Pulmonary Medicine

Normal Sleep Physiology and Its Assessment

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What every physician needs to know:

Sleep is a natural, periodic and reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. Defining features of sleep include minimal movement, assumption of a stereotypic posture, reversibility, and reduced response to stimulation.

Sleep is essential to life; however, the precise function of sleep remains elusive. Although sleep is often viewed as a passive process, judging by the appearance of a sleeping subject, it is actually a period of challenge for the ventilatory system.

Several hypotheses attempt to explain the function of sleep. One theory defines sleep as a process that provides restoration and recovery of vital functions that have been degraded by continued wakefulness. A second theory proposes that sleep provides an opportunity for energy conservation by reducing metabolic rate and body temperature. An ecological theory posits that reduced motor activity during sleep decreases the likelihood of attracting predators.

"Sleep architecture" refers to the orderly progression of sleep stages in cycles of 90-120 minutes' duration. A normal sleep cycle begins with transitioning from wakefulness to N1 sleep and then descending to N2 and N3, followed by a period of REM sleep. The first occurrence of Stage R sleep occurs after ninety minutes. In general, N3 sleep tends to predominate in the first half of the night, while Stage R predominates in the second half of the night as REM periods become increasingly longer toward the morning. For an average individual in his or her second decade, Stage N1 is 2-5 percent of total sleep time, Stage N2 is 45-55 percent, Stage N3 is 13-23 percent, and Stage R is 20-25 percent.

The distinction between tonic and phasic REM reflects significant physiological changes and not simple EEG morphology. For example, intercostal muscle activity is diminished significantly during phasic REM sleep, manifested by paradoxical breathing during this stage of sleep. Patients with COPD may experience most pronounced hypoventilation and oxyhemoglobin desaturation during phasic REM sleep.

Several sleep disorders blur the boundaries between different states of consciousness because of the intrusion of the features of one state into another state. Examples include narcolepsy, REM behavior disorder, and sleepwalking.

Narcolepsy is a condition of excessive daytime sleepiness in which features of REM sleep, such as muscle paralysis, intrude into wakefulness. It manifests in sudden attacks of muscle weakness caused by a loss of muscle tone that is triggered by strong emotions.

The occurrence of REM sleep without atonia is the hallmark of a clinical condition called REM behavior disorder (RBD). Afflicted patients act out their dreams and may cause injury to themselves or others.

Sleepwalking is characterized by vocalization and ambulation, features of wakefulness, while in NREM sleep.

Circadian rhythms are twenty-four-hour cycles of behavior and physiology that are generated by endogenous biological clocks. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus has been identified as the site of the circadian pacemaker. The circadian period in humans synchronizes to the twenty-four-hour day by external influences, mainly light.

Consequences of sleep deprivation

Sleep deprivation exists when the individual sleeps less than required for optimal functioning, health, and performance. The two broad categories of sleep deprivation are reduced total sleep time and poor sleep quality. Poor-quality sleep may be caused by frequent awakenings or arousals, with subsequent impairment in daytime functioning, fatigue, or daytime sleepiness.

Sleep deprivation is associated with significant adverse consequences. Studies in animals have shown that total sleep deprivation in the rat is ultimately fatal. Sleep deprivation in humans is associated with significant safety risks, such as increased incidence of motor vehicle and industrial accidents. In fact, several catastrophic industrial accidents, including the nuclear reactor accident in Chernobyl and the Exxon Valdez oil spill, have been due, at least in part, to sleepy operators.

Sleep deprivation may occur because of sleep fragmentation secondary to sleep apnea or periodic leg movements in sleep. Afflicted patients report non-refreshing sleep and excessive daytime sleepiness despite adequate total sleep time. Sleep fragmentation may account for some of the neuro-cognitive consequences of sleep apnea.

Large-scale studies have shown that chronic sleep deprivation exerts substantial and dose-related effects on neurobehavioral performance measures, increased mood disturbance, decreased motivation, and decreased driving ability with increased risk of motor vehicle accidents. In addition, sleep curtailment may have orexigenic effects and may be conducive to weight gain. This last is an intriguing new finding with significant implications that may link sleep loss with the burgeoning obesity epidemics in the US. However, this view will remain speculative until it is confirmed by large-scale population studies.

Sleep deprivation is also associated with impaired quality of life, adverse cardiovascular consequences, and even increased mortality. Sleep deprivation may also impair ventilatory responses to hypercapnia and hypoxia in healthy subjects. Impaired response to chemical stimuli may contribute to worsening respiratory function in patients with COPD, obesity, or sleep apnea.

Classification:

Classification of sleep stages requires three measurable neurophysiologic variables: electoencephalography [EEG], eye movements (electrooculography [EOG]), and muscle activity (electromyography [EMG]).

Standardized criteria that use all three variables were published in the first sleep-scoring manual by Rectschaffen and Kales in 1968. The American Academy of Sleep Medicine (AASM) published a modified scoring manual in 2007, which is the basis for this review.

Wakefulness

The EEG pattern during wakefulness is characterized by mixed-frequency, low-amplitude activity, often in association with high chin muscle tone, eye blinks, and random, rapid eye movements. Quiet, relaxed wakefulness is characterized by an 8-13Hz sinusoidal activity called alpha waves, best captured over the occipital region, and is attenuated by eye opening.

Non-rapid eye movement (NREM) sleep

NREM sleep comprises the majority of nocturnal sleep. NREM sleep is divided into three stages:

N1 sleep is a transitional state characterized by a slowing of EEG frequency without increasing EEG amplitude from wakefulness. The dominant EEG activity is low-amplitude activity with a frequency range of 4-7 Hz (theta activity) and the appearance of occasional slow, rolling eye movements. Some degree of environmental awareness is retained during N1sleep.

N2 sleep is characterized by loss of environmental awareness and a corresponding change in EEG. The appearance of sleep spindles and K complexes indicate the transition to N2 sleep; both are transient wave forms that are superimposed on a background of dominant theta activity. Sleep spindles are rhythmic sinusoidal waves of 12-14 Hz frequency that are best captured on central EEG leads. In contrast, K-complexes are diphasic waves that have a well-delineated sharp upstroke (negative) component, followed by a slow (down stroke) positive component. K-complexes also appear during transient arousals and in association with transient alpha waveforms.

N3 sleep is characterized by the appearance of slow waves in the delta range. By definition, slow waves are of low frequency (generally 0.5 to 2 Hz) and have large amplitude (>75 μV). N3 sleep is scored when delta activity comprises at least 20 percent of an epoch. Aging is associated with decreased N3 stage in men but not in women.

Rapid eye movement (REM) sleep

This stage of sleep is often described as “paradoxical” sleep because of active CNS and paralyzed periphery. Several conditions may alter sleep state distribution and functions, and several conditions, including sleep apnea and periodic leg movement, may cause sleep fragmentation.

The rapid-eye-movement (REM) stage of sleep is often described as “paradoxical” sleep because active CNS is coupled with paralyzed periphery. In fact, the EEG is fast with low amplitude (resembling N1 sleep) and reduced chin EMG activity. This phase of REM sleep is referred to as a tonic REM sleep. REM sleep occurs in cycles every 90-110 minutes. It is often reduced in the laboratory environment, especially if complex instrumentation is used. In addition, Stage R is characterized by dreaming, relative atonia of all muscle groups except the diaphragm, and erections in men.

Rapid eye movements are the defining characteristic of this sleep stage, as clusters of rapid eye movements occur (phasic REM sleep) interspersed with periods of no eye movements (tonic REM sleep). The distinction between tonic and phasic REM reflects significant physiological changes and not simple EEG morphology. For example, intercostal muscle activity is diminished significantly during phasic REM sleep, manifested by paradoxical breathing during this stage of sleep. Patients with COPD may experience most pronounced hypoventilation and oxyhenoglobin desaturation during phasic REM sleep.

Are you sure your patient has abnormal sleep physiology?

Abnormalities of sleep physiology produce clinical manifestations that often simulate other conditions, such as anxiety, depression, chronic headaches, hypertension, and general fatigue. Likewise, chronic health conditions may produce symptoms that simulate abnormal sleep physiology. Consequently, physicians must take a careful sleep history when patients present with generalized health complaints or conditions, such as hypertension, that may be caused or aggravated by abnormal sleep physiology.

A measure to determine the degree of sleepiness assists clinicians in establishing whether a patient has an abnormal sleep physiology.

Objective Tests of Sleepiness

The Multiple Sleep Latency test (MSLT) is an objective, valid, and reliable test for assessment of daytime sleepiness. It is the standard for objective tests of an individual's tendency to fall asleep. In brief, the MSLT consists of five nap opportunities offered during regular waking hours in the sleep laboratory. Sleep latency is calculated from the average of latencies of all five nap periods. If sleep is not reached, the nap is considered to have a sleep latency of twenty minutes.

Indications and Limitations

Medications that may alter sleep or sleep state distribution should be discontinued at least two weeks prior to testing because they can impact the ability to fall asleep.

MSLT should be preceded by polysomnography to ascertain the possible causes of sleep fragmentation, which may influence daytime sleepiness.

The MSLT is indicated as part of the standard testing for the diagnosis of narcolepsy because it can detect both excessive hypersomnia and the early onset of REM (sleep-onset rapid eye movements, or SOREMs), which are key features of narcolepsy. Nevertheless, the MSLT cannot be used to confirm or exclude the diagnosis. In addition, the test is not indicated when the etiology of sleepiness is apparent, as in patients with obstructive sleep apnea syndrome. The MSLT may be helpful in the evaluation of patients with suspected idiopathic hypersomnia.

The MSLT alone is not sufficient to evaluate driving risk; there is no specific threshold for safe driving.

Maintenance of Wakefulness Test (MWT)

The maintenance of wakefulness test is a “mirror image” of MSLT in that it measures the ability to remain awake for a defined period of time. The MWT measures aspects of alertness/sleepiness, so it is not a substitute for MSLT. The primary variable is also mean sleep latency. A threshold of less than eight minutes is considered abnormal, a value longer than forty minutes during all four sessions indicates absence of daytime sleepiness, and a value between eight and forty minutes is of uncertain significance.

The MWT suffers from the same limitations as MSLT: long duration, high cost, and resource intensivity. It is often requested by third parties to evaluate driving risk, despite the absence of robust supportive data.

Subjective Tests of Sleepiness

The Epworth Sleepiness Scale (ESS)

The ESS is a subjective, self-administered instrument that can be completed in a few minutes. It measures sleepiness under normal, relaxed, daily conditions. The questionnaire addresses eight specific situations: sitting and reading, watching television, sitting inactively in a public place, riding as a passenger in a car for one hour without a break, lying down to rest in the afternoon when circumstances permit, sitting and talking with someone, sitting quietly after lunch without alcohol, and sitting in a car while stopped for a few minutes in traffic.

Each situation receives a score of zero to three based on the likelihood of sleep occurring under the condition. The total score ranges from 0-24; a total of 10 points is considered the threshold for excessive daytime sleepiness. The correlation between ESS and objective indices of sleep or performance is weak and should not be used as a screening tool for sleep apnea or other conditions of excessive sleepiness. The ESS is routine part of initial and follow-up assessment for patients with sleep disorders.

Stanford Sleepiness Scale (SSS)

The SSS is a validated, subjective measure of sleepiness for short-term subjective sleepiness. The patient is asked to select one out of seven items that describe his or her current level of sleepiness:

1 = feeling active, vital, alert, wide awake

2 = functioning at a high level, not at peak, able to concentrate

3 = relaxed, awake, not at full alertness, responsive

4 = a little foggy, not at peak, let down

5 = fogginess, losing interest in remaining awake, slowed

6 = sleepiness, prefer to be lying down, fighting sleep, woozy

7 = almost in reverie, sleep onset soon, losing struggle to remain awake

Items 4-7 during regular waking hours represent significant sleepiness. The SSS is rarely used clinically but is used primarily as a research tool.

Beware: there are other diseases that can mimic abnormal sleep physiology.

Alcohol, stimulants, tobacco, depression, or withdrawal from sedatives or antidepressants may also cause sleep fragmentation.

A sleep evaluation requires a focused sleep history, general medical history, and physical examination to exclude non-sleep-related conditions and to select patients with suspected sleep abnormalities for further diagnostic evaluation.

How and/or why did the patient develop abnormal sleep physiology?

A wide range of conditions underlie abnormal sleep physiology. These conditions are listed in Table I.

Table I

Causes of abnormal sleep physiology
Insomnia
Sleep-related breathing disorders
Circadian rhythm sleep disorders
Hypersomnia of central origin
Parasomnias
Sleep-related movement abnormalities
Isolated symptoms and normal variants
Other sleep disorders, such as restless partner, environmental noise

Which individuals are at greatest risk of developing abnormal sleep physiology?

Sleep state distribution is altered with aging, manifested by an increase in the number of arousals, increased N1 sleep, and decreased N3 sleep. Epidemiologic evidence suggests that decreased N3 is seen in men and not in women. Whether sleep fragmentation in the elderly is due to aging or to concomitant chronic conditions is unclear.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Patients with underlying undiagnosed chronic health conditions may present with symptoms suggestive of a primary disturbance in sleep physiology. Depending on the clinical circumstance, diagnosis is assisted by performance in echocardiography, thyroid function tests, glucose, measures of renal function, and iron balance studies.

What imaging studies will be helpful in making or excluding the diagnosis of abnormal sleep physiology?

None

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of abnormal sleep physiology?

Depending on the clinical presentation, several studies assist the evaluation of abnormal sleep physiology:

  • Polysomnography

  • Multiple sleep latency test

  • Tests for assessment of depression and anxiety

  • Actigraphy to establish a sleep log.

What diagnostic procedures will be helpful in making or excluding the diagnosis of abnormal sleep physiology?

None

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of abnormal sleep physiology?

None

If you decide the patient has abnormal sleep physiology, how should the patient be managed?

See individual chapters on sleep apnea, narcolepsy, restless leg syndrome, insomnia, and so on.

What is the prognosis for patients managed in the recommended ways?

See individual chapters on sleep apnea, narcolepsy, restless leg syndrome, insomnia, and so on.

What other considerations exist for patients with abnormal sleep physiology?

Respiratory Changes

Loss of wakeful stimulus to breatherenders ventilation critically dependent on chemorecepter and mechanorecepter stimuli.

Upper airway narrowing and increased upper airway resistance are normal physiologic events during sleep. Snoring occurs when upper airway resistance increases significantly, leading to “fluttering” of the soft palate in response to turbulent flow. In extreme cases of upper airway narrowing, complete closure may occur, leading to obstructive sleep apnea.

Breathing through high-resistance tubing is associated with increased ventilatory effort to maintain alveolar ventilation. However, this response is lost during sleep, as “loads” are not perceived; therefore, ventilation decreases and PaCO2 increases.

During sleep, ventilation becomes dependent on chemoreceptor influences. Therefore, if hypocapnia is induced, complete inhibition of ventilation may occur (i.e., central apnea). The level of hypocapnia that causes central apnea is referred to as “the apneic threshold.” Hypocapnia is the most important mechanism of central sleep apnea.

Implications

Snoring occurs when upper airway resistance increases significantly, leading to “fluttering” of the soft palate because of turbulent flow. In extreme cases of upper airway narrowing, complete closure may occur, leading to obstructive sleep apnea.

Elevated PaCO2(Hypercapnia) is common during sleep. This is one of very few physiologic situations in which hypercapnia is tolerated.

Most of the studies on sleep effect have been in NREM sleep, as REM is difficult to achieve under instrumented conditions. REM sleep is associated with muscle atonia, which affects many upper airway dilators and intercostals, although the diaphragm is spared. Minute ventilation decreases even more in REM sleep, and respiratory rate becomes more irregular, with the rate becoming more irregular in phasic REM sleep.

Cardiovascular changes

NREM sleep is characterized by autonomic stability because of increased parasympathetic tone compared to wakefulness. Therefore, NREM sleep is associated with decreased heart rate, cardiac output, blood pressure and cerebral blood flow. In contrast, REM sleep is associated with heart rate variability, with transient increase in blood pressure, heart rate and coronary blood flow during bursts of rapid eye movements, likely because of increased sympathetic activity. In addition, cerebral blood flow is increased during REM sleep relative to NREM sleep.

Endocrine Changes

The levels of circulating hormones are influenced either by the sleep-wake cycle or circadian rhythm. Secretion of growth hormone and prolactin is tightly linked to the sleep-wake cycle, with the GH peak during slow-wave sleep and the prolactin peak shortly after sleep onset.

In contrast, cortisol and testosterone secretion follows a circadian pattern; both are maximally secreted in the morning. Finally, circulating levels of thyroid-stimulating hormone (TSH) are influenced by both circadian rhythms and the sleep-wake cycle. TSH levels increase in the evening under circadian influences but decrease after sleep onset, primarily during slow-wave sleep.

Gastrointestinal changes

Basal gastric acid secretion follows a circadian rhythm, with peak secretion between 10:00 p.m. and 2:00 a.m. and relative absence of basal secretion in the absence of meal simulation. The frequency of swallowing and esophageal peristaltic waves decreases significantly during sleep NREM.

One of the important effects of sleep is increased acid contact time because of the sleep-related decreases in salivation, swallowing, and peristalsis. Moreover, the sensation of “heartburn” is attenuated during sleep, so gastro-esophageal reflux during sleep may contribute to the development of esophagitis, chronic cough, and exacerbations of nocturnal bronchial asthma.

What’s the evidence?

Silber, MH, Ancoli-Israel, S, Bonnet, MH, Chokroverty, S, Grigg-Damberger, MM, Hirshkowitz, M. "The visual scoring of sleep in adults.". J Clin Sleep Med. vol. 3. 2007. pp. 121-131.

(A helpful article for scoring sleep in patients suspected of having abnormal sleep physiology.)

Iber, C, Ancoli-Israel, S, Chesson, AL, Quan, SF. "The AASM manual for the scoring of sleep and associated events.". American Academy of Sleep Medicine. 2007.

(This resource provides clinicians with the established system for scoring sleep studies.)

Ohayon, MM, Carskadon, MA, Guilleminault, C, Vitiello, MV. "Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan.". Sleep. vol. 27. 2004. pp. 1255-1273.

(This quantitative review provides normative values to identify abnormal sleep physiology.)

Redline, S, Kirchner, HL, Quan, SF, Gottlieb, DJ, Kapur, V, Newman, A. "The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture.". Arch Intern Med. vol. 164. 2004. pp. 406-418.

Collop N, A, Salas, RE, Delayo, M, Gamaldo, C. "Normal sleep and circadian processes.". Crit Care Clin. vol. 24. 2008. pp. 449-60.

Orr, WC, Chen, CL. "Sleep and the gastrointestinal tract.". Neurol Clin. vol. 23. 2005. pp. 1007-1024.

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