Crit Care Clin 24 (2008) 449460

Normal Sleep and Circadian Processes

Nancy A. Collop, MDa,b,*, Rachel E. Salas, MDb,c,
Michael Delayo, BS, RPSGTd,
Charlene Gamaldo, MDb,c
a

Division of Pulmonary/Critical Care Medicine, 1830 East Monument Street, Room 555,
Johns Hopkins University, Baltimore, MD 21205, USA
b
Johns Hopkins Hospital Sleep Disorders Center, 601 North Caroline Street, Suite 1261,
Baltimore, MD 21287, USA
c
Department of Neurology, Johns Hopkins University, 601 N. Wolfe Street,
Meyer 6-113, Baltimore, MD 21287, USA
d
Sleep Services of America, 890 Airport Park Road, Glen Burnie, MD 21061, USA

Sleep is a natural process occurring in animals and human beings. It is

a complicated state involving both behavioral and physiologic processes.
Several brain centers are involved in the production and regulation of sleep
using a variety of hormones, neurotransmitters, and peptides. Sleep can be
dierentiated from coma by its reversibility. This article reviews the aspects
of normal sleep, physiologic changes that occur in the human body with
sleep, and how sleep changes over the lifespan.

Normal sleep staging

Sleep is an essential physiologic process for most living organisms. Sleep
is divided into nonrapid eye movement (NREM) sleep and rapid eye
movement sleep (REM). Older sleep staging developed by Rechtschaen
and Kales [1] divided NREM sleep into four stages, numbered 1, 2, 3,
and 4. According to the newly released American Academy of Sleep Medicine scoring criteria, NREM sleep is now characterized by three stages
(N1, N2, N3), with N3 encompassing the older classication of stages 3
and 4 [2]. These stages are based on a constellation of physiologic parameters and are dened by electrophysiologic waveforms and frequencies

* Corresponding author. Division of Pulmonary/Critical Care Medicine, 1830 East

Monument Street, Room 555, Johns Hopkins University, Baltimore, MD 21205.
E-mail address: ncollop1@jhmi.edu (N.A. Collop).
0749-0704/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2008.02.002
criticalcare.theclinics.com

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using electroencephalographic (EEG) monitoring. Sleep stage 1 (N1) comprises about 2% to 5% of sleep and consists of a low voltage, mixed frequency pattern, usually in the theta range (4 Hz8 Hz) that has
transitioned from the alpha rhythm (8 Hz13 Hz) seen in wakefulness
(Figs. 1 and 2).
Sleep stage 2 (N2), which usually lasts for approximately 10 to 25 minutes
each time it cycles, comprises about 45% to 55% of total sleep and is characterized by K-complexes and sleep spindles (Fig. 3). Sleep stages 3 and 4
(N3), also known as slow wave sleep (SWS), make up about 15% to 20%
of total sleep. In the old classication stage 3 was characterized by high voltage (75 mV), low-frequency delta waves (less than 2 Hz), accounting for
20% to 50% of an epoch, with stage 4 using the same voltage and frequency
criteria as stage 3, but with the high voltage delta activity accounting for
more than 50% of an epoch (Fig. 4). Sleep stage REM (R) makes up about
20% to 25% of total sleep and is depicted by a low-voltage, high frequency
pattern usually in the theta or beta range (Fig. 5). Stage REM is also characterized by muscle tone attenuation and rapid eye movements. REM sleep
(R) can be divided into phasic REM and tonic REM, depending on certain
criteria (Box 1).
Four to six full NREM-REM cycles are observed during one night. The
rst cycle is usually 70 to 100 minutes, compared with 90- to 120-minute cycles thereafter. The SWS cycle length is longest in the rst third of the night,
whereas the REM sleep cycle length peaks in the last third of the night. Typical hypnograms for children, young adults, and the elderly are shown in
Fig. 6.

Fig. 1. Stage Wake (0). This 30-second epoch demonstrates quiet wakefulness. The predominant rhythm is alpha frequency (8 cps13 cps) noted in the EEG channels (C3A2, C4A1,
O1A2, O2A1). Alpha rhythm occupying greater than 50% of the 30-second epoch denotes
an epoch of wake.

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Fig. 2. Stage 1 or N1 sleep. This 30-second epoch demonstrates stage 1 sleep. Stage 1 sleep is
designated by greater than 50% of the epoch lled with theta rhythm (3 cps8 cps) in the EEG
leads, and slow rolling eye movements.

Sleep-wake cycles: a delicate symphony

The sleep-wake state is a delicate interplay of neurobiologic systems
(Table 1). The Borbely two-process model is the most accepted theory,
which describes the orchestrated balance necessary to achieve a normal
sleep-wake cycle. The two-process model consists of the sleep-wake propensity, resulting from a combination of an intrinsic circadian pacemaker
(process C) and a homeostatic process (process S). An individuals

Fig. 3. Stage 2 or N2 sleep. This 30-second epoch demonstrates stage 2 sleep. Stage 2 sleep is
characterized by K complexesdnegative deection (up) followed by positive deection (down)
(thick arrow)dor sleep spindles (12 cps14 cps) (thin arrow). K complexes and sleep spindles
must be 0.5 to 5 seconds in duration.

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Fig. 4. Stage 3 or N3 sleep. This 30-second epoch demonstrates stage 3 sleep. Stage 3 sleep is
designated when 20% to 50% of the 30-second epoch is lled with delta activity (0.5 cps2 cps,
75uv amplitude). Delta waves are seen from second 18 to 26 on this epoch.

homeostatic sleep drive is directly determined by the duration of wakefulness. In the morning, if there was an adequate amount of sleep, process S
is at it lowest point. As the day proceeds and the duration of wakefulness
is prolonged, process S increases linearly until the person goes to sleep and
henceforth reduces the S drive (Fig. 7). The circadian process C operates
independently of the duration of wakefulness; this process cycles in a xed
and rhythmic pattern to promote alertness.

Fig. 5. Stage REM or R sleep. This 30-second epoch demonstrates stage REM sleep. This represents phasic REM with frequent rapid eye movements, chin muscle atonia, and sawtooth
waves (in box).

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Box 1. Tonic and phasic REM characteristics

Tonic REM
Appearing throughout a REM period
Electromyographic suppression
Low voltage desynchronized EEG
High arousal threshold
Hippocampal theta rhythm
Elevated brain temperature
Poikilothermia
Olfactory bulb activity
Penile tumescence
Phasic REM
Occurs intermittently during REM period
Rapid eye movements
Middle ear muscle activity
Tongue movements
Somatic muscle-limb twitches
Variability of autonomic activity (cardiac and respiratory)
Ponto-geniculo-occipital spikes
During the day, when the homeostatic sleep drive is mounting, wakefulness is maintained because the circadian process works to oset this rising
drive toward sleep. The timing of circadian rhythm and the homeostatic
sleep drive normally align to achieve xed and consolidated sleep-wake
schedules. However, individuals can experience a dip in their circadian alerting drive in the late afternoon, which explains the common after-lunch dip
(siesta) in alertness [3]. Under sleep-deprived conditions, the interplay between the homeostatic and circadian process becomes less coordinated and
the sleep-wake state becomes unstable [4]. During wakefulness, sleep-deprived individuals can even display evidence of involuntary sleep intrusions
[5,6]. The circadian after-lunch dip in alertness also becomes amplied in the
face of sleep loss [7,8].
Neurophysiologic centers essential to sleep-wake cycles: overivew
The sleep and wake state are both active neurophysiologic states involving several neurotransmitters that project to numerous areas along the neuroaxis (see Table 1). The posterior hypothalamus, tuberomammillary
nucleus, and regions of the brain stem are all collectively involved in maintaining wakefulness with the release of excitatory neurotransmitters orexin,
histamine, and acetycholine, respectively, to specic cortical and subcortical
sites. During wakefulness, adenosine, a normal metabolic bioproduct, continues to build in the system and serves as a soporic neurotransmitter to

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Fig. 6. Hypnograms. Typical hypnograms for children, young adults, and elderly individuals
(From Chokroverty S. Sleep Disorder Medicine, 2nd ed. Boston, Butterworth-Heinemann;
1999. p.11; with permission.)

help transition into the sleep state. Adenosine represents the neurophysiologic marker of the homeostatic sleep drive. Therefore, like the process S,
which increases with the duration of wakefulness, so too does the amount
of adenosine along the neuroaxis. Upon entering sleep, normally in the
NREM cycle rst, GABA (primarily from the ventral lateral pre-optic nucleus of the anterior hypothalamus) is released to facilitate the sleep state
by inhibiting the excitatory centers involved in maintaining wakefulness. Between 45 to 120 minutes later the cholinergic REM, on cells in the LDT and
PPT centers of the brain stem as well as the basal forebrain, are activated,
allowing the individual to enter REM sleep.
Recruitment of other centers along the neuroaxis occur in REM sleep, and
for that reason REM is considered the metabolically active sleep cycle. In
fact, REM sleep uses some of the same systems involved in promoting wakefulness. The projections and neurotransmitters active in both REM and
NREM also produce a concurrent inhibitory function, thus allowing the individual to cycle between the NREM and REM states four to ve times during a typical night, until eventually invoking the wake promoting system.

Table 1
Neurotransmitters of sleep
Wake/REM

NREM

Origin

Projections

Gamma aminobutyric
acid (GABA)
Adenosine

()/

Posterior hypothalamus, ARAS, thalamus

Increase with
wakefulness/
/
/
/()
/()
/?

ARAS, thalamus, VLPO,

basal forebrain, cortex
Diuse cortical by-product
of wake state
Posterior hypothalamus
Basal forebrain/LDT/PPT
Locus coeruleus
Dorsal raphe nucleus
Lateral and posterior hypothalamus

Histamine
Acetylcholine (ACH)
Norepinephrine (NE)
Serotonin (SE)
Orexin/hypocretin

Brain stem and basal forebrain cholinergic cells

Thalamus, brain stem
Thalamus, posterior hypothalamus, basal forebrain
Cortex, hippocampus, thalamus, hypothalamus
Same as NE
Locus coeruleus, dorsal raphe nucleus, LDT, PPT

As demonstrated by the () and () symbols, the impact of these neurotransmitters involves the timing of their release during the specic phases as well as
their inhibitory or excitatory role at their projected sites. The role of some neurotransmitters are still unclear in some of the phases, as demonstrated by the (?)
of the impact of orexin/hypocretin during REM sleep.
Abbreviations: ARAS, Ascending reticular activating system of the brain stem; LDT: Lateral dorsal tegmentum of the brain stem; PPT, Pedunculopontine
tegmentum of the brain stem; VLPO, Ventro-lateral preoptic nucleus of the anterior hypothalamus.

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Neurotransmitter

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Fig. 7. Process C and process S. The two-process model involving a sleep homeostatic process
(S) and a circadian process (C). (From Chokroverty S. Sleep Disorder Medicine, 2nd ed. Boston,
Butterworth-Heinemann; 1999. p.143; with permission.)

Sleep-wake cycles over the lifespan

From birth to age 1 the sleep stages are less clearly dened. Infants typically go to sleep via active sleep, which is most similar to adult REM
sleep. Sleep periodicity is less, typically 50 to 60 minutes, and is throughout
the 24-hour period rather than consolidated into nighttime. As infants become young children, they develop more slow wave sleep, which may comprise one third to one half of the sleep period. Slow wave sleep decreases
dramatically during the second decade and that decrease continues throughout the lifespan [9]. Aging as adults is associated with increased nocturnal
awakenings, prolonged time awake after onset of sleep, decreased sleep efciency [1012], and decreased slow-wave sleep [13]. There is a weakening
of homeostatic processes in the regulation of sleep and waking, such that
maintaining alertness throughout the waking day is challenged by failure
to consolidate sleep at night. REM sleep remains relatively stable throughout the lifespan, following the early years when it comprises approximately
50% of sleep time.
Older individuals have a more dicult time maintaining alertness in the
late afternoon and evening than younger individuals. These ndings suggest
that the bodys circadian arousal signal (process C) fades with age [14].
There is an age-dependent impairment in phase shifting, and attening of
the diurnal sleep-wake rhythm amplitude, resulting in increased daytime
napping of the elderly.

Physiologic changes during sleep

Cardiovascular
NREM and REM states profoundly aect cardiovascular processes. In
NREM sleep, there is autonomic stability with dominance of parasympathetic tone and vagal nerve input. This results in prominent sinus

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arrhythmia, with coupling of respiratory variation. During inspiration,

heart rate increases to accommodate the increased venous return and during
expiration, heart rate slows. This pattern is normal and suggests normal
functioning; reduced heart rate variability is seen in disease states and
with aging. In severe coronary disease, the relative bradycardia and hypotension associated with NREM sleep may result in sleep associated
ischemia.
REM sleep results in signicant changes in sympathetic nervous system
tone with marked activation occurring in conjunction with intense rapid
eye movements. These phasic REM periods cause increases in heart rate
and blood pressure by as much as 35% [15]. These phasic periods have
also been associated with signicant reduction in coronary artery ows in
situations of severe coronary stenosis [16]. In contrast, abrupt decreases in
heart rate are also noted in REM sleep, primarily during the tonic phase
of REM. This is thought to occur because of increased vagus nerve tone
and suppression of sinus node activity. The transitions from NREM to
REM have also been noted to result in both heart rate increases as well
as pauses and even frank asystole.
Respiratory
The onset of sleep is associated with signicant changes in ventilation.
Minute ventilation falls with sleep onset and arterial partial pressure of carbon dioxide rises. This is predominately because of a decrease in tidal volume, with little change in respiratory rate. In REM sleep, minute
ventilation falls even further; respiratory rate is much more irregular again,
with the most variability observed during the phasic part of REM. It is
thought that during NREM sleep, metabolic control of ventilation is predominant, whereas during REM sleep, behavioral control is more active, although metabolic control continues to play a role [17].
The carbon dioxide concentration is one of, if not the, most potent ventilatory determinants. However with sleep onset, carbon dioxide levels increase progressively through the NREM stages and into REM. The
hypercapnic ventilatory response therefore clearly falls with sleep onset
and the slope is progressively decreasing from wake to NREM to REM
(Fig. 8). This fall in the hypercapnic response may be less in females. Hypoxic ventilatory responses fall in both genders during REM sleep; but there
is less change in females during NREM sleep (Fig. 9). Similarly, there are
dierent thresholds to arouse from sleep. In hypoxic conditions, arousals
occur at lower oxygen levels in REM sleep compared with NREM. During
hypercapnic conditions, the stimulus to arouse requires the highest carbon
dioxide levels during N3 sleep compared with N1, N2, or REM [18].
Another eect on respiration during sleep involves the upper airway muscle tone. Upper airway muscle activity is reduced with sleep onset, resulting
in an increase in transpulmonary resistance. This increase in upper airway

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Fig. 8. Ventilatory response to O2 with sleep stages. This gure represents the change in minute
ventilation in response to decreasing oxygen saturation levels that occur during the dierent
stages of sleep. Gray line REM, Dotted line Stage 2, Broken line Stages 3/4, Black
line Awake.

resistance causes the reduction in minute ventilation [19]. Additionally, neuromechanic input, the pattern of inspiratory airow, the air temperature,
and the phase of the respiratory cycle can further alter upper airway muscle
activity during sleep.
Endocrine
Perhaps no physiologic system of the human body is more sensitive to
sleep and circadian rhythms than the endocrine system. Most hormones
uctuate their levels according to a circadian rhythm or with sleep/wake cycles. Growth hormone (GH) and prolactin (PRL) secretion are essentially
absent when sleep does not occur. GH tends to have its highest pulsation
associated with the rst NREM sleep period. This is much more consistent

Fig. 9. Ventilatory response to carbon dioxide with sleep stages. This gure represents the
change in minute ventilation in response to increasing carbon dioxide levels that occur during
the dierent stages of sleep. Gray line REM, Broken line Stage 2, Dotted line Stages 3/4,
Black line Awake.

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in men than in women, and GH secretion also tends to decrease with age, in
a similar pattern as the percentage of N3 sleep decreases [20]. PRL levels increase with sleep onset and are also associated with stage N3 (deep sleep),
with a similar age related decline occurring in both.
Most other hormone levels uctuate with circadian rhythms, including
cortisol, thyrotropic hormones, and those related to glucose metabolism
and appetite. Adrenocorticotropic hormone and cortisol tend to increase
in the early hours of the morning and decline through the day, with the lowest levels around midnight. Sleep deprivation, either total or partial, results
in overall increase in evening cortisol levels, which have been postulated to
potentially facilitate abnormalities associated with glucocorticoid excess,
such as insulin resistance. Indeed, when glucose tolerance is measured during periods of chronic sleep deprivation, the insulin response is dramatically
slower when compared with before and after the sleep deprivation episodes
[21].
Thyroid stimulating hormone synchronizes with circadian rhythm and
body temperature, with peak levels associated with the beginning of sleep
followed by a continuing decline during sleep. Chronic sleep deprivation results in overall reduction of thyroid stimulating hormone levels.
Gastrointestinal
Gastrointestinal function is altered during sleep. There is a circadian
rhythm in basal gastric acid secretion, with the peak in secretion actually occurring during the rst few hours of sleep. The acid levels do not correlate
with sleep stages. The eect of sleep on gastric and intestinal motility are inconsistent and likely small, if present. Salivary ow is reduced, as is the frequency of swallowing.
Esophageal function has been studied intensely because of the association
with reux [22]. The upper esophageal sphincter tone changes little during
sleep. The motility of the esophagus is reduced during sleep, with the frequency of both primary and secondary contractions progressively diminishing from stages N1 to N3, but secondary contractions increase during REM.
The lower esophageal sphincter has transient reductions in tone, which are
conducive to reux episodes. Additionally, acid clearance time is typically
prolonged during sleep.

Summary
Sleep is associated with distinct changes in not only the central nervous
system but all physiologic systems. These distinct changes vary considerably
between the dierent stages of sleep and become altered more with aging. In
subsequent articles in this issue, it will be demonstrated how sleep deprivation, medications and dierent sleep disorders disrupt the delicate balance of
these physiologic systems.

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