Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects

M.D.

Preface

Sleep, that gentle tyrant,¹ has aroused the interest of mankind since time immemorial, as reflected in the writings of the Eastern and Western religions and civilizations (e.g., Upanishads,² circa 1000 B.c. wrote about the dreaming and a deep dreamless sleep; see Chapter 2). Even though there are many poetic, philosophical, and religious references to the phenomenon, and to the mystical nature of sleep, the science of sleep was very slow to evolve. In the last 40 years, however, an explosive growth took place in the basic and clinical aspects of sleep research. Recent major discoveries and advances include the discovery of REM sleep and the cyclic pattern of non-REM-REM sleep stages throughout a human being’s night sleep; the standardized sleep-scoring technique; the discovery of the mechanism of sleep apnea and better management of this disorder; better understanding of the nature of narcolepsy; an awareness of the parasomnias, their treatment, and their differentiation from epilepsy; phototherapy for circadian rhythm and other sleep disorders; pharmacotheraphy for insomnias; and better understanding of the treatment of sleep apnea and hypoventilation related to neuromuscular disorders. Other significant recent developments include the formation of the Association of Sleep Disorders Centers, growing numbers of sleep disorders centers, formal certification for accreditation of such centers, formation of the American Board of Sleep Medicine to test practitioners’ competency in sleep disorders medicine, publication of the scientific journal Sleep, and incorporation of the subject of sleep in other subspecialty board examinations (e.g., American Board of Clinical Neurophysiology; Added Qualifications in Clinical Neurophysiology). Growing awareness in the medical profession of the importance of sleep is reflected in the development of training programs in sleep disorders medicine, approval by the American Academy of Neurology for a section on sleep, and the formation of the National Commission on Sleep Disorders Research (NCSDR). The latter is significant because experts in the sleep field are now voicing their concerns in the political arena. The study of sleep has come a long way, and in this Decade of the Brain it is hoped that sleep medicine will find its rightful place as an independent specialty in the broad field of medicine.

Dement³ defined sleep disorders medicine as the branch of medicine that deals with the sleeping brain and all manifestations and pathologies deriving therefrom. Sleep disturbances affect as many as one-third of all American adults, and about 40 million Americans suffer from chronic disorders of sleep and wakefulness. The majority of those affected remain undiagnosed and untreated (executive summary and findings NCSDR).⁴ Therefore, education in sleep disorders medicine is urgently needed. This book aims to provide clinicians in many disciplines who have an interest in sleep and sleep disorders with a comprehensive scientific basis for understanding sleep, as well as to present information on the diagnosis and treatment of a wide variety of sleep disorders, which are, increasingly, being recognized. The purpose, therefore, is to produce a comprehensive treatise on sleep disorders medicine, not only for beginners but also for those who are already engaged in the art and science of sleep medicine. Thus, it is meant to be a practical exposition of the subject that also provides an appropriate foundation in the basic science. With these objectives in mind the monograph is divided into three sections: basic aspects of sleep; sleep technology; and the clinical science of sleep. The monograph is directed to all who are interested in sleep disorders medicine and should, therefore, be useful to neurologists, internists (particularly those subspecializing in pulmonary, cardiovascular, or gastrointestinal medicine), psychiatrists, psychologists, pediatricians, otolaryngologists, neurosurgeons, general practitioners dealing with many apparently undiagnosed sleep disorders patients, and neuroscientists with an interest in sleep research.

I must express my gratitude to all the contributors, who are investigators in the forefront of sleep research, for finding time to write the scholarly chapters for this monograph. Special thanks are due to William C. Dement, M.D., Ph.D., one of the foremost sleep researchers of our time, for writing the Introduction, and to Christian Guilleminault, M.D., a giant in the field of sleep disorders medicine, for agreeing to contribute two chapters.

I should like to express my gratitude and appreciation to Norman Edelman, M.D., Dean of Robert Wood Johnson Medical School and a member of the National Commission on Sleep Disorders Research, for his thoughtful Foreword.

I must thank Peter McGregor and Michael Thorpy, M.D., also a contributor in this volume, for making available the tracings for two figures used in the text. Wayne Hening, M.D., Ph.D., in addition to being a contributor, made helpful suggestions for several of my own chapters.

I wish to thank all those authors, editors, and publishers who allowed me to reproduce illustrations that were first published in other books and journals. Specific permission is acknowledged in the appropriate figures.

I am also grateful to the American Sleep Disorders Association for giving me permission to reproduce the Glossary of Terms that appeared in the International Classification of Sleep Disorders in 1990.

It is a pleasure to acknowledge my appreciation to Lena DiMauro for her splendid support and for typing and retyping the manuscripts during all stages of preparation and to James Cummings for help with making numerous copies of the chapters.

I wish also to thank Debbie MacDonald, Assistant Editor, and Susan Pioli, Publisher, Medical Division, and others of the Butterworth-Heinemann publishing company for their excellent help.

Finally, it is my utmost pleasure to acknowledge my wife, Manisha Chokroverty, M.D., for her support, patience, tolerance, and caring throughout the arduous, long process of preparation for publication.

¹Webb WB. Sleep: The Gentle Tyrant. Bolton, Mass.: Anker Publishing, 1992.

²Wolpert S. A New History of India. New York: Oxford University Press, 1982; 48.

³Dement WC. A personal history of sleep disorders medicine. J Clin Neurophyisol 1990;7:17-47.

⁴National Commission on Sleep Disorders Research. Report of the National Commission on Sleep Disorders Research. DHHS Pub. No. 92-XXXX. Washington, D.C.: U.S. Government Printing Office, 1992.

1

Introduction

W.C. Dement

Publisher Summary

This chapter presents an introduction to sleep disorders and related medicines. The existence of sleep disorders medicine is based primarily on the fact that there are really two fully functioning brains: (1) the brain awake and (2) the brain asleep. The cerebral activity of wakefulness and of sleep has contrasting consequences. In addition, the brain’s two major functional states influence each other. Problems during wakefulness affect sleep, and disordered sleep or disordered sleep mechanisms impair the functions of wakefulness. Perhaps the most important clinical symptom in sleep disorders medicine is an awareness of sleep-related impaired alertness—that is, a complaint of excessive sleepiness. The fundamental concept of sleep disorders medicine is that some function, for example, breathing, may appear normal in the waking state and pathological in sleep. In addition, there are a host of non-sleep disorders that are, or may be, modified by the sleeping state. Health issues in human beings must include the organism in sleep as well as when awake. Therefore, patient care is a 24-hour commitment.

The existence of sleep disorders medicine is based primarily on the fact that there are really two fully functioning brains–the brain awake and the brain in sleep. The cerebral activity of wakefulness and the cerebral activity of sleep have contrasting consequences. In addition, the brain’s two major functional states influence each other. Problems during wakefulness affect sleep, and disordered sleep or disordered sleep mechanisms impair the functions of wakefulness. Perhaps, the most important clinical symptom in sleep disorders medicine is an awareness of sleep-related impaired alertness, in other words, a complaint of excessive sleepiness.

The fundamental concept of sleep disorders medicine is that some function (e.g. breathing) may appear normal in the waking state and pathological in sleep. In addition, there are a host of non-sleep disorders that are, or may be, modified by the sleeping state. It should no longer be necessary to argue that health issues in human beings must include the organism in sleep as an equal partner to health issues concerning the organism awake. Patient care is therefore a 24-hour commitment. This latter statement enhances one aspect of sleep medicine, circadian regulation of sleep and wakefulness. It is worth noting that, of all the 24-hour professions whose clocks should be shifted to promote full alertness and optimal performance at night, it is the medical profession who holds human lives in the palm of their hands.

WHAT IS SLEEP DISORDERS MEDICINE?

Sleep disorders medicine is a clinical specialty which deals with the diagnosis and treatment of patients who complain about disturbed nocturnal sleep, excessive daytime sleepiness, or some other sleep-related problem.¹ The spectrum of disorders and problems in this area is extremely broad, ranging from merely troublesome ones such as a day or two of mild jet lag to the catastrophic ones such as sudden infant death syndrome (SIDS), fatal familial insomnia, or a tragic accident involving a patient with sleep apnea who falls asleep at the wheel. The dysfunctions may be primary, apparently involving the basic neural mechanisms of sleep and arousal, or secondary, in association with other medical, psychiatric, or neurologic illnesses. This young field has not yet established that sleep mechanisms play a causal role in a number of possibly related illnesses, such as endogenous depression, but progress is being made.

The final fundamental principle that must be mentioned is that the sleep disorders specialist must examine the sleeping patient in one way or another and must take into account and evaluate the impact of sleep on waking functions. Sleep disorders medicine also, in common with other specialties, has an enormous responsibility for the societal implications of its illnesses, particularly impaired alertness due to inadequate sleep or sleep problems. Physicians should always be sensitive to the level of alertness in their patients and the potential consequences of a sleep-related accident.

A BRIEF HISTORY

Well into the nineteenth century, the phenomenon of sleep escaped systematic observation, in spite of the fact that it occupies a third of a human lifetime. (For newborn infants this aphorism must be restated: rapid eye movement (REM) sleep occupies one-third of their days, non-REM (NREM) sleep occupies a third, and wakefulness, barely established, is utilized by the organism mainly for feeding.) All other things being equal, we may assume that there were a wide variety of reasons for preferring not to study sleep, one of which was the unpleasant necessity for staying awake at night. For other discussions of this historical puzzle see Dement.²

Although in the 1960s there were hints (e.g., a fee-for-service narcolepsy clinic at Stanford University and research on non-sleep-related illnesses like asthma and hypothyroidism at UCLA³,⁴ sleep disorders medicine can quite clearly be identified as having begun at Stanford University in 1970, with the routine utilization of respiration and cardiac sensors together with the time-honored continuous electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG) in all-night polygraphic recordings. Continuous all-night recordings utilizing this array of data gathering was finally named polysomnography by Holland and coworkers,⁵ and patients paid for the tests as part of a clinical fee-for-service.

The Stanford model included responsibility for medical management and care of patients beyond mere interpretation of the test and an assessment of daytime sleepiness. After several false starts, the latter effort culminated in the development of the Multiple Sleep Latency Test,⁷,⁸ and the framework of the discipline of sleep medicine was essentially complete.

The comprehensive evaluation of sleep in patients who complained about their daytime alertness led rapidly to a series of discoveries and clarifications, which included the high prevalence of obstructive sleep apnea in patients complaining of sleepiness, the role of periodic limb movement in insomnia, the sleep misperception syndrome, first called pseudoinsomnia, and so on. As in the beginning of any medical practice, though for most specialties that goes back almost before recorded history, the case series approach, wherein patients were evaluated and carefully tabulated, was very important.⁸,⁹

THE PRESENT

Although it got a late start, the field of sleep disorders medicine has grown very rapidly. The number of sleep disorders centers has increased almost exponentially (Figure 1-1). The number of practitioners has also increased rapidly. The amount of material for which a sleep specialist must be responsible has increased both in breadth and in depth, and in order to document sufficient knowledge and skills, the American Board of Sleep Medicine was incorporated in 1990. Before that, the American Sleep Disorders Association offered certifying examinations and the successful candidates became Accredited Clinical Polysomnographers. The professional societies and their annual meetings have increased in size, and the organized body of knowledge, as presented herein and elsewhere, has increased dramatically.

FIGURE 1-1 Shown graphically is the rapid growth of the number of sleep disorders centers accredited by the American Sleep Disorders Association (ASDA). Reproduced with permission from ASDA(APSS Newsletter 1993; 8(2)).

It was the assimilation of this body of knowledge and several years’ experience in diagnosing and treating any and all patients with a sleep-related problem or complaint that produces the sleep specialist. Their number, however, is far too small to bring the benefits of sleep disorders medicine to the 50 million Americans who have sleep problems. There is a continuing need for effective presentation of the organized body of knowledge of sleep medicine, and this book fulfills that need. Any field worth its salt has several different textbooks, and sleep medicine should be no exception.

REFERENCES

1. Walsh, J.Sleep Disorders Medicine. Rochester, MN: Association of Professional Sleep Societies, 1986.

2. Dement, W. A personal history of sleep disorders medicine. Clin Neurophysiol. 1990; 7:17–47.

3. Kales, A, Beall, GN, Bajor, GF, et al. Sleep studies in asthamatic adults: Relationship of attacks to sleep stage and time of night. J Allergy. 1968; 41:164–173.

4. Kales, A, Heuser, G, Jacobson, A, et al. All night sleep studies in hypothyroid patients, before and after treatment. J Clin Endoctrinol Metab. 1967; 27:1593–1599.

5. Holland V, Dement W, Raynal D., Polysomnography responding to a need for improved communication. Presented at annual meeting of Sleep Research Society, Jackson Hole, Wyoming, 1974.

6. Carskadon, M, Dement, W. Sleep tendency: An objective measure of sleep loss. Sleep Res. 1977; 6:200.

7. Richardson, G, Carskadon, M, Flagg, W, et al. Excessive daytime sleepiness in man: Multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol. 1978; 45:621–627.

8. Dement, W, Guilleminault, C, Zarcone, V. The pathologies of sleep: A case series approach. In: Tower D, ed. The Nervous system, vol 2. The Clinical Neurosciences. New York: Raven Press; 1975:501–518.

9. Guilleminault, C, Dement, W. 235 Cases of excessive daytime sleepiness. Diagnosis and tentative classification. J Neurol Sci. 1977; 31:13–27.

PART I

BASIC ASPECTS OF SLEEP

Outline

Chapter 2: An Overview of Sleep

Chapter 3: Neurophysiology of Sleep: Basic Mechanisms Underlying Control of Wakefulness and Sleep

Chapter 4: Biochemical Pharmacology of Sleep

Chapter 5: Physiologic Changes in Sleep

2

An Overview of Sleep

Sudhansu Chokroverty

Publisher Summary

This chapter presents an overview of the sleep process. Sleep and wakefulness, the two basic processes of life, are like two different worlds with independent controls and functions. Newborns have a polyphasic sleep pattern and spend about two-thirds of their time sleeping in the first few days of life. This multiphasic sleep pattern gradually changes into the monophasic adult pattern later in life. On falling asleep, a newborn baby goes immediately into rapid eye movement (REM) sleep or active sleep that is accompanied by restless movements of the arms and legs and facial muscles. In premature babies, it is often difficult to differentiate REM from wakefulness. By the age of about 3 months, the usual non-REM (NREM) cyclic pattern is evident. Polyphasic sleep changes to biphasic sleep in preschool children and finally to monophasic sleep in adults. It reverts to bi- or multiphasic sleep in elderly persons. Contrary to general belief, human sleep does not necessarily cause restitution. It is misleading to conclude tissue restitution increases during human sleep. Rodents may exhibit increased tissue restitution during sleep but sleep is not the stimulus for such restitution.

HISTORICAL PERSPECTIVE

Since the dawn of civilization and the creation of the world, the mysteries of sleep have intrigued poets, artists, philosophers, and mythologists alike. This intrigue, awe, and delight are reflected in literature, folklore, religion, and medicine. Upanishad¹,² (circa 1000 B.C.), the famous ancient Indian textbook of philosophy, sought to divide human existence into four states: the waking, the dreaming, the deep dreamless sleep, and the superconscious (the very self). One finds the description of pathologic sleepiness (possibly a case of Kleine-Levin syndrome) in the mythologic character Kumbhakarna in the great Indian epic Ramayana³,⁴ (circa 1000 B.C.). Kumbhakarna would sleep for months at a time and would get up to eat and drink voraciously before falling asleep again.

The definition of sleep and its functions have baffled scientists since the beginning. Moruzzi,⁵ while describing the historical development of the deafferentation hypothesis of sleep, quoted the concept Lucretius articulated 2000 years ago that sleep is the absence of wakefulness. A variation of the same concept was expressed by Hartley⁶ in 1749, and then in 1830 by Macnish.⁷ Macnish⁷ defined sleep as suspension of sensorial power in which the voluntary functions are in abeyance but the involuntary powers, such as circulation or respiration, remain intact.

Throughout the literature, a close relationship between sleep and death has been perceived, but the rapid reversibility of sleep episodes differentiates it from coma and death. There are myriad references to sleep, death, and dream in poetic and religious writings: The deepest sleep resembles death (the Bible, I Samuel 26:12); sleep and death are similar …. sleep is one-sixtieth [i.e., one piece] of death. (the Talmud, Berachoth 576); There she [Aphrodite] met sleep, the brother of death (Homer’s Iliad, circa 700 B.C.); To sleep perchance to dream…. For in that sleep of death what dreams may come? (Shakespeare’s Hamlet); How wonderful is death; Death and his brother sleep (Shelley).

Sleep and wakefulness, the two basic processes of life, are like two different worlds, with independent controls and functions. Borbely,² in his monograph Secrets of Sleep, gives an interesting historical introduction to sleep, and the reader is referred there.

What is the origin of sleep? The word sleep or somnolence is derived from the Latin word somnus, the German words sleps, slaf, or schlaf, and the Greek word hypnos.² Hippocrates,² the father of medicine, postulated a humoral mechanism for sleep and stated that it was caused by the retreat of blood and warmth into the inner regions of the body, whereas the Greek philosopher Aristotle² thought sleep was related to food, which generates heat and causes sleepiness. Paracelsus,² a sixteenth-century physician, wrote that natural sleep lasted ⁶ hours, which would eliminate tiredness and would refresh the sleeper. He also spoke about the length of sleep and suggested people not sleep too much or too little but wake when the sun rises and to go to bed at sunset. These views of Paracelsus’ are strikingly similar to modern teachings about sleep. The views about sleep in the seventeenth and eighteenth centuries were expressed by Alexander Stuart,² the British physician and physiologist, and by the Swiss physician, Albrecht von Haller.² According to Stuart,² sleep was due to a deficit of the animal spirits; von Haller² wrote that the flow of the spirits to the nerves was cut off by the thickened blood in the heart. Nineteenth-century scientists used principles of physiology and chemistry to explain sleep. Both Humboldt² and Pfluger² thought that sleep resulted from a reduction or lack of oxygen in the brain. None of the suggestions are based on solid scientific experiments, which were not conducted until the twentieth century. Ishimori,⁸ in 1909, and Legendre and Pieron,⁹ in 1913, observed sleep-promoting substances in the cerebrospinal fluid of animals during prolonged wakefulness.

The discovery of the EEG waves in dogs by the English physician Caton¹⁰ in 1875 and of the alpha waves from the surface of the human brain by the German physician Hans Berger¹¹ in 1929 initiated contemporary sleep research. It is interesting to note that Kohlschutter,² a nineteenth-century German physiologist, thought sleep was deepest in the first few hours and became lighter as time went on. Modern sleep laboratory studies generally confirmed these observations. The golden age of sleep research began with the discovery in 1937, by the American physiologist Loomis¹² and coworkers of different stages of sleep reflected in EEG changes. The discovery by Aserinsky and Kleitman,¹³ in the laboratory of the University of Chicago, of rapid eye movement (REM) sleep electrified the scientific community and propelled sleep research to the forefront. This was followed by the now famous Rechtschaffen and Kales¹⁴ technique of sleep scoring based on Electroencephalography (EEG), Electromyography (EMG), and Electrooculography (EOG), which has become the gold standard for sleep scoring throughout the world.

SLEEP ARCHITECTURE AND SLEEP PROFILE¹⁵-¹⁷

The beginning of stage I non-REM (NREM) sleep in adults is heralded by the diminution of the alpha waves of wakefulness (Figure 2-1) in the EEG to fewer than 50% in an epoch (Figure 2-2) which are replaced by the theta (and some beta) waves, accompanied by slow, rolling eye movements demonstrated in the EOG recordings. Muscle tone in the EMG decreases slightly. Within a few minutes, the hypnogram shows bursts of 12- to 16-Hz sleep spindles intermixed with K complexes. The vertex sharp waves are noted toward the end of stage I and are also present in stage II NREM sleep (Figure 2-3), which is dominated by the spindles. The EOG does not register eye movements at this stage, and EMG tone is less than in wakefulness or stage I sleep. The EEG contains theta and (fewer than 20%) delta waves. Stage II sleep lasts about 30 to 60 minutes. Sleep next progresses to the stages of slow-wave sleep (stages III and IV NREM sleep) characterized by the delta waves, which constitute 20% to 50% in stage III (Figure 2-4) and more than 50% in stage IV (Figure 2-5). Toward the end of the deep sleep (delta sleep), body movements are registered as artifacts in the polysomnographic recordings. Stage III and IV NREM sleep is briefly interrupted by stage II NREM sleep, which is followed by the first REM sleep about 60 to 90 minutes after sleep onset. REM sleep (Figure 2-6) is characterized by rapid eye movements, desynchronization of the EEG, often accompanied by sawtooth waves, and marked reduction or absence of muscle tone in the EMG recording. The first REM period lasts only a few minutes and is followed by progression to stage II, and then stage III and IV, NREM sleep before the second REM sleep begins. Thus, a full sleep cycle consists of a sequence of NREM and REM, and each cycle lasts about 90 to 110 minutes. Generally, 4 to 6 such cycles are observed during a night’s sleep. The first two cycles are dominated by the slow-wave sleep (stages III and IV NREM sleep), and subsequently these stages are noted only briefly, sometimes not at all. On the other hand, the REM sleep cycle increases from the first to the last cycle, and the longest REM cycle, toward the end of the night, may last as long as an hour. Thus, the slow-wave sleep is dominant in the first third of the night and REM sleep is dominant in the last third. This characteristic sleep cycling is noted in both humans and animals.

FIGURE 2-1 PSG recording shows wakefulness. Note 9 to 10 Hz alpha activity in the EEG (C4-A1A2; 02-A1A2: International nomenclature) mixed with some low-amplitude beta activity. Chin EMG shows much tonic activity. Waking eye movements are seen in the EOGs (right eye [R] and left eye [L] are referred to linked ear—AlA2). Paper speed, 10 mm/sec. (Timer: 3 sec) Calibration: 50 μV for EEG and eye channels, and 20 μV for EMG channel.

FIGURE 2-2 PSG shows stage 1 NREM sleep. EEGs (top 2 channels) show a decrease of alpha activity to less than 50% and low-amplitude mixed-frequency activities in the range of 3 to 7 Hz. Note vertex sharp waves in the midportion of the EEGs. EOGs (right eye and left eye) show slow, rolling eye movements (SEMs). Tonic EMG persists. Timer: 3 sec. Calibration: 50 μV for EEG and eye channels, 20 μV for EMG channel.

FIGURE 2-3 Stage 2 NREM sleep. Note 14-Hz sleep spindles in the EEG channels. No eye movements are seen. Tonic EMG persists though EMG activity is less than in wakefulness and stage 1. Timer: 3 sec. Calibration: 50 μV for EEG and eye channels, 20 μV for EMG channel.

FIGURE 2-4 PSG shows stage 3 NREM sleep. EEG (top 2 channels) shows 20% to 50% of the epoch occupied by waves of 2 Hz or less with amplitudes greater than 75 μV from peak to peak. Timer and calibration are as in FIGURE 2-1.

FIGURE 2-5 Stage 4 NREM sleep. More than 50% of the epoch in the EEG (top 2 channels) now consists of 2 Hz or slower waves having an amplitude greater than 75 μv. EOGs (third and fourth channels from top) are contaminated with EEG waves. Timer and calibration are as in Figure 2-1.

FIGURE 2-6 REM sleep stage is shown in the PSG. EEG (top 2 channels) shows low-amplitude, mixed-frequency theta, including some alpha activity without any sleep spindles or K complexes. REMs are seen in the EOGs (third and fourth channels from above). EMG shows marked reduction or absence of tonic activities. Timer and calibration are as in Figure 2-1.

THE ONTOGENY OF SLEEP

Newborns have a polyphasic sleep pattern and spend about two-thirds of their time sleeping in the first few days of life. This multiphasic sleep pattern gradually changes into the monophasic adult pattern later in life.¹⁶,¹⁸-²⁰ On falling asleep, a newborn baby goes immediately into REM sleep or active sleep, which is accompanied by restless movements of the arms and legs and the facial muscles. In premature babies it is often difficult to differentiate REM from wakefulness. By the age of about 3 months, the usual NREM-REM cyclic pattern is evident. Polyphasic sleep changes to biphasic sleep in preschool children, and finally to monophasic sleep in adults. It reverts to bi- or multiphasic sleep in elderly persons. During the first few months of an infant’s life REM sleep decreases. By 2 to 3 years of age REM sleep occupies only about 20% of the total sleep time. The EEG begins to show adult sleep pattern with the appearance of spindles around age 3 months,²¹ and K complexes at 6 months.²² Although a NREM-REM cycle is noted in children, it is shorter lived than in adults. At age 1 year the cycle may last 45 to 50 minutes, whereas at age 5 to 10 years it increases to 60 to 70 minutes. Around age 10 years adult REM sleep cycle (90 to 110 minutes) and REM percentage (20% to 25%) are observed. In older people delta waves are less pronounced but the percentage of REM sleep remains relatively constant. Older adults have difficulty sleeping and often awaken frequently and in the early morning. Elderly persons often complain increasingly about poor sleep. The evolution of sleep stage distribution in newborns, infants, children, adults, and elders is shown schematically in Figure 2-7. Figure 2-8 shows night sleep histograms of a child, a young adult, and an elderly person.

FIGURE 2-7 Graphic representation of percentages of REM and NREM sleep in different ages. Note the dramatic changes in REM sleep in the early years. Adapted and modified from Roffwarg HP, Muzzio JN, Dement WC. Ontogenic development of the human sleep-dream cycle. Science 1966, 152 604-619.

FIGURE 2-8 Night sleep histogram from a child, a young adult, and an elderly person. Note significant reduction of stage 4 NREM sleep as one grows older. (Reproduced with permission from Kales A, Kales JD. Sleep disorders: Recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med 1974;290:487.)

Sleep Habits

Sleep specialists sometimes divide people into two groups, evening types and morning types.² The morning types feel rested and fresh, and wake up early and work efficiently in the morning. These people get tired soon and they go to bed early. In contrast, evening types have difficulty getting up early and they feel tired in the morning; they feel fresh and energetic toward the end of the day. These people perform best in the evening and they go to sleep late and wake up late. The body temperature rhythm shows two different curves in these two types of people.² The body temperature reaches the evening peak an hour earlier in morning types than in evening types. What determines morning or evening type is not known but heredity may play a role.

Need for and Quantity of Sleep

The average adult’s sleep requirement is about 7 to 8 hours, regardless of environmental or cultural differences.²⁰,²³-²⁵ Webb and Friel²⁶ observed that about 1.1% of college students sleep less than 5½ hours and 3.2% sleep 9½ hours.

The most important epidemiologic study to determine a relationship between the length of sleep and the health of the individual was conducted by Kripke and coworkers.²⁷ They found that the chances of death from coronary artery disease, cancer, or stroke are greater for those who sleep less than 4 hours or more than 9 hours than for those who sleep an average of 7 to 8 hours. No personality trait or other psychological factor has been found that might differentiate long or short sleepers from average sleepers.

Taub and Berger²⁸ have clearly shown that our efficiency decreases if we sleep too much. These authors have also drawn attention to the fact that sometimes exhaustion and irritability may follow excessive sleep, which they refer to as the Rip Van Winkle effect²⁹

The study by Benoit and colleagues³⁰ showed that long sleepers spend more time asleep but have fewer stages III and IV and more stage II sleep than short sleepers.

Dream and Sleep

Humankind has been fascinated by dreams since time immemorial, and since the discovery of REM sleep by Aserinsky and Kleitman¹³ dream research has taken a new direction. It is now believed that most dreams occur on awakening from REM sleep, but dreams also occur on awakening from NREM sleep.²,²⁰ There are some differences, however. REM sleep dreams appear to be more highly emotionally charged, complex, and bizarre, whereas NREM dreams are characterized by more realistic and rational fact. In this connection it should be remembered that, people on awakening from REM sleep are generally oriented but on awakening from NREM sleep subjects generally are somewhat disoriented and confused.

What is the significance of dreams? The most significant contemporary dream research has been conducted by Hobson and McCarley,³¹ who suggested that dreams result from activation from the neural networks in the brain. According to Koukkou and Lehmann³² dreams result from restructuring and reinterpretation of data stored in memory. This resembles Jouvet’s³³ hypothesis of REM sleep relating to recently acquired information. According to molecular biologists Crick and Mitchison,³⁴ the function of dream is to unlearn, that is, to remove unnecessary and useless information from the brain. In conclusion, the biologic significance of dreams at present remains unknown.

PHYLOGENY OF SLEEP

Studies have been conducted to find out if, like humans, other mammals have sleep stages.²,³⁵-³⁸ The EEG recordings of mammals resemble the EEG sleep stages of humans. Similarly, both REM and NREM sleep stages can be differentiated by recording EEG, EMG, and EOG in these animals. Dolphins and Australian spiny anteaters [the monotremes, or egg-laying mammals, echidna] show no REM sleep.²,³⁹,⁴⁰ Like humans, also, mammals can be short or long sleepers. There are considerable similarities between sleep length and length of sleep cycles in small and large animals. Small animals with a high metabolic rate have a shorter life span and sleep longer than larger animals with lower metabolic rates.⁴¹ Similarly, smaller animals have a shorter REM-NREM cycle than larger animals.

A striking finding in dolphins is that during sleep half the brain shows the characteristic EEG features of sleep while the other half shows the EEG features of waking.⁴² Each sleep episode lasts some 30 to 60 minutes, then the roles of the two halves of the brain reverse.

Both vertebrates and invertebrates display sleep and wakefulness.⁴³ Most animals also show the basic rest-activity rhythms during a 24-hour period.

In conclusion, the purpose of studying the phylogeny of sleep is to understand the neurophysiologic and neuroanatomic correlates of sleep as one ascends the ladder of phylogeny from inframammalian to mammalian species.

CIRCADIAN SLEEP-WAKE RHYTHM

The existence of circadian rhythms has been known since the eighteenth century, when the French astronomer de Mairan²,⁴⁴ noted in a heliotrope plant a diurnal rhythm manifested by closing of the leaves at sunset and opening at sunrise, even when the plants were kept in darkness, shielded from direct sunlight. These findings of 24-hour rhythm in the movements of plant leaves suggested to de Mairan an internal clock in the plant. Experiments by chronobiologists Pittendrigh⁴⁵ and Aschoff⁴⁶ clearly proved the existence of 24-hour rhythms in animals.

The term circadian rhythm, coined by chronobiologist Halberg² and coworkers, is derived from the Latin circa, which means about, and dian, which means day. Experimental isolation from all environmental time cues (German Zeitgebers), as in a cave or underground bunkers to study free-running rhythms in humans has clearly demonstrated the existence of a circadian rhythm independent of environmental stimuli.²,²⁰ This cycle lasts approximately 25 hours (range 24.7 to 25.2 hour) instead of the 24 hours of a day-night cycle.² Normally, environmental cues of light and darkness would synchronize or entrain the rhythms to the night-day cycle; however, the existence of environment-independent, autonomous rhythm suggests that the human body also has an internal biologic clock.²

The experiments in rats in 1972 by Stephan and Zucker⁴⁷ and by Moore and Eichler⁴⁸ clearly demonstrated the site of the biologic clock in the suprachiasmatic nucleus in the hypothalamus, above the optic chiasm. Experimental stimulation, ablation, and lesion of these nuclei altered circadian rhythms. The existence of the suprachiasmatic nucleus in humans was recently confirmed.⁴⁹ We do not know enough of the neuroanatomical connections, except that there is a retinohypothalamic pathway⁵⁰ that sends the environmental cues of light to the suprachiasmatic nucleus. We also do not know enough about the neurotransmitters involved in this nucleus. Daily rhythms are noted in several other human physiologic processes. Body temperature rhythm is sinusoidal; cortisol and growth hormone secretion rhythms are pulsatile.²⁰ It is well-known that plasma levels of prolactin, growth hormone, and testosterone are all increased during sleep at night²⁰ (see Chapter 5). Sleep decreases body temperature whereas activity and wakefulness increase it. It should be noted that during free-running experiments there is internal desynchronization, and body temperature rhythm dissociates from the sleep rhythm as a result of that desychronization.²,²⁰ This raises the question of whether there is more than one circadian or internal clock or circadian oscillator.² The existence of two oscillators was postulated by Kronauer and coworkers.⁵¹ They suggested a 25-hour rhythm for temperature, cortisol, and REM sleep and observed that the second oscillator is somewhat labile and consists of the sleep-wake rhythm. Other authors,⁵² however, suggested that one oscillator could explain both phenomena. It is important to have an idea about circadian rhythms, because several sleep disturbances are related to alterations in them, such as those associated with shift work and jet lag. The circadian rhythms can be manipulated to treat certain disorders, and thus was born chronotherapy. Examples are phase advance or phase delay of sleep rhythms and application of bright light at certain periods of the evening and morning.

THE FUNCTIONS OF SLEEP

Neither humans nor animals can do without sleep, although the amount of sleep necessary to individual persons or species varies much. A lack of sleep leads to sleepiness, but we do not know the exact functions of sleep. One way to study the functions of sleep is to observe the effects of sleep deprivation. Experiments in rats using the carousel device by Rechtschaffen and coworkers⁵³ have provided evidence that sleep is essential for survival. All rats deprived of sleep for 10 to 30 days died after having lost weight, despite increasing their food intake. At the same time, they lost temperature control. It took longer for rats deprived of REM sleep to die.

Total Sleep Deprivation

What are the effects on physical and mental health of deprivation of NREM sleep, REM sleep, and all sleep? Sleep deprivation, whether in shift workers or in travelers who cross several time zones, impairs the ability to function optimally.

One of the early experiments in sleep deprivation was conducted by Patrick and Gilbert in 1896,⁵⁴ who studied the effects of a 90-hour period of sleep deprivation on three healthy young men. One of them reported sensory illusions, which disappeared completely when at the end of the experiment he was allowed to sleep for 10½ hours. All subjects had difficulty staying awake, but they felt totally fresh and rested after they were allowed to sleep.

A spectacular experiment in this century was conducted in 1965.⁵⁵ A 17-year-old California college student named Randy Gardner tried to set a new world record for staying awake. Dement and associates observed him during the later part of the experiment. He went 264 hours and 12 minutes without sleep and then slept 14 hours and 40 minutes. On waking, he recovered fully. Thus, the conclusion of the experiment is that it is possible to deprive people of sleep for a prolonged period without causing serious mental impairment. An important observation is the loss of performance with long sleep deprivation, and this is due to the loss of motivation-and the frequent occurrence of microsleep.

In another experiment, Johnson and MacLeod⁵⁶ showed that it is possible to intentionally reduce the total amount of sleeping time by 1 to 2 hours without suffering any adverse effect. The recent experiment by Carskadon and Dement⁵⁷,⁵⁸ showed that sleep deprivation increases the daytime tendency to sleep. This has been conclusively proven by the multiple sleep latency test in such subjects.⁵⁸,⁵⁹

Following sleep deprivation during the recovery sleep period, the percentage of slow-wave sleep (stages III and IV NREM) increases considerably.² Similarly, after a long period of sleep deprivation, the REM sleep percentage increases during the recovery sleep. (This increase was not shown after short period of sleep deprivation, up to 4 days.²) Thus, these experiments suggest that different mechanisms regulate NREM and REM sleep.²

Partial Sleep Deprivation

Measurements of mood and performance after partial sleep deprivation (e.g., restricting sleep to 4.5 to 5.5 hours for 2 to 3 months) showed minimal deficits in performance, which may have been related to decreased motivation. Thus, both total and partial sleep deprivation produced minimal deleterious effects in humans.²,²⁰,⁶⁰,⁶¹

Selective REM Sleep Deprivation

Dement⁶² performed REM deprivation experiments (awakening the person for 5 minutes at the moment the polysomnographic [PSG] recording demonstrated onset of REM sleep). PSG showed increased REM pressure (i.e., earlier and more frequent onset of REM sleep during successive nights) and REM rebound (i.e., quantitative increase of REM percentage during recovery nights). These findings were subsequently replicated by Borbely² and others,⁶³,⁶⁴ but Dement’s third observation–a psychotic reaction following REM deprivation–proved to be inaccurate in subsequent investigations.⁶³

Stage IV Sleep Deprivation

Agnew and coworkers⁶⁵ reported that following stage IV NREM sleep deprivation for two consecutive nights there was an increase in stage IV sleep during the recovery night. Two important points were raised by this groups’ later experiments⁶⁴: (1) REM rebound was more significant than stage IV rebound during recovery nights, and (2) it was more difficult to deprive a person of stage IV than of REM sleep.

It should be noted that the effects of total sleep deprivation, as well as REM sleep deprivation, are similar in animals and humans, suggesting that the sleep stages and the fundamental regulatory mechanisms for controlling sleep are also the same in all mammals.

Theories of Sleep’s Function

Several theories of the functions of sleep²⁰ have been proposed, and these are described briefly below.

The restorative theory. Proponents of this theory⁶⁶–⁶⁹ ascribed body tissue restoration to NREM and brain tissue restoration to REM sleep. The findings of increased anabolic⁷⁰-⁷² hormone (e.g., growth hormone, prolactin, testosterone, luteinizing hormone) secretion and decreased levels of catabolic⁷³ hormones (e.g., cortisol) during sleep, along with the subjective feeling of being refreshed after sleep, may support such a contention.²⁰ Increased slow-wave sleep² following sleep deprivation further supports the role of NREM sleep in restoring the body. The critical role of REM sleep for the development of the central nervous system of young organisms, and increased protein synthesis in the brain during REM sleep, are cited as evidence of restoration of brain functions by REM sleep.⁷⁴

The Energy Conservation Theory. Zepelin and Rechtschaffen⁴¹ found that animals with a high metabolic rate sleep longer than those with slower metabolism, suggesting that energy is conserved during sleep. Also, during sleep, metabolism in general is reduced, which helps conserve energy.

The Adaptive Theory. In both animals and humans, sleep is an adaptive behavior that allows the creature to survive under a variety of environmental conditions.⁷⁵,⁷⁶

The Instinctive Theory. This theory views sleep as an instinct,⁶⁶,⁷⁷ which relates to the theory of adaptation and energy conservation.

The Theory of Memory Reinforcement and Consolidation. This theory applies particularly to REM sleep, which is thought to facilitate memory and learning. In fact, McGaugh and coworkers⁷⁸ suggested that sleep-waking-related fluctuations of hormones and neurotransmitters may be modulating memory processes. Crick and Mitchison³⁴ proposed that REM sleep would remove undesirable data from the memory. According to Hobson⁷⁹ these two theories are not necessarily incompatible.

Horne⁸⁰ summarized the following conclusions about the functions of sleep:

1. Sleep deprivation does not cause any permanent behavioral, psychological, or physical illnesses.

2. Contrary to the general belief, human sleep does not necessarily cause restitution. It is misleading to conclude tissue restitution increases during human sleep. Rodents may exhibit increased tissue restitution during sleep, but sleep is not the stimulus for such restitution.

3. Cerebral hemisphere is always in a state of readiness during wakefulness and cannot relax without sleep. Thus, the cerebrum needs sleep for recovery and restitution. The human cerebrum needs a portion—not 8 hours—of sleep. He termed this portion core sleep, which characteristically occupies the first three sleep cycles.

4. Core sleep of Home refers to the EEG delta activity and consists of slow-wave sleep (stages III and IV NREM sleep). This also includes REM sleep within the first three sleep cycles. Horne termed the remaining half of the REM sleep, along with the stage II sleep, optional sleep, which is dispensible and has a circadian rhythm. Following sleep deprivation the core sleep is restituted but the optional sleep is lost. Short sleepers have less optional sleep than core sleep. When people adapt to sleeping 5.5 to 6 hours from their normal 7 to 8 hours they do so by reducing the optional sleep.

5. Slow-wave sleep, but not REM sleep, is related to cerebral recovery.

6. There are two types of sleepiness, core sleepiness resulting from the loss of core sleep, which impairs cerebral functioning, and optional sleepiness secondary to the loss of optional sleep, which may affect motivation. Human sleep centers around slow-wave sleep, not REM sleep. Home⁸⁰ further suggested that a better way to classify sleep would be as core and optional instead of REM and NREM.

7. REM sleep is not necessary for memory consolidation, and the experimental findings in animals could represent the artifacts of experiments.

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3

Neurophysiology of Sleep: Basic Mechanisms Underlying Control of Wakefulness and Sleep

Robert W. McCarley

Publisher Summary

This chapter discusses the basic mechanisms underlying control of wakefulness and sleep. Sleep may be divided into two phases. The first phase of sleep, rapid eye movement (REM) sleep, is most often associated with vivid dreaming and a high level of brain activity. The other phase of sleep, non-REM (NREM) sleep or slow-wave sleep, is usually associated with reduced neuronal activity; thought content during this state in humans usually is non-visual and consists of ruminative thoughts. In utero, mammals spend a large percentage of time in REM sleep, some 50%–80% of a 24-hour day. At birth, animals born with an immature nervous system spend a larger percentage of sleep time in REM sleep than adults of the same species. Sleep in the human newborn occupies two thirds of any day, and REM sleep accounts for half of the total sleep time or about a third of the entire 24-hour period. The percentage of REM sleep declines rapidly during early childhood so that by approximately age 10 years, the percentage of REM sleep is the same as for adults, 20% of total sleep time.

This chapter presents an overview of the current state of the art of knowledge of the neurophysiology and cellular pharmacology of sleep mechanisms. This field is at the beginning of a Golden Age of learning about sleep mechanisms, owing to the capability of current cellular neurophysiologic techniques to provide focused, detailed, and replicable studies that will enrich and extend the knowledge of sleep phenomenology and pathology derived from electroencephalography (EEG) analysis. Because this chapter has a cellular and neurophysiologic focus, much of the emphasis is on mechanisms relevant to rapid eye movement (REM) sleep, because more is known about the cellular physiology and pharmacology of this state than about non-REM (NREM) sleep, though an important series of recent studies bear on the mechanisms for spindle and delta wave generation. A more detailed treatment of most of the topics outlined here is available in a recent book,¹ which also contains extensive references to the research literature. For readers interested in an update on the terminology and techniques of cellular physiology, one of the standard neurobiology texts could be consulted (e.g. Kandel and Schwartz²), or one of the many brief overviews (e.g. McCarley³; that overview also covers sleep neurophysiology, and this chapter draws from this account but also presents more recent developments). This chapter does not survey in any detail the literature on humoral factors in sleep, and the reader is referred to recent reviews.⁴,⁵

This chapter begins with brief and elementary overviews of sleep architecture and phylogeny/ontogeny, to provide a basis for the later mechanistic discussions. Next is a discussion of REM sleep and the relevant anatomy and physiology. Neural mechanisms of EEG desynchronization during waking and REM sleep and of spindles and delta waves during NREM sleep are treated in the final section.

SLEEP ARCHITECTURE

Sleep may be divided into two phases. REM sleep is most often associated with vivid dreaming and a high level of brain activity. The other phase of sleep, NREM sleep or slow-wave sleep, is usually associated with reduced neuronal activity; thought content during this state in humans usually is nonvisual and consists of ruminative thoughts.

As shown in Figure 3-1, as one goes to sleep the low-voltage fast EEG of waking gradually gives way to a slowing of frequency and, as sleep moves toward the deepest stages, an abundance of delta waves, high amplitude EEG waves with a frequency between 0.5 and 4 Hz. The first REM period usually occurs about 70 minutes after the onset of sleep. REM sleep in humans is defined by the presence of low-voltage fast EEG activity, suppression of muscle tone (usually measured in the chin muscles), and the presence, of course, of rapid eye movements. The first REM sleep episode in humans is short. After this first episode, the sleep cycle repeats itself with the appearance of NREM sleep, and then about 90 minutes after the start of the first REM period another REM episode. This rhythmic cycling persists throughout the night. The REM sleep cycle is 90 minutes long in humans, and the duration of each REM episode after the first is approximately 30 minutes. This time course is schematized in Figure 3-2, together with a representation of the intensity of REM-related neuronal activity. Over the course of the night, delta wave activity tends to diminish and NREM sleep has waves of higher frequencies and lower amplitude.

FIGURE 3-1 (Left) Examples of EEG patterns associated with the stages of sleep and the time course of sleep stages. During wakefulness there is a low-voltage fast EEG pattern, often with alpha waves. Stage 1 descending (i.e., occurring before deeper sleep) has a low-voltage fast EEG. As sleep deepens the EEG wave frequency slows. During stage 3, delta waves (0.5 to 4 Hz) appear, and in stage 4 they are present more than 50% of the time. Often, stages ², ³ and ⁴ are lumped together as NREM sleep. Note that during REM sleep the EEG pattern returns to a low-voltage fast pattern. The percentage of time spent in REM sleep increases with successive sleep cycles, whereas the percentage of stages 3 and 4 decreases. (EEG is recorded from the vertex, Cz, and each trace is about 30 seconds long.) (Adapted from Kandel E, Schwartz JH, Jessel TM, eds. Principles of Neural Science. New York: Elsevier, 1991.)

FIGURE 3-2 Schematic diagram of a night’s course of REM sleep in humans depicts the occurrence and intensity of REM sleep as depending on the activity of populations of REM-on (REM-promoting) neurons (solid line). As the REM-on neuronal activity reaches a certain threshold, the full set of REM signs occurs (black areas under curve indicate REM sleep). Note, however, that, unlike the steplike EEG pattern of stage in Figure 3-1, the underlying neuronal activity is a continuous function. The first REM episode is of short duration and less intense because of circadian modulation of the REM sleep oscillator. As I will discuss later, the neurotransmitter acetylcholine is important in REM production, acting to excite populations of brain stem reticular formation neurons to produce the set of REM signs. Other neuronal populations, that utilize the monoamine neurotransmitters serotonin and norepinephrine, are REM-suppressive; the time course of their activity is sketched by the dotted line. These curves were generated by a mathematical model, the limit cycle reciprocal interaction model,³² which rather accurately models the time course and percentage of REM sleep and is discussed further in the text.

Sleep Ontogeny and Phylogeny

Periods of immobility and rest are present in many lower animals, including insects and lizards. Because they lack a cortical brain structure like that of humans, it is difficult to say whether the absence of slow waves in these animals means they are not having the equivalent of human slow-wave sleep or whether this