Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 253
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem 8 Bolstering Somnology and Sleep Disorders Research Programs CHAPTER SUMMARY The National Center on Sleep Disorders Research (NCSDR) and the Trans-NIH Sleep Research Coordinating Committee were established to coordinate the sleep-related research, training, and education activities at the National Institutes of Health (NIH). At the same time that the science and magnitude of the public health and economic burden requires greater investment, the output from the NCSDR and Trans-NIH Sleep Research Coordinating Committee has not kept pace. As a consequence, NIH funding for sleep-related activities has reached a plateau, and the future outlook for somnology and sleep medicine is unclear. A detailed examination of the past and current investment in sleep-related research demonstrates that there are only 331 funded research projects and 253 independent investigators, far below the requirements of the field. Further, of the 253 principal investigators only 151 researchers are primarily involved in clinical sleep research and 126 primarily focus on basic research projects. The challenge for the field is to develop a collaborative and focused approach with a strong research infrastructure. To bolster clinical and basic research efforts, catalyze collaborative research efforts, and attract the breadth of talented researchers who will be able to move somnology and sleep disorders research and clinical care forward to achieve optimal outcomes requires a coordinated and integrated strategy. The NCSDR, its advisory board, and the Trans-NIH Sleep Research Coordinating Committee need to take a proactive role in providing continued leadership. Further, a research network is of particular importance in the
OCR for page 254
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem field because of the need for a coordinated interdisciplinary research approach to basic and clinical research, clinical care, public education, and training. Therefore, the NIH should establish Somnology and Sleep Medicine Centers of Excellence within a National Somnology and Sleep Medicine Research and Clinical Network. The field of somnology and sleep medicine is poised to take great strides in elucidating and addressing the etiology, pathogenesis, and public health burden of chronic sleep loss and sleep disorders. This strong position is the result of the National Institutes of Health (NIH) establishing the Trans-NIH Sleep Research Coordinating Committee and the National Center on Sleep Disorders Research (NCSDR). However, at the same time that the science and magnitude of the problem requires greater investment, NIH funding to sleep-related activities has reached a plateau. Consequently, the future outlook for somnology and sleep medicine is unclear. The next significant advances necessitate leveraging these resources to their utmost potential in conducting research and refining diagnosis and treatment interventions for sleep loss and sleep disorders. This chapter provides an overview of the current coordination of sleep-related activities at the NIH, including an evaluation of the NCSDR. Included in the evaluation is a detailed a summary of sleep-related research activities sponsored by the NIH between 1995 and 2004. The chapter culminates with a discussion on the next steps required to accelerate progress, including the establishment of a National Somnology and Sleep Medicine Research and Clinical Network. NIH COORDINATION OF SLEEP-RELATED ACTIVITIES To a greater extent than many medical and research disciplines, the field of somnology and sleep medicine cuts across many disciplines, including but not limited to cardiology, dentistry, endocrinology, epidemiology, geriatrics, molecular biology, neurology, neurosciences, nursing, nutrition, otolaryngology, pediatrics, pharmacology, psychiatry, and pulmonology. In 2004, there were 331 sleep-related research project grants sponsored by 17 institutes at the NIH (Table 8-1, Appendix G). The NIH has two mechanisms to coordinate its sleep-related activities, the Trans-NIH Sleep Research Coordinating Committee and the NCSDR.
OCR for page 255
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem TABLE 8-1 NIH Institute Support of Somnology and Sleep Disorders Research Project Grants (R01) in 2004 Institute Number of Grants National Heart, Lung, and Blood Institute 102 National Institute of Mental Health 88 National Institute of Neurological Disorders and Stroke 49 National Institute on Aging 31 National Institute of General Medical Sciences 22 National Institute of Nursing Research 19 National Eye Institute 15 National Institute on Drug Abuse 13 National Institute on Alcohol Abuse and Alcoholism 12 National Institute of Diabetes and Digestive and Kidney Diseases 11 National Institute of Child Health and Human Development 10 National Cancer Institute 7 National Institute of Arthritis and Musculoskeletal and Skin Diseases 5 National Institute on Deafness and Other Communication Disorders 4 National Center for Complementary and Alternative Medicine 3 National Institute of Allergy and Infectious Diseases 1 Fogarty International Center 1 NOTE: Institutes and centers in bold are not members of the Trans-NIH Sleep Research Coordinating Committee. Trans-NIH Sleep Research Coordinating Committee In 1986, the Director of the NIH established the Trans-NIH Sleep Research Coordinating Committee to facilitate an interchange of information about somnology and sleep disorders research. This coordinating committee meets every 2 to 3 months to discuss current sleep-related activities within the NIH and develop new programs. Currently 13 NIH institutes and offices are members of the Trans-NIH Sleep Research Coordinating Committee. The director of the NCSDR chairs the Coordinating Committee, and its members are program staff from the various NIH institutes with an interest in somnology and sleep disorders. Although most institutes that support sleep-related research are members of the coordinating committee, a few are not (Table 8-1), including the National Institute of General Medical Sciences and the National Eye Institute. In 2004 these two institutes each supported more sleep-related grants than 8 of the 13 current members—close to 10 percent of all sleep-related research project grants. The Trans-NIH Sleep Research Coordinating Committee offers the somnology and sleep medicine field an exceptional resource for increasing and coordinating NIH support of interdisciplinary sleep-related research
OCR for page 256
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem and career development programs. Over the last 10 years, through requests for applications (RFAs) and program announcements (PAs), members of the coordinating committee have cosponsored 16 out of the 18 research project grant initiatives (Appendix F). This has the advantage of spreading out the costs of an initiative over multiple institutes, thus being able to support greater investment. However, as will be discussed in greater detail later in this chapter, recently the coordinating committee has not taken a proactive role in developing new research programs. National Center on Sleep Disorders Research In direct response to the 1993 report of the National Commission on Sleep Disorders Research, Wake Up America: A National Sleep Alert, a provision of the NIH Revitalization Act instructed the Director of the NIH and the National Heart, Lung, and Blood Institute (NHLBI) to establish the NCSDR. As described in the congressional language, the mission of the NCSDR is to “conduct and support of biomedical and related research and research training, the dissemination of health information, and the conduct of other programs with respect to various sleep disorders, the basic understanding of sleep, biological and circadian rhythm research, chronobiology and other sleep related research” (U.S. Congress, Senate, 1993). As mandated by Congress the NCSDR has the authority: for the conduct and support of research, training, health information dissemination, and other activities with respect to sleep disorders, including biological and circadian rhythm research, basic understanding of sleep, chronobiological and other sleep-related research; and to coordinate the activities of the NCSDR with similar activities of other federal agencies, including the other agencies of the NIH, and similar activities of other public entities and nonprofit entities. (See Appendix D for complete congressional language.) The NCSDR establishment within the NHLBI allowed it to call upon the existing successful programs at the NHLBI in sleep-disordered breathing as well as the NHLBI’s expertise in public education programs. It was realized at the inception of the NCSDR that there was a major need to educate both public and health care professionals about sleep and sleep disorders. Because many NIH institutes have a strong interest in somnology and sleep disorders research and fund portfolios of grants in this area, it was not envisioned that all funding for sleep-related programs would be done through the NCSDR. Rather, the NCSDR would facilitate development of research and training programs in areas of identified need. In addition, it would be a center that facilitated and coordinated research across
OCR for page 257
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem the many institutes of the NIH with an interest in sleep-related research, as well as across the many federal agencies that have an interest in sleep deprivation and sleep disorders. These agencies include: the Centers for Disease Control and Prevention (CDC) (prevalence and impact of sleep disorders, inadequate sleep); the Department of Defense (impact of sleep deprivation and nighttime activity on human performance); the Department of Transportation (crashes occurring from falling asleep at the wheel); the Occupational Safety and Health Administration (impact of sleep deprivation and sleep disorders on industrial accidents and shift work sleep disorder); and the Department of Veterans Affairs (VA) (impact of sleep disorders on health of veterans, posttraumatic stress disorder). It is of note that although one out of every five Americans perform shift work, the Department of Labor withdrew its membership from the NCSDR advisory board in 2003. Following the departure of the department’s representative the Department of Labor chose not to appoint a replacement member. The committee hopes that the Department of Labor will reconsider this, as it can make an important contribution to the national effort to decrease the burden of sleep loss and sleep disorders. Several federal agencies have research and public education programs including the Department of Defense, the Department of Transportation, and the CDC. However, the NCSDR has not made clear or demonstrated far-reaching coordination of these activities, with potential missed opportunities for integrating sleep-related programs among federal agencies and departments. The original mandate to the NCSDR, as envisioned in the authorizing legislation, saw the CDC playing a major role in public education and surveillance. As described in Chapter 5, the CDC is involved in many public education campaigns and national surveys. Apart from the recent addition of sleep-related questions in the National Health and Nutrition Examination Survey (NHANES), this has not occurred. There are insufficient data about the sleep patterns of Americans, and the CDC’s expertise should be sought in conducting surveillance, monitoring sleep disorders and sleep habits, and developing public health campaigns about sleep loss and sleep disorders. The NCSDR budget is a line item on the NHLBI administrative budget and includes the director, a public health analyst, an executive assistant, and an office assistant. From a separate NHLBI budget source, the NCSDR receives an allocation each year to support the activities of the Sleep Disorders Research Advisory Board and other programmatic activities, including workshops. Thus, the budget available to the director of the NCSDR is limited. The member institutes in the Trans-NIH Sleep Research Coordinating Committee provide support for their representative to the Committee, and NCSDR provides administrative support as needed for the Trans-NIH Sleep Research Coordinating Committee from its fiscal resources
OCR for page 258
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem already described. The Office of Prevention, Education, and Control support other NHLBI personnel who work on educational programs and two such individuals (personal communication, M. Twery, NIH, January 24, 2006). The Advisory Board of the National Center on Sleep Disorders Research The original NCSDR authorizing legislation established an advisory board to the NCSDR, composed of 12 members of the public—8 scientific members and 4 public members who either are advocates for or have a particular sleep disorder. Included in the advisory board are 10 ex officio members who represent relevant federal agencies (Table 8-2). The advisory board meets biannually. As directed in the authorizing congressional language “The advisory board shall advise, assist, consult with, and make recommendations to the Director of the National Institutes of Health and the Director of the Center concerning matters relating to the scientific activities carried out by and through the Center and the policies respecting such activities, including recommendations with respect to the [research] plan” (U.S. Congress, Senate, 1993). As will be discussed in further detail below, throughout the 12 years since its establishment the advisory board has had varying levels of activity in these responsibilities. Since its inception, the advisory board has had 29 members. It is NIH policy that the appointed members of advisory councils or other mandated boards cannot serve for terms of more than 4 years and that reappointment is not permitted. This presents a strain on a small field such as somnology and sleep medicine, as those most knowledgeable about the field are frequently selected. It is important that the composition of the advisory board consists of members who are credible and who have the respect of the somnology and sleep medicine community, as well as an understanding of large research and educational enterprises, background as a practicing TABLE 8-2 Ex Officio Members of the NCSDR Advisory Board Director of the National Institutes of Health (NIH) Director of the National Center on Sleep Disorders Research (NCSDR) Director of the National Heart, Lung, and Blood Institute (NHLBI) Director of the National Institute of Mental Health Director of the National Institute on Aging Director of the National Institute of Child Health and Human Development Director of the National Institute of Neurological Disorders and Stroke Assistant Secretary for Health Assistant Secretary of Defense (Health Affairs) Chief Medical Director of the Veterans Affairs (VA)
OCR for page 259
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem researcher, and awareness of a wide variety of public policy issues. Individuals who have been involved in the advisory board are provided in Appendix E, together with, where appropriate, their academic honors and area of expertise. As a result of the small numbers of senior members in the field, the tradition of academic leadership has been difficult to maintain on the advisory board. The board would benefit from advice made by senior investigators who have credibility and a sound understanding of both scientific and clinical advances, as well as an appreciation for policy issues. It is the opinion of this committee that after an appropriate interval senior members of the somnology and sleep medicine fields should be permitted to be reappointed to serve an additional term on the advisory board, along with the most promising juniors member of the field. This should be permitted until the field has a large enough cadre of experienced leaders. NATIONAL SLEEP DISORDERS RESEARCH PLAN One of the requirements of the advisory board is to periodically develop a comprehensive research plan. The first research plan was published in 1996. Its recommendations were based on analyses of the needs of the field and the investment in sleep-related programs by the federal government. The recommendations reflected the need to support three areas of research: (1) basic research using state-of-the-art approaches to elucidate the functions of sleep and the fundamental molecular and cellular processes underlying sleep; (2) patient-oriented research to understand the cause, evaluate the scope, and improve the prevention, diagnosis, and treatment of sleep disorders; and (3) applied research to evaluate the scope and consequences of sleepiness and to develop new approaches to prevent impaired performance during waking hours (NHLBI, 1996). Sixteen specific recommendations were crafted in such a way that the outcomes of the effort were easily measurable (see grant analysis below). The second research plan, published in 2003, provided a brief overview of each topic area and an update of the research progress made since the 1996 report. The report contained over 191 individual recommendations. It has yet to be established, but the large number of recommendations may decrease the effectiveness of the document. The report did provide relative weight to some recommendations, but this may limit the implementation of the remaining recommendations. Based on the recommendations the advisory board identified a limited number of research priorities: Understand the neurobiology and function of sleep. Assess the impact of reduced sleep across age. Find the causes of various sleep disorders. Establish normative standards for sleep need and sleep variables.
OCR for page 260
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Discover/improve treatments for sleep disorders. Study if sleep disorders are associated with, and how they affect, the progression of other diseases. Educate health care professionals and the public about healthy sleep habits and sleep disorders. Apply novel technologies to the study of sleep. Develop data and examine prevention, intervention, treatment, and other sleep-related programs specific to women and minorities. In the research plan, training was considered the highest priority and a separate category was created to underline its importance. Although the 2003 plan is more comprehensive than the 1996 plan, it lacks specificity in each recommendation, and no strategy was established to advance the research agenda. The large number of recommendations and the broad focus make it difficult to establish measures to evaluate the research plan’s effectiveness. The 2003 research plan laid out an ambitious set of priorities but did not provide a strategy to implement the recommendations. Scientific Advances Since the 2003 Sleep Disorders Research Plan Below is a brief update of the state of science since 2003. However, as only 2 years have passed since the publication of the 2003 plan, this review is not meant to serve as an in-depth evaluation of the plan or an in-depth review of the current state of the field. Rather, its purpose is to demonstrate the potential the field has to continue to make great scientific strides. The outline for this update uses the organization originally used in the executive summary of the 2003 National Sleep Disorders Research Plan. As the following sections will demonstrate, although there has been scientific progress leading to an even greater number of unanswered questions, over the last few years the field has not grown but has reached a plateau. Circadian Neurobiology Research in this area is expanding because of advances in basic research. The major molecular and anatomical components associated with the generation of circadian rhythms have been known for about a decade. Genetic variants associated with delayed and advanced sleep phase are increasingly reported in a small minority of patients with familial occurrence (Xu et al., 2005). However, the clinical implications of altered circadian rhythms are yet to be explored. Some examples include the need to better define the causes and consequences of delayed phase in adolescence and to understand advanced phase in the elderly (Carskadon et al., 2004; Monk, 2005).
OCR for page 261
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem The importance of circadian rhythms extends beyond the brain. It is now recognized that the circadian clock does not solely operate within the suprachiasmatic nucleus but also at multiple levels in peripheral and central organs (Yamazaki et al., 2000; Yoo et al., 2004). Researchers have continued to elucidate with increasing detail the molecular mechanisms regulating these multiple molecular clocks. For example, peripheral clock markers can now be generated and studied in human fibroblasts (Brown et al., 2005). In addition, the genetic disruption of molecular mechanisms regulating circadian rhythms is recognized as deleterious at multiple levels within the organism. For example, the Clock-mutated mouse was found to suffer from metabolic abnormalities and to be prone to obesity (Turek et al., 2005). It is also increasingly likely that Clock genes have effects on the sleep process itself. This research may explain, for example, why shift workers are prone to certain diseases (Harrington, 1994; Boggild and Knutsson, 1999). Sleep Neurobiology and Basic Sleep Research The importance of the hypothalamus in sleep regulation, beyond the generation of circadian rhythms and their genesis within the suprachiasmatic nuclei, is increasingly clear (Saper et al., 2005). The recognition of the ventrolateral preoptic area as a sleep generator, together with the identification of the hypocretin (orexin) system as a wake promoting system, has fueled intense research in this area. How these two systems interact neuroanatomically, and how they affect other classical neurobiological systems, such as the monoamine and cholinergic systems, is being elucidated (Saper et al., 2005). Projection sites and novel sleep regulatory nuclei are being identified. The impact of this research is being felt beyond the field; for example, the role of the hypocretin system in regulating dopaminergic systems and addiction potential for drugs of abuse is the subject of intense investigation (Harris et al., 2005). The function of sleep is also increasingly explored through phylogenetic approaches—the study of sleep in various animal species (Rattenborg et al., 2004; Lyamin et al., 2005). Sleep is a vital behavior conserved across evolution, suggesting it serves one or more critical functions. One important function may be the development of the neonatal brain, as many animals sleep a lot just after birth. The necessity of sleep may also be seen in animals that are in constant motion (e.g., swimming aquatic mammals or migrating birds) as they have developed unihemispheric sleep to allow for the generation of sleep under these difficult ecological circumstances. Interestingly, several reports are now suggesting that in specific instances, sleep can be suppressed completely for very long periods (up to months), such as during long-range migration in certain birds (Rattenborg et al., 2004) or even more surprisingly just after birth in some cetaceans (Lyamin et al.,
OCR for page 262
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem 2005). These recent results suggest it may be possible to sustain life without sleep in special circumstances, which challenges existing dogma and suggests an area ripe for further advances. This field of research is also benefiting from genetic studies in animal models. Knockout mice models (mice that are bred so that they lack certain genes) are now systematically being evaluated for sleep abnormalities. Gene variants, including a number of variants that affect sleep, have been isolated in various mouse strains that have specific electroencephalogram patterns (Tafti et al., 2003). These and other genetic mechanisms should be explored in future studies (Maret et al., 2005). Sleep Disorders in Neurology The discovery in 1999 and 2000 that hypocretin/orexin is involved in the pathophysiology of most narcolepsy-cataplexy cases is now being translated into clinical practice. Measuring cerebral spinal fluid (CSF) hypocretin-1 (orexin-A) is used in some cases to diagnose narcolepsy and is listed as a diagnostic tool in the revised International Classification of Sleep Disorders (AASM, 2005; Bader et al., 2003; Mignot et al., 2003). This diagnostic procedure may be especially important considering the recent report of high prevalence of sleep onset during rapid eye movement (REM) sleep instead of during nonrapid eye movement (NREM) sleep in the general population, a finding that may suggest a large number of false positives for this test and/ or a high prevalence of narcolepsy without cataplexy (Singh et al., 2005). Sleep disturbances are recognized as a major issue in Parkinson’s and Lewy body disease (Rye, 2004), also suggesting a role for dopamine in sleep regulation. Not only can Parkinson’s disease patients have a narcolepsy-like daytime sleepiness, but REM behavior disorder is now recognized as an important component of these disorders, often preceding Parkinson’s disease by several decades. Investigators are also increasingly interested in other disorders where hypocretin abnormalities might explain sleep disturbances (Nishino and Kanbayashi, 2005), most notably Huntington’s chorea, a disorder where mice models show a preferential hypocretin cell loss (Petersen et al., 2005). Similar sleep studies are also occurring with Alzheimer’s dementia and stroke patients, where central and obstructive sleep apnea (OSA) may play an important role in both causing and exacerbating the condition. Finally, rapid progress is occurring in our understanding of restless legs syndrome (Trenkwalder et al., 2005). Pathophysiology and treatment may be closely linked to the dopaminergic system and iron metabolism. Genetic studies suggest the existence of at least three potential loci, located on chromosomes 12, 14, and 9, and investigators are narrowing down on possible candidate genes. It is likely that those actually causing diseases will soon be identified (Manconi et al., 2004).
OCR for page 263
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Sleep-Disordered Breathing Genetic epidemiological studies conducted over the prior decade have clearly established that sleep-disordered breathing, although a complex trait, has a strong genetic basis with evidence of oligogenic inheritance (Buxbaum et al., 2002). Areas of linkage for the apnea-hypopnea index (AHI) appear to differ by ethnicity (Palmer et al., 2003, 2004). Association and fine mapping studies have quantified the potential role of several candidate genes in the pathogenesis of sleep apnea (Gottlieb et al., 2004b; Larkin et al., 2005a), with results implicating a gene near the APOe4 locus (Larkin et al., 2005a). There is also evidence that sleep-disordered breathing and obesity, a major public health problem, are partly linked by pleiotropic genetic mechanisms (Palmer et al., 2003, 2004). Thus, future studies of the genetics of sleep-disordered breathing also likely will illuminate the genetic basis of obesity. Applying advances in genome association methods to population studies of sleep apnea will be important in discovering genes for this and related diseases. Large scale epidemiological studies in the 1990s quantified the prevalence of OSA in middle aged and elderly populations (Ancoli-Israel et al., 1991, 1995; Young et al., 1993). More recently, population-based studies also identified sleep-disordered breathing to be common in American school-aged children, with an especially high prevalence in African American children (Rosen et al., 2003). Other studies have identified the predilection of other groups to sleep apnea. These include commercial drivers (Howard et al., 2004), whose occupations place them at particular risk for sleepiness-associated injuries (Gurubhagavatula et al., 2004). Further work is needed to develop and apply screening approaches for identifying individuals at high risk for sleep apnea (see technology section). However, in the case of commercial drivers, a two-stage screening strategy using questionnaires and simplified tests was shown to be effective (Gurubhagavatula et al., 2004). Given that commercial drivers with sleep apnea are likely to be at an increased risk for crashes, occupational screening of this group may provide an important opportunity to test the model for occupational screening for sleep disorders. There is developing evidence that sleep apnea leads to oxidative stress (Lavie, 2003). This likely results from the cyclical doxygenation-reoxygenation, akin to ischemia reperfusion, that occurs with apneic events, causing free radial production and increased levels of inflammatory molecules. C-reactive protein, a biomarker for cardiovascular disease, may be elevated in OSA. C-reactive protein declines with treatment with continuous positive airway pressure (CPAP) (Yokoe et al., 2003). Increasing oxidative stress is not only relevant to the cardiovascular risk of sleep apnea but also to its effects on neurocognition. Cyclical intermittent hypoxia leads to oxidative damage of various groups of
OCR for page 282
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem NIH Institutional Clinical and Translational Science Award The NIH has established the Institutional Clinical and Translational Science Award, which has the purpose of developing programs to overcome the growing barriers between clinical and basic research, facilitate the sharing of knowledge to the clinic and back again to the basic research laboratory, and aid academic institutes in developing efficient capabilities to perform clinical and translational science. Through these programs, the NIH aims to: (1) attract and develop a cadre of well-trained multi- and interdisciplinary investigators and research teams; (2) develop programs that spawn innovative research tools and information technologies; and (3) synergize multi- and interdisciplinary clinical and translational research and researchers to catalyze the application of new knowledge and techniques to clinical practice at the front lines of patient care (NIH, 2006b). As supported by all the same arguments already presented throughout this report, somnology and sleep medicine programs are ideal recipients. As the NIH highlights, to ensure the successful establishment and long-term sustenance of these groundbreaking programs, it is important that the developed program accrue significant institutional support, be granted status as a major administrative entity within the applicant institution, and that the program director have authority, perhaps shared with other high-level institutional officials, over requisite space, resources, faculty appointments, protected time, and promotion (NIH, 2006b). National Somnology and Sleep Medicine Research Network A research network is of particular importance in the field because of the need for a coordinated interdisciplinary research approach to basic and clinical research, clinical care, public education, and training. The proposed National Somnology and Sleep Medicine Research Network would improve the efficiency and capacity to research on rare sleep disorders. The Somnology and Sleep Medicine Centers of Excellence discussed above would spearhead this dedicated focus on basic, clinical, and translational research and would promote collaborations among all sites conducting research relevant to somnology and sleep medicine. Similar to cancer centers, the Somnology and Sleep Medicine Centers of Excellence would act as local, regional, and national resources for the scientific community and the community at large. This will require coordination among all participating centers. Although online technologies greatly enhance the nearly instantaneous sharing of ideas across the nation and globally, the research network envisioned by the committee would involve not only a strong virtual component but also a structured plan for periodic and regular meetings and workshops to set priorities and strengthen interactions.
OCR for page 283
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem The committee strongly believes that the somnology and sleep medicine field is now sufficiently mature for the development of a National Somnology and Sleep Medicine Research Network and could successfully compete for network funding from the NHLBI and other members of the Trans-NIH Sleep Research Coordinating Committee that have substantial commitments to somnology and sleep disorders research. Individual Somnology and Sleep Medicine Centers of Excellence could compose the cornerstone of this network, and institutions that do not have sufficient scope and size to successfully compete for a Somnology and Sleep Medicine Center of Excellence would be active affiliate members of this network. The committee envisions a sustained network for somnology and sleep medicine in the United States that would facilitate public education, career development opportunities, translational research, and implementation of multi-center clinical trials. The process of developing components of the National Somnology and Sleep Medicine Research Network can draw on the experiences of several such networks that already exist, but with more focused objectives, such as the aforementioned National Cancer Institute centers. The NHLBI currently sponsors 12 networks. The National Institute of Child Health and Human Development sponsors the National Center for Medical Rehabilitation Research regional research networks. Each network is coordinated and administered out of one academic institution, which coordinates the efforts of institutions that are affiliated with the network. The leading coordinating institutions are structured to facilitate major collaborations among affiliated institutions, with the potential to connect with researchers from other facilities within the region. They support multidisciplinary research cores, information transfer, and pilot projects with the goal of facilitating ongoing projects and stimulating the development of future research activities in medical rehabilitation (NCMRR, 2005). Another example of a regional network is the Muscular Dystrophy Cooperative Research Centers. Cosponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, as well as the Muscular Dystrophy Association, these centers work collaboratively on both basic and clinical research projects. Each center has one or more core facility to support them and must also make core resources or services available to the national muscular dystrophy research community. The National Somnology and Sleep Medicine Research Network envisioned by the committee would be structured to facilitate and require active involvement of the participants and substantive interactions between basic and clinical researchers. As will be described in detail in Chapter 9, the committee calls on new and existing academic programs in somnology and sleep medicine to be organized to meet the criteria of three types of interdis-
OCR for page 284
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem ciplinary sleep programs—Type I, Type II, or Type III. A Type I clinical interdisciplinary sleep program is designed to provide optimal interdisciplinary clinical care for individuals who suffer sleep loss or sleep disorders. Although not consisting of large research components, a Type I program should have a data collection and management system that provides clinical data to a coordinating center within the network. A Type II training and research interdisciplinary sleep program includes the characteristics of a Type I program, but in addition is designed to provide optimal education, training, and research in somnology and sleep medicine. A Type III regional interdisciplinary sleep program coordinator includes the characteristics of Type I and II programs; however, a Type III program is designed to serve as a regional comprehensive center and coordinator for education, training, basic research, and clinical research in somnology and sleep medicine within the National Somnology and Sleep Medicine Research Network. The Committee also envisions that all Type I and II programs would be affiliate members of the National Somnology and Sleep Medicine Network. Although there are only a limited number of academic institutions that currently have the capacity to be a Type III regional interdisciplinary sleep program, this should not delay the establishment of the research network. Initially the network could consist of a limited number of programs. The network would benefit greatly from cultural, ethnic, and environmental diversity. Therefore, a long-range goal should be to have 8 to 10 geographically distributed regional coordinating centers. In summary, the National Somnology and Sleep Medicine Research Network should do the following: Coordinate and support the current cadre of basic and clinical researchers. Train new investigators and fellows through local and remote mentoring programs. Provide core facilities for basic research. Support multisite clinical research in children, adolescents, adults, and elderly people. Create and support virtual networking centers to facilitate the sharing of data and resources online and enhance collaborations with researchers not working in research centers. Create a data coordinating center that includes an Internet-based clearing house for the publication of all data produced in cooperation with the research and clinical network. Work with the CDC to integrate and support surveillance and population-based research. Create and coordinate public health education campaigns.
OCR for page 285
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Efforts to develop a National Somnology and Sleep Medicine Research and Clinical Network are consistent with many of the goals of the NIH Roadmap (NIH, 2006b), including an emphasis on translational research that results in clinically useful therapies and a need for multidisciplinary efforts to be used to address this complex medical condition. Recommendation 8.2: The National Institutes of Health should establish a National Somnology and Sleep Medicine Research Network. The National Center on Sleep Disorders Research, in collaboration with the Trans-NIH Sleep Research Coordination Committee, should establish a National Somnology and Sleep Medicine Research Network. Type III regional interdisciplinary sleep programs designated by the National Institutes of Health would act as regional centers working with basic research laboratories and sleep cores at NIH-designated clinical translational research centers. It is envisioned that the networks would do the following: Coordinate and support the current and future cadre of basic and clinical researchers. Train new investigators and fellows. Provide core capabilities for basic, clinical, and translational research. Support multisite clinical research in children, adolescents, adults, and elderly. Create and support virtual networking centers to facilitate the standardization and sharing of data and resources online and enhance collaborations with researchers not working in research centers. Create a data coordinating center that includes an Internet-based clearing house for the publication of all data produced in cooperation with the research and clinical network. Together with the Agency for Healthcare Research and Quality develop standards for research, outcomes, and clinical practice. Work with the Centers for Disease Control and Prevention to integrate and support surveillance and population-based research. Establish Sleep Laboratories in the NIH Clinical Research Program As described in the 2003 research plan, “[t]he role of sleep disturbances and sleep disorders in the morbidity of most chronic conditions is understudied … [and] poorly understood” (NHLBI, 2003). The report further went on to call for greater study of the “bidirectional relationship between
OCR for page 286
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem sleep processes and disease development, progression, and morbidity.” Given these priorities, it is of note that the intramural clinical research program at the NIH does not have a sleep laboratory. Consequently, many experimental sleep therapies and the relationship between sleep processes and disease development are not being examined. If there is adequate investment in extramural sleep-related programs, the field can continue to make great strides; therefore, the committee does not support use of limited resources to invest in an intramural somnology and sleep disorders research program. However, because appropriate sleep patterns constitute one of the basic tenets of health, the committee strongly urges the NIH intramural clinical research program to ascertain the need for potentially establishing a sleep study laboratory so that evaluation of sleep may be integrated into ongoing relevant clinical research protocols at NIH. Recommendation 8.3: The National Institutes of Health should ascertain the need for a transdisciplinary sleep laboratory that would serve as a core resource in its intramural clinical research program. The director of the National Institutes of Health Intramural Research Program should ascertain the need for a transdisciplinary sleep laboratory within the intramural clinical research program that would serve as a core resource for the community of intramural clinical investigators across all institutes. REFERENCES AASM (American Academy of Sleep Medicine). 2005. The International Classification of Sleep Disorders. Westchester, IL: AASM. Alvarez GG, Ayas NT. 2004. The impact of daily sleep duration on health: A review of the literature. Progress in Cardiovascular Nursing 19(2):56–59. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S. 2003. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genetics 33(4):459–461. Amin RS, Kimball TR, Kalra M, Jeffries JL, Carroll JL, Bean JA, Witt SA, Glascock BJ, Daniels SR. 2005. Left ventricular function in children with sleep-disordered breathing. American Journal of Cardiology 95(6):801–804. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. 1991. Sleep-disordered breathing in community-dwelling elderly. Sleep 14(6):486–495. Ancoli-Israel S, Klauber MR, Stepnowsky C, Estline E, Chinn A, Fell R. 1995. Sleep-disordered breathing in African-American elderly. American Journal of Respiratory and Critical Care Medicine 152(6 Pt 1):1946–1949. Babu AR, Herdegen J, Fogelfeld L, Shott S, Mazzone T. 2005. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Archives of Internal Medicine 165(4):447–452.
OCR for page 287
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Bader G, Gillberg C, Johnson M, Kadesjö B, Rasmussen P. 2003. Activity and sleep in children with ADHD. Sleep 26:A136. Barger LK, Cade BE, Ayas NT, Cronin JW, Rosner B, Speizer FE, Czeisler CA, Harvard Work Hours HaS Group. 2005. Extended work shifts and the risk of motor vehicle crashes among interns. New England Journal of Medicine 352(2):125–134. Boggild H, Knutsson A. 1999. Shift work, risk factors and cardiovascular disease. Scandinavian Journal of Work Environment Health 25(2):85–99. Brown SA, Fleury-Olela F, Nagoshi E, Hauser C, Juge C, Meier CA, Chicheportiche R, Dayer JM, Albrecht U, Schibler U. 2005. The period length of fibroblast circadian gene expression varies widely among human individuals. PLoS Biology 3(10):e338. Buxbaum SG, Elston RC, Tishler PV, Redline S. 2002. Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis. Genetic Epidemiology 22(3):243–253. Carskadon MA, Acebo C, Jenni OG. 2004. Regulation of adolescent sleep: Implications for behavior. Annals of the New York Academy of Science 1021:276–291. Cavallo A, Mallory ML, Association of Medical School Pediatric Department Chairs Inc. 2004. Sleep deprivation, residency training, and ACGME rules: Practical guidelines. Journal of Pediatrics 145(6):717–718. Cizza G, Skarulis M, Mignot E. 2005. A link between short sleep and obesity: Building the evidence for causation. Sleep 28(10):1217–1220. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz JR, Niebler GE, Dinges DF. 2005. Modafinil for excessive sleepiness associated with shift-work sleep disorder. New England Journal of Medicine 353(5):476–486. de la Eva RC, Baur LA, Donaghue KC, Waters KA. 2002. Metabolic correlates with obstructive sleep apnea in obese subjects. Journal of Pediatrics 140(6):654–659. Dolan-Sewell RT, Riley WT, Hunt CE. 2005. NIH State-of-the-Science Conference on Chronic Insomnia. Journal of Clinical Sleep Medicine 1(4):335–336. Fregosi RF, Quan SF, Kaemingk KL, Morgan WJ, Goodwin JL, Cabrera R, Gmitro A. 2003. Sleep-disordered breathing, pharyngeal size and soft tissue anatomy in children. Journal of Applied Physiology 95(5):2030–2038. Gillette MU, Roth T, Kiley JP. 1999. NIH funding of sleep research: A prospective and retrospective view. Sleep 22(7):956–958. Gottlieb DJ, Chase C, Vezina RM, Heeren TC, Corwin MJ, Auerbach SH, Weese-Mayer DE, Lesko SM. 2004a. Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children. Journal of Pediatrics 145(4):458–464. Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T. 2004b. APOE ¤4 is associated with obstructive sleep apnea/hypopnea: The Sleep Heart Health Study. Neurology 63(4):664–668. Gottlieb DJ, Punjabi NM, Newman AB, Resnick HE, Redline S, Baldwin CM, Nieto FJ. 2005. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Archives of Internal Medicine 165(8):863–867. Gozal D, Burnside MM. 2004. Increased upper airway collapsibility in children with obstructive sleep apnea during wakefulness. American Journal of Respiratory and Critical Care Medicine 169(2):163–167. Gurubhagavatula I, Maislin G, Nkwuo JE, Pack AI. 2004. Occupational screening for obstructive sleep apnea in commercial drivers. American Journal of Respiratory and Critical Care Medicine 170(4):371–376. Harrington JM. 1994. Shift work and health—A critical review of the literature on working hours. Annals of the Academy of Medicine, Singapore 23(5):699–705. Harris GC, Wimmer M, Aston-Jones G. 2005. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058):556–559.
OCR for page 288
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Harsch IA, Schahin SP, Radespiel-Troger M, Weintz O, Jahreiss H, Fuchs FS, Wiest GH, Hahn EG, Lohmann T, Konturek PC, Ficker JH. 2004. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. American Journal of Respiratory and Critical Care Medicine 169(2):156–162. Howard ME, Desai AV, Grunstein RR, Hukins C, Armstrong JG, Joffe D, Swann P, Campbell DA, Pierce RJ. 2004. Sleepiness, sleep-disordered breathing, and accident risk factors in commercial vehicle drivers. American Journal of Respiratory and Critical Care Medicine 170(9):1014–1021. Landrigan CP, Rothschild JM, Cronin JW, Kaushal R, Burdick E, Katz JT, Lilly CM, Stone PH, Lockley SW, Bates DW, Czeisler CA. 2004. Effect of reducing interns’ work hours on serious medical errors in intensive care units. New England Journal of Medicine 351(18):1838–1848. Larkin EK, Patel SR, Redline S, Mignot E, Elston RC, Hallmayer J. 2005a. Apolipoprotein E and obstructive sleep apnea: Evaluating whether a candidate gene explains a linkage peak. Genetic Epidemiology 30(2):101–110. Larkin EK, Rosen CL, Kirchner HL, Storfer-Isser A, Emancipator JL, Johnson NL, Zambito AM, Tracy RP, Jenny NS, Redline S. 2005b. Variation of C-reactive protein levels in adolescents: Association with sleep-disordered breathing and sleep duration. Circulation 111(15):1978–1984. Lavie L. 2003. Obstructive sleep apnoea syndrome—An oxidative stress disorder. Sleep Medicine Reviews 7(1):35–51. Lockley SW, Cronin JW, Evans EE, Cade BE, Lee CJ, Landrigan CP, Rothschild JM, Katz JT, Lilly CM, Stone PH, Aeschbach D, Czeisler CA, Harvard Work Hours HaS Group. 2004. Effect of reducing interns’ weekly work hours on sleep and attentional failures. New England Journal of Medicine 351(18):1829–1837. Lyamin O, Pryaslova J, Lance V, Siegel J. 2005. Animal behaviour: Continuous activity in cetaceans after birth. Nature 435(7046):1177. Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-Strambi L, Granieri E. 2004. Restless legs syndrome and pregnancy. Neurology 63(6): 1065–1069. Marcus CL, Katz ES, Lutz J, Black CA, Galster P, Carson KA. 2005. Upper airway dynamic responses in children with the obstructive sleep apnea syndrome. Pediatric Research 57(1):99–107. Maret S, Franken P, Dauvilliers Y, Ghyselinck NB, Chambon P, Tafti M. 2005. Retinoic acid signaling affects cortical synchrony during sleep. Science 310(5745):111–113. Marin JM, Carrizo SJ, Vicente E, Agusti AG. 2005. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: An observational study. Lancet 365(9464):1046– 1053. Mignot E, Chen W, Black J. 2003. On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy. Sleep 26(6):646–649. Monk TH. 2005. Aging human circadian rhythms: Conventional wisdom may not always be right. Journal of Biological Rhythms 20(4):366–374. Morin CM. 2004. Cognitive-behavioral approaches to the treatment of insomnia. Journal of Clinical Psychiatry 65(suppl 16):33–40. NCI (National Cancer Institute). 2004. The Cancer Centers Branch of the National Cancer Institute: Policies and Guidelines Relating to the Cancer Center Support Grant. [Online]. Available: http://www3.cancer.gov/cancercenters/CCSG_Guide12_04.pdf [accessed December 19, 2005]. NCMRR (National Center for Medical Rehabilitation Research). 2005. NCMRR Research Networks. [Online]. Available: http://www.nichd.nih.gov/about/ncmrr/networks.htm [accessed December 19, 2005].
OCR for page 289
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem NHLBI (National Heart, Lung, and Blood Institute). 1996. National Sleep Disorders Research Plan, 1996. Bethesda, MD: National Institutes of Health. NHLBI. 2003. National Sleep Disorders Research Plan, 2003. Bethesda, MD: National Institutes of Health. NIH (National Institutes of Health). 2004. Program Announcement: PA-05-046. [Online]. Available: http://grants.nih.gov/grants/guide/pa-files/pa-05-046.html [accessed March 6, 2006]. NIH. 2005. Request For Applications: RFA-HL-06-003. [Online]. Available: http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-06-003.html [accessed March 6, 2006]. NIH 2006a. Program Announcement PAR-05-144: Developing Centers for Innovation in Services and Intervention Research (DCISIR). [Online]. Available: http://grants.nih.gov/grants/guide/pa-files/PAR-05-144.html [accessed January 27, 2006]. NIH. 2006b. Request For Applications: RFA-RM-06-002. [Online]. Available: http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-06-002.html [accessed February 6, 2006]. NIMH (National Institute of Mental Health). 2006. Program Announcement: PAR-02-123. [Online]. Available: http://grants.nih.gov/grants/guide/pa-files/PAR-02-123.html [accessed January 27, 2006]. Nishino S, Kanbayashi T. 2005. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Medicine Reviews 9(4):269–310. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. 2004. Functional neuroimaging evidence for hyperarousal in insomnia. American Journal of Psychiatry 161(11):2126–2128. Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, Taylor MR, Zwillich CW. 2004. Obesity-associated hypoventilation in hospitalized patients: Prevalence, effects, and outcome. American Journal of Medicine 116(1):1–7. Owens JA, Rosen CL, Mindell JA. 2003. Medication use in the treatment of pediatric insomnia: Results of a survey of community-based pediatricians. Pediatrics 111(5 Pt 1):e628–e635. Palmer LJ, Buxbaum SG, Larkin E, Patel SR, Elston RC, Tishler PV, Redline S. 2003. A whole-genome scan for obstructive sleep apnea and obesity. American Journal of Human Genetics 72(2):340–350. Palmer LJ, Buxbaum SG, Larkin EK, Patel SR, Elston RC, Tishler PV, Redline S. 2004. Whole genome scan for obstructive sleep apnea and obesity in African-American families. American Journal of Respiratory and Critical Care Medicine 169(12):1314–1321. Petersen A, Gil J, Maat-Schieman ML, Bjorkqvist M, Tanila H, Araujo IM, Smith R, Popovic N, Wierup N, Norlen P, Li JY, Roos RA, Sundler F, Mulder H, Brundin P. 2005. Orexin loss in Huntington’s disease. Human Molecular Genetics 14(1):39–47. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE, Sleep Heart Health Study Investigators. 2004. Sleep-disordered breathing, glucose intolerance, and insulin resistance: The Sleep Heart Health Study. American Journal of Epidemiology 160(6):521–530. Rattenborg NC, Mandt BH, Obermeyer WH, Winsauer PJ, Huber R, Wikelski M, Benca RM. 2004. Migratory sleeplessness in the white-crowned sparrow (Zonotrichia leucophrys gambelii). PLoS Biology 2(7):E212. Rosen CL, Larkin EK, Kirchner HL, Emancipator JL, Bivins SF, Surovec SA, Martin RJ, Redline S. 2003. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: Association with race and prematurity. Journal of Pediatrics 142(4): 383–389. Rosen CL, Storfer-Isser A, Taylor HG, Kirchner HL, Emancipator JL, Redline S. 2004. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics 114(6):1640–1648. Roth T, Roehrs T. 2003. Insomnia: Epidemiology, characteristics, and consequences. Clinical Cornerstone 5(3):5–15.
OCR for page 290
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Row BW, Liu R, Xu W, Kheirandish L, Gozal D. 2003. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. American Journal of Respiratory and Critical Care Medicine 167(11):1548–1553. Rye DB. 2004. The two faces of Eve: Dopamine’s modulation of wakefulness and sleep. Neurology 63(8 Suppl 3):S2–S7. Saper CB, Scammell TE, Lu J. 2005. Hypothalamic regulation of sleep and circadian rhythms. Nature 437(7063):1257–1263. Singh M, Drake C, Roehrs T, Koshorek G, Roth T. 2005. The prevalence of SOREMPs in the general population. Sleep 28(Abstract Suppl):A221. Spiegel K, Tasali E, Penev P, Van Cauter E. 2004. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Annals of Internal Medicine 141(11):846–850. Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, Franken P. 2003. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nature Genetics 34(3):320–325. Taheri S, Lin L, Austin D, Young T, Mignot E. 2004. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Medicine 1(3):210–217. Tauman R, Ivanenko A, O’Brien LM, Gozal D. 2004. Plasma C-reactive protein levels among children with sleep-disordered breathing. Pediatrics 113(6):e564–e569. Trenkwalder C, Paulus W, Walters AS. 2005. The restless legs syndrome. Lancet Neurology 4(8):465–475. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. 2005. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308(5724):1043–1045. U.S. Congress, Senate. 1993. National Institutes of Health Revitalization Act of 1993; bill to establish a National Center on Sleep Disorders Research within the National Heart, Lung, and Blood Institute. 103rd Cong., S.104:285b–287. Veasey SC, Davis CW, Fenik P, Zhan G, Hsu YJ, Pratico D, Gow A. 2004a. Long-term intermittent hypoxia in mice: Protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep 27(2):194–201. Veasey SC, Zhan G, Fenik P, Pratico D. 2004b. Long-term intermittent hypoxia: Reduced excitatory hypoglossal nerve output. American Journal of Respiratory and Critical Care Medicine 170(6):665–672. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML. 2003. Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. American Journal of Medical Genetics: Part A 123(3):267–278. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptacek LJ, Fu YH. 2005. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434(7033):640–644. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. 2005. Obstructive sleep apnea as a risk factor for stroke and death. New England Journal of Medicine 353(19):2034–2041. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H. 2000. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288(5466):682–685. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. 2003. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 107(8):1129–1134.
OCR for page 291
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, Menaker M, Takahashi JS. 2004. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proceedings of the National Academy of Sciences of the United States of America 101(15):5339–5346. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. 1993. The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine 328(17):1230–1235.
OCR for page 292
Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem This page intially left blank
Representative terms from entire chapter: