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  1. 1. National Center on Sleep Disorders Research 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN U . S . D E P A R T M E N T O F H E A L T H A N D H U M A N S E R V I C E S N a t i o n a l I n s t i t u t e s o f H e a l t h N a t i o n a l H e a r t , L u n g , a n d B l o o d I n s t i t u t e
  2. 2. 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research Trans-NIH Sleep Research Coordinating Committee NIH Publication No. 03-5209 July 2003
  3. 3. FOREWORD T he National Center on Sleep Disorders Much has changed since 1996. Stimulated in Research (NCSDR) was established significant part by the 1996 Plan, sleep research within the National Heart, Lung, and funding by NIH has doubled. New research Blood Institute (NHLBI) via a provision of the and new knowledge have vastly expanded National Institutes of Health (NIH) Revitalization the array of questions to be addressed, and Act of 1993. The NCSDR was mandated to: new technologies have yielded new tools and mechanisms for a highly interdiscipli- • Conduct and support research, training, nary broad-based approach to sleep research. health information dissemination, and It is in this context that revision of the 1996 other activities with respect to a basic National Sleep Disorders Research Plan was understanding of sleep and sleep dis- deemed necessary. The 2003 Revision sum- orders, including research on biological marizes the specific sleep research achieve- and circadian rhythms, chronobiology, ments since the 1996 Plan, identifies present and other sleep-related topics. gaps in our knowledge and understanding, and concludes with prioritized recommenda- • Coordinate NCSDR activities with similar tions for future research. As with the 1996 activities of other Federal agencies, Plan, the 2003 Plan is envisioned not as a including other components of the blueprint, but as a dynamic springboard for NIH, and similar activities of other the creativity of individual scientists, whose public and nonprofit entities. insights and initiative underlie research progress. We are confident that these The legislation further provided for establish- recommendations will contribute in sub- ment of a Sleep Disorders Research Advisory stantial ways to advancing the frontiers of Board and for development of a National biomedical knowledge related to sleep, enabl- Sleep Disorders Research Plan. The Plan ing timely diagnosis and effective treatment, called for strengthening existing sleep and improving the health of our Nation research programs, creating new programs through community-based public health to address important research gaps and education and intervention programs. opportunities, applying state-of-the-art techniques and technologies to the study of sleep, and developing strategies for better understanding daytime sleepiness and reducing its negative impact on society. Elias Zerhouni, M.D. Director, National Institutes of Health FOREWORD iii
  4. 4. PREFACE Steve Henriksen, Ph.D. T he 1996 National Sleep Disorders Research Plan, developed under Hannah C. Kinney, M.D. the leadership of the NCSDR and Carol A. Landis, D.NSc., R.N.* the Trans-NIH Sleep Research Coordinating Emmanuel Mignot, M.D., Ph.D.* Committee (SRCC), has been an important Judith A. Owens, M.D. resource and stimulus for progressive expan- Jerry M. Siegel, Ph.D. sion of sleep-related programs within NHLBI Esther Sternberg, M.D. and NIH (see Appendix C). Indeed, since Debra E. Weese-Mayer, M.D. 1996 sleep-related initiatives totaling more *Member, 2002 Sleep Disorders Research Advisory Board than $110 million have been funded, and the total for all sleep-related research The 2003 Revised Sleep Disorders Research grants within NIH has doubled. Plan, submitted by this Task Force and approved by the Sleep Disorders Research To build on the achievements of the past Advisory Board (SDRAB), summarizes the 6 years and identify new opportunities for dramatic expansion in interdisciplinary progress, we embarked on a comprehensive sleep-related research and resulting new revision of the 1996 Plan, reviewing accom- knowledge achieved since the original 1996 plishments, remaining knowledge gaps, Plan. The sleep research recommendations promising new scientific directions, and should serve as a valuable stimulus and unforeseen new challenges. A Task Force, guide to researchers in many disciplines consisting of 14 basic science and clinical for prioritizing and planning future research research scientists representing a broad directions that will lead to expanding knowl- interdisciplinary range of biomedical edge of the interrelationships between sleep, expertise, was appointed to undertake health maintenance, and disease prevention. this task. Its members are: David P. White, M.D., Chair Thomas Balkin, Ph.D. Gene Block, Ph.D.* Claude Lenfant, M.D. Daniel Buysse, M.D. Director David F. Dinges, Ph.D. National Heart, Lung, and Blood Institute David Gozal, M.D. PREFACE v
  5. 5. INTRODUCTION The end result can be exacerbation S leep-related problems affect 50 to 70 million Americans of all ages. of the primary medical condition and Sleep-related problems have the same further impairment in health and safety, clinical relevance in women as men, and mood and behavior, and quality of life. some sleep problems are more common in women. Important disparities in prevalence As part of the authorizing legislation estab- and severity of individual sleep disorders have lishing the National Center on Sleep Disorders been identified in racial and ethnic minorities Research (NCSDR) within the National Heart, and underserved populations. Sleep problems Lung, and Blood Institute, a Sleep Disorders and disorders have major impacts on society, Research Advisory Board (SDRAB) was estab- but have not received sufficient attention in lished to provide a primary source of advice clinical practice, in the education of health on matters related to planning, conduct, care providers and future biomedical support, and evaluation of research in sleep researchers, or in public health education and sleep disorders. The SDRAB consists of and intervention programs. 12 non-Federal members appointed by the Director, NIH, 8 of whom are representatives The three broad categories of sleep of health and scientific disciplines related to problems include: sleep disorders and 4 of whom represent the interests of individuals with a sleep disorder • Sleep Restriction: This results from (see Appendix B). The Director, NCSDR, imposed or self-imposed lifestyles serves as Executive Secretary of the SDRAB. and work schedules. Many children, adolescents, and adults regularly fail The Trans-NIH Sleep Research Coordinating to get sufficient sleep to function Committee (SRCC) was established in 1986 effectively during waking hours. by the Director of NIH for the purpose of facilitating interchange of information on • Primary Sleep Disorders: More than sleep and sleep-related research. When the 70 types of sleep disorders chronically NCSDR was established in 1993, responsi- affect people of all ages. Fifty percent or bility for the Trans-NIH SRCC was transferred more of patients remain undiagnosed to the NCSDR and its Director serves as Chair and therefore untreated. of the Trans-NIH SRCC. The Trans-NIH SRCC • Secondary Sleep Disorders: People having in 1993 was comprised of only five NIH a chronic disease associated with pain or Institute representatives, but membership infection, a neurological or psychiatric has progressively increased in parallel with disorder, or an alcohol or substance increasing interdisciplinary scope of sleep abuse disorder often experience poor sleep research and especially since release of the quality and excessive daytime sleepiness. first Sleep Disorders Research Plan in 1996. INTRODUCTION vii
  6. 6. Ten NIH Institutes/Centers are now members Many comments were received and were of the Trans-NIH SRCC: carefully considered by the Task Force in completing the 2003 National Sleep Heart, Lung, and Blood (NHLBI) Disorders Research Plan. Carl E. Hunt, M.D.; Michael Twery, Ph.D. Aging (NIA) This Plan fully represents the deliberations Andrew Monjan, Ph.D., M.P.H. and recommendations of the Task Force, Arthritis, Musculoskeletal, and Skin summarizes the dramatic advances in Diseases (NIAMS) knowledge since 1996, and identifies Deborah Ader, Ph.D. current gaps in our knowledge base. The Alcohol Abuse and Alcoholism (NIAAA) recommendations for future research will Ellen Witt, Ph.D. not only guide prioritization of future sleep Child Health and Human Development (NICHD) research within NIH and other Federal and Marian Willinger, Ph.D. non-Federal entities, but should also be Drug Abuse (NIDA) helpful in identifying opportunities for Harold Gordon, Ph.D. new investigators from an ever-increasing Mental Health (NIMH) diversity of scientific and clinical disciplines. Israel Lederhendler, Ph.D. The recommendations regarding training Neurological Disorders and Stroke (NINDS) of sleep research scientists, the education Merrill M. Mitler, Ph.D. of health care professionals, and community- Nursing Research (NINR) based public education programs should Mary Leveck, Ph.D., R.N. also stimulate much-needed progress in Complementary and Alternative these areas. Medicine (NCCAM) Nancy Pearson, Ph.D. The Task Force appointed to revise the Sleep Disorders Research Plan was assisted by the NCSDR and the Trans-NIH SRCC. A draft of the updated plan was broadly circulated to Carl E. Hunt, M.D. solicit comments from biomedical professionals Director involved in sleep-related research and clinical National Center on Sleep Disorders Research practice, and from relevant professional and National Heart, Lung, and Blood Institute public organizations representing individual NCSDR e-mail: ncsdr@nih.gov scientific disciplines and sleep disorders. NCSDR Web site: http://www.nhlbi.nih.gov/sleep viii 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  7. 7. CONTENTS EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Sleep-Disordered Breathing . . . . . . . . . . . . . . . . . . .76 Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80 SECTION I—BASIC SLEEP SCIENCE Narcolepsy and Other Hypersomnias . . . . . . . . . . . .84 Circadian Biology . . . . . . . . . . . . . . . . . . . . . . . . . .13 Restless Legs Syndrome/Periodic Limb Sleep Neurobiology . . . . . . . . . . . . . . . . . . . . . . . . .16 Movement Disorder . . . . . . . . . . . . . . . . . . . . . . . .87 Pharmacology and Pharmacogenetics of Sleep in Other Neurological Disorders . . . . . . . . . . .90 Sleep and Waking . . . . . . . . . . . . . . . . . . . . . . . . . .19 Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92 Sleep in Psychiatric, Alcohol, and SECTION II—RESTRICTED SLEEP: Substance Use Disorders . . . . . . . . . . . . . . . . . . . . .95 NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS Sleep Deprivation in Adults . . . . . . . . . . . . . . . . . . .25 SECTION VI—PEDIATRICS Sleep Deprivation in Children and Adolescents . . . . .28 Sleep and Early Brain Development and Plasticity . .101 Adolescent Sleep . . . . . . . . . . . . . . . . . . . . . . . . .104 SECTION III—ENABLING TECHNOLOGY Sleep in Medical Disorders . . . . . . . . . . . . . . . . . . .106 Analysis of Sleep-Wake States . . . . . . . . . . . . . . . . .33 Neuropsychiatric Disorders in Childhood Genetics and Proteomics: Phenotype Issues and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109 and Methodological Approaches . . . . . . . . . . . . . . .35 Functional Neuroimaging of Sleep and SECTION VII—EDUCATION AND TRAINING Wake States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38 Scientific Training . . . . . . . . . . . . . . . . . . . . . . . . .113 Post Mortem Brain Analysis in Sleep Disorder Patients . . . . . . . . . . . . . . . . . . . . . .41 Clinical Education and Training . . . . . . . . . . . . . . .115 Public and Patient Education . . . . . . . . . . . . . . . . .118 SECTION IV—SLEEP AND HEALTH Normal Sleep, Sleep Restriction, and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120 Health Consequences . . . . . . . . . . . . . . . . . . . . . . .47 Sleep, Sex Differences, and Women’s Health . . . . . .52 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 Racial and Ethnic Disparities . . . . . . . . . . . . . . . . . .57 Sleep and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . .60 APPENDICES Sleep and Safety . . . . . . . . . . . . . . . . . . . . . . . . . . .63 Appendix A: National Sleep Disorders Research Plan Revision Task Force . . . . . . . . . . . . . . . . . . . .127 Sleep in Medical Conditions . . . . . . . . . . . . . . . . . .67 Appendix B: National Sleep Disorders Research Advisory Board . . . . . . . . . . . . . . . . . . . . . . . . . .129 SECTION V—SLEEP DISORDERS Appendix C: NIH Sleep-Related Initiatives, Immunomodulation, Neuroendocrinology, 1996 to 2002 . . . . . . . . . . . . . . . . . . . . . . . . . . . .133 and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73 CONTENTS ix
  8. 8. EXECUTIVE SUMMARY P ROCEDURE relatively equal in importance and are there- fore not listed in any prioritized order. The first National Sleep Disorders Research Plan was released by the National Institutes of Several specifics of the overall process of Health (NIH) in 1996. Considerable scientific the Task Force merit further comment. First, and clinical growth of the field has occurred there was considerable discussion on how since then, necessitating a reassessment and to address pediatric sleep science, since update of research opportunities and recom- some developmental processes are only mendations. This 2003 revision of the National encountered in infants and children, while Sleep Disorders Research Plan summarizes others represent a continuum from infancy the new knowledge acquired since the 1996 to old age. Reflecting this continuum, the Plan and provides an updated and expanded adult and pediatric sections were combined guide for scientific research on sleep and whenever possible (e.g., insomnia, sleep, and its disorders. breathing). Separate sections focusing only on pediatric science were developed where The sections selected for inclusion in this there was no direct adult relevance. revised Plan provide a broad perspective on the field of sleep and sleep disorders, Second, there was considerable discussion and highlight the crosscutting and highly of how sleep and its disorders relative to interdisciplinary evolution of this field. women’s health should be addressed in this Each section provides: document. It was decided to both create a specific section on sex differences and • A brief overview of the topic. women’s health in sleep, to emphasize scientific content unique to women, and • The major research accomplishments to include in other sections, wherever appro- since release of the 1996 National Sleep priate, information as to how a particular Disorders Research Plan. disorder or physiologic process might differ- • The research recommendations for the entially affect women and men. In this way, future, including a listing of the two top there would be adequate emphasis of all recommendations, in italics, followed by a the diverse ways in which sleep concerns listing of any additional recommendations. impact on maintenance of health and pre- vention of disease in women. Similarly, This executive summary presents the Task there is a separate section in this revised Force’s highest recommendations for future Plan devoted exclusively to racial and ethnic research. All the recommendations highlight- disparities in sleep and health, and relevant ed in this Executive Summary are considered content is also included in other sections wherever appropriate. EXECUTIVE SUMMARY 1
  9. 9. P ROGRESS S INCE THE 1996 N ATIONAL Sleep Neurobiology: The discovery in 1998 to S LEEP D ISORDERS R ESEARCH P LAN 1999 of hypocretin/orexin and its role in the development of narcolepsy in animal models The years since release of the original National and in humans revolutionized our understand- Sleep Disorders Research Plan in 1996 have ing of this debilitating disorder and promises been remarkably eventful not only in terms import ant advances in the diagnosis and of progress in the sleep sciences but also in therapy of human narcolepsy. Discovery of terms of lifestyle and activities of daily life the neuromodulatory role of hypocretin/orexin that impact on sleep habits and behaviors. also greatly improved our understanding of America is increasingly becoming a 24-hour the basic neurobiologic processes that con- per day society with constantly escalating trol sleep and wakefulness. Anatomic areas expectations for around-the-clock services, promoting sleep, such as the ventrolateral information, and entertainment. After the preoptic (VLPO) area of the hypothalamus, events of September 11, 2001, we have have also been characterized. New anatomi- also become a much more vigilant society. cal and physiological approaches have led to All these lifestyle changes directly impact advances in our understanding of the location not only the number of hours Americans and interconnections between hypothalamic sleep each day but also when during the and brainstem circuits controlling rapid eye 24 hours that sleep occurs. movement (REM) sleep, non REM sleep, and wake states. Factors regulating the activity of We are now beginning to understand the these sleep-controlling neurons have been impact of chronic sleep loss or sleeping at identified. Circuitry and neurotransmitter adverse circadian times on our ability to mechanisms controlling muscle tone across function optimally and on our physical and the sleep cycle, of relevance to numerous mental health. How sleep loss, sleep displace- sleep pathologies, have also been identified. ment (e.g., shift work, jet lag), and a wide range of sleep disorders affect one’s ability Circadian Biology: A growing number of to maintain health and healthy functioning, “clock genes” have been identified since however, remains relatively poorly understood. 1996 that play a critical role in mammalian Thus, despite the scientific progress made circadian timing. In addition, there is clear since 1996 in both clinical and basic science evidence that non-suprachiasmatic nucleus related to sleep and its disorders, there (SCN) tissues have clock genes and can remains the challenge and the need to dis- demonstrate circadian rhythms. Thus, cover the functions of sleep, to understand circadian modulation is now established to and develop better treatments for the many occur both centrally and peripherally, further disorders affecting sleep, and to explain the emphasizing the importance of circadian nature of human physiology during wake- chronobiology in the timing of sleep and fulness and the individual stages of sleep. waking as well as a wide variety of physio- Without progress in these areas, countless logic functions. Now these genetic studies millions will continue to suffer the conse- are also being applied to humans, in particular quences of dysfunction and abuse of this patients with advanced sleep phase syndrome. most basic regulatory process. Progress in every area cannot be included in this Execu- Sleep-Disordered Breathing (SDB): The con- tive Summary, but the most important gains sequences of SDB (obstructive sleep apnea, in knowledge and understanding will be dis- sleep apnea) in both adults and children cussed to provide a context for the research have become increasingly clear over the last recommendations that follow. few years. In adults, the contribution of sleep 2 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  10. 10. apnea to the development of systemic increasingly recognized since 1996. Insomnia hypertension is becoming more evident, and has been identified as a risk factor for the data are accumulating that other adverse onset of subsequent depression, anxiety, cardiovascular outcomes (stroke, congestive and substance use disorders. In addition, heart failure, myocardial infarction) may result the efficacy and durability of behavioral from this disorder. In children, there is increas- therapies for insomnia have been demon- ing evidence that sleep apnea may contribute strated in controlled clinical trials. to behavioral problems as well as learning and cognitive deficits. Thus, the diagnosis and Sleep Deprivation: Although previous studies treatment of this disorder is important from a have demonstrated many of the ill effects of variety of perspectives and across all ages. total sleep deprivation, the impact of chronic partial sleep deprivation (restriction) had not Pediatrics: The recognition that having infants been extensively investigated even though sleep supine (on their back) can substantially it is a much more common phenomenon. reduce the incidence of Sudden Infant Death However, recent studies indicate that 4 to 6 Syndrome (SIDS) is now appreciated as a pro- hours of sleep per night yields a progressive, foundly important early infant intervention cumulative deterioration in neurobehavioral that has saved thousands of lives. Recent function including vigilance, neurocognitive research regarding the physiologic, psycho- performance, and mood. This reduction in logical, and developmental aspects of sleep performance is also associated with changes in infants, children, and adolescents has in cerebral activation during cognitive tasks. contributed to an increased understanding Physiologic changes (insulin resistance and of the unique aspects of sleep and develop- increased sympathetic activation) appear to ment. The study of pediatric disorders such as occur as well. Both the neurocognitive and Congenital Central Hypoventilation Syndrome physiologic effects of chronic sleep loss and Rett Syndrome has led to a better basic suggest there is optimal sleep duration and understanding of autonomic regulation and that there is a cost for failing to achieve it. respiratory control. Recent findings regarding However, the exact duration of sleep required the complex relationship between sleep pat- at different periods of life remains poorly terns and hormonal changes in adolescence understood, as do the mechanisms driving have broadened our understanding of puber- these neural and metabolic processes. tal influences on sleep and circadian biology. The extent of sleep restriction and sleep dis- Sleep Education: There is now broad recogni- turbances among children and adolescents tion of the curriculum inadequacies regarding is now recognized to be much greater than sleep and its disorders within most medical previously believed, and the consequent schools and residency training programs. impact on mood, neurobehavioral and A Sleep Academic Award Program was academic functioning, safety, and health established by NIH in 1996 to address these is considerable. Recognition of the link educational gaps, and this program has led between sleep disturbances and neurobe- to the development of undergraduate and havioral disorders in childhood, such as postgraduate sleep curricula, educational attention deficit hyperactivity disorder tools, and methods to enhance sleep knowl- (ADHD), has profound public health impli- edge. The awardees, working with national cations for both the treatment and pre- professional societies, have also begun to vention of psychiatric comorbidity. address sleep and fatigue in medical training. There have also been several public health Insomnia: The high prevalence, risk factors, education initiatives, including an effort to and consequences of insomnia have been establish lifelong healthy sleep habits in EXECUTIVE SUMMARY 3
  11. 11. school-age children begun in 2001 with wakefulness also need elucidation. Finally, Garfield, the “Star Sleeper” as the“spokescat” the phylogeny of sleep needs to be further for healthy sleep. A high school biology cur- investigated to help define the functions riculum on sleep, sleep disorders, and biologi- of sleep. cal rhythms has also been created, as have programs to combat drowsy driving. Thus, The neurobiologic basis of the two-process a variety of educational activities have sleep system (homeostatic and circadian) recently been implemented that may have needs to be better characterized regarding substantial impact on knowledge and public the anatomical, physiological, and function- health behaviors. al links between the two systems and the contribution of each to altered sleep quality We need to consolidate and extend the and timing. research progress made to date and to Further research is needed to better under- translate new knowledge and discoveries stand how developmental maturation from into effective therapies and improved lifestyle the fetus to the adult influences all of the behaviors for all Americans (as described neurobiologic processes described above. in the Department of Health and Human This would include studies addressing how Services “Healthy People 2010” initiative). sleep itself influences neural development Sleep-related research must continue across and how such development affects sleep the full spectrum from basic science to clinical at the neurobiologic level. investigation to community-based translational programs in order to apply what is known to Investigation is needed of the neurobio- improve public health and quality of human logical function of sleep as a whole and life. The scientific areas most important in the independent functions of NREM and extending and translating the research gains REM sleep. Without some grasp of the made to date are summarized in the following functional role of sleep in the behavior paragraphs. The order in which they are listed and survival of an organism, it remains does not reflect any prioritization; indeed, very difficult to understand the develop- these individual recommendations are all ment, neurobiology, and importance important and of equivalent high priority. of sleep to physiologic function. Enhance our understanding of the impact of R ESEARCH R ECOMMENDATIONS reduced or restricted sleep on behavior, and neurobiologic and physiologic functions across An improved understanding of all aspects the age spectrum from childhood through of the neurobiology and functions of sleep old age. Studies in this area should address: is needed. These aspects include: The neurobiologic processes mediating The neurocircuitry whereby the previously sleepiness, state instability, and decre- described and yet-to-be-identified cellular ments in specific aspects of neurocognitive systems that modulate state are connected performance and alertness: this includes to each other and to other neural systems identification of brain structures, proteins, needs to be characterized. In addition, the and genes that mediate the neural basis neuropharmacology and neuromodulators of sleepiness and the neurocognitive per- that mediate neural signaling in sleep and formance changes resulting from sleep wakefulness, and their hierarchy in this loss. Also, the neurobiologic processes process, need to be better understood. mediating the restoration of stable The genetic and proteomic mechanisms wakefulness, alertness, and perform- involved in the generation of sleep and ance require further investigation. 4 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  12. 12. A systematic delineation is needed of the Sleep-Disordered Breathing (SDB), processes involved in, the mechanisms including sleep apnea and disorders of underlying, and the developmental ventilatory control: Studies should address aspects of acute and chronic sleep the processes that control both upper air- deprivation on non-neural systems. way patency and ventilation itself with a These systems include endocrine, particular focus on the influence of sleep cardiovascular, immune, hematopoietic, on these biologic processes. The neural renal, gastrointestinal and muscle. connections, neuromodulators, and molecular events mediating these state- The effects of sleep loss on behaviors that dependent processes affecting respiration diminish the safety of both the individual during sleep need to be studied. and society in general need to be studied. This includes but is not limited to the trans- Primary disorders leading to hypersom- portation industry, the armed services, the nolence: The neural mechanisms leading space industry, health care, law enforce- to hypersomnolence in conditions such ment, and at-risk jobs in the construction, as narcolepsy or primary central nervous manufacturing, and service sectors. system hypersomnolence need to be investigated. The focus of these studies Improve our understanding of the processes should be how the neurobiologic causes of that lead to specific sleep disorders in children hypersomnolence differ from or resemble and adults. The following disorders are included the effects of sleep loss. in this summary due to both their prevalence and their impact on afflicted patients: An assessment of normal human sleep phenotypes and the normal range of vari- Insomnia, defined as difficulty initiating or ation in this phenotype in adults and children maintaining sleep: Studies should include (including racial and ethnic differences) is need- the development of animal models of ed, not only to establish normative standards insomnia, the study of specific insomnia but also to serve as a model for recommended phenotypes, and the application of neuro- sleep behaviors. This assessment should include physiologic, neurochemical, neuroanatomic, sleep duration, sleep stage distribution, sleep and functional neuroimaging approaches timing, sleep disruption, sleep quality, and to the study of insomnia in humans. other variables by which sleep and sleepi- Understanding why women are at higher ness can be quantitatively evaluated. risk for insomnia should also be a goal. Finally, genetic, genomic, and proteomic Once normal sleep phenotypes are de- studies are also needed. fined, the associated genotypes should be fully evaluated. Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD): Studies Abnormal sleep phenotypes should subse- should address the role of altered central quently be recognizable, and genotyping dopaminergic mechanisms and abnormal of these individuals should then be pursued iron metabolism in the pathogenesis of to define the genetic underpinning of these conditions. Further development, abnormal sleep or altered circadian rhythm refinement, and validation of animal profiles. The impact of single nucleotide models of RLS and PLMD are also needed. polymorphisms (SNPs) on normal sleep The use of neuropathologic techniques phenotypes should be testable as well. in the evaluation of brains and spinal cords of affected patients is also likely to be useful. EXECUTIVE SUMMARY 5
  13. 13. The phenotype of patients with specific Insomnia: Although the efficacy and sleep disorders should be carefully defined durability of behavioral therapies have in order to set the stage for subsequent been demonstrated for primary insomnia, genetic testing. long-term trials evaluating the efficacy and safety of hypnotic medications Methods to define normal and abnormal have not been conducted and are a phenotypes through questionnaires or high priority. The development of novel simple non-invasive testing should be a pharmacologic and nonpharmacologic goal. Population surveillance and assess- therapies, as well as complementary and ment of associated morbidities will then alternative medicine therapies, for insomnia be possible on a large scale. of all types (including insomnia in high-risk New treatments for sleep disorders are needed. populations) remains a priority as well. Adapting these therapies to individual patients, Finally, the effectiveness of behavioral, using pharmacogenetic and other approaches, psychological, and popular mind-body is an important research priority. The outcomes approaches and treatments should be of such treatments, including complementary evaluated in routine care settings. and alternative medicine (CAM) therapies, Narcolepsy: The neurobiology of narco- need to be assessed at all levels including lepsy is now better understood, and the adherence, effectiveness, morbidity, quality of role of hypocretin is well recognized. life, health care costs, safety, and performance/ Exciting possibilities for new research productivity. Such studies will likely require worthy of exploration include therapies carefully designed and appropriately powered involving hypocretin peptide supplemen- clinical trials in order to yield evidence-based tation, the development of hypocretin guidelines for improved management and receptor agonists, cell transplantation, treatment of sleep disorders and hence and gene therapy. substantial public health benefit: Restless Legs Syndrome (RLS): Without Sleep-Disordered Breathing (SDB)—Adult a better understanding of the etiology, and Pediatric: Continuous positive airway pathogenesis, and neurophysiology of pressure (CPAP) devices have improved RLS, treatment strategies are limited substantially and remain an effective form and not effective in all patients. RLS of therapy for adult SDB. However, they and Periodic Limb Movement Disorder are cumbersome and have achieved only (PLMD) can have profound negative moderate acceptance by patients. Other impacts on quality of life including approaches, such as oral appliances and daytime functioning, work performance, upper airway surgery, have relatively limited and social and family life. Therefore, success rates for more than mild to moder- methods to determine the extent of ate SDB. Therefore, current forms of nocturnal sleep disturbance and day- therapy need to be improved, and novel time sleepiness both in children and therapies need to be developed. In children, adults with RLS can potentially enhance the indications for surgical intervention opportunities to develop novel and need to be better defined. In addition, effective treatments. new surgical and nonsurgical treatments for SDB in children are also needed, includ- ing those that address major risk factors such as overweight and obesity. 6 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  14. 14. Further investigation is needed into the Psychiatric, Alcohol and Substance Use relationship between the processes of sleep Disorders: The complex relationships and and the development and progression of causal pathways linking insomnia and sleep diseases of both neural and non-neural tissues. deprivation to these disorders require How sleep and its disorders contribute to the further investigation. The impact of sleep development of disease processes and alter disturbances on treatment outcomes and their natural history is minimally understood. recurrence risk is also significant. Specific Conversely, the impact of various diseases on examples include the risk for subsequent sleep should also be studied. The interaction depression among individuals with insom- between sleep and a variety of disease pro- nia, the importance of sleep and dream cesses therefore needs to be studied at the disturbances in the development of post- epidemiologic, behavioral, physiologic and traumatic stress disorder, and the role of basic neurobiologic levels. Examples of these insomnia and sleep deprivation in increas- potential interactions include: ing risk for relapse to alcoholism and drug addiction. Medical Conditions: Many medical dis- orders can impair sleep quality and can, Pediatric Genetic and Neurodevelopmental in turn, be adversely affected by poor Disorders: Several genetic and neurodevel- sleep. Common examples include conges- opmental disorders have associated sleep tive heart failure, pain, and obstructive and/or SDB abnormalities. These include lung disease. Congestive heart failure, for both rare syndromes and more frequent example, can lead to a cycling respiratory conditions such as Attention Deficit pattern resulting in sleep fragmentation Hyperactivity Disorder (ADHD). Specific and decrements in both quality of life and areas for further investigation include: performance. The recurrent arousal from (1) understanding the pathophysiology sleep secondary to the intermittent hypoxia of autonomic nervous system (ANS) dys- associated with this respiratory pattern can regulation in order to better understand potentially lead to a progression of heart maturation of the ANS and the abnormali- failure and hence to reduced survival. ties that occur in SDB; (2) investigating the anatomical contributions of the Neurological Disorders: Neurological condi- upper airway to the obstruction found tions such as neurodegenerative disorders in children with craniofacial malformation (Alzheimer’s disease, Parkinson’s disease), in order to better understand etiology of head trauma, encephalitis, stroke, and the more common causes of SDB; and epilepsy are associated with insomnia, (3) understanding how genetic disorders somnolence, motor activity during sleep, produce primary insomnia, daytime som- and/or breathing abnormalities during nolence, or movement disorders during sleep. Studies should evaluate whether sleep. Rare genetic disorders associated sleep disorders predispose to specific with sleep abnormalities provide unique neurological conditions, whether neuro- models that may facilitate exploration of logical conditions can produce sleep dis- novel pathophysiologic mechanisms and orders, and whether sleep disorders impair the discovery of new sleep-related genes recovery for selected neurological disorders. that may be relevant to other, more common sleep disorders. EXECUTIVE SUMMARY 7
  15. 15. The education of health care providers and Recent scientific advances have led to the the public about the role of healthy sleep development of new technologies and habits as an important lifestyle behavior methodologies, but these new approaches and about sleep disorders is important. have not been systematically applied to the Current evidence suggests minimal learning sleep sciences. In addition, new methods and opportunities at all levels (undergraduate, approaches not currently available are needed postgraduate, and continuing education). in the sleep field to answer scientific ques- The development and implementation tions and to better diagnose and manage of sleep educational programs needs to patients. Prominent examples include: encompass all relevant health profession- als, including physicians, nurses, dentists, Mechanisms needed to study the neuro- pharmacists, nutritionists, psychologists biology of a variety of sleep disorders, and other mental health practitioners). possibly including the development of Furthermore, since many individuals relevant human brain banks. Examples use dietary supplements and other natural include SDB and RLS/PLMD, sleep products as sleep aids, research findings disorders in which little is known regarding the effectiveness and safety neuropathologically. of such products should be widely dis- Animal models of normal sleep as well seminated to health care providers and as individual sleep disorders would be the public. In addition, a rigorous evalu- highly useful in understanding not only ation of the impact of these educational normal sleep physiology, but also the programs is needed to assess their pathogenesis of a variety of disorders efficacy in changing: and their behavioral and physiologic • Professional knowledge, attitudes, consequences. skills and behavior Functional neuroimaging techniques • Clinical practice (e.g., PET, fMRI, MRS, MEG, NIR, SPECT) are increasingly available to study sleep, • Patient and health care providers sleep deprivation, and sleep disorders, health and quality of life thereby providing insights into the patterns of regional brain activity that Public education programs about healthy characterize both normal and abnormal sleep and sleep disorders should continue sleep/wake states. Application of these with an emphasis on culturally, ethnically techniques to the study of sleep and and racially appropriate materials. These sleepiness should be continued and efforts should include school-based pro- expanded as further improvements grams for both elementary and high and refinements become available. school students as well as adult educa- tional programs. An assessment of the Sleep monitoring in rodents, although impact of these programs on knowledge, currently utilized in a few laboratories, attitudes, and sleep practices of children needs to be standardized and then made and adults should be a component of more broadly available so that mouse/rat this process. sleep phenotypes can be easily defined in genetically altered animals. 8 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  16. 16. New methods to measure and quantify period, and in women during the the structure of sleep in humans are menopausal transition. greatly needed. Such methods should be outcome focused, such that what • Studies of how sleep disturbance in is measured predicts not only the res- pregnancy affects fetal development torative processes of sleep but also the and health both acutely and postnatally. consequences of disrupting this process. Racial and ethnic minorities have significant Methods to relatively easily define health disparities. Improved data are needed circadian phase are also needed. to develop and implement effective prevention, Effective new measures and methods intervention, treatment, and other sleep-related to quantify sleep and other relevant programs and services for racial and ethnic physiological signals (such as respiration) minorities. Elimination of disparities in sleep in the home are greatly needed to disorder outcomes should address not only facilitate both large epidemiologic investi- social and environmental factors, such as gations and the broader evaluation of education and access to health care, but also patients with potential sleep disorders. relevant gene-environment interactions. Relevant studies should include: Quantifiable, noninvasive, relatively rapid methods to measure sleepiness in children • Identifying the neurophysiological and adults are greatly needed to scientifical- and neuroanatomical correlates and ly understand its causes and consequences, gene-environment interactions contri- and to predict performance such that the buting to racial and ethnic disparities safety of the individual and society can in prevalence and severity of individual be protected. sleep disorders. Informatics can be directly applied to • Developing effective strategies to clinical, neurophysiologic, imaging, and reach racial and ethnic minorities in genetic questions as they apply to sleep public health education programs and its disorders, but are not currently for sleep-related conditions. widely utilized in this field. Thus. the use of these methods should be expanded. R ESEARCH T RAINING Women, from adolescence to post menopause, Although clinical activities and opportunities are underrepresented in studies of sleep and in the sleep field are expanding, a larger and its disorders. Enhanced efforts are needed to more interdisciplinary scientific work force is better understand the neurophysiology of needed if we are to fully address the scientific sleep and the neuropathology of sleep disor- questions discussed above. Attracting new ders in women. These efforts should include: basic and clinical investigators to this field represents a major challenge for the field if • Basic and clinical studies to establish we are to meet the expanding research how sex-related differences in sleep needs and opportunities. Some of the and its regulation influence the risk for, potential barriers include: and mechanisms of, sleep disorders. • The perceived difficulty of defining • Longitudinal studies in women includ- sleep phenotypes in mice/rats, thereby ing both subjective and objective sleep making molecular and genetic studies indicators before and during menarche, more difficult. in women of childbearing age includ- ing pregnancy and the postpartum EXECUTIVE SUMMARY 9
  17. 17. • The perceived difficulty of studying a can then contribute to development of “state” in very reduced preparations new sleep centers. or cell lines. In addition to attracting new investigators • The challenges posed to clinical research to the sleep field, there is a need to expand by the need for objective measurement the number of trained scientists from other of sleep-wake physiology and behavior, relevant disciplines electing to focus on using cumbersome and expensive sleep-related research. These disciplines technology, and the need to control a include informatics, epidemiology and wide range of factors, limit effective genetic epidemiology, clinical trials, functional measurement of sleep-wake processes imaging, genetics, and molecular biology. in naturalistic environments. Without collaborators demonstrating these • “Sleep science” does not have Division specific skills, sleep science will not be able or Departmental status at most medical to utilize currently available technologies centers. As a consequence, designated and methodologies and hence will have space, faculty positions, access to diminished potential for progress. Ongoing graduate students, and potential for training and expanded collaborative oppor- collaboration are all limited. tunities are needed, as is a comprehensive plan to attract, train and retain new scien- Novel strategies to increase the number tists, and to continue expanding the skills and scope of sleep investigators need to of current investigators. be identified and implemented. There is an acute need for additional dedicated Sleep C ONCLUSION Medicine training programs and for investi- gators in other training programs (e.g., Considerable progress has been made neurobiology, genetics, aging, pulmonology, since release of the original National Sleep neurology, psychiatry, pediatrics, and neu- Disorders Research Plan in 1996. Resources ropathology) to train sleep scientists. Sleep is expended by the National Institutes of Health a highly interdisciplinary field, and successful (NIH) to study sleep and its disorders have sleep centers therefore require scientific and steadily increased (see Appendix C). New clinical expertise from multiple disciplines, scientific techniques that facilitate research with a sufficient critical mass of investigators discovery are being applied to sleep questions, focused on sleep in order to achieve scientific and have led to an improved understanding of progress. The association between basic sleep normal sleep physiology and the pathogenesis investigators and clinical scientists at these of a variety of sleep disorders. As a result, both sleep centers also promotes translational access to care for patients with sleep disorders research that can yield results more immedi- and the quality of care are substantially better. ately applicable to patient care and public However, many research questions remain health interventions. Due to a lack of a unanswered, and new questions need to critical mass of sleep investigators at most be addressed; therapy for a number of sleep medical centers, this goal may demand a disorders remains suboptimal; and the research more regional or national approach than is workforce addressing sleep science is inade- needed for most other disciplines. This may quate. This Revised National Sleep Disorders also require an iterative process by which Research Plan presents a comprehensive integrated, multidisciplinary sleep centers summary of focused research, training, and are carefully developed with substantial education recommendations that addresses training programs and the increasing dis- these opportunities and needs. persal of well-trained program graduates 10 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  18. 18. SECTION I BASIC SLEEP SCIENCE • Circadian Biology • Sleep Neurobiology • Pharmacology and Pharmacogenetics of Sleep and Waking
  19. 19. CIRCADIAN BIOLOGY B ACKGROUND the murine clock gene affect both sleep duration and the response to sleep loss, Circadian oscillators are critically involved indicating that some genes may be in the regulation of the sleep/wakefulness involved in both the timing and cycles, although the relationship is complex pressure to sleep. and not fully understood. It is generally recognized that the sleep/wakefulness • Confirmation of the multi-oscillatory, rhythm is not driven directly by the circadian distributed nature of the mammalian clock, but rather emerges from an interac- timing system: Dynamic measurements tion of the circadian clock located within the of molecular rhythms from several clock suprachiasmatic nucleus (SCN), and a distinct genes reveal that many organs and non- sleep-wake homeostatic process (e.g., the SCN regions of the brain express circadian “sleep homeostat”) in which the drive or rhythms, although not as robust as the need for sleep depends upon the prior rhythm generated by the SCN. These amount of wakefulness and sleep. Sleep observations raise issues about the role disorders may arise from dysfunction at of non-SCN rhythm generators in the several levels within these two timing systems. control of the sleep/wakefulness cycle Alterations in the circadian pacemaker within and the development of sleep disorders. the SCN, changes in the sleep homeostat, and • Discovery of temporal complexity within alterations in the coupling between the two the SCN. Recent experiments reveal timing systems may each be causal in sleep regional specialization in the capacity disturbances. A complete understanding of to express circadian rhythms. It is evident he origins of normal and abnormal sleep will that not all SCN neurons enjoy the same require a detailed understanding of both the phase relationship to one another. circadian and sleep/wakefulness systems. Molecular rhythms of the right and left SCN appear out of phase in behaviorally P ROGRESS IN THE L AST 5 Y EARS split animals, and phase differences among SCN neurons may be responsible for en- • Identification of the first mammalian coding day-length information. clock genes. Within the past 5 years, • Discovery that circadian photoreception eight “clock genes” have been identified is functionally and anatomically separate that play a critical role in mammalian cir- from vision and that this nonvisual system cadian timing. A recent study indicates may affect many physiological and behav- that alterations in the hPer2 gene are ioral systems. These findings are important associated with advanced sleep phase because sleep/wake rhythms are regulated syndrome. In addition, mutations of SECTION I—BASIC SLEEP SCIENCE 13
  20. 20. by photoreception via the SCN, and the R ESEARCH R ECOMMENDATIONS sleep/wakefulness cycle can influence photoreception (e.g., eye closure during • Recognition of the importance of the sleep). These photoreceptors may be neurobiological basis of the two-process linked directly to sleep centers in the sleep system and these two separate tim- brain, since there are retinal afferents of ing processes controlling sleep rhythmicity unknown functions that project directly will continue to provide an important to these centers. conceptual framework for the dissection of altered sleep regulation. The anatomical, • Discovery of new neurotransmitter physiological, and functional links between systems and anatomical areas of the the two systems are virtually unknown. brain, especially the hypothalamus, and The search for the neurobiological basis of in particular discovery of the orexins/ these two processes and their interaction hypocretins in the regulation of rapid should remain at the center of basic eye movement (REM) sleep. These ana- research in this area. A more complete tomical and neurochemical targets are characterization of the contribution of linked to the SCN and provide new these two processes to altered sleep avenues for studying the interactions timing and quality, particularly in relation of the circadian clock and sleep-waking to development and aging, is important. timing systems. • The circadian physiology of sleep disorders • Discovery that chronic partial sleep loss and the pathophysiology of certain disor- for as little as 1 week can lead to meta- ders of the timing of sleep remain to be bolic and endocrine changes that are fully characterized and understood at a precursors for specific disease states fundamental level. Circadian desynchrony (e.g., obesity and diabetes) and are also is considered to be at the core of certain relevant to aging. Decreased total sleep disorders that involve both insomnia and time is often associated with circadian sleepiness (e.g., delayed sleep phase syn- dysfunction either on a voluntary basis drome; shift work sleep disorder). Given (e.g., shift work) or involuntary basis the number of people affected by these (e.g., aging), making it imperative to disorders and the behavioral debilitation, determine the importance of circadian it is important to determine whether any factors that lead to decreased sleep and of the key circadian parameters (e.g., free- the health consequences associated with running period [tau], phase-response curve chronic sleep loss. [PRC], light sensitivity, internal coupling • Discovery that the rest phase of the rest- between sleep and other circadian- activity cycle of the fruit fly shares many mediated physiology, etc.) are altered in behavioral and pharmacological features these disorders. It will also be important associated with sleep. This should allow to search for linkages between circadian this model organism to be used to rhythms and sleep disorders not normally further explore the molecular and genetic associated with circadian timing (e.g., basis of sleep and the adverse effects of Restless Legs Syndrome). sleep deprivation. 14 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  21. 21. • The availability of clock gene mutations in • Quantitative modeling of a mammalian mammals will allow study of the effects circadian clock is needed. The molecular of alterations of the circadian pacemaker processes and interactions that appear on the sleep/wakefulness rhythm. In addi- to generate rhythmicity will need to be tion, these genes may have effects on described in a mathematically rigorous sleep that are independent of the SCN. fashion. The central clock mechanism has It will be important to determine how grown in complexity with an attendant loss these genes act to regulate sleep, inde- of conceptual clarity. Modeling may allow pendent of the central pacemaker, and for a better focus on critical processes. to assess the effects of circadian period, phase, and amplitude on the sleep/wake- • Although it is clear that there are significant fulness rhythm. sleep problems associated with adjustment to shift work and transmeridian flight, our • Although the free-running period (tau) understanding about entrainment kinetics of the human circadian rhythm may not is very limited. In particular, little is known change during aging, animal studies about entrainment kinetics in older individu- suggest an impact on other circadian als who have more difficulty in maintaining parameters (e.g., amplitude). It will be stably entrained biological rhythms. Recent important to explore the effects of aging research indicating that different circadian on central and peripheral circadian gene- rhythm generators within the brain and rators and how age-related changes in other organs reset with different kinetics circadian function affect sleep. suggests that the physiology of internal and external synchronization is important. • How circadian dysregulation and sleep Molecular and neurophysiological tools loss interact to affect health is an impor- are now available in several animal model tant but poorly understood topic. This systems to address these problems. issue is of particular importance to the aged and to disadvantaged populations. • Animal research indicates that circadian Multiple jobs and unusual work cycles photoreception enjoys distinct photore- can lead to circadian disruption. It will ceptors within the retina and specialized also be important to understand the neural pathways. A full functional and long-term effects of chronic sleep loss molecular characterization of this system in adolescents. Good model systems in humans is required. and more sophisticated long-term data collection will be essential. • Development of a methodology for non-invasive in vivo measurement of human circadian phase is needed. This may require the identification of new markers and/or the development of novel detection systems. SECTION I—BASIC SLEEP SCIENCE 15
  22. 22. SLEEP NEUROBIOLOGY B ACKGROUND P ROGRESS IN THE L AST 5 Y EARS Sleep time is defended by an accumulation • Molecular biological approaches have of “sleep debt”—the need for more sleep contributed to understanding sleep that results from sleep restriction. Recent control mechanisms. These approaches study findings in animals and humans have led to one of the greatest achieve- suggest that a complete and sustained loss ments of sleep research since the discovery of sleep can result in death. It is likely that of REM sleep; the identification of the an understanding of the effects of sleep loss hypocretin (orexin) system and its central will reveal basic principles of brain function role in narcolepsy and behavioral control. relevant to a broad spectrum of neurological and behavioral disorders. Sleep is known • Genetic expression studies of sleep in to strongly affect the activity of most drosophila (fruit flies) have produced brain neurons. important discoveries about the genetic basis of sleep. Moreover, they have estab- Modern sleep neurobiology research has not lished this species, with its well-documented yet achieved consensus as to the function of and readily manipulated genome as a valid sleep. What determines the brain’s memory model of sleep genetics, making further for sleep loss? What is the neurological defi- rapid progress likely. Studies of murine ciency being regulated by the sleep debt mutants have progressed along the same memory? Does rapid eye movement (REM) lines. A better understanding of the popu- sleep have different functions than non-REM lations of genes activated by sleep, waking, (NREM) sleep? and sleep deprivation, and the time course of this activation has been made possible Functional significance of the marked dif- by the application of recent developments ferences in the amount of sleep within the in simultaneous assessment of the activity animal kingdom is unknown. Similarly, the of large numbers of genes. considerable variation in the duration of the • Studies using polymer-encapsulated sleep cycle (Wake-NREM-REM) in different suprachiasmatic nuclei (SCN) and related species of mammals from a high of 2 hours studies of diffusible factors released by the to as little as 15 minutes is poorly understood, SCN have identified some of the major as are the determinants and health signifi- mediators of circadian-sleep relations. cance of the variations of sleep duration within the human population. • 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 16 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  23. 23. and NREM amounts, and sleep morphology sleep-control systems. Other peptides (e.g., delta power, eye movement intensity) important in the control of sleep states with development remains mysterious, have been described and localized although some progress has been made to brainstem and forebrain sleep in characterizing the neurophysiology and control regions. neurochemistry of sleep changes across the lifespan. • Limited progress has been made in understanding the phylogeny of sleep. • Progress has been made in the electro- REM sleep has been found in primitive physiology of sleep at the neuronal level. mammals. Some birds may show inter- The mechanisms responsible for generat- hemispheric asymmetry during sleep ing and synchronizing rhythmic neuronal based on electroencephalogram (EEG) activity in NREM sleep have been localized recordings. Unihemispheric sleep and to thalamic regions, and the ionic currents unihemispheric sleep debt have been mediating rhythmic discharge have been found in marine mammals. identified. Cell groups in the hypothalamus and basal forebrain critical in the control of R ESEARCH R ECOMMENDATIONS NREM and REM sleep have been identified with anatomical and electrophysiological • Determine the function of sleep as a techniques. Some recent evidence suggests whole and of the differential roles of that localized brain mechanisms may medi- REM and NREM sleep. It will be helpful ate sleep debt. to study genetic mutant murine and invertebrate models with unusual sleep • Important roles of amino acid and properties. A resource that can be better monoamine mechanisms in regulating utilized is the variation in sleep time and muscle tone at the motor-neuronal level quality in the animal kingdom. As the cost across the sleep cycle have been demon- of sequencing continues to be reduced, strated. The circuitry controlling neuro- it becomes practical to sequence the transmitter release has been clarified. genomes of diverse species to determine These advances are important in under- the genetic basis of these differences. standing numerous sleep disorders, Advances in technology have made it including Sleep-Disordered Breathing practical to better record and character- (SDB), cataplexy, REM sleep behavior ize the great differences in sleep duration disorder (RBD), and other parasomnias. and quality between species. Recent work • The neurochemical phenotypes of major demonstrates that sleep is present uni- groups of neurons contributing to REM hemispherically in some mammals. In other and NREM sleep regulation have been animals, REM sleep appears to occur with- identified. Previously appreciated mono- out the low-voltage activity seen in most aminergic (serotonin, norepinephrine, mammals. In still other mammals, blood epinephrine, dopamine, histamine) pressure, heart rate, respiratory changes, mechanisms have been shown to inter- eye movements, erections, and other phe- act with amino acid (glutamate, GABA, nomena characteristic of human sleep do glycine) neurotransmitter systems at fore- not occur. These variations in mammalian brain and brainstem levels. Anatomical and in nonmammalian species, particularly connections between the neurons critical if understood in an ecological context and to REM and NREM sleep have been traced. at the cellular level, can provide a major Hypocretin/orexin has been identified as insight into the functions of sleep. an important modulator of activity in SECTION I—BASIC SLEEP SCIENCE 17
  24. 24. • Bridge the gap between what is now • An understanding of sleep debt at the known about the anatomy and neuro- biochemical and genetic level is needed, chemistry of sleep, wake and waking building on the new knowledge of sleep arousal-generating systems, and the control at the neuronal level. The bio- nature of the information processing chemical and genetic substrates of that occurs at the synapses within these waking and arousal during waking systems. Identification of the functional and of REM sleep and NREM sleep role played by each neurochemical link debt need to be understood. and the analysis of neurotransmitter interactions would, for example, facili- • Interactions between sleep states and tate the development of drugs to control thermoregulatory, metabolic, cardio- muscle tone over the sleep-wake cycle. vascular, and respiratory regulation at all levels of the neuroaxis need to • The pathophysiology and neurochemistry be better described and understood. of sleep disorders needs to be better under- The roles of sex, sex hormones, sexual stood. How abnormal operation of sleep maturity, pregnancy, and lactation in regulatory systems results in sleep disorders sleep control need to be investigated needs to be clarified. The anatomical and at a mechanistic level. pathophysiologic causes of RBD, SDB, periodic limb movements during sleep, and parasomnias are poorly understood. Although major advances have occurred in our understanding of narcolepsy (see Section V), further work is needed 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. Studies in this area repre- sent a great opportunity for clarifying basic issues of sleep control and sleep pathology. 18 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  25. 25. PHARMACOLOGY AND PHARMACOGENETICS OF SLEEP AND WAKING B ACKGROUND also result from genetic differences in pharmacodynamic effects and drug The use of sedative/hypnotic and psycho- metabolism. However, a wide gap still stimulant drugs to treat medical conditions exists in understanding the potential role such as Attention Deficit Hyperactivity these diverse factors play in sleep/wake Disorder (ADHD), insomnia, heart disease, pharmacology. Future insights into the narcolepsy, Restless Legs Syndrome (RLS), pharmacology of arousal states must and other medical disorders (see Section V) include greater focus on pharmacogenetic- can result in profound effects on normal based studies, both in humans and in sleep/wake architecture and perceived sleep appropriate animal models of sleep/wake quality. In addition, over-the-counter and and circadian rhythm disorders. herbal remedy markets exist to cater to the need to either stay awake or to fall P ROGRESS IN THE L AST 5 Y EARS asleep. The two most common substances employed in this capacity are caffeine The original 1996 Sleep Disorders Research and ethanol. Plan provided no explicit recommendations regarding the specific investigation of the Self-medication can lead to dose-related pharmacology and pharmacogenetics of impairments in sleep/wake architecture and sleep and arousal. Implicit in the recom- in other physiological parameters that in- mendations, however, was an appreciation directly impair sleep/wake quality. The use of the impact and scope that drugs have and misuse of other prescription and recre- on normal sleep/wake processes. Conversely, ational drugs—including psychostimulants both primary and secondary sleep disorder (methamphetamine, cocaine), sedative/ phenotypes can be triggers for prescription hypnotics (barbiturates, benzodiazepines), and nonprescription drug use that may, as a opiates (heroin, oxycodone), androgenic side effect, exacerbate disturbances in sleep. steroids, and so-called “club drugs” (e.g., Building on existing knowledge regarding MDMA)—can be accompanied by adverse the effects of a wide spectrum of drugs on physiological consequences, including sig- sleep and waking behavior, the 1996 Plan nificant alterations in circadian rhythms has resulted in important, incremental and sleep/wake architecture. progress in several relevant areas. In addition to these drug-induced effects • The increase in the number of investigator- on normal sleep/wake rhythms, individual initiated applications and responses to differences (including important gender and NIH-sponsored initiatives has led to funded age factors) in the pharmacological response research bearing directly on pharmacologic to drugs are also important. In addition to perturbations of the sleep/wake cycle. gender and age effects, these differences SECTION I—BASIC SLEEP SCIENCE 19
  26. 26. Relevant areas of research have included: • Research has delineated the molecular (1) efficacy of caffeine on sleep inertia basis of narcolepsy and circadian rhythm and cognitive performance, (2) pharma- disorders (see Section V). Genes responsible cotherapy for sleep/wake disorders in for these disorders have been positionally aging, (3) rational pharmacotherapy cloned and found to code for specific of primary insomnia, (4) treatment of proteins, some of which are receptors for hypnotic dependence, and (5) the effects other small molecules that could be targets of hormone replacement therapy on for chemically synthesized drugs. These sleep measures in postmenopausal might be effective for sleep/wake pharma- women. Results from these and other cology. Indeed, the clinical utility of drugs studies have led to a better understand- such as modafinil and gammahydroxybu- ing of drug efficacy in several medical tyrate (GHB) for narcolepsy, and selective conditions as well as the extent of indi- dopamine receptor agonists for treatment vidual differences in drug effects on of RLS, has been demonstrated. In addition, sleep/wake measures. while short-term pharmacologic treatment for insomnia has been demonstrated to be • We now have a better understanding efficacious, most Insomnia is chronic, not of the effects of prenatal and postnatal short-term. No carefully conducted studies cigarette smoke exposure in Sudden Infant have examined the longer-term pharma- Death Syndrome (SIDS) (see Section VI), cologic treatment of insomnia, including the effects of opioids on rapid eye move- issues such as efficacy, safety, or the ment (REM) sleep suppression, the effects relative advantages of different agents. of leptin on ventilatory and respiratory control, and the effects of psychopharma- • Genome screening and single nucleotide cological therapy on sleep in the major polymorphism (SNP) analysis have been mental disorders. Furthermore, there initiated in Sleep-Disordered Breathing have been important advances in our (SDB), RLS, Alzheimer’s disease, and fatal understanding of the effects of the major familial insomnia (see Section V). These drug classes on sleep disorders in animal diseases have major sleep/wake disruptions models and the brain circuits where these and are potentially subject to new forms drugs are believed to act. of pharmacotherapy. Individual differences in the response to such treatments may • Preclinical neuroscience research has relate to genetic differences. provided new insights into the complex circuitry, neurotransmitters, and neuromod- • New knowledge has been achieved ulatory substances involved in sleep/wake regarding the pharmacotherapy of regulation and their interaction with brain insomnia in alcoholics, the physiological circuits involved in circadian rhythm control. correlates of chronic alcohol ingestion in Findings from research in fruit flies, animals, both basic and clinical studies, and the and humans have added considerably to interactions between adolescent sleep, our knowledge of the complex regulation life-style and alcohol use. In addition, of behavioral state. Because of these find- sleep and the effects of alcohol in ings, greater opportunity exists to better alcohol-dependent subjects are now understand the actions of drugs on the better understood, although more work brain, and also to investigate novel classes needs to be done. Alcohol has been of drugs that have nontraditional mecha- shown to alter circadian clock function nisms of action on receptor systems within when exposure takes place in the early these newly refined brain circuits. postnatal period in rat pups. Studies on selectively bred mice and rats have 20 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  27. 27. demonstrated both ethanol-related meta- R ESEARCH R ECOMMENDATIONS bolic variations as well as wide variations in ethanol-induced narcosis, indicating • Consolidate the recent gains made in the strong genetic regulation of ethanol descriptive anatomy and neurochemistry pharmacology. Ethanol appears to have of sleep/wake generating systems by sensitive, pharmacological actions primarily investigating the hierarchies of neuro- on brain NMDA (N-methyl-D-aspartate) transmitter interactions within these com- and GABA (gamma-aminobutyric acid) plex circuits. These studies would facilitate receptor subtypes, offering the possibility the development of drugs to treat sleep of novel pharmacotherapy. In human stud- and waking disorders and also lead to a ies, virtually every type of sleep problem better understanding of the neuropharma- has been observed in alcohol-dependent cology of behavioral states. patients. Their sleep patterns are fragment- ed and typical encephalographic (EEG) • Encourage studies of the relative efficacy, rhythms are altered. Sleep changes persist safety, and long-term effects of psycho- for months or even years of abstinence, stimulants (e.g., methylphenidate, d- and alterations in sleep architecture appear amphetamine, modafinil, and caffeine), to be predictive of relapse to alcoholism. and hypnotics (particularly benzodiazepine Other studies indicate that alcohol aggra- receptor agonists and antidepressants) vates SDB and further increases the decre- related to sleep/wake measures in animal ments in cognitive performance resulting models and humans, including appropriate from sleep deprivation. Both gender and patient populations. These pharmacological ethnic differences in the response to assessments should also be assessed with ethanol and other abused drugs have regard to potential interactions and efficacy been studied, but additional research is of behavioral and hormonal therapies. needed. Future studies should include • In both basic and clinical populations, studies of sleep/wake measures during study interindividual, gender, racial/ethnic, drug withdrawal and during relapse to and age-related differences in baseline drug taking. sleep, circadian physiology, and responses • Morphine and similar opioid drugs cause to both prescription and nonprescription selective decreases in REM sleep through pharmacological agents. actions on brainstem cholinergic neurons, • Investigate acute and long-term sleep/ neurons known to participate in the wake consequences of all classes of initiation of this sleep state. This may abused drugs (including ethanol) as have relevance for the treatment of pain unique, self-administered pharmacologi- as well as for understanding treatment cal agents. Both clinical and basic studies efficacy of opioids in RLS. are needed. • Sleep effects of therapeutic psychostimu- • Encourage pharmacological studies lant treatment in ADHD in both adolescents of genetically/molecularly engineered and adults have received some attention, animal models for sleep disorders. Exist- but results are so far inconsistent. Also, ing genome databases can be used to gender differences have not been ade- elucidate sleep/wake-related response quately studied. Particularly in adults, to drug effects and to facilitate the underlying sleep/wake abnormalities discovery of new targets for sleep/wake have been reported in ADHD patients disorder medications. that can be exacerbated with medication, particularly dextroamphetamine. SECTION I—BASIC SLEEP SCIENCE 21
  28. 28. • Encourage development of state-of-the art technologies to measure the effects of drugs on sleep, circadian physiology, and alertness in animal models and human subjects (e.g., genomics, expression arrays, proteomics, neurochemical, chemical, imaging, encephalographic analysis, etc.). • Evaluate whether the identification and treatment of sleep disturbances can improve the clinical course of patients with alcoholism and other substance use disorders. 22 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
  29. 29. SECTION II RESTRICTED SLEEP: NEUROBIOBEHAVIORAL AND PHYSIOLOGICAL EFFECTS • Sleep Deprivation in Adults • Sleep Deprivation in Children and Adolescents
  30. 30. SLEEP DEPRIVATION IN ADULTS B ACKGROUND these few studies only a very small subset have included adequate and objective Studies on the effects of sleep loss on verification of compliance with the sleep neurobehavioral functions, especially neu- restriction regimen being studied. rocognitive performance, have two primary emphases: (1) specification of the properties Nevertheless, partial sleep deprivation is of tasks (e.g., cognitive versus physical; long more pervasive than total sleep deprivation. versus short duration) that make them sensi- Epidemiological studies suggest that mean tive to sleep loss; and (2) specification of the sleep duration has decreased substantially as aspects of performance (e.g., cognitive pro- proportionally more people are awake more cessing speed versus accuracy, declarative of the time. These decreases are due, in part, versus implicit memory processes) that are to expanded possibilities for nighttime activi- impacted by sleep loss. There has been con- ties that accompanied the introduction of troversy regarding the likely nature of sleep electric light and other technologies and to loss-induced performance deficits (e.g., the more recent trend toward expansion of whether they reflect true deficits in physio- both manufacturing and service sectors to logical function of the brain, a motivational 24-hour-per-day operations. Sleep restriction effect reflecting reprioritization of the rein- appears to be an almost inevitable conse- forcement hierarchy, an initiation of sleep quence of nighttime shift work. onset mechanisms in the face of waking performance, or some combination of these Because of the scarcity of chronic sleep processes). This controversy remains unre- restriction experiments despite a wealth of solved due to lack of understanding of the total sleep deprivation/performance studies, function(s) of sleep, the physiological pro- theoretical and practical questions remain: cesses affecting recuperation during sleep, and the neurobiology of sleepiness. • What are the physiological processes mediating neurobehavioral performance Implicit in this research has been the assump- deficits resulting from sleep loss? tion that total and partial sleep deprivation • What accounts for the wide individual produce qualitatively similar decrements in differences that emerge in the ability to brain function and/or motivation levels that maintain performance during sleep loss? differ only in degree. As a result, the over- whelming majority of studies in which the • Do the physiological and neurobehavioral relationship between sleep and performance responses to chronic partial sleep loss differ has been explored have utilized the more effi- from those resulting from total sleep loss? cient total sleep deprivation procedures, and very few studies have examined the effects • Relative to the adverse neurocognitive of chronic sleep restriction. Furthermore, of and physiological effects of sleep loss, SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 25