NIH National Sleep Disorders Research Plan

Department of Health and Human Services

Public Health Service
National Institutes of Health
National Sleep Disorders Research Plan
January 1996


CONTENTS

Foreword
Executive Summary
Overview
Basic Science Research Recommendations
Patient-Oriented Research Recommendations
Applied Research Recommendations
Research Training Recommendations
Selected References


FOREWORD

The National Center on Sleep Disorders Research (NCSDR) was established within the National Heart, Lung, and Blood Institute (NHLBI) as a result of the National Institutes of Health (NIH) Revitalization Act of 1993. Its mandate is the following:

  • The conduct and support of research, training, health information dissemination, and other activities with respect to sleep disorders, including biological and circadian rhythm research, basic understanding of sleep, chronobiological and other sleep related research

  • To coordinate the activities of the Center with similar activities of other Federal agencies, including the other agencies of the National Institutes of Health, and similar activities of other public entities and nonprofit entities.

The legislation further provided for establishment of a Sleep Disorders Research Advisory Board composed of nonfederal experts and ex officio federal members and it mandated development of this National Sleep Disorders Research Plan.

The Plan is broad in scope and multidisciplinary in nature. Its vision is "to improve the health, safety, and productivity of Americans by promoting basic, clinical, and applied research on sleep and sleep disorders." To achieve this vision, the Plan's recommendations call for strengthening existing sleep research programs and creating new programs that address important research gaps and opportunities.

Two themes cut across all the Plan's recommendations. The first is the need to apply today's most advanced techniques and technologies to the study of sleep. In basic science, the tools of cellular and molecular biology and molecular genetics are particularly relevant, as are neuroimaging, neurophysiology, neuropharmacology, and computational neuroscience. For public health and patient-oriented research, modern techniques from epidemiology, clinical outcomes research, experimental therapeutics, and behavioral sciences should be utilized.

The second theme is the need to understand daytime sleepiness and reduce its negative impact on society. Investigation of this significant public health problem requires a multidisciplinary approach that includes all types of research (e.g., basic, clinical, applied) and all research methods.

Needs and opportunities receiving special emphasis in the Plan include the following:

  • Understanding the cellular, molecular, and genetic basis of sleep and its disorders.

  • Determining the epidemiology of sleep and sleepiness in health and disease.

  • Identifying the effects of sleep loss on the waking function of the brain, other systems, and behavior.

  • Elucidating the pathophysiology and optimal management of common sleep disorders and developing new technologies to accomplish this task.

  • Learning to manage sleep-wake function to optimize health and performance in the 24-hour society, including developing new technologies to address evaluation, diagnosis, and prevention of the causes of sleepiness.

  • Discovering the functions of sleep.

  • Training investigators to expand the pool of sleep researchers.

The Plan is envisioned not as a blueprint, but as a dynamic springboard for the creativity of individual scientists, whose insights and initiative underlie research progress. We are confident that its recommendations will provide a solid foundation to assist the NIH in achieving its mandate of improving the health of the nation.

Harold Varmus, M.D.
Director, NIH

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EXECUTIVE SUMMARY

Sleep-related problems affect millions of Americans, occur in all age groups, and have a major impact on society. Three broad categories of problems have been identified:

  • Sleep disorders. More than 70 types of sleep disorders chronically affect millions of Americans. Many people are unaware of their illness and are not receiving adequate treatment for it.

  • The sleep-disease connection. This problem has two facets. First, some psychiatric, substance abuse, and medical disorders disturb sleep; and the resulting sleep abnormalities further exacerbate the original problem, creating a vicious circle. Second, sleep affects the expression of many diseases (e.g., asthma, in which episodes occur more commonly during sleep).

  • Sleep deficits resulting from lifestyles and work schedules. Many people (e.g., student night owls, jet-lagged business travelers, shift workers) regularly fail to get the sleep they need to function effectively during waking hours.

Recognizing the serious, pervasive public health threat posed by sleep problems, the Congress established the National Center on Sleep Disorders Research (NCSDR) within the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), in 1993. The NCSDR authorizing legislation also mandated development of a National Sleep Disorders Research Plan:

  • After consultation with the Director of the Center and the advisory board...the Director of the National Institutes of Health shall develop a comprehensive plan for the conduct and support of sleep disorders research.

  • The plan...shall identify priorities with respect to such research and shall provide for the coordination of such research conducted or supported by the agencies of the National Institutes of Health.

  • The Director of the National Institutes of Health (after consultation with the Director of the Center and the advisory board...shall revise the plan...as appropriate.

The Plan described herein was developed by the Research Subcommittee of the Sleep Disorders Research Advisory Board, which comprised Drs. J. Christian Gillian, chair, Allan I. Pack, and Thomas Roth. Their report was reviewed and approved by the full Advisory Board, the Trans-NIH Sleep Research Coordinating Committee, and the NHLBI.

The Plan is broad in scope and multidisciplinary in nature. Its vision is "to improve the health, safety, and productivity of Americans by promoting basic, clinical, and applied research on sleep and sleep disorders." To achieve this vision, the Plan's recommendations call for strengthening existing sleep research programs, training new investigators, and creating new programs that address important research gaps and opportunities.

The following are key recommendations:

Basic Science Research:

  • Increase efforts to understand the basic mechanisms responsible for sleep by applying molecular biological approaches in concert with techniques of cellular and systems neurobiology.

  • Conduct basic studies to understand the brain mechanisms responsible for sleepiness. Study the basic mechanisms underlying the interaction between circadian and neurophysiological systems that regulate sleep and wakefulness.

  • Increase attention to genetic factors controlling the basic mechanisms of sleep.

  • Increase research efforts to elucidate the fundamental functions of sleep.

Patient-Oriented Research:

  • Identify the genetic basis of sleep disorders that have a genetic or familial component.

  • Conduct epidemiological research to assess prevalence, risk factors, and long-term consequences of common sleep disorders and determine the role of ethnicity, age, and gender in their causation.

  • Conduct outcomes research and clinical trials on the management of common sleep disorders.

  • Develop new technological approaches for diagnosis of sleep disorders, screening for sleep disorders among high-risk populations in whom sleepiness presents a particular danger (e.g., transportation workers), monitoring the effectiveness of therapy, and detecting abnormalities of sleep as early biological markers of psychiatric illnesses.

  • Elucidate the pathogenesis/pathophysiology of sleep disorders and their consequences.

  • Provide the research infrastructure needed to carry out patient-oriented research.

Applied Research:

  • Conduct epidemiological research to define the prevalence, etiology, risk factors, morbidity, and costs of sleepiness in the general population.

  • Define the decrement and recovery processes associated with chronic partial sleep deprivation.

  • Develop efficient, objective measures of daytime sleepiness.

  • Evaluate the utility of interventions to prevent and manage sleepiness, with the goal of improving productivity and safety.

Research Training:

Enhance the number of trained investigators and trainees in biological and behavioral research related to basic sleep mechanisms and patient-oriented research.

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OVERVIEW

Congressional interest in sleep led to establishment in 1988 of the National Commission on Sleep Disorders Research. The Commission studied the scope of the problem and the current state of research and found that sleep disorders are a significant public health and economic problem that warrants major national attention. Establishment of the NCSDR within NIH was a major recommendation of the Commission.

With the establishment of the NCSDR in 1993, the Congress recognized the opportunity to multiply the impact of the nation's dynamic sleep research and training programs. Developing a National Sleep Disorders Research Plan, as called for in the NCSDR legislation, was an important step in this process.

How the Plan Was Developed

To develop a coordinated plan that many agencies could implement, the NCSDR used a collaborative planning model. A Research Subcommittee of the Sleep Disorders Research Advisory Board was appointed and given primary responsibility for preparing the Plan.

The first step in their process was soliciting suggestions from interested organizations and scientists around the country. The Subcommittee then consolidated these ideas and set priorities, producing recommendations for filling identified research gaps and taking advantage of suggested opportunities. Each member of the group focused on one category of need, including basic, clinical, and applied sleep research and research training. Subcommittee members and several members of the Trans-NIH Sleep Research Coordinating Committee reviewed the individual recommendations.

The final Plan presented here also reflects additional review, revision, and approval from the full Sleep Disorders Research Advisory Board, the complete Trans-NIH Sleep Research Coordinating Committee, and the NHLBI. By working together to develop the Plan, agencies with an interest in sleep and sleep disorders research set the stage for collaborative implementation of the Plan's recommendations.

Vision of the Research Plan

To improve the health, safety, and productivity of Americans by promoting basic, clinical, and applied research on sleep and sleep disorders.

To achieve this vision, the Plan's recommendations call for maintaining and strengthening existing research programs on sleep and wakefulness. These include the study of sleep mechanisms, using systems neuroscience approaches. Other research programs focus on such important issues as age-related sleep disorders, sleep-related cardiopulmonary disorders, the effects of mental illness and substance abuse disorders on sleep, neurological disease and sleep, and sudden infant death syndrome, and the effects of lifestyle and work schedules on sleep and wakefulness.

Strengthening current programs is necessary to accomplish the vision, but it is not sufficient. The Plan's recommendations also reflect the need to support three specific types of research:

  • Basic research, using state-of-the-art approaches, to elucidate the functions of sleep and the fundamental molecular and cellular processes underlying sleep.

  • Patient-oriented research to understand the cause, evaluate the scope, and improve the diagnosis and treatment of sleep disorders.

  • Applied research to evaluate the scope and consequences of sleepiness and to develop new approaches to prevent impaired performance during waking hours.

Training scientists and health-care workers who have the capacity to study and treat sleep disorders and their related health problems is another important focus of the plan.

The following sections describe important directions that should be undertaken in these key areas. General recommendations are numbered, and specific needs and opportunities are highlighted in bulleted form.

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BASIC SCIENCE RESEARCH RECOMMENDATIONS

Sleep state remains one of the major mysteries of the brain: Why do people sleep and how are sleep and wakefulness controlled? The answers to these questions may be expected to have a positive impact on medical care, including improved diagnosis and management of sleep disorders, and on policy decisions about sleep, work, and rest schedules. The ability to improve sleep and reduce sleepiness also has potential to improve the productivity and well-being of millions of Americans.

Progress made during the past decade provides a strong foundation for rapidly advancing knowledge. New research technologies, particularly cellular and molecular biology and genetics, can build on and complement what has been learned from traditional systems techniques about brain areas and specific neuronal groups involved in sleep. In addition, the study of basic sleep mechanisms can provide a new paradigm for applying an integrated systems/cellular/molecular/genetic approach to understanding a complex behavior.

Another advance that has positioned the field for progress is the recognition of rapid eye movement (REM) and nonREM sleep states and their regulation. It is now clear that many features of REM sleep are mediated in the brain by specific cholinergic neurons in the dorsal tegmentum. The activity of these neurons is influenced by noradrenergic and serotonergic neurons originating in the locus coeruleus and dorsal raphe, respectively.

Much also has been learned about specific neural pathways, various neurochemical receptors, and patterns of electrical activity within the specific REM-promoting and REM-inhibiting neurons. These findings have important implications for understanding the pathophysiology of sleep disorders in which REM sleep is disturbed.

Electrophysiological and anatomical studies have provided a new understanding of the neurophysiological mechanisms underlying changes in the electroencephalogram (EEG) during sleep and wakefulness. For example, delta waves (high-amplitude, low-frequency EEG waves) define stages 3 and 4 sleep in humans and slow-wave sleep in many mammalian species. Delta sleep is relatively abundant in children and adolescents, but begins to decline as adults age. It is increased following sleep deprivation and is reduced in such clinical disorders as insomnia, Alzheimer's disease, alcoholism, and psychiatric dysfunction. Sleep spindles and delta waves also occur out of phase with each other in nonREM sleep, reflecting different levels of hyperpolarization of the thalamocortical membrane.

It is also known that the neuronal mechanisms responsible for cortical EEG patterns reside in diverse brain areas, including the basal forebrain, the brainstem, the thalamus, and the hypothalamus. The role of specific neurotransmitters, receptors, and ion channels has been clarified.

As these examples suggest, the groundwork has been established to achieve rapid advances in understanding the basic brain mechanisms and functions of sleep. The field is ready to move ahead by using multidisciplinary approaches and integrating the classical methods of systems physiology and cellular neurobiology with exciting new methods available in genetics and molecular biology. The recommendations that follow are intended to catalyze this important advance.

Recommendations

  1. Increase efforts to understand the basic mechanisms responsible for sleep by applying molecular biological approaches in concert with techniques of cellular and systems neurobiology.

    • Investigate the mechanisms of sleep regulation and homeostasis at molecular, cellular, and systems levels.

    • Develop methods to study cellular and molecular mechanisms of sleep regulation in mammalian and nonmammalian species and simpler biological systems.

    • Take advantage of the naturally occurring changes in sleep processes, both early in fetal and postnatal life and late in life, to advance understanding of the molecular/cellular and neurophysiological mechanisms regulating sleep.

    Over the last several years the major focus for sleep research has been to understand the neurophysiological basis of many of the phenomena that occur during sleep (e.g., slow waves, muscle atonia). The fundamental control of sleep has received much less attention. Sleep is a homeostatic process in which increased amounts of sleep occur after prolonged periods of wakefulness, but how the homeostatic process is regulated remains a major question.

    The prevailing concept is that homeostasis is the result of an accumulation of sleep-promoting compounds during wakefulness. A large number of such compounds have been identified. Some seem to affect nonREM sleep; others, REM sleep. Knowledge of these compounds is largely confined to demonstration that their administration increases sleep, but there is also evidence that administration of antagonists reduces sleep or the amount of recovery sleep following sleep deprivation.

    Such studies, combined with the results from early sleep research, provide the impetus for application of molecular biological approaches to the major unsolved puzzle, regulation of sleep. It is important to address how levels of sleep-promoting compounds are controlled in the sleep-wake cycle. Is transcriptional regulation of genes the control mechanism? If so, what are the signals that regulate the genes in relation to the sleep-wake cycle? As genes related to the sleep-wake cycle are found, it will be important to address whether altering their transcription alters the sleep process. For example, does sleep deprivation increase transcription of such genes as IL-1beta, TNF, or specific prostaglandins? Where are these genes regulated (e.g., cell type, location), and what are the signals that account for transcriptional regulation? Understanding this will provide a more fundamental knowledge of sleep.

    Studies complementing this approach are needed to determine whether experimental alteration of specific genes alters sleep behavior. For example, use of tissue-specific or gene knockout techniques should be explored to determine if changes in gene transcription (e.g., IL-1beta knockout or transgenic animals) affect the sleep-wake state or response to sleep deprivation. Studies in behavioral biology have shown the power of this approach. For example, deletion of single genes affects memory and learning and produces highly aggressive behavior.

    This work, of necessity, demands research in species (e.g., mice) that facilitate genetic studies and will involve recording sleep behavior in large numbers of such animals. Current EEG-based techniques to monitor sleep are limiting in this regard. New technologies will be needed to simplify the analysis of sleep-wake cycles in mice and other mammalian species.

    If, as is believed, sleep is a fundamental and essential biological process, then it should be present in nonmammalian species also. Nonmammalian species present exciting model systems to learn more about the basic control mechanism of a neurobiological process. This has been true for memory (Aplysia), neuronal development (C. elegans), and circadian rhythm (Drosophila).

    Study of sleep in nonmammalian species is hampered, however, by difficulty in recognizing and characterizing the state. Current definitions of sleep based on the EEG are not applicable. A redefinition of the sleep state will facilitate its identification and investigation in simpler model systems. For example, does the rest period in Drosophila that is coupled to the circadian clock have features similar to sleep in mammals? Is there evidence of altered brain metabolism during the rest period? New definitions may be based on rest/activity and recovery rest following a period of deprivation of the rest period, or on metabolic changes in the brain. Development of new approaches to enable study in nonmammalian species should be strongly encouraged.

    Developmental and age-related changes in sleep mechanisms present other significant opportunities for integrating molecular, cellular, and systems neurobiology approaches. In fetal and postneonatal life, large amounts of REM sleep occur that may be critical for neuronal development. Late in life, however, sleep is shallow and fragmented, and older people have less recovery sleep after sleep deprivation than younger adults. Although it is clear that some fundamental changes take place in the processes regulating sleep across the life span, the neurobiological basis of these changes is not known. Are they age-related changes associated with neural circuits controlling sleep, or do they occur at a more fundamental level, such as in the transcription of critical genes? Study of naturally occurring age-related changes in sleep processes may uncover fundamental discoveries about sleep mechanisms.

    Improved understanding of sleep-regulating processes at the cellular and molecular levels promises to open a new world of scientific endeavor. For example, current knowledge of most compounds used to promote both sleep and wakefulness is empirical. Although much is already known of how sleeping pills and stimulants work at a cellular and molecular level, further clarification of the basic mechanisms of sleep and wakefulness may lead to new therapies, not only for ameliorating sleep disorders, but also for optimizing function during wakefulness.

  2. Conduct basic studies to understand the brain mechanisms responsible for sleepiness.

    • Understand at the molecular/cellular level the changes that take place in the brain when it is deprived of sleep.

    • Address the effects of sleepiness on different brain regions and on the tasks they perform.

    • Conduct basic studies to determine whether different causes of sleepiness (e.g., sleep deprivation, circadian factors, central nervous system pathology, drugs) impair performance by similar or different mechanisms.

    Although daytime sleepiness has been identified as a major public health problem and an important symptom of many sleep disorders, its basic neural mechanisms are still unknown. One fundamental question is whether the brain mechanisms in acute or chronic sleep deprivation in normal individuals are similar to those in patients with sleep disorders (e.g., sleep apnea).

    Most recent research on sleepiness and its behavioral consequences has been performed in humans. To address current questions, it is necessary to move from descriptive studies in humans to mechanistic studies in the brain. Why do many people feel sleepy in mid-afternoon? What happens in the brain to make people fall asleep while driving, despite the obvious importance of staying awake behind the wheel? Answering these questions requires an understanding of the neurobiology of wakefulness, including the possibility that some molecules are likely to accumulate or decrease in the brain during wakefulness. It is important to determine how these molecules are temporally regulated and what neuronal populations have a degraded performance as a result. Again, a combined systems/cellular/molecular approach, using the whole range of modern neurobiological techniques, offers important potential.

    Sleepiness, even in the absence of falling asleep, degrades performance in some brain areas and functions, but not in others. For example, the ability to perform complicated movements is less likely to be impaired than is the ability to learn or pay attention. Sleepiness particularly affects higher level processing and, hence, cognition, foresight, and situational awareness. The mechanism for this differential behavioral effect is unknown.

    Because sleep deprivation affects some functions more than others, understanding this differential effect may provide an important clue to the basic mechanisms of sleep. Achieving this understanding will require a combination of approaches, such as functional brain imaging, cognitive neuroscience, behavioral biology, multi-unit recording, neurochemical assays, and molecular biological techniques. Because of the apparent impact of sleepiness on higher functions, basic studies of sleepiness should include humans as well as animals.

    The common assumption that all situations leading to sleepiness (e.g., acute total sleep deprivation, chronic partial sleep loss, sleep fragmentation, drugs, and such sleep disorders as sleep apnea and narcolepsy) do so by common mechanisms is unproven and may be unwarranted. For example, an adaptive process may limit the impact of sleepiness in individuals who are chronically sleep- deprived. Addressing such issues at a basic level will complement the applied studies recommended in another section of this report.

  3. Study basic mechanisms underlying the interaction between the circadian and neurophysiological systems that regulate sleep and wakefulness.

    • Investigate interactions between the sleep and circadian systems at every level (e.g., neuroanatomical, neurophysiological, neuropharmacological, behavioral, and gene regulation).

    • Take advantage of animal species that have different interactions between the sleep and circadian systems (e.g., nocturnal and diurnal animals) to elucidate the nature of this interaction.

    Both homeostatic and circadian factors are known to contribute to regulation of sleep and wakefulness throughout the 24-hour day. Although the propensity to sleep increases with duration of wakefulness, the timing, duration, and characteristics of sleep are strongly affected by the circadian pacemaker. The pacemaker also probably modulates levels of alertness and performance throughout wakefulness (e.g., the normal increase in sleepiness experienced by humans in mid-afternoon). Exciting opportunities now exist to understand the interaction between biological clocks and sleep-wake behaviors.

    The circadian pacemaker lies in the suprachiasmatic nucleus in the anterior hypothalamus. Lesions of the suprachiasmatic nucleus abolish the circadian sleep-wake cycle in animals. Nevertheless, the basic mechanisms by which the suprachiasmatic nucleus interacts with and is regulated by the sleep-wake system and affects states of consciousness are unclear.

    Conversely, sleep and wakefulness also can affect the circadian pacemaker. For example, exercise can reset the phase position of the biological clock. The mechanisms by which sleep, wakefulness, and behavior affect the circadian pacemaker are unknown, although it is clear that these systems interact in a complex fashion. Theories (e.g., dual process or opponent process model) to describe the nature of the interaction have been proposed, based on behavioral studies conducted in humans and animals, but little, if any, research has been done on the neurobiological basis of the interaction. Neurobiological mechanisms that may mediate the interaction include direct projections from the suprachiasmatic nucleus, neuroendocrine profiles or humoral mechanisms under the influence of the circadian pacemaker, and circadian regulation of expression of genes involved in sleep control.

    Differences in the nature of the interaction between sleep mechanisms and circadian systems in different species may also provide important information. For example, lesions of the suprachiasmatic nucleus increase total sleep time in monkeys, but not in rats. Some species have highly consolidated sleep bouts while others have multiple shorter bouts. In addition, some animals sleep by day, some sleep by night, and others are awake at dawn and dusk. Understanding the basis of this interaction may lead to new approaches to change the timing and quality of sleep and, thus, provide solutions to such problems as jet lag, shift work, and circadian derangements in the timing of sleep.

  4. Characterize the genetic factors controlling the basic mechanisms of sleep.

    • Encourage studies using genetic approaches (e.g., family and twin studies, inbred strains) to identify genes involved in the control of sleep.

    • Encourage studies to identify and study animals with specific mutations that cause abnormalities in sleep.

    • Encourage molecular epidemiological approaches to study differences in sleep patterns.

    Although genetic factors are believed to play a role in sleep, relatively little is known about their contribution. Early attempts to characterize the inheritance of sleep patterns in inbred mice revealed qualitative and quantitative differences in amount of sleep and its daily distribution. Moreover, crossbreeding demonstrated that some traits, such as the amount of REM sleep and the diurnal ratio of sleep to wakefulness, are heritable.

    Twin studies in humans have suggested that sleep duration and nonREM sleep measures (stages 2-4) are under genetic influence. One study in normal volunteers found that REM latency (the time from the onset of sleep until the first REM period) was shorter in normal controls who were positive for the HLA-DR2 antigen than in those who were negative, suggesting a genetic contribution to the onset of REM sleep. Other encouraging data suggest that certain features of sleep are highly correlated in monozygous twins.

    Genetic factors also have been implicated in several sleep disorders, including narcolepsy, restless legs syndrome (RLS), some forms of insomnia and parasomnias, and sleep apnea. A point mutation at codon 178 and a polymorphism on codon 129 on the prion gene on chromosome 20 appears to account for fatal familial insomnia, a rare disorder in which patients suffer from a progressive reduction in total sleep time, abnormalities in autonomic function, and loss of neurons and astrogliosis in specific nuclei of the thalamus. These observations suggest that sleep as a behavior can now be characterized in intricate detail; it is less affected by confounding factors than are some other behaviors. Such studies could use linkage analysis in families to identify genes involved in control of specific aspects of sleep. Molecular epidemiology techniques provide another powerful approach. Developing new technologies to measure sleep characteristics in large numbers of individuals in different families may considerably speed the process. Studies in humans could be complemented by studies in inbred strains of rodents, in which confounding factors may be minimized by controlled breeding.

    Animals with specific mutations also present an opportunity to try new approaches. Mutations affecting the period of circadian systems were initially found in Drosophila, leading to major new discoveries regarding the molecular mechanisms of the biological clock. Mutations have been associated with altered clock periods (Tau mutant) in hamsters and with short circadian periods (clock mutant) in mice. The latter offers particular opportunities to understand the molecular basis of the circadian clock in mammals.

    Identifying mutants with sleep abnormalities is more difficult than identifying circadian mutants. New methods are needed to screen for genetic mutants that affect sleep and wakefulness.

    One specific sleep disorder, narcolepsy, is found in dogs and is inherited as an autosomal recessive trait. Limited knowledge of the dog genome has impeded analysis to identify the gene involved. Because the mouse genome is well characterized, a mouse model with narcolepsy may facilitate rapid identification of the gene.

    A better understanding of sleep, at both the behavioral and genetic levels, and of the pathogenesis of common sleep disorders is expected to facilitate development of new therapeutic and preventive approaches.

  5. Increase research efforts to elucidate the fundamental functions of sleep.

    One of the major barriers to understanding and investigating sleep is that the functions of this state are unknown. Why people sleep remains one of the major unanswered questions of modern biology. Various hypotheses that relate sleep to metabolic, immune, endocrine and brain functions (e.g., restoration of neuronal energy stores, memory enhancement during sleep) have been proposed to answer this question. Each of these theories has some evidence to support it, but none has, to date, been a major focus of investigation. For example, is adenosine regulated in relation to the sleep-wake state or increased by prior sleep deprivation? What metabolic pathways cause changes in adenosine levels? Attempts to develop and investigate comprehensive hypotheses about the function of sleep should be encouraged.

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PATIENT-ORIENTED RESEARCH RECOMMENDATIONS

The societal impact, scientific knowledge, and current levels of research vary widely among the more than 70 identified sleep disorders. Recommendations detailed in this section, recognizing that understanding of specific sleep disorders is currently at different stages of development, address the greatest needs and best opportunities for progress in patient-oriented research.

Although some disorders are well defined, with objective criteria available and prevalence established, others are in the early descriptive stages and have no rigorous research definition. To facilitate rapid progress, the recommendations focus principally on disorders that are better defined at this time.

Recommendations

  1. Identify the genetic basis of sleep disorders that have a genetic component.

    • Determine the genetic basis of narcolepsy in humans. Studies are needed on families in which multiple members have narcolepsy and on pairs of twins among whom one member is narcoleptic.

    • Determine the genetic basis of RLS and other disorders that have a genetic component. As with narcolepsy, studies on families and twins are needed.

    With knowledge about the human genome growing every day, rapid identification of genetic components in a number of sleep disorders is now feasible. Scientists now have particularly exciting opportunities to identify the basis of genetic influence for narcolepsy and, possibly, RLS. In addition, understanding the genetic basis of these disorders may provide important new knowledge about sleep itself.

    Considerable evidence suggests that narcolepsy has a genetic component. For example, a canine narcolepsy model with an autosomal recessive inheritance pattern has been described. In addition, human narcolepsy shows a very strong linkage with HLA antigen DR-2. Families in whom multiple members have narcolepsy are well described. A first-degree relative of a narcoleptic is known to have about one percent risk of developing the disease: this represents a relative risk 20 to 40 times that of the general population. However, only 10 to 20 percent of monozygotic twins are concordant for narcolepsy, which indicates that other factors are necessary for the disease to be expressed.

    Based on family studies, RLS also seems to have a genetic component. Inspection of a number of identified pedigrees suggests that RLS is inherited as an autosomal dominant trait, but that full expression of the disease may not occur until later in life.

    In narcolepsy, sleep control may be relatively well understood, because control of REM sleep is so abnormal in this disease. In RLS, which is characterized by periodic leg movements, studies may reveal more information about involuntary motor control.

    Advances in the genetics of sleep disorders offer many potential benefits, including reliable diagnostic tests; ability, if deemed appropriate, to screen for carriers; and opportunities for gene therapy.

  2. Conduct epidemiological research to assess prevalence, risk factors, and long-term consequences of common sleep disorders and determine the role of ethnicity, age, and gender in their causation.

    • Using subjective and objective criteria and careful differential diagnosis, identify the prevalence of the chronic insomnias; identify risk factors for and determine consequences of different subtypes.

    • Identify the prevalence of risk factors (including the role of ethnicity) for obstructive sleep apnea in children and its consequences.

    Insomnia is more clearly a set of complaints than a specific disease. Careful differential diagnosis, identification of comorbid diagnoses, and establishment of primary and secondary diagnoses are needed. Many underlying causes, which are usually age-dependent, appear to exist, but depression seems to be an important cause at any age.

    Current prevalence estimates are based on self-report. Epidemiological studies using objective measures are needed to determine the overall scope of the problem and the underlying patterns of sleep difficulty (e.g., difficulty initiating sleep, early morning awakening). These data will provide an important foundation for assessing the consequences of insomnia and treatment outcomes.

    The prevalence of obstructive sleep apnea in middle-aged and elderly populations has been relatively well characterized. The scope of the problem in children is unknown, however. It is clear that the nature of sleep disturbances resulting from sleep-disordered respiration is different in children than in adults, as are risk factors for the disease. Among children, the major risk factor is likely to be tonsillar/adenoidal enlargement. Sleep apnea appears to be more common among black young adults, and probably also among black children, although this has not been proven.

    Obstructive sleep apnea may have unique consequences in children. For example, it is likely that the sleepiness caused by sleep apnea impairs school performance and learning. Current treatment strategies also are different for children than for adults, but efficacy has not been established.

  3. Conduct outcomes research and clinical trials on the management of common sleep disorders.

    • Conduct defined clinical trials to assess the relative efficacy and effectiveness of different treatment modalities for insomnia.

    • Conduct clinical trials to assess the efficacy and effectiveness of different treatment modalities for sleep apnea.

    Little is known about the long-term outcomes of behavioral treatments and pharmacotherapy for various subtypes of insomnia. Optimal treatment is likely to be different for patients with varying severities of sleep apnea. Clinical trials focusing on this variable are needed.

  4. Develop new technological approaches for diagnosis of sleep disorders, screening for sleep disorders among high-risk populations in whom sleepiness presents a particular danger (e.g., transportation workers), monitoring the effectiveness of therapy, and detecting abnormalities of sleep as early biological markers of psychiatric illnesses.

    • Develop more cost-effective approaches (including in- home techniques) for diagnosis of obstructive sleep apnea.

    • Develop ambulatory approaches (including those that can be delivered in non-laboratory settings) to assess the extent/level of sleepiness caused by sleep disorders.

    • Develop approaches for in-home assessment of sleep disturbances and therapeutic effectiveness. Systems that communicate information to the physician about the use of treatments such as CPAP and intra-oral devices, sleep patterns of those with insomnia, and degree of movements during sleep would have important clinical value.

    Currently, diagnosis of many sleep disorders and assessment of the magnitude of sleepiness is usually done using in- laboratory techniques, which can be expensive and inconvenient. New approaches using in-home studies are beginning to be used for some disorders. Other technologies that are accurate and cost-effective should be developed and used. In addition, clinical decisionmaking concepts should be applied to facilitate their optimal use.

    The availability of inexpensive, reliable, ambulatory monitoring devices to study sleep-wake patterns may contribute to identification and treatment of millions of Americans with undiagnosed sleep disorders. By enabling employers to identify and treat employees with undiagnosed sleep disorders cost-effectively, they may reduce the danger and cost of catastrophic accidents. Improvements in treatment are also likely, because physicians will have objective tools to assess treatment effectiveness and make clinical decisions. Finally, new technological approaches will facilitate extension of earlier epidemiological studies that suggested that insomnia and hypersomnia are risk factors for mortality and morbidity in several conditions, including mood disorders.

  5. Elucidate the pathogenesis/pathophysiology of sleep disorders and their consequences.

    • Investigate why obesity leads to sleep apnea and whether the presence of apnea exaggerates obesity.

    • Elucidate the association between psychiatric disorders and insomnia (i.e., determine why patients with insomnia are more likely to develop a major depressive illness).

    • Understand how sleep affects movement control and neurological function, thus rendering movement disorders of various types more common during sleep.

    The major risk factor for obstructive sleep apnea in middle age is obesity; although the problem has been less extensively studied in women, in the general population of men the best predictor of sleep apnea is increased collar size. The mechanism by which obesity produces apnea is, however, unknown. It has been suggested that the peripharyngeal fat pads compress the upper airway in obese individuals, but certain data are incompatible with this hypothesis.

    Some evidence in genetic models of rats suggests that appetite control, control of weight, and ventilatory control are interrelated. Other studies have indicated that sleep apnea disturbs endocrine function and leads to insulin resistance. Thus, obesity may be exaggerated by the presence of apnea, creating a vicious circle. This area offers new possibilities for studying the relationship between obesity and sleep disorders.

    Depression is one of the most common factors associated with insomnia. Over the last 2 decades, sleep patterns in depressed individuals have been examined with varying results. More information is needed to determine the brain mechanisms that link depression and sleep disturbance and to identify the biological basis for the effect of sleep deprivation on mood. In addition, understanding the sleep mechanisms associated with mania may be informative, because affected patients go for long periods with little sleep and little sleepiness. Elucidating the basis for these associations may increase understanding of insomnia and provide fundamental knowledge about brain behavior.

    Pathophysiological studies of movement disorders of sleep constitute another potentially fruitful area of inquiry. Periodic leg movements are more common in sleep than in wakefulness and increase as a function of age. What is unique about the sleep state that permits these movements to occur? Is the age-related change indicative of progressive neurodegeneration in critical pathways and, if so, where does it occur? Are there other explanations? Other movement disorders (e.g., REM behavior disorder) exist that occur only in sleep, but the pathogenetic mechanisms are completely unknown. Studies of these phenomena during sleep may provide fundamental knowledge about sleep disorders themselves and about movement control.

  6. Provide the research infrastructure needed to carry out patient-oriented research.

    • Establish a Sleep Clinical Research Network to facilitate patient-oriented research in sleep disorders.

    • Establish registries with emphasis on families/twins for disorders to facilitate genetic research.

    • Create cell-line banks for disorders to facilitate genetic and other studies.

    • Develop a more rigorous set of definitions for sleep disorders, with criteria that facilitate research.

    Cost-effective infrastructures, such as the General Clinical Research Centers, should be developed to facilitate research on sleep and sleep disorders. Moreover, a research nosology of sleep disorders should be developed, including definitions of the criteria to be used for clinical research studies.

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APPLIED RESEARCH RECOMMENDATIONS

Sleepiness is a problem for otherwise healthy persons, as well as for those suffering from a wide spectrum of sleep disorders and conditions affecting sleep-wake functions. It is known that sleepiness affects millions of Americans and has major negative consequences for safety, productivity, and well-being. Applied research in this context is defined as research on sleepiness and its consequences apart from any sleep pathology. In general, it involves research on people who are sleep-deprived because of their lifestyles.

In addition to promoting a better understanding of the nature and extent of this public health problem in society, the recommendations in this section focus on the human performance issues that sleepiness raises. To achieve the critical goal of improving safety and productivity, research must determine how and why sleep loss creates impairment, how to measure sleepiness and alertness objectively, and how to prevent and manage the condition most effectively. Current knowledge about the nature of performance deficits provides an important point of departure for further progress. The challenge now is to evaluate sleepiness and its countermeasures systematically, while developing new technologies with practical application at home and on the job.

Recommendations

  1. Conduct epidemiological research to define the prevalence, etiology, risk factors, morbidity, and costs of sleepiness in the general population.

    • Identify the distribution of sleepiness in the general population, using multiple criteria for sleepiness, including standardized questionnaires and objective measures.

    • Identify the relative prevalence among sleepy individuals of different etiologies of sleepiness.

    • Identify the consequences of sleepiness in various at-risk populations.

    Currently available prevalence rates of daytime sleepiness are quite variable and use nonstandardized assessment tools. The distribution of sleepiness in the general population should be definitively determined using standardized measures of sleepiness. At least two validated sleepiness questionnaires are available for use in such studies, as well as mood scales that include a sleepiness/alertness dimension.

    Studies identifying specific populations at increased risk of daytime sleepiness also are needed. Among the populations that warrant investigation are young adults, high school students, shift workers, working parents, transportation workers, medical students, residents, nurses, and individuals who snore.

    In addition, the morbidity associated with daytime sleepiness should be evaluated using a variety of methodologies. Needed are large-scale, cross-sectional studies evaluating the relationship between sleepiness and motor vehicle accidents and longitudinal studies of specific subpopulations using selected outcome measures. For example, it is important to examine the relationships between levels of sleepiness and school grades in students or productivity in shift workers. Where data are available (e.g., the transportation industry and industries that have shift work and extended work schedules), the dollar costs of sleepiness should be assessed. Factors affecting costs include decreased productivity, increased error rates, and increased accident rates.

    Finally, laboratory studies are needed to define the etiology of daytime sleepiness. Each of the various at-risk groups should be studied, because the cause of sleepiness (e.g., sleep loss, sleep fragmentation, circadian disturbances) is likely to be different for different groups. New methodologies must be developed that can identify subjects who have a chronic sleep debt.

    This information is critical to the development of programs to combat sleepiness. An understanding of the scope of the problem will enable decision makers to estimate accurately the resources required to address it. With detailed information on the populations at risk, planners will be able to identify educational and other interventions to solve specific problems.


  2. Define the decrement and recovery processes associated with chronic partial sleep deprivation.

    • Determine how the severity of sleepiness relates to varying rates of accumulated sleep loss.

    • Identify the biological and behavioral adaptive processes modulating the consequences of chronic partial sleep loss.

    • Determine the aspects of human performance that are influenced by chronic partial sleep loss and the level of sleepiness that is associated with impairment of various functions.

    • Elucidate the nature of recovery of alertness associated with different sleep schedules.

    Decrements in alertness and performance are the primary and most profound effects of sleep loss. Studies have shown that a reduction of only 2 hours of sleep in a single night produces measurable impairments in alertness. However, the level of risk associated with sleep loss for different lengths of time is still undefined.

    The nature of impairment due to chronic sleep loss also must be evaluated systematically. Recent data suggest that cognitive performance, including functions such as foresight and situational awareness, is most affected by sleep loss. Long, monotonous performance tasks are associated with micro-sleeps, but these micro-sleeps do not account for all the performance decrements.

    Brain imaging studies have shown that region-specific reductions in metabolic activities occur during sleep deprivation. However, the physiological basis of alertness/performance decrements during sleep loss are unknown. More information is needed on the effects of chronic partial sleep loss on a broad range of behavioral measures, as well as on different assays of brain functions.

    Recent studies have begun to evaluate the rate of performance recovery following acute total sleep deprivation. Results suggest that the recovery process does not require an hour of recovery for each hour of lost sleep. Many investigators have hypothesized that the recovery value of sleep is related to the depth of sleep. However, recovery studies have not generally supported this view. Studies parametrically defining the recovery of performance following different schedules of recovery sleep are needed to resolve this issue.

    Identifying the degree and the nature of sleepiness associated with different amounts and rates of sleep loss may lead to countermeasures that increase productivity and safety in a variety of work settings. With this information, for example, employers may be able to design work schedules to minimize dangerous levels of sleepiness. The new data also will permit identification of sleepiness levels at which countermeasures should be applied.

  3. Develop efficient, objective measures of daytime sleepiness.

    • Develop physiological, biochemical, and behavioral assays of sleepiness.

    • Evaluate assays of sleepiness in an occupational setting to determine their predictive value for alertness testing.

    • Develop methods to monitor levels of alertness continuously over extended periods of time.

    Assessments of sleepiness have been performed using measures that vary in reliability, sensitivity, and difficulty of administration. Of the various self-report, performance, and physiological parameters, the multiple sleep latency test (MSLT) has proven to be the most reliable and the most sensitive to various causes of sleepiness, including sleep loss, sleep fragmentation, sleep disorders, circadian variations, and drugs. The Maintenance of Wakefulness Test (MWT), which assesses the ability to remain awake while sedentary, is a measure of the capacity to override sleepiness. However, both the MSLT and the MWT require a specialized facility and many hours to administer. Research to develop behavioral, physiological, and biochemical assays of sleepiness is needed. Such assays should be able to measure sleepiness at a single point in time and be sensitive to the various causes of sleepiness.

    To date, assays of sleepiness have been evaluated primarily for sensitivity. However, another potentially important characteristic of a sleepiness measure is its predictive value. For example, the productivity and safety of workers in a variety of occupational settings may depend on the ability to predict their potential to maintain alertness. Studies are needed to evaluate various measures of sleepiness for their predictive value in fitness-for-duty testing and to translate and validate laboratory measures of sleepiness for use in practical workplace tests.

    The ability to maintain optimal performance depends on the duration of the work shift as well as the context in which the work is being carried out. Thus, development of monitors that can continuously evaluate level of alertness is important for enhancing workplace productivity and safety.

    Sleepiness is commonplace in our society, and its chronicity may compromise an individual's ability to perceive levels of sleepiness accurately. When people do not recognize how sleepy they are, they may put themselves and others at risk. Development of technologies to detect and monitor sleepiness objectively has the potential to overcome this problem and provide solutions.

  4. Evaluate the utility of interventions to prevent and manage sleepiness, with the goal of improving productivity and safety.

    • Evaluate the effectiveness of caffeine and prescription drugs in counteracting the effects of sleep loss. Evaluate the effectiveness of nonpharmacological approaches (e.g., good sleep hygiene) to prevent and manage sleepiness. Develop different sleep-wake schedules, including the distribution of short-sleep periods and shifting core body temperature cycles, and evaluate their utility for inhibiting the onset of sleepiness and providing temporary relief from sleepiness.

    • Develop new pharmacological agents to increase alertness, using developing knowledge of the neuropharmacology of the sleep-wake system.

    • Develop countermeasures for specific causes of sleepiness, including methods to alter the output of the circadian clock to optimize sleep and wakefulness.

    Effective management of sleepiness in normal individuals ultimately will depend on understanding the basic mechanisms of sleep and drowsiness and the mechanisms by which these states affect the ability to function effectively. This understanding will come from studies conducted as part of the basic sciences component of the Plan. In the interim, studies should be conducted to evaluate the effectiveness of interventions used to prevent and alleviate sleepiness. Currently, the two most commonly used interventions to offset sleepiness are naps and pharmacological agents.

    Although napping is often used as a countermeasure for sleepiness, its effectiveness has not been evaluated systematically. In particular, the timing and duration of naps in relation to the degree of sleepiness experienced require study. Systematic investigation of various work schedules and their impact on the quality and quantity of sleep and working performance may have important practical relevance for the workplace.

    Caffeine is commonly used to combat sleepiness, but studies of its utility in both normal and chronically sleepy persons are needed. Data on normal volunteers undergoing sleep deprivation may provide information about use of caffeine as a prophylactic measure, and data on chronically sleepy individuals may enlighten scientists about its effectiveness as a countermeasure for sleepiness. In conducting such studies, it is important to define efficiency (e.g., dose-response curve), duration of effectiveness, and populations in which caffeine is effective.

    In certain situations (e.g., the military), use of prescription agents to counteract sleepiness is necessary. However, the safety and efficiency of various stimulants remain to be established in clinical trials. Trials are also needed to evaluate the safety and efficacy of new agents (e.g., melatonin and adenosine antagonists).

    Research on shift work has focused on developing schedules to minimize the negative effects of shift changes on sleep and waking functions. More recently, melatonin and bright lights have been shown to adjust the timing of sleep and wake function systematically. Clinical trials of light and melatonin, alone and in combination, are warranted in shift workers.

    The ability to prevent and manage sleepiness for defined periods of time is critical to safety, and many employers recognize the importance of this issue. Although some research is being done in a variety of occupational settings to monitor levels of sleepiness, there is a need to develop new ideas and techniques and to evaluate their potential in field trials.

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RESEARCH TRAINING RECOMMENDATIONS

Accomplishing the vision of the Plan requires adequate numbers of sleep researchers and investigators with multidisciplinary skills. One approach is to attract established researchers with expertise in allied disciplines into the sleep field. At the same time, it is important to develop a new cadre of sleep investigators, not only to nurture existing strengths, but also to pursue new and critical research directions identified in the Plan. At present, the number of sleep researchers is small, and only a few investigators are studying the molecular biology of sleep and the genetic basis and epidemiology of sleep disorders. Thus, multidisciplinary research training is necessary in both basic and patient-oriented research. Trainees require breadth, as well as depth, to develop the perspective that is essential to a successful research career.

  1. Enhance the number of trained investigators and trainees in biological and behavioral research related to basic sleep mechanisms and patient-oriented research.

    • Nurture ongoing training efforts in sleep research, which are small in number, and primarily focus on training in systems neuroscience and behavioral approaches.

    • Train new investigators to employ cellular, molecular biological, and genetic approaches and modern methods of patient-oriented research.

    Systems neuroscience, particularly the neurophysiological aspect, is a strong component of current sleep research. However, the number of investigators in this field is small in comparison to the size of the task. Thus, continuing to train investigators in this approach to the study of sleep is an important need.

    Existing programs are inadequate to train the cadre of individuals needed to implement the recommendations in the research plan. Innovative collaborative training mechanisms, with interactive training provided by investigators from different disciplines with complementary skills, are needed. Training investigators in patient-oriented research is critical because many of the clinical and applied research recommendations in the Plan cannot be carried out without them.

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