Todd J. Swick, MD a,b,*

a School of Medicine, University of Texas-Houston, Houston, TX, USA

b The Houston Sleep Center, Houston, TX, USA

* University of Texas-Houston, 7500 San Felipe, Suite 525, Houston, TX 77063.

E-mail address: tswick@houstonsleepcenter.com

Abstract

Neurology, by virtue of its study of the brain, is the primary medical science for the elucidation of the anatomy, physiology, pathology and ultimately, the function of sleep. There has been nothing short of a revolution in the science of sleep over the past 50 years. From the discovery of REM sleep to the identification of Hypocretin/Orexin the basic science and clinical field of sleep medicine has blossomed. This article will explore the anatomy, physiology, biochemistry and, to a limited extent, pathophysiology of the sleep/wake centers of the brain. The field of chronobiology will also be touched upon.

Keywords

• Acetylcholine • Serotonin • Dopamine • Norepinephrine • Histamine • Orexin • Melatonin • Circadian rhythm

Historical context

The Greco-Roman concepts of sleep were based on their belief that there were gods and goddesses that controlled the minor and major events of their lives. They identified the goddess of night (Nyx) who had two sons: Hypnos (the god of sleep) and his brother, Thanantos (the god of death). Hypnos sprinkled drops of poppy milk into people’s eyes so that the opium would make them fall asleep and then fanned sleeping persons with his wings to enable them to sleep in comfort. As late as the beginning of the Common Era, Ovid wrote that Hypnos lived with his “thousand children,” the Dreams, in a cave in the Caucasus. The river of Lethe (the river of forgetfulness) was believed to run through this cave.1

In ancient Greece, if citizens were unable to sleep because of their problems, they visited one of the many sanitariums dedicated to Asclepios (the Greek god of medicine), where the afflicted spent 3 weeks in rest, thought, and meditation, soothed by gentle music, and then, having their balance restored, would be able to sleep again (obviously predating the concept of managed care).2

From the time of the Middle Ages until the Renaissance, there were discrete changes in the concept of sleep. More concrete explanations of sleep were enunciated by Lucretius, the Epicurean poet and philosopher, when he described “sleep as the absence of wakefulness”.3 This was the prevailing view through the centuries. As medical science advanced with the discovery of the circulatory system and as the young field of neurology was explored, there was renewed interest in the science of sleep and wakefulness.

In 1866, the Surgeon General of the United States, William A. Hammond, wrote a treatise, “On Wakefulness: With an Introductory Chapter on the Physiology of Sleep,” arguing against the prevailing opinion of his day that sleep began as a consequence of “congestion of the cerebral vessels.” He pointed out several observations that were quoted in contemporary textbooks of medical physiology of his time: (1) stupor never occurs in healthy individuals, whereas sleep is a necessity of life; (2) it is easy to awaken a person from sleep, whereas it often is impossible to arouse him from stupor; (3) in sleep the mind is active and in stupor it is as if it were dead; and (4) congestion of cerebral vessels causes stupor, not sleep. He quotes another nineteenth-century physician, Dr Arthur Durham: “During sleep, the brain is in a comparatively bloodless condition and the blood in the encephalic vessels is not only diminished in quantity but moves with diminished rapidity. Whatever increases the activity of the cerebral circulation tends to preserve wakefulness and whatever decreases the activity of the cerebral circulation and, at the same time, is not inconsistent with the general health of the body tends to induce and favor sleep”.4

Although still surrounded by myth and less than perfect science, the concept of the neural control of sleep was established. From 1916 through 1928, the world was ravaged by an epidemic of influenza with tens of thousands of deaths, the victims sustaining many neurologic signs and symptoms. During the acute phase of the illness, some patients exhibited severe insomnia and many more exhibited severe hypersomnia, whereas many survivors exhibited signs of Parkinsonism.

In 1917, von Economo published his first paper on encephalitis lethargica and on December 3, 1929, he read a paper before the College of Physicians and Surgeons of Columbia University in New York City entitled, “Sleep as a Problem of Localization.” He stated that patients who had insomnia had lesions in the anterior portion of their hypothalamus and that patients who had hypersomnia had lesions in the posterior aspect of the hypothalamus. He designated this area of the “interbrain” as the “center for regulation of sleep.” Thus, the prevailing concept espoused by such luminaries as Lhermitte and Dejerine that “sleep cannot be localized” was put to rest.5,6

In 1928, Berger demonstrated that the brain produced clearly identifiable electrical activity that could be recorded using surface electrodes and that there existed a different pattern of electrical activity of the brain during consciousness compared with sleep.6,7

In 1935, Bremer reported on the effects of transection of the brainstem of cats at the pontine-midbrain level (cerveau isolé) versus transection at the medullary-spinal cord level (encéphale isolé). He found that the cerveau isolé animals maintained a continuous sleep-like state with synchronous slow wave activity, whereas the encéphale isolé cats looked awake and their electroencephalograms (EEGs) contained synchronous and desynchronized activity resembling sleep-wake cycling. Bremer went on to hypothesize that sleep was a passive process and that wakefulness required a high level of continuous sensory input from the periphery to maintain activity within the cerebral hemispheres.8

Bremer’s work rekindled research concerning the observations of y Cajal and Papez. In 1909 y Cajal described an extensive network of neurons that ascended and descended through the brainstem. This was refined further by observations of Papez who in 1926 published a more complete description of the reticular formation and its caudal projections down into the spinal cord in cats.9,10

In 1942, Morison and Dempsey published a series of articles that described a diffuse “nonspecific” thalamocortical recruiting system. They differentiated this “nonspecific” system from the primary sensory input (ie, “specific” system [described by Lorente de No in 1938], acting through direct thalamic relays).11,12

In 1949, Moruzzi and Magoun identified the ascending reticular activating system “whose direct stimulation activates or desynchronizes the EEG, replacing high-voltage slow waves with low-voltage fast activity.” They went on to state, “the effect is exerted generally upon the cortex and is mediated, in part, at least, by the diffuse thalamic projection system”.13

By the middle of the twentieth century it was established that sleep and wakefulness were different states that are controlled by the brain and that sleep was not a passive period of time devoid of activity. Jouvet and colleagues described more precise localizations of the neural loci of sleep and its constituents where results of lesion studies demonstrated that the brainstem contains the site of rapid eye movement (REM) sleep neural activity. Transections of a cat brain at a level just above the midbrain-pons junction preserved the appearance of REM-sleep activity, whereas transections in the pons abolished the appearance of REM sleep.14-16

With the discoveries of REM and non-REM (NREM) sleep by Aserinsky and Kleitman and REM/NREM cycling by Dement and Kleitman, the door finally was opened for researchers to gain more exact insights into the study of the science of sleep and wakefulness.17-19

Sleep and wake states

People exist in one of three behavioral states during normal functioning: (1) wakefulness; (2) NREM sleep; and (3) REM sleep (Fig. 1). These states are characterized by specific changes in EEG, eye movements, and muscle activity. Wakefulness is characterized by well-recognized patterns on surface EEG recording. Alpha activity (8–12 Hz waves of <50 μV amplitude) occurs when individuals are resting with their eyes closed. The rhythms are most evident in the parieto-occipital areas of the head. Alpha rhythm is attenuated or blocked by attention, especially visual (eye-opening) and mental effort. Eye movements are purposeful and conjugate. Muscle tone is variable but never absent.