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Normal human sleep.

The human sleep/wake cycle is an approximate 24-hour cycle of rest and activity ubiquitous in nature and present in all life forms. Knowledge of normal human sleep physiology and sleep modifiers is essential for the identification and treatment of many clinical problems directly related either to phenomena occurring during sleep or to disruptions of the timing or duration of sleep. In particular, significant clinical populations exhibit sleep-related respiratory disturbances, so the understanding of the basic structure and determinants of human sleep is especially important for the respiratory care professional.

Behaviorally, sleep is a reversible state, different from wakefulness, characterized by perceptual disengagement from, and lack of responsiveness to, the environment. Early studies showed that at the moment of sleep onset subjects could no longer respond to a flash of light (by pressing a button). The fact that sleep is a reversible state differentiates sleep from coma or anesthesia. Sleep is usually accompanied by postural recumbency, although sleep can occur in a variety of different circumstances, as any sleep-deprived student sitting in a classroom can attest.


Measurements of brain wave activity, eye movements, and muscle activity are essential in describing the various stages of sleep. A seminal finding in the 1950s was that sleep is not a unitary state; rapid eye movements (REMs) occur periodically during sleep, and REM periods are associated with dreaming. Building on this work, a growing team of sleep researchers reached a 1968 consensus on a set of criteria that could be used in basic and clinical research to define various sleep parameters, such as sleep onset and the different sleep stages. By measuring eye movement activity (electrooculogram, or EOG) in concert with electromyographic activity (EMG) and electroencephalography (EEG), it is possible to define five clearly differentiated stages of sleep. During sleep, four stages of nonREM (NREM) sleep cycle with REM sleep in approximately 90-120 minute intervals. Small numbers of brief episodes of arousal are also possible.

In normal young adults, sleep onset usually takes about 10 to 20 minutes and usually occurs through NREM sleep. Changes in EEG, EOG, and EMG activity show clearly the transition between wakefulness and sleep. An EEG recorded from the occipital cortex features a very distinct waveform known as the alpha rhythm, which has a frequency of 8 to 13 cycles per second. At sleep onset, the occipital EEG activity changes from a highly rhythmic, well-organized alpha rhythm to a lower-amplitude, more desynchronized EEG. At the same time, slow, rolling eye movements appear in the EOG. A phenomenon commonly reported in association with sleep onset is called sleep starts. This phenomenon is characterized by the cessation of increased drowsiness and impending sleep onset; however, the transition is abruptly interrupted by the sensation of falling (or some similar sensation), during which a startle response occurs, and there is a generalized motor output. The episode is usually brief and the individual then falls asleep. It has been posited that sleep starts are a result of changes in CNS control of motor activity at sleep onset. It is considered normal and may be precipitated by sleep deprivation or stress.

Another normal variant is a phenomenon called sleep paralysis. Sleep paralysis usually occurs in the transition from sleep to wakefulness and is characterized by an inability to move. This sensation is frightening but lasts only seconds to a few minutes.

NREM Sleep

Non-REM sleep is conventionally divided into four stages based on EEG, EMG, and EOG criteria. Stage 1 sleep is characterized by a low-voltage, mixed-frequency EEG. Stage 2 sleep is defined by the presence of EEG phenomena called K-complexes and sleep spindles. Stages 3 and 4 NREM, also referred to as slow-wave sleep, or delta sleep, show a predominance of high-voltage ([greater than or equal to]75 [micro]V), low-frequency (0.5-2 Hz) waves in the cortical EEG. Slow-wave sleep is often referred to as synchronized sleep because of these high-amplitude slow waves, which contrast dramatically with the relatively low-amplitude (30-50 [micro]V), desynchronized activity characteristic of REM sleep and waking. Arousal thresholds are lowest in Stage 1 NREM or in REM, and highest in delta sleep (Stages 3-4). When research subjects are awakened from NREM sleep, they are less likely to report dreaming than those awakened from REM sleep.

REM Sleep

REM sleep is characterized by EEG activation (relatively highfrequency, low-amplitude EEG in the range of 5-7 Hz). Cortical EEG patterns during waking and REM are similar in terms of frequency and amplitude. The other hallmarks of REM sleep are EMG atonia and the occurrence of rapid eye movements. Although we are essentially paralyzed during REM sleep, certain muscle groups (e.g., diaphragm and cardiac muscle) continue to function and escape the generalized hyperpolarization of spinal cord motoneurons. Metabolic studies of cerebral metabolism during sleep show that the CNS is more active in REM compared with NREM sleep. REM sleep has been referred to as paradoxical sleep because of the temporal coincidence of muscular atonia and behavioral quiescence with an EEG similar to that of wakefulness. Tonic REM is a term used to describe the portion of the REM period characterized by low-voltage, high-frequency EEG and EMG atonia. Tonic REM is punctuated by episodes of phasic REM, which is characterized by episodes of conjugate rapid eye movements, increased variability in heart rate and breathing, and brief increases in EMG.


A sleep histogram can be generated by scoring of polygraphically determined sleep (in 20-30 second segments) over time. Using EEG, ECIG, and EMG activity criteria, the sleep histogram quantifies the nature and progression of sleep throughout the sleep period and is one of the clinician's most important tools for evaluating sleep pathology.


In normal young adults, REM first appears within 70 to 120 minutes after sleep onset; this interval is called the first sleep cycle. It is followed by a return to NREM sleep, with the second and subsequent REM periods increasing in duration. Typically, most high-amplitude slow-wave activity characteristic of delta sleep is seen in the first third of the night. REM periods occur every 90 minutes or so, with the longest durations in the final third of the night. Non-REM sleep comprises about 75% of the total sleep period, and REM sleep is typically 25%. In NREM, Stage 1 is generally 5-10% of total sleep time, Stage 2 is about 45-50%, Stage 3 is about 12%, and Stage 4 is about 13-15%.


Research over the past four decades has continued to provide evidence that NREM and REM sleep are indeed discreet physiologic states. Although the specific function(s) of sleep are still controversial, NREM sleep is thought to be related to homeostatic processes, replenishing some physiologic function. Moreover, NREM appears to be driven by sleep need; that is, the amount of NREM is related to prior wakefulness. On the other hand, REM sleep may not be driven principally by homeostatic functions. Theories about the function of REM sleep range from a role for REM in memory consolidation to psychological functions (i.e., dreams as a window to the unconscious), to speculation that REM sleep is simply the random firing of neuronal activity in the CNS.

The key physiologic differences between NREM and REM sleep have been summarized by Orem and Keeling. One generalization is that homeostatic processes continue to function in an organized manner during NUM, but are disrupted in REM sleep. Changes in some homeostatic systems, such as those subserving respiratory and temperature control, are characterized by decreases in the sensitivity of the responsiveness of the regulatory system or in the threshold level of the relevant controlled variable (e.g., carbon dioxide and oxygen levels in the blood). Body temperature is actively regulated at a lower level in NREM compared with wakefulness. In REM sleep, however, carefully integrated homeostatic processes such as shivering in a cold environment or sweating in a warm environment are disrupted. Respiratory responses to hypoxia and hypercapnia are reduced in NREM sleep compared with wakefulness, and these chemosensory responses are further reduced in REM. In NREM, heart and respiratory rates show little variability and absolute levels are reduced relative to wakefulness. In contrast, cardiac activity and breathing show increased variability in REM sleep. Relatively high rates of cerebral blood flow and metabolism in REM indicate an active brain. Blood flow to the penis normally increases during REM sleep, and the resulting increase in penile tumescence that occurs has been used in sleep laboratories to help clinicians distinguish between psychogenic and physiologic erectile dysfunction.

In other cases, physiologic function is augmented during sleep vs. wakefulness. For example, growth hormone release is highest during NREM sleep at the beginning of the sleep period.


Thus far the discussion has considered data from normal young adults. The quantity and quality of sleep, however, are determined by many interacting variables including age, circadian rhythms, prior sleep history, temperature, drug use, and sleep habits. All of these factors must be evaluated critically for the proper diagnosis and treatment of sleep disorders.

AGE--Sleep is highly age dependent. In premature infants and young full-term infants, the underlying polygraphic and behavioral measures that define sleep states do not become fully comparable with adult sleep measures for several months. For example, the sleep cycle may start with a period of REM instead of NREM. Several other sleep characteristics in infants show important developmental differences compared with adults. Total sleep time in infants is 16 to 18 hours per day, compared with about 8 hours in adults. In addition, infants spend about 50% to 60% (rather than adult levels of 20% to 25%) of their sleep time in REM sleep. The arousal thresholds during delta sleep in infants are very high, and the relatively increased amount of total sleep time and increased percentage of REM sleep suggest critical roles for the developing CNS.

Prepubescent children are very effective sleepers. They go to sleep quickly and sleep efficiently through the course of the night. When they awaken in the morning, they function at high levels throughout their entire waking period, and then go back to sleep again and sleep well. During puberty, certain profound influences are extended onto the sleep system. Research in adolescents suggests that teenagers probably need about 10 hours of sleep per day, although they want to go to sleep later and later. The period or the time during which they sleep tends to be delayed compared with individuals who go to sleep between 10 pm and midnight. By staying up until midnight and preferring to sleep until 10 am or 12 pm or later on weekends, teenagers become sleep deprived because of the early wake-up times needed for school; in fact, in the United States there is a trend for progressively earlier school start times. Because school start times are driven primarily by public transportation time schedules and not school schedules or student needs, students may be sleepy in the classroom and could be mislabeled as lazy, uninterested, or as having learning disabilities.

In early adulthood, decrements in the amount of Stage 3 and 4 sleep are common. During the next decades, total sleep time may be compromised by work, family obligations, and social schedules.

Sleep characteristics show profound changes in the elderly. Nocturnal sleep is less deep and more disrupted, so that more time in bed and daytime napping occurs in an attempt to achieve optimum sleep levels. Older individuals have more incidents of sleep apnea and sleeprelated breathing disorders, which can lead to excessive daytime sleepiness.


It is important to keep in mind that there are wide individual differences in sleep need. Some individuals ("short sleepers") need less than 5 hours of sleep; others require 10 to 12 hours of sleep to function. Although most people report a need of between 7 and 8.5 hours of sleep, the full spectrum of what is considered normal ranges from 3 to 12 hours.


The sleep cycle is part of a 24-hour, or circadian, rhythm. The timing of sleep and wakefulness is determined largely by environmental (i.e., light) and internal (i.e., neural pacemaker) factors that are part of a "biologic clock." The body temperature rhythm in humans is routinely used as a means of assessing the output of the circadian system, and has strong influences on both the timing and duration of sleep.

When subjects were studied in environments free of time cues, the sleep-wake and body temperature cycles became uncoupled and ran free with different circadian periodicities. Bedtime and sleep onset are most likely to occur near the body temperature nadir. If sleep onset occurs near the body temperature minimum, waking tends to occur on the following rising phase of the body temperature rhythm. If sleep onset occurs near the body temperature maximum, however, waking still occurs on the following rising phase of the body temperature rhythm. Further studies have shown that sleep onset near the body temperature cycle minimum results in maximum sleep and REM sleep propensities, and sleep onset near the rising phase of the body temperature rhythm disturbs sleep and minimizes REM sleep. These findings explain how the temporal shifts in body temperature relative to sleep onset that occur as a consequence of jet lag or shift work can wreak havoc on sleep. For example, the desire to go to bed after an exhausting transcontinental flight, or after a switch from daytime to graveyard shifts, may strongly conflict with the drive of the circadian system to "be awake" as body temperature rises.

It is of interest that the small dip in body temperature in the midafternoon, and the coincident decrease in arousal and performance, are linked to an increased desire to nap. Understanding these physiologic precursors of the "nap" have helped dispel the negative connotations often associated with napping.

In summary, alterations in the timing of core temperature and sleep that result from a change in the phase relationship of these rhythms (i.e., because of jet lag or shift work) have significant effects on sleep propensity and sleep architecture. Such uncoupling between body temperature and sleep may result in disorders of initiating and maintaining sleep. Light therapy, or exposure to carefully timed pulses of bright light, can counteract the detrimental effects of jet lag or shift work by phase-shifting the body temperature rhythm relative to sleep.


As previously discussed, there are strong correlations among the duration of sleep, REM sleep propensity, and the phase of the body temperature rhythm at sleep onset. Separate from and in addition to these circadian effects, environmental and body temperatures have a powerful influence on both the amount and distribution of sleep and wakefulness; thus, it is important to understand the impact of the thermal environment on sleep. In the cold, arousal from sleep, sleep latency, and movement time increase; decreases in sleep time are mostly caused by decreased REM sleep and Stage 2 NREM sleep. In a warm environment, the nocturnal sleep period is characterized by increased wakefulness and by reductions in both REM sleep and NREM sleep. When human subjects were exposed to a range of ambient temperatures, total sleep time, NREM sleep Stages 3 & 4, and REM sleep were maximum at thermoneutrality (the ambient temperature at which resting metabolic rate is minimum, at 29[degrees]C), and progressively decreased as environmental temperature deviated from thermoneutrality. Duration of REM sleep peaked in the thermoneutral zone, significantly decreasing outside of thermoneutrality. Thermally induced changes in sleep may occur following a thermal stress and are characterized by sleep fragmentation or sleep loss during exposure to the thermal stress.

Both exercise and passive heating (i.e., by a warm bath) elevate body temperature and influence sleep. Both passive heating and high-intensity exercise increase NREM delta sleep, with little change in REM. These effects appeared to be caused primarily by the influence of core temperature on sleep, but are dependent on the temporal relationship between elevated body temperature and sleep onset. For example, passive heating in the early evening increased delta sleep in each of the following NREM sleep cycles, but late evening heating resulted in increased delta sleep in the first sleep cycle only. These findings suggest that a hot bath prior to bedtime may be useful for treating insomnia. This recommendation may seem to conflict the previous statement. To clarify, it is important to recognize that active heating (exercise) requires a much longer time for cooling than passive (such as a warm bath). The more rapid decrease in core body temperature after the bath may help to promote sleep onset.


Another important consideration is that either sleeplessness or sleepiness are common side effects of many pharmacologic agents, including over-the-counter, prescription, and recreational drugs. Alcohol ingested close to bedtime may be initially sedating; however, as it is metabolized, it may disrupt nocturnal sleep. Aspirin results in a small reduction in Stage 4 NREM sleep, which appears to be linked to a small decrease in oral temperature prior to sleep onset. Some therapeutic agents, such as antidepressants, can cause dramatic reductions in REM sleep; in fact, the decrease in REM sleep may play a key role in the antidepressant action. Beta-Blockers, commonly used to treat hypertension, can cause insomnia. Many antihistamines have a sedative effect. Caffeine is widely used to combat sleepiness, but may result in difficulty sleeping if taken in high quantities or too close to bedtime.

Most drugs affect body temperature, so drug-induced changes in sleep may be secondary to effects on the thermoregulatory system. For these reasons, proper interpretation of quantitative polysomnography in the sleep laboratory requires a clear knowledge of the patient's current drug and medication use.


A number of guidelines can be adopted to optimize sleep. These include the following: (1) avoiding caffeine 4 to 6 hours before bedtime; (2) avoiding nicotine near bedtime and during nighttime awakenings; (3) using alcohol in moderation and knowing that alcohol use near bedtime may cause sedation and help with sleep onset, but may cause awakenings later in the night; (4) eating a light snack near bedtime may help sleep, but eating a heavy meal too close to bedtime may interfere with sleep; (5) avoiding strenuous exercise within 3 to 4 hours of bedtime (although exercise late in the afternoon can help to deepen sleep), and (6) minimizing noise, light, and excessive temperatures.


For millions of Americans, a good sleep regimen alone is not sufficient to allay the suffering from sleep disorders. Most sleep problems can be broadly categorized as (1) disorders of initiating or maintaining sleep, (2) disorders of excessive sleep or sleepiness, (3) parasomnias or abnormal events during sleep, such as sleepwalking or nocturnal enuresis, or (4) abnormalities in the timing of sleep. Any pathology that may occur during the nocturnal sleep period can disrupt the continuity and consolidation of sleep, and hence impair daytime functioning. Among the most common presenting complaints of patients with an underlying sleep disorder is excessive daytime sleepiness (EDS). Because EDS has many causes, a comprehensive medical examination and sleep evaluation are essential for proper diagnosis and treatment.

Analysis of a patient's sleep history can suggest possible sleeprelated pathology and guide the decision for specific testing (polysomnography). Having a bedtime ritual and ensuring that the sleep environment is free from cues that may cause increased arousal or stress (i.e., television, work) are important.

Whether excessive sleepiness results from environmental or physiologic factors, or a combination of both, the results have huge implications for health, productivity, and safety. If sleep is insufficient or disrupted, the drive to sleep will eventually overcome all efforts to remain awake; the sleep "debt" accrued must be paid. The term microsleep is used to describe brief episodes of sleep (lasting just a few seconds) that invade the waking state. Microsleep episodes occur following sleep deprivation, whether the sleep deprivation is voluntary (e.g., the "allnighter") or owing to the presence of a sleep disorder (such as insomnia or sleep apnea syndrome). The possible consequences of a sleep debt and overwhelming desire to sleep are sobering. One needs only to think of the effects of excessive sleepiness on a nuclear power plant operator, air traffic controller, commercial airline pilot, school bus driver, or a child trying to learn. Indeed, studies of catastrophic accidents have revealed that fatigue and lack of sleep were important factors.

by Sharon A. Keenan, PhD, RPSGT
COPYRIGHT 2005 Focus Publications, Inc.
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Title Annotation:SLEEP MEDICINE
Author:Keenan, Sharon A.
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Geographic Code:1USA
Date:Jan 1, 2005
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