SLEEP DISORDERS

Upon successful completion of this course, you should be able to:

• Identify and discuss the scope of the problem identified here as “sleep disorders”
• Explain the key elements of “restricted sleep”, including the neurobehavioral and physiological effects
• Describe the impact of sleep on health, including sex differences, racial and ethnic disparities, aging, safety, and medical conditions
• Discuss what is referred to as “enabling technology” in regard to analysis of sleep-wake states, and postmortem brain analysis in sleep disorder patients
• Define what is meant by terms such as sleep disorders, including sleep-disordered breathing, insomnia, narcolepsy, restless legs syndrome and parasomnias

INTRODUCTION

Sleeplessness in America is a safety issue and a health problem. It is estimated that 50 to 70 mil-lion Americans suffer from a chronic disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health. Sleep disorders are chronic conditions frequently associated with other comorbidities (e.g., cardiovascular disease, depression, diabetes), which often require complex treatments. Hundreds of billions of dollars a year are spent on direct medical costs associated with doctor visits, hospital services, prescriptions, and over-the-counter medications. Sleep is essential to the workings of every organ. And it seems that the connection between sleep and health starts at the brain's central command post, the hypothalamus. There, sleep or lack of it can work to activate, or inhibit, hormone production. There, too, is where the body gets the signal to go to bed, to wake up and to adjust temperature, blood pressure, digestive secretions and immune activity.

Inadequate sleep works on hormone production in other areas as well. Without enough sleep, the central nervous system becomes more active, inhibiting the pancreas from producing adequate insulin, the hormone the body needs to digest glucose. On a public health level, it is important to recognize that almost 20 percent of all serious car crash injuries in the general population are associated with driver sleepiness, independent of alcohol effects. However, despite all these facts, awareness among the general public and health care professionals is low. This course is designed to increase awareness among nurses of this serious national problem.

The three broad categories of sleep problems include:

Sleep Restriction: This results from imposed or self-imposed lifestyles and work schedules. Many children, adolescents, and adults regularly fail to get sufficient sleep to function effectively during waking hours.

Primary Sleep Disorders: More than 70 types of sleep disorders chronically affect people of all ages. Fifty percent or more of patients remain undiagnosed and therefore untreated.

Secondary Sleep Disorders: People having a chronic disease associated with pain or infection, a neurological or psychiatric disorder, or an alcohol or substance abuse disorder often experience poor sleep quality and excessive daytime sleepiness. The end result can be exacerbation of the primary medical condition and further impairment in health and safety, mood and behavior, and quality of life.

As part of the authorizing legislation establishing the National Center on Sleep Disorders Research (NCSDR) within the National Heart, Lung, and Blood Institute, a Sleep Disorders Research Advisory Board (SDRAB) was established to provide a primary source of advice on matters related to planning, conduct, support, and evaluation of research in sleep and sleep disorders. The SDRAB consists of 12 non-federal members appointed by the Director, NIH, eight of whom are representatives of health and scientific disciplines related to sleep disorders and 4 of whom represent the interests of individuals with a sleep disorder (see Appendix). The Director, NCSDR, serves as Executive Secretary of the SDRAB.

The Trans-NIH Sleep Research Coordinating Committee (SRCC) was established in 1986 by the Director of NIH for the purpose of facilitating interchange of information on sleep and sleep-related research. When the NCSDR was established in 1993, responsibility for the Trans-NIH SRCC was transferred to the NCSDR and its Director serves as Chair of the Trans-NIH SRCC.

The Trans-NIH SRCC in 1993 was comprised of only 5 NIH Institute representatives but membership has progressively increased in parallel with increasing interdisciplinary scope of sleep research and especially since release of the first Sleep Disorders Research Plan in 1996. Ten NIH Institutes/Centers are now members of the Trans-NIH SRCC:

NIH INSTITUTE/CENTER REPRESENTATIVES

Heart, Lung, and Blood (NHLBI) Carl E. Hunt, MD; Michael Twery, PhD
Aging (NIA) Andrew Monjan, PhD, MPH
Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) Deborah Ader, PhD
Alcohol Abuse and Alcoholism (NIAAA) Ellen Witt, PhD
Child Health and Human Development (NICHD) Marian Willinger, PhD
Drug Abuse (NIDA) Harold Gordon, PhD
Mental Health (NIMH) Israel Lederhendler, PhD
Neurological Disorders and Stroke (NINDS) Paul Nichols, PhD
Nursing Research (NINR) Karin F. Helmers, PhD, RN
Complementary and Alternative Medicine (NCCAM) Nancy Pearson, PhD

The Task Force appointed to revise the Sleep Disorders Research Plan was assisted in their efforts by the NCSDR and the Trans-NIH SRCC. A draft of the updated plan was broadly circulated to solicit comments from biomedical professionals involved in sleep-related research and clinical practice, and from relevant professional and public organizations representing individual scientific disciplines and sleep disorders. Many comments were received and were carefully considered by the Task Force in completing the 2003 National Sleep Disorders Research Plan.

Carl E. Hunt, MD
Director
National Center on Sleep Disorders Research
NCSDR e-mail: ncsdr@nih.gov
NCSDR website: http://www.nhlbi.nih.gov/sleep

I Procedure

The first National Sleep Disorders Research Plan was released by the National Institutes of Health (NIH) in 1996. Considerable scientific and clinical growth of the field has occurred since then, necessitating a reassessment and update of research opportunities and recommendations. This 2003 Revised Sleep Disorders Research Plan summarizes the new knowledge acquired since the 1996 Plan and provides an updated and expanded guide for scientific research on sleep and its disorders.

The sections selected for inclusion in this Revised Plan provide a broad perspective on the field of sleep and sleep disorders, and highlight the crosscutting and highly interdisciplinary evolution of this field. Each section provides:

A brief overview of the topic.

The major research accomplishments since release of the 1996 National Sleep Disorders Research Plan. The research recommendations for the future, including a listing of the two top recommendations followed by a listing of any additional recommendations.

This executive summary presents the Task Force’s highest recommendations for future research. All the recommendations highlighted in this Executive Summary are considered relatively equal in importance and are therefore not listed in any prioritized order.

Several specifics of the overall process by the Task Force merit further comment. First, there was considerable discussion on how to address pediatric sleep science since some developmental processes are only encountered in infants and children while others represent a continuum from infancy to old age. Reflecting this continuum, the adult and pediatric sections were combined whenever possible (e.g., insomnia, sleep and breathing). Separate sections focusing only on pediatric science were developed where there was no direct adult relevance.

Second, there was considerable discussion of how sleep and its disorders should be addressed in this document relative to women’s health. It was ultimately decided to both create a specific section on sex differences and women’s health in sleep to emphasize scientific content unique to women and to include in other sections, wherever appropriate, information as to how a particular disorder or physiologic process might differentially affect women and men. In this way, there would be adequate emphasis of all the diverse ways in which sleep concerns impact on maintenance of health and prevention of disease in women. Similarly, there is a separate section in the 2003 Revised Plan devoted exclusively to racial and ethnic disparities in sleep and health, and relevant content is also included in other sections wherever appropriate.

II Progress

Since the 1996 National Sleep Disorders Research Plan. The years since release of the original National Sleep Disorders Research Plan in 1996 have been remarkably eventful not only in terms of progress in the sleep sciences, but also in terms of lifestyle and activities of daily life that impact on sleep habits and behaviors. America is increasingly becoming a 24-hour per day society with ever-escalating expectations for around-the-clock services, information and entertainment. After the events of September 11th, 2001, we have also become a much more vigilant society. All of these lifestyle changes are directly impacting not only the number of hours Americans sleep each day but also when during the 24 hours that sleep occurs.

We are now beginning to understand the impact of chronic sleep loss or sleeping at adverse circadian times on our ability to function optimally and on our physical and mental health. How sleep loss, sleep displacement (e.g., shift work, jet lag), and a wide range of sleep disorders affect one’s ability to maintain health and healthy functioning in this 24/7 world, however, remains relatively poorly understood. Thus, despite the scientific progress made since 1996 in both clinical and basic science related to sleep and its disorders, there remains the challenge and the need to discover the functions of sleep, to understand and develop better treatments for the many disorders affecting sleep, and to explain the nature of human physiology during wakefulness and the individual stages of sleep. Without progress in these areas, countless millions will continue to suffer the consequences of dysfunction and abuse of this most basic regulatory process. Progress in every area cannot be included in this Executive Summary, but the most important gains in knowledge and understanding will be discussed to provide a context for the research recommendations that follow.

Sleep Neurobiology: The discovery in 1998-99 of hypocretin/orexin and its role in the development of narcolepsy in animal models and in humans revolutionized our understanding of this debilitating disorder and promises important advances in the diagnosis and therapy of human narcolepsy. Discovery of the neuromodulatory role of hypocretin/orexin also greatly improved our understanding of the basic neurobiologic processes that control sleep and wakefulness. Anatomic areas promoting sleep such as the ventrolateral preoptic (VLPO) area of the hypothalamus have also been characterized. New anatomical and physiological approaches have led to advances in our understanding of the location and interconnections between hypothalamic and brainstem circuits controlling REM, nonREM, and wake states.

Factors regulating the activity of these sleep-controlling neurons have been identified. Circuitry and neurotransmitter mechanisms controlling muscle tone across the sleep cycle, of relevance to numerous sleep pathologies, have also been identified.

Circadian Biology: A growing number of “clock genes” have been identified since 1996 that play a critical role in mammalian circadian timing. In addition, there is clear evidence that non-suprachiasmatic nucleus (SCN) tissues have clock genes and can demonstrate circadian rhythms. Thus, circadian modulation is now established to occur both centrally and peripherally, further emphasizing the importance of circadian chronobiology in the timing of sleep and waking as well as a wide variety of physiologic functions. Now these genetic studies are also being applied to humans, in particular patients with advanced sleep phase syndrome.

Sleep-Disordered Breathing (SDB): The consequences of SDB (obstructive sleep apnea, sleep apnea) in both adults and children have become increasingly clear over the last few years. In adults, the contribution of sleep apnea to the development of systemic hypertension is becoming more evident and data are accumulating that other adverse cardiovascular outcomes (stroke, congestive heart failure, myocardial infarction) may result from this disorder. In children, there is increasing evidence that sleep apnea may contribute to behavioral problems as well as learning and cognitive deficits. Thus, the diagnosis and treatment of this disorder is important from a variety of perspectives and across all ages.

Pediatrics: The recognition that having infants sleep supine (on their back) can substantially reduce the incidence of Sudden Infant Death Syndrome (SIDS) is now appreciated as a profoundly important early infant intervention and has saved thousands of lives. Recent research regarding the physiologic, psychological and developmental aspects of sleep in infants, children, and adolescents has contributed to an increased understanding of the unique aspects of sleep and development. The study of pediatric disorders such as Congenital Central Hypoventilation Syndrome and Rett Syndrome has led to a better basic understanding of autonomic regulation and respiratory control. Recent findings regarding the complex relationship between sleep patterns and hormonal changes in adolescence have broadened our understanding of pubertal influences on sleep and circadian biology.

The extent of sleep restriction and sleep disturbances among children and adolescents is now recognized to be much greater than previously believed, and the consequent impact on mood, neurobehavioral and academic functioning, safety, and health is considerable. Recognition of the link between sleep disturbances and neurobehavioral disorders in childhood, such as attention deficit hyperactivity disorder (ADHD), has profound public health implications for both the treatment and prevention of psychiatric co-morbidity.

Insomnia: The high prevalence, risk factors, and consequences of insomnia have been increasingly recognized since 1996. Insomnia has been identified as a risk factor for the onset of subsequent depression, anxiety, and substance use disorders. In addition, the efficacy and durability of behavioral therapies for insomnia have been demonstrated in controlled clinical trials.

Sleep Deprivation: Although previous studies have demonstrated many of the ill effects of total sleep deprivation, the impact of chronic partial sleep deprivation (restriction) had not been extensively investigated even though it is a much more common phenomenon. However, recent studies indicate that 4 to 6 hours of sleep per night yields a progressive, cumulative deterioration in neurobehavioral function including vigilance, neurocognitive performance, and mood. This reduction in performance is also associated with changes in cerebral activation during cognitive tasks. Physiologic changes (insulin resistance and increased sympathetic activation) appear to occur as well. Both the neurocognitive and physiologic effects of chronic sleep loss suggest there is optimal sleep duration and that there is a cost for failing to achieve it.

However, the exact duration of sleep required at different periods of life remains poorly understood, as do the mechanisms driving these neural and metabolic processes. Sleep Education: There is now broad recognition of the curriculum inadequacies regarding sleep and its disorders at most medical schools and residency training programs. A Sleep Academic Award Program was established in 1996 to address these educational gaps. This program has led to the development of undergraduate and postgraduate sleep curricula, educational tools, and methods to enhance sleep knowledge. The awardees, working with national professional societies, have also begun to address sleep and fatigue in medical training.

There have also been several public health education initiatives, including an effort to establish lifelong healthy sleep habits in school-age children begun in 2001 with Garfield, the “Star Sleeper” as the “spokescat” for healthy sleep. A high school biology curriculum on sleep, sleep disorders, and biological rhythms has also been created, as have programs to combat drowsy driving. Thus, a variety of educational activities have recently been implemented that have substantial potential impact on knowledge and public health behaviors.

We need to consolidate and extend the research progress made to date and to translate new knowledge and discoveries into effective therapies and improved lifestyle behaviors for all Americans (as described in the Department of Health and Human Services ‘Healthy People 2010’ initiative). Sleep-related research must continue across the full spectrum from basic science to clinical investigation to community-based translational programs in order to apply what is known to improve public health and quality of human life. The scientific areas most important in extending and translating the research gains made to date are summarized in the following paragraphs. The order in which they are listed does not reflect any prioritization; indeed, these individual recommendations are all important and of equivalent high priority.

III Research Recommendations

An improved understanding of all aspects of the neurobiology and functions of sleep is needed. These aspects include:

• The neurocircuitry whereby the previously described and yet-to-be-identified cellular systems that modulate state are connected to each other and to other neural systems needs to be characterized. In addition, the neuropharmacology and neuromodulators that mediate neural signaling in sleep and wakefulness and their hierarchy in this process need to be better understood. The genetic and proteomic mechanisms involved in the generation of sleep and wakefulness also need elucidation. Finally, the phylogeny of sleep needs to be further investigated to help define the functions of sleep.
  
  
• The neurobiologic basis of the two-process sleep system (homeostatic and circadian) needs to be better characterized regarding the anatomical, physiological and functional links between the two systems and the contribution of each to altered sleep quality and timing.
  
  
• Further research is needed to better understand how developmental maturation from the fetus to the adult influences all of the neurobiologic processes described above. This would include studies addressing how sleep itself influences neural development and how such development affects sleep at the neurobiologic level.
  
  
• Investigation is needed of the neurobiological function of sleep as a whole and the independent functions of NREM and REM sleep. Without some grasp of the functional role of sleep in the behavior and survival of an organism, it remains very difficult to understand the development, neurobiology, and importance of sleep to physiologic function.
  
  
• Enhance our understanding of the impact of reduced or restricted sleep on behavior, and neurobiologic and physiologic functions across the age spectrum from childhood through old age. Studies in this area should address:
  
  
• The neurobiologic processes mediating sleepiness, state instability, and decrements in specific aspects of neurocognitive performance and alertness: this includes identification of brain structures, proteins, and genes that mediate the neural basis of sleepiness and the neurocognitive performance changes resulting from sleep loss. Also, the neurobiologic processes mediating the restoration of stable wakefulness, alertness and performance require further investigation.
  
  
• A systematic delineation is needed of the processes involved in, the mechanisms underlying, and the developmental aspects of acute and chronic sleep deprivation on non-neural systems.

These systems include endocrine, cardiovascular, immune, hematopoietic, renal, gastrointestinal and muscle. The effects of sleep loss on behaviors that diminish the safety of both the individual and society in general need to be studied. This includes but is not limited to the transportation industry, the armed services, the space industry, health care, law enforcement and at-risk jobs in the construction, manufacturing and service sectors.

• Improve our understanding of the processes that lead to specific sleep disorders in children and adults. The following disorders are included in this summary due to both their prevalence and their impact on afflicted patients:
  
  
• Insomnia (difficulty initiating or maintaining sleep): This should include the development of animal models of insomnia, the study of specific insomnia phenotypes and the application of neurophysiologic, neurochemical, neuroanatomic and functional neuroimaging approaches to the study of insomnia in humans. Understanding why women are at higher risk for insomnia should be a goal as well. Finally, genetic, genomic and proteomic studies are also needed.
  
  
• Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD): Studies should address the role of altered central dopaminergic mechanisms and abnormal iron metabolism in their pathogenesis. Further development, refinement and validation of animal models of RLS and PLMD are also needed. The use of neuropathologic techniques in the evaluation of brains and spinal cords of affected patients are likely to be useful as well.
  
  
• Sleep-Disordered breathing (sleep apnea) and disorders of ventilatory control: These studies should address the processes that control both upper airway patency and ventilation itself with a particular focus on the influence of sleep on these biologic processes. The neural connections, neuromodulators and molecular events mediating these state-dependent processes affecting respiration during sleep need to be studied.
  
  
• Primary disorders leading to hypersomnolence: The neural mechanisms leading to hypersomnolence in conditions such as narcolepsy or primary central nervous system hypersomnolence need to be investigated, and the focus these studies should be how the neurobiologic causes of hypersomnolence differ from or resemble the effects of sleep loss.
  
  
• An assessment of normal human sleep phenotypes and the normal range of variation in this phenotype in adults and children (including racial and ethnic differences) is needed, not only to establish normative standards but also to serve as a model for recommended sleep behaviors. This assessment should include sleep duration, sleep stage distribution, sleep timing, sleep disruption, sleep quality, and other variables by which sleep and sleepiness can be quantitatively evaluated.

Once normal sleep phenotypes are defined, the associated genotypes should be fully evaluated.

• Abnormal sleep phenotypes should subsequently be recognizable and genotyping of these individuals should then be pursued to define the genetic underpinning of abnormal sleep or altered circadian rhythm profiles. The impact of single nucleotide polymorphisms (SNPs) on normal sleep phenotypes should be testable as well. The phenotype of patients with specific sleep disorders should be carefully defined in order to set the stage for subsequent genetic testing.
  
  
• Methods to define normal and abnormal phenotypes through questionnaires or simple noninvasive testing should be a goal. Population surveillance and assessment of associated morbidities will then be possible on a large scale.
  
  
• New treatments for sleep disorders are needed. Adapting these therapies to individual patients using pharmacogenetic and other approaches is an important research priority.
  
  
• The outcomes of such treatments, including complementary and alternative medicine (CAM) therapies, need to be assessed at all levels including adherence, effectiveness, morbidity, quality of life, health care costs, safety, and performance/productivity. Such studies will likely require carefully designed and appropriately powered clinical trials in order to yield evidence-based guidelines for improved management and treatment of sleep disorders and hence substantial public health benefit:
  
  
• Sleep-Disordered Breathing (Sleep Apnea): Adult and Pediatric: Continuous positive airway pressure (CPAP) devices have improved substantially and remain an effective form of therapy for adult Sleep-Disordered breathing (SDB). However, they are cumbersome and have achieved only moderate acceptance by patients. Other approaches such as oral appliances and upper airway surgery have relatively limited success rates for more than mild to moderate SDB.
  
  
• Current forms of therapy hence need to be improved and novel new therapies need to be developed. In children, the indications for surgical intervention need to be better defined. In addition, new surgical and non-surgical treatments for SDB in children are needed as well, including those that address major risk factors such as overweight and obesity.
  
  
• Insomnia: Although the efficacy and durability of behavioral therapies have been demonstrated for primary insomnia, long-term trials evaluating the efficacy and safety of hypnotic medications have not been conducted and are a high priority. The development of novel pharmacologic and non-pharmacologic therapies, as well as complementary and alternative medicine therapies, for insomnia of all types (including insomnia in high-risk populations) remains a priority as well.
  
  
• Finally, the effectiveness of behavioral, psychological, and popular mind-body approaches and treatments should be evaluated in routine care settings.
  
  
• Narcolepsy: The neurobiology of narcolepsy is now better understood and the role of hypocretin well recognized. Exciting possibilities for new research worthy of exploration include therapies involving hypocretin peptide supplementation, the development of hypocretin receptor agonists, cell transplantation, and gene therapy.
  
  
• Restless Legs Syndrome (RLS): Without a better understanding of the etiology, pathogenesis, and neurophysiology of RLS, treatment strategies are limited and not effective in all patients. RLS and Periodic Limb Movement Disorder (PLMD) can have profound negative impacts on quality of life including daytime functioning, work performance, and social and family life.
  
  
• Therefore, methods to determine the extent of nocturnal sleep disturbance and daytime sleepiness both in children and adults with RLS can potentially enhance opportunities to develop novel and effective treatments.
  
  
• The relationship between the processes of sleep and the development and progression of diseases of both neural and non-neural tissues are areas in need of further investigation. How sleep and its disorders contribute to the development of disease processes and alter their natural history is minimally understood. On the other hand, the impact of various diseases on sleep should also be studied. The interaction between sleep and a variety of disease processes hence needs to be studied at the epidemiologic, behavioral, physiologic and basic neurobiologic levels. Examples of these potential interactions include:
  
  
• Medical Conditions: Many medical disorders can impair sleep quality and can, in turn, be adversely affected by poor sleep. Common examples include congestive heart failure, pain, and obstructive lung disease. Congestive heart failure, for example, can lead to a cycling respiratory pattern resulting in sleep fragmentation and decrements in both quality of life and performance.
  
  The recurrent arousal from sleep secondary to the intermittent hypoxia associated with this respiratory pattern can potentially lead to a progression of heart failure and hence to reduced survival.
  
  
• Neurological Disorders: Neurological conditions such as neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease), head trauma, encephalitis, stroke and epilepsy are associated with insomnia, somnolence, motor activity during sleep, and/or breathing abnormalities during sleep. Studies should evaluate whether sleep disorders predispose to specific neurological conditions, whether neurological conditions can produce sleep disorders, and whether sleep disorders impair recovery for selected neurological disorders.
  
  
• Psychiatric, Alcohol and Substance Use Disorders: The complex relationships and causal pathways linking insomnia and sleep deprivation to these disorders require further investigation. The impact of sleep disturbances on treatment outcomes and recurrence risk is also significant.
  
  
• Specific examples include the risk for subsequent depression among individuals with insomnia, the importance of sleep and dream disturbances in the development of post-traumatic stress disorder, and the role of insomnia and sleep deprivation in increasing risk for relapse to alcoholism and drug addiction.
  
  
• Pediatric Genetic and Neurodevelopmental Disorders: Several genetic and neurodevelopmental disorders have associated sleep and/or Sleep-Disordered breathing abnormalities. These include both rare syndromes and more frequent conditions such as ADHD.
  
  
• Specific areas for further investigation include
  (1) understanding the pathophysiology of autonomic nervous system (ANS) dysregulation in order to better understand maturation of the ANS and the abnormalities that occur in Sleep-Disordered Breathing (SDB);
  (2) investigating the anatomical contributions of the upper airway to the obstruction found in children with craniofacial malformation in order to better understand etiology of the more common causes of SDB; and
  (3) understanding how genetic disorders produce primary insomnia, daytime somnolence, or movement disorders during sleep. Rare genetic disorders associated with sleep abnormalities provide unique models that may facilitate exploration of novel pathophysiologic mechanisms and the discovery of new sleep-related genes that may be relevant to other, more common sleep disorders.
  
  
• The education of health care providers and the public about the role of healthy sleep habits as an important lifestyle behavior and about sleep disorders is important. Current evidence suggests minimal learning opportunities at all levels (undergraduate, postgraduate, and continuing education). The development and implementation of sleep educational programs needs to encompass all relevant health professionals, including physicians, nurses, dentists, pharmacists, nutritionists, psychologists and other mental health practitioners). Furthermore, since many individuals use dietary supplements and other natural products as sleep aids, research findings regarding the effectiveness and safety of such products should be widely disseminated to health care providers and the public. In addition, a rigorous evaluation of the impact of these educational programs is needed to assess their efficacy in changing:
  
  
• Professional knowledge, attitudes, skills and behavior
  
  
• Clinical practice
  
  
• Patient and healthcare provider health and quality of life
  
  
• Public education programs about healthy sleep and sleep disorders should continue with an emphasis on culturally, ethnically and racially appropriate materials. These efforts should include school-based programs for both elementary and high school students as well as adult educational programs. An assessment of the impact of these programs on knowledge, attitudes and sleep practices of children and adults should be a component of this process.
  
  
• Recent scientific advances have led to the development of new technologies and methodologies, but these new approaches have not been systematically applied to the sleep sciences. In addition, new methods and approaches not currently available are needed in the sleep field to answer scientific questions and to better diagnose and manage patients. Prominent examples include:
  
  
• Mechanisms needed to study the neurobiology of a variety of sleep disorders, possibly including the development of relevant human brain banks. Examples include Sleep-Disordered Breathing and Restless Legs Syndrome/Periodic Limb Movement Disorder, sleep disorders for which little is known neuropathologically.
  
  
• Animal models of normal sleep as well as individual sleep disorders would be highly useful in not only understanding normal sleep physiology, but the pathogenesis of a variety of disorders and their behavioral and physiologic consequences.
  
  
• Functional neuroimaging techniques (e.g., PET, fMRI, MRS, MEG, NIR, SPECT) are increasingly available to study sleep, sleep deprivation, and sleep disorders—providing insights into the patterns of regional brain activity that characterize both normal and abnormal sleep/wake states. Application of these techniques to the study of sleep and sleepiness should be continued and expanded as further improvements and refinements become available.
  
  
• Sleep monitoring in rodents, although currently utilized in a few laboratories, needs to be standardized and then made more broadly available so that mouse/rat sleep phenotypes can be easily defined in genetically altered animals.
  
  
• New methods to measure and quantify the structure of sleep in humans are greatly needed. Such methods should be outcome focused such that what is measured predicts not only the restorative processes of sleep, but also the consequences of disrupting this process. Methods to relatively easily define circadian phase are also needed.
  
  
• Effective new measures and methods to quantify sleep and other relevant physiological signals (such as respiration) in the home are greatly needed to facilitate both large epidemiologic investigations and the broader evaluation of patients with potential sleep disorders.
  
  
• Quantifiable, non-invasive, relatively rapid methods to measure sleepiness in children and adults are greatly needed to scientifically understand its causes and consequences, and to predict performance such that the safety of the individual and society can be protected.
  
  
• Informatics can be directly applied to clinical, neurophysiologic, imaging, and genetic questions as they apply to sleep and its disorders, but are not currently widely utilized in this field. Thus the use of these devices must be expanded.
  
  Women from adolescence to post-menopause are underrepresented in studies of sleep and its disorders. Enhanced efforts are needed to better understand the neurophysiology of sleep and the neuropathology of sleep disorders in women. These efforts should include:
  
  
• Basic and clinical studies to establish how sex-related differences in sleep and its regulation influence the risk for, and mechanisms of, sleep disorders.
  
  
• Conduct longitudinal studies in women including both subjective and objective sleep indicators before and during menarche, women of childbearing age including pregnancy and the postpartum period, and women during the menopausal transition.
  
  
• Study how sleep disturbance in pregnancy affects fetal development and health both acutely and postnatally.
  
  
• Racial and ethnic minorities have significant health disparities. There is a need for improved data to develop and implement effective prevention, intervention, treatment, and other sleep-related programs and services in racial and ethnic minorities.
  
  
• Elimination of disparities in sleep disorder outcomes should address not only social and environmental factors such as education and access to health care, but also relevant gene-environment interactions. Relevant studies should include:
  
  
• Identifying the neurophysiological and neuroanatomical correlates and gene-environment interactions contributing to racial and ethnic disparities in prevalence and severity of individual sleep disorders.
  
  
• Developing effective strategies to reach racial and ethnic minorities in public health education programs for sleep-related conditions.

IV Research Training

Although clinical activities and opportunities in the sleep field are expanding, a larger and more interdisciplinary scientific work force is needed if we are to fully address the scientific questions discussed above. Attracting new basic and clinical investigators to this field represents a major challenge for the field if we are to meet the expanding research needs and opportunities. Some of the potential barriers include:

• The perceived difficulty of defining sleep phenotypes in mice/rats, thereby making molecular and genetic studies more difficult.
  
  
• The perceived difficulty of studying a “state” in very reduced preparations or cell lines.
  
  
• The challenges posed to clinical research by the need for objective measurement of sleep-wake physiology and behavior using cumbersome and expensive technology, and the need to control a wide range of factors, limit effective measurement of sleep-wake processes in naturalistic environments.
  
  
• “Sleep science” does not have Division or Departmental status at most medical centers. As a consequence, designated space, faculty positions, access to graduate students and potential for collaboration are all limited.
  
  
• Novel strategies to increase the number and scope of sleep investigators need to be identified and implemented. There is an acute need for additional dedicated Sleep Medicine training programs and for investigators in other training programs (e.g., neurobiology, genetics, aging, pulmonology, neurology, psychiatry, pediatrics and neuropathology) to train sleep scientists.
  
  
• Sleep is a highly interdisciplinary field and successful sleep centers therefore require scientific and clinical expertise from multiple disciplines with a sufficient critical mass of investigators focused on sleep in order to achieve scientific progress. The association between basic sleep investigators and clinical scientists at these sleep centers also promotes translational research that can yield results more immediately applicable to patient care and public health interventions.
  
  Due to a lack of a critical mass of sleep investigators at most medical centers, this goal may demand a more regional or national approach than is needed for most other disciplines. This may also require an iterative process by which integrated, multidisciplinary sleep centers are carefully developed with substantial training programs and the increasing dispersal of well-trained program graduates can then contribute to development of new sleep centers.
  
  
• In addition to attracting new investigators to the sleep field, there is a need to expand the number of trained scientists from other relevant disciplines electing to focus on sleep-related research. These disciplines include informatics, epidemiology and genetic epidemiology, clinical trials, functional imaging, genetics, and molecular biology. Without collaborators having these specific skills, sleep science will not be able to utilize currently available technologies and methodologies and hence will have diminished potential for progress. Ongoing training and expanded collaborative opportunities are needed, as is a comprehensive plan to attract, train and retain new scientists, and to continue expanding the skills of current investigators.

V Conclusion

Considerable progress has been made since release of the original National Sleep Disorders Research Plan in 1996. Resources expended by the National Institutes of Health to study sleep and its disorders have steadily increased (Appendix C). New scientific techniques that facilitate research discovery are being applied to sleep questions. This has led to an improved understanding of normal sleep physiology and the pathogenesis of a variety of sleep disorders.

As a result, both access to care for patients with sleep disorders and the quality of care are substantially better. However, many research questions remain unanswered and new questions need to be addressed, therapy for a number of sleep disorders remains suboptimal, and the research workforce addressing sleep science is inadequate. This Revised National Sleep Disorders Research Plan presents a comprehensive summary of focused research, training and education recommendations that addresses these opportunities and needs.

CIRCADIAN BIOLOGY
SLEEP NEUROBIOLOGY
PHARMACOLOGY AND PHARMACOGENETICS OF SLEEP AND WAKING

CIRCADIAN BIOLOGY

Background

Circadian oscillators are critically involved in the regulation of the sleep/wakefulness cycles, although the relationship is complex and not fully understood. It is generally recognized that the sleep/wakefulness rhythm is not driven directly by the circadian clock, but rather emerges from an interaction of the circadian clock located within the suprachiasmatic nucleus (SCN), and a distinct sleep-wake homeostatic process (e.g., the “sleep homeostat”) in which the drive or need for sleep depends upon the prior amount of wakefulness and sleep.

Sleep disorders may arise from dysfunction at several levels within these two timing systems. Alterations in the circadian pacemaker within the SCN, changes in the sleep homeostat, and alterations in the coupling between the two timing systems may each be causal in sleep disturbances. A complete understanding of the origins of normal and abnormal sleep will require a detailed understanding of both the circadian and sleep / wakefulness systems.

Progress In The Last 5 Years

• Identification of the first mammalian clock genes: Within the past 5 years 8 “clock genes” have been identified that play a critical role in mammalian circadian timing. A recent study indicates that alterations in the hPer2 gene are associated with advanced sleep phase syndrome. In addition, mutations of the murine Clock gene affect both sleep duration and the response to sleep loss, indicating that some genes may be involved in both the timing and pressure to sleep.
  
  
• Confirmation of the multi-oscillatory, distributed nature of the mammalian timing system:
  
  
• Dynamic measurements of molecular rhythms from several clock genes reveal that many organs and non-SCN regions of the brain express circadian rhythms, although not as robust as the rhythm generated by the SCN. These observations raise issues about the role of non-SCN rhythm generators in the control of the sleep/wakefulness cycle and the development of sleep disorders.
  
  
• Discovery of temporal complexity within the SCN:
  
  
• Recent experiments reveal regional specialization in the capacity to express circadian rhythms. It is evident that not all SCN neurons enjoy the same phase relationship to one another. Molecular rhythms of the right and left SCN appear out of phase in behaviorally split animals and phase differences among SCN neurons may be responsible for encoding day length information.
  
  
• Discovery that circadian photoreception is functionally and anatomically separate from vision and that this non-visual system may affect many physiological and behavioral systems:
  
  These findings are important because sleep/wake rhythms are regulated by photoreception via the SCN and the sleep/wakefulness cycle can influence photoreception (e.g., eye closure during sleep). These photoreceptors may be linked directly to sleep centers in the brain since there are retinal afferents of unknown function that project directly to these centers.
  
  
• Discovery of new neurotransmitter systems and anatomical areas of the brain, especially the hypothalamus, and in particular discovery of the orexins/hypocretins in the regulation of REM sleep: These anatomical and neurochemical targets are linked to the SCN and provide new avenues for studying the interactions of the circadian clock and sleep-waking timing systems.
  
  
• Discovery that chronic partial sleep loss for as little as one week can lead to metabolic and endocrine changes that are precursors for specific disease states (e.g., obesity and diabetes) and are also relevant to aging: Decreased total sleep time is often associated with circadian dysfunction either on a voluntary basis (e.g., shift work) or involuntary basis (e.g., as in aging), making it imperative to determine the importance of circadian factors that lead to decreased sleep and the health consequences associated with chronic sleep loss.
  
  
• Discovery that the rest phase of the rest-activity cycle of the fruit fly shares many behavioral and pharmacological features associated with sleep: This should allow this model organism to be used to further explore the molecular and genetic basis of sleep and the adverse effects of sleep deprivation.

Research Recommendations

• The neurobiological basis of the two-process sleep system. Recognition of the importance of these two separate timing processes controlling sleep rhythmicity will continue to provide an important conceptual framework for the dissection of altered sleep regulation. The anatomical, physiological and functional links between the two systems are virtually unknown. The search for the neurobiological basis of these two processes and their interaction should remain at the center of basic research in this area. A more complete characterization of the contribution of these two processes to altered sleep timing and quality, in particular with development and aging, is important.
  
  
• Circadian physiology of sleep disorders. The pathophysiology of certain disorders of the timing of sleep remains to be fully characterized and understood at a fundamental level. Circadian desynchrony is considered to be at the core of certain disorders that involve both insomnia and sleepiness (e.g., delayed sleep phase syndrome; shift work sleep disorder). Given the number of people affected by these disorders and the behavioral debilitation, it is important to determine whether any of the key circadian parameters (e.g., free-running period (tau), PRC, light sensitivity, internal coupling between sleep and other circadianmediated physiology, etc.) are altered in these disorders. It will also be important to search for linkages between circadian rhythms and sleep disorders not normally associated with circadian timing (e.g., Restless Legs Syndrome).
  
  
• The availability of clock gene mutations in mammals will allow study of the effects of alterations of the circadian pacemaker on the sleep/wakefulness rhythm. In addition, these genes may have effects on sleep that are independent of the SCN. It will be important to determine how these genes act to regulate sleep independent of the central pacemaker, and. to assess the effects of circadian period, phase and amplitude on the sleep/wakefulness rhythm.

Although the free-running period (tau) of the human circadian rhythm may not change during aging, animal studies suggest an impact on other circadian parameters (e.g., amplitude). It will be important to explore the effects of aging on central and peripheral circadian generators and how age-related changes in circadian function affect sleep.

How circadian dysregulation and sleep loss interact to affect health is an important but poorly understood topic. This issue is of particular importance to the aged and to disadvantaged populations. Multiple jobs and unusual work cycles can lead to circadian disruption. It will also be important to understand the long-term effects of chronic sleep loss in adolescents. Good model systems and more sophisticated long-term data collection will be essential.

In vivo measurement of circadian phase. There is a need to develop methodology for noninvasive measurement of human circadian phase. This may require the identification of new markers and/or the development of novel detection systems.

Quantitative modeling of a mammalian circadian clock. The molecular processes and interactions that appear to generate rhythmicity will need to be described in a mathematically rigorous fashion. The central clock mechanism has grown in complexity with an attendant loss of conceptual clarity. Modeling may allow for a better focus on critical processes.

Although it is clear that there are significant sleep problems associated with adjustment to shift work and transmeridian flight, our understanding about entrainment kinetics is very limited. In particular, little is known about entrainment kinetics in older individuals who have more difficulty in maintaining stably entrained biological rhythms. Recent research indicating that different circadian rhythm generators within the brain and other organs reset with different kinetics suggests that the physiology of internal and external synchronization is important. Molecular and neurophysiological tools are now available in several animal model systems to address these problems.

Animal research indicates that circadian photoreception enjoys distinct photoreceptors within the retina and specialized neural pathways. A full functional and molecular characterization of this system is required in humans.

SLEEP NEUROBIOLOGY

Background

Sleep time is defended by an accumulation of “sleep debt”, the need for more sleep that results from sleep restriction. Recent study findings in animals and humans suggest that a complete and sustained loss of sleep can, in rare and extreme cases, result in death. It is likely that an understanding of the effects of sleep loss will reveal basic principles of brain function relevant to a broad spectrum of neurological and behavioral disorders. Sleep is known to strongly affect the activity of most brain neurons.

Modern sleep neurobiology research has not yet achieved consensus as to the function of sleep. What determines the brain’s memory for sleep loss? What is the neurological deficiency being regulated by the sleep debt memory? Does active (REM) sleep have different functions than quiet (nonREM) sleep?

Functional significance of the marked differences in amount of sleep within the animal kingdom is unknown. Similarly, the considerable variation in the duration of the sleep cycle (WakenonREM-REM) in different species of mammals from a high of 2 hours to as little as 15 minutes is poorly understood, as are the determinants and health significance of the variations of sleep duration within the human population.

Progress In The Last 5 Years

• Molecular biological approaches have contributed to understanding sleep control mechanisms. These approaches have led to one of the greatest achievements of sleep research since the discovery of REM sleep, the identification of the hypocretin (orexin) system and its central role in Narcolepsy and behavioral control.
  
  
• Genetic expression studies of sleep in drosophila (fruit flies) have produced important discoveries about the genetic basis of sleep. Moreover, they have established this species, with its well-documented and readily manipulated genome as a valid model of sleep genetics, making further rapid progress likely. Studies of murine mutants have progressed along the same lines. A better understanding of the populations of genes activated by sleep, waking and sleep deprivation and the time course of this activation has been made possible by the application of recent developments in simultaneous assessment of the activity of large numbers of genes.
  
  
• Studies using polymer-encapsulated suprachiasmatic nuclei (SCN) and related studies of diffusible factors released by the SCN have identified some of the major mediators of circadian-sleep relations.
  
  
• Less progress has been made in elucidating at a molecular level the phenomenon of sleep debt. The functional and biochemical regulation of changes in sleep time, REM and nonREM amounts and sleep morphology (e.g. delta power, eye movement intensity) with development remains mysterious, although some progress has been made in characterizing the neurophysiology and neurochemistry of sleep changes across the lifespan.
  
  
• Progress has been made in the electrophysiology of sleep at the neuronal level. The mechanisms responsible for generating and synchronizing rhythmic neuronal activity in nonREM sleep have been localized to thalamic regions and the ionic currents mediating rhythmic discharge have been identified. Cell groups in the hypothalamus and basal forebrain critical in the control of nonREM and REM sleep have been identified with anatomical and electrophysiological techniques. Some recent evidence suggests that localized brain mechanisms may mediate sleep debt.
  
  
• Important roles of amino acid and monoamine mechanisms in regulating muscle tone at the motor-neuronal level across the sleep cycle have been demonstrated. The circuitry controlling neurotransmitter release has been clarified. These advances are important in understanding numerous sleep disorders including Sleep-Disordered breathing (sleep apnea), cataplexy, REM sleep behavior disorder and other parasomnias.
  
  
• The neurochemical phenotypes of major groups of neurons contributing to REM and nonREM sleep regulation have been identified. Previously appreciated monoaminergic (serotonin, norepinephrine, epinephrine, dopamine, histamine) mechanisms have been shown to interact with amino acid (glutamate, GABA, glycine) neurotransmitter systems at forebrain and brainstem levels. Anatomical connections between the neurons critical to REM and nonREM sleep have been traced. Hypocretin/orexin has been identified as an important modulator of activity in sleep control systems. Other peptides important in the control of sleep states have been described and localized to brainstem and forebrain sleep control regions.
  
  
• Limited progress has been made in understanding the phylogeny of sleep. REM sleep has been found in primitive mammals. Some birds may show interhemispheric EEG asymmetry during sleep. Unihemispheric sleep and unihemispheric sleep debt has been found in marine mammals.

Research Recommendations

• Determine the function of sleep as a whole and of the differential roles of REM and nonREM sleep. It will be helpful to study genetic mutant murine and invertebrate models with unusual sleep properties. An under-exploited resource is the variation in sleep time and quality in the animal kingdom. As the cost of sequencing continues to be reduced, it becomes practical to sequence the genomes of diverse species to determine the genetic basis of these differences. Advances in technology have made it practical to better record and characterize the great differences in sleep duration and quality between species.
  
  
• Recent work demonstrates that sleep is present unihemispherically in some mammals. In other animals, REM sleep appears to occur without the low voltage activity seen in most mammals. In still other mammals, blood pressure, heart rate, respiratory changes, eye movements, erections and other phenomena characteristic of human sleep do not occur. These variations in mammalian and in non-mammalian species, particularly if understood in an ecological context and at the cellular level, can provide a major insight into the functions of sleep.
  
  
• Bridge the gap between what is now known about the anatomy and neurochemistry of sleep, wake and waking arousal generating systems and the nature of the information processing that occurs at the synapses within these systems. Identification of the functional role-played by each neurochemical link and the analysis of neurotransmitter interactions would, for example, facilitate the development of drugs to control muscle tone over the sleep-wake cycle.
  
  
• The pathophysiology and neurochemistry of sleep disorders needs to be better understood. How abnormal operation of sleep regulatory systems results in sleep disorders needs to be clarified. The anatomical and pathophysiologic causes of REM sleep behavior disorder, Sleep-Disordered Breathing (SDB), periodic limb movements during sleep, and parasomnias are poorly understood. Major advances have occurred in our understanding of Narcolepsy (Section V). Further work is needed, however, to clarify the cause of Narcolepsy without cataplexy and how disorders of the hypocretin/orexin system and other systems produce the multiple symptoms of narcolepsy. Work in this area represents a great opportunity for clarifying basic issues of sleep control and sleep pathology.
  
  
• An understanding of sleep debt at the biochemical and genetic level is needed, building on the new knowledge of sleep control at the neuronal level. The biochemical and genetic substrates of waking and arousal during waking and of REM sleep and nonREM sleep debt need to be understood.
  
  
• Interactions between sleep states and thermoregulatory, metabolic, cardiovascular and respiratory regulation at all levels of the neuroaxis need to be better described and understood. The role of sex, sex hormones, sexual maturity, pregnancy and lactation in sleep control needs to be investigated at a mechanistic level.

PHARMACOLOGY AND PHARMACOGENETICS OF SLEEP AND WAKING

Background

The use of sedative/hypnotic and psychostimulant drugs to treat