What is sleep?

Structure and Functions

All multicellular animals cycle through daily fluctuations in biological activity known as circadian rhythms, with the alternation of sleep and wakefulness being the most obvious example. In humans, a polycyclic sleep/wake cycle—several periods of sleep and arousal during a twenty-four-hour period—becomes evident in the fetus during the latter stages of pregnancy. As children progress from infancy through childhood, they gradually settle into a mainly diurnal pattern, with one long period of sleep during the day. A complex interaction of several external and internal events determines the timing and duration of sleep.

The key exogenous factor that influences sleep is light. In the absence of the alternation of day and night, people will usually develop a sleep/wake cycle that is a little longer (from a few minutes to an hour) than a twenty-four-hour day. Two neurological structures detect light and synchronize the body’s sleep/wake cycle with the presence or absence of light. The pineal gland
is a photosensitive endocrine gland centrally located in the brain that secretes the hormone melatonin, which causes drowsiness. When darkness increases, the pineal gland steps up production of melatonin; levels of melatonin decline as light increases. Melatonin levels also affect the structure of the brain that plays the key role in regulating circadian rhythms, the suprachiasmatic
nucleus
of the hypothalamus (SCN). The SCN serves as the body’s primary biological clock, containing cells that will pulse in rhythmic activity in the absence of light. The activity of these cells, however, is influenced by output from the pineal gland and also from the eye’s retinal cells, providing two avenues by which light can affect the SCN. Light causes the SCN to alter levels of Tim, a protein which, when it interacts with two other proteins known as Per and Clock, will induce sleepiness at high levels. Levels of Tim, in turn, will increase activity in certain cells of the SCN. Thus, light serves as the zeitgeber (time-giver) for the sleep/wake cycle by changing the activity of the pineal gland and SCN, thereby altering levels of sleep-inducing chemicals.

Although damage to the pineal gland and SCN will significantly disrupt the quality and quantity of sleep, periods of sleep will still occur. That observation, in addition to the fact that animals will develop sleep/wake cycles in the absence of light changes, points to other, internal mechanisms that control sleep and arousal. One of these mechanisms is body temperature. Body temperature fluctuates from approximately 98 degrees Fahrenheit (36.7 degrees Celsius) to 99 degrees Fahrenheit (37.2 degrees Celsius) during the day. Rising body temperature is associated with arousal; declining body temperature is correlated with drowsiness. Vigorously rubbing the hands together can increase blood flow to the hands, dropping the blood supply to the brain, thereby decreasing the temperature of the brain and making it easier to fall asleep. While blood flow has an impact on the level of alertness, it is the flow of several neurotransmitters—chemicals that bridge the synaptic gap between one neuron (nerve cell) and another—that play the crucial role in regulating sleep and
arousal.

Neurotransmitters generally have excitatory or inhibitory effects on arousal, but their impact on sleep is dependent on the neurological structures that they affect. Overall, more neurotransmitters appear to facilitate arousal rather than sleepiness. Acetylcholine and glutamate are the primary neurotransmitters for learning, so it is not surprising that they mediate the brain’s alertness to external stimuli. The pontomesencephalon portion of the reticular formation—the brain’s major arousal system—releases these two neurotransmitters, which activate regions of the brain from top (the cortex) to bottom (the medulla). Acetylcholine is also released by excitatory basal forebrain cells that have direct connections with the thalamus, the brain’s center for the integration and processing of sensory information. Close to the bottom of the brain in the pons is the locus coeruleus, which promotes wakefulness and helps to consolidate memories. Norepinephrine, the neurotransmitter that is involved in the display of active emotions such as fear or anger, is released from this structure and arouses many areas of the brain. Between the locus coeruleus and the basal forebrain is the hypothalamus, which influences many aspects of motivation and emotion, particularly through its regulation of the pituitary gland, the master gland of the endocrine system. Anterior cells of the hypothalamus release histamine, which, like acetylcholine, has widespread arousing effects on the brain. Taking antihistamine drugs to subdue the symptoms of allergies and colds will militate against those arousing effects. Lateral cells of the hypothalamus produce orexin, a neurotransmitter that is necessary for staying awake, especially as the day transpires.

Three neurotransmitters promote the induction and maintenance of sleep; two of them exert their effects via the basal forebrain. Gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter, is released by inhibitory cells in the basal forebrain and dampens arousal in the cortex and thalamus. Adenosine decreases activity in the acetylcholine-producing cells of the basal forebrain, thereby inhibiting arousal. Caffeine derives its stimulating effects by blocking adenosine receptors. Moderate levels of serotonin have a calming effect and can facilitate the induction of sleep. However, serotonin (and norepinephrine) can decrease the quantity of REM sleep. Other chemicals, such as prostaglandins, work in conjunction with these three neurotransmitters to promote the induction and maintenance of sleep.

The interplay of various levels of neurotransmitters and hormones effect changes in the electrical activity of the brain. Recordings of the electrical potentials of brain cells made with an electroencephalograph (EEG) have resulted in the identification of four succeeding distinct patterns of brain wave activity that occur in approximately ninety-minute cycles. Prior to falling asleep, a person manifests mostly alpha EEG readings—high amplitude (top-to-bottom distance), medium wavelength (peak-to-peak distance) brain wave activity—characteristic of an alert, relaxed state. When a person slips into the first stage of sleep, a theta EEG pattern—low amplitude, short wavelengths—predominates. As sleep progresses, brief periods of very short wavelengths (sleep spindles) and bursts of high amplitude waves (K-complexes) punctuate the theta EEG pattern, marking the appearance of stage 2 sleep. Eventually, high amplitude and long wavelength brain activity—a delta EEG record—becomes more prevalent and stage 3 sleep is evident. Finally, delta EEG waves predominate
as the person settles into stage 4 sleep. The individual will then cycle back through the third and second stages before reaching stage 1 sleep again, completing the ninety-minute biorhythm. The second period of stage 1 sleep is usually accompanied by the first appearance of rapid eye movement (REM) sleep in humans (many species lack the eye movements), a phenomenon in which brain activity is high but many signs of physiological arousal, such as muscle tension, are low. The time spent in each stage varies, depending on how long the person has been sleeping: stages 3 and 4 predominate during the first half of a sleep period, while stages 1 and 2 predominate (stage 4 sleep is often absent) during the second half.

Differences in sleep stage characteristics and their associated phenomena have led some researchers to distinguish between two basic types of sleep: S-sleep (more neural synchrony, similar activity in diverse brain regions), which combines stages 3 and 4, and D-sleep (more neural desynchrony, diverse brain regions active at different times), which combines stages 1 and 2. S-sleep is characterized by many signs of a deeper physical rest: lower body temperature, generally lower autonomic arousal, difficult arousal. Moreover, sleep loss and physical injuries or deprivations tend to increase the percentage of S-sleep over D-sleep. In contrast, more signs of psychological restoration are associated with D-sleep: increased cortical blood flow and more vivid and prevalent dreams, especially during REM sleep. Additionally, deprivation of REM sleep tends to impair memory and increase irritability more so than deprivation of S-sleep. Because the distinctions between S-sleep and D-sleep are not always clear-cut—for example, S-sleep is essential for some types of memory formation—some researchers prefer to distinguish between REM sleep and non-REM (NREM) sleep.

Disorders and Diseases

Species vary in the amount of sleep that they require during a day, ranging from approximately two hours for a horse to twenty hours for a bat. Humans begin life averaging around sixteen hours of sleep a day as babies, progress to needing about half that much through most of adolescence and adulthood, and then typically get six to seven hours of sleep a day in later adulthood (partially due to age-related decreases in melatonin). No matter what the species or the age of the individual, problems with both the quantity and quality of sleep impair physical and psychological well-being.

Poor quantity of sleep, resulting in feeling tired during waking hours, is the primary characteristic of the most common class of sleep disorders known as insomnias. Insomnias may be characterized by difficulty initially falling asleep (onset), problems in staying asleep (maintenance), or inability to fall back asleep when waking up early (termination). Termination and maintenance insomnia become more likely as people leave early adulthood. Rising body temperature is a factor in both onset and termination insomnia; breathing problems often induce maintenance insomnia.

Trouble breathing, leading to a drop of oxygen in the blood and frequent awakenings, is the main symptom of sleep apnea. Apnea can be caused by many factors, including obstructions of airway passages (often the result of obesity), the use of drugs (such as alcohol and tranquilizers, which relax breathing muscles), or deterioration of areas in the brain that control breathing (the pre-Botzinger complex of the medulla). Left untreated by surgery or breathing aids, apnea can result in numerous health problems, such as loss of cells in multiple areas of the brain, memory deficiencies, heart problems, and diabetes.

Insomnias and apnea, as well as numerous other sleep disorders, can also lead to poor quality of sleep. In particular, depressed amount of REM sleep is a common problem associated with sleep dysfunctions. Neurological depressants, such as alcohol and tranquilizers, have commonly been used to treat insomnia. Unfortunately, such drugs can lead to iatrogenic (caused by medical treatment) insomnia in which a drug initially facilitates sleep but then tolerance develops, in which an increasing amount of the drug is needed to induce its primary effects, and insomnia recurs. Moreover, neurological depressants typically suppress REM sleep, further exacerbating the insomniac’s condition.

In stress-induced insomnia, EEG records reveal that brain activity drifts in a twilight zone between sleep and wakefulness, with minimal REM sleep. People suffering from significant reactions to trauma, such as in post-traumatic stress disorder (PTSD), frequently reexperience their traumatic encounters in nightmares that are so vivid and horrifying that they are unable to stay asleep during REM periods. In contrast, it is the sleep partners of individuals with REM behavior disorder who have problems staying asleep, as the person with the dysfunction thrashes wildly about, perhaps acting out her or his dreams.

Overactive motor activity is also the primary symptom of two NREM disorders: restless leg syndrome, which is characterized by twitching and high muscle tension of the legs, and myoclonus, which involves body twitching, particularly of the arms and legs, while asleep. The extreme overactive muscle sleep disorder, however, is sleepwalking. Sleepwalking normally occurs in stage 4 sleep and is more common in children and adolescents. What sleepwalking is to motor activity, night terrors (extremely terrifying dreams) are to psychological activity. As with sleepwalking, night terrors are more common in children and adolescents and occur during stage 4 sleep. Sleeptalking is not restricted to any particular age-group or sleep stage.

Narcolepsy is a sleep dysfunction in which the main problem is evident during waking hours rather than during the sleep period. The four primary symptoms of narcolepsy are intense periods of sleepiness, cataplexy (muscle weakness), hypnogogic imagery (dreamlike hallucinations while slipping into sleep), and sleep paralysis

(muscle immobility while moving into and out of sleep periods). Because most of the symptoms are associated with REM sleep, narcolepsy has been interpreted as a wakeful experience of REM-like sleep. Low levels of orexin have been implicated as a cause of this disorder.

Perspective and Prospects

In his book The Promise of Sleep (1999), William C. Dement, one of the foremost researchers of sleep, describes the breakthrough research in the early 1950s that gave birth to the modern era of sleep understanding. Dement, working with Nathaniel Kleitman and Eugene Aserinsky, conducted the first research to measure simultaneously the electrical activity of the eyes and brain while people were sleeping. The results of their work led to the identification of four distinct stages of sleep, the discovery of a ninety-minute sleep cycle, and the detection of REM sleep. REM sleep was later found to correspond with a discovery by Michel Jouvet called paradoxical sleep, so named because animals in this type of sleep manifest high brain activity but relaxed postural muscles. Dement and Kleitman also discovered that people awakened from REM sleep were usually dreaming. These discoveries of the 1950s opened up new avenues of research, from empirical studies of dreaming to the interrelationship between sleep and health, and led to the development of better methods to diagnosis and treat sleep disorders.

By the mid-twentieth century, benzodiazepines (tranquilizers, such as Halcion, Valium, and Xanax), which facilitate the action of GABA and adenosine, became the primary treatment for diverse kinds of sleep disorders. Such side effects such as REM suppression, increased likelihood of apnea, and drowsiness during waking hours, however, prompted researchers to search for alternatives to these highly addictive drugs. Safer alternatives for insomnia were developed in the late twentieth century as nonbenzodiazepine, GABA-facilitating sleep aids (such as Ambien, Lunesta, and Sonata) became more popular. Rozerem, a melatonin receptor stimulant, offered physicians a new approach to treating insomnia in the twenty-first century. While chemicals, such as dopaminergic agents (Sinemet) for restless leg disorder and stimulants (Ritalin) for narcolepsy, can be useful in treating various sleep disorders, for the person suffering from insomnia the best advice is often to avoid the chemicals—such as
alcohol, caffeine, and nicotine—that will interfere with the natural mechanisms designed to promote sleep.

In July 2013, researchers at the Veterans Administration Medical Center in Mississippi published a study showing that sleep apnea treatment, specifically continuous positive airway pressor, or CPAP, helps alleviate symptoms of post-traumatic stress disorder.

Bibliography

Dement, William C., and Christopher Vaughan. The Promise of Sleep: A Pioneer in Sleep Medicine Explores the Vital Connection Between Health, Happiness, and a Good Night’s Sleep. New York: Delacorte Press, 1999.

Hirshkowitz, Max, Patricia B. Smith, and William C. Dement. Sleep Disorders for Dummies. Hoboken, N.J.: For Dummies, 2004.

Jacobs, Gregg D. Say Goodnight to Insomnia. London: Rodale, 2009.

Kryger, Meir H., Thomas Roth, and William C. Dement, eds. Principles and Practice of Sleep Medicine. 4th ed. New York: Saunders/Elsevier, 2005.

"Sleep Apnea May Boost Risk of Sudden Cardiac Death." MedlinePlus. June 11, 2013.

Preidt, Robert. "Poor Sleep May Worsen Heart Woes in Women, Study Finds." MedlinePlus. June 7, 2013.

Preidt, Robert. "Sleep Apnea Treatment Eases Nightmares in Vets with PTSD: Study." MedlinePlus. July 17, 2013.