Sleep and Normal Human Physiology

James D. Geyer

Stephenie Dillard

Paul R. Carney

Yhni Thai

Sachin Talathi

INTRODUCTION

Although the function of sleep remains unknown, much is known about its physiologic consequences. Very few, if any, bodily systems are untouched by the drastic changes in consciousness and brain behavior. Some changes are mild and of limited clinical consequence and are secondary to changes in other systems. Others are quite dramatic and of great clinical significance. This chapter reviews the latter group and will serve as the background for understanding physiologic changes accompanying various disorders discussed in the other chapters. It provides a basic review of sleep-related physiology in the autonomic nervous system, respiratory system, cardiovascular system, immune system, gastrointestinal system, renal system, genital/reproductive system, and temperature regulation. Wherever possible, the differences between sleep-related physiologic changes and circadian effects are noted.

AUTONOMIC NERVOUS SYSTEM

Anatomy

Many of the physiologic changes occurring during sleep are related, at least in part, to alteration of autonomic nervous system activity. Basic laboratory evaluation of some of the changes in autonomic function has been challenging because, not only do the sympathetic and parasympathetic effects change from one organ system to the next, but there is great variability in those effects among various animal species. When comparing animal models, some species vary only in the degree of effect, whereas others show totally opposite responses to the same stimulus, making extrapolation to humans difficult, if not impossible.

The central autonomic nervous system is located in the brain stem, with the nucleus tractus solitarius (located in the dorsal aspect of the medulla just ventral to the dorsal vagal nucleus) serving as a central node in the system (1). The general visceral afferents arise from the gastrointestinal, cardiovascular, and respiratory systems. Multiple central autonomic efferent pathways arising from the nucleus tractus solitarius lead to the lateral hypothalamus, paraventricular hypothalamic nucleus, stria terminalis in the forebrain, central nucleus of the amygdala, midbrain central gray matter, dorsal pontine lateral parabrachial nucleus, and ventral medulla (1).

Multiple nuclei, including the ventral medullary nuclei, paraventricular hypothalamic nucleus, and pontine raphe nuclei, provide input into the intermediolateral nucleus, the sympathetic preganglionic center located in the spinal cord. The parasympathetic preganglionic neurons are located primarily in the nucleus ambiguus and the dorsal motor nucleus of the vagus. The vagus nerve is a major component of the primary common pathway for the autonomic nervous system (1).

NORMAL AUTONOMIC CHANGES IN SLEEP

Significant sleep-related changes in autonomic function affect the cardiovascular system, respiration, thermal control, musculoskeletal activity, pupillary reflex, and genital function. In general, at sleep onset, there is an increase in parasympathetic tone and a concomitant decrease in sympathetic tone, which continues during nonrapid eye
movement (NREM) sleep (2). With the transition to tonic rapid eye movement (REM) sleep, the parasympathetic activity continues to increase and the sympathetic activity is further suppressed. During phasic REM sleep, there is an increase in the sympathetic activity, which occurs in bursts (2).

The increase of parasympathetic tone in NREM sleep and tonic REM sleep results in pupillary constriction. The autonomic changes initiated with phasic REM sleep (central parasympathetic inhibition and increased sympathetic tone) result in phasic pupillary dilatation.

Musculoskeletal System

Somatic Skeletal Muscle

The somatic skeletal muscles typically have their highest muscle tone during wakefulness. The tone then decreases with sleep onset and during NREM sleep but should achieve its lowest level during REM sleep. Anyone who has watched a family pet dream is aware of the transient bursts of myogenic activity that occur during phasic REM sleep. Failure to decrease muscular activity during this phase of sleep results in REM sleep behavior disorder.

Projections from the nucleus reticularis pontis oralis located in the dorsal pontine tegmentum synapse in the medullary reticular formation and then project to the spinal cord. Firing of these neurons during REM sleep results in the release of the neurotransmitter glycine in the spinal cord, which generates inhibitory postsynaptic potentials (IPSPs). The IPSPs, in turn, decrease the firing of the motor neurons, thus generating relative atonia (3).

Cranial motor neurons also appear to be affected by IPSPs originating from the dorsal pontine tegmentum. These pathways are less well understood but may be mediated by the inhibitory neurotransmitter GABA_B (3).

Upper-Airway Muscles

The genioglossus muscles serve to pull the tongue down and forward. During inspiration, the activity in this muscle occurs as phasic bursts superimposed on tonic discharges. These discharges diminish during NREM sleep and are further suppressed during REM sleep, resulting in a partial atonia, which can allow the tongue to fall back toward the retropharyngeal space (4). This alteration of upper-airway anatomy is partially responsible for obstructive sleep apnea (OSA). Genioglossal activity is enhanced by tricyclic antidepressants, such as protriptyline and nortriptyline, and is suppressed by alcohol, benzodiazepines, and some anesthetic agents, lending support to the theory that inhibition of this muscle is GABA-mediated.

The masseter muscles close and elevate the mandible. Phasic activity in the masseter muscles starts at approximately the same time as the genioglossus activity.

The palatoglossus and levator palatini have phasic activity on inspiration and tonic activity during expiration. The tensor veli palatini has tonic activity during both inspiration and expiration. The palatoglossus, levator palatini, and tensor veli palatini have decreased tone during sleep, which reaches its minimal level during REM sleep (5).

The hyoid musculature contributes to the size and shape of the upper airway. The interactions of the various hyoid muscles are quite complex and beyond the scope of this discussion. Bursts of activity are present in the hyoid musculature during inspiration during both wakefulness and NREM sleep.

The posterior cricoarytenoid muscle is the primary vocal cord abductor. It has phasic burst activity during inspiration in both wakefulness and NREM sleep. With the onset of REM sleep, the expiratory burst activity becomes fragmented and less sustained (6).

Diaphragmatic Activity

The diaphragm serves as the primary bellows for respiratory function and air movement. As one would expect, the rhythmic firing of the diaphragm occurs in both wakefulness and during all phases of sleep, but the percentage of motor units firing is decreased during REM sleep (7). There may also be some variability of the decrease in diaphragmatic activity during a single breath. In addition, brief pauses in diaphragmatic activity may occur during normal phasic REM sleep.

Thermal Regulation

Body temperature typically falls by several degrees Celsius during nocturnal sleep. The body retains its thermoregulatory capability during NREM sleep, but the thermoregulatory response is attenuated during REM sleep (8). At sleep onset, the metabolic rate falls to a greater degree than can be explained by decreased motor activity and digestive function alone.

The normal 1°C to 2°C drop in body temperature during nocturnal sleep is accomplished by two separate mechanisms. Approximately one-half of the decrease is related to circadian temperature variation, which is independent of sleep (9). This is superimposed on a sleep-related reduction in the body’s thermal setpoint, which occurs because of a combination of increased heat dissipation and decreased heat generation (10). This effect typically peaks during the third sleep cycle, resulting in the minimum body temperature for the night (10).

The reduction in body temperature associated with NREM sleep appears to be related to a change in the thermal sensitivity of the preoptic nucleus of the hypothalamus, which contributes to both slow-wave sleep (SWS) and thermoregulation. During REM sleep, there is a loss of this thermoregulatory response and body temperature tends
to increase with cyclic variability. These changes are not related to motor atonia, but are determined by an alteration of central thermal regulation or, potentially, an alteration in the afferent neural input to the thermoregulatory center.

Total sleep time, slow wave, and REM sleep are maximized at thermoneutrality (∽ 29°C) (11). The wake time, sleep latency, and movement time all increase in a cold environment, and there is a decrease in total sleep time, REM sleep, and stage 2 sleep (11). Likewise, in a warm environment, wake time is increased with reductions in both REM and NREM sleep. Fragmentation of sleep occurs at higher environmental temperatures, and elevated environmental temperature causes more sleep fragmentation than does environmental noise.

An increase in waking body and brain temperature is associated with an increase in slow wave sleep (12). A warm bath, aerobic exercise, heating pads, and so forth can increase the percentage of SWS occurring approximately 4 hours after exposure. There is also evidence that fever will decrease SWS and REM sleep, while increasing wake time and light sleep. These changes appear to be secondary to the elevated brain temperature itself and are at least partially independent of the humoral byproducts of infection, such as cytokines (13).

Renal Function

Renal perfusion and glomerular filtration rate decrease during NREM sleep, resulting in decreased urine production, largely due to sleep-related cardiovascular function. Furthermore, water reabsorption increases during NREM sleep. Urine production decreases even further during REM sleep. There is a decrease in secretion of aldosterone during sleep, primarily due to the supine position. Only a small portion of the decrease in aldosterone secretion can be attributed to changes unique to the sleep state.

Genital Function

There are few changes in genital function during NREM sleep. In men, REM sleep is associated with penile tumescence (erection) (14). The erection typically begins at the beginning of REM sleep and continues throughout the REM sleep period. In most instances, the erection is lost at the end of the REM sleep period but, in some cases, may continue into wakefulness. Similar changes occur in the erectile tissue of women during REM sleep. Sleep-related erections occur as a result of increased blood flow to the erectile tissue, which is caused by increased parasympathetic activity resulting in local vasodilatation, decreased venous outflow, and increased bulbocavernosus muscular activity. The detumescence is a result of the increased sympathetic activity at the end of REM sleep. In addition to these autonomic changes, it is also likely that the central nervous system (CNS) may also provide input into these sleep-related erections.

Sleep-related erections are not typically affected by presleep sexual activity, fantasies, or reported dream content.

Gastrointestinal Function

The effects of sleep on the gastrointestinal system are driven by a combination of increased parasympathetic activity, circadian rhythm factors, CNS activity, and the subserosal neural plexus activity. The study of the gastrointestinal system is inherently difficult and becomes even more so during sleep because of the potential for sleep disruption caused by monitoring devices; therefore, controversy remains regarding a number of aspects of digestion during sleep.

Salivation

Salivation decreases during sleep, in large part because of increased parasympathetic activity. Saliva is an important component of gastric acid neutralization, and the decrease in salivary flow can contribute to an increase in nocturnal gastroesophageal reflux. Swallowing decreases the duration of acid contact with the esophageal mucosa. The prolonged contact during sleep increases the risk of esophagitis secondary to acid reflux.

Esophageal Motility

The frequency of swallowing is markedly decreased during sleep (15). When swallowing does occur, the ensuing esophageal peristalsis appears to be normal and unchanged when compared with swallowing occurring during wakefulness (16). In a more recent study, the frequency of primary peristaltic contractions was shown to decline from wakefulness to stage 4 sleep (17).

Most episodes of nocturnal reflux appear to correspond to decreases in lower esophageal sphincter pressure (18). The relative negative pressure of the midesophagus then draws the regurgitated stomach contents even further into the esophagus.

The upper esophageal sphincter, the cricopharyngeal muscle, is a skeletal muscle that is tonically contracted to prevent aspiration. There is a minimal decrease in the upper esophageal sphincter pressure during sleep. Although the cricopharyngeal muscle is a skeletal muscle, there is minimal change in pressure throughout REM sleep.

Gastric Function

Gastric acid secretion follows a circadian rhythm, with the peak basal acid secretion occurring between 10 PM and 2 AM (19). Patients with duodenal ulcer disease have the same pattern when compared with normal controls, except that their total acid secretion is increased. This circadian pattern is mediated by the vagus nerve.
There appears to be a significant night-to-night and subject-to-subject variability in acid secretion. The data regarding impact of sleep stage on acid secretion is contradictory, with one study revealing no significant change in acid secretion or serum gastrin levels across sleep stages (20).

The gastric smooth muscle generates an endogenous electrical cycle, which drives gastric motor function and occurs at a frequency of approximately three cycles per minute. There is some evidence that the power of this rhythm decreases during NREM sleep, with some recovery toward baseline during REM sleep.

Intestinal Function

Intestinal absorption is directly related to the transit time. The motor activity, beginning in the stomach, appears to propagate along the intestinal tract. Some studies have shown variability in the frequency of migrating motor complexes during sleep (21,22). There is a circadian rhythm-associated decrease in migrating motor complex velocity during sleep. Studies have, however, shown conflicting results.

Colonic Function

There is a decrease in the colonic myoelectric activity and contractile activity, which, in turn, results in decreased colonic motility. On awakening in the morning, the colonic motility increases significantly. Sudden nocturnal awakening seems to result in segmental colonic contractions without propagation (23).

Anorectal Function

Rectal motor activity increases during sleep with retrograde contractions. Despite the presence of cyclic rectal contractions, the anal pressure remains above the rectal pressure. Both of these factors inhibit defecation during sleep.

Endocrine Function

Most hormones follow a predictable fluctuating pattern through a 24-hour cycle. Circadian rhythms, ultradian rhythms, and stage of sleep may all affect hormone secretion.

Growth Hormone

Plasma growth hormone concentration typically peaks approximately 90 minutes after sleep onset, usually during stages 3 and 4 sleep. However, there are several exceptions to this secretory pattern (24). Secretion of growth hormone is not related to sleep prior to 3 months of age, and growth hormone concentration peaks prior to sleep onset in 25% of young males (25). Senior adults have a less significant relationship between sleep and growth hormone concentration (26). Although sleep causes the greatest fluctuations in growth hormone levels, there is also some evidence of ultradian and circadian effects, albeit to a lesser extent. Patients with OSA or narcolepsy have a decreased correlation between sleep and growth hormone concentration (27). In acromegaly, growth hormone concentration is high and unrelated to delta sleep (28).

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