep but fluctuate
greatly during REM sleep .
• Brady-tachycardia seen during phasic REM sleep is due to
variations of both parasympathetic and sympathetic activities
• Cardiac output decrease during both NREM and REM sleep.
• Pulmonary blood pressure increase slightly during sleep
• Arterial blood pressure decrease by 10% during NREM
sleep ,during phasic REM sleep fluctuate due to sympathetic
activities .
• Cerebral blood flow decrease 5-20% during NREM sleep
,during REM sleep an increase in blood flow by up to 40%
Endocrine physiology
• Melatonin release peaks during sleep
• Growth hormone peak 90 minutes after sleep onset
(closely associated with slow wave sleep)
• Cortisol secretion is independent of sleep. Its peak
is in the early morning .
• Thyroid stimulating hormone decrease during sleep.
• Testosterone increase during sleep .
• No relation between GTH ,LH, FSH and sleep .
• Prolactin level increase during sleep .
Gastro-intestinal physiology
• Lower esophageal sphincter tone show no circadian
variation .
• Transient lower esophageal sphincter relaxation lead to
GERD during awakening from sleep rather than during
sleep .
• Most events of GERD occur during stage 2 may be due to
increased vagal tone which decreases lower esophageal
sphincter tone.
• Basal gastric acid secretion displays a circadian
rhythmicity, with a peak secretion between 10:00 pm and
2:00 am (as a result of increased parasympathetic activity)
and a nadir in the morning between 5:00 and 11:00 am.
• Swallowing 25/h during the day but 5/h during sleep
• Gastric emptying decrease during sleep but esophageal
motility shows little circadian variation .
Studying sleep
• Electroencephalogram (EEG)
• Electromyogram (EMG)
• Electro-oculogram (EOG)
Brain wave activity
Wakefulness
– Alpha waves
– Beta waves
Beta Activity
• A waveform of 14 to 30 Hz
• Originates in the frontal and central regions
• Present during wakefulness and drowsiness
• May become persistent during drowsiness,
diminish during SWS, and reemerge during REM
sleep
• Enhanced or persistent activity suggests use of
sedative-hypnotic medications
Alpha Activity
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A waveform of 8 to 14 Hz
Originates in the occipital regions bilaterally
Seen during quite alertness with eyes closed
Eye opening causes the alpha waves to decrease
in amplitude
• Has a crescendo-decrescendo appearance
• Has diminished frequency with aging
Theta Activity
• A waveform of 3 to 7 Hz
• Originates in the central vertex region
• The most common sleep frequency
Delta Activity
• A waveform of 0.5 to 2 Hz
• Seen predominantly in the frontal region
• Delta activity has an amplitude criterion of 75 µV
• Stage-3 sleep defined when 20% to 50% of the
epoch is scored as delta activity
• Stage-4 sleep defined when >50% of the epoch is
scored as delta activity
• In AASM ,stage 3,4 are named N3
Sleep Spindles
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A waveform of 12 to 14 Hz
Originates in the central vertex region
Has a duration criterion of 0.5 to 2-3 seconds
Typically occurs in stage N2 sleep but can be seen
in other stages
K Complexes
• Defined as slow waves, with a biphasic morphology
(first negative and then positive deflection)
• Predominantly central vertex in origin
• Duration must be at least 0.5 seconds
• Indicative of stage N2 sleep.
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Vertex sharp wave :
• Sharply contoured waves
• Duration < 0.5 sec
• Maximal over the central region (derivations
containing C3, C4, Cz) and distinguishable from
the background activity (higher amplitude).
• Occurs in stage N1 often near transition to stage N2
Saw-tooth waves
• Saw-tooth waves occur during REM sleep,
although they are not always present during this
sleep stage.
• They are triangular waves of 2 to 6 Hz of highest
amplitude in the central derivations.
• The presence of saw-tooth waves is not required to
score stage R.
Arousal:
• An arousal is scored if there is an abrupt shift of
EEG frequency including alpha, theta, and/or
frequencies greater than 16 Hz (but not spindles)
that lasts at least 3 seconds, with at least 10
seconds of stable sleep preceding the change.
An abrupt shift in EEG frequency immediately follows the K complex
that lasts greater than 3 seconds. To be considered associated with a
K complex, an arousal must commence no later than 1 second after K
complex termination.
Slow Wave Sleep deprivation is
associated with reduction in cognitive
performance
REM Deprivation
• Moodiness
• Inability to consolidate complex learning
REM appears to be important for psychological wellbeing
Interventions - caffeine
‘World’s most popular drug’
• Mild CNS stimulant
• 3.5 - 6 hr half-life
• 250 mg improves psychomotor function if sleep
deprived, 500 mg side effects w/o improvement
• Tachy-phylaxis
• Withdrawal headaches
• Affects sleep latency and sleep quality
Sedative-Hypnotics
• Alcohol causes sleep fragmentation and
decreased REM
• Most sedative-hypnotics disrupt the
architecture of sleep
The only way to completely reverse the
physiologic need for sleep is to sleep