A Brief History Of Sleep Medicine

• Overview
• A Brief Synopsis of Sleep in the 19th Century
• The First Half of the 20th Century
• The Last Half of the 20th Century and Beyond
• Conclusion

Overview - The Pursuit of Sleep

In 1996, the American Medical Association recognized sleep medicine as a specialty. That date belies the importance and interest in sleep that has been going on essentially since time began. It is difficult to determine even an estimated point in time when an interest in sleep occurred. Likewise, it is nearly impossible to pick a date, person, or event that points to the beginning of sleep research. Would it include the discovery of opium, a widely offered treatment for insomnia in ancient Egyptian times (~1300 B.C.) and the first hypnotic medication used? Or would the history of sleep medicine begin much later with Hippocrates' theory of sleep in Corpus Hippocraticum (~400 B.C.)?

The advances in medicine over time have contributed significantly to the understanding of sleep and sleep research. There are few, if any, medical specialties that do not intersect with the past, present, and future understanding and study of sleep. Neurology, psychology, psychiatry, physiology, cardiology, otolaryngology (ear, nose and throat), dentistry, and the list goes on - they are all integral areas of study in the pursuit of sleep. Sleep medicine is truly a multidisciplinary science.

A Brief Synopsis of Sleep in the 19th Century

Sleep theories abounded in the 19th century and there were many schools of thought for the cause of sleep.

1. One of the more popular ideas was that sleep was related to the blood vessels, specifically that sleep was due either to congestion or pressure of blood in the brain, or a lack of blood in the brain.
2. Two chemical approaches were also possible concepts for the cause of sleep. The chemical approach implied that sleep was caused by 1) a lack of oxygen to the brain or 2) an accumulation of toxic substances, such as cholesterol, carbon dioxide, "urotoxins," or "leucomaines." As these toxins built up during the day, they caused sleep; on the other hand, as one slept, the toxins slowly drained away.
3. A new understanding of the central nervous system, a demonstration of the electrical activity of the nervous system, and the newly named neuron brought on neural theories for the cause of sleep by the mid-19th century. One type of neural theory was that neurons were paralyzed during sleep, preventing communication between other nerve cells.
4. Based on earlier experiments, behavioral theories were presented in the late 1800s that proposed an "inhibitory reflex" as the cause of sleep. In other words, sleep occurred as the result of something being turned off or removed.
5. This inhibitory theory was expanded to state that a loss of wakefulness was based on a loss of stimulation to the senses. This theory was refuted at the end of the century with the finding of the brainstem's role in sleep and wakefulness.

In the early 1800s, a significant experiment performed by two neuro-anatomists revealed the anatomy of sleep and wakefulness to some degree. In 1809, Luigi Rolando noted that a permanent state of sleepiness occurred after he removed the cerebral hemispheres in the brains of birds.

Marie Jan Pierre Flourens repeated the experiment in pigeons in 1822. It was significant to many researchers that the results of both experiments were identical. Because of their contribution to the study of sleep, renowned physicians, physiologists, and neurologists began questioning the cause and origin of sleep.

It was also during this time that chronobiology was applied to sleep in humans. Chronobiology is the study of time periods and the environment on biological events, also known as biological rhythms. In the 18th century, Carolus Linnaeus' studies on the consistent opening and closing of flower petals initiated interest in the effects of environmental.

Experiments by scientists studying plants, such as the botanists de Candolle and Pfeffer, suggested the effects of biological cycles and environmental surroundings. By experimenting on themselves, Davy in 1845 and Ogle in 1866 observed changes in their body temperatures. They assumed that biological cycles, which include body temperature and such functions as sleep, are regular despite external cues. In other words, a person would go to sleep at approximately the same time even in surroundings without natural light.

The physiological differences in the states of sleep, dreaming versus quiet sleep, were recognized as early as ancient Greece. In 1868, William Griesinger reported eye movements in association with sleep. Before his release of The Interpretation of Dreams in 1900, Freud noted muscle paralysis during sleep that hindered the dreamer from acting out their dreams.

A large obstacle in the awareness of sleep disorders was overcome with the clinical descriptions of insomnia, sleep apnea, and narcolepsy. Presumably, these disorders were noticed well before the 19th century; however, documentation with a detailed description seen in one or more individuals had never been performed.

It is interesting to note that obstructive sleep apnea was first described not by a clinical doctor, but by Charles Dickens in 1836. Entitled The Posthumous Papers of the Pickwick Club, Dickens depicted an excessively sleepy, overweight boy named Joe who snored and may have had right-sided heart failure. Obstructive sleep apnea was thereafter called the "Pickwickian syndrome." However, OSA was not recognized as a clinical disorder until nearly 100 years later.

The First Half of the 20th Century

Sleep research in the early 1900s was greatly influenced by new diagnostic instruments, surgical options, and clinical procedures. The vascular theories were quickly losing popularity for the explanation of sleep. Theories that lacked a solid foundation were challenged and rejected. The scientific method, reproducible experiments, and defining studies were becoming the standard.

Chronobiology

In the early 1900s, Karl von Frisch and Ingeborg Beling observed bees visiting flowers only at certain times of the day. They saw the same behavior in the bees when they created a man-made feeding station. Auguste Forel also performed experiments in 1910 using bees to investigate the accuracy of a biological timing system. Forel's experiment is credited with encouraging studies into circadian rhythms. In 1906, Sutherland Simpson and J.J. Galbraith used a light-dark cycle to show how environmental factors effect mammalian behavior.

Curt Richter noted the circadian behavior of rodents in his 1922 thesis. He continued his research in the investigation of internal biological timing systems by showing in the 1960s that lesions in the hypothalamus, an area in the front of the brain, caused disruptions in circadian rhythms. In 1935, Erwin Bunning determined in plants the genetic origin of the "biological clock," the term he coined. In following years, the existence and location of a "biological clock" would be proven.

Electrophysiology

With the improvement of electrophysiological techniques, specifically the electroencephalogram (EEG), it was determined that the brain is not inhibited during sleep, but is, in fact, very active, particularly in REM sleep. In 1929, Johannes Berger demonstrated differences in brain activity between wakefulness and sleep by recording electrical impulses. His discovery led to the development and use of the EEG as a clinical and diagnostic tool for brain dysfunction. By using the EEG, Alfred Loomis, E. Newton Harvey, and Garret Hobart in 1937 classified sleep into five different stages, A through E.

Neurochemistry

Chemical theories were revisited with the findings of French scientists Rene Legendre and Henri Pieron. In 1907, Legendre and Pieron extracted an agent they called "hypnotoxin" from the blood serum of sleep-deprived dogs. When given to dogs that were not sleep-deprived, hypnotoxin induced sleep. However, attempts by other researchers to repeat the experiment were unsuccessful until 60 years later. In 1913, Pieron wrote a book entitled Le Probleme Physiologique du Sommeil, in which sleep is characterized physiologically in a modern, scientific approach. For that reason, Pieron's book is regarded as a milestone in sleep medicine.

Pieron and Legendre's findings were greatly diminished by the ongoing research by Ivan Pavlov, considered one of the greatest physiologists of our time. Pavlov's conditioning studies on dogs led him to believe that sleep was caused by brain inhibition. He believed that a continuous impulse acting on the central nervous system led to sleepiness.

Although interesting, Pavlov's theory lacked data on a specific physical mechanism. In addition to Pavlov, Pieron, and Legendre, other researchers such as Bekhterev and Claparede were influenced by this so-called "inhibition" theory. Bekhterev compared sleep to a loss of a biological reflex, specifically for the protection of the brain from harmful metabolic toxins. Claparede took it one step further by viewing sleep as a block in the brain caused by "hypnotoxins," chemicals that induced the brain to sleep.

Neurophysiology

Meanwhile, two opposite neurophysiological schools of thought emerged regarding sleep and wakefulness. One described sleep as the result of turning on a "sleep center" and the other proposed the turning off of a "waking center." In general, most physiologists in the 1800s rejected the idea of a localized sleep center. However, in 1929, Constantin Von Economo suggested that a site for the regulation of sleep existed.

He based his theory on his observations of patients with viral encephalitis, an infection that causes the brain to swell. He noted excessive sleepiness in patients with damage in the back of the hypothalamus and insomnia in patients with damage in the preoptic area (behind the eyes) and in the front of the hypothalamus. Later that same year, Nobel Prize winner Walter Rudolph Hess, and then in 1932, Steven Walter Ranson, confirmed Von Economo's conclusions that stimulation in the same area induced sleep.

In the 1920s, Nathaniel Kleitman, often regarded as the "Father of American Sleep Research," began his research on the regulation of sleep and wakefulness. His later research focused on how sleep and wakefulness relate to circadian rhythms and the effects of sleep deprivation. Kleitman investigated the cerebral cortex, the outer folded layer of the brain, as the site of wakefulness. This part of the brain is responsible for consciousness, mental ability, and voluntary movement.

In 1929, he proposed that inactivity and fatigue of the central nervous system and the loss of surrounding stimulation caused sleep. Kleitman's approach to sleep at that time was summarized in his 1939 discourse entitled Sleep and Wakefulness, a monumental work that encouraged the development of sleep disorders medicine.

It wasn't until 1946 that Horace Magoun and Ruth Rhines showed that the lower reticular formation in the brainstem was responsible for the inhibition of skeletal muscles during sleep. The reticular formation is a network of nerves throughout the brainstem, connecting motor and sensory nerves. This discovery led to further research into the brainstem as the source of an inhibited pathway of sleep, as well as a new emphasis on a physiological mechanism for the cause of sleep.

By the mid-1900s, the combined efforts of many researchers concluded that sleep was the loss of wakefulness stimuli from the ascending reticular activating system in the brainstem, the system of nerve pathways in the brain that are concerned with levels of consciousness.

The Last Half of the 20th Century...And Beyond

Sleep research grew by leaps and bounds in the latter half of the 20th century. Accepted data from researchers all over the world in chronobiology, neurochemistry, electrophysiology, neurophysiology, as well as in sleep disorders medicine and pharmacology, all contributed to the understanding of sleep and sleep-related problems. Due to the vast numbers of researchers and their contributions, below is merely a brief history of the most recent advancements in sleep medicine.

Chronobiology

In the 1950s, Gustav Kramer and Klaus Hoffman verified the existence of an inborn biological clock with the use of a clever model. Kramer used a bird called a starling to show that the direction of the sun in the sky was used as an internal compass for their migration. Hoffman expanded the study to demonstrate that the bird's internal clock remained accurate even in dim light, influenced by the local environment and time zone.

Also during this time, Colin Pittendrigh studied the influence of temperature and amount of light on the circadian clock. He placed fruit fly larvae in different conditions. Most metabolic activities rise or fall depending on temperature, so Pittendrigh initially thought the flies would emerge early with an increase in temperature. Regardless of temperature or amount of light, the larvae hatched on schedule, showing that the cycle of the circadian clock is not dependent on environmental factors.

By the '60s, the existence of a biological clock in all organisms was widely accepted. A decisive experiment by Jules Aschoff and Kurt Wever with human circadian rhythms took place in Munich in 1962. By isolating human subjects in an underground WWII bunker in the absence of environmental time cues, Aschoff and Wever established that an unrestricted pattern of sleep and wakefulness was slightly longer than 24 hours.

Michel Siffre repeated the experiment in 1974. He used himself as the subject and lived in a dark ice glacier for three months; he noted the same pattern. The discovery of the "clock" itself in 1972 is attributed to two groups working independently: Robert Moore and Victor Eichler; and F.K. Stephan and Irving Zucker. They found what is now called the suprachiasmatic nuclei (SCN) in both sides of the front area of the hypothalamus.

So, what biological functions are regulated by circadian rhythms? Elliot D. Weitzman discovered that cortisol, a steroid hormone that influences cell metabolism, was secreted on a 24-hour cycle. Weitzman, in collaboration with Charles Czeisler, also showed that body temperature, the sleep-wake cycle, and hormones secreted within the brain (neuroendocrine) were internally organized.

They monitored subjects in an environment without time cues for as long as six months. Complementary to Simpson and Galbraith's 1906 experiment on mammal behavior, Czeisler and colleagues demonstrated the importance of the light-dark cycle on the guidance of human circadian rhythms.

Advances and growth in molecular genetics has boosted interest in the operation of the biological clock on a molecular level. Molecular genetics is the study of heredity and genes and their interactions. In 1971, researchers identified genes responsible for the functioning of internal clocks. Since the mid-80s, three genes were isolated, their proteins identified and coded (Isaac Edery in 1994).

Evidence that the genes interacted and coordinated as a functional unit was soon found (1996). Scientists hope that their molecular findings could lead to more effective treatments in the near future for sleep disorders, the effects of jet lag and shift work, seasonal affective disorder, and manic depression.

Electrophysiology and Neurophysiology Work Together

A breakthrough in sleep research occurred with the documentation of dreaming sleep by physiologist Nathaniel Kleitman and his student Eugene Aserinsky in 1953. They reported periods of eye movements and twitching during sleep, which they called "rapid eye movement (REM) sleep." When Kleitman and Aserinsky awoke their subjects during REM sleep, they described vivid dreams.

Another student of Kleitman's, William C. Dement, described the cyclic nature of sleep in 1955. Kleitman and Dement expanded these findings in 1957-58 using the EEG to record the cyclic pattern of REM and non-REM sleep in humans. Dement's 1958 paper on the sleep cycle in cats showed that humans were not the only mammals that experience REM sleep and dreaming. It created an explosion of fundamental research from all fields of science. Sleep could no longer be characterized as a single state.

EEG documentation of REM sleep led Michel Jouvet to label sleep as a distinct state of alertness, which he called "paradoxical sleep." He also demonstrated muscle paralysis as related to REM sleep in 1959. Jouvet's later work investigated the role of the brainstem; in 1967, he identified specific brainstem cells (neurons) that were important in the maintenance of non-REM and REM sleep. Subsequent researchers, Robert McCarley and J. Allen Hobson, proposed a model in 1975 that described "on" and "off" REM cells that mutually interact.

In 1968, Allan Rechtschaffen and Anthony Kales devised a standardized method of scoring EEG recordings in their manual entitled A Manual of Standardised Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. In 1978, Mary Carskadon, in association with William Dement at Stanford University, created the multiple sleep latency test (MSLT). That same year, Gary Richardson and his group reported the first effective means of testing daytime sleepiness using the MSLT. Since then, numerous other diagnostic tests, such as the Epworth Sleepiness Test and the Stanford Sleepiness Scale, have been developed to enhance clinicians' tools for analyzing sleep disorders.

Neurochemistry

Neurochemistry and biochemistry investigate the functions and interactions of biological substances such as proteins, neurochemicals, peptides, and other compounds. Based on Legendre's work with "hypnotoxin" in dogs, John Pappenheimer and his group transfused cerebrospinal fluid from sleep-deprived goats to induce sleep in 1967.

The sleep-inducing agent was called "Factor S" and in 1982, was identified as a specific peptide, i.e. a group of linked amino acids. Osamu Hayaishi found a biomolecule in the preoptic nuclei that possessed the ability to induce sleep in rats. With the preoptic nucleus as a candidate, speculation about the existence of the elusive "sleep center" continues.

Sleep Disorders Medicine

The conditions that arise from abnormal sleep are a core element in the increased knowledge of sleep. Primary sleep disorders, such as insomnia, narcolepsy, and obstructive sleep apnea, were more than likely the reason sleep-specific research was performed in the beginning.

Insomnia has been recognized and treated with effective hypnotic medications for centuries. It wasn't until the 1900s that characteristics, different types, and non-pharmacological treatments were applied to insomnia.

For instance, polysomnography testing was applied to insomnia shortly after the discovery of obstructive sleep apnea in 1965. Conditioned insomnia was recognized in 1979, Weitzman characterized sleep onset insomnia, such as delayed sleep phase syndrome, in 1981, and Andre Kahn described food allergy insomnia in 1984.

Hypnotism and mental relaxation were proven effective insomnia treatments by 1969. Other insomnia treatments not requiring medication included Richard Bootzin's behavioral technique called "stimulus control" (1972) and Arthur Spielman's "sleep restriction therapy" (1987), both of which are still in use today.

Stimulants were first used in 1931 for the treatment of narcolepsy. Since then, John Dynes and Knox Findley applied the EEG to the diagnosis of the disorder in 1941 and later in 1978, Richardson used the MSLT to diagnose narcolepsy. William Dement and his group maintained a colony of narcoleptic dogs at Stanford University in the 70s. His work has led to a deeper understanding of the biochemical and neurological basis of narcolepsy.

After Dickens' observations about Joe in the Pickwick Club, Charles Sidney Burwell in 1956 brought recognition to obstructive sleep apnea syndrome, which he termed "Pickwickian syndrome." In 1965, Henri Gastaut documented polysomnographic features of apnea in a group of Pickwickian patients. This led to a great deal of research on how the brain functions and controls vital functions such as respiration during sleep.

Treatments soon developed: tracheostomy, although in use since the first century, was applied to sleep apnea by Wolfgang Kuhlo and Erich Doll in 1972; uvulopalatopharyngoplasty (UPPP) was an accepted treatment for snoring by 1964 (Tanenosuke Ikematsu) and was later applied to obstructive sleep apnea by Shiro Fujita in 1981. Nasal continuous positive airway pressure (CPAP) was also in use by 1981, the same year Colin Sullivan described it. As a non-surgical option for the treatment of OSA, it quickly became the treatment of choice.

Pharmacology has always been an invaluable component in the treatment of sleep disorders. Hypnotic medications were widely used since the introduction of barbital in 1903; however, by the 1980s, the recommendations declined with increased awareness to the disadvantages of prolonged and chronic hypnotic use. Psychoactive drugs were popularized in the 1950s with the advent of phenothiazines.

By the 1970s, benzodiazepines replaced hypnotic medications, particularly barbiturates. Today, research and drug trials with existing medications typically used for other symptoms are being investigated as a treatment for certain symptoms of sleep disorders. In addition, research into new drugs used for the specific treatment of sleep disorders is well under way.

Many other sleep disorders have been documented and characterized in the 20th century by dedicated sleep specialists, far too many to name individually: circadian rhythm sleep disorders (jet lag and the effects of shift work), REM-behavior disorder, parasomnias, such as sleepwalking, sleep eating, Klein-Levin syndrome, and hypersomnia, among others. To date, there are approximately 84 recognized sleep disorders.

Sleep Organizations

Several influential books had an impact on the development of sleep medicine, the first of which was Pieron's Le Probleme Physiologique Du Sommeil in 1913. Sleep and Wakefulness by Kleitman in 1939 and Diagnostic Classification of Sleep and Arousal Disorders by the Association of Sleep Disorder Centers headed by Howard Roffwarg in 1979 became decisive volumes to the classification of sleep.

The first comprehensive textbook on basic sleep medicine was Principles and Practice of Sleep Disorders Medicine in 1989, edited by Meir Kryger, William Dement, and Thomas Roth.

Within the past forty years, sleep research has become viewed as valuable and pertinent. In 1961, organized sleep medicine in the United States began with the founding of the Association for the Psychophysiological Study of Sleep (APSS), composed of a group of clinical sleep researchers.

In 1970, William Dement established the Stanford University Sleep Research Center, the first of its kind and the predecessor of national clinical sleep disorders centers for the diagnosis and treatment of patients. The Association of Sleep Disorders Centers (ASDC), founded in 1976, established a nationally recognized accreditation process for sleep disorders centers. Then in 1978, the peer-reviewed medical journal Sleep was created to assemble clinical articles devoted to sleep research.

Below is a listing of societies and events by date:

• 1971 - European Sleep Research Society (ESRS) is founded
• 1976 - The Association of Sleep Disorders Centers (ASDC) was founded
• 1978 - Association of Polysomnographic Technologists (APT) was founded by Peter McGregor
• 1978 - The Japanese Society for Sleep Research (JSSR) is founded
• 1982 - The Belgian Association for the Study of Sleep (BASS) is founded
• 1983 - The Association for the Psychophysiology Study of Sleep is renamed the Sleep Research Society (SRS)
• 1984 - The Clinical Sleep Society (CSS) is recognized as a branch of the ASDC
• 1985 - The Scandinavian Sleep Research Society (SSRS) is founded
• 1986 - The ASDC, CSS, APT, and SRS becomes the federated Association of Professional Sleep Societies (APSS)
• 1986 - The Latin American Sleep Society (LASS) is founded
• 1986 - The Sleep Society of Canada (SSC) is founded
• 1987 - The ASDC changes its name to American Sleep Disorders Association
• 1989 - The British Sleep Society (BSS) is founded
• 1990 - The National Sleep Foundation is created
• 1992 - The United States Congress appoints the National Commission on Sleep Disorders Research to determine the extent of sleep disorders on safety
• 1993 - Legislation is passed to create the National Center for Sleep Disorders Research in the U.S.
• 1996 - The American Medical Association recognized sleep medicine as a specialty
• 1999 - The American Sleep Disorders Association is renamed the American Academy of Sleep Medicine (AASM)
• 1999 - The formation of TALK ABOUT SLEEP

Conclusion

New diagnostic tools, from X rays and electroencephalograms (EEGs) to computerized axial tomography (CAT scan) and nuclear magnetic resonance imaging (NMR), revolutionized procedures, diagnoses, and treatments of sleep disorders in the latter half of the 20th century. Likewise, advances are occurring at an unprecedented rate into the 21st century because of the dedication of researchers and clinicians in the field of sleep medicine.