Neurocontrol of Sleep

Sleep has been described as “a reversible behavioral state of perceptual unresponsiveness to the environment with documentable, distinguishable physiological patterns of neural and muscle activity.”¹ The diagnostic test performed to evaluate the quality of sleep is called a sleep study, or polysomnogram (PSG). The PSG documents more than 20 individual physiological parameters during all phases of the sleep cycle. The term polysomnogram is derived from its prefix, root, and suffix definitions: “poly” means “many,” “somno” means “sleep,” and “gram” means “writing.” This quantitative diagnostic study records physiological data during each second of sleep from wakefulness through the three sleep stages of nonrapid eye movement (NREM) to the rapid eye movement (REM) stage. Through the PSG, the sleep process can be classified in an objective, quantifiable way. However, the precise mechanisms responsible for sleep onset and waking from sleep continue to be the focus of intensive investigation. Although the brain plays a definitive role in sleep regulation, the specific anatomical region of the brain responsible for the sleep control is a subject of controversy. It is now well established that the hypothalamus is the key regulator of sleep and wakefulness.² Since sleep research is now focused on the hypothalamus, new pharmaceutical and therapeutic breakthroughs for neurological sleep disorders have been developed.

The brain is composed of five major regions: the medulla oblongata, which is the most posterior portion of the brain that fuses with the spinal cord; the pons, located superiorly to the medulla oblongata; the midbrain or mesencephalon, located just above the pons; the telencephalon or cerebrum, which consists of five paired lobes within two convoluted hemispheres; and the diencephalon, which sits superior to the brainstem nestled between the two cerebral hemispheres. The diencephalon includes the thalamus, the hypothalamus, the optic chiasm, and the pineal gland (Figure 15-1). Sleep researchers have identified more than 70 distinct sleep disorders but have yet to identify the precise neurochemical mechanisms that “turn on and turn off” sleep and wakefulness. As mentioned, the central focus of study in sleep regulation is currently the hypothalamus.

Biomedical sleep research has definitively determined that the primary biological “sleep clock” resides in the suprachiasmatic nucleus (SCN) of the hypothalamus where it controls the timing of the sleep cycle, or the circadian rhythm. When SCN function is disrupted, the circadian rhythm becomes random and sporadic. However, even though the onset of sleep may vary throughout a 24-hour period, the total sleep time remains the same. Located just above the optic chiasm, the SCN is believed to control certain neurologically secreted chemicals that regulate the sleep cycle. Light plays a very important role in the normal regulation of the SCN. Light is an environmental cue or stimulator known as the zeitgeber, or “time-giver,” that regulates the sleep/wake cycle. The role that light plays as a circadian rhythm “cue” can be observed through the disrupted sleep habits of individuals living in geographical areas of prolonged winter darkness. A decrease in the amount of daylight exposure significantly alters the normal sleep/wake cycle during the winter seasons. The optic chiasm is thought to relay light/dark cues from the eye to the hypothalamus as a reference for the circadian rhythm. It is now understood that the SCN of the hypothalamus merely tracks day and night cycles, whereas the ventrolateral preoptic nucleus (VLPO) in the hypothalamus initiates sleep by inhibiting the brain’s arousal centers in the brainstem (Figure 15-2).

The role of the hypothalamus in controlling the regulation of sleep/wake mechanisms has been confirmed. Various neurotransmitters released by the hypothalamus are believed to produce sleep by inhibiting the brain’s arousal centers. The neurotransmitters that mediate arousal in the cortex include histamine, serotonin, norepinephrine, acetylcholine, and hypocretin (orexin) (Figure 15-3). Sleep research has shown that disruption of the VLPO and the lateral region of the hypothalamus results in arousal. The loss of the VLPO and the lateral hypothalamus structures have been associated with the symptoms of insomnia or narcolepsy respectively.³

Oropharynx

The upper airways comprise three primary anatomical regions: the nose, pharynx, and larynx. As discussed in Chapter 1, normal pharyngeal muscle tone prevents the base of the tongue from falling backward in the oral cavity and obstructing the oropharyngeal airway. Sleep or unconscious states result in a loss of pharyngeal muscle tone and the relaxation of the soft tissue that constitutes the oropharynx and the tongue. Under the influence of gravity, the relaxed tongue falls into the oropharynx, partially or totally occluding the airway. Partial occlusions result in low-pitched snoring sounds, whereas complete occlusion results in apnea, characterized by ventilatory efforts without airflow. Several other soft tissue anatomical structures in the oropharynx may contribute to partial or total obstruction.

Obligate nose breathing during sleep causes problems when the nose is obstructed. Many individuals experience difficulty sleeping when nose breathing is limited because of nasal congestion that accompanies a cold or allergy. At the onset of sleep when obligate nose breathing begins, restricted nasal air passages usually cause sleepless or restless nights. Anatomical abnormalities such as a deviated septum create a permanent limitation of airflow through one or both of the nares. Poor quality of sleep is often a major complaint of individuals with nasal septum abnormalities. The assessment of a potential sleep disorder should always begin with inspection of each naris for patency and unrestricted airflow. If allergies are an issue, medications that diminish nasal swelling or secretions to reduce airflow restriction should be considered. If anatomical obstruction is the primary cause of airflow limitations, corrective surgery may be the best remedy for the sleep disorder. If the nose is occluded during sleep, secondary mouth breathing becomes necessary. Regardless of nose or mouth breathing, the oropharyngeal airway must remain patent to allow ventilation.

Within the oral cavity, five specific structures can obstruct airflow. Mallampati was the first to categorize the amount of “open space” in the oropharynx by the visualization of five structures: the tongue, the soft palate, the hard palate, the uvula, and the tonsils.⁴ Originally used to classify the difficulty level of oral endotracheal intubation, the Mallampati score is determined by direct visualization of the oropharynx through the open mouth. There are four categories of decreasing airway space (Figure 15-4). A class 1 score is considered normal, in which all five anatomical structures are visible. In class 2, all five structures can be identified, but only the upper portions of the tonsils and uvula are visible. Class 3 allows only the tongue, the soft and hard plate, and the base of the uvula to be seen. Class 4 allows visualization of only the hard palate and tongue. The higher the Mallampati classification number, the more anatomical crowding with less oropharyngeal room for airflow. Sleep research has shown a positive correlation between a high Mallampati score and the risk for obstructive sleep disorders when nasal obstruction is present.⁵

Because the mandible anatomically supports and positions the tongue and is part of the oropharyngeal structure, the size of the mandible may limit airflow during sleep. A small, recessed lower jaw, or retrognathia, results in a more retrograde or posteriorly positioned tongue. A posterior position of the tongue makes it easier for the tongue to fall back and block the oropharynx as the pharyngeal muscles relax. An enlarged tongue, or macroglossia, as seen in individuals with Down syndrome, hypothyroidism, and acromegaly, can also crowd the oropharynx decreasing the size of the airway lumen. A shortened or widened neck may also crowd the anatomical structures, narrowing or obstructing the oropharyngeal lumen. A neck circumference greater than 17 inches in men or greater than 16 inches in women is highly correlated with the incidence of obstructive sleep apnea (OSA).6,7

Nonrapid Eye Movement

NREM sleep is composed of three stages with each progressive stage transitioning to a deeper state of sleep. Stage 1 NREM represents the onset of sleep for adults and children. During stage 1 NREM, the eyes roll gently and slowly while low-amplitude EEG brainwaves are noted during the sleep study. This change in EEG brain wave pattern is associated with the transition from awake to sleep. Only 5% to 10% of the entire sleep period is spent in stage 1 NREM, and within 2 to 10 minutes, sleep usually progresses to stage 2 NREM. EEG tracings show sharp spikes called “K-complexes” and “sleep spindles,” which serve as markers for the transition from stage 1 NREM to stage 2 NREM. In adults, approximately 40% to 50% of the total sleep period is spent in stage 2 NREM.⁸

Stage 3 NREM is the deepest stage of sleep and represents approximately 25% of the sleep period. The EEG displays delta waves, or slow-wave sleep, characterized by high-amplitude waves. “Delta sleep” is thought to represent restorative sleep, during which the brain is in its deepest state of sleep. Stage 3 NREM is characterized by a very low level of patient responsiveness; it is difficult to awaken a person from this stage of sleep. Essential growth hormones are released during this stage.8–10

During all three stages of NREM sleep, the muscles of the body exhibit tone and movement; individuals often turn in their sleep and reposition themselves in the bed. Although control of core body temperature and regulation of respiration is maintained during NREM, the respiratory rate slows and tidal volume decreases, causing an increase of 2 to 4 mm Hg in PaCO₂. Minute ventilation is approximately 13% to 15% lower in NREM sleep than during wakefulness. Systemic blood pressure may decrease by 5% to 10% during NREM stages 1 and 2 and decrease 8% to 14% during NREM stage 3 sleep. With advancing age, total time spent in stages 1 and 2 progressively increases, whereas stage 3 sleep decreases significantly.10,11

Rapid Eye Movement

REM sleep is associated with a loss of core body temperature regulation, whereas cerebral blood flow and cerebral temperature increase owing to increased brain activity. Systemic blood pressure becomes variable and elevated during REM. These normal physiological effects of REM place patients with preexisting pulmonary or cardiac disease at greater risk for exacerbations of their disease.

EEG tracings during REM strongly resemble the level of brain activity seen in the awake state (i.e. alpha-like, low-voltage, random, high-frequency waveforms) (see Figure 15-5). As sleep progresses, adults and children cycle back to NREM stages and return to the REM stage three to five times. The time spent in REM normally increases with each cycle for a total of approximately 25% of the sleep period. Electromyography (EMG) shows skeletal muscle tone at its lowest level during the REM stage, suggesting a paralyzed state. This partial paralysis results in a further decrease of the minute ventilation in healthy adults and children, producing a few associated episodes of hypoxemia and hypercapnia, which are normal during REM. Loss of skeletal muscle tone during REM affects pharyngeal muscles; upper airway resistance increases as pharyngeal tissues relax and narrow the upper airway lumen. As previously mentioned, relaxation of the tongue and soft tissues of the oropharynx are the primary cause of increased upper airway resistance, possibly leading to upper airway obstruction. Additionally, REM sleep is associated with heart rate variability and cardiac arrhythmias.^8–11

In summary, during normal sleep, an individual dozes into stage 1 NREM and progresses to stage 2 NREM and then to stage 3 NREM as sleep deepens. During NREM, the brain is in a state of rest while the body is still active and can respond to stimuli. A cycling between stage 1, 2, and 3 NREM continues for 60 to 90 minutes before transitioning to REM, which normally lasts 5 to 30 minutes. Once REM sleep is initiated, brain activity heightens, and dreaming almost always occurs. Partial skeletal muscle paralysis occurs resulting in variability of ventilation, blood pressure, and heart rate. For patients with OSA, the normal progression to REM with partial paralysis results in oropharyngeal soft tissue relaxation and upper airway obstruction. With a loss of airflow and ventilation, oxygen saturation obtained by pulse oximeter (SpO₂) declines, whereas PaCO₂ increases. Consequently, medullary chemoreceptors sensitive to CO₂ are activated and disrupt the onset of REM, “pulling the patient out of REM” and back into stage 1 or 2 NREM sleep; this event is a type of sleep arousal. This sequence is repetitive and fragments sleep; as the patient regains muscular control in the NREM stage, ventilation is restored, and PaO₂, PaCO₂, and pH values are normalized. Recovery of normal arterial blood gas parameters occurs when the subject reestablishes an open airway with a loud snort or gasp, followed by an increased respiratory rate. The individual then slips back into the next NREM stage only to be disrupted from REM sleep repeatedly throughout the night. Patients with SDB commonly lack years of REM sleep; their histories often reveal that they have not dreamed for many years.

Sleep architecture refers to the pattern in which an individual moves back and forth between sleep stages throughout the night. Although the approximate percentage of sleep time spent in the three stages of NREM and the REM stage previously described represents normal sleep architecture, each person has a distinct pattern unique to his or her own sleep cycle. The graphic representation of a patient’s sleep architecture is known as a sleep histogram and is a standard part of every sleep study; it depicts the summative time spent in each phase of sleep at a glance (Figure 15-6). When a patient’s NREM and REM cycles become fragmented on a regular basis, the patient is said to have poor sleep hygiene. Poor sleep hygiene is often due to the lack of a sleep routine or the lack of appropriate sleep cues that signal the body to prepare for sleep, which is typical of the sleep habits of a night shift worker.^9–11