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    NHLBI SLEEP INT Final NHLBI SLEEP INT Final Document Transcript

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • • 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
    • SECTION I BASIC SLEEP SCIENCE • Circadian Biology • Sleep Neurobiology • Pharmacology and Pharmacogenetics of Sleep and Waking
    • 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
    • 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
    • • 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
    • 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
    • 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
    • • 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
    • 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
    • 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
    • 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
    • • 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
    • SECTION II RESTRICTED SLEEP: NEUROBIOBEHAVIORAL AND PHYSIOLOGICAL EFFECTS • Sleep Deprivation in Adults • Sleep Deprivation in Children and Adolescents
    • 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
    • is there habituation/adaptation or also continue to expand from the clinical potentiation/sensitization to repeated to the operational realm. exposure to sleep loss? Napping strategies and sleep scheduling • Are there physiological and/or behavioral will constitute at least part of any compre- adaptations or dysfunctions in sleep or hensive strategy to maintain alertness and circadian physiology in response to chronic performance during extended continuous sleep restriction (e.g., a change in sleep operations. Cell phones, beepers, and other itself or the brain’s recovery response to communication devices can put some chronically inadequate sleep)? workers in a perpetual “on-call” status in • Are the neurobehavioral and physiological which sleep might be interrupted by need effects of chronic partial sleep loss different for rapid decisions and/or other duty-related at different circadian phases? tasks. Studies of sleep inertia (and sleep in- ertia countermeasures), therefore, will be of • What are the physiological processes that increasing relevance and importance. Finally, affect restoration of cognitive performance exploration into the physiological effects of capacity during recovery sleep, and are acute and chronic sleep loss in vital organ these processes reflected in any currently systems other than the brain has only measured sleep parameters? just begun. • How much recovery sleep is required following chronic partial sleep loss versus P ROGRESS IN THE L AST 5 Y EARS total sleep deprivation? • Functional brain imaging studies and • What are the effects on neurobehavioral electroencephalographic (EEG) brain- functions of long-term (weeks, months, mapping studies show that the patterns years) exposure to a typical work or school of functional connectivity between brain schedule of 5 or more days of sleep restric- regions, evident during performance of tion followed by 2 days of recovery? specific cognitive tasks, are altered by sleep loss. This suggests that maintenance Research on sleep loss countermeasures in of performance during sleep loss may healthy adults, including pharmacological depend upon regional functional plasticity. and nonpharmacological interventions, such as napping strategies, has practical and • Recent experiments have documented theoretical relevance. Studies on the efficacy, precise dose-response effects of chronic long-term effectiveness, and safety of sleep restriction on waking neurobehavioral repeated use of traditional stimulants (e.g., and physiological functions, suggesting that caffeine, d-amphetamine, methylphenidate) the cumulative waking neurocognitive and novel wake-promoting agents (e.g., deficits and state instability that develop modafinil) for maintenance of performance from chronic sleep loss have a basis in a in healthy adults engaged in emergency neurobiological process that can integrate and/or continuous operations are needed. homeostatic pressure for sleep across days. Complementary studies of sleep-inducing • There have been increased efforts to and/or phase-shifting drugs (e.g., benzodi- determine the roles of rapid eye move- azepine agonists, melatonin) to enhance ment (REM) sleep and non-rapid eye sleep and subsequent alertness/performance movement (NREM) sleep in memory con- (e.g., shift work, transmeridian travel, or solidation, although definitive evidence recovery from continuous operations) will for such relationships remains elusive. 26 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Plasticity in visual cortices during a critical • Discover the physiological processes period in some animal studies is NREM mediating restoration/recovery of alertness sleep-dependent. This suggests that one and performance by sleep. This includes function of sleep is to facilitate the func- elucidation of the basic mechanisms that tional organization of the brain, and that contribute to the time course of recovery there are sleep-dependent aspects of puta- within and between days, as well as tively related processes such as long-term determining whether there are longer- potentiation (LTP) and DNA repair. duration time constants for reversal of the cumulative neurobehavioral deficits that • Genetic array techniques have identified accrue during chronically restricted sleep. the patterns of gene expression that characterize and differentiate sleep and • Determine whether and how factors such wakefulness. This information will help as cognitive activity/workload and physical in understanding the most basic cellular activity/work modulate sleepiness. processes mediating performance and alertness deficits following sleep loss, and • Identify factors accounting for individual the restoration of performance capacity differences in sleep need and in the and alertness during subsequent sleep. apparent differential vulnerability among people with similar sleep needs in their • Studies have identified those aspects of neurocognitive and physiological responses performance that are most susceptible to to sleep deprivation. Once the stability and sleep inertia, their differential time courses, reliability of these individual differences and have begun to identify sleep inertia are established, a search for stable and countermeasures (e.g., caffeine). reliable biological and behavioral predic- tors to establish a phenotype can then be investigated. R ESEARCH R ECOMMENDATIONS • Determine the physiological basis and • Determine the physiological and behavioral behavioral characterization of sleep processes mediating the state instability inertia effects, and study the compara- (manifested as increased variability in alert- tive effects of possible countermeasures ness and neurobehavioral performance) for sleep inertia. that result from acute versus chronic sleep loss. Compare these processes with those • Assess the physiological modulation mediating the alertness and performance of sleepiness by stimulant and wake- deficits that characterize pathologies promoting pharmacological agents, such as narcolepsy, Sleep-Disordered focusing on their sustained efficacy and Breathing (SDB) (see Section V), and safety for acute and chronic sleep depri- closed head injury. vation, the impact of repeated dosing, and the effect of these agents on re- • Identify the full range of psychological, covery sleep homeostasis and on the behavioral, and physiological (e.g., “recycle rate” (the speed with which endocrine, immune, cardiovascular, liver, full recovery from sleep loss is achieved, muscle, etc.) consequences of long-term preparing the individual for initiation of cumulative partial sleep deprivation and another episode of sleep restriction/ their underlying mechanisms. deprivation). SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 27
    • SLEEP DEPRIVATION IN CHILDREN AND ADOLESCENTS B ACKGROUND Empirical studies involving both normal and sleep-deprived pediatric populations Many fundamental questions regarding (e.g., children with sleep disorders, basic physiologic processes mediating sleepi- adolescents) have described the extent ness and alertness and the neurobiological and consequences of inadequate or dis- processes underlying the cumulative neuro- rupted sleep in children. A few studies have behavioral effects of chronic and intermittent examined mood, behavior, and performance sleep restriction are important in understand- changes resulting from acute sleep loss in ing their effects on the developing brain. Very children in experimental settings, but results little is known about the extent to which the have been inconsistent. Profiles of neuro- relative plasticity of neural systems in children behavioral and cognitive deficits related to affects their vulnerability to adverse neuro- chronic sleep loss and cumulative sleep debt behavioral, cognitive, emotional and physical in children are even less well defined, and consequences of sleep loss, and how sleep little is known about the functional impair- restriction affects a variety of neurodevelop- ments that can develop in “real world” mental processes. activities such as school performance, social relationships, behavior at home, Compared to adults, little is known about and extracurricular and safety-sensitive the magnitude and distribution, causes, activities (e.g., sports, driving). consequences, and assessment of sleep loss and sleepiness in children and adolescents. Furthermore, few studies have attempted Because the neurobehavioral manifestations to use neuroimaging or metabolic tech- of sleepiness in children may differ substan- niques in children and adolescents to tially from those of adults, the first challenge correlate changes secondary to sleep loss is to operationally define sleepiness in chil- with alterations in specific brain functions dren. Objective, reliable, and cost-effective known to occur in adults, e.g., complex measures of sleepiness and alertness in tasks modu-lated by the prefrontal cortex. children are lacking—particularly measures Despite potentially important adverse effects that could be applied to large epidemiologi- of sleep loss on neuroendocrine, metabolic, cal samples. In addition, subjective self-report immunologic, cardiovascular, and other data regarding sleepiness are largely unavail- physiologic systems in the developing able in children, and behavioral manifestations organism, the relationship between sleepi- of sleepiness not only vary with age and devel- ness and these physiologic parameters in opmental level but also are often not reliably children is largely unexplored. interpreted by parents and other caretakers. 28 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • An additional challenge is to examine vari- Neuropsychological profiles of impairment ables that may serve as relative risk-promoting have been less consistent, however, with or protective factors for the effects of sleep more reliable effects on attention/response loss in children, including those that may be inhibition, and variable effects on motor genetically determined. These variables may skills, memory, verbal creativity, problem yield important information about the solving, and general cognitive abilities. development of interindividual differences in vulnerabilities to sleep loss that extend R ESEARCH R ECOMMENDATIONS into adulthood. In addition, understanding these variables will allow definition of vul- • Establish the incidence and prevalence nerable populations, including racial and of chronic sleep loss and sleepiness in ethnic minorities and underserved children, children using objective, standardized, in whom early intervention may be necessary and cost-effective methods of assessing for maintenance of health and prevention of sleepiness and/or its functional conse- long-term sequelae. quences at all stages of maturational development. Specific vulnerable and P ROGRESS IN THE L AST 5 Y EARS at-risk populations for adverse conse- quences of sleep loss and sleepiness • Epidemiologic studies have begun to should be identified, as well as relative explore selected relationships between risks and protective factors for the ex- chronic partial sleep deprivation and pression of sleep-deprivation effects. sleep disruption related to primary sleep The biological and behavioral factors disorders, mood and performance deficits that result in sleep loss in children and in children and adolescents, and academic adolescents also need to be identified. failure. Studies of sleep in children with primary behavior and learning problems • Identify deficits in specific neuropsycho- have further supported an association logical domains and patterns of impair- between sleep restriction and performance ment resulting from acute and chronic impairments. Evidence indicates that chil- sleep loss in children at various develop- dren experience significant daytime sleepi- mental stages, including higher level ness as a result of disturbed or inadequate cognitive processes, such as attention, sleep, and most studies suggest a strong motivation and emotional regulation. link between sleep disturbance and Neuroimaging and other novel tech- behavioral problems. niques should be utilized to examine the neurophysiologic effects of sleep • Studies delineating the neurobehavioral, loss on cognition and performance cognitive, and emotional effects of sleep in the developing human. loss in experimental settings in adoles- cents and older school-aged children • Examine the bidirectional effects of have broadened our understanding of sleep loss and sleepiness on the immune, the similarities and differences that exist neuroendocrinologic, metabolic, cardio- between adults and children and between vascular, and other physiologic systems, children of different ages. Decreased and identify developmentally appropri- positive mood in association with sleep ate biologic markers for the effects of disturbance is a consistent finding. sleep loss. SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 29
    • SECTION III ENABLING TECHNOLOGY • Analysis of Sleep-Wake States • Genetics and Proteomics: Phenotype Issues and Methodological Approaches • Functional Neuroimaging of Sleep and Wake States • Post Mortem Brain Analysis in Sleep Disorder Patients
    • ANALYSIS OF SLEEP-WAKE STATES B ACKGROUND adverse outcomes such as neurocognitive impairment or cardiovascular disease). The monitoring of sleep states is accomplished As a result, new methods to both measure using several electroencephalographic (EEG) and quantify SDB and its consequences leads in combination with electrooculographic are needed. (EOG) and submental electromyographic (EMG) signals. These variables are scored in Currently utilized methods for recording combination using a system described by sleep and breathing not only have the quan- Rechtschaffen and Kales (R and K) in the titative problems described above but are early 1960s to yield non rapid eye movement also cumbersome and expensive. They do not (NREM) stages 1 to 4 sleep and rapid eye allow for the evaluation of large populations movement (REM) sleep. Although this system suspected of having potential sleep disorders has been useful, it also has weaknesses. The or for the completion of substantial epidemio- principal weakness is the inability to easily logic evaluation of normal or at-risk popula- detect and quantify microarousals or subtle tions. Simple, noninvasive methodologies to disruptions of sleep. Thus, the full impact of directly or indirectly monitor sleep, respiration, many sleep disorders on sleep architecture and other physiologic variables thus need cannot be meaningfully quantified. In addition, to be developed both for the screening measures of sleep staging, sleep continuity, and diagnosis of sleep disorders and for and sleep disruption do not accurately predict epidemiologic investigation. subsequent performance. Although there are several possible explanations for this poor P ROGRESS IN THE L AST 5 Y EARS relationship, the limitations of the R and K, despite new definitions applied to it, preclude • Meaningful standardization of the measurement of sleep micro-architecture and methods, equipment, and definitions its disruptions. Therefore, new methods are for SDB and associated syndromes has needed to monitor and quantify sleep. been accomplished. The quantification of breathing abnormalities • Numerous studies, ranging from a during sleep also presents a unique challenge. single signal (generally oximetry) to full Until recently, there were no standard defini- polysomnography, have investigated tions of apneas, hypopneas, or the clinical simplified systems to measure sleep syndromes associated with these events. and respiration in the home, but have However, even after the standardization of yielded varied results. However, none of equipment, measurement techniques, and these approaches has been sufficiently definitions, the current methods of assess- effective to be commonly utilized in ment of Sleep-Disordered Breathing (SDB) routine clinical practice. seem to predict little regarding associated SECTION III—ENABLING TECHNOLOGY 33
    • • New assessments of EEG signals • Portable ambulatory systems to measure (primarily frequency analyses) and sleep and other physiologic variables heart rate variability have provided (respiration, leg movements, etc.) reliably new insight not only into sleep itself, in the home environment are needed. but also into the consequences of These systems should be inexpensive, sleep disruption. easy to use both for screening and for diagnosis of sleep disorders, and be R ESEARCH R ECOMMENDATIONS applicable for large-scale epidemiologic studies. Furthermore, these systems • New methods are needed to measure should measure variables that are and quantify the structure of sleep. outcome-focused such that the These methods should be outcome results can be utilized to both predict focused such that what is measured consequences and define the need predicts not only the restorative processes for therapy. of sleep, but also the results of disrupting • New methods are needed to define this process. Sophisticated, computer- circadian phase in the clinical setting based signal-processing methodologies such that the role of circadian abnor- should be applied, using both linear malities in disorders such as insomnia and nonlinear dynamic approaches. can be determined. Such methods The result should be a quantitative would also allow for more precise assessment of both the macro and manipulation of circadian phase micro structure of sleep. when appropriate. • New approaches are needed for the measurement, assessment, and quanti- fication of physiologic/biologic variables during sleep. Such methods should be easily accomplished to permit broad applicability, quantitative, and predictive of the consequences of the sleep disorder under assessment. The focus should be on novel, noninvasive approaches that do not require labor-intensive, expensive scoring, perhaps including microtech- nology, should be. 34 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • GENETICS AND PROTEOMICS: PHENOTYPE ISSUES AND METHODOLOGICAL APPROACHES B ACKGROUND many candidate genes. Sequencing of candidate genes may not yield mutations Sleep behavior is extremely variable across or may identify mutations that are not and within animal species, suggesting the relevant to the phenotype. In this case, importance of genetically based differences. the use of complementary approaches such Limited genetic epidemiological data indi- as DNA expression arrays and proteomics to cate that many sleep disorders have a strong identify novel genes of interest may be a genetic component. Advances in genetics powerful approach to identify relevant and genomics have been spectacular and candidate genes. include sequencing the genomes of various organisms and high-throughput studies using Molecular correlates of sleep and diurnal genetic arrays and polymorphic markers. rhythms would be important for a wide Animal models of sleep and circadian dis- range of clinical studies. Much human orders with selected genetic alterations are research relies on blood samples, which now being generated. Similar developments are easily obtained, but often there is little in the area of protein characterization and knowledge about chronobiologic variations the more general field of proteomics are in the parameters being measured, and no now rapidly developing. The field of sleep regard for the time of day or the sleep disorders medicine is now well-positioned to history of the subject when the sample is take advantage of these new technologies. taken. The impact of sleep and diurnal variation on other systems is exemplified A solid foundation in the area of phenotyp- by blood coagulation and thrombotic ten- ing sleep and its disorders in both animals dencies. Myocardial infarctions or strokes and humans is needed before proceeding occur more often in the morning, and blood with genetic analysis. The discovery of new properties such as platelet aggregation may methods and improvements in existing sleep change during the day. It would be useful recording techniques in humans are also to have molecular markers to assess chrono- needed. When performing genetic studies, biologic and sleep history variability. it is important to consider potential study design limitations. The strength and location P ROGRESS IN THE L AST 5 Y EARS of linkage regions identified, for example, depends on the strength and precise pheno- • There have been advances in technology type selected. Thus, linkage regions may development in the area of sleep pheno- not be identified if the power of the study typing in mice. In the clinical arena, sleep is insufficient, and large numbers may be recording devices have been made more required for such studies to be successfully portable and easier to use. Similar progress accomplished. Even if linkage regions are has been made in automated sleep scoring identified, these may be large and contain SECTION III—ENABLING TECHNOLOGY 35
    • algorithms that utilize concepts such as • Genome screening and genetic asso- neural networks, fuzzy math, and wavelet ciation studies have been initiated in fitting, allowing for more rapid analysis Sleep-Disordered Breathing (SDB) and and the possibility of high-throughput Restless Legs Syndrome (RLS) (see Section sleep phenotyping. V). Significant linkage results have been reported and await confirmation. In the • Eight genes that significantly contribute candidate gene area, an association to the generation of circadian periodicity between APOE e4 and sleep apnea have been isolated in mammals. Recently, has been reported and will need to studies in humans have shown, for the be replicated. first time, a correspondence between human and animal sleep phenotypes. R ESEARCH R ECOMMENDATIONS Most strikingly, a mutation in the gene HPER2—a gene known to be involved in • Develop new methods to measure sleep, the regulation of circadian rhythmicity in circadian physiology, and sleepiness in mammals—was demonstrated to cause large numbers of animals and human Familial Advanced Sleep Phase Syndrome subjects. One goal is to develop and (FASPS) in a human family. Additionally a validate surrogate measures. Another polymorphism in CLOCK, another gene goal is to define normal sleep-pattern involved in the generation of circadian variation in the general human population. rhythmicity, was found to influence Normative data will also be critical to define morningness-eveningness tendencies in and validate existing or novel sleep disorder humans. These studies are likely to be phenotypes. These data will be needed to extended and lead to discovery of other elucidate corresponding genetic factors. human mutations and polymorphisms affecting circadian regulation. • Continue the study of animal models, such as the fruit fly, zebra fish, and mice • Similar progress has been made using to enhance our understanding of physi- a genetic approach in narcolepsy (see ology and circadian biology. Use of these Section V). Using a positional cloning models to study sleep or the regulation approach, mutations in the hypocretin of rest/activity should be a priority, as this receptor 2 gene) have been isolated in a may lead to the discovery of novel sleep- canine model of narcolepsy. The knocking- regulatory pathways. Powerful new out of preprohypocretin, a gene initially genetic approaches, such as those used believed to be involved in appetite regula- to discover circadian clock genes (e.g., tion, led to the establishment of a murine mutagenesis screens), can be used to find model of narcolepsy. These findings were new genes that are involved in the homeo- found to be directly applicable to human static need to sleep and in interactions narcolepsy-cataplexy, as it has been now between the circadian and sleep-wakeful- shown that most patients have a hypo- ness systems. Other approaches, such as cretin deficiency. This last finding is “quantitative trait loci,” should be consid- remarkable as the disorder in humans is ered insofar as true “sleep knockouts” genetically complex and HLA-associated. may be not viable in mutagenesis screens. These results demonstrate the importance of careful phenotyping of human sleep • Identify new disease phenotypes, including disorders to reduce disease heterogeneity rare familial sleep disorders or subtypes of and the importance of animal models. current sleep disorders based on treatment 36 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • response or other characteristics. The study • Genetic array and proteomic studies of multiplex families where sleep disorders in selected tissue samples or protein- appear to be segregating as a single gene protein interaction experiments should could lead to the positional cloning of be encouraged. These new techniques novel sleep disorder-related genes. This can be extremely useful to discover may facilitate our understanding of other, novel components within a molecular more common sleep disorders, as well as or a disease pathway. increase our understanding of the normal physiology of sleep. • Mouse models are increasingly used in genetic and behavioral studies, and • Study interindividual differences in have been created but not yet widely baseline sleep, circadian physiology and utilized in narcolepsy. A large number of response to sleep deprivation in a large mice with various genetic alterations are number of subjects to better define being created in multiple laboratories but normal and pathological conditions. are rarely tested for sleep abnormalities. Recent results indicate large interindividual Finding sleep abnormalities in some of differences in how people react to sleep these models could lead to the discovery deprivation. Additionally, subjective sleepi- of novel sleep regulating pathways that ness varies significantly in patients with may be involved in selected sleep disorders. equivalent degrees of SDB and sleep To remedy this situation, there is a need fragmentation. The study of these inter- for developing and distributing genetically individual differences has both clinical determined animal models for sleep dis- and basic research relevance. orders. Collaborative efforts should be explored to phenotype sleep in mice • Twin prevalence and segregation analysis models for investigators that are work- studies need to be conducted for all sleep ing outside of the field of sleep research. disorders across various populations in order to estimate heritability and envi- ronmental contributions for each sleep disorder. This will help prioritization and design of further genetic studies. • Genome screening studies using classical family design and candidate gene-based research should be continued and ex- tended. Since most sleep disorders are genetically complex, large numbers will be needed and there is a need to encourage the blending of epidemiological and genetic designs. Ethnic variation in the expression and the genetic basis of various sleep dis- orders has been identified and will require further exploration. Studies of SDB, RLS, and other disorders such as hypersomnia will benefit from this approach. SECTION III—ENABLING TECHNOLOGY 37
    • FUNCTIONAL NEUROIMAGING OF SLEEP AND WAKE STATES B ACKGROUND during functional challenge. Furthermore, these techniques are likely to enhance Although the physiological and adaptive identification of both normal and abnormal functions of sleep remain to be clarified, sleep/wake processes. it is clear that sleep and wakefulness are neurologically mediated. Sleep researchers P ROGRESS IN THE L AST 5 Y EARS have employed behavioral observations, clinicopathologic observations, correlative • Functional neuroimaging techniques studies with polysomnographic measures, (primarily PET) reveal that non-rapid eye and extrapolations based on invasive research movement (NREM) sleep is associated with in non human subjects in order to characterize deactivation of centrencephalic regions and understand the brain processes mediating (brainstem, thalamus, basal ganglia) and and constituting sleep and wakefulness. Each multimodal association cortices (e.g., of these approaches continues to yield new prefrontal and superior temporal/inferior knowledge about sleep and the brain, and parietal regions). Rapid eye movement each provides a unique view, or “level of (REM) sleep is characterized by reactivation analysis,” of sleep and brain functioning of all centrencephalic regions deactivated ranging from the behavior of single neurons during NREM sleep except the multimodal to the behavior of the entire organism. The association areas. Thus, deactivation of ultimate result of this multifaceted approach the multimodal association areas has is likely to be a comprehensive and coherent been shown to be a defining character- understanding of sleep. istic of sleep. Functional brain imaging techniques, such • PET studies during sleep-deprived wakeful- as positron emission tomography (PET), ness reveal regional cerebral deactivations functional magnetic resonance imaging that are especially prominent in prefrontal (fMRI), Magnetic Resonance Spectroscopy and inferior parietal/superior temporal (MRS), single photon emission computed cortices, and in the thalamus. These tomography (SPECT), magnetoelectroen- patterns are similar to that found during cephalography (MEG), and near-infrared NREM sleep, but the deactivations are of optical imaging (NIR) have enabled new lesser magnitude than during NREM sleep. and unique analyses in the study of sleep This pattern is consistent with, and helps and waking. These techniques allow measure- explain, the nature of cognitive perform- ment of metabolic and neurochemical activity ance deficits that occur during sleep loss. throughout the brain, and can discern dynam- Considered together with results of sleep ic patterns of regional cerebral activity during studies, this pattern suggests that NREM various brain states, including stages of sleep sleep initiation and sleep-deprived wakeful- and levels of alertness during wakefulness or ness in healthy individuals are manifesta- tions of related neurobiological processes. 38 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Relative activation/deactivation patterns R ESEARCH R ECOMMENDATIONS revealed by fMRI techniques during per- formance of cognitive tasks suggest that • Perform neuroimaging studies that maintenance of performance following measure absolute as well as relative sleep loss may be a function of the extent changes in brain metabolic activity and to which other cortical brain regions can neurotransmitter levels. Such studies are be recruited for task performance in the needed to: (1) determine the effects of sleep-deprived state. This is one of a sensory and cognitive demands on subse- number of possible ways that individual quent levels and patterns of regional brain differences may occur in the ability to activity during both sleep and wakefulness maintain alertness and performance and as a function of state changes, and following sleep loss. (2) to establish the functional neuro- anatomy of sleep, wakefulness, alertness, • PET, SPECT, and fMRI studies reveal and cognitive capability. that a subset of depressed patients show initially elevated activation in • Apply the enhanced capabilities afforded anterior cingulate and medial orbital cor- by improved functional neuroimaging, tices. In these patients, sleep deprivation including greater temporal and spatial reduces this regional hyperactivation, and resolution, to study sleep and sleep dis- improvements in mood are a function of orders. These applications will help to the extent to which this activity is reduced. determine the physiological correlates of These studies suggest possible mechanisms phasic events like eye movements during by which antidepressant drugs may exert REM, sleep-dependent changes in activity their effects. levels of specific thalamic nuclei, and brain changes subserving microsleeps and lapses • PET scans reveal that the midbrain reticu- of attention. lar activating system remains relatively active during stage 2 sleep—a finding • Utilize functional neuroimaging techniques that may account for the relatively height- to determine the functional neuroanatomy ened arousability that characterizes this of REM sleep, NREM sleep, and waking in stage of sleep. patients in sleep disorders such as narco- lepsy, REM behavior disorder, and Restless • PET scans taken at 5 versus 20 minutes Legs Syndrome. Such studies will yield after awakening suggest that reemergence insight into the pathophysiology of these of conscious awareness upon awakening disorders. Similar studies in patients with occurs as a function of centrencephalic other disorders known to impact sleep reactivation, and reestablishment of a processes (e.g., depression, chronic pain specific pattern of functional interconnec- conditions) will yield insight into the tivity between brain regions. These data pathophysiology of these disorders. also suggest that restoration of alertness (e.g., dissipation of sleep inertia effects) • Determine the effects of sleep and alert- occurs as a function of reactivation and ness-promoting pharmacological agents reestablishment of functional intercon- on patterns of regional brain activation/ nectivity patterns involving prefrontal deactivation and on occupancy/activation cortices. These findings could constitute at specific receptor sites. Such studies will an important first step toward specification elucidate the mechanisms by which these of the physiological basis of post-sleep agents impact sleep/wake processes, and waking cognitive capability. will facilitate the development of new SECTION III—ENABLING TECHNOLOGY 39
    • agents that might more specifically target sleep/wake-relevant sites and receptors. • Develop new approaches to obtain polysomnographic measures and other physiological signals during MRI scanning to facilitate the study of sleep and alertness unaffected by electromagnetic interference from the MRI scanner. 40 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • POST MORTEM BRAIN ANALYSIS IN SLEEP DISORDER PATIENTS B ACKGROUND a devastating disorder whose basic mechan- ism(s) has been elusive. The post mortem study of brains of patients with sleep disorders has significantly con- Sudden Infant Death Syndrome (SIDS) repre- tributed to our understanding of human sents a sleep disorder in which neuropatholog- sleep regulation and its dysfunction. Human ic examination with modern neurochemical brain analysis at autopsy in sleep disorders techniques suggests abnormalities in a specific is important for two major reasons: (1) it brainstem region and neurotransmitter system, generates hypotheses from observations namely the medullary serotonergic system). directly in human tissues about the cellular These findings from human infant brains will and molecular mechanisms of human disease generate hypotheses to be tested in animal for testing in animal models, cell culture sys- models. Narcolepsy, on the other hand, repre- tems, and genetic models; and (2) it tests the sents a sleep disorder in which seminal obser- relevance to human disease of observations vations in genetic animal models resulted in made in animal models and cell culture subsequent delineation of the neuropathology systems by examining specific cellular and in affected human patients, e.g., deficiencies molecular markers in human tissue samples. in the hypothalamic hypocretin system. Currently, human neuropathology involves These two examples underscore the critical analysis at the structural, neurochemical, need to analyze the human brain at autopsy in cellular, and molecular levels, and its modern patients with sleep disorders. National autopsy tools hold promise of much-needed insights networks and brain tissue banks may be need- into central and autonomic mechanisms in ed to collect brain tissues from patients with sleep disorders. A potentially revolutionary common, rare, or non-lethal sleep disorders, tool for human brain analysis is microarray and to disseminate affected and control brain analysis of gene expression in autopsied samples to interested sleep researchers. Some tissues. The potential of this genomic tech- national, NIH-supported brain tissue banks are nology in human neuropathology to uncover well established, and have proven vital to the critical molecular abnormalities is illustrated success of human brain research in neurode- by its recent application to post mortem brain generative disorders such as Alzheimer’s dis- analysis in schizophrenia. With cDNA micro- ease and genetic disorders such as Rett syn- arrays, altered gene expression was found in drome). An informal survey of national brain the frontal cortex in schizophrenic patients tissue banks, however, reveals virtually no compared to autopsy controls. The most accrual of brains from patients with any pri- changed gene, which was never before mary sleep disorders except SIDS. Specialized linked to schizophrenia, was a regulator training of neuropathologists in the neu- of G-protein signaling 4, suggesting schizo- roanatomy, neurochemistry, and neuropatholo- phrenia is a disease of the synapse and thus gy of sleep will be needed, however, to make providing an opportunity to better understand optimum use of this new research resource. SECTION III—ENABLING TECHNOLOGY 41
    • P ROGRESS IN THE L AST 5 Y EARS R ESEARCH R ECOMMENDATIONS • The neuropathologic post mortem evalua- • Utilize established national brain tissue tion of brains in patients with narcolepsy banks for increased accrual and dissemi- confirmed observations from animal models nation of brain samples and associated that the major lesion is in the hypocretin histories from patients affected by both neurons of the lateral hypothalamus. A primary and secondary sleep disorders reduced number of hypocretin neurons, (see Section V). The spinal cord should associated with gliosis, was reported in be likewise stored in certain cases in which the hypothalamus of human patients with spinal cord involvement is postulated, e.g., narcolepsy, as well as, in a separate study, Restless Legs Syndrome. The accrual of the absence of hypocretin mRNA in the central nervous system (CNS) samples hypothalamus and lack of hcrt-1 and from control cases without sleep hcrt-2 levels in the cerebral cortex and disorders will also be needed. pons (target sites). • Establish a National Autopsy Network • The neuropathologic post mortem evalua- for Sleep Disorders, and perhaps Centers tion of brains in patients with Fatal Familial for individual sleep disorders, in order to Insomnia (FFI), a prion disorder, established assure accrual of brains from patients with that the major lesions are in certain subnu- sleep disorders, including those that are clei of the thalamus that are interrelated to rare and/or non-lethal. Such a network, the limbic system, and suggested a specific for example, would alert pathologists role for these thalamic regions in sleep and that the brain of an individual with Sleep- autonomic control that can now be tested Disordered Breathing (SDB) or insomnia in animal models. dying of an unrelated cause is of interest to sleep scientists and should be obtained • Neuropathologic insights from analysis and processed as needed for neuropatho- of SIDS and control brains at autopsy logic analysis. Blood, cerebrospinal fluid revealed that a substantial subset of SIDS (CSF), and brain and spinal cord tissues victims have abnormalities in serotonergic should be collected in addition to a receptor binding in regions of the medulla detailed sleep history. involved in chemoreception, respiratory drive, blood pressure responses, and • Apply state-of-the-art neurochemical, upper airway control. Dysfunction of cellular, and molecular markers to the serotonergic neurotransmission in the study of sleep disorders in human brain medulla in affected infants may put them tissue, especially those without a pathol- at risk for sleep-related sudden death ogic correlate at the light microscopic when stressed by hypoxia and/or hyper- level. Techniques should include gene carbia in a critical developmental period. expression microarray technology, pro- tein analysis with mass spectroscopy, • Neuropathologic post mortem analysis tissue receptor autoradiography, in situ in patients with dementia and REM hybridization for mRNA in tissue sections, Behavior Disorder (RBD) revealed an immunocytochemistry with single and association between Lewy body dementia double labeling, stereological cell count- and RBD. Lewy bodies were present in ing, and electron microscopy combined affected patients in regions of the brain- with immunological markers. stem involved in arousal, REM sleep, and autonomic control. 42 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Apply state-of-the-art genomic approaches • Ensure neuropathology limbs to large, to post mortem brain analysis for novel multi-institutional studies of human sleep gene discovery and gene expression profil- disorders for analysis and storage of speci- ing in sleep disorders. Possible approaches mens (e.g., brain, CSF, blood), and for include microarrays, quantitative real-time correlation of neurochemical, cellular, PCR assays, and serial analysis of gene and/or genetic markers with clinical expression (SAGE). These methods, among pathophysiology. many others, provide information about normal and abnormal gene expression • Analyze the spatial and temporal profiles in a tissue or cell. Details must be refined of sleep-related molecules across devel- regarding applicability of this technology opment including aging in relevant brain in human brain tissues with variable agonal regions (e.g., hypothalamus, basal fore- conditions (e.g., pH changes) and post brain, brainstem, thalamus, cerebral mortem intervals. The methods for relating cortex) in human post mortem brain. expression data to disease-model databases and gene sequence databases (e.g., single nucleotide databases) will also require refinement. Multifactorial and multilevel analyses will need to combine massive gene expression datasets with the clinical diagnosis, medication, family history of the illness, and genetic heritage of each subject. SECTION III—ENABLING TECHNOLOGY 43
    • SECTION IV SLEEP AND HEALTH • Normal Sleep, Sleep Restriction, and Health Consequences • Sleep, Sex Differences, and Women’s Health • Racial and Ethnic Disparities • Sleep and Aging • Sleep and Safety • Sleep in Medical Conditions
    • NORMAL SLEEP, SLEEP RESTRICTION, AND HEALTH CONSEQUENCES B ACKGROUND to good health, and public health agencies have no way of knowing whether there are Government publications, such as “Healthy population shifts in the quality and quantity People 2000” and its sequel “Healthy People of sleep obtained by different age groups. 2010,” contain recommendations for ade- quate nutrition and physical fitness for healthy Descriptions of sleep phenotypes and defini- functioning, but no recommendations or stan- tions of normal sleep patterns and require- dards for normal sleep duration and quality. ments must incorporate the wide range of Epidemiological data have never been normal developmental and physical matura- obtained defining normal sleep and wake- tional changes across the life span. Although fulness as measured systematically by both cross-sectional studies yield important infor- subjective and objective indicators in infants, mation regarding sleep in discrete age groups, children, adolescents, young adults, middle- they do not address the evolution and persis- aged and older adults. Only limited elec- tence of sleep/wake patterns across time. troencephalographic (EEG) sleep data as a There is a need to understand the complex function of age and gender are available reciprocal relationship between sleep and from laboratory studies published more than cognitive/emotional development from the 25 years ago. Data used to describe “normal” prenatal period through adolescence and EEG sleep from infancy to old age were based through adulthood. Prospective longitudinal on 1 or 2 nights of sleep recordings in a small studies utilizing validated screening and number of subjects in a laboratory setting. assessment tools are thus needed to deline- Most of these studies were conducted prior ate the development of sleep patterns and to the establishment of accepted sleep moni- behaviors and to generate predictive models. toring and scoring standards. In fact, the most widely used reference of “normal” P ROGRESS IN THE L AST 5 Y EARS human EEG sleep is based on studies in which EMG recordings were not used in the Sleep and Environment scoring of rapid eye movement (REM) sleep. • Sensory stimulation resulting from environ- Despite beliefs about the importance of mental noise, light, motion, temperature, sleep for health and normal growth and and even odors can produce activation development, there are no standards of sleep at levels antithetical to the initiation and physiology based on current polysomnographic maintenance of sleep. Thus, sleep envi- criteria. Furthermore, there is no comprehen- ronments in which sensory stimulation sive database defining normal sleep-wake is minimal (e.g., dark, quiet, comfortable behavioral patterns by age or sex across the temperature) tend to be preferred subjec- life span. Thus, health care providers have no tively and tend to enhance sleep initiation normative reference for comparison with an and maintenance. individual’s sleep pattern alone or as it relates SECTION IV—SLEEP AND HEALTH 47
    • • Recent efforts by some hotels to offer – Environmental noise/light: Ambient rooms that are especially conducive to noise and vibration have occasionally sleep, and by some transportation indus- been studied as factors improving or tries to improve the sleep environments impairing sleep quality, but little is of both customers and employees, reflect known regarding the extent to which recognition of the importance of sleep various types of noise and vibration and a sleep-conducive environment. affect sleep. A few experiments have found that light at night can enhance • Despite knowledge of the importance of alertness, and that properly timed light environmental variables for sleep quality exposure can hasten phase shifts of and duration and of considerable varia- circadian biology (e.g., shift workers). tions in sleep environments across ethnic There have been no studies, however, and socioeconomic strata, there has been to determine whether turning on room little scientific investigation of environmen- lights at night adversely affects sleep tal factors potentially critical for healthy quality or quantity. sleep and waking. Subjects requiring scientific investigation include: – Health disparities and vulnerable populations: Socioeconomically dis- – Cosleeping or bed-sharing (sleeping advantaged populations may be more with one or more other persons in likely to sleep in environments that are the bed): Although evidence suggests hot, humid, cold, noisy, and/or crowded. that the somesthetic stimulation resulting There has been no systematic study of from bed-sharing can have a negative the effects of these factors on sleep effect on sleep continuity and architec- quality and quantity either alone or in ture, the relative benefits and adverse combination, and no study of potential consequences of this practice have not effects of these factors on waking func- been adequately explored. tions including school and work perform- – Sleep location: Sleep at home versus ance. Children and adolescents, the sleep in public places in which control elderly, and shift workers are popula- over environmental stimulation is mini- tions who may be especially vulnerable mal (e.g., on an airplane), or in the to the adverse effects of environmental work environment (e.g., sleeper berths variables on sleep quantity and quality. on trucks, trains, and planes). It is important to determine the extent to – Sleep position: This has been deter- which each of these environmental factors mined to be important in Sudden Infant affect sleep quality and contribute to sleep Death Syndrome (SIDS) and in modu- loss, sleep pathology, daytime sleepiness, lating the severity of Sleep-Disordered and daytime functioning. Scientific data Breathing (SDB), but sleep position has in these areas would be fundamental to not been studied relative to the potential answer questions regarding the determi- for sleep fragmentation (e.g., sleeping nants of a good night’s (or day’s) sleep. semi-recumbent versus fully recumbent). – Sleep surface: Virtually ignored in sleep science, many consider optimal sleep surface to be crucial to obtaining a good night’s sleep. 48 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • Health Consequences of Insufficient diabetes, obesity, heart disease, and Sleep and Chronic Sleep Debt depression. Findings from a recent study of young adult men placed on a restricted • Adequate sleep is essential for healthy sleep schedule of 4 hours each night for 6 functioning and survival. Inadequate sleep consecutive nights showed altered metabo- and unhealthy sleep practices are common, lism of glucose with an insulin resistance however, especially among adolescents and pattern similar to that observed in elderly young adults. In the 2002 National men. The implications from this study, Sleep Foundation annual survey, nearly if replicated, are that chronic sleep loss 40 percent of adults ages 30 to 64, and may contribute to obesity, diabetes, heart 44 percent of young adults ages18 to 29 disease, and other age-related chronic reported that daytime sleepiness is so disorders. As promising as these data are severe that it interferes with work and for providing solid scientific evidence of the social functioning at least a few days each health consequences of chronic insufficient month. Excessive daytime sleepiness is a sleep, most people report habitual night- major public health problem associated time sleep in the range of 6 hours. Data with interference with daily activities, are needed to determine the extent to including cognitive problems, motor which habitual sleep durations of 6 to vehicle crashes (especially at night), poor 8 hours are associated with increased job performance, and reduced productivity. disease risk in men and in women. Optimum daytime performance with mini- mal sleepiness in adolescents and young adults appears to require at least 8 to 9 Sleep Duration and Quality: hours of sleep at night with few inter- Relationship to Morbidity and Mortality ruptions. A majority of adolescents and • The relationship between sleep (quantity adults, however, report habitual sleep and quality) and estimates of morbidity durations of fewer than 7 hours per night and mortality remains controversial. Data during the week and fewer than 8 hours from epidemiological studies suggest that of sleep each night on weekends. a habitual short sleep duration (less than 6 hours of sleep per night) or long sleep • The beneficial effects of healthy sleep duration (more than 9 hours of sleep per habits and the adverse consequences of night) is associated with increased mortal- poor or insufficient sleep have not been ity. A recent epidemiological report found well studied. Sleep is essential for survival, that self-reported sleep duration averaging yet only in the last decade has scientifically either less or more than 7 hours of sleep credible, experimentally based data from daily was associated with higher mortality. humans been gathered on dose-response It is not clear how sleep duration increases relationships between chronic restriction risk. Moreover, although such epidemio- of sleep by 1 to 4 hours a night and accu- logical studies have used very large con- mulating daytime sleepiness and cognitive venience samples, they have relied on impairments. Most individuals develop retrospective self-report, the least accu- cognitive deficits from chronic sleep debt rate index of sleep. after only a few nights of reduced sleep quality or quantity, and new evidence sug- • There have been no epidemiological gests additional important health-related prospective studies examining the relation- consequences from sleep debt related, ship between sleep and health outcomes for example, to common viral illnesses, (morbidity and mortality) that included SECTION IV—SLEEP AND HEALTH 49
    • estimates of sleep based on both subjec- – How are patterns of growth and tive and objective measures. Past practices development from infancy to ado- of adding questions about habitual sleep lescence and from adolescence to duration to large epidemiological studies adulthood negatively impacted by designed to answer questions about, for insufficient sleep? example, the relationship between nutri- tion and risk for heart disease or between – What is the influence of prematurity smoking and cancer risk are not sufficient. on the development of sleep patterns? Although studies of sleep patterns and Do infants considered “poor” or behavior would be prohibitively expensive “problem” sleepers develop insomnia and require multiple sites with subjective as children and/or adults? and objective measures of sleep in a very – What sleep patterns in young and large sample, important questions regard- middle-aged adults predict good ing the relationship between sleep duration quality sleep in the elderly? Is the and quality and morbidity and mortality amount of sleep more important than can only be addressed through such large the time of day when sleep occurs? studies. Furthermore, recent studies have shown that sleep duration of at least 8 – Do daytime naps make up for lost hours is necessary for optimal performance sleep at night? and to prevent physiological daytime sleepi- ness and the accumulation of ”sleep debt.“ – What are the health consequences of Findings from these and other studies can long-term exposure to chronic sleep only be reconciled with data suggesting restriction such as those imposed by that habitual sleep durations of eight hours a typical work or school schedule are associated with higher mortality by a of 5 or more days of sleep restriction large comprehensive study of the effects followed by 2 days of partial recovery? of sleep on health and risk for disease. – Does the duration of recovery sleep, or the timing of recovery sleep in the daily Without knowledge of what needs sleep cycle, or both, determine the benefits fulfills or what sleep patterns (duration and of sleep for healthy functioning? quality) best predict health (or morbidity and mortality), it is very difficult for sleep – How much recovery sleep is required researchers and clinicians to answer ques- following exposure to chronic sleep tions such as: restriction in order to restore physio- logical and neurobehavioral capability – What are normal sleep patterns? to baseline? – How much sleep is needed by infants, – Does habituation/adaptation in the children, teenagers, adults, and the body’s physiological systems develop elderly for healthy functioning? to sleep loss or chronic sleep restriction and at what cost to one’s health? – What is the minimum amount of sleep required for optimal function- – How important are environmental ing and for health? variables, such as sleep surface and light, in affecting sleep quality – How much of the patterning of and quantity? sleep is genetic and how much is environmental? 50 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • R ESEARCH R ECOMMENDATIONS • Identify how sleep disturbances in early childhood impact cognitive and social • Epidemiological longitudinal studies to development, behavior and performance, define normal sleep behavior (timing, as well as subsequent development of duration, quality) and phenotypes using sleep disorders in adolescents and adults. state-of-the art objective and subjective technologies. Such studies are needed • Studies to identify and evaluate counter- across the life span and especially in measures and novel approaches to prevent vulnerable populations, and should sleep deprivation in children and adults. focus on the transition from infancy Countermeasures to improve the sleep to adolescence, adolescence to middle of shift workers, especially daytime sleep age, and middle age to advanced age. after the night shift, are needed. Practical Prospective studies representing the methods need to be developed to phase diversity of human cultures are needed shift circadian rhythms to align with to define normal sleep phenotypes across daytime sleep. Factors in need of study cultures and in different ethnic and socio- include: work and sleep schedule combi- economic groups. nations, light exposure during night shifts (intensity, timing, duration, wavelength), • Epidemiological longitudinal studies to and daylight exposure following comple- prospectively assess the relationships tion of the night shift. among sleep duration (short and long), sleep quality (good and poor), and health • The effects on sleep physiology and day- outcomes (morbidity and mortality). There time functions of relevant environmental is a need to determine the incidence and variables (in isolation and combination) prevalence of “sleep debt” in vulnerable need to be investigated, especially in populations including children, adolescents, vulnerable populations such as children, young adults, shift workers, new parents. adolescents, the elderly, the socioeco- those exposed to prolonged work hours, nomically disadvantaged, and shift those of low socioeconomic status. There workers. Factors to study include sleep- is also a need to determine the functional ing alone versus sleeping with one or and health-related consequences of sleep more other persons in the bed (including debt on increased disease risk, such as children), sleep position, sleep surface, related to depression, obesity, diabetes, personal risk, and environmental stimuli and cardiopulmonary diseases. such as noise, vibration, light, tempera- ture, and humidity. • The genetic, environmental, and psycho- social factors that impact children’s sleep, and the relative contributions of each, need to be identified. SECTION IV—SLEEP AND HEALTH 51
    • SLEEP, SEX DIFFERENCES, AND WOMEN’S HEALTH B ACKGROUND states and circadian rhythms. It is important to understand how sex-related differences Women, from adolescence to postmeno- in sleep and its regulation influence the risk pause are underrepresented in studies of for and mechanisms of sleep disorders and sleep and its disorders. Although sleep com- other diseases. plaints are twice as prevalent in women, 75 percent of sleep research has been conducted Evidence from animal studies supports the in men. More sleep studies in the past 5 years presence of sex-related differences through- have included women, but small sample sizes out the lifespan in susceptibility to disease in prohibit meaningful sex comparisons. Thus, general and to sleep disorders in particular. sex differences in sleep and sleep disorder As classic examples of sexual dimorphism, characteristics, in responses to sleep depriva- both the long-term neurobehavioral conse- tion, and in sleep-related physiology remain quences of sleep-associated intermittent unappreciated. Furthermore, findings from hypoxia, as occurs in Sleep-Disordered studies based primarily in men are often Breathing (SDB), and the consequences considered to be representative of “normal” induced by early life maternal separation even when it is recognized that there are stress exposures, are reduced in female ani- important sleep-related physiological differ- mals when compared to male littermates. ences in women, including timing of nocturnal The mechanistic roles of sex-related hor- growth hormone secretion and differential mones and their receptors and signaling time course of delta activity across the night. pathways in mediating the emerging sex- dependent differences in susceptibility to Sexual dimorphism in the central nervous specific neural insults are only now begin- system has been well documented but the ning to be explored, and the new insights functional implications of sex differences in achieved should have major implications the neurotransmitter and peptide systems for the development of novel therapeutic that modulate sleep and wake are unknown. interventions. There is a need to study sex differences in sleep and homeostatic regulation across Physiologic changes in neuroendocrine species to more fully understand the role hormones, body temperature, mood, and that sleep plays in normal development, emotional state during puberty, the men- maturation, adaptation, aging, and disease strual cycle, pregnancy, and menopause propensity. Sex hormones influence sleep have profound effects on sleep quality, and circadian rhythms, and sleep affects daytime functioning, and well-being neuroendocrine functioning, in particular in adolescent girls and adult women. the episodic secretion of gonadatropin hor- It generally has been assumed that sleep mones. There are potentially different effects prior to puberty is similar in girls and boys, of endogenous sex hormone cycling on neu- and that sex differences first emerge during ronal groups involved in regulating behavioral this developmental transition. The validity of 52 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • this assumption, however, and the extent of sensitivity to endogenous hormone fluctua- sex differences in sleep and sleep disorders tions, but these hypotheses require further in children and adolescents are not known. testing. Potential health consequences or There have been no cross-sectional or longi- disease risk that are engendered by this tudinal studies of subjective and objective repetitive “incident” insomnia that can occur measures of sleep coupled with measures every month for 40 years of a woman’s life of neuroendocrine functioning during and are not known. However, menstrual cycle after puberty. Despite the propensity for symptoms and premenstrual dysphoria mood disorders to emerge during adolescence correlate with excessive daytime sleepiness. and the greater prevalence in girls compared Women with significant dysmenorrhea may to boys, little is known about how changes be at higher risk for developing insomnia in sleep, sex hormones, and sleep deprivation and depression. affect mood and emotional problems in this age group. Hormonal changes and physical discomfort are common during pregnancy, and both Although being female is a risk factor for can affect sleep. Although nearly all preg- insomnia, and insomnia is a risk factor nant women will experience disturbed sleep for depression, little is known about how by the third trimester, there have been only changes in sex hormones during the mens- two longitudinal sleep studies of subjective trual cycle impact sleep physiology and mood and objective sleep measures during pregnan- in adolescent girls and women. In fact, most cy. There have been no reports of intervention of what is known about sex hormones and studies to improve sleep quality during preg- sleep is derived from studies of exogenous nancy. Some have assumed that disturbed hormones in adult rodents and humans. Little sleep is a “natural” consequence of preg- is known about endogenous sex hormones, nancy, labor, delivery, and postpartum that changes in sleep physiology, and the develop- resolves over time, since few women seek ment of dysphoric mood and dysmenorrhea assistance to improve sleep. Research has not during the menstrual cycle. There have been shown a relationship between sleep quality only a few sleep laboratory studies in small and quantity and any perinatal adverse out- samples of adult women during all phases come, length of labor, or type of delivery. of the menstrual cycle. Findings show wide More studies are needed, however, to clarify individual variation, with no consistent rela- the extent to which sleep-related problems tionships between menstrual phase and during pregnancy may have adverse fetal, changes in sleep physiology. perinatal, or infant-related consequences. There are considerable methodological Very little is known about the effects of challenges in studying sleep across phases late stage pregnancy sleep disturbances of the menstrual cycle. Without normative on labor and delivery, emotional distress, or data based on ovulating and nonovulating postpartum depression. However, nighttime women, however, neither the researcher nor labor and a history of sleep disruption in late the clinician have reference points to aid in stage pregnancy are related to a higher inci- the interpretation of menstrual cycle effects dence of postpartum “blues.” Certain sleep on sleep or its disorders. Although not all disorders, such as Restless Legs Syndrome women of childbearing age experience pre- (RLS), Periodic Limb Movement Disorder menstrual symptoms and secondary insomnia, (PLMS), SDB, or insomnia, may emerge insomnia and related symptoms may occur during pregnancy, and the extent to which associated with onset of menses. Insomnia these disorders resolve or place women at related to menses may be related to a fall in higher risk for sleep disorders later in life is endogenous progesterone or a differential not clear. Pregnancy induces changes in the SECTION IV—SLEEP AND HEALTH 53
    • upper airway and in functional residual risk factor for SDB. It has been suggested capacity that predispose women to snoring, that menopause-induced sex hormone defi- SDB, and reduced oxygen stores. Pregnant ciency might explain the increased prevalence women who snore may be at risk for pre- of SDB in post-menopausal women and that eclampsia and/or SDB. The number of preg- women on HRT might be at lower risk. Given nant women with SDB may be substantial, concerns about disease risk, such as related but the prevalence has not been defined to thromboembolic events, cardiovascular in either uncomplicated or complicated disease, and breast cancer) associated with pregnancy. Women with pre-eclampsia and HRT for the treatment of menopausal symp- excessive weight gain during pregnancy are toms, fewer women in the future may at greater risk for the development of SDB receive HRT. Hence, more women may and pregnancy-induced hypertension, which experience menopause-related insomnia have been associated with adverse perinatal or HRT withdrawal symptoms that could outcomes, but few polysomnographic studies exacerbate insomnia. Alternative and estab- have been done in these women. lished therapies for insomnia need to be systematically evaluated in women during Many women during the menopausal and after menopause. transition (perimenopause, menopause, postmenopause) complain of sleep distur- In addition to perimenopausal and bances that are attributed to vasomotor menopausal effects on sleep in women, symptoms (e.g., hot flushes and night sweats) surveys show that more than 80 percent of rather than to menopausal status. Estimates working women report fatigue and exhaus- of self-reported menopausal-related insomnia tion, and half of them obtain inadequate range from 33 to 51 percent, but the actual sleep. Women shift workers with altered prevalence of sleep disturbances in midlife sleep and circadian rhythms are at increased women, particularly as a function of race, risk for menstrual irregularities, infertility, ethnicity, and body size is not well defined. miscarriage, and low birth weight infants. Although there have been only a few sleep Women remain the main caregivers for chil- studies with both subjective and objective dren and elderly family members. These measures, a majority of midlife women with responsibilities may add a significant stress self-reported poor sleep quality report high burden and increased vulnerability for sleep psychological distress without objective evi- disturbances with negative impacts on health dence of poor sleep efficiency. Whether these and quality of life. In addition, significant life women are physiologically hyperaroused (e.g., events, such as spontaneous abortions, still- increased hypothalamic-pituitary-adrenal axis birth, or death of a child or spouse, have or sympathetic activity) without significant been associated with development of post- impact on standard indices of laboratory traumatic symptoms, including sleep distur- sleep remains to be clarified. bances. Women who consume alcohol as a method of coping with work, family, and Data on changes in sleep physiology in social demands are at increased risk for women during the menopausal transition alcohol-induced sleep disturbances. are sparse and no longitudinal sleep studies have been conducted. Compared to placebo, P ROGRESS IN THE L AST 5 Y EARS short-term hormone replacement therapy (HRT) has shown beneficial effects on Sleep and the Menstrual Cycle/ improving subjective and objective sleep Premenstrual Syndrome quality in women with menopausal symp- toms, but not all studies show the same • Sleep architecture is unaffected by effects. Menopause may be a significant menstrual cycle phase. Body temperature 54 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • is elevated and circadian rhythm ampli- • Pre-eclamptic women show evidence tude is reduced during sleep, however, in of SDB associated with increased blood the high progesterone phase (luteal) of pressure. Pregnant women who snore the menstrual cycle, but the underlying have a twofold greater incidence of hyper- mechanism is not known. Compared to tension, pre-eclampsia, and fetal growth men, women have a blunted drop in body restriction compared to nonsnorers. temperature and an earlier nadir of the circadian body temperature rhythm. • Self-reported sleep quality, derived from sleep diaries, shows considerable sleep • Women on oral contraceptives have disturbances in the early postpartum reduced slow wave sleep and REM period. Sleep efficiency improves during latency. Body temperature throughout the first year postpartum, but it is unclear the menstrual cycle is similar to that of whether sleep quantity and quality return normal cycling women in the luteal phase. to pre-pregnancy levels. • Dysmenorrhea is associated with signifi- • There is a relationship between sleep cantly disturbed sleep quality prior to and mood during pregnancy, and through menses. Compared to control women, the first 3 to 4 months postpartum. women with dysmenorrhea had altered Increased disturbances in self-reported sex hormones, body temperature, and sleep and decreased reported total sleep sleep throughout the menstrual cycle. time are associated with depressed mood postpartum. Sleep in Pregnancy and Postpartum Sleep and Menopausal Transition • Longitudinal studies indicate that age, combined with anemia, is related to first • Longitudinal studies of midlife women trimester fatigue and that reduced sleep showed increased self-reported insomnia, time is related to fatigue during the third night sweats, and hot flushes across trimester. Both reduced sleep time and the menopausal transition from late anemia are related to fatigue postpartum. perimenopause to postmenopause. Significant changes in sleep are evident Self-reported sleep disturbance in in the first trimester of pregnancy, with middle-aged women also has been increased total sleep time coupled with associated with worse mood, higher more awakenings, but postpartum sleep blood pressure, higher waist/hip ratios, efficiency is lower than in prepregnancy. and chronic dissatisfaction with sleep. Slow wave sleep percentage is reduced throughout pregnancy compared to • The prevalence of self-reported insomnia prepregnancy and postpartum. One study is 17 percent in a community-based cohort found that REM sleep was reduced during of racially mixed perimenopausal menstru- pregnancy, but was reduced in another ating women. Reduced estradiol, increased longitudinal study, most notably during hot flashes, and psychosocial factors are all the third trimester. associated with poor sleep quality after con- trolling for current sleep medication use. • RLS occurs in about 20 percent of preg- nant women and may be associated • Sleep quality, as measured by polysom- with reduced levels of folate. nography (PSG), does not appear to be different in peri- or postmenopausal • Thirty percent of pregnant women women compared to premenopausal begin snoring for the first time during women. Also, there do not appear to the second trimester. be any differences in PSG sleep quality in women who use HRT versus those SECTION IV—SLEEP AND HEALTH 55
    • who do not. These observations imply • Conduct longitudinal studies of sleep that sleep disturbances in midlife women during pregnancy and through the post- are not a “normal” part of the meno- partum period that include both subjective pausal transition. and objective sleep indicators and include baseline measurements. Fuller description • HRT (estrogen preparations) is effective of the extent of sleep disorders develop- in reducing menopausal symptoms and ing during pregnancy and postpartum is self-reported sleep disturbances (insomnia needed so that novel and existing therapies and daytime sleepiness), and in increasing can be instituted to reduce health risks to REM sleep and the amount of slow-wave the mother and the fetus. The relationship sleep in the first third of the night. In one between extent of disturbed sleep during randomized trial, comparing two different the late stages of pregnancy and delivery forms of progesterone in combination and the development of postpartum with estrogen therapy, PSG sleep effi- depression warrants study as a basis for ciency improved, with reduced wake designing novel interventions. Effects after sleep onset in the group receiving of sleep disturbance postpartum on micronized progesterone. maternal-infant interactions also require • The prevalence of SDB in postmenopausal further study. women on HRT is significantly lower than • Determine the extent to which the in postmenopausal women not on HRT, prevalence of insomnia and sleep dis- indicating that menopause may be a sig- orders increases during the menopausal nificant risk factor for SDB in women, and transition, identify factors that predict HRT may reduce that risk. The hypothesis which premenopausal women are at high that healthy postmenopausal women not risk for developing insomnia, and evaluate on HRT have more SDB compared to alternative and traditional therapies for women on HRT has also been confirmed improving sleep in menopausal women. in a large population-based study. • Obtain normative sleep data on girls before, during, and after puberty, as well R ESEARCH R ECOMMENDATIONS as on women of childbearing age, to assess changes associated with different • Establish how sex-related differences in phases of the menstrual cycle, changes sleep and its regulation influence the in endogenous sex hormones, and in mechanisms and risks of developing response to exogenous hormones. disease and sleep disorders. Studies of sex differences in sleep and homeostatic • Determine the extent to which adolescent regulation across species are needed to girls and young women with significant more fully understand the role that sleep dysmenorrhea are at risk for insomnia plays in normal development, maturation, and depression. adaptation, aging, and disease propensity. Animal models of sleep disorders need • Study how sleep disturbance in pregnancy to be developed that incorporate careful affects fetal development and health as delineation of sex-related differences in well as the maturation of fetal physiology susceptibility to development of these related to sleep, and the extent to which disorders and their consequences. Studies fetal effects may be associated with long- of the specific cellular and molecular term pediatric consequences. mechanisms underlying sex differences in sleep disorders throughout the lifespan should be pursued. 56 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • RACIAL AND ETHNIC DISPARITIES B ACKGROUND significant differences in the prevalence of SDB in African Americans and have Racial and ethnic minorities have significant suggested distinct pathophysiological health disparities compared to the rest of the mechanisms. Among young African population. To achieve the objectives of the Americans, the likelihood of having “Healthy People 2010” initiative, there is a SDB is twice that in young Caucasians. need for more consistent and reliable racial Frequent snoring is more common and ethnic data. Such data are needed to among African American and Hispanic develop and implement effective prevention, women and Hispanic men compared to intervention, treatment programs, policies, non-Hispanic Caucasians, independent and services. For sleep disorders and for of other factors including obesity. health status in general, efforts to elimi- nate disparities in health outcomes need • SDB appears to be in part genetic, with to address not only social and environmental increased prevalence not only in African factors, such as education and access to Americans but also Asians and Hispanics health care, but also possible biological compared to Caucasians. African or genetic differences, including gene- Americans appear to have a different environment interactions. maxillo-mandibular structure than Caucasians, which may contribute to Many clinical conditions appear to contrib- increased risk for SDB. African Americans ute to racial and ethnic disparities in health with SDB develop symptoms at a younger outcomes. A few account for most of these age than Caucasians but appear less likely disparities, including smoking-related diseases, to be diagnosed and treated in a timely hypertension, HIV, diabetes and trauma. The manner. This delay may at least in part be leading cause of death in African Americans due to reduced access to care. Additional and Hispanic Americans is heart disease. studies are also needed to explore the Sleep disorders, particularly Sleep-Disordered extent to which ethnic disparities in other Breathing (SDB), may contribute to the in- diseases, such as stroke and diabetes, are creased prevalence and severity of heart related to a sleep problem such as SDB. disease, and may also contribute to these • The adverse impact of low socioeconomic disparities through other mechanisms not status (SES) on health status may in part yet clarified. be mediated by decrements in sleep dura- tion and quality. Low SES is frequently P ROGRESS IN THE L AST 5 Y EARS associated with diminished opportunity for sufficient sleep or environmental conditions • Since release of the original Sleep Disorders compromising sleep quality. Hispanic chil- Research Plan in 1996, studies across ethni- dren have less Stage 3 and 4 sleep and cally diverse populations have identified more Stage 2 sleep than their Caucasian SECTION IV—SLEEP AND HEALTH 57
    • counterparts, suggesting that there dippers with high systolic blood pressure may also be racial/ethnic differences in (SBP) during the day or high SBP or dias- sleep quality. tolic blood pressure (DBP) during the night were more likely to have more severe SDB. • Sleep loss has been shown to be asso- African Americans who are non dippers ciated with decreased glucose tolerance, may therefore benefit from screening elevated evening cortisol levels, and for SDB. increased sympathetic activity. Sleep loss may thus contribute to increased risk • Studies have also identified an increased for chronic conditions such as obesity, prevalence of SDB in African American diabetes, and hypertension, all of which children compared to Caucasian children. have increased prevalence in underserved, African American children are also 50 underrepresented minorities. Racial and percent less likely to have had their tonsils ethnic disparities related to obesity may and adenoids removed (T&A) and more also contribute to disparities in health likely to have residual disease if a T&A outcomes related to SDB. Obesity is has been performed. In children with more common in African Americans and sickle cell disease, there is not only a Mexican Americans than in Caucasians. higher risk of SDB, but also higher prevalence and associated morbidity • African Americans are at increased risk due to vaso-occlusive crises. for cardiovascular disease, diabetes, infec- tions, certain cancers and alcoholism. • Racial and ethnic disparities also appear Recent studies suggest that alcoholics to exist in the prevalence of other sleep of African American descent may have disorders. Non-Caucasian adults report an more profound sleep abnormalities and insomnia rate of 12.9 percent compared abnormal immune function than Cau- to only 6.6 percent for Caucasians. casian alcoholics and healthy individuals. Genetic studies have shown a higher Disordered sleep and sleep loss may degree of genetic polymorphisms and disrupt the maintenance of internal lower linkage disequilibrium in some physiological mechanisms. Therefore, populations, especially African Americans. investigating the interrelationships Narcolepsy studies conducted in African between alcoholism, sleep loss and Americans have resulted in identification ethnicity and irregularities in hormonal, of specific HLA alleles that are involved autonomic nervous, and immune systems in mediating HLA class II susceptibility to may yield new insights regarding mecha- narcolepsy (e.g., HLA-DQB1*0602). nisms for the increased mortality rate among African American alcoholics. • The relationship between health-related quality of life (HRQOL) and SDB has been • Blood pressure normally drops (dips) examined in elderly African Americans by about 10 percent during the night. screened for snoring and daytime sleepi- African Americans, however, tend to be ness who completed a sleep recording, “nondippers” compared to Caucasians, a comprehensive sleep questionnaire independent of weight, gender and SDB. (Quality of Well-Being Scale, QWB), Studies in elderly African Americans and and the Medical Outcomes Study Core Caucasians suggest that for many older Measures of HRQOL. Those with moder- African Americans with hypertension, ate to severe SDB had significantly lower blood pressure does not fall the expected Physical Component outcomes summary amount at night, and that this nondipping scores than those with no SDB. Mild but is associated with more severe SDB. Non not more severe SDB is independently 58 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • related to both general physical function- R ESEARCH R ECOMMENDATIONS ing and general mental health functioning. The QWB scores of this SDB sample were • Conduct studies to identify the neuro- similar to those found in patients with physiological, neuroanatomical, genetic, depression and chronic obstructive and gene-environmental interactions pulmonary disease, suggesting that contributing to racial and ethnic dis- sleep disturbances may impact daily parities in prevalence and severity of living and health as much as other individual sleep disorders. medical conditions. • Develop strategies to reach under- • African Americans appear to have fewer represented minorities in public health chronic sleep complaints than Caucasians. education programs designed to maintain The largest differences are in waking during health and prevent development and the night, with African Americans having a progression of sleep-related conditions. prevalence of wakefulness during sleep of only about 60 percent that in Caucasians. • Determine the extent to which higher The prevalence of insomnia for African prevalence of SDB, and lower rates of Americans is also lower (19.8 percent ver- diagnosis and treatment, contributes sus 23.6 percent). African American women to the higher prevalence of learning have a higher incidence of insomnia than problems and academic underachieve- African American men, perhaps related in ment in African American children. part to higher risk for chronic persisting • Determine the best public health symptoms. Caucasian males and females approaches among underserved, under- do not differ in incidence. Depressed mood represented populations for increasing is associated with insomnia in both racial access to and knowledge of sleep groups. Continued presence of fair or poor medicine resources. health and physical mobility difficulties are associated with incident insomnia • Determine the bidirectional link between in Caucasians, but not among African parameters of sleep, sympathetic nervous Americans. The latter, however, show an system activity, and cellular immunity in association between incident insomnia African Americans with alcohol dependence. and incident development of perceived fair or poor health. African Americans • Determine the extent to which racial aged 75 years or more are less likely and ethnic disparities in health outcomes than Caucasian or Hispanic Americans related to sleep disorders may contribute to attribute sleep problems, as well as to differential responses to treatment or heart disease and arthritis, to being part to differences in adherence to treatment of the normal aging process (about 32 recommendations. percent versus 46 percent and 43 per- • Determine whether ethnic differences in cent, respectively). alcohol-induced sleep disturbances con- • Interviews and polysomnography (PSG) tribute to the sympathetic nervous system have been conducted on Hmong people and immunological effects of alcohol. to collect data on sleep disorders and • Develop effective strategies to include especially SDB in this ethnic group at racial and ethnic minorities in overall high risk for Sudden Unexpected efforts to recruit increased numbers of Nocturnal Death Syndrome. Hmong biomedical investigators to sleep-related subjects appear to have a high research, and in sleep-related curriculum prevalence of SDB. development for health care professionals. SECTION IV—SLEEP AND HEALTH 59
    • SLEEP AND AGING B ACKGROUND dementia, whether in the home or in institutions. Treatments for sleep problems Aging is associated with changes in sleep in the elderly can also be associated with amount, sleep quality, and specific sleep morbidity including, for example, the asso- pathologies and disorders. For instance, ciation between hypnotic use and falls or increased age is associated with increased hip fractures. prevalence of insomnia complaints, daytime sleepiness, Sleep-Disordered Breathing (SDB), Recent neuroscience findings regarding Restless Legs Syndrome (RLS), and Periodic sleep regulation have largely focused on Limb Movement Disorder (PLMD) (see Section young, healthy organisms, and have not V). Insomnia alone affects about one third of explored how age modifies these regulatory the older population in the United States. mechanisms, or whether such age-related Nocturnal sleep difficulties can result in changes can be modified. In humans, there excessive daytime sleepiness, attention and is little consensus regarding which sleep memory problems, depressed mood, and changes are normative developmental lowered quality of life. Evidence also suggests changes, and which changes are pathologi- that SDB has been associated with dementia cal. This has direct implications for identify- and cognitive deficits in the elderly. ing when an intervention is advisable. Given the potential for greater risk of adverse Other factors associated with aging, includ- effects in the elderly, there is also a need to ing medical and psychiatric disorders, changes develop a broader range of efficacious, safe in environment, and psychosocial stressors, treatments for all sleep disorders. This issue is such as bereavement, can also be indepen- particularly salient for individuals with signifi- dent contributors to sleep problems. Sleep cant medical or neuropsychiatric comorbidity. disturbances can also lead to changes in physiological systems, especially production P ROGRESS IN THE L AST 5 Y EARS of appropriate hormone levels and proper metabolic functioning. In addition, the cir- • Epidemiologic studies have identified con- cadian regulation of sleep-wake rhythms is sistent risk factors for late-life insomnia, altered with age, such that older adults sleep and have examined the course of this at an earlier phase of their circadian cycle disorder (see Section V). In addition, (see Section I). These changes are seen in the epidemiology of SDB in older adults the sleep of the healthy elderly, unrelated has been well described (see Section V). to complaints about disturbed sleep, but are SDB has also been identified as a risk magnified in those with medical and neuro- factor for adverse cardiovascular outcomes psychiatric disorders (see Section V). Disrupted in the elderly, including hypertension and sleep-wake patterns are also a major source coronary heart disease. of stress among caregivers of patients with 60 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Excessive daytime sleepiness, a possible R ESEARCH R ECOMMENDATIONS marker for SDB, has been found to be associated with diagnosis of incident • Investigate the neurobiological mecha- dementia and incident cognitive decline nisms of age effects on sleep, particularly 3 years later, after adjusting for age and those related to homeostatic and circadian other factors. In contrast, insomnia is not mechanisms. Circadian studies should associated with either incident cognitive investigate the neurobiological causes decline or dementia. and consequences of age-related changes in circadian rhythm parameters other than • The period of endogenous circadian period (e.g., amplitude, waveform), which rhythms in healthy older persons does may be directly related to changes in SCN not differ from that of healthy young output or efferent pathways and down- adults. However, older individuals have stream effector systems. Both basic science greater difficulty sleeping at specific and human studies are needed. Genetic, circadian phases, which may account for neuroanatomic, neurophysiologic, and some of the increased sleep complaints neurochemical approaches may be useful seen in aging. in such studies. Conversely, studies inves- • Behavioral and psychological interventions tigating the potential effects of sleep, have been found to be efficacious and circadian regulation, and sleep disorders durable treatments for older adults with on the aging process and the diseases insomnia. On the other hand, behavioral associated with late age are also a and environmental interventions have high priority. shown limited efficacy among institu- • Test the efficacy and effectiveness of sleep tionalized individuals with dementia. disorder treatments among individuals • Evidence supporting the efficacy of with a broader range of medical comor- melatonin for treating Insomnia in the bidities, e.g., individuals with “usual” elderly is equivocal. Low doses of mela- aging. These studies should include tonin that raise blood levels to the normal conditions such as insomnia and SDB, young adult nighttime range significantly and populations such as nursing improve sleep quality in individuals suffer- home residents. ing from age-related insomnia in some • Develop a range of novel, safe, and studies, but not in others. efficacious treatments for sleep dis- • Studies have shown the important sleep orders in the elderly. These may include regulatory functions of a hypothalamic the development of new behavioral, circuit involving the ventrolateral preoptic pharmacologic, hormonal, behavioral, nucleus (VLPO). No differences in numbers and physical/environmental (e.g., light) of VLPO neurons are noted with increasing treatments for conditions such as age, nor are there any differences in levels Insomnia, sleep-wake disruptions of adenosine A1 receptor mRNA. Age, in dementia, and SDB. Long-term however, may affect adenosine receptor trials investigating the efficacy and function rather than number. While the adverse effects of pharmacologic suprachiasmatic nucleus (SCN) appears to and behavioral/ psychological treat- function normally with aging, aging may ments for insomnia are needed in impair the function of both entrainment older patients with both primary and (afferent) systems and target (efferent) secondary forms of insomnia. The use of systems downstream from the SCN. techniques such as pharmacogenomics SECTION IV—SLEEP AND HEALTH 61
    • should be employed to identify which • Better define the prevalence of specific treatments are likely to be most efficaci- sleep disorders in aging. Such studies ous in specific patients or populations should employ clinical diagnostic criteria (see Section I). for sleep disorders as well as polysomno- graphic monitoring. The relationships • Better define the boundaries of normal between sleep disorders and cognitive and abnormal age-related sleep changes, decline in aging also need investigation. as well as guidelines for intervention. Examples include defining normative • Investigate the relationship between age-related changes in sleep, and daytime and nighttime care procedures thresholds for when SDB or periodic and sleep quality and circadian function in limb movements during sleep require the institutionalized elderly. These studies intervention. should also investigate modifications of care procedures designed to minimize adverse effects on sleep. 62 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SLEEP AND SAFETY B ACKGROUND year may be due to medical errors. Based on surveys of medical residents and other Demands on human wakefulness and information, it is widely believed that alertness through increased requirements substantial numbers of these adverse for shift work, oncall and prolonged work events result from fatigue due to prolonged hours, and increased use of time for waking work hours and inadequate sleep among activities, have resulted in more people being doctors and nurses. awake more of the time. Paralleling these increased demands has been a growing These problems of sleepiness and fatigue, appreciation of the risks posed by fatigue. and the contributions of inadequate sleep In this context, fatigue is defined as a re- and night work, to human error and acci- duced capacity for cognitive performance dents have high costs in both lives lost and due to time-on-task, inadequate sleep, economic impact. Options, therefore, for adverse circadian timing, or the interaction mitigating sleepiness and fatigue need to be of these factors. Fatigue can adversely affect explored. The Department of Transportation public health and safety, due, for example, (DOT) is investing significant resources to to oil spills, truck, bus and automobile better understand and manage fatigue in crashes, railroad and commuter train transportation systems. For example, recent disasters, aviation accidents, power research supported by the Federal Motor plant mishaps, and medical errors. Carrier Safety Administration suggests that both work schedules and sleep disorders are The National Highway Traffic Safety primary contributors to fatigue and sleepi- Administration (NHTSA) estimates that ness among truck drivers. Long and irregular 100,000 to 150,000 motor vehicle crashes work schedules that require operators to each year and 4 percent of all fatal crashes juggle work demands with family and social are caused by drowsy driving. Drowsy driving demands lead to reduced or disrupted sleep crashes have a fatality rate and injury severity and, therefore, to fatigue. level similar to alcohol-related crashes. Risk factors for drowsy driving crashes include: Excessive fatigue and its risks are largely late night/early morning driving, people with preventable when the causes are identified untreated excessive sleepiness, people who and mitigated. For example, establishing sleep 6 or fewer hours per day, young adult cost-effective techniques for identifying males (ages 16 to 24), commercial truck and treating transportation workers (such drivers, and night shift workers. as commercial truck drivers) who have Sleep- Disordered Breathing (SDB) could lessen Recent reports from the National Academy the likelihood of fatigue-related accidents. of Sciences, Institute of Medicine, concluded Preventing cumulative sleep debt by provid- that as many as 100,000 patient deaths per ing adequate recovery sleep opportunities SECTION IV—SLEEP AND HEALTH 63
    • for workers could reduce the risks of fatigue- in basic neurobehavioral functions, includ- related performance failures and catastrophic ing vigilance performance, cognitive speed outcomes in many industries. Moving school and accuracy, short-term memory, and start times to a later hour for adolescents executive functions. Such data are vital could reduce the likelihood of drowsy-driving to establishing reliable, evidence-based automobile crashes and injuries in school recommendations for sleep need. activities in this at-risk group. Finding ways to prevent fatigue-related medical errors by • Research has identified some technolo- physicians and nurses could save thousands gies that can detect fatigue and drows of patient lives each year, and improve ness before they result in a serious the learning and safety of the doctors performance error. Some of these and nurses. technologies include biobehavioral and physiological assessments, but few Although ensuring public and personal have undergone rigorous double-blind safety through adequate sleep is a broad validation in controlled experiments. issue of interest to many Federal, State, • Mathematical models of the regulation and private entities, the National Institutes of sleep have been extended to predict of Health have a unique role in ensuring waking performance capability based on that scientifically sound evidence is acquired sleep history, circadian phase estimates, on the basic biomedical and health-related and additional behavioral and biological factors mediating sleep need, behavioral variables. There is considerable belief that alertness, and risk. such models can be used to precisely identify schedules that minimize fatigue. P ROGRESS IN THE L AST 5 Y EARS • Recognition that fatigue-related errors • Scientific evidence increasingly demon- and accidents are inherent in 24/7 opera- strates that fatigue is a significant causal tions has led to fatigue management and contributing factor to adverse events using countermeasures that are preventive including motor vehicle and other fatigue- (e.g., education about the biological basis related accidents. However, there is no of fatigue) and operational (e.g., naps in general consensus that these data are the workplace). These fatigue manage- definitive and compelling. ment interventions have only recently been developed, however, and have not • Field and simulator studies in safety- yet been widely studied to determine the sensitive occupations (e.g., medical and extent to which they will be effective. surgical residents, truck drivers, airline pilots) have demonstrated that perform- • Work-related sleep loss and fatigue in ance in real-world tasks degrades under medical professionals, particularly during conditions of partial sleep loss and night training, has until recently received little work. Such studies highlight that the attention. There have been relatively few biology of neurobehavioral deficits from controlled studies that have examined sleep loss and fatigue is not dependent the impact of sleep loss and fatigue in on one’s profession, motivation, or the medical setting, and many published compensation. studies are methodologically flawed. The consequences related to sleep loss and • Experiments have demonstrated that shift work among physicians and nurses chronic reductions in sleep duration by include effects on performance of pro- healthy adults result in cumulative deficits fessional duties, learning and memory, 64 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • personal health and family consequences, • Establish the biological benefits for brain and safety and liability. While the issue of function, performance, and safety of nap work hours for physicians and nurses is sleep interventions (number of naps, their currently being debated nationally, there durations and circadian timing) as a sleep remains a need for research to elucidate loss countermeasure and fatigue manage- the effects of education and training ment strategy. Increasingly, 24/7 industries of physicians and nurses in sleep and permit opportunities for naps in the work- fatigue management. place (e.g., sleeper berths on trucks, bunks on airplanes, sleeping areas on trains, on- call rooms for residents). There is a need R ESEARCH R ECOMMENDATIONS for laboratory, simulator and field experi- ments on nap sleep physiology and waking • Identify the effects of varying amounts neurobehavioral functions to establish the of time for sleep, rest, and recovery effectiveness of naps used repeatedly as (e.g., days off) on biological and behavioral countermeasures. There are many experi- resilience to fatigue-inducing work sched- ments on naps in response to acute sleep ules. One of the most contentious but loss, but few that determine whether least well-understood features of fatigue chronic use of naps or split sleep oppor- and its consequences for safety concerns tunities can effectively maintain waking the role of recovery days off work. There neurobehavioral functions. If optimal are very limited data on the chronic (over napping strategies can be found to weeks and months) effects of inadequate manage sleepiness and its neurobehavioral recovery opportunities outside the circadian effects, this can form a basis for evaluating cycle. There is a need to establish time- evidenced-based model fatigue manage- constants for fatigue buildup as a function ment to determine the extent to which of different recovery opportunities. Another fatigue-related neurobehavioral deficits need is to identify ways to scientifically and risks can be reduced. design and evaluate work schedules that prevent the accumulation of excessive • Assess the impact of sleep loss and fatigue fatigue by allowing restorative sleep in the context of medical training, includ- at reasonable intervals. ing quality of patient care and patient safety/medical errors, learning and memory • Establish the validity and reliability of in medical education, and the health and innovative biobehavioral technologies well-being of resident physicians (motor and monitoring techniques that can detect vehicle crashes, mental health, etc.). drowsiness, fatigue and sleep propensity in Evaluate the effectiveness of fatigue medical and other workplaces. As devices management educational programs in predicated on detecting changes in the improving the health and well being of biology of wakefulness, these technologies medical trainees, including evaluation of have great potential. To be used effectively the effectiveness of controlled counter- as either diagnostic devices or safety measures (napping, caffeine, etc.) and devices, however, they should meet rigor- evaluation of the impact of “systemic” ous standards for determining whether interventions (work hour restrictions, what is being measured is related to the “night float” etc.) on sleep loss, per- neurobehavioral deficits induced by formance, and medical errors. sleepiness and fatigue. SECTION IV—SLEEP AND HEALTH 65
    • • Develop cost-effective methods to screen • Assess the extent to which educational populations working in safety-sensitive programs on the biological basis of fatigue, occupations to identify those who are and mitigation of the performance deficits most likely to have sleep disorders that produced by it, are: (1) effective in facilitat- produce excessive sleepiness and ing improved sleep, alertness, and the use performance-impairing risks. A major of fatigue countermeasures, and (2) result impediment to removing the risks posed in reduced risks of adverse events due to by sleepiness due to unrecognized sleep sleep loss and circadian biology. disorders in the workplace is the lack of valid, simple, cost-effective tools for • Determine the extent to which mathe- identifying who is most likely to benefit matical models of waking performance from a full evaluation. Such tools are capability (relative to dynamic interactions needed, however, to enable physicians of sleep and circadian biology) can be used to certify that people in specific safety- to precisely identify and develop work-rest sensitive occupations are fit to perform schedules that minimize fatigue. Although their jobs safely. efforts have been underway to identify the strengths and weaknesses of such • Develop novel techniques to facilitate computational models, more research worker acclimation to therapeutic inter- is needed to ensure they accurately ventions and effective use of therapies reflect the underlying biology of circadian for sleep disorders (e.g., CPAP adherence). rhythms and homeostatic sleep need as It is not sufficient to diagnose and to treat they pertain to work-rest schedules. workers without a treatment compliance program in place. • Perform studies on the effects of chronic pharmacological enhancement of wake- fulness in healthy persons on biology, behavior, and safety. This should extend from unregulated stimulants (e.g., caffeine), to regulated stimulants (e.g., amphetamines), and novel wake-promot- ing substances. These studies should include identification of long-term effec- tiveness, side effects, and complications of use and abuse. 66 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SLEEP IN MEDICAL CONDITIONS B ACKGROUND e.g., arthritis, cancer, heart failure, and ESRD. In chronic pain-related conditions without Individuals with a variety of common medical known structural pathology (e.g., FM, CFS, illnesses—including adult and juvenile arthritis, IBS), the most striking observation in these asthma, cancer, cardiopulmonary diseases, “unexplained disorders,” is a self-report of chronic fatigue syndrome (CFS), diabetes, poor and nonrestorative sleep that is often end-stage renal disease (ESRD), fibromyalgia out of proportion to modest changes in (FM), human immunodeficiency virus (HIV), objective measures of sleep. This discrepancy irritable bowel syndrome (IBS), obesity, and between subjective and objective sleep indi- temporomandibular joint disorders (TMJD)— cators has been studied extensively in FM frequently experience sleep disturbances. and is most evident when patients are It is recognized that medical illnesses can selected on the basis of appropriate case adversely affect sleep quality, and that pain, definition, compared to women of similar infection, and inflammation can induce age, and screened for psychiatric disorders, symptoms of excessive daytime sleepiness particularly depression. Insomnia in these and fatigue. It is less clear, however, how chronic conditions is known to exacerbate sleep quality affects disease progression and symptoms of pain, fatigue, and daytime morbidity. In addition, patients with these sleepiness, negatively impact work per- medical illnesses may also have a primary formance, social and family relationships, sleep disorder (see Section V) that further quality of life, and increase use of health contributes to significant morbidity. The role care services. Controversy still exists, how- of sleep disturbances and sleep disorders in ever, regarding the clinical significance the morbidity of most chronic conditions is and diagnostic value of abnormal sleep understudied in children and adults and, as physiology in these unexplained disorders. a result, is poorly understood. Similarly, how sleep disturbances affect responses and Sleep is considered restorative and important adherence to medical therapy for the pri- for illness recovery. It remains unknown, mary illness and the best ways to manage however, whether sleep actually facilitates disturbed sleep in most chronic conditions is recovery processes. Clinicians advise patients understudied. The relationship between sleep to “get plenty of sleep” during an acute processes and the development, progression, febrile illness or following surgery or trauma, and management of chronic diseases, there- but sleep is often fragmented and disrupted. fore, requires further study. These sleep disturbances are considered “incident” or “transient” forms of insomnia Insomnia associated with abnormal sleep that are treated readily with hypnotic medi- architecture is most evident in disorders cations and often resolve with recovery. characterized by known structural pathology, However, mutually exacerbating effects of SECTION IV—SLEEP AND HEALTH 67
    • disturbed sleep and primary illness may be people with HIV infection. However, sleep a significant barrier to full recovery. The role disturbances in children and adults with of acute illness-related insomnia in the HIV remains understudied, underdiag- development and pathogenesis of chronic nosed, and, therefore, undertreated. conditions both in children and adults is understudied and perhaps underestimated. • “Unexplained disorders” are more In addition, the impact of acute care envi- prevalent in females than in males, but ronments in exacerbating sleep disruption the biologic basis of this sex difference and further limiting successful implemen- is poorly understood. Failure to identify tation of medical or behavioral regimens a structural basis for these disorders has is understudied. led some researchers and clinicians to embrace sociocultural explanations that can bias research and care. P ROGRESS IN THE L AST 5 Y EARS • Altered timing and reduced nocturnal • Asthma and other pulmonary diseases concentrations of sleep-dependent hor- commonly exacerbate during sleep, mones (e.g., growth hormone, prolactin, but the mechanisms involved are melatonin) have been described in a poorly understood. number of chronic conditions and are possibly linked with altered sleep physi- • There is an association between ology and reduced sleep continuity. daytime sleepiness and cardiovascular disease-related morbidity and mortality • Lack of altered circadian rhythms (e.g., hypertension, myocardial infarction, observed in FM patients coupled with and congestive heart failure). lower concentrations of sleep-dependent hormones (growth hormone and prolactin) • Severity of diabetes is directly associated in other studies, underscores the possibility with severity of disturbed sleep, and of dysfunctional homeostatic sleep regu- partial sleep deprivation of healthy lation as a basis for symptoms of poor adults increases insulin resistance. sleep and fatigue. • Patients with ESRD have disrupted • Pain is a major factor associated with nocturnal sleep with excessive daytime disrupted sleep in many chronic conditions. sleepiness and the timing of dialysis Experimental studies in healthy young men treatment affects mortality. ESRD patients and in animals show reduced responsive- on dialysis have among the highest inci- ness to noxious stimuli during sleep, but dence of both SDB and periodic leg the mechanisms involved in sleep-related movements (PLMs) in sleep, and PLMs pain modulation are unknown. are a significant predictor of survival and mortality in this population. • Neuroimaging studies have identified areas of the thalamus and basal ganglia • Sleep disturbance and fatigue are highly that may be hypofunctional in women prevalent and disabling symptoms in a with FM and hence may contribute to majority of individuals infected with HIV. abnormal sleep physiology. Recent findings suggest that symptoms of sleep disturbance and fatigue are inde- pendently associated with survival among 68 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • R ESEARCH R ECOMMENDATIONS • Conduct interdisciplinary basic science studies of the effects of pain and • As the United States’ population ages, inflammation on sleep physiology the number of people living with chronic both in animals and in humans. medical illnesses will increase dramatically in the next two decades. It will be impor- • Conduct experimental challenge studies tant to identify chronically ill populations using sleep delay or partial sleep depri- at highest risk for sleep disturbances, vation to assess the extent of homeo- determine the factors most associated static sleep regulation dysfunction in with disturbed sleep, and the best chronic illnesses. ways to improve such sleep disturbances. • Study sleep, neuroendocrine and auto- There is also a need to understand how nomic functioning in newly diagnosed sleep disturbances affect adherence to patients with FM compared to patients treatments for chronic disease and ways with CFS and with primary insomnia. that improving sleep may improve treat- Studies of children, adolescents, and ment outcomes. young women should be particularly • Study the bidirectional relationship informative. between sleep processes and disease • In patients with chronic illness, determine development, progression, and morbidity. the effectiveness of self-management Determine identifiable, measurable charac- strategies (e.g., cognitive-behavioral teristics of sleep quality that could serve and sleep hygiene) designed for treating as potential indicators of primary disease primary insomnia, in relieving symptoms diagnosis, progression, and severity. Such and improving clinical outcomes. markers might indicate how sleep regula- tion and timing are reciprocally coupled to disease pathophysiology. • Epidemiological and clinical research is needed in children and adults to elucidate the benefits of sleep, the risks associated with insufficient sleep during an acute illness, and the extent of unresolved acute illness-related insomnia. The beneficial outcomes associated with improved sleep during illness using behavioral, pharma- cological, and environmental approaches need to be explored. SECTION IV—SLEEP AND HEALTH 69
    • SECTION V SLEEP DISORDERS • Immunomodulation, Neuroendocrinology, and Sleep • Sleep-Disordered Breathing • Insomnia • Narcolepsy and Other Hypersomnias • Restless Legs Syndrome/Periodic Limb Movement Disorder • Sleep in Other Neurological Disorders • Parasomnias • Sleep in Psychiatric, Alcohol, and Substance Use Disorders
    • IMMUNOMODULATION, NEUROENDOCRINOLOGY, AND SLEEP B ACKGROUND the host is exposed. Many cytokines affect sleep, each in different ways (e.g., IL-1, Both the neuroendocrine output arm and -2, -15, -18, tumor necrosis factor (TNF), the immune stimulus arm of brain-immune inter-feron). Different combinations of communications affect sleep. Relevant cytokines expressed during infection may immune factors include the broad family have different overall effects on sleep. of immune molecules termed cytokines that include interleukins (IL), chemokines, and Genetic factors that determine sleep pat- other immune products that allow immune terns interact with environmental factors cells to communicate. Cytokines are pleio- to contribute to final effects on disease out- tropic, both affecting and originating from come. Genetic host factors, in interaction many other cells and organs than simply with environmental factors, influence the those of the immune system, and are key set point of neuroendocrine stress response communicator molecules that affect many and cytokine production patterns that inter- aspects of nervous system and neuroendo- act with cytokine patterns produced in crine system function. Resultant sleep alter- response to different pathogens/antigens. ations induced by cytokines probably affect the course of and susceptibility to a variety Control of complex phenotypes such as of diseases including infectious, inflam- sleep is likely to have the same character- matory/autoimmune, and endocrine. istics as other complex phenotypes, includ- Reciprocal interactions between neuroen- ing behavior or complex illnesses such as docrine and immune factors and sleep inflammation/arthritis. Thus, it is likely that include the following: many genes, each with small effect (poly- genic/multigenic), regulate different aspects • Immune molecules alter sleep architecture. of sleep. Inheritance of sleep phenotypes could therefore be additive, as in other • Sleep deprivation alters neuroendocrine complex phenotypes, and hence depend and immune responses. not on single genes but on inherited regions • Immune system activation and neuroen- of DNA. Finally, such complex phenotypes docrine responses alter sleep. often exhibit large environmental variance. Therefore, an important area of study will • Sleep quality probably affects the course be to address and dissect gene-environment of and susceptibility to infectious disease. interactions and to systematically assess the effect of environmental factors on genetic During infection, patterns of cytokines factors in sleep phenotypes and disease out- produced depend on a combination of host come. Potential environmental variables that responses and specific pathogens to which could be examined in the context of defined SECTION V—SLEEP DISORDERS 73
    • genetic backgrounds impacting on sleep R ESEARCH R ECOMMENDATIONS include: (1) relative effects of different neuroendocrine and neural stress response • Identify the effects of interactions between pathways; (2) effects, pathways and mechan- the neuroendocrine and immune systems isms of different pathogen and cytokine on sleep phenotype and disease outcome exposures; and (3) early developmental in defined genetic models. These studies factors (maternal-infant interactions). should identify the molecular and cellular mechanisms and neuroanatomical path- P ROGRESS IN THE L AST 5 Y EARS ways of these interactions and their effects on sleep architecture, sleep responses to • Progress has been made in identifying cytokines, and infectious disease outcome. individual and interfacing effects of • Further define the role of sleep, sleep different cytokines on sleep architecture deprivation, and chronic sleep restriction and identifying interactions between the on host defense. Human studies are individual components of the hormonal needed to determine the extent to which stress response system (including CRH sleep disturbance and sleep deprivation and cortisol) and the neuronal stress are related to markers of nonspecific in- response system (including sympathetic flammatory responses (e.g., leukocytes, nervous system responses). cytokines, C-reactive protein). Studies are • Progress has included genetic linkage needed in transgenic or knock-out animals, and segregation analysis of linkage including linkage and segregation studies, regions to identify molecules that affect to identify the functional significance to infectious, cytokine, and sleep interactions. infection resistance and susceptibility of In addition, knock-out animal models and candidate genes in linkage regions or of inbred strains have been used to elucidate newly discovered cytokines, candidate the role of individual immune and endo- neurohormones, or other molecules. crine molecules in sleep. • Study the biology of the relationships • Short-term sleep deprivation is associated among cytokines, neuroendocrine func- with complex altered immune responses, tion, and sleep, including studies of the but the influence on disease outcome is relationships of the neuroendocrine stress unclear. There is some evidence that sleep response and cytokine induction of sleep loss and chronic sleep restriction may in animal models and human studies. be associated, in addition to cytokines, Analysis of gene-environment interactions with other inflammatory markers (e.g., and of sleep responses to infectious agents C-reactive protein) that could impact the in genetically manipulated animal models development and severity of cardiovascular is relevant to the question of how sleep disease as well as daytime sleepiness and alters disease susceptibility and outcome. fatigue in sleep disorders. Specific pharmacological agents (e.g., specific cytokine or neuroendocrine antagonists/agonists) will be useful to assess the effects of specific neurotrans- mitters/neurohormones/interleukins/ cytokines on sleep phenotypes. 74 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Conduct genetic studies to identify neuroendocrine and immune genes relevant to sleep phenotypes. Approaches to identify potential candidate genes of interest could include animal studies utilizing candidate gene knock-out and transgenic animals, expression microarrays, and linkage and segregation studies includ- ing congenics studies. Studies in humans and animals could include sequencing of candidate genes and phenotype charac- terization of subjects with candidate gene mutations or of transgenic or knock-out animal models. • Conduct animal and human studies to integrate circadian biology and homeo- static sleep regulation with cytokine biology. This approach could include both in vitro and in vivo studies. SECTION V—SLEEP DISORDERS 75
    • SLEEP-DISORDERED BREATHING Adult collapse is incomplete. The reversibility, with therapy, of apnea-induced hypertension and B ACKGROUND other presumed adverse cardiovascular outcomes is largely untested. The expla- Sleep-Disordered Breathing (SDB) describes nations for reduced prevalence of SDB in a group of disorders characterized by abnor- women compared to men, and why women malities of respiratory pattern (pauses in present for therapy even less often than the breathing) or the quantity of ventilation prevalence numbers would suggest, remain during sleep. Obstructive sleep apnea unclear. It is unclear to what extent SDB in (OSA), the most common such disorder, the elderly represents the same disorder is characterized by the repetitive collapse as is encountered in younger populations or partial collapse of the pharyngeal airway and thus deserves similar therapy. during sleep and the need to arouse to resume ventilation. Sleep is thus disrupted, Cheyne-Stokes respiration, another type yielding waking somnolence and diminished of SDB, is characterized by a crescendo— neurocognitive performance. The recurrent decrescendo pattern of respiration and is sleep arousal in association with intermit- commonly seen during sleep in patients with tent hypoxia and hypercapnia has been congestive heart failure. The presence of this implicated in the occurrence of adverse respiratory pattern appears to be an impor- cardiovascular outcomes. In addition, there tant risk factor for the progression of heart is evolving evidence that SDB may contribute failure. More data are needed, however, to to insulin resistance and other components clarify the mechanisms leading to Cheyne- of the metabolic syndrome. Despite con- Stokes respiration, the impact of this abnor- siderable progress, most patients remain mal ventilatory pattern on cardiac function, undiagnosed, and the principal therapeutic and the effect of treatment on survival. approach—continuous positive airway pres- sure (CPAP)—remains somewhat cumber- some and therefore is not associated with P ROGRESS IN THE L AST 5 Y EARS optimal compliance rates. • Reversibility with CPAP therapy of many of the neurocognitive and quality of life SDB is exacerbated by alcohol intake. detriments associated with SDB is suggest- In addition, current understanding of the ed by relatively small, short-term trials. neurobiologic mechanisms responsible for the sleep-induced changes in upper air- • The strength of the association between way motor control that lead to pharyngeal SDB and systemic hypertension in animal 76 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • models and large, prospective epidemio- R ESEARCH R ECOMMENDATIONS logic studies is becoming more evident. Cross-sectional data also suggest an • Investigate and advance understanding important association between SDB of the genetic, neurobiologic, and physio- and stroke, myocardial infarction, and logic mechanisms that are pathophysio- congestive heart failure. logically important in the development, potentiation, and maintenance of SDB. • Studies addressing control of the pharyn- Studies are also needed to access the geal musculature, both awake and asleep, interaction between cardiac dysfunction have demonstrated the ability of these and the ventilatory control system in the muscles to respond to local stimuli awake, pathogenesis of Cheyne-Stokes respiration. thereby compensating for deficient anato- my/collapsibility and maintaining airway • Conduct adequately powered clinical patency. The loss of these reflex mecha- trials, particularly in high-risk populations, nisms during sleep is an important factor to assess the impact of therapy of SDB in the pathogenesis of SDB. on functional status, psychiatric disorders, neurocognitive function, and other disease • Increasing evidence suggests a familial/ processes (hypertension, cardiovascular genetic influence on predisposition to disease, metabolic syndromes, etc.). SDB, independent of obesity. This genetic Studies assessing the impact of success- influence may be mediated differently ful therapy of Cheyne-Stokes respiration in different racial and ethnic groups on cardiac dysfunction, quality of life (see Section IV). and survival are also needed. • The efficacy of oral appliances (primarily • Design new and improved modalities for mandibular advancing devices) in patients the treatment of SDB, including pharma- with mild to moderate SDB and of upper cologic, surgical, oral appliance, behavioral, airway surgical procedures over a range muscle stimulation, positive airway pressure of apnea severity has been evaluated. (including CPAP compliance), and other However, more information is needed novel approaches. Methods to individual- before the respective roles of these ize these therapies to the different SDB approaches can be clearly delineated. phenotypes are also needed, for example, • Data suggest that positive airway pres- improved upper airway imaging approaches sure therapy can, over several weeks, to define site of collapse. eliminate Cheyne-Stokes respiration • Develop novel noninvasive screening/ in heart failure patients and lead to diagnostic methodologies that are less improved transplant-free survival. expensive and more widely applicable than standard full polysomnography. This might include biomarkers as indicators of the presence of SDB, its severity, or its consequences. SECTION V—SLEEP DISORDERS 77
    • Pediatric • Improved phenotypic characterization of SDB and its manifestations are facilitating B ACKGROUND extrapolation of basic science concepts to the pediatric population. Extended popula- Snoring, a symptom of increased upper tion studies are needed that incorporate airway resistance during sleep, is extremely gene databases and also include multi- frequent in children, and affects 18 to 20 per- organ multifunctional categorization of cent of infants, 7 to 13 percent of children SDB-related morbidity and response to ages 2 to 8, and 3 to 5 percent of older chil- therapy. Such studies would allow for dren. The pathophysiology of SDB in children development of databases permitting is still poorly understood. Indeed, while adeno- correlation analyses of large datasets tonsillar hypertrophy is certainly a major con- and exploration of multiple hypotheses tributor to SDB, other factors, such as obesity, generated from basic research findings. craniofacial genetics, and neural control mech- anisms of upper airway patency, also appear • As part of such phenotype delineation, to be important. It is clear that the spectrum development of more sensitive and accu- of disease and morbidity associated with SDB rate tools for definition of disease and in children is expanding. As such, degrees of morbidity is needed. Currently available severity that might have once been consider- tools are insensitive to morbidity and do ed clinically irrelevant are now recognized not provide accurate determinations of the as having substantial neurobehavioral and degree of homeostatic disturbance that cardiovascular consequences. occurs during sleep and during daytime. P ROGRESS IN THE L AST 5 Y EARS R ESEARCH R ECOMMENDATIONS • In recent years, it has become apparent • Develop longitudinal normative data on that SDB and snoring are not as innocuous sleep and cardiorespiratory patterning as previously thought. Indeed, epidemio- in children. logical and pre-post treatment analyses • Identify genes and gene products that have identified substantial morbidities may contribute to the pathophysiology that primarily affect cardiovascular and of SDB. Conducting these studies in neurobehavioral systems. These morbidi- pediatric populations may have distinct ties include pulmonary hypertension, advantages, because they are less likely arterial hypertension, nocturnal enuresis, to be “contaminated” by age-associated reduced somatic growth, learning and comorbidities present in adult populations. cognitive deficits, and behavioral prob- Some of the “at-risk genes” may be opera- lems that resemble attention deficit- tive only during infancy and childhood, hyperactivity disorder. e.g., genes responsible for immune modu- • Failure to diagnose and treat in a timely lation and lymphatic tissue growth, while manner may prevent some of these mor- other genes, such as those underlying bid complications from being completely obesity or craniofacial phenotype, appear reversible, leading to long-lasting residual applicable to both children and adults. In consequences. However, the point of transi- addition, environmental factors or gene- tion between what constitutes pathology gene interactions during childhood may and what is normal remains to be defined. modify the phenotypic expression of the disease during adulthood. 78 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • There is considerable variation in the • One of the major limitations in diagnos- magnitude of SDB associated morbidi- ing SDB is the need for relatively complex, ties in both children and adults, and this burdensome, and costly procedures, such heterogeneity in end-organ injury could as overnight polysomnography. Research be due to differences in gene and protein efforts need to focus on development of responses to the various components of reliable screening methods that are appli- SDB. Identification of such genes/proteins, cable to children and to provide accurate their functions and interactions, and their indicators of either the presence/absence posttranslational modifications, using cur- of the disease or the occurrence of end- rently available genomic and proteomic organ morbidity. Such developments approaches, may provide opportunities include, for example, application of new for development of promising targets for biomedical sensor technologies, multi- intervention and for reducing morbidity. modality imaging strategies, development of disease-related artificial intelligence net- • Longitudinal studies are needed to assess works, and systematic exploration of gene the long-term impact of SDB during child- and protein markers in biological fluids. hood and into adulthood. Attention to outcomes among obese children is particu- • First-line treatment of pediatric SDB rou- larly important considering the increasing tinely relies on surgical removal of the prevalence of obesity in children. tonsils and adenoids. However, since this treatment does have measurable morbidity, mortality, and financial cost, novel interven- tional approaches need to be developed. SECTION V—SLEEP DISORDERS 79
    • INSOMNIA Adult Effective treatments for insomnia have been developed, but important issues still remain. B ACKGROUND For instance, the exportability of behavioral treatments to usual care settings and the Insomnia is defined as difficulty falling asleep, effectiveness (as opposed to efficacy) of difficulty staying asleep, or short sleep dura- insomnia treatments have yet to be deter- tion, despite having an adequate opportunity mined. Finally, there is a need to develop for sleep. It is the most common sleep com- novel pharmacologic treatments based on plaint, affecting approximately 30 to 40 per- new findings in sleep neurobiology. cent of the adult population. Even when more stringent criteria are required, such as day- time impairment or marked distress, insomnia P ROGRESS I N T HE L AST 5 Y EARS disorders have a prevalence of approximately • The efficacy and durability of standardized 10 percent. Evidence suggests that insomnia behavioral treatments for insomnia have has significant consequences on quality of been demonstrated in a number of well- life, health care utilization, and subsequent controlled clinical trials. psychiatric disorders. Efficacious short-term behavioral and pharmacologic treatments • The epidemiology of insomnia in adults for insomnia are available, and progress has has been well described. Consistent risk been made in epidemiology and risk-factor factors, such as psychological symptoms, identification, identification of adverse out- medical illness, and female sex, have comes, and in identifying effective treatments. been identified. However, much remains unknown regarding • Independent studies have demonstrated the causes, characterization, consequences, that insomnia is a risk factor for subse- and optimal management of insomnia dis- quent development of psychiatric disorders orders. For instance, we do not have a con- and for worse outcomes among individuals sistent phenotype(s) for insomnia disorders with concurrent psychiatric disorders. that could be applied to human and animal studies. Despite major research advances in • A small but growing body of evidence the neurobiology of sleep and circadian has demonstrated “hyperarousal” among rhythms (see Section I), the implications of patients with insomnia, including increased these findings for insomnia have not been central nervous system activation (indexed carefully investigated. Instead, the pathophy- by increased high-frequency EEG activity), siology of insomnia has been examined from sympathetic nervous system activation, a number of clinically derived theoretical and hypothalamic-pituitary-adrenal (HPA) frameworks, with little replication of the axis activation. findings reported in individual studies. 80 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • R ESEARCH R ECOMMENDATIONS • Further studies of behavioral/psychologi- cal treatments are needed. These studies • Basic and preclinical studies are needed should include: (1) the use of behavioral/ that focus on the neurobiology of insom- psychological treatments in routine care nia. These should include: (1) the develop- settings (e.g., primary care offices), ment of animal models of insomnia with (2) the development of alternative deliv- specific insomnia phenotypes; (2) the ery methods (e.g., simplified treatment application of neurophysiological, neuro- regimens, computer or Internet adminis- chemical, neuroanatomic, and functional tration), (3) studies in patients with neuroimaging approaches to human medical or psychiatric comorbidity, and studies; and (3) genetic, genomic, and (4) large-scale effectiveness studies. Prior- proteomic studies. ity should also be placed on investigating the specific efficacious components of • Pharmacological treatment studies are these behavioral treatments. needed to define the efficacy, safety, abuse liability and role of long-term • More precisely define the potential physi- hypnotic treatment. Priority should be cal health risks, morbidity, and functional given to studies defining the optimal consequences of insomnia, distinct from duration and pattern of administration of the morbidity and consequences of asso- traditional hypnotic medications, including ciated medical and psychiatric conditions. investigations of their use in populations with high rates of utilization, such as with • Examine the extent of use, efficacy, and psychiatric disorders. Studies are also need- adverse effects associated with alternative ed on widely used but poorly documented treatment approaches, including nutritional treatments, such as sedating antidepres- supplements, herbal remedies, and non- sants, and on the development and testing pharmacological treatments. of novel pharmacologic agents based on neuroscience findings (e.g., drugs affect- Pediatric ing corticotropin release, adenosine, or hypocretin systems). B ACKGROUND • Insomnia phenotypes need to be charac- Difficulties in initiating and maintaining sleep terized and include: (1) development and are extremely common in children. The over- validation of clinical phenotypes (e.g., all prevalence of sleep onset delay/bedtime define diagnostic criteria), (2) physiological resistance has been reported to be in the characterization and biomarkers (which range of 15 to 25 percent in healthy school- may include measures of EEG, HPA axis, aged children and even higher in adolescents. sympathetic nervous system, and func- However, because behaviorally-based sleep tional neuroanatomy using neuroimaging problems in children are often defined by techniques), and (3) indices of discriminant caregivers, the range of sleep behaviors that validity versus mood and anxiety disorders. may be considered “normal” or “pathologic” Definition of insomnia phenotypes should is wide and the definitions highly variable. In also address subjective-objective discre- addition, population-based normative data pancies in sleep measures, as well as on sleep patterns across childhood are lack- the relationship between insomnia and ing, creating further challenges in defining co-existing sleep, psychiatric, and “abnormal” sleep in infants, children, and physical disorders. SECTION V—SLEEP DISORDERS 81
    • adolescents. Therefore, a common nosology Little is understood, on either a pathophy- for defining sleep disorders in children needs siologic or behavioral level, about the inter- to be developed and evaluated. action between sleep disorders and acute and chronic health conditions such as asthma, diabetes, and juvenile rheumatoid arthritis. In Insomnia in Special Populations chronic pain conditions, these interactions Sleep disturbances in pediatric special needs are likely to significantly impact morbidity populations are extremely common, and and quality of life. often a source of considerable stress for families. Prevalence of sleep problems in children with severe mental retardation has P ROGRESS IN THE L AST 5 Y EARS been estimated to be as high as 80 percent, • In addition to risk factors such as social and to be 50 percent in children with less and communication developmental severe cognitive impairment. The prevalence abnormalities and cognitive impairment, of sleep problems in children with autism is a primary arousal dysfunction in children estimated to be 50 to 70 percent. with neurodevelopmental disorders may contribute to sleep problems. Significant problems with initiation and maintenance of sleep, shortened sleep • There may also be a primary disturbance duration, irregular sleeping patterns, and of melatonin production and synchroniza- early morning waking have been reported tion in autistic children, and some autistic in many neurodevelopmental disorders, in- children seem to respond to treatment cluding autism and pervasive developmental with exogenous melatonin. Studies have disorder, Asperger’s syndrome, Smith-Magenis documented improvements in sleep onset syndrome, Angelman’s syndrome, tuberous delay, night wakings, early morning waking sclerosis, San Filippo syndrome, Rett syn- and total hours of sleep using a small dose drome, and William syndrome. Other studies (0.3 to 0.5 to 2.5 to 5 mg) of melatonin have suggested that similar rates of sleep approximately 1 hour before desired bed- problems also occur in both younger and time in up to 80 percent of children with older blind children, with the most common disorders such as cortical blindness, Rett concerns being difficulty falling asleep, night syndrome, autism, tuberous sclerosis, and wakings, and restless sleep. Asperger’s syndrome. However, melatonin is not effective in all developmentally delayed The types of sleep disorders in these children children with sleep problems, and little is are not unique to this population, but are known overall about long-term side effects. more frequent and more severe than in the general population and often reflect the • Some, studies have examined the role of child’s developmental level rather than sleep disturbances in chronic medical con- chronological age. Multiple sleep disorders ditions of childhood, such as sickle cell are also likely to occur simultaneously. The disease and asthma, disorders particularly incremental impact of disrupted and/or in- common in high-risk and minority popu- adequate sleep on cognitive, emotional, lations. The interaction between sleep social development, and behavior in these and physical and emotional dysfunction in already at risk children is potentially profound. acute and chronic pain conditions such as burns and juvenile rheumatoid arthritis, 82 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • has also begun to be explored. Additional R ESEARCH R ECOMMENDATIONS factors, such as the impact of hospitaliza- tion, family dynamics, underlying disease • Develop a common definition and docu- processes, and concurrent medications are ment the prevalence and functional impact also important in assessing the bidirectional of pediatric insomnia across the age spec- relationship of insomnia and chronic illness trum in the general population and in in children. high-risk populations, such as special needs children (e.g., neurodevelopmental • Clinical psychology and pediatric studies disorders, sensory deficits) and children have examined the efficacy of empirical with chronic medical conditions (e.g., behavioral treatment for sleep problems diabetes, asthma). Normative data should in small samples. Most of these studies be collected regarding sleep practices and have relied on parental assessment of patterns in order to define “abnormal” treatment success. Additional outcomes sleep. Studies should also examine the research to systematically assess efficacy developmental aspects of insomnia in of various treatment modalities for sleep children—including the role of early disorders, including behavioral manage- sleep patterns and behaviors, parenting ment protocols, is needed to generate practices, temperament, and genetics— recommendations for “best practices.” as well as risks and protective factors for • Pharmacologic intervention in conjunc- the persistence of insomnia into adoles- tion with behavioral techniques has been cence and adulthood. shown to be effective in some cases. • Develop and evaluate optimal evidence- However, little is known overall about based treatment strategies and manage- the safety and efficacy of pharmacologic ment protocols for pediatric insomnia: interventions for sleep disturbances in children, alone or in combination with – In otherwise healthy children, using behavioral therapy. Medications used to standardized measures for such out- treat insomnia in children include diphen- come variables as sleep quality and hydramine, chloral hydrate, trazadone, quantity, sleepiness/alertness, mood, clonidine, and benzodiazepines. Hypnotic behavior, academic functioning and medications, however, can result in un- parental stress. predictable side effects, development of tolerance necessitating increasingly higher – In children with special needs, includ- doses, paradoxical effects (agitation instead ing evidence-based behavioral and of sedation), and withdrawal effects. pharmacologic treatments for insomnia Rebound sleep onset delay on discon- and circadian rhythm disturbances, and tinuation and morning “hangover” can including outcome measure, such as be significant problems as well. Little is neurocognitive performance measures known about the scope and patterns and assessment of impact on quality of use of pharmacologic interventions in of life for children and caregivers. pediatric sleep disorders, about possible • Examine the interrelationships between indications, and about potential target insomnia and chronic medical conditions populations for short-term use of hypnotics in children, including effects on disease in conjunction with behavioral interventions. processes, pain management, quality of life, and caregiver well-being. SECTION V—SLEEP DISORDERS 83
    • NARCOLEPSY AND OTHER HYPERSOMNIAS B ACKGROUND in first-degree relatives is 20 to 40-fold higher than in the general population for Narcolepsy is a disabling neurological disorder narcolepsy-cataplexy. HLA susceptibility characterized by sleepiness and symptoms of genes play a minor role in overall genetic abnormal rapid eye movement (REM) sleep susceptibility. Human narcolepsy is currently such as sleep paralysis, hypnagogic halluci- treated symptomatically with dopaminergic nation, cataplexy and, frequently, disturbed amphetamine-like stimulants, gammahydroxy- nocturnal sleep. Narcolepsy is most commonly butyrate, and monoaminergic antidepressant diagnosed using nocturnal polysomnography therapy. Behavioral and social interventions and the Multiple Sleep Latency Test (MSLT). are also helpful. In this test, sleep latencies and the occur- rence of REM sleep are evaluated during 4 The study of narcolepsy is facilitated by to 5 naps, scheduled every 2 hours during the existence of two animal models: canine the daytime. Narcoleptic patients typically and murine narcolepsy. A 10-year positional display short mean sleep latency, indicative cloning study identified canarc-1 as the of daytime sleepiness and more than two hypocretin (orexin) receptor-2 gene (Hcrtr2). REM episodes in the MSLT. This was followed by the discovery that preprohypocretin knockout mice also have Narcolepsy-cataplexy affects 1 in 2,000 narcolepsy and by the discovery that human people and is the fourth most common narcolepsy is associated with decreased condition treated in sleep disorder clinics. hypocretin transmission. Hypocretin-1 and The exact prevalence of essential hypersomnia 2 (orexin-1 and 2) are excitatory neuropep- and narcolepsy without cataplexy, two related tides encoded by a single gene selectively disorders characterized by sleepiness and expressed in a small subset of lateral hypo- abnormal MSLT results, is unknown. These thalamic neurons. Hypocretin neurons proj- two disabling disorders are at least of similar ect widely in the central nervous system and frequency as narcolepsy with cataplexy, but have especially dense monoaminergic cell few research data are available. group projections. Two hypocretin receptors (Hcrtr1 and Hcrtr2) with differential neuro- In humans, narcolepsy-cataplexy is genetically anatomical distribution are currently known. complex, human leukocyte antigen (HLA) associated, and environmentally influenced. In humans, narcolepsy cases are not asso- Fine mapping studies in the HLA class II ciated with hypocretin ligand or receptor region indicate a primary role for HLA-DQ. mutations but, rather, with undetectable Multiplex families are rare, but relative risk cerebral spinal fluid (CSF) hypocretin-1 levels. 84 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • Only a single hypocretin gene mutation in R ESEARCH R ECOMMENDATIONS an unusual patient with a very early onset (age 6 months) disorder and severe symp- • Conduct basic research on hypocretins in tomatology has been reported to date. In animal models. Even though recent findi- sporadic cases, neuropathological studies ngs have stimulated some basic research indicate a dramatic loss of both hypocretin-1 studies on hypocretins, the exact role of and hypocretin-2 in the brain and a disap- this system in the regulation of normal pearance of hypocretin-containing cells in sleep and other behaviors is still unknown. the hypothalamus. Together with the obser- vation that hypocretin-1 is potently wake- • Study the epidemiology and pathophysi- promoting in vivo, these results demonstrate ology of narcolepsy without cataplexy, that narcolepsy-cataplexy is due to a hypo- essential hypersomnia, and periodic cretin deficiency. HLA association in humans hypersomnia. Our understanding of suggests the possibility of an autoimmune narcolepsy has been largely limited to disorder directed against hypocretin-contain- cases with cataplexy, and little information ing cells in the lateral hypothalamus. is available on these other conditions. With the increased availability of wake-promoting The cause(s) of narcolepsy without cata- medications, such as modafinil, there is an plexy and of other hypersomnias of central urgent need to evaluate the prevalence, origin (e.g., idiopathic hypersomnia) are treatment strategies, and etiologies of currently unknown. these related conditions. • The field is ready for direct clinical appli- P ROGRESS IN THE L AST 5 Y EARS cations. Measuring CSF hypocretin-1 has been shown to be a reliable diagnostic • Our understanding of narcolepsy- procedure for narcolepsy-cataplexy in cataplexy has been revolutionized in limited case series, and efforts should be the last 5 years. The discovery in 1999 made to further validate and distribute that hypocretin gene alterations produce this new diagnostic procedure. Further- narcolepsy in canines and mice rapidly more, efforts should be made to design led to the finding that human narco- alternate diagnostic procedures based on lepsy is associated with decreased the knowledge that narcolepsy is caused hypocretin transmission. by hypocretin abnormalities. These may involve (but should not be limited to) • Novel pharmaceutical treatments have measuring hypocretin levels in blood or been developed including modafinil, imaging studies of the hypothalamus. a wake-promoting compound, and gammahydroxybutyric acid (GHB), a • Study the effectiveness of replacing sedative used for treating disturbed noc- hypocretins or hypocretin-producing turnal sleep and cataplexy. These are cells. Since animal models are available useful therapeutic treatments but only to test this hypothesis and design new symptomatically treat the condition. treatments, studies should be conducted in both animals and humans. Hypocretin peptide supplementation, the develop- ment of hypocretin receptor agonists, cell transplantation, and gene therapy are all possible treatments. SECTION V—SLEEP DISORDERS 85
    • • Studies designed to identify the causes of • Since narcolepsy typically starts in child- destruction of hypocretin-containing cells hood or early adolescence, management in human narcolepsy are needed. Studies of these patients is particularly challenging are also needed to define the immune and clinical protocols need to be developed. connection in narcolepsy and/or to dis- Studying narcolepsy as closely as possible cover why narcolepsy is HLA-associated. to its onset, generally during childhood, In this regard, the study of cases of recent may also provide unique clues to the onset (most likely still at the stage of active cause of the disorder. destruction) may be critical. • Commonly used therapies in narcolepsy • Studies to find other narcolepsy genes, include napping and other behavioral and identify rare cases of narcolepsy with- treatments, but data establishing efficacy out known hypocretin abnormalities, are sparse. More research in this area are needed to better understand these is needed. pathologies. • Studies in twins indicate that not only • Studies of new medications such as genetic background but also environ- modafinil and gammahydroxybutyric mental factors are involved in the patho- acid (GHB) are needed to determine physiology of narcolepsy. Studies are their mode of action. Efforts to study needed to characterize these factors and the mode of action of current narcolepsy determine the potential effectiveness of treatments could lead to improving current prevention strategies. treatments. Additionally, there is a need for studies on the effect of drugs used in other areas of neurology and psychiatry as novel indications in narcolepsy (e.g., stimulants for daytime sleepiness, anti- depressants for cataplexy, sedative agents for disturbed nocturnal sleep). 86 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • RESTLESS LEGS SYNDROME/PERIODIC LIMB MOVEMENT DISORDER B ACKGROUND on the basis of history and symptoms, periodic limb movement disorder (PLMD) relies upon Restless Legs Syndrome (RLS) is a sensori- quantification of repetitive stereotypic leg motor disorder characterized by periodic movements associated with a brief arousal irresistible urges to move the legs, usually during sleep monitoring. Patients manifest- associated with unpleasant and uncomfort- ing PLMD have complaints of daytime fatigue able sensations in the legs. These symptoms and sleepiness or insomnia. As in RLS, PLMD occur during wakefulness, but are exacerbated may involve altered central dopamine mecha- or engendered by rest/inactivity and partially nisms since dopaminergic agents or other relieved by movement. The diurnal pattern drugs that interact with dopamine mechan- of symptoms likely reflects modulation by isms, (e.g., opiates) are equally effective the circadian system. RLS is reported to treatments for most patients. The incidence profoundly disturb sleep, yet the extent of of PLMD, as with RLS, is higher in the elderly. nocturnal sleep disturbance and of daytime Without better understanding of the etiology, sleepiness has not been established. Estimates pathogenesis, and neurophysiology of these of RLS in various populations range from 2 disorders, treatment strategies are limited and to 15 percent, but incidence and prevalence can therefore be unsatisfactory. Both disorders have not been precisely defined, particularly can have profound negative impacts on the as a function of gender and ethnicity. Several quality of life including daytime functioning, reports indicate a higher prevalence of RLS in work performance, and social and family life. women than in men, and also in individuals of Northern European ancestry. The etiology Controversy exists about the clinical signifi- and pathogenesis of RLS are thought to cance of PLMs during sleep in the absence involve alterations in efficiency of central of sensory complaints consistent with RLS. dopamine neurotransmission, based largely PLMs can occur without associated electroen- on the clinical observation that dopaminergic cephalographic (EEG) micro-arousals and in drugs relieve symptoms. The inheritance the absence of sleep complaints or of daytime pattern of RLS suggests an autosomal domi- symptoms. If associated with micro-arousals, nant mode of transmittance, but the genes the frequency of PLMs does not correlate accounting for this observation are not with objective measures of daytime sleepiness known. RLS is also associated with iron defi- or with indices of disrupted sleep. This lack ciency, and it is quite common in end-stage of a correlation may reflect insensitivity in the renal disease (ESRD) and during pregnancy. methods used for scoring EEG micro-arousals and sleep fragmentation. Abnormal limb About 85 to 90 percent of patients with RLS movements during sleep have been associ- also exhibit periodic limb movements (PLMs) ated with physiological correlates of arousal in during sleep. Unlike RLS, which is diagnosed autonomic or cortical functioning, suggesting SECTION V—SLEEP DISORDERS 87
    • that PLMs are part of an underlying arousal • Central nervous system (CNS) imaging disorder. It is possible that abnormal limb studies have shown reduced iron con- movements during sleep may be associated centrations in some brain regions. These with an unidentified neurophysiological reductions correlate with RLS severity alteration in microstructure of the EEG and low cerebral spinal fluid (CSF) ferritin sleep pattern. combined with high serum and CSF transferrin levels. P ROGRESS IN THE L AST 5 Y EARS • The RLS case definition was updated and revised in 2002, thereby providing • Several potential animal models of RLS a basis for the development of specific and PLMD have been developed based questionnaires to advance clinical recog- upon interruption of normal dopamin- nition, and to clarify RLS prevalence. ergic responsivity. • EEG patterns of cortical activation precede • Imaging studies suggest reduced central PLMs and indices of autonomic arousal, dopamine receptor binding with age, suggesting that PLMs are associated with but only small and inconsistent decreases an underlying arousal disorder. in dopaminergic transmission have been reported in traditional nigrostriatal dopa- minergic pathways in patients with RLS. R ESEARCH R ECOMMENDATIONS This finding suggests that alterations might exist in extrastriatal dopamin- • Determine the role of altered central ergic pathways. dopaminergic mechanisms, iron metabo- lism, and other possible mediators in the • RLS and PLMD are more common in pathogenesis of RLS and PLMD through children with attention deficit hyperactivity animal and human studies. The develop- disorder (ADHD) providing an opportunity ment, refinement, and validation of to address developmental aspects of these animal models for RLS and PLMD are disorders and responsivity to dopamin- needed. Modern techniques of neropath- ergic interventions. ology in the evaluation of brains and spinal cords from patients with RLS and • Neurophysiological studies in humans PLMD should be used to identify potential suggest that RLS is associated with in- abnormalities underlying these disorders. efficiencies of spinal cord inhibition that may be brainstem mediated and • Identify and further characterize genes state dependent. involved in RLS and PLMD. • RLS shows high familial aggregation. • Determine the extent of nocturnal sleep A recent study of genes involved in disturbance and daytime sleepiness in central dopaminergic transmission and children and adults with RLS and PLMs. metabolism showed no evidence of in- volvement in RLS. However, other recent • Develop and validate questionnaires studies have identified a susceptibility based on the new RLS case definition, locus for RLS on chromosome 12q in and determine the population-based a large French-Canadian family, and a incidence, prevalence, and morbidity, polymorphism in a gene involved in particularly in children and as a function catecholamine (monoamine oxidase A) of gender, race, and ethnic distribution. metabolism in women with RLS. 88 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • • Establish the developmental changes in • Improve available treatment strategies adults explaining the higher incidence for RLS and PLMD. Dopamine agonists, of RLS and PLMD in the elderly. opioids, and anticonvulsants are used most frequently, and are effective in • Pregnancy and uremia provide reversible reducing RLS symptoms and PLMs, but models to study the development and the necessary large multicenter trials remission of RLS and the role of altered and long term studies have not been iron metabolism. Conduct clinical trials conducted. These studies should include of iron supplementation in RLS patients assessment of quality of life and assess with low ferritin levels. the sensitivity of existing questionnaires to treatment changes. SECTION V—SLEEP DISORDERS 89
    • SLEEP IN OTHER NEUROLOGICAL DISORDERS B ACKGROUND Treatment of sleep disorders that fragment sleep, such as Sleep-Disordered Breathing Sleep disturbances and sleep disorders are (SDB), has improved seizure control in commonly associated with neurological case series. diseases, and neurological impairments of sleep reveal much about the brain circuitry Sleep disorders can also occur as a conse- involved in sleep regulation. Many neuro- quence of treating neurological disorders. logical disorders are now recognized to For example, pathological sleepiness may cause disruptions of sleep. For example, occur during treatment of PD and other pathological sleepiness is associated with movement disorders with dopamine-related neurological and neurodegenerative dis- drugs. In addition, many drugs used to treat orders such as Parkinson’s disease (PD), neurological disorders can cause excessive Alzheimer’s disease (AD), and progressive sleepiness or wakefulness. supranuclear palsy. Pathological sleepiness is also associated with neuromuscular Sleep disorders also interact in complex disorders such as myotonic dystrophy, in- ways with neurological disorders and are flammatory conditions such as encephalitis frequent after head trauma, stroke, enceph- or multiple sclerosis, and with traumatic or alitis, or in association with neuromuscular ischemic injury to the brain. In addition, disorders. For example, stroke has been conditions such as REM Sleep Behavior shown to be associated with SDB, and SDB Disorder (RBD) are recognized as precursors likely decreases potential for recovery in of PD. Conversely, Fatal Familial Insomnia (FFI), stroke patients. Stroke may also produce a prion disorder related to Creutzfeldt-Jakob SDB by interacting with the central regula- disease, causes prolonged wakefulness. tion of breathing. Similarly, the intermittent hypoxia that accompanies SDB may hasten Sleep is a powerful modulator of epilepsy, the neurodegenerative cascade in disorders with some epilepsy syndromes occurring such as PD and AD. exclusively or predominantly during sleep. These include benign childhood epilepsy Neurological disorders provide models with centrotemporal spikes, autosomal for understanding sleep circuitry in the dominant nocturnal frontal lobe epilepsy, brain. In addition, understanding sleep and continuous spike-wave activity during mechanisms and disorders will be integral sleep. Sleep deprivation has also been to treating these neurological diseases. described as a risk factor for epileptic seizures, although alcohol use and work- related stress are confounding factors. 90 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • P ROGRESS IN THE L AST 5 Y EARS R ESEARCH R ECOMMENDATIONS • Studies of patients with Parkinson’s disease • Evaluate the prevalence and impact of reveal a range of sleep disorders, including sleep disorders and disturbances in neuro- PLMS, RBD, and daytime sleepiness. These logical conditions, such as neurodegenera- disorders are part of the disease spectrum, tive disorders (e.g., Alzheimer’s disease, occur commonly, and suggest an important Parkinson’s disease), movement disorders, role for dopaminergic pathways in sleep/ post head trauma, encephalitis, stroke, wake regulation. Dopamine-like drugs are and epilepsy. These studies should evalu- useful in treating these disorders, and it is ate whether sleep disorders predispose to recognized that when these drugs stimulate specific neurological conditions, whether dopamine D2/D3 receptors they can cause neurological conditions can produce sleep “attacks” of excessive sleepiness, potentially disorders, and whether sleep disorders resulting in automobile and other accidents. impair recovery from selected neurologi- cal disorders. Studies of sleep in animal • An important advance has been the models of neurological disorders should empirical application of wake-promoting also be conducted. drugs to treat sleep disorders in various neurological conditions. The use of wake- • Study natural models of locally disrupt- promoting compounds in treating fatigue ing sleep circuits (tumors, trauma, multiple and sleepiness in various neurological sclerosis plaques, infarcts, neurodegenera- disorders such as PD, head trauma, and tive conditions, paraneoplastic syndrome, multiple sclerosis is increasing, but these etc.). Studies should be performed that treatments deserve controlled study. combine imaging techniques or neu- ropathology with sleep/sleep disorders • Vagus nerve stimulation (VNS), an approved analyses. treatment for medically refractory epilepsy, has been shown to cause apneas and shal- • Study the impact of pharmacological low breaths (hypopneas) during sleep, but and nonpharmacological neurological these effects are ameliorated by reducing treatments on sleepiness and sleep (for VNS stimulus frequency. In addition, VNS example, in epilepsy, multiple sclerosis, PD). has been shown to reduce daytime sleepi- ness in epilepsy patients. These findings • Study sleep and sleepiness in inflammatory emphasize the interconnections of the states (encephalitis, infarcts, multiple sclero- vagus nerve with brainstem networks sis, autoimmune disorders, etc.). that regulate respiration and alertness. • Determine if sleep disruption due to sleep • Advances in all of these disorders depend disorders or sleep deprivation lowers the upon understanding the brain circuitry threshold for epileptic seizures, and explore involved in sleep regulation. Elucidation the mechanisms responsible for this effect. of important components of the wake • Perform controlled studies to determine and sleep promoting circuitry in the if treatment of sleep disorders improves hypothalamus and the brainstem has seizure control. occurred over the last 5 years. Drug development is currently under way to take advantage of this new information in order to treat pathological wakefulness or sleepiness and to cause sedation, when necessary, with fewer side effects. SECTION V—SLEEP DISORDERS 91
    • PARASOMNIAS Adult Numerous secondary parasomnias, such as sleep-related expiratory groaning or B ACKGROUND esophageal spasm, have been reported. Typically, descriptions have been provided Parasomnias are undesirable behavioral, for single cases or very small case series, autonomic nervous system, or experiential making scientific evaluation difficult. These phenomena during sleep, usually character- phenomena are likely to be quite common, ized by increased motor and/or autonomic but they are often unrecognized, misdiag- activity, sleep-wake state dissociation, altered nosed, or ignored in clinical practice. The responsiveness to the environment, and pathophysiology, morbidity, and functional retrograde amnesia. Specific parasomnias consequences of secondary parasomnias arise during sleep-wake transitions, non are unknown. rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep, and are often classified as either primary parasomnias— P ROGRESS IN THE L AST 5 Y EARS disorders of sleep states per se—or second- • Epidemiological studies have shown that ary parasomnias—disorders of other organ disorders of arousal occur in about 10 systems that arise during sleep. Virtually all percent of adults, and are usually not primary parasomnias represent an admixture associated with significant underlying or simultaneous occurrence of elements of psychiatric or psychological disorders. both wakefulness and sleep These disorders are very common in children but may begin during adult- The most common primary parasomnias are hood or persist into adulthood. There disorders of arousal and REM sleep disorders. is growing evidence for genetic deter- Disorders of arousal include confusional minants of these disorders of arousal. arousals, sleepwalking, and sleep terrors, all characterized by partial arousals from NREM • Exogenous triggers, including sleep depri- sleep. REM sleep parasomnias include night- vation, alcohol ingestion, and medications mares, characterized by frightening dreams have been identified for disorders of and autonomic arousal, and REM behavior arousal in predisposed individuals. disorder (RBD), characterized by absence of the muscle atonia normally present during • The basic sleep architecture and sleep REM sleep. The behaviors associated with macrostructure is normal in patients with primary parasomnias may lead to injury of disorders of arousal. “Hypersynchronous the patient or bed partner and may have delta” activity has not been substantiated forensic implications. as an EEG marker for disorders of arousal. 92 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • However, quantitative EEG analyses in EEG studies (e.g., investigations of cyclic patients with disorders of arousal indicate alternating pattern in disorders of arousal). instability of slow-wave sleep, particularly Psychophysiological and neurophysiologi- during the first slow-wave sleep period of cal studies could help to identify factors the night. This instability may be related that trigger and maintain chronic para- to cyclic alternating patterns. somnias. A brain bank for RBD and other parasomnias would be particularly useful • RBD, which may have a prevalence rate to study their structural and genetic origins. as high as 0.5 percent, has two striking The identification of genetic and environ- demographic features: 90 percent of mental factors involved in the etiology and affected individuals are male, and most pathogenesis of primary parasomnias may cases begin after 50 years of age. be facilitated by the presence of distinctive Clonazepam is efficacious in 90 phenotypes for these disorders. Animal percent of cases. models for parasomnias could involve • At least 50 percent of RBD cases are techniques such as genetic manipulations, related to recognized neurologic condi- brain lesions and brain stimulation, sleep tions, particularly narcolepsy and the deprivation, and other behavioral pro- synucleinopathies (Parkinson’s disease, vocation techniques, and pharmacologic multiple system atrophy, and dementia manipulations. In particular, animal stud- with Lewy bodies). RBD may precede the ies investigating motor control and sleep appearance of other features of the under- could help to further elucidate the patho- lying disease by as many as 10 years. RBD physiology of parasomnias. may also be iatrogenic, due primarily to • Investigate pharmacologic and behavioral medications such as selective serotonin treatments for primary and secondary reuptake inhibitors (SSRIs). parasomnias in clinical trials. Intervention • Functional neuroimaging studies have studies could help to identify both common documented reduced dopamine trans- and distinctive mechanisms of action for porters and decreased dopaminergic different treatments in different disorders. innervation of the basal ganglia in • Further define the relationships between patients with RBD. the different parasomnias, and between • Other conditions characterized by parasomnias and other neurological dis- sleep-wake state dissociations have orders. For instance, the relationship been identified, and may be related between disorders of arousal and noc- to RBD. These include parasomnia over- turnal seizures, particularly nocturnal lap syndrome, agrypnia excitata, and frontal lobe epilepsy, should be further status dissociatus. investigated. Relationships between RBD, neuropsychiatric disorders, and specific medications need to be better defined. R ESEARCH R ECOMMENDATIONS • Obtain clinical and physiological infor- • Better define the pathophysiology and mation regarding secondary parasomnias neuroanatomic substrates of primary as a first step toward identifying the preva- parasomnias in human and animal studies. lence, etiology, and efficacious treatment In humans, specific methods could include of these disorders. functional neuroimaging and quantitative SECTION V—SLEEP DISORDERS 93
    • Pediatric R ESEARCH R ECOMMENDATIONS B ACKGROUND • Examine interactions between the developing central nervous system, Although parasomnias are among the genetics, other aspects of sleep most common clinical sleep disturbances physiology, and environmental experienced in childhood, little is known factors in determining phenotypic about the underlying neurophysiologic expression of partial arousal mechanisms and neurotransmitter systems parasomnias in childhood. responsible for their development and relative importance. • Examine the role of various neurotransmitter systems in Although a genetic predisposition exists the neurophysiology of partial for many parasomnias, the specific genes arousal parasomnias. involved have yet to be identified, and little is known about the interaction between • Evaluate the efficacy of, and genetic phenotype, other aspects of sleep underlying mechanisms for, physiology, such as arousal threshold, and pharmacologic and nonpharma- sleep inertia and environmental factors. cologic treatment strategies Treatment strategies involving pharmaco- for partial arousal parasomnias logic and behavioral interventions have and rhythmic movement disorders been developed, but most outcome studies in childhood. have included very small sample sizes and short-term follow up. P ROGRESS IN THE L AST 5 Y EARS • Several studies have reported an association between partial arousal parasomnias and both migraine head- aches and Tourette’s syndrome in children, thus raising the possibility that serotonergic pathways may be involved. Case reports of novel treatment strategies for partial arousal parasomnias have suggested that behavioral interventions, such as scheduled awakenings and hypnotherapy, may be effective nonpharmacologic treat- ment options, but little is known about he underlying mechanism responsible for the clinical response. 94 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SLEEP IN PSYCHIATRIC, ALCOHOL, AND SUBSTANCE USE DISORDERS B ACKGROUND as reduced rapid eye movement (REM) latency or increased REM sleep, have been Virtually all psychiatric and substance associated with poor treatment outcomes use disorders are associated with sleep in psychiatric disorders, including relapse or disruption. Epidemiological and clinical recurrence of depression and alcoholism. studies indicate that psychiatric disorders are the most common cause of chronic insomnia. Increasing attention has been paid to sleep Alcohol dependence leads to complaints of abnormalities in post traumatic stress dis- insomnia and sleep disruption that can per- order (PTSD) and nightmares, both in terms sist for months into abstinence and recovery. of descriptive studies (e.g., findings regarding Psychiatric disorders can also be associated REM and NREM dream disturbances, move- with daytime sleepiness, fatigue, abnormal ment disorders), and therapeutic studies circadian sleep patterns, disturbing dreams, (e.g., dream rehearsal therapies). Polysom- and nightmares. Conversely, evidence in- nographic markers for adult depression, creasingly suggests that primary insomnia such as decreased latency to REM sleep (without concurrent psychiatric disorder) is onset, have not been consistently found a risk factor for later developing psychiatric in depressed children and adolescents, disorders, particularly depression, anxiety, but other EEG measures (such as inter- and substance use disorders and intrahemispheric coherence) have been identified as potential correlates of mood Preliminary studies suggest that sleep dis- disorders in children. African Americans orders such as Sleep-Disordered Breathing are particularly vulnerable to the effects of (SDB), Restless Legs Syndrome (RLS), and alcohol dependence, and polysomnographic sleep-related movement disorders may and spectral analytic studies show a striking be unrecognized or under recognized in loss of delta sleep and delta power in this children and adults presenting with psy- population. Furthermore, studies using chiatric symptoms and psychiatric disorders, structural and functional neuroimaging and occur with increased prevalence in paradigms have begun to elucidate possible alcohol-dependent persons. The relationship mechanisms linking sleep disturbance and between sleep and psychiatric disorders is psychiatric illness. further supported by the observation that sleep deprivation can ameliorate depressive Psychoactive substances have acute and symptoms and exacerbate manic symptoms, chronic effects on sleep architecture. Several and that alcohol-dependent persons show aspects of sleep are compromised in indi- impairment in the homeostatic recovery of viduals taking these drugs, depending on sleep following sleep deprivation. Moreover, the drug. Difficulty in initiating and maintain- insomnia and certain types of electroen- ing sleep as well as poor sleep quality are cephalographic (EEG) sleep patterns, such common in patients who take opiates. SECTION V—SLEEP DISORDERS 95
    • In fact, heroin addicts seeking treatment of the complex cytokine network to sleep often report sleep disturbances, notably in- disturbance in alcohol-dependent persons. somnia, as precipitating causes of relapse. Despite initial progress in the study of sleep A similar dysregulation in the normal cycles disturbances among children with depression, of sleep may contribute to severe dependence little is known about the characteristics or observed with gammahydroxybutyrate (GHB) consequences of sleep disturbances in most where regular users report constant waking childhood psychiatric disorders. After focus- and must take more to reinstate sleep. Even ing almost exclusively on the relationships patients stabilized on methadone may have between sleep and depression, psychiatric SDB, daytime sleepiness, and poorer sleep sleep research has only recently begun to efficiency. Infants born to substance-abusing focus attention on other disorders, such mothers have a several times greater risk as PTSD. The application of sleep and of Sudden Infant Death Syndrome (SIDS). circadian rhythm therapies to psychiatric Chronic cocaine users also have lower sleep disorders has also been limited, and their efficiency and significant sleep onset delay. efficacy not consistently demonstrated. By contrast, abstinence from cocaine as well Clinical neuroscience studies are only begin- as amphetamines produces hypersomnia. ning to move beyond the examination of Since some investigators have observed sleep EEG sleep correlates of psychiatric disorders disruption despite long abstinence in chronic to the investigation of common mechanisms cocaine users, the mechanisms underlying and the consequences of disordered sleep sleep architecture and homeostasis and the in psychiatric and substance dependent mechanisms underlying effects of psycho- populations. Abnormalities of immune active drugs may have much in common. system functioning are coupled, for example, Further understanding of these relationships with disordered sleep in alcohol-dependent will advance both fields. populations. Finally, insomnia and sleep dis- turbances are known to be risk factors for Most of the recent research progress has psychiatric disorders including alcohol depen- been related to improved understandings dence, but long-term followup studies have of the associations between psychiatric not yet been done to determine whether disorders and various sleep symptoms intervention can reduce these risks and (e.g., insomnia and nightmares), sleep the progression of these disorders. EEG patterns (e.g., delta EEG activity), and sleep disorders (e.g., SDB and movement P ROGRESS I N T HE L AST 5 Y EARS disorders). Less progress has been made in identifying fundamental pathophysiological • Insomnia has been identified as a risk mechanisms linking psychiatric disorders and factor for the subsequent development sleep. Despite some promising early leads, of psychiatric disorders, including mood, for example, sensitive and specific sleep anxiety, and substance use disorders. biomarkers of psychiatric disorders have not been validated. Similarly, endogenous • Insomnia has also been correlated with circadian rhythm disturbances have not poor outcomes in depression, schizo- been identified in most patients with phrenia, and alcohol dependence. depression or other psychiatric disorders. • Structural and functional neuroimag- Based on basic observations that cytokines ing studies have begun to identify regulate sleep in animals, increasing atten- neuroanatomic correlates of sleep tion has focused on the role of cytokines disturbance in depression and schizo- in the regulation of sleep in humans and phrenia, and of therapeutic sleep the contribution of abnormal regulation deprivation in depression. For instance, 96 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • slow-wave sleep deficits in schizophrenia • Drugs can damage brain areas and neural are associated with negative symptoms systems involved in sleep maintenance. and frontal cortical volume loss. Patients For example, studies primarily in animals with depression have higher absolute have shown that MDMA (“ecstasy”) cerebral glucose metabolic rate than causes reduction in serotonin in axons healthy subjects, and blunted activation and axon terminals. Cocaine causes severe of limbic structures (amygdala, anterior depletion of dopaminergic neural systems. cingulate) during REM sleep compared to wakefulness. Improvement of depression R ESEARCH R ECOMMENDATIONS following 1 night of sleep deprivation is associated with decreased relative metabo- • Evaluate whether insomnia and hyper- lism in the anterior cingulate cortex. somnia are modifiable risk factors for poor outcomes in mood, anxiety, and • Reduced latency to REM sleep has been psychotic disorders, alcoholism, and identified as a familial sleep biomarker for substance abuse disorders. Three types of increased risk of developing depression. studies are needed: (1) Studies to investi- • Differences in sleep responses to choli- gate whether insomnia and hypersomnia nergic and serotonergic drugs have been are modifiable risk factors for the develop- identified in patients with depression ment of new-onset psychiatric disorders; compared to healthy controls. (2) Studies to investigate whether insomnia or specific EEG sleep characteristics are • Individuals with PTSD have a high inci- modifiable risk factors for poor outcomes dence of SDB, motor dyscontrol, and among individuals with existing psychiatric dream disturbances during both NREM disorders; and (3) Prospective, long-term and REM sleep. longitudinal studies to follow the concur- rent course of sleep and psychiatric disor- • The efficacy of dream imagery rehearsal ders from childhood into adulthood and for traumatic nightmares has been demon- to elucidate possible mechanisms for the strated in early clinical trials. relationship between sleep disturbance • Abnormalities of sleep quantity and sleep and psychiatric disorders. These studies depth persist for months into recovery will be aided by the identification of from alcohol dependence, and are more sensitive, specific, and objective markers profound in African American alcoholics of insomnia and hypersomnia. compared to Euro-American alcoholics. • Further evaluate the relationships between The decay of delta sleep in alcoholics is stress and sleep in clinical disorders such coupled with impairment in the regulation as PTSD and other forms of acute and or plasticity of slow-wave sleep. chronic stress. Studies are specifically • Dysregulation of cytokine expression is a needed to: (1) further characterize the biomarker of abnormal sleep in recovering nature of stress-related sleep disturbances alcohol-dependent persons. (e.g., insomnia, nightmares and other dream disturbances, movement dis- • Sleep disturbances are apparent in indi- orders during sleep); (2) examine causal viduals taking psychoactive drugs and relationships between stress and sleep have been found to persist long after disturbances; and (3) investigate the withdrawing from these drugs. For some, efficacy of behavioral and pharmacological sleep disturbance can be so severe as to interventions for treating stress-related reverse treatment success and precipitate sleep disturbances. a relapse to addiction or dependence. SECTION V—SLEEP DISORDERS 97
    • • Evaluate the neurobiological characteristics of the coexisting psychiatric disorder and mechanisms of sleep disturbances in should also be examined. Examples include primary insomnia, depressive disorders, the concurrent treatment of insomnia in and anxiety disorders to better define individuals with major depression, and the inter-relationships. Such studies should the use of dream-imagery rehearsal in include approaches such as functional individuals with PTSD. neuroimaging studies and neurochemical studies in living human subjects and in • Assess the efficacy of behavioral and brain tissue. pharmacological interventions targeting sleep in improving the clinical course of • Identify relationships between neuro- alcoholism and risk of relapse. biological mechanisms involved in the development of regulatory aspects of • Further investigate the neurobiological arousal, affect, and sleep in childhood basis for the beneficial effects of sleep and adolescence, including the role of deprivation in mood disorders. Such various neurotransmitter systems. Examine studies should also be useful generally to the relationship between critical periods address fundamental questions regarding of brain development and sleep-wake the mechanism of antidepressant treat- cycle regulation, and the impact of sleep ments. Functional imaging methodologies, disturbances and insufficient sleep in early including receptor ligand studies, may be childhood in modifying the normal evolu- particularly relevant. tion of these various regulatory systems. • Investigate the prevalence and impact of These studies should also assess: (1) poten- primary sleep disorders (e.g., SDB and tial links between entrainment of circadian sleep-related movement disorders) on rhythms in the first year of life and cir- psychiatric disorders. cadian irregularity during childhood and subsequent vulnerability to psychiatric • Investigate sleep effects of medications illness, (2) potential effects of stressful commonly used to treat psychiatric distur- or traumatic events on hyper and hypo bances in adults, children, and adolescents. arousal mechanisms in children, and Studies should include short and long-term (3) development of sleep patterns and investigations examining beneficial and maladaptive coping mechanisms. adverse effects of these medications on subjective measures, sleep architecture, • Determine the role of cytokines in the respiration during sleep, and motor homeostatic regulation of sleep in humans control during sleep. and whether abnormalities in the cytokine network lead to disturbances of sleep in • Investigate the brain mechanisms underly- psychiatric populations also at risk for ing sleep architecture that are also affected infectious or inflammatory disorders. by psychoactive drugs, including temporary Studies are also needed to determine acute effects and long-term effects related whether proinflammatory cytokine to chronic drug taking. Knowledge of the antagonists can ameliorate sleep distur- neural changes brought on by drug effects bance in alcohol populations who show should help to better understand which of evidence of immune activation. these neural mechanisms are associated with sleep cycles. Conversely, an improved • Evaluate the efficacy and safety of behav- knowledge base of neural systems involved ioral and pharmacologic treatments for in sleep can aid in the understanding of sleep disturbances in both adults and the process of drug reward, addiction, children with psychiatric disorders. The and dependence. influence of such treatments on outcome 98 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SECTION VI PEDIATRICS • Sleep and Early Brain Development and Plasticity • Adolescent Sleep • Sleep in Medical Disorders • Neuropsychiatric Disorders in Childhood and Sleep
    • SLEEP AND EARLY BRAIN DEVELOPMENT AND PLASTICITY B ACKGROUND mediates brain maturation. The resulting hypothesis is that one function of REM Sleep may have important roles in adult sleep is to generate specific patterns of brain plasticity related to learning and memory intrinsic activity in neuronal populations consolidation. Unlike adults, the human fetus whose development is dependent upon and neonate spend a remarkable proportion activity. The classic example of activity- of their time sleeping, with approximately 80 dependent maturation is the visual system, percent of their day in rapid eye movement in which spontaneous neural activity in each (REM) sleep and the remainder in non rapid retina in the fetus (before visual experience) eye movement (NREM) sleep and wakefulness. is necessary for the anatomic segregation By 5 to 6 months of age, human infants spend of eye-specific synaptic connections in the only 20 to 30 percent of their time in REM lateral geniculate nucleus. Research studies sleep, with the remainder of time equally in experimental models support the idea spent in NREM sleep and wakefulness. Reasons that activity-dependent maturation occurs for such increased requirements for sleep, par- during sleep. ticularly REM sleep, in early life are not well understood, but improved understanding Understanding the roles of sleep in brain of these developmental requirements may maturation and plasticity is of critical impor- provide insight into the functions of sleep tance since perturbations during fetal life or throughout life. early postnatal life can have major impact on developmental processes and thus on The high percentage of time spent in REM adult phenotype. Suppression of neonatal sleep during the critical period in human REM sleep in rats, for example, alters venti- brain growth and maturation in late fetal latory pattern, metabolism, and regional and early postnatal life may indicate that brain concentrations of neurotransmitters the neural activity controlled by REM state and their receptors at maturity, suggesting mechanisms may be developmentally func- adverse adult consequences on brain rewir- tional and contribute directly to physiological ing due to disruptions in sleep in early life. and structural brain maturation. REM sleep Furthermore, early hyperoxic exposures as may be important in providing early stimu- may occur in mechanically ventilated prema- lation and activity requirements of the ture infants, or sleep-associated episodic growing brain. Subsequent recognition of hypoxemia such as occurring in apnea of activity-dependent development of neural prematurity, may result in permanent impair- connections in utero provides a specific ments in cardiovascular and respiratory mechanism by which endogenously control- control. Thus, despite the existence of redun- led, correlated, spontaneous neural activity dant protective mechanisms and increased SECTION VI—PEDIATRICS 101
    • system plasticity at these early stages of P ROGRESS IN THE L AST 5 Y EARS development, the fetus and newborn are likely to be extremely susceptible to disrup- • Sleep has been shown to enhance the tion of the normal homeostatic processes effects of a preceding period of monocu- for normal tissue and organ growth and lar deprivation on visual cortical responses function. Furthermore, although the inter- during the peak critical period of the matu- actions between sleep processes and early ration of the visual cortex. These findings life perturbations are unknown, it is reason- demonstrate that sleep and sleep loss able to assume that these early disruptive modify experience-driven cortical plasticity events may alter the hierarchical organization in vivo, and support a crucial role for sleep of functional gene clusters and lead to both in early life upon brain development. early and late increases in vulnerability to specific disease states. • Sleep and sleep loss have been shown to modify the expression of several Those at greatest risk for early disruptions in genes and gene products that appear sleep and sleep-related brain maturation are to be important for synaptic plasticity. premature infants in intensive care nurseries. • Studies in neonatal animals indicate that Sleep deprivation in this setting is a major suppression of REM sleep can lead to problem, due largely to the absence of a behavioral, anatomic, and biochemical diurnal rhythm of light/dark cycles, and deficiencies, including respiratory prob- sleep interruption by constant medical and lems, that extend into adulthood. nursing procedures. The functional short- Neonatal active sleep may be a critical term and long-term implications associated factor in the normal development and with disruption of the normal sleep cycles expression of respiration. at such early stages of development are just beginning to be understood. Premature • The functional properties of the supra- infants exposed to bright/dim light cycles in chiasmatic nucleus are developing and the nursery are more likely to sleep longer, become functional from mid-to-late begin to feed earlier, and grow better than gestation in experimental animals, allow- those under constant bright lights. There ing for sleep-wake rhythm entrainment has been extensive progress in understand- before and at birth. ing the functional properties and cellular and molecular mechanisms regulating sleep- • National guidelines for the regulation wake periodicities and the circadian clock, of light intensity in neonatal intensive but little is known about the maturation care units have been established. of such systems, especially considering the huge alterations in sleep-wake schedules that accompany fetal and early postnatal development. 102 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • R ESEARCH R ECOMMENDATIONS • Investigate the neurochemical, cellular, and molecular aspects of human sleep • Establish the ontogeny of fundamental ontogeny, including the use of mapping biological mechanisms mediating the techniques in post mortem human fetal regulation of sleep and waking needs and infant brains. to better understand the normal and abnormal consequences of the develop- • Study the short- and long-term conse- ment of such systems. quences of medical conditions associated with disruption of normal pregnancy and/ • Conduct studies to elucidate the under- or early postnatal life, (e.g., maternal ciga- lying mechanisms of changes in circadian rette smoking, cocaine or opiate addiction, rhythmicity during early postnatal life in materno-fetal insufficiency, prematurity). full-term and premature animal models These results may yield a better under- and in humans. standing of altered sleep and cardiorespira- tory control in early life and may provide • Conduct studies to assess the effects insight into regulatory mechanisms ulti- of prematurity per se and of treatment mately responsible for the occurrence conditions (e.g., light-darkness cycles) of disorders such as apnea of prematurity, in intensive care nurseries on cognitive sudden infant death syndrome (SIDS), function and brain development, and congenital central hypoventilation on the physiological maturation of syndrome, and developmental circadian regulation. neurobehavioral deficits. • Increase basic understanding of the specific effects of sleep state on neural plasticity and synaptic connectivity in developing mammals. SECTION VI—PEDIATRICS 103
    • ADOLESCENT SLEEP B ACKGROUND preference has also been explored as an important factor determining the timing Sleep and the unique features of physical, of sleep/wake cycles. cognitive, and social-emotional development that take place in adolescence must be con- • Studies of homeostatic regulation of sidered separately and in relationship to sleep and wakefulness have demon- sleep in children and in adults. Not only strated that sleep needs in adolescence do the biological changes associated with do not decline significantly, and optimal puberty profoundly affect sleep and wake- sleep amounts remain about 9 hours fulness, but many environmental and social into late adolescence. However, epi- factors are also implicated. Several sleep demiological research on “normal” disorders are particularly prevalent (delayed sleep patterns and amounts suggests sleep phase syndrome) or emergent (narco- that adolescents only average 7 to 7.5 lepsy) in adolescence. Furthermore, the hours of sleep per night, resulting in public health consequences of inadequate the accumulation of a considerable sleep (academic failure, drowsy driving) and sleep debt over time. These data suggest the potential for primary and secondary pre- that chronic partial sleep deprivation is vention in this age group are important. a serious problem in this age group and that particular subgroups may be at relatively higher risk. P ROGRESS IN THE L AST 5 Y EARS • Environmental and social factors also • Studies of normal sleep and sleep impact significantly upon delayed sleep patterns in adolescents have identified onset in adolescents, including. For important issues regarding the basic example, many adolescents have highly developmental physiology of sleep and irregular sleep/wake patterns from week- circadian rhythms in adolescence. The day to weekend. Another important factor role of pubertal/hormonal influences on potentially contributing to insufficient sleep circadian sleep-wake cycles and melatonin is the early start time of many middle and secretion has been recognized, and the high schools in the United States. effects include development of a relative • Chronic sleep restriction in adolescents phase delay (later sleep onset and wake leads to significant neurobehavioral con- times) in early puberty and the develop- sequences related to decline in alertness ment of a physiologically based decrease levels, including negative impact on mood, in daytime alertness levels in mid-to-late vigilance, reaction time, attention, memory, puberty. The genotypic expression in behavioral control, and motivation. These adolescence of delayed circadian phase 104 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • impairments may, in turn, be associated • Define the specific neurophysiologic with significant declines in school and mechanisms involved in the relationship work/occupational performance, increased between sleep and circadian timing risk-taking behaviors (use of alcohol, illicit and puberty. drugs, nicotine, caffeine, stimulants), and injuries. Adolescent males, for example, • Determine the extent, patterns, and are one of the highest risk groups for psychosocial factors responsible for motor vehicle crashes associated with chronic sleep restriction in adolescence. falling asleep. These studies should include cross-cultural analyses and should also include special and high-risk populations such as ado- R ESEARCH R ECOMMENDATIONS lescents with comorbid psychiatric conditions, mood disorders, attention • Ascertain the impact of chronic partial deficit hyperactivity disorder (ADHD), sleep deprivation on health outcomes, and chronic illness. including susceptibility to infection, metabolic consequences, immune function, • Determine the impact of interventions and use of potentially harmful alertness- to address chronic sleep restriction in promoting agents, such as caffeine and adolescents, including later school stimulant medications. Delineate the start times and high school education effects of chronic partial sleep deprivation programs about sleep. and sleepiness in adolescents on higher level cognitive or “executive” functions, • Determine the biopsychosocial and such as verbal creativity and working genetic factors that result in delayed memory, on motivation, and on affect sleep phase syndrome in adolescents, regulation. The assessment of health out- and assess the safety and efficacy of comes should also include occupational various treatment modalities, including and sports injuries, and motor vehicle administration of exogenous melatonin, crashes, and should determine scope of chronotherapy, and bright light therapy. the problem, high-risk groups, and inter- actions with other high-risk behaviors and substances (alcohol, marijuana, etc.). SECTION VI—PEDIATRICS 105
    • SLEEP IN MEDICAL DISORDERS Genetic Diseases and Syndromes tongue disorders. The micrognathia syn- Affecting Sleep and Breathing dromes include Treacher Collins Syndrome, an autosomal dominant syndrome (5q32-33.1, B ACKGROUND TCOF1), and Pierre Robin Sequence. Infants with these syndromes can experience pro- A large number of unique genetic disorders found SDB that requires aggressive inter- have primary or secondary sleep abnormali- vention to prevent physiologic compromise. ties. Understanding the pathophysiology The midfacial hypoplasia syndromes include of the autonomic nervous system (ANS) Apert Syndrome (10q26, FGFR2), Crouzon dysregulation that occurs in many of these Syndrome (10q26, FGFR2), and Pfeiffer pediatric disorders could improve our under- Syndrome (8p11.2-p11.1 or 10q26, FGFR1 standing of the maturation of the ANS and or 2). These are all autosomal dominant and the abnormalities that occur in common typically represent a fresh mutation. Children sleep disorders such as Sleep-Disordered with midfacial hypoplasia often have increas- Breathing (SDB). Investigating anatomical ingly severe SDB with advancing age due to mechanisms for the upper airway obstruc- maldevelopment and surgical intervention. tion found in children with craniofacial mal- Another example of midfacial hypoplasia formation could shed light on mechanisms is achondroplasia, an autosomal dominant for upper airway obstruction in SDB. Under- skeletal dysplasia (4p16.3, FGFR3) in which standing how other disorders produce pri- respiratory compromise is caused by an mary insomnia or daytime hypersomnolence abnormal rib cage, small foramen magnum, may also shed light on novel sleep-regulatory and SDB. Disorders with a protuberant mechanisms. tongue include the mucopolysaccharidoses, (e.g., Hunter Syndrome and Hurler Syndrome) Studies have demonstrated SDB and symp- and Down Syndrome (Trisomy 21), all with toms compatible with ANS dysregulation in identified genetic mutations and often with children with Idiopathic Congenital Central severe SDB requiring early intervention. Hypoventilation Syndrome (CCHS), Rett Syndrome (Xq28, MECP2), and Familial Disorders of the neuromuscular system Dysautonomia (9q31, IKBKAP). Few sleep impose a substantial burden at the multi- studies have been performed, however, in system level. Many of these children exhibit children with craniofacial malformations, dysfunction of the respiratory and upper chromosomal/genetic abnormalities, or in airway musculature that contributes to the children with neuromuscular diseases. development of SDB. For example, 15 to 20 percent of children with Duchenne Muscular Genetic and familial craniofacial syndromes Dystrophy will develop sleep disturbances, are often subdivided into those with microg- and this prevalence is even greater among nathia, midfacial hypoplasia, and protuberant patients with spinal muscular atrophy and 106 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • myelomeningocele. Since no well-defined P ROGRESS IN THE L AST 5 Y EARS clinical or biological criteria currently exist that enable prediction of which affected • The phenomenon of generalized ANS children will have a sleep disturbance, there dysfunction has become clearer among is significant under recognition of these prob- children with CCHS and Rett syndrome. lems. The morbidity and impact on quality Patients with Rett syndrome exhibit of life due to sleep disturbances in this pop- unique respiratory disturbances that ulation are, therefore, currently unknown. are state-dependent. SDB is frequently observed in the above- • Patients with Prader Willi syndrome described syndromes as a result of anatomic present with universal reductions in malformation, neuromuscular weakness, or their hypoxic ventilatory responses and morbid obesity. In addition, however, central with frequent alterations in their breath- factors also appear to be involved in addition ing patterns during sleep. Animal models to or independently of symptoms related to for some of these genetic conditions SDB. This may be the case for Prader Willi have become available, thereby opening Syndrome (15q12, SNRPN) and Angelman important opportunities for the study of Syndrome (15q11-q13, UBE3A), in which day- respiratory control and sleep interactions. time sleepiness and low hypocretin levels have • The study of control of breathing patterns been reported independently of SDB, suggest- in wakefulness and sleep in inbred mice ing hypothalamic dysregulation of sleep regu- strains has allowed for identification of lation. These disorders also frequently produce putative chromosomal locations for several complex behavioral and medical problems with of the respiratory control components. secondary effects on sleep, particularly dis- turbed nocturnal sleep and sleep apnea. It is • Despite extensive progress in understand- often difficult, therefore, to identify disease- ing the molecular and genetic mechanisms specific sleep phenotypes. underlying many of the neuromuscular diseases, the progress achieved in under- Other unique genetic syndromes without overt standing and defining when patients with SDB may also have associated primary central these disorders will manifest sleep distur- nervous system (CNS) sleep disorders. Fragile X bances has been extremely limited. Syndrome (Xq28, FRAXF; Xq28, L1CAM) chil- dren experience sleep disturbances and low melatonin levels, while subjects with Norrie R ESEARCH R ECOMMENDATIONS disease (genetic alterations in a region encom- passing the monoamine oxidase genes at • Conduct extended population studies in Xp11.4, NDP; Xp11.2, BMP15) or Niemann children, incorporating gene databases Pick Type C (18q-q12, NCPC1; 18q12.1-q12.2, and including multi organ and multifunc- DSG2) may experience cataplexy and sleep dis- tional categorization of disease-related turbances. Subjects with myotonic dystrophy morbidity and response to therapy, to (DM1, 19q13) often have abnormal breathing improve phenotypic and genotypic during sleep and possibly centrally mediated characterization of SDB with ANS dysfunc- hypersomnolence. Smith-Magenis syndrome tion and craniofacial maldevelopment. (SMS), including multiple congenital anomal- • Increase our understanding of primary ies and mental retardation (17p11.2, SMCR; sleep disturbances in genetic disorders 17q, PSORS2), is also associated with severe of children, with the goal of discovering sleep disturbances. new sleep-regulating mechanisms. SECTION VI—PEDIATRICS 107
    • • Conduct studies in naturally occurring Sudden Infant Death Syndrome (SIDS) diseases of ANS dysfunction to better SIDS is the sudden and unexpected death understand the ontogeny of the ANS of an infant under 1 year of age that remains from infancy through adulthood. unexplained after an autopsy, examination of • Conduct studies in naturally occurring the death scene, and thorough review of the diseases with anatomical malformations medical and family history. With the introduc- of the face and upper airway, to better tion of the Back to Sleep programs over the understand SDB, and its pathophysiology past decade, a remarkable decline in the and consequences with advancing age. incidence of SIDS has occurred worldwide. In the United States alone, the aggressive • Determine how and if SDB in these educational campaign targeting infant sleep unique diseases during childhood is position and other modifiable factors known linked to other diseases in adulthood. to be related to SIDS has resulted in a de- crease from 7,000 babies dying annually to • Develop novel interventional approaches fewer than 3,000. The National Institute to treat SDB in these special children, of Child Health and Human Development in collaboration with craniofacial and (NICHD) has completed a 5-year SIDS dental colleagues. plan divided into four sections: Etiology • Develop animal models to test hypotheses and Pathogenesis, Prognostics and Diag- generated from delineation of phenotype- nostics, Prevention, and Health Disparities. genotype correlations. The NICHD plan, in each of these sections, discusses: background, and makes specific • Establish the clinical correlates of sleep recommendations to address gaps in knowl- disruption and SDB in children with edge, intervention activities, and infrastruc- neuromuscular disease. ture needs. For a comprehensive review of SIDS and concomitant research recom- • Determine the implications of sleep mendations, readers are directed to the disturbances on end-organ morbidity and NICHD document, available online at mortality as well as on health related cost http://www.nichd.nih.gov/strategicplan/ and quality of life in children with neuro- cells/SIDS_Syndrome.pdf). muscular disease. 108 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • NEUROPSYCHIATRIC DISORDERS IN CHILDHOOD AND SLEEP B ACKGROUND P ROGRESS IN THE L AST 5 Y EARS Attention Deficit Hyperactivity Disorder (ADHD) • Studies of children with ADHD have is one of the most common psychiatric dis- examined the relationship between sleep orders in childhood, affecting approximately architecture, sleep patterns and behaviors, 5 to 10 percent of children. The etiology of and sleep disturbances and ADHD. When sleep disturbances observed in association using primarily parental (or self-report) with ADHD is likely to be multifactorial and surveys or polysomnography (PSG), results to vary among patients. In addition to medi- have been mixed and, at times, contradic- cation-related sleep effects, and the influence tory. While most “objective” studies have on sleep behavior of such common comorbid not found consistent significant differences conditions as oppositional defiant disorder, in sleep architecture and patterns between depression, and anxiety disorders, primary children with ADHD and controls, most sleep disorders, such as Sleep-Disordered parental report studies have reported sleep Breathing (SDB) and Restless Legs Syndrome/ problems including difficulty falling asleep, Periodic Limb Movement Disorder (RLS/PLMD) night wakings and restless sleep in children may present with “ADHD-like” symptoms with ADHD. These consistent discrepancies or exacerbate underlying ADHD. Primary between parental and more objective sleep abnormalities in central nervous system (CNS) measures remain an important research regulation of arousal, behavioral inhibition and clinical question. In addition, method- and self-regulation, and/or vigilance associ- ological concerns with many of these ated with ADHD have also been postulated studies include small sample sizes and to result in sleep disturbances, suggesting selection bias, variability in diagnostic a more primary or fundamental sleep-wake criteria for ADHD, variability in defining dysregulation in at least some children. Con- the control groups, and failure to consider siderable evidence suggests brain systems the effects of potential confounders, such regulating sleep and attention/arousal are as diagnostic subgroup of ADHD, medica- linked and that abnormalities in similar tion status, the presence of comorbid neurotransmitters, such as the noradrener- psychiatric conditions, and age. Virtually gic and dopaminergic systems, may be found no studies have examined sleep disturb- in ADHD and in sleep disturbances. These rela- ance in adolescents and young adults tionships are at present still poorly understood. with ADHD. SECTION VI—PEDIATRICS 109
    • • Studies have examined the complex adulthood. Describe the impact of ADHD relationship between primary sleep dis- on morbidity, including adverse behavioral orders, such as SDB and PLMD, and the outcomes such as injuries and motor constellation of neurobehavioral symptoms vehicle crashes, substance abuse, and that comprise the syndrome of ADHD academic failure. Describe the risks and (inattention, hyperactivity, impulsivity, protective factors for sleep disturbances executive function impairment). in children and adolescents with ADHD, and the impact of potential confounders, • Some small studies have explored the use such as comorbid psychiatric disorders of medications, such as clonidine for sleep and ADHD medication use. disturbances associated with ADHD, but no systematic studies of behavioral and/or • Examine the relationships and clarify clinical trials of pharmacologic treatment directionality between primary sleep dis- have been conducted. orders, such as SDB and RLS/PLMD, and symptoms of hyperactivity and inattention in children and adolescents. Prevalence R ESEARCH R ECOMMENDATIONS studies of primary sleep disorders in children diagnosed with ADHD are • Examine the neuroanatomical and also needed. neurophysiologic relationships between regulation of sleep and of attention and • Evaluate the efficacy of various treatment arousal, including the roles of the nor- modalities for sleep problems in ADHD, adrenergic, dopaminergic, and other including behavioral interventions and neurotransmitter systems. Develop pharmacotherapy, and the impact of animal models that present phenotypes treatment on the natural history of the associated with ADHD. disorder into adulthood. • Describe the scope and magnitude • Examine the long-term effects of of sleep disturbances in children and psychopharmacologic treatment for adolescents with ADHD, compared to ADHD, especially with psychostimulants, the general population, including the on sleep and sleep patterns of children natural history of sleep disturbances as and adults with ADHD. ADHD progresses into adolescence and 110 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SECTION VII EDUCATION AND TRAINING • Scientific Training • Clinical Education and Training • Public and Patient Education
    • SCIENTIFIC TRAINING B ACKGROUND P ROGRESS IN THE L AST 5 Y EARS A critical mass of appropriately trained scien- • Despite growth in the number of trainees tists across multiple disciplines is necessary in sleep science at all levels in the past to address fundamental scientific questions 5 years, this growth has been modest regarding mechanisms and functions of and has not kept pace with the number of sleep, its circadian regulation, and its role basic and clinical science research questions. in human health, safety, and quality of life. Sleep research is highly multidisciplinary. The • Efforts to determine the barriers to attract- Sleep Research Society’s current membership, ing more students to scientific work on for example, includes more than two dozen sleep have focused on: (1) lack of depart- academic disciplines. mental or graduate program support for the study of sleep, (2) lack of sleep science This diversity notwithstanding, the number training opportunities in established labora- of scientists being trained in sleep research tories, (3) insufficient numbers of physicians remains inadequate for the many basic and engaged in sleep research, and (4) uncer- patient-oriented research questions needing tainty about career opportunities in sleep investigation. Implementation of recommen- research. Recent multidisciplinary confer- dations in this Plan, for example, will require ences involving sleep researchers have scientific training opportunities in all relevant sought to attract trainees from other areas and at all career levels. Encouragement scientific areas to the study of sleep. and mentoring of trainees (Ph.D. and M.D.) at the graduate, postgraduate, fellowship, S CIENTIFIC T RAINING and early career levels is a particularly urgent R ECOMMENDATIONS need. Scientific trainees learn cutting-edge techniques in stable academic laboratories, • Enhance and sustain entry of new investi- which, in turn, requires a critical mass of gators in the basic sciences and patient- established investigators in sleep research. oriented research, as well as researchers Expanded opportunities to become engaged with multidisciplinary backgrounds into in sleep research would enhance the entry the sleep research field. Expand programs of young investigators into the field, thereby in sleep research training, including the seeding the future with the needed numbers training of investigators in new, basic, of sleep researchers in many scientific areas. and behavioral research areas targeted at sleep research questions (genetics, pro- teomics, molecular biology, neuroimaging, SECTION VII—EDUCATION AND TRAINING 113
    • bioinformatics, etc.) and patient- • Encourage innovative collaborative oriented sleep research areas (clinical training mechanisms, with interactive trials, epidemiology, preventive medicine). training provided by investigators from Expand dedicated sleep training programs different disciplines with complementary and provide incentives to existing non skills. Training investigators in patient- sleep training programs to include sleep oriented sleep research will be critical research tracks where there is a critical in addressing the clinical and applied mass of investigators. This would build research recommendations in this upon existing training infrastructures Research Plan. Residency research and also would be cost effective. tracks that include sleep research elec- tives are needed. Medical school research • Increase the number of investigators in tracks that focus on sleep should also sleep neuroscience. Systems neuroscience, be encouraged. particularly neurophysiological, is a strong component of current sleep research. • Develop research training programs that However, the number of investigators encourage and support the initiation of in this field is small in comparison to small sleep research projects by medical the number of scientific questions. students, nursing and other allied health professionals, and postgraduate trainees • Encourage training of basic scientists in related disciplines. and clinical investigators with interest in sleep research in development, as well as endocrine, metabolic, cardiovascular, and immune functions, given evidence that sleep may have important roles in these areas. Currently there are few opportuni- ties to combine training in these areas with sleep research. Training awards that specifically provide incentives to both trainees and established investi- gators should help close this gap. 114 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • CLINICAL EDUCATION AND TRAINING B ACKGROUND as a specialty and in formalizing training infrastructure to sustain sufficient growth Education and training are integral to meet- in the field, empirical data from survey and ing the goals of sleep medicine in improving clinical outcome studies indicate that, in clinical practice and patient-oriented out- general, physician education regarding the comes. Successful educational interventions recognition, diagnosis, management, and require the development, implementation, prevention of clinical sleep disorders in both and dissemination of materials covering a adults and children is inadequate. Substantial wide range of topics, including the basic knowledge deficits exist at the medical school neurobiology of sleep and circadian rhythms, level, as well as at the post-graduate training clinical sleep disorders and evidenced-based and continuing education levels. treatment, the consequences of sleep depri- vation, and the role of sleep in health and Important public health implications result disease. Education and training must be from the large gaps between scientific targeted toward all relevant professional knowledge, clinical teaching and practice. and public audiences, and must include For example, it is known that physicians evaluation of the impact of such programs outside sleep medicine significantly under- on public health. diagnose or misdiagnose sleep disorders, leading to increased morbidity and decreased quality of life. Furthermore, early intervention Physician Education and Training efforts to detect and prevent sleep disorders The practice of sleep medicine is inherently are likely to be significantly compromised by multidisciplinary, drawing physicians from this lack of education and training. many areas such as geriatrics, neurology, internal medicine and pediatrics (including To address these concerns, the need exists pulmonology, neonatology, critical care), to further define a knowledge base in sleep psychiatry, and surgery. Because of this medicine and circadian biology, develop a diversity, the field of sleep medicine con- basic sleep curriculum for medical schools, tinues to evolve standards, practices, and and create appropriate educational tools training opportunities. In April 2002, for as a foundation for enhanced learning example, the American Academy of Sleep at all levels. Current medical education Medicine submitted an application to the activities are involved with curriculum Accreditation Council on Graduate Medical development, and will require application Education requesting the establishment of of rigorous methodological criteria for a Residency Review Committee approval of outcome measures and demonstration of fellowship training programs in sleep medicine. efficacy of teaching methods and tools. Despite advances in defining sleep medicine SECTION VII—EDUCATION AND TRAINING 115
    • Knowledge, competence, and behavioral sleep disorders in patients being treated by change objectives involve different methods other medical specialties. Psychologists have of assessment. Specific knowledge acquisi- become increasingly important in the evalua- tion, for example, is usually measured with tion and behavioral treatment of insomnia. standard written tests, skills acquisition with Dentists have become actively involved in performance-based assessment, and behav- the treatment of sleep apnea with mandib- ioral changes with self-report or structured ular devices. These health care initiatives observational methods. would benefit from coordination of evalu- ation research to determine the impact on Assessment of impact on clinical practice behavioral change, clinical practice, and may depend upon a variety of health out- ultimately on the quality of patient care come measures, including quality of life in sleep medicine across these disciplines. and disease prevalence data, tracking of health care utilization, and cost-benefit P ROGRESS IN THE L AST 5 Y EARS analyses. However, little research in sleep education has yet been directed toward • In a 1978 survey of sleep education evaluation of these types of outcomes in medical schools in the United States, elated to professional knowledge, attitudes, the American Sleep Disorders Association and changes in clinical practice behavior. found that less than 10 percent of schools Some evaluation tools do exist, such as offered adequate training and 46 percent knowledge surveys and standardized clinical included no sleep medicine at all in the examinations, but most are not validated, curriculum. In 1990, a medical education and few are widely available. Although survey reported relatively little progress, clinical care is likely to be improved by con- with 37 percent of medical schools offer- tinuing medical education efforts targeted ing no sleep education. In those schools at improving knowledge and skills, and that did, the average time devoted to fostering behavioral change in practicing sleep in the 4-year curriculum was less physicians, sleep medicine has not been than 2 hours. Subsequent surveys of post- included in research on effective strategies graduate training programs in adult and to change physician behavior. Prospective, pediatric medicine have found similar multicenter, structured trials are needed results, with lack of time in the curriculum to accomplish these goals. and of qualified instructors cited as major barriers. Surveys of practicing physicians Education and Training of conducted in the last 5 years reveal similar Other Health Professionals gaps in knowledge and clinical practice despite increasing recognition of the Dentists, nurses, pharmacists, and psycholo- importance of sleep in the health and gists are increasingly involved in identification well-being of their patients. and treatment of sleep disorders. These disci- plines should also be targeted for educational • In 1996, the National Center on Sleep interventions. The educational needs of these Disorders Research (NCSDR) developed various disciplines overlap with those of phy- the Sleep Academic Award (SAA) Pro- sicians, but additional educational resources gram to help address these educational and strategies are needed to address their gaps. Twenty medical schools in the unique concerns. For example, nurses poten- United States were awarded 5-year tially have a key role in the identification of 116 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • grants to develop model medical school C LINICAL E DUCATION AND curricula in sleep medicine, to promote T RAINING R ECOMMENDATIONS interdisciplinary learning environments, and to improve the quality of sleep • Develop sleep education programs at education and education research at the medical school, postgraduate, and all levels, including the public arena. continuing medical education levels, and The SAA Program has raised awareness develop a coordinated, structured, and of sleep education in both the sleep and scientifically rigorous approach to evaluate general medical communities, and has the impact of sleep education programs laid the foundation for continued sleep and tools across multiple institutions and education development by facilitating clinical settings. Outcome measures should the creation of screening and evaluation include assessment of changes in: tools such as the ASK-ME Survey of sleep knowledge, regional and national faculty – Physician knowledge, attitudes, skills, development workshops, and public edu- and behavior cation programs on sleep. Development – Clinical practice of MedSleep, a Web-based repository of over 50 sleep education tools and – Patient health and quality of life products developed by the awardees and available to all health professional • Evaluate the effectiveness of strategies and educators, was the result of a collabo- to address these training gaps. This rative effort between the SAA Program should be based on a needs assessment and the American Academy of Sleep of educational gaps in sleep training Medicine (AASM). among other health professions includ- ing but not restricted to nursing, dentistry, • The SAA Program, in collaboration with pharmacy, clinical psychology and other the AASM and the American Medical mental health disciplines. Outcome Association (AMA), has initiated a measures should include assessment collaborative education and research of changes in: effort to address the issue of sleep and fatigue in medical training. Several – Professional knowledge, attitudes, research projects, including a multiple site skills, and behavior collaborative study, have evolved from this – Clinical practice initiative. In 2001, a national conference was held to define specific research goals – Patient health and quality of life and objectives regarding consequences of sleep loss in physicians and to develop effective interventions. SECTION VII—EDUCATION AND TRAINING 117
    • PUBLIC AND PATIENT EDUCATION B ACKGROUND Limb Movement Disorder (RLS/PLMD) are another key component. Target audiences Support and promotion of health education may be defined as high risk for sleep disorders are necessary steps to establish links between and/or sleep deprivation by virtue of age basic science and clinical outcomes and to (elderly, adolescents), demographics (minority, facilitate the translation of research findings medically underserved), gender (pregnant or to address public health concerns, such as menopausal women, young adult males), those outlined in the U.S. Department of other health risks (obesity), and work sched- Health and Human Services “Healthy People ules (shift workers, commercial drivers). 2010” initiative. Health education initiatives support primary prevention and increase Educational campaigns directed toward high- recognition of sleep disorders in the general risk populations (e.g., adolescents) and toward community, as well as broaden the scope of receptive audiences (e.g., elementary school secondary and tertiary prevention efforts in children) may be efficient and cost-effective patients with diagnosed sleep disorders. Public ways to enhance prevention and early detection education campaigns provide information to of sleep problems. These campaigns also should increase knowledge, to enable modification include groups that can facilitate behavioral of health risks, and also to help foster a sup- change but may be hard to reach, including portive social environment for facilitating posi- teachers, coaches, school nurses/health edu- tive behavioral change. To accomplish these cators, parents, and pediatricians). Specific goals, effective teaching tools and strategies educational strategies should include culturally need to be developed and mechanisms need sensitive materials appropriate for a range of to be implemented for evaluation of sleep literacy levels and novel methods of translation educational materials for the general public. and dissemination of information (e.g., Web- based products). Finally, outcome measures It is important to delineate the educational to assess the effectiveness of educational needs of the target audience, to define and interventions include changes in knowledge, prioritize the educational messages, and to attitudes, health-related behaviors, and ulti- identify potential opportunities and barriers mately in the health of the target audience. related to health-related behavioral change. Process measures describing the extent to which Specific topics that have been identified as information is disseminated, programs are uti- key components in public and patient sleep lized, and target audiences are reached may education programs include those related to be surrogate measures for evaluating results. basic regulation of sleep and circadian rhythms, sleep deprivation (extent, signs, causes, and P ROGRESS IN THE L AST 5 Y EARS consequences), and sleep hygiene. Prevalent, serious, and/or frequently under recognized The National Center on Sleep Disorders sleep disorders, including SDB, insomnia, nar- Research (NCSDR), part of the National colepsy, and Restless Legs Syndrome/Periodic Heart, Lung, and Blood Institute (NHLBI), 118 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • coordinates public and patient sleep dis- implemented to encourage awareness of orders education in collaboration with the sleep as a health issue and to foster healthy Office of Prevention, Education, and Control sleep habits in children and adolescents. (OPEC). These efforts facilitate the translation These interventions include the “Sleep and dissemination of research and scientific well. Do well. Star Sleeper” campaign consensus to the general public, patients, for children ages 7 to 11, and a high and health professionals. Recent sleep school supplemental curriculum on the education programs include: biology of sleep, “Sleep, Sleep Disorders, and Biological Rhythms”. The school-aged • Initiation of a 5-year media-based public intervention highlights Garfield as the awareness campaign on Sleep-Disordered “spokescat” for healthy sleep and includes Breathing (SDB). classroom activities, national and local media components, and a Web site with • Development of fact sheets for the public content targeted specifically for children, and patients on sleep disorders including teachers, and pediatricians. SDB, insomnia, narcolepsy, RLS, and prob- lem sleepiness. Companion booklets for primary care physicians have been devel- R ESEARCH R ECOMMENDATIONS oped and published in the journal American Family Physician. Partnerships with profes- • Develop effective and innovative educational sional organizations, such as the American approaches based on needs assessments Academy of Family Practice, the American of high risk and target groups that include Academy of Pediatrics, the American Sleep both quantitative and qualitative research Apnea Association, the American Academy methodologies. These approaches should of Sleep Medicine, and other national identify specific educational opportunities organizations involved in sleep research and barriers, target sleep health educational and education, have enabled wider interventions, and improve strategies for dissemination of these materials than dissemination of educational materials to would otherwise have been possible. patients and the general public. • Development of the NCSDR Web site, • Evaluate the effectiveness of: www.nhlbi.nih.gov/sleep, where edu- – Public sleep education initiatives on pub- cational materials are available and can lic health outcomes in high risk, minority, be viewed and downloaded. and medically underserved populations. • Development of a “Sleep IQ” quiz to – School-based sleep education programs raise public awareness of the signs of on knowledge, attitudes, and sleep sleep deprivation and the symptoms of practices of children and adolescents, sleep disorders. parents, and teachers. • Development of a drowsy-driving edu- – Educational efforts directed to relevant cational campaign targeted at high school State regulatory agencies (e.g., Depart- students in partnership with the National ments of Motor Vehicles) and related Highway Traffic and Safety Administration. to adverse consequences of sleep • Initiation of Latino education efforts about deprivation and sleep disorders on sleep disorders, including translation of safety including drowsy driving, and selected materials into Spanish and devel- to identifying education efforts that opment of lay health educator programs. have positive impact on public School-based interventions were education and safety. SECTION VII—EDUCATION AND TRAINING 119
    • ABBREVIATIONS AD Alzheimer’s disease ADHD Attention Deficit Hyperactivity Disorder ANS Autonomic Nervous System ASPS Advanced Sleep Phase Syndrome CCHS Congenital Central Hypoventilation Syndrome CFS Chronic Fatigue Syndrome CNS Central Nervous System CPAP Continuous Positive Airway Pressure DHHS Department of Health and Human Services EMG Electromyogram EOG Electrooculogram ESRD End Stage Renal Disease FM Fibromyalgia fMRI Functional Magnetic Resonance Imaging IL Interleukin MEG Magnetoelectroencephalography MRS Magnetic Resonance Spectroscopy NCSDR National Center on Sleep Disorders Research NHLBI National Heart, Lung, and Blood Institute NIH National Institutes of Health NIR Near-Infrared Optical Imaging NREM Non-Rapid Eye Movement Sleep OSA Obstructive Sleep Apnea PD Parkinson’s disease PET Positron Emission Tomography PLMD Periodic Limb Movement Disorder PSG Polysomnography RBD REM Sleep Behavior Disorder REM Rapid Eye Movement Sleep RLS Restless Legs Syndrome SCN Suprachiasmatic Nucleus SDB Sleep-Disordered Breathing SIDS Sudden Infant Death Syndrome SPECT Single Photon Emission Computed Tomography TMJD Temporomandibular Joint Disorder 120 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • INDEX cancer 50, 54, 58, 67 cardiopulmonary 51, 67 Accreditation Council on Graduate cataplexy 17-18, 36, 84-86, 107 Medical Education 115 catecholamine 88 achondroplasia 106 Cheyne-Stokes respiration 76-77 adenosine 61, 81 chloral hydrate 83 adenotonsillar hypertrophy 78 cholinergic 21, 97 adolescence 3, 9, 47, 50-53, 83, 86, 98, chronic fatigue syndrome 67 104-105, 110 chronic partial sleep loss 14, 25-26 advanced sleep phase syndrome 2, 36 circadian iii, 2-5, 9, 13-16, 19-22, 26, 34-37, African American 57-59, 95, 97 48, 51-52, 54-55, 60-66, 68, 75, 80, 83, aging 10, 14-15, 20, 43, 52, 56, 59, 60-62 87, 95-96, 98, 102-05, 113, 115, 118 airway patency 5, 77-78 clock genes 2, 13, 36 alcohol vii, 7, 20-21, 54, 59, 63, 76, 90, 92, clonidine 83, 110 95-98, 105 Congenital Central Hypoventilation Alzheimer’s disease 7, 20, 41, 90-91 syndrome 3, 106 amygdala 97 congestive heart failure 3, 7, 68, 76-77 anemia 55 continuous positive airway pressure 6, 76 Angelman’s syndrome 82 corticotropin 81 anticonvulsants 89 cost-benefit 116 antidepressant 21, 39, 81, 84, 98 craniofacial 7, 78, 106-08 Apert Syndrome 106 Creutzfeldt-Jakob disease 90 apnea 2-3, 5, 33, 36, 76-77, 91, 101, 103, curriculum 3-4, 59, 115-16, 119 107, 116, 119 cytokines 73-74, 96, 98 arousal 7, 18-19, 42, 76, 82, 87-88, 92-94, d-amphetamine 21, 26 98, 109-10 daytime sleepiness iii, vii, 29, 48-50, 53, arthritis 59, 67, 73, 82 56, 60-61, 67-68, 74, 84, 86-88, 91, Asperger’s syndrome 82 95-96, 107 asthma 67-68, 82-83 delayed sleep phase syndrome 14, 104-105 attention deficit hyperactivity disorder delta sleep 95, 97 3, 88, 109 dementia 42, 60-61, 93 autism 82 depression 3, 7, 39, 49, 51, 53, 56, 59, 67, autonomic nervous system 7, 92, 106 95-98, 109 basal ganglia 38, 68, 93 dextroamphetamine 21 bed-sharing 48 diabetes 14, 49, 51, 57-58, 67-68, 82-83 benzodiazepine 19, 21, 26, 83 diphenhydramine 83 blindness 82 disparities vii, 1, 9, 48, 57-59, 108 body temperature 52, 54-55 dopamine 17, 20, 87-91, 93 brain bank 8, 93 Down syndrome 106 brainstem 2, 17, 21, 38, 41, 43, 88, 91 drosophila 16 caffeine 19-21, 26-27, 65-66, 105 drowsiness 65 INDEX 121
    • drowsy driving 4, 63, 104, 119 hypnotherapy 94 dysmenorrhea 53, 55-56 hypocretin 2, 6, 14, 16-18, 36, 41-42, 81, electromyographic 33 84-86, 107 electrooculographic 33 hypopneas 33, 91 encephalitis 7, 90-91 hypothalamus 2, 14, 17, 42-43, 85, 91 encephalographic 21-22 injuries 64, 105, 110 end-stage renal disease 67, 87 insomnia 1, 3, 5-7, 14, 19-20, 34, 42, 50, 53-56, 58-61, 67-69, 80-83, 87, 95-98, epilepsy 7, 90-91, 93 106, 116, 118-119 esophageal spasm 92 insulin resistance 3, 49, 68, 76 ethanol 19, 21 interleukins 73-74 extrastriatal 88 intermittent hypoxia 7, 52, 90, 136-37 fatal familial insomnia 20, 42, 90 knock-out 74-75 fatigue 3, 54-55, 63-68, 74, 87, 91, 95, 117 lateral geniculate nucleus 101 fibromyalgia 67 leptin 20 functional magnetic resonance imaging 38 Lewy bodies 42, 93 gammahydroxybutyric 85-86 light exposure 48, 51 gene-environment 9, 59, 73-74 limbic system 42 genetic 2, 4-7, 9-10, 14, 16-21, 27, 35-37, low birth weight 54 41, 43, 50-51, 57-59, 61, 73-75, 77-78, 81, 83-84, 86, 92-94, 105-07, 113, magnetic resonance spectroscopy 38 134-135 magnetoelectroencephalography 38 glucose tolerance 58 MDMA 19, 97 gonadatropin 52 medical and surgical residents 64 hallucination 84 melatonin 26, 61, 68, 82, 104-05, 107 health care utilization 80, 116 memory 16, 25-26, 29, 60, 64-65, 101, health education vii, 3, 9, 118-19 104-05 health-related quality of life 58 menopause 9, 52, 54, 56 Healthy People 2010 4, 47, 57, 118 menstrual 53-56 heart disease 19, 49-50, 57, 59-60 mental retardation 82, 107 Hispanic 57, 59 metabolic syndrome 76-77 HIV 57, 67-68 methylphenidate 21, 26 homeostatic sleep regulation 68 minority 82, 118, 119 hormone replacement therapy 20, 54 modafinil 20-21, 26, 85-86 host defense 74 mood disorders 53, 95, 98, 105 human leukocyte antigen 84 Morphine 21 hyperarousal 80 motor vehicle crashes 49, 63, 65, 105, 110 hypercapnia 76 multiple sclerosis 90-91 hyperoxic 101 Multiple Sleep Latency Test 84 hypersomnia 37, 84-85, 96-97 murine 13, 16-17, 36, 84 hypertension 3, 54-55, 57-58, 60, 68, 76-78 muscular atrophy 106 122 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • myotonic dystrophy 90, 107 pediatric 1, 3, 6-7, 10, 28, 56, 78-79, 81-83, naps 50, 64-65, 84 94, 106, 115-16, 119 narcolepsy 2, 5-6, 16, 18-20, 27, 36-37, performance deficits 25, 27, 29, 66 41-42, 58, 84-86, 93, 118-119 periodic limb movement disorder 5-6, 53, National Center on Sleep Disorders Research 60, 87, 109, 118 iii, vii, viii, 116, 118 Pfeiffer syndrome 106 National Heart, Lung, and Blood Institute pharmacogenomics 61 iii, v, vii, 118 Pharmacology 19-21 near-infrared optical imaging 38 phase delay 104 neonatal 101-02 phenotype 5-6, 8-9, 17, 19, 27, 35-37, 47, neurobehavioral 3, 25-29, 50, 52, 64-65, 51, 73-75, 77-78, 80-81, 93-94, 101, 78, 103-04, 110 107-08, 110 neurobiology 2, 4, 6, 10, 16, 25, 80-81, Pierre Robin sequence 106 115, 134, 136-37 plasticity 26-28, 97, 101-03 neurodevelopmental 7, 28, 82-83 polysomnography 33, 59, 77, 79, 84, 109 neuroendocrine 28, 52-53, 69, 73-75 positron emission tomography 38 neuroimaging 5, 8, 28-29, 38-39, 68, 81, post traumatic stress disorder 7, 95 93, 95, 98, 113 Prader Willi syndrome 107 neurology 10, 86, 115 pre-eclampsia 54-55 neuropathology 9, 10, 41, 43, 91 pregnancy 9, 18, 52-56, 87, 89, 103 night sweats 54-55 prematurity 50, 101, 103 nightmares 92, 95-97 preprohypocretin 36, 84 nigrostriatal 88 prion disorder 42, 90 non-REM sleep 4, 16-18, 26-27, 33, 38-39, progesterone 53, 55-56 92, 96-97, 101 progressive supranuclear palsy 90 nonrestorative 67 prolactin 68 noradrenergic 109 psychiatric vii, 3, 7, 60, 67, 77, 80-81, 92, nutrition 47, 50 95-98, 105, 109-10, 135 obesity 6, 14, 49, 51, 57-58, 67, 77-79, psychoactive 95, 97-98 107, 118 psychostimulants 19, 21, 110 ontogeny 103, 108 puberty 52-53, 56, 104-05 opiates 19, 87, 95, 103 public health iii, vii, 3-4, 6, 9-10, 47, 49, 59, oral appliances 6, 77 63, 104, 115, 118, 119 oral contraceptives 55 quality of life vii, 6-8, 54, 58, 60, 67, 76-77, oximetry 33 82, 87, 89, 108, 113, 115-17 pain vii, 7, 21, 39, 67-69, 82-83 racial and ethnic minorities vii, 9, 57, 59 parasomnia 17, 18, 92-94 Rechtschaffen and Kales 33 Parkinson’s disease 7, 90-91, 93 REM behavior disorder 39, 42 partial sleep deprivation 3, 25, 27, 29, 68, REM latency 55, 95 104-05, 137 INDEX 123
    • REM sleep 2, 4, 16-18, 21, 39, 42, 55-56, sleep terrors 92 84, 90, 92, 95, 97, 101-02 Sleep-Disordered Breathing 2, 5-6, 17, 20, respiration 5, 9, 33, 34, 76, 91, 98, 102 27, 33, 36, 42, 48, 52, 57, 60, 63, 76, restless legs syndrome 5-6, 14, 19, 36, 39, 90, 95, 106, 109, 119 42, 53, 60, 87, 95, 109, 118, 135 sleep-wake 10, 13, 18, 33, 47, 60-61, 92-93, reticular activating system 39 98, 102, 104, 109 Rett syndrome 3, 41, 82, 106-07 sleepwalking 92 rhythmic movement disorders 94 Smith-Magenis syndrome 82, 107 San Filippo syndrome 82 smoking 50, 57, 103 schizophrenia 41, 97 snoring 54-55, 57-58, 78 school start times 64, 105 socioeconomic status 51, 57 sedative/hypnotics 19 special needs populations 82 selective serotonin reuptake inhibitors 93 stroke 3, 7, 57, 77, 90-91 serotonergic 41-42, 94, 97 substance use disorders 3, 7, 95-96 sex differences 1, 52-53, 56 Sudden Infant Death syndrome 3, 20, 41, 48, 96, 103, 108 sexual dimorphism 52 Sudden Unexpected Nocturnal Death shift work 2, 14-15, 25-26, 63-64 syndrome 59 sickle cell disease 58, 82 suprachiasmatic nucleus 2, 13, 61 single photon emission computed sympathetic nervous system 59, 74, 80-81 tomography 38 temporomandibular joint disorders 67 Sleep Academic Award 3, 116 thalamus 38, 42-43, 68 sleep architecture 21, 33, 54, 67, 73-74, 92, 95-96, 98, 109 training iii, viii, 3, 9, 10, 41, 64, 65, 113-17 sleep debt 16-18, 28, 49-51, 63, 104 transgenic 74-75 sleep deprivation 3, 7-8, 14, 16, 21, 25-28, trauma 7, 57, 67, 90-91 37, 39, 51-53, 73-74, 90-91, 93, 95, trazadone 83 97-98, 102, 105, 118-19 Treacher Collins syndrome 106 sleep efficiency 54-55, 96 truck drivers 63-64 sleep inertia 20, 26-27, 39, 94 tuberous sclerosis 82 sleep paralysis 84 uremia 89 sleep position 48, 51, 108 vagus nerve stimulation 91 sleep quality vii, 4-5, 7, 19, 48-55, 57-58, ventilatory control 5, 77 60-62, 67, 69, 73, 83, 95 ventrolateral preoptic nucleus 61 sleep restriction vii, 3, 16, 25-29, 47, 50, visual cortical responses 102 74, 104-05 William syndrome 82 sleep surface 48, 50-51 124 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • APPENDICES • Appendix A: National Sleep Disorders Research Plan Revision Task Force • Appendix B: National Sleep Disorders Research Advisory Board • Appendix C: NIH Sleep-Related Initiatives, 1996 to 2002
    • APPENDIX A: NATIONAL SLEEP DISORDERS RESEARCH PLAN REVISION TASK FORCE Chair: David P. White, M.D. Associate Professor of Medicine Harvard Medical School Division of Sleep Medicine Brigham and Women’s Hospital Boston, MA dpwhite@rics.bwh.harvard.edu Thomas J. Balkin, Ph.D. Steven J. Henriksen Ph.D. Chief, Department of Behavioral Biology The Scripps Research Institute Walter Reed Army Institute of Research Department of Neuropharmacology Silver Spring, MD La Jolla, CA thomas.balkin@na.amedd.army.mil steven@scripps.edu Gene D. Block, Ph.D. Hannah C. Kinney, M.D. Vice President and Provost Associate Professor of Neuropathology University of Virginia Department of Pathology Charlottesville, VA Harvard Medical School gdb@virginia.edu Children’s Hospital Boston, MA Daniel Buysse, M.D. hannah.kinney@TCH.Harvard.edu Associate Professor of Psychiatry University of Pittsburgh Carol A. Landis, D.N.Sc., R.N. Western Psychiatric Institute and Clinic Professor, Biobehavioral Nursing and Pittsburgh, PA Health Systems BuysseDJ@MSX.UPMC.EDU Scientific Director, Biobehavioral Laboratories Center for Women’s Health Research David F. Dinges, Ph.D. University of Washington Professor of Psychology in Psychiatry Seattle, WA Chief, Division of Sleep and Chronobiology calandis@u.washington.edu Department of Psychiatry University of Pennsylvania School of Medicine Emmanuel Mignot, M.D., Ph.D. Philadelphia, PA Director, Center for Narcolepsy dinges@mail.med.upenn.edu Stanford University School of Medicine Stanford, CA David Gozal, M.D. mignot@leland.stanford.edu Professor and Vice-Chair for Research Department of Pediatrics Judith A. Owens, M.D., M.P.H. University of Louisville Associate Professor of Pediatrics Louisville, KY Brown Medical School d0goza01@gwise.louisville.edu Director, Pediatric Sleep Disorders Clinic Hasbro Children’s Hospital Providence, RI Owensleep@aol.com APPENDICES 127
    • Jerome Siegel, Ph.D. Consultants Professor of Psychiatry and Biobehavioral Sciences Clifford B. Saper, M.D., Ph.D. Center for Sleep Research Harvard Medical School VA GLAHS-Sepulveda Boston, MA North Hills, CA JSiegel@UCLA.edu Mark W. Mahowald, M.D. University of Minnesota Esther Sternberg, M.D. Minneapolis, MN Director, Integrative Neural-Immune Program Chief, Section on Neuroendocrine Immunology and Behavior National Institute of Mental Health/NIH Bethesda, MD es93d@nih.gov Debra E. Weese-Mayer, M.D. Professor of Pediatrics Rush University Chicago, IL Debra_E_Weese-Mayer@rush.edu 128 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • APPENDIX B: NATIONAL SLEEP DISORDERS RESEARCH ADVISORY BOARD Chair: Stuart F. Quan, M.D. (2005) Professor of Medicine, Respiratory Sciences Center The University of Arizona College of Medicine 1501 North Campbell Avenue Tucson, AZ 85724 squan@resp-sci.arizona.edu Gene D. Block Ph.D. (2004) Susan Redline, M.D., M.P.H. (2006) Vice President and Provost Chief, Division of Clinical Epidemiology University of Virginia Department of Pediatrics Charlottesville, VA 22904-2477 Case Western Reserve University gdb@virginia.edu Rainbow Babies and Childrens’ Hospital 11400 Euclid Avenue Sarah J. Caddick, Ph.D. (2004) Cleveland, OH 44106 Executive Director sxr15@po.cwru.edu Wadsworth Foundation 3601 Fremont Ave N. Ste. 303 Clifford B. Saper, M.D., Ph.D. (2005) Seattle, WA 98103 Professor and Chair sarahc@wadsworthfoundation.org Department of Neurology and Program in Neuroscience Mary Carskadon, Ph.D. (2003) Harvard Medical School Professor Beth Israel Deaconess Medical Center Department of Psychiatry and Human Behavior 330 Brookline Avenue Brown University School of Medicine Boston, MA 02215 E. P. Bradley Hospital Sleep Research Laboratory csaper@caregroup.harvard.edu 1011 Veterans Memorial Parkway East Providence, RI 02915 Michael J. Sateia, M.D. (2006) mary_carskadon@brown.edu Professor of Psychiatry Director, Section of Sleep Medicine Kathryn A. Lee, Ph.D. (2006) Dartmouth-Hitchcock Medical Center Professor, Family Health Care Nursing Lebanon, NH 03756 School of Nursing Michael.J.Sateia@dartmouth.edu University of California, San Francisco 2 Koret Way, Box 0606 Dara D. Spearman (2003) San Francisco, CA 94143 2816 Pittsfield Boulevard kathy.lee@nursing.ucsf.edu Ann Arbor, MI 48104 dspearma@med.umich.edu Sandra McGinnis (2003) 176 Governors Road Phillip L. Williams (2004) Ponte Vedra Beach, FL 32082 4472 Golf Club Lane james.mcginnis@mx3.com Brooksville, FL 34609 pwilli16@tampabay.rr.com Rafael Pelayo, M.D. (2006) Assistant Professor Department of Psychiatry and Behavioral Sciences Stanford University 401 Quarry Road, PBS 3350 Stanford, CA 94305 pelayo@stanford.edu APPENDICES 129
    • SLEEP DISORDERS RESEARCH ADVISORY BOARD E X O FFICIO M EMBERS Colonel Gregory Belenky, M.D. Merrill M. Mitler, Ph.D.* Director, Division of Neuropsychiatry Program Director, Systems and Walter Reed Army Institute of Research Cognitive Neuroscience Washington, DC 20307-5100 National Institute of Neurological Disorders gregory.belenky@na.amedd.army.mil and Stroke/NIH 6001 Executive Boulevard, Room 2108, MSC 9521 Robert Wolfe Greene, M.D., Ph.D. Bethesda, MD 20892-9521 University of Texas mitlerm@ninds.nih.gov Southwestern Medical Center 4500 South Lancaster Road Andrew Monjan, Ph.D., M.P.H.* Dallas, TX 75214 Chief of Neurobiology and Neuropsychology robertw.greene@utsouthwestern.edu Neuroscience and Neuropsychology of Aging Program Carl E. Hunt, M.D., SDRAB Executive Secretary National Institute on Aging/NIH Director Gateway Building, Suite 3C307 National Center on Sleep Disorders Research Bethesda, MD 20892 National Heart, Lung, and Blood Institute/NIH am39m@nih.gov Two Rockledge Center, Suite 10038 6701 Rockledge Drive MSC 7920 Marian Willinger, Ph.D.* Bethesda, MD 20892-7920 Health Scientist Administrator huntc@nhlbi.nih.gov Pregnancy and Perinatology Branch National Institute of Child Health and Israel Lederhendler, Ph.D.* Human Development/NIH Coordinator for Sleep Research 6100 Executive Boulevard, Room 4B03D National Institute of Mental Health/NIH Bethesda, MD 20892 Neuroscience Center, MSC 9637 mw75q@nih.gov 6001 Executive Boulevard, Room 7169 Bethesda, MD 20892-9637 Eve E. Slater, M.D. ilu@helix.nih.gov Assistant Secretary for Health Department of Health and Human Services Claude Lenfant, M.D. Washington, DC 20201 Director National Heart, Lung, and Blood Institute/NIH Elias Zerhouni, M.D. 9000 Rockville Pike Director, National Institutes of Health Building 31, Room 5A52 One Center Drive Bethesda, MD 20892 Building 1, Room 126, MSC 0148 lenfantc@nhlbi.nih.gov Bethesda, MD 20892 execsec1@od.nih.gov * Member of the Trans-NIH Sleep Research Coordinating Committee 130 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • SLEEP DISORDERS RESEARCH ADVISORY BOARD L IAISON M EMBERS Deborah Ader, Ph.D.* Nancy Pearson, Ph.D.* National Institute of Arthritis and National Center for Complementary Musculoskeltal and Skin Diseases and Alternative Medicine/NIH 45 Center Drive, Room# 5AS19H 6707 Democracy Boulevard, Room 401 Bethesda, MD 20892 Bethesda, MD 20892 aderd@mail.nih.gov pearsonn@mail.nih.gov Daniel P. Chapman, Ph.D., M.S. Christopher Platt, Ph.D. Centers for Disease Control and Prevention Program Director, Neuroscience 4770 Buford Highway, N.E., Mailstop K-45 Division of Integrative Biology and Neuroscience Atlanta, GA 30341 National Science Foundation dpc2@cdc.gov 4201 Wilson Boulevard, Room 685 Arlington, VA 22230 Harold Gordon, Ph.D.* cplatt@nsf.gov Program Official, Clinical Neurobiology Branch Division of Treatment Research and Development Thomas G. Raslear, Ph.D. National Institute on Drug Abuse/NIH Senior Human Factors Program Manager 6001 Executive Boulevard, Room 4233, Office of Research and Development MSC 9551 Federal Railroad Administration Bethesda, MD 20892-9551 United States Department of Transportation hg23r@nih.gov Washington, DC 20590 thomas.raslear@fra.dot.gov Mary Leveck, Ph.D., R.N.* Deputy Director, National Institute of Roger R. Rosa, Ph.D. Nursing Research National Institute for Occupational Safety Building 31, Room 5B05 and Health Bethesda, MD 20892-2178 200 Independence Avenue, N.W., Room 715H mary.leveck@nih.gov Washington, DC 20201 rrosa@cdc.gov Adrienne Oneto Chief, Health Surveys Branch George Ruby, M.D. Bureau of the Census, Demographic United States Department of Surveys Division Occupational Safety and Health Administration Building 3, Room 3442 Division of Science Technology and Medicine Washington, DC 20233 Department of Labor Adrienne.C.Oneto@census.gov 200 Constitution Ave., N.W., Room N3653 Washington, DC 20210 george.ruby@osha.gov * Member of the Trans-NIH Sleep Research Coordinating Committee APPENDICES 131
    • Bette Siegel, Ph.D. BioAstronautics Division, Code UB, Room 8Q13 NASA Headquarters, 300 E Street, S.W. Washington, DC 20546 bette.siegel@nasa.gov Ellen Witt, Ph.D.* National Institute on Alcohol Abuse and Alcoholism/NIH Willco Building, Suite 402 6000 Executive Boulevard, MSC 7003 Bethesda, MD 20982-7003 ewitt@willco.niaaa.nih.gov * Member of the Trans-NIH Sleep Research Coordinating Committee 132 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • APPENDIX C: 1996 NATIONAL SLEEP DISORDERS RESEARCH PLAN RECOMMENDATIONS AND RESULTING NIH SLEEP-RELATED RESEARCH INITIATIVES (1996 TO 2002) The title of each RFA/PA and total funding awarded for each initiative (cumulative through Fiscal Year 2002) are listed in descending chronological order by year of initiative release under the relevant research recommendations from the 1996 National Sleep Disorders Research Plan. In some instances, an individual initiative applies to more than one recommendation and is therefore listed under each relevant recommendation. APPENDICES 133
    • 1996 National Sleep Disorders Research Plan Research Recommendations B ASIC S CIENCE R ESEARCH R ECOMMENDATIONS Increase efforts to understand the basic mechanisms responsible for sleep by applying molecular biological approaches in concert with techniques of cellular and systems neurobiology. Conduct basic studies to understand the brain mechanisms responsible for sleepiness. Study basic mechanisms underlying the interaction between the circadian and neurophysiological systems that regulate sleep and wakefulness.. Characterize the genetic factors controlling the basic mechanisms of sleep. Increase research efforts to elucidate the fundamental functions of sleep. Total Costs Participating Awarded Initiative Title Institutes/Centers (through FY 2002) Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253 and Blood Diseases: HL01-009*† Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605 Oxygen Sensing During Intermittent Hypoxia: HL00-004* NHLBI 10,673,975 Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381 Phenotypic Characterization of Sleep in Mice: HL99-001 NHLBI, NIMH, 13,512,185 NIA, NINDS Bioengineering Research Grants: PAR 99-009 NCI, NCRR, NEI, NHGRI, 546,594 NHLBI, NIA, NIAAA, NIAID, NIAMS, NICHD, NIDA, NIDCD, NIMH, NINDS, NINR, NLM Research on Musculoskeletal Fitness and NIAMS, NICHD, NINR 999,146 Sports Medicine: PA97-025* SCOR in Neurobiology of Sleep and Sleep NHLBI 18,553,207 Apnea: HL96-014*† Molecular Biology and Genetics of Sleep NHLBI, NIMH, NICHD 7,335,059 and Sleep Disorders: HL96-015* Basic and Clinical Research on Sleep and NIA, NIAAA, NICHD, 28,384,156 Wakefulness: PA95-014* NIDA, NHLBI, NIMH, NINDS, NINR * Also listed under Patient-Oriented Research Recommendations † Also listed under Applied Research Recommendations 134 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • PATIENT-O RIENTED R ESEARCH R ECOMMENDATIONS Identify the genetic basis of sleep disorders that have a genetic component. Conduct epidemiological research to assess prevalence, risk factors, and long-term consequences of common sleep disorders and determine the role of ethnicity, age, and gender in their causation. Conduct outcomes research and clinical trials on the management of common sleep disorders. Develop new technological approaches for diagnosis of sleep disorders, screening for sleep disorders among high-risk populations in whom sleepiness presents a particular danger (e.g., transportation workers), monitoring the effectiveness of therapy, and detecting abnormalities of sleep as early biological markers of psychiatric illnesses. Elucidate the pathogenesis/pathophysiology of sleep disorders and their consequences. Provide the research infrastructure needed to carry out patient-oriented research. Total Costs Participating Awarded Initiative Title Institutes/Centers (through FY 2002) Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253 and Blood Diseases: HL01-009*† Sleep and Sleep Disorders in Children: HL01-006 NHLBI, NIMH, 1,499,621 NINR, NICHD Restless Legs Syndrome and Periodic Limb NINDS, NHLBI, 334,178 Movement Disorder: PA01-086 NIA, NIMH Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605 Ancillary Studies in Conjunction with SHOW Trial: DK-00-017 NIDDK, NHLBI, NINR, 1,143,165 NIAMS, NIDCR Oxygen Sensing During Intermittent Hypoxia: HL00-004 NHLBI 10,673,975 Biobehavioral Research for Effective Sleep: PA00-046*† NINR, NHLBI, NIA, 1,717,977 NIAAA, NICHD, NIDA, NIMH, NCI Data Coordinating Center for Sleep Heart NHLBI 2,913,228 Health Study: HL99-014 Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381 Occupational Safety and Health Research: PA99-143† NIOSH, NCI, NHLBI, 381,250 NIA, NIAAA, NIAID, NIAMS, NIDCD, NIEHS Obstructive Sleep Apnea in Children: HL98-004† NHLBI, NIDR, NICHD 10,826,226 ( CONTINUED ON PAGE 138) APPENDICES 135
    • PATIENT-O RIENTED R ESEARCH R ECOMMENDATIONS ( CONTINUED ) Total Costs Participating Awarded Initiative Title Institutes/Centers (through FY 2002) Sleep Academic Award: HL97-015, HL96-021, HL96-006‡ NHLBI $ 4,995,123 Institutional National Research Service Award in NHLBI, NIA, NIAAA, 737,625 Sleep Research: PA97-064† NICHD, NIDA, NIMH, NINDS, NINR Research on Musculoskeletal Fitness and Sports NIAMS, NICHD, NINR 999,146 Medicine: PA97-025* Molecular Biology and Genetics of Sleep and Sleep NHLBI, NIMH, NICHD 7,335,059 Disorders: HL96-015* SCOR in Neurobiology of Sleep and Sleep NHLBI 18,553,207 Apnea: HL96-014*† Basic and Clinical Research on Sleep and NHLBI, NIA, NIAAA, 28,384,156 Wakefulness: PA95-014*† NICHD, NIDA, NIMH, NINDS, NINR * Also listed under Basic Science Research Recommendations † Also listed under Applied Research Recommendations ‡ Also listed under Research Training Recommendations 136 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • A PPLIED R ESEARCH R ECOMMENDATIONS Conduct epidemiological research to define the prevalence, etiology, risk factors, morbidity, and costs of sleepiness in the general population. Define the decrement and recovery processes associated with chronic partial sleep deprivation. Develop efficient, objective measures of daytime sleepiness. Evaluate the utility of interventions to prevent and manage sleepiness, with the goal of improving productivity and safety. Total Costs Participating Awarded Initiative Title Institutes/Centers (through FY 2002) Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253 and Blood Diseases: HL01-009*† Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605 Biobehavioral Research for Effective Sleep: PA00-046† NINR, NHLBI, NIA, 1,717,977 NIAAA, NICHD, NIDA, NIMH, NCI Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381 Implementation of the National Occupational NIOSH, NCI, NHLBI, 423,750 Research Agenda: OH99-02 NIA, NIDCD, NIEHS Occupational Safety and Health Research: PA99-143† NIOSH, NCI, NHLBI, 381,250 NIA, NIAAA, NIAID, NIAMS, NIDCD, NIEHS Human Brain Project (Neuroinformatics): PAR 99-138 NIMH, NIDA, NSF, 370,125 NIA, NICHD, NIDCD, NLM, NASA, FIC, DOE, NIAAA, NHLBI, NIDCR, NCI, NINDS Obstructive Sleep Apnea in Children: HL98-004† NHLBI, NIDR, NICHD 10,826,226 Institutional National Research Service Award in NHLBI, NIA, NIAAA, 737,625 Sleep Research: PA97-064† NICHD, NIDA, NIMH, NINDS, NINR Innovative Approaches to Developing New NCRR 222,740 Technologies: PAR-97-014 SCOR in Neurobiology of Sleep and NHLBI 18,553,207 Sleep Apnea: HL96-014*† Basic and Clinical Research on Sleep and NHLBI, NIA, NIAAA 28,384,156 Wakefulness: PA95-014*† NICHD, NIDA, NIMH, NINDS, NINR * Also listed under Basic Science Research Recommendations † Also listed under Patient-Oriented Research Recommendations APPENDICES 137
    • R ESEARCH T RAINING R ECOMMENDATIONS Enhance the number of trained investigators and trainees in biological and behavioral research related to basic sleep mechanisms and patient-oriented research. Total Costs Participating Awarded Initiative Title Institutes/Centers (through FY 2002) Sleep Academic Award: HL97-015, HL96-021, HL96-006* NHLBI $4,995,123 * Also listed under Patient-Oriented Research Recommendations GRAND TOTAL $ 114,969,569 NIH T OTAL S LEEP D ISORDERS R ESEARCH F UNDING , 1996 TO 2002 Institute/ Center 1996 1997 1998 1999 2000 2001 2002 Dollars in thousands NHLBI 16,450 19,219 22,932 31,845 35,128 37,579 45,155 NINDS 9,453 11,598 13,639 15,231 12,495 17,603 22,918 NICHD 7,368 7,217 9,131 7,116 6,797 7,084 7,344 NIA 7,800 9,179 11,818 13,296 13,034 14,533 14,600 NIMH 27,231 28,601 34,027 39,219 40,667 50,742 56,647 NIDA 1,201 1,042 1,586 2,163 2,553 2,517 3,235 NIAAA 551 728 766 736 1,132 1,681 4,342 NINR 2,842 3,565 3,394 3,503 4,635 5,375 8,091 NCRR 3,247 3,570 5,542 6,637 7,117 7,193 11,490 NCCAM † N/A N/A N/A N/A N/A 177 900 NIAMS † N/A N/A N/A N/A N/A N/A 300 NHGRI N/A N/A N/A N/A N/A 599 0 Total 76,143 84,719 102,835 119,746 123,558 145,083 175,022 * Detailed listings of NIH Sleep Related Grants for Fiscal Years 1999 through 2002 can be found online at: http://www.nhlbisupport.com/sleep/research/research3.htm † Became Trans-NIH Sleep Research Coordinating Committee Member Institute in FY 2002 138 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN
    • F OR M ORE I NFORMATION The NHLBI Information Center is a service of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. The NHLBI Information Center provides information to health profes- sionals, patients, and the public about the treatment, diagnosis, and prevention of heart, lung and blood diseases. For more information, contact: NHLBI Information Center P.O. Box 30105 Bethesda, MD 20824-0105 Phone: 301-592-8573 TYY: 240-629-3255 Fax: 301-592-8563 Web site: http://www.nhlbi.nih.gov DISCRIMINATION PROHIBITED: Under provisions of applicable public laws enacted by Congress since 1964, no person in the United States shall, on the grounds of race, color, national origin, handicap, or age, be excluded from participation in, be denied the benefits of, or be subjected to discrimination under any program or activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. In addition, Executive Order 11141 prohibits discrimination on the basis of age by contractors and subcontractors in the performance of Federal contracts, and Executive Order 11246 states that no federally funded contractor may discriminate against any employee or applicant for employment because of race, color, religion, sex, or national origin. Therefore, the National Heart, Lung, and Blood Institute must be operated in compliance with these laws and Executive Orders.
    • U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Heart, Lung, and Blood Institute NIH Publication No. 03-5209 July 2003