Biollogia Sueño Semana 2

B a s i c Bi o l o g y o f S l e e p
John Harrington, MD, MPH*, Teofilo Lee-Chiong, MD
KEYWORDS
Sleep REM NREM Circadian rhythms
Sleep can be defined as a complex reversible state characterized by behavioral

quiescence, diminished responsiveness to external stimuli, and a stereotypical
species-specific posture. Unlike other states of reduced awareness and receptivity
to environmental influences, such as coma, delirium, or encephalopathy, both com-
ponents of sleep, non–rapid eye movement (NREM) and rapid eye movement (REM),
are generated and maintained by central nervous system (CNS) networks that use
specific neurotransmitters located in specific areas of the brain.
CONTROL OF SLEEP AND WAKING
Three physiologic processes control sleep latency (ie, time taken to fall asleep), dura-
tion and quality, and alertness, namely, (1) sleep homeostasis, (2) circadian rhythm,
and (3) sleep inertia.1,2 In addition, the timing of sleep and waking is also determined
by behavioral influences, such as social activities, meals, and work responsibilities.
Sleep homeostasis is the increase in sleep pressure related to the duration of imme-
diate prior wakefulness. This sleep pressure declines with sustained sleep. Slow wave
(delta) activity (SWA) is often used as a marker of homeostatic sleep pressure among
adults. Like sleep homeostasis, SWA increases during sustained wakefulness and
diminishes after sustained NREM sleep. Thus, it is more difficult to arouse a person
when SWA is high. The neurotransmitter adenosine is believed to regulate this homeo-
static sleep drive.
The circadian rhythm, on the other hand, is independent of the sleep-wake cycle. Its
main function is promoting wakefulness. Most individuals have 2 circadian rhythm–
related peaks in alertness, during the late morning and early evening, and 2 periods
of circadian troughs in alertness, in the early morning and early midafternoon. Increase
in circadian alertness resists the increase in homeostatic sleep pressure during the
waking period, and a decreasing circadian alertness opposes the decreasing homeo-
static sleep throughout the sleep period, thereby maintaining constant alertness
during the biological day and consolidated sleep during the biological night.
Sleep inertia, or a period of relative confusion and disorientation during the transition
between sleep and waking, is responsible for the sensation of sleepiness at the start of
the biological day when sleep homeostasis is at its lowest level.2
Division of Sleep Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
* Corresponding author.
E-mail address: harringtonj@njhealth.org
Dent Clin N Am 56 (2012) 319–330

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320 Harrington & Lee-Chiong
NEUROANATOMY OF SLEEP AND WAKING
The states of wake, NREM sleep, and REM sleep are each generated by discrete but
interconnected neural networks that use specific neurotransmitters. There are several
key sleep-wake neurotransmitters, including glutamate (main CNS excitatory neuro-
transmitter), g-aminobutyric acid (GABA, main NREM neurotransmitter), acetylcholine
(main REM sleep neurotransmitter), and glycine (responsible for inhibition of spinal
motor neurons that cause muscle atonia during REM sleep).3
Main neurotransmitters (and their neurons) involved in generating waking include
acetylcholine (basal forebrain and pedunculopontine tegmentum/laterodorsal
tegmentum in the brainstem), dopamine (substantia nigra), glutamate (reticular forma-
tion, thalamus, and hypothalamus), histamine (tuberomammillary nucleus), hypocretin
(lateral hypothalamic perifornical region), norepinephrine (locus coeruleus), and sero-
tonin (dorsal raphe). Main neurotransmitters (and their neurons) involved in the gener-
ation of sleep include acetylcholine (for REM sleep), adenosine (basal forebrain),
GABA (ventrolateral preoptic region), and melatonin (pineal gland).4
Acetylcholine is both a wake and a REM sleep neurotransmitter and is responsible
for cortical electroencephalographic (EEG) desynchronization seen during these 2
stages. Cholinergic agonists (eg, physostigmine) increase REM sleep, whereas cholin-
ergic antagonists (eg, tricyclic antidepressants) decrease REM sleep.
Adenosine, a sleep neurotransmitter, is, as stated earlier, responsible for the home-
ostatically driven sleep pressure. A byproduct of the breakdown of adenosine tri-
phosphate (ATP) released by glutamate-stimulated astrocytes, levels of adenosine
progressively increase during prolonged wakefulness and decrease during sleep.
Adenosine acts by inhibiting wake-promoting regions of the brain (via A1 receptors)
and activating ventrolateral preoptic nucleus (VLPO) neurons (via A2A receptors).
Adenosine receptor blockers (eg, caffeine) increase wakefulness and decrease EEG
SWA during sleep.
Dopamine is a wake neurotransmitter; D1 receptor agonists (eg, amphetamines) that
enhance dopamine release increase wakefulness, and dopamine antagonists (haloper-
idol and chlorpromazine) promote sleep. Glutamate is another wake and REM neuro-
transmitter, levels of which increase during waking and REM sleep and decrease
during NREM sleep. Glutamate stimulates the release of ATP by astrocytes. Histamine,
a wake neurotransmitter, is blocked by first-generation histamine-1 receptor blockers
(eg, diphenhydramine) and by low-dose doxepin, leading to sedation. GABA agonists
(eg, barbiturates, benzodiazepines receptor agonists, and sodium oxybate) cause
sedation and sleepiness.
Hypocretin (orexin) promotes wakefulness and suppresses REM sleep, and dysfunc-
tion of this neurotransmitter is associated with narcolepsy-cataplexy. Agonists of
norepinephrine (eg, isoproterenol), a wake neurotransmitter, increase arousal and
wakefulness. Precursors and reuptake inhibitors of serotonin, a wake neurotransmitter,
promote wakefulness.
Through their effects on one or more of these neurotransmitters, drugs and
substances can be sedating, alerting, or both, because of direct action on the neuronal
receptors, adverse reaction, or withdrawal effect. For example, stimulants can prolong
sleep onset latency and decrease total sleep time by increasing levels of dopamine
and norepinephrine (seen with amphetamine, cocaine, and methylphenidate), by aug-
menting the actions of hypocretin and dopamine (believed to account for the effects of
modafinil and armodafinil), by decreasing adenosine levels (caffeine), or by enhancing
acetylcholine release (nicotine). Stimulants, as a class, decrease sleepiness and
fatigue, increase alertness, and enhance daytime performance and memory.5 On
Basic Biology of Sleep 321
the other hand, sedating medications (eg, benzodiazepine receptor agonists express-
ing affinity for GABAA receptors and ramelteon, a melatonin receptor agonist) gener-
ally shorten sleep onset latency; long acting formulations of sedating agents may also
increase both total sleep time and sleep efficiency (ratio of total sleep time to total time
in bed).6
Aminergic neurons, activity of which decreases during NREM and REM sleep rela-
tive to waking, and cholinergic neurons, which are active during wake and REM sleep,
interact to switch between wakefulness and sleep (NREM and REM).
CIRCADIAN RHYTHMS
Biological rhythms are ubiquitous, being present in prokaryotic and eukaryotic

microbes, plants, insects, and animals, including humans. These rhythms are charac-
terized by specific amplitude (maximal excursion from peak to nadir), peak, nadir,
phase, and frequency (number of oscillations per unit time). The term circadian refers
to 1 oscillation approximately every 24 hours. Phase is the temporal position of the
endogenous rhythm in relation to an external reference, such as the 24-hour light-
dark cycle. A phase is considered advanced if it is shifted to an earlier time in the
24-hour cycle or delayed if it occurs later during the cycle. Most intrinsic human circa-
dian rhythms are not exactly 24 hours (commonly about 24.2 hours) and tend to free
run at this longer frequency in the absence of environmental time cues. The process by
which external cues adjust the phase (forward or backward) of the intrinsic circadian
rhythms is called entrainment, and the environmental cues that are capable of entrain-
ing intrinsic circadian rhythms are referred to as zeitgebers.7 Light is the dominant zeit-
geber, but other factors such as exogenous melatonin and timing of activities are
capable of phase shifting intrinsic circadian rhythms. Light provided at night before
minimum core body temperature (CTmin) can cause phase delay of the sleep-wake
rhythm, and morning light provided after CTmin can cause a phase advance.
The suprachiasmatic nucleus (SCN) is the master circadian rhythm generator in
mammals, promoting wakefulness during the day and consolidating sleep during
the night. The main afferent pathway involves photic stimuli reaching the retina and
from the retina to the SCN via the retinohypothalamic tract.8 Retinal ganglion cells
contain melanopsin and are most sensitive to shorter wavelength light (blue to blue-
green). Other photic (GABAergic, histaminergic, and cholinergic) and nonphotic (sero-
tonergic) pathways also exist. The SCN has efferent projections to several CNS areas,
including the hypothalamus and pineal gland, where melatonin is synthesized and
released. Like light exposure, melatonin can influence the sleep-wake rhythm, phase
delaying and advancing the rhythm when given in the morning and evening,
respectively.
PHYSIOLOGY DURING SLEEP
There are significant changes to several physiologic variables that occur during sleep,
including autonomic, respiratory, cardiac, renal/genitourinary, gastrointestinal, endo-
crine, thermoregulatory, and immunologic measures.
Autonomic Nervous System

Compared with levels during wake, sympathetic activity diminishes and parasympa-
thetic activity increases during NREM sleep; these changes are magnified further
during tonic REM sleep. Sympathetic activity transiently increases during phasic
REM sleep.9
Respiratory System
Although metabolic factors (ie, pH, PaO2, and PaCO2) and behavioral factors control
respiration during wakefulness, the latter is lost during sleep, leaving only metabolic
factors to remain operational during sleep. Thus, during early N1 sleep, periodic
breathing with episodes of central apneas/hypopneas and hyperpneas can develop
as PaCO2 levels fluctuate below and above the apneic threshold, respectively. Respi-
ration becomes regular in frequency and amplitude during stable N3 sleep but may
become irregular again during REM sleep with variable tidal volumes and respiratory
rates.10 Hypoxic and hypercapnic ventilatory responses, upper airway dilator muscle
tone, and activity of accessory muscles of respiration decrease during NREM sleep
compared with wakefulness and diminish further during REM sleep. Compared with
waking levels, PaO2 levels generally decrease by about 2 to 12 mm Hg, oxygen satu-
ration levels decrease by about 2%, and PaCO2 levels increase by 2 to 8 mm Hg.
Cardiovascular System
Heart rate, cardiac output, blood pressure (BP), and systemic vascular resistance
change with sleep, being relatively lower during NREM and tonic REM sleep than
during wakefulness and higher during phasic REM sleep and awakenings than during
NREM and tonic REM sleep.9 In addition, nighttime systolic BP is commonly about
10% less than daytime levels, a phenomenon referred to as BP dipping.11
Renal/Genitourinary System
Urine production diminishes during sleep because of reduced glomerular filtration as
well as increased water reabsorption and renin release. During REM sleep, penile
tumescence may develop in men and clitoral tumescence and vaginal engorgement
in women.
Gastrointestinal System
Basal gastric acid secretion displays a circadian rhythmicity, with peak levels between
10 PM and 2 AM and lowest levels between 5 AM and 11 AM. Other sleep-related changes
in the gastrointestinal system include decrease in salivary production, swallowing rate,
and esophageal and intestinal motility.
Endocrine System
Secretion of hormones is influenced by circadian rhythms, sleep, or both.12 For
instance, cortisol secretion is linked primarily to circadian rhythms, whereas growth
hormone (GH) secretion is linked primarily to sleep, specifically N3 sleep. Secretion
of thyrotropin, by comparison, is linked to both sleep and circadian rhythms. Levels
of GH increase, and levels of both cortisol and adrenocorticotropic hormone (ACTH)
decrease during the first half of the sleep period. During the second half of the sleep
period, GH levels decrease, whereas cortisol and ACTH levels increase. Release of
GH and prolactin occurs primarily during N3 sleep; in contrast, thyrotropin and cortisol
secretion is inhibited by sleep.
Thermoregulatory System
Core body temperature generally peaks in the late afternoon and early evening (6 PM–
8 PM) and decreases at the onset of sleep, with temperature nadir (4 AM–5 AM) occurring
about 2 hours before usual wake time (CTmin). Sleep, itself, is associated with several
changes in thermoregulation, namely, decline in core body temperature, decrease in
thermal set point, increase in heat loss because of peripheral vasodilatation, and
decrease in metabolic heat production with loss of heat generation due to shivering in
REM sleep. All these changes result in reduced thermoregulatory responses to
thermal challenges. Both sleep quality and architecture are determined by changes
in body temperature at bedtime: (1) sleep is suppressed if the individual is exposed
to extremely hot or cold environmental temperatures, (2) sleep is enhanced if it is
attempted during the falling phase of the temperature rhythm after maximum core
body temperature, and (3) waking occurs during the rising phase of the temperature
rhythm after CTmin.13
Immunologic System
Proinflammatory cytokines, such as interleukin (IL) 1b and tumor necrosis factor
a (TNF-a), enhance NREM sleep, whereas anti-inflammatory cytokines, such as IL-
4, IL-10, and transforming growth factor b, suppress sleep.14 Acute infectious and
inflammatory processes can give rise to sleepiness due, at least in part, to these
changes in immune processes. Obstructive sleep apnea can also be considered an
inflammatory disorder because it is associated with increased levels of proinflamma-
tory markers, such as C-reactive protein, IL-6, and TNF-a, as well as decreased levels
of anti-inflammatory markers.
MEASUREMENT OF SLEEP
Polysomnography (PSG) is commonly used to objectively characterize sleep and its

various stages. PSG consists of continuous and simultaneous recordings of several
physiologic variables during the sleep period, such as EEG, electro-oculography
(EOG), and chin electromyography (EMG). Other monitors may be used during PSG,
including electrocardiography, airflow and snoring sensors, thoracic and abdominal
movement detectors, oximetry, and limb EMG, to identify abnormal sleep-related
respiratory events, limb movements, or behaviors.15
EEG consists of placement of scalp electrodes based on the International 10–20
system, in which each electrode is provided with a letter (region of the brain) and
a numerical subscript, such as F (frontal), C (central), O (occipital), M (mastoid), odd
numbers (left-sided electrodes), even numbers (right-sided electrodes), and Z (midline
electrodes). Using the recommended EEG electrode placements, F4M1, C4M1, and
O2M1, the summed potential activity of cortical neurons are recorded as waves of
different frequencies (cycles per second or Hz), namely, beta (>13 Hz), alpha (8–13
Hz), theta (4–7 Hz), or delta (<4 Hz). Beta waves are seen during alert wakefulness;
alpha waves during waking with eyes closed; theta waves during N1, N2, and REM
sleep; and delta waves during N3 sleep.
EOG records the difference in potentials (dipole) between a positively charged
cornea and a negatively charged retina. Recommended EOG electrode placements
are E1M2 and E2M2, with E referring to the outer canthus of the eye. These electrode
locations create voltage changes with eye movements (ie, positive voltage causing
a downward tracing deflection when the eye moves toward an electrode and a negative
voltage with an upward tracing deflection when the eye moves away from an elec-
trode). Two general patterns of eye movements can often be seen: (1) slow rolling
eye movements that are present during waking with closed eyes, N1 sleep, or brief
awakenings and (2) REMs that occur during wakefulness with open eyes (eye blinks)
or REM sleep.
Chin EMG uses 3 electrodes, one on the midline above the inferior edge of the
mandible and one each on either side of the midline below the inferior edge of the
mandible.
Sleep is conventionally classified as either NREM or REM sleep. NREM sleep is

further subdivided into N1, N2, and N3 sleep. In scoring wake and sleep stages,
PSG data are divided into 30-second periods or epochs, and each epoch is assigned
a single sleep stage that comprises the greatest percentage of that epoch. An epoch is
classified as stage wake if more than 50% of the epoch has alpha EEG waves with eye
closure. Other characteristic features include conjugate vertical eye blinks, reading
eye movements, voluntary rapid open eye movements, and a relatively high chin
EMG tone (Fig. 1). When alpha EEG waves are replaced by low-voltage, mixed
frequency (4–7 Hz) waves that occupy more than 50% of the epoch, the epoch is
scored as stage N1 sleep. In persons in whom alpha waves are not generated, the
epoch is considered N1 if the EEG consists of 4- to 7-Hz waves with slowing of activity
by 1 Hz or more compared with stage wake. During stage N1 sleep, vertex sharp
waves and slow eye movements (but not REMs) may be observed. There are no K
complexes and sleep spindles in the EEG tracings, and chin EMG tone is commonly
lower than during relaxed wakefulness (Fig. 2).
Stage N2 sleep is defined by the presence of either K complexes (high-amplitude
biphasic wave with duration of 0.5 seconds or more) or sleep spindles (oscillations
with a frequency of 12–14 Hz lasting 0.5–1.5 seconds) during the first half of the epoch
or during the last half of the previous epoch, and if criteria for stage N3 (see later) are
absent (Fig. 3). The epoch is classified as stage N3 sleep if 20% or more of it is occu-
pied by slow wave (0.5–2 Hz and >75 mV) EEG activity (Fig. 4). Stage REM consists of
low-amplitude mixed-frequency EEG activity, rapid EOG movements, and relatively
lower chin EMG tone compared with other sleep stages (Fig. 5). Stages N1, N2, N3,
and REM typically account for 5%, 45%, 25%, and 25% of total sleep time, respec-
tively, among healthy unmedicated adults.
Fig. 1. Stage wake.
Fig. 2. Stage N1 sleep.
Fig. 5. Stage REM sleep.
IDENTIFYING ABNORMAL SLEEP-RELATED EVENTS
PSG is indicated for the diagnosis of sleep-related breathing disorders (SRBD) and
periodic limb movements during sleep (PLMS), titration of positive airway pressure
therapy for SRBDs, and evaluation of hypersomnia, atypical parasomnias, and sus-
pected nighttime seizures.
The recommended monitor for identifying apneas is the oronasal thermal sensor. An
apnea is defined as a decrease in peak thermal sensor amplitude by at least 90% of
baseline for 10 seconds or more and can be obstructive (inspiratory effort is present
throughout the entire event) (Fig. 6), central (inspiratory effort is absent throughout
the entire event) (Fig. 7), or mixed (central event followed by an obstructive event)
(Fig. 8). Measuring respiratory effort using either esophageal manometry or induc-
tance plethysmography is, therefore, important because it can help distinguish
between obstructive, central, and mixed apneas. A nasal air pressure transducer
and end-tidal carbon dioxide (CO2) or summed calibrated inductance plethysmog-
raphy can also be used to detect apneas in adults and children, respectively.
The nasal air pressure transducer is the recommended technique for identifying
hypopneas, but inductance plethysmography or oronasal thermal sensors are also
useful. Hypopnea is characterized by a decrease in nasal pressure by at least 30%
of baseline for a duration of 10 seconds or more and accompanied by at least 4%
oxygen desaturation (Fig. 9). Oxygen saturation is monitored using pulse oximetry,
and alveolar hypoventilation can be inferred from end-tidal or transcutaneous CO2.
EMG placed over the lower extremities (anterior tibialis) is used to detect PLMS.
Additional EMG electrodes can be attached to the upper extremities (extensor digito-
rum communis) to help identify REM sleep behavior disorder, a type of parasomnia.
Fig. 6. Obstructive apnea.
Fig. 7. Central apnea.
Fig. 8. Mixed apnea.
Fig. 9. Obstructive hypopnea.
Fig. 10. Periodic limb movements in the leg EMG tracing.
PLMS are scored if there are 4 or more consecutive leg movements, each 0.5 to 10.0
seconds in duration and occurring 5 to 90 seconds between movements (Fig. 10).
SUMMARY
Sleep and waking are generated and regulated by specific, but interrelated, neural
processes. Wake-promoting systems activate thalamocortical systems, and coordi-
nated removal of arousal systems leads to hyperpolarization of thalamocortical neurons
(wake-sleep switch). Activation of GABA and pontine cholinergic neurons promote
sleep and generate REM sleep, respectively. Genetically determined circadian rhythms
also influence the timing and quality of wakefulness and sleep. Widespread changes in
physiologic processes occur during sleep, and these may influence the presentation as
well as the severity of specific medical disorders.
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B a s i c Bi o l o g y o f S l e e p

John Harrington, MD, MPH*, Teofilo Lee-Chiong, MD

Sleep can be defined as a complex reversible state characterized by behavioral

CONTROL OF SLEEP AND WAKING

Dent Clin N Am 56 (2012) 319–330

NEUROANATOMY OF SLEEP AND WAKING

Biological rhythms are ubiquitous, being present in prokaryotic and eukaryotic

PHYSIOLOGY DURING SLEEP

Autonomic Nervous System

Polysomnography (PSG) is commonly used to objectively characterize sleep and its

Sleep is conventionally classified as either NREM or REM sleep. NREM sleep is

Fig. 1. Stage wake.

Fig. 2. Stage N1 sleep.

Fig. 3. Stage N2 sleep.

Fig. 4. Stage N3 sleep.

Fig. 5. Stage REM sleep.

IDENTIFYING ABNORMAL SLEEP-RELATED EVENTS

Fig. 6. Obstructive apnea.

Fig. 7. Central apnea.

Fig. 8. Mixed apnea.

Fig. 9. Obstructive hypopnea.

Fig. 10. Periodic limb movements in the leg EMG tracing.

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