Annual Report of the Trans-NIH Sleep Research Coordinating Committee FY 2002

Annual Report
of the
Trans-NIH Sleep Research Coordinating Committee
FISCAL YEAR 2002

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Sleep Disorders Information
Scientific Information and Resources

INTRODUCTION

The Trans-NIH Sleep Research Coordinating Committee (SRCC), established in 1986 by the Director, National Institutes of Health (NIH) for the purpose of facilitating interchange of information on sleep and sleep-related research, meets quarterly to discuss ongoing activities in various NIH sleep-related programs. The committee membership in Fiscal Year 2002 included representatives from the following NIH Institutes and Centers:

National Heart, Lung, and Blood Institute (NHLBI)
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Child Health and Human Development (NICHD)
National Institute on Drug Abuse (NIDA)
National Institute of Mental Health (NIMH)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Nursing Research (NINR)
National Center for Complementary and Alternative Medicine (NCCAM)

In addition, the National Center for Research Resources (NCRR) also has a sleep-related portfolio and this information is included in the attached grant listing and budget tables.

The NHLBI was mandated to establish the National Center on Sleep Disorders Research (NCSDR) in 1993 as an advocacy and coordinating center for research related to sleep and sleep disorders. In conjunction with this mandate, the Director, NIH transferred responsibility for the Trans-NIH Sleep Research Coordinating Committee to the NCSDR. The NCSDR maintains a complete file of annual reports from the initiation of the Committee in 1986.

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ACTIVITIES OF THE NATIONAL CENTER ON SLEEP DISORDERS RESEARCH
Carl E. Hunt, MD, Director

Fiscal Year 2002 (ending September 30, 2002) has been an active year for the NCSDR. We have participated in the planning and conduct of workshops, new initiatives, and public education programs.

The enabling legislation creating the NCSDR directed the Director of NIH to develop a National Sleep Disorders Research Plan and to revise it as appropriate. In response to this mandate, a major project was initiated in Fiscal Year 2001 to revise the original Plan released in 1996. The 2003 National Sleep Disorders Research Plan revision will summarize the dramatic expansion in interdisciplinary sleep-related research and resulting new knowledge achieved since the 1996 Plan.

New Initiatives Released in Fiscal Year 2002

Pathophysiologic Mechanisms of Obesity-Associated CVD (RFA: $16 Million)
Sponsors: NHLBI; NIDDK
Objectives:
Biologic basis of obesity-related cardiovascular diseases and disorders, including:
- Atherosclerosis
- Thrombosis
- Hypertension
- Cardiomyopathies
- Heart Failure
- Arrhythmias/Sudden Death
- Sleep (Metabolic Syndrome)

Interrelationship Between Sleep and Heart, Lung, and Blood Diseases (RFA: $3.4 Million)
Sponsors: NHLBI; NIDA
Objectives:
Identify measurable characteristics of sleep useful for study of sleep and sleep disorders
- Diagnosis and severity
- Assess effectiveness of treatment or intervention

Pathophysiology and Treatment of Chronic Fatigue Syndrome (CFS) (PA)
Sponsors: ORWH; ODS; OBSSR; NCCAM; NIAAA; NIAID; NIAMS; NICHD; NHLBI; NIEHS; NINR
Objectives:
Provide a better understanding of both CFS pathogenesis and pathophysiology with the goal of developing improved diagnostic and intervention strategies.

Sleep-Related Workshops In Fiscal Year 2002

Sleep, Fatigue, and Medical Training: Setting an Agenda for Optimal Learning and Patient Care (October 2001)
Sponsors: American Academy of Sleep Medicine; Sleep Research Society; American Medical Association; NCSDR (NHLBI). (Supported by a Conference Grant from the Agency for Healthcare Research and Quality)
Objectives:
The specific objectives of the conference were: (1) To discuss how sleep deprivation and fatigue affect performance; (2) To evaluate the effectiveness of countermeasures and other strategies designed to overcome the effects of fatigue; (3) To discuss how data from other industries may be applicable to the medical setting; and (4) To identify gaps in knowledge that must be filled before establishing any new meaning policies regarding sleep, fatigue, and medical training.

Cardiovascular and Sleep-Related Consequences of Temporomandibular Joint Disorders (December 2001)
Sponsors: NHLBI: Division of Heart and Vascular Diseases (DHVD); NCSDR
Objectives:
Review what is known, and subsequently develop research priorities, about cardiovascular and sleep-related consequences of temporomandibular disorders (TMD), including: (1) Pathophysiology and clinical consequences of sleep and TMD; (2) Physiology and biomechanics of breathing and swallowing; and (3) Neurological integration of the cardiovascular, respiratory, and pain pathways that influence these systems in health and in disease.

Restless Legs Syndrome (RLS): Diagnosis and Diagnostic and Epidemiological Tools (May 2002)
Sponsors NIA; Restless Legs Syndrome Foundation
Co-Sponsors: NINDS; NIMH; NINR; NCSDR/NHLBI
Objectives:
To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies.

Cardiovascular Consequences of Sleep Disordered Breathing (September 2002)
Sponsors: NCSDR (NHLBI)
Objectives:
This workshop assessed a broad array of new physiological, molecular, and genetic findings pertaining to the relationship of sleep apnea and risk of cardiovascular diseases, and recommended directions for developing the research needed to elucidate the underlying pathophysiological mechanisms.

Revision Of Sleep Disorders Research Plan

The scope of the original Sleep Disorders Research Plan released by NIH in 1996 included basic science studies on the regulation and function of sleep and studies on sleep disorders, including basic research, clinical epidemiology, genetics, effects and cost of treatment. The Research Plan also addressed training needs for the field of sleep medicine. Implementation of recommendations from this Research Plan led to substantial growth in research funding by NIH, with a 130% increase in total grant dollars in Fiscal Year 2002 compared to 1996 and a 21% increase from Fiscal Year 2001 to Fiscal Year 2002. The 1996 Research Plan also provided direction for extensive public health education and intervention programs related to sleep and sleep disorders.

Much, however, has changed since 1996. New research and new knowledge have vastly expanded the array of questions to be addressed, and new technologies have yielded new tools and mechanisms for a highly interdisciplinary broad-based approach to sleep research. To build on these achievements, a Task Force was appointed in Fiscal Year 2002 to review accomplishments, identify remaining knowledge gaps and promising new scientific directions, determine unforeseen new challenges, and to establish prioritized recommendations for future research related to sleep and sleep disorders. The Task Force members are listed below:

Chair: Dr. David White

Members:
Dr. Thomas Balkin
Dr. Gene Block*
Dr. Daniel Buysse
Dr. David Dinges
Dr. David Gozal
Dr. Steve Henriksen
Dr. Hannah Kinney
Dr. Carol Landis*
Dr. Emmanuel Mignot*
Dr. Judith Owens
Dr. Jerry Siegel
Dr. Esther Sternberg
Dr. Debra Weese-Mayer
Dr. Clifford Saper* (Consultant)

(*2002 Sleep Disorders Research Advisory Board Member)

The Task Force appointed to revise the Sleep Disorders Research Plan met three times and conducted multiple conference calls. Administrative and staff support were provided by NCSDR and the Trans-NIH SRCC. A draft of the revised plan was broadly circulated to solicit comments from biomedical professionals involved in sleep-related research and clinical practice, and relevant professional and public organizations representing individual scientific disciplines and sleep disorders. A special session was held at the 2002 Annual Meeting of the Associated Professional Sleep Societies to present the plan and receive comments, and the draft Plan was posted on the NCSDR web site for two months. Many comments were received and were carefully considered by the Task Force in preparation of the final Plan.

The 2003 revision of the National Sleep Disorders Research Plan will be released by NIH during Fiscal Year 2003. This Plan will fully represent the deliberations and recommendations of the Task Force, summarize the dramatic advances in knowledge since 1996, and identify current gaps in our knowledge base. The recommendations for future research will not only guide prioritization of future sleep research within NIH and other Federal and non-Federal entities, but should also be helpful in identifying opportunities for new investigators from an ever-increasing diversity of scientific and clinical disciplines. The recommendations regarding training of sleep research scientists, the education of health care professionals, and community-based public education programs should also stimulate much-needed progress in these areas.

Other Activities During Fiscal Year 2002

National Children's Study:
Drs. Carl E. Hunt and Mary Carskadon were appointed to the Development and Behavior Working Group to represent sleep-related issues during the planning and protocol-development phase of this large longitudinal study of 100,000 children age 0-21. Additional information about this study is available on line at http://nationalchildrensstudy.gov/ Dr. Carskadon has been appointed by NCSDR/SDRAB as Chair of an ad hoc subcommittee to develop protocol recommendations for a core set of sleep-related data to be collected on all mothers and children. This subcommittee will complete its activities in Fiscal Year 2003.

American Academy of Pediatrics Annual Meeting (October, 2002)
Special Presentation: Sleepiness and Adolescents: A Deadly Combination
Moderators: Carl E. Hunt, MD; David Kaplan, MD
Speakers:
Mary Carskadon, PhD
Ronald Dahl, MD
Richard Millman, MD

Sleep-Related Workshops Planned For Fiscal Year 2003

Effects of Sleep Disorders and Sleep Restriction on Adherence to Cardiovascular and Other Disease Treatment Regimens (March 11-12, 2003)
Sponsors: NHLBI (NCSDR, Division Of Lung Diseases, Division Of Epidemiology And Clinical Applications, Division Of Heart And Vascular Diseases, Division of Blood Diseases and Resources); NINDS
Objectives:
(1) Further understanding of the relationship of sleep disorders and altered sleep-wake schedules to adherence of treatment for cardiovascular and other disease treatment regimens; (2) Delineate possible mechanisms through which sleep and its disorders impact adherence; and (3) identify potential opportunities for new research and for improved public health applications.

Congress on Sleep, Health and Aging (March 30-31, 2003)
Sponsors: National Sleep Foundation (NSF), in cooperation with NIA, NIMH, NCSDR (NHLBI), AAMC, Canadian Institutes of Health Research
Objectives:
(1) Review the knowledge base about sleep and its disorders and the impact they have on health for those with chronic and age-related diseases, and (2) develop strategies to bridge the gap between science and the bedside.

Neuro-Immune Mechanisms and Chronic Fatigue Syndrome (CFS). Will Understanding Central Mechanisms Enhance the Search for the Causes, Consequences, and Treatment of CFS (June 12-13, 2003)
Sponsors: Office of Research on Women's Health, and the Trans-NIH Working Group for Research on Chronic Fatigue Syndrome (CFS)
Objectives:
(1) To help elucidate the scientific understanding of CFS by examining the interface between the brain, immune system, and symptoms of CFS and related disorders. Explore the mechanisms by which hormones, cytokines, and other mediators act as intermediaries between the brain and other body systems. (2) Explore how new methodologies used in the study of these mediators and their central and peripheral actions could be applied to CFS and related disorders.

Publications

Hunt CE, Buysse DJ, Germain A, Hall M, Landis CA, Lee KA, Mignot E, Phillips B. Sleep and Sleep Disorders in Women. Clinical Updates in Women's Health Care. American College of Obstetrics & Gynecology Monograph Series. 2003; volume 2, in press.

Summary of Public Communications

NCSDR receives inquiries from or about patients with a sleep disorder or sleep related concern, and from health care professionals, students or writers regarding sleep problems and sleep disorders. In Fiscal Year 2002, 27% of these inquiries to NCSDR were received by e-mail. This is consistent with the prior year (Fiscal Year 2001) in which 30% of all public inquiries were via e-mail. The NCSDR also has extensive media contacts related to newspapers, professional and lay publications, radio, the Internet and television that are coordinated by the Press Office [NHLBI, Office of the Director (OD)]. The Health Information Network [NHLBI, Office of Prevention, Education and Control (OPEC)] also coordinates media campaigns and activities regarding sleep information. These communications are summarized in the following table.

PUBLIC NCSDR CONTACTS (E-Mail, Phone, Letters)

Snoring/Breathing/Apnea

197

Insomnia

109

Narcolepsy

86

Restless Legs Syndrome

71

General Sleep Problem or General Information

401

TOTAL PUBLIC CONTACTS-NCSDR

864

PRESS OFFICE (NHLBI/OD) MEDIA CONTACTS

Electronic Media (Internet, E-Mail)
8

Live (Radio, TV, Telephone Interviews)
25

Print Media
16

TOTAL-PRESS OFFICE MEDIA CONTACTS

49

MEDIA COVERAGE, OPEC AUDIENCE IMPRESSIONS (CY 2002)

Parents Magazine
500,000

Washington Parents
100,000

CBS Early Show
6,000,000

Sleep Savvy
100,000

San Antonio Express News
600,000

Baltimore Sun
800,000

Parade Magazine
93,000,000

Yahoo! News
9,000,000

Medscape.com
2,900,000

Intelihealth
1,800,000

Boston Herald
600,000

Los Angeles Times
1,000,000

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ACTIVITIES OF TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE MEMBER INSTITUTES

NATIONAL HEART, LUNG AND BLOOD INSTITUTE
Michael Twery, PhD
NHLBI Representative to the Trans-NIH sleep research coordinating committee

Scientific Research and Initiatives

The National Heart, Lung, and Blood Institute (NHLBI) sleep research program covers a wide spectrum ranging from neuroscience, genetics, and circadian rhythm to anatomy, physiology, behavioral science, epidemiology, clinical research, and health education. The program is aimed at understanding the molecular, genetic, and physiological regulation of sleep and the relationship of sleep disorders to cardiopulmonary disease. NHLBI is a major supporter of investigator-initiated sleep research at NIH. The Institute initiated requests for applications (RFA) on Oxygen Sensing During Intermittent Hypoxia (RFA HL-00-004), Sleep and Sleep Disorders in Children (RFA HL-01-006), and the Interrelationship Between Sleep and Heart, Lung, and Blood Diseases (RFA HL-01-009). The Program on Genomic Applications for Heart, Lung, and Blood Research (HL-99-024) is identifying new animal models of sleep disorders, training sleep researchers in functional genomic approaches, and collaborating with sleep researchers in new studies of sleep disorder genetic epidemiology. An Innovative Research Grant Program (RFA HL-01-016) and a new program for Ancillary Pharmacogenetics Studies in Heart, Lung, Blood, and Sleep Disorders (RFA HL-03-001) encourage the addition of sleep research questions to ongoing investigations of heart, lung, and blood diseases. A new initiative to be awarded in fiscal year 2003 is on the Role of Sleep and Sleep-Disordered Breathing in Metabolic Syndrome (RFA HL-03-008) will stimulate research on the relationship of sleep deprivation and sleep-disordered breathing (SDB) to characteristics of the metabolic syndrome including obesity, high blood pressure, dyslipidemia, insulin resistance, and vascular inflammation.

Key to many new scientific findings is the Specialized Centers of Research (SCOR) program on the Neurobiology of Sleep and Sleep Apnea (RFA HL-96-014). The objective of this SCOR program is to integrate the molecular, cellular, and genetic approaches to sleep control with clinical investigations on the etiology and pathogenesis of sleep disorders particularly sleep apnea. In addition, the ongoing multi-center Sleep Heart Health Study is employing clinical and epidemiological approaches to examine whether subjects with high blood pressure have sleep apnea; whether sleep apnea is a contributing risk factor for the development of cardiovascular and cerebrovascular disease; and how age, gender, and ethnicity influence the association between apnea, hypertension, and stroke. Innovative biomedical technologies are being developed to improve diagnostic and treatment approaches for sleep-disordered breathing under the Small Business Innovation Research (SBIR) Program.

NHLBI is also enhancing the awareness of medical students, physicians, and other health care professionals about sleep and sleep disorder diagnosis through the Sleep Academic Award program established in twenty medical schools. Sleep Academic Awardees have published over 35 reports on sleep medicine education since the program began in 1997. The American Academy of Sleep Medicine is facilitating electronic distribution of medical education resources developed under the Sleep Academic Award program through their website. NHLBI also supports programs to train students, scientists, and physicians in basic and clinical research in sleep, pulmonary physiology, and medicine. A number of new findings in the NHLBI sleep program are highlighted by research into the epidemiology of sleep apnea and cardiovascular disease; a potential link between sleep apnea and abnormalities in metabolism affecting appetite; and sleep apnea and school performance in children.

Sleep Disturbance Linked to Coronary Heart Disease Risk

Sleep duration has been previously associated with the risk of all-cause mortality. New findings reveal that sleep duration is associated with an increased risk of coronary events in women independent of physiological factors such as age, obesity, and HDL cholesterol level, and lifestyle factors such as the use of aspirin, post-menopausal hormone therapy, smoking, alcohol consumption, and physical exercise. A study of 71,000 middle age women for over ten years found that 70% slept less than the reference group that slept eight hours per night. Sleep durations of seven, six, or less than five hours/night were associated with a 9%, 18%, and 45% increased risk of coronary events respectively compared to that of women sleeping eight hours. The study also found that 5% slept nine hours or longer. Intriguingly, increased sleep duration was also associated with a 38% increased risk of coronary events compared to women sleeping eight hours. Women sleeping nine hours or longer reported snoring more frequently than other groups in this study. Snoring fragments sleep, and has been previously associated with an increased risk of sleep-disordered breathing, stroke, hypertension, and heart disease. The causes of long and short sleep duration in women are not well understood. Women who slept less than eight hours frequently reported that sleep was restricted by a shift work lifestyle. Hormonal status may also be a factor. Findings from a new study of 700 women indicate that the prevalence of sleep-disordered breathing in post-menopausal women is double that of pre-menopausal women.

Other recent studies have attempted to elucidate potential pathophysiological mechanisms linking SDB and cardiovascular disease. These studies indicate that mild to moderate SDB is associated with elevated levels of vascular endothelial growth factor (VEGF). The expression of this cytokine is highly sensitive to hypoxia, and has been correlated with the severity of vascular inflammation and the degree of new collateral artery formation in heart disease. Treatment of SDB in adults with continuous positive airway pressure (CPAP) lowers VEGF expression to normal levels. Children with SDB comparable to adults exhibit greater increases in VEGF. Whether this increased response reflects a greater susceptibility to SDB and age-dependent mechanisms is not clear. Whether CPAP lowers VEGF expression in children with SDB is also not known. Recent findings indicate that the severity of SDB is correlated with elevated levels of several vascular cell adhesion molecules and free radical species implicated in the development of atherosclerotic plaques. Adhesion molecule levels were not elevated during treatment of SDB with CPAP. Whether CPAP treatment can reverse atherosclerotic injury and cardiovascular disease resulting from sleep-disordered breathing needs to be studied.

Lack of Sleep Stimulates Appetite and Disturbs Metabolism

New findings indicate that shortening sleep duration can fuel appetite and lead to unhealthy eating habits. A clinical study restricting the time in bed (sleep time) of lean young adult males to four hours per night increased total cortisol secretion, increased sympathetic tone, and decreased secretion of the hunger suppressing hormone, leptin. Nutritional assessment revealed that shortened sleep produced an increase in appetite for food equivalent to 1,000 calories per day with a preference for sweets and starchy foods. Carbohydrate metabolism was impaired during shortened sleep duration as indicated by a 40% slower rate of decline in blood glucose level after intravenous administration. Blood chemistry and appetite returned to normal when subjects were fully rested on 7 to 8 hours of sleep. Follow-up studies comparing hormonal changes in lean men and women with normal (7-8 hours per night) and short (less than 6.5 hours per night) sleep durations indicate that the short sleepers need to make 30 percent more insulin than normal sleepers in order to maintain blood sugar levels. The short sleepers were also found to exhibit insulin and blood sugar profiles comparable to those reported in the pre-diabetic elderly. These findings are consistent with other studies where chronic sleep disturbance (sleep-disordered breathing) is associated with an increased risk of diabetes.

Other studies indicate that a mild reduction in sleep duration produces hormonal changes comparable to those associated with an increased risk of obesity, diabetes, heart disease, and hypertension. Chronic voluntary sleep curtailment is a hallmark of modern society lifestyle. Nationally, the average nightly sleep has declined from an estimated 9 hours in 1910 to an average of 7.5 hours today. This trend generally parallels that of obesity prevalence. The relationship between shortened sleep duration and obesity may be greater in populations characterized by vulnerability to sleep disturbances such as pregnant women, shift workers, and low socioeconomic status groups. Whether the metabolic consequences of sleep curtailment during weekdays can be prevented by "catch-up" sleep on weekends is not known. Impaired sleep and untreated sleep disorders are known to impair quality of life and cognitive function. The present findings suggest that a regular pattern of shortened sleep duration may contribute to a persistent unhealthy lifestyle characterized by carbohydrates craving and reduced physical activity. Whether the practicing physician should take into consideration the potential role of sleep duration in treatment decisions and behavioral interventions for the control of obesity and comorbid conditions is an important question. Whether life-styles producing a chronic pattern of shortened sleep duration are associated with an increased risk of obesity, diabetes, and cardiovascular disease is another question.

Sleep Disordered Breathing Linked to Hyperactivity & Learning Problems in School Children

Previous studies have demonstrated that sleep-disordered breathing (SDB) in children is associated with poor academic performance. New findings from a survey of over 800 children ages 3 to 12 indicates that habitual snoring is associated with a greater than 2 fold increased risk of hyperactivity. Among young boys under age 8, habitual snoring was associated with a greater than 4 fold increased risk of hyperactive behavior. The findings indicate that excessive daytime sleepiness is also linked to inattention and hyperactivity. The mechanism linking snoring and sleepiness with hyperactivity is not understood, but sleep disruption, sleep deprivation, inadequate oxygen saturation, or other physiologic changes could play important roles. Children who are sleepy are likely to shift their attention frequently and create stimulation to keep themselves awake, especially at young ages when wakefulness is essential to rapid learning. If habitual snoring and sleepiness is a cause of hyperactive behavior, these findings suggest that a substantial percentage of hyperactive children (15%) suffer from co-morbid SDB and could be effectively treated by identification and treatment of the. Among hyperactive young boys, this figure rises to 39%. Other studies have linked adequate sleep to enhanced perceptual learning and associative memory functions. These findings indicate that learning and memory tasks are highly dependent on obtaining quality sleep. Reductions in the amount of deep (REM) sleep are associated with impaired learning and memory consolidation. Similar results have been obtained on the effect of napping. While short naps (30 minutes) lacking REM sleep were found to prevent performance deterioration associated with task "burnout" during sustained periods of training on a visual task, long naps (60 minutes) with REM sleep boosted performance. These findings indicate that sleep is likely to be a major contributor to learning potential in children, and that sleep restriction and sleep disorders may erode this potential.

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NATIONAL INSTITUTE ON AGING
Andrew Monjan, PhD, MPH
NIA Representative to the Trans-NIH Sleep Research Coordinating Committee

Problems with sleep are common with advancing years, and occur in over half of those people age 65 years and more. It has been estimated that insomnia affects about a third of the older population in this country. This inability to have restful sleep at night also results in excessive daytime sleepiness, attention and memory problems, depressed mood, falls, and lowered quality of life. Other factors associated with aging, such as disease, changes in environment, or concurrent age-related processes also may contribute to problems of sleep. Data indicate that in the elderly, age by itself does not predict incident complaints of insomnia, even in the presence of lowered sleep efficiency and decreased proportion of slow wave sleep. Rather, the prevalence of insomnia and other sleep disorders is high in the population due to the growing numbers of elderly and the associated comorbidities common in late life that affect sleep. It is now evident that disturbance in sleep can also lead to adverse changes in other body systems, especially the production of appropriate levels of hormones and proper metabolic functioning.

Program Activities

Program growth in the NIA Sleep portfolio grew to $14.5 million in Fiscal Year 2001 and experienced a slight increase to $14.6 million in Fiscal Year 2002 (see Financial Report Table, page 37). NIA cosponsored with the Restless Legs Syndrome (RLS) Foundation a workshop on "RLS: Diagnosis and Diagnostic and Epidemiological Tools" held May 1-3, 2002. NIA also is represented on the Sleep Disorders Research Advisory Board of the National Center on Sleep Disorders Research, NHLBI, and is working with them on the 2003 National Sleep Disorders Research Plan. NIA is working with the National Sleep Foundation (NSF) to develop their first Leadership Congress on Sleep, Health and Aging, which will be held March 31-April 1, 2003 In conjunction with this meeting, the NSF is conducting a national survey of sleep in older adults, and will report their findings at a press conference on April 2, 2003. NIA staff also were represented at a "Sleep, Health and Longevity Workshop" sponsored by the International Longevity Center-USA on October 3-6, 2002.

Research Advances

Sleep-Disordered Breathing (SDB) encompasses obstructive sleep apnea, hypopnea (shallow breaths), and upper airway resistance syndrome. Patients with obstructive sleep apnea or hypopnea may have frequent and repetitive episodes of oxygen desaturation, and all SDB patients have frequent arousals from sleep and resultant sleep deprivation. The clinical symptoms include loud snoring and excessive daytime sleepiness. The intermittent hypoxemia and episodes of brain activation (arousal) are associated with abrupt increases in systemic blood pressure, and SDB patients do not demonstrate the expected nocturnal dip in blood pressure.

Estimates from the Wisconsin Sleep Cohort Study suggest that 9% of women and 24% of middle-aged men have some degree of undiagnosed SDB (mild or worse) and that 2% of women and 4% of men would meet clinical guidelines for treatment. These data are essentially the same as in a study in Pennsylvania showing a prevalence of clinically defined sleep apnea of 1.2% in women and 3.9% in men with an age range of 20-100 years (mean 49 years). The prevalence of SDB in today's older population reflects the accumulation of cases with onsets occurring up to 30 years earlier. If today's middle-aged adults with an increased prevalence of overweight and obesity follow current population trends, then future prevalence rates for SDB in older age groups will be higher than current estimates. In the Wisconsin cohort, 690 randomly selected participants were evaluated twice at 4-year intervals for SDB. The percentage change in the apnea-hypopnea index (AHI; apnea events + hypopnea events per hour of sleep) and odds of developing moderate-to-severe SDB (defined by an AHI=15+ events/hour of sleep), were evaluated with respect to change in weight. Relative to stable weight, a 10% weight gain predicted a significant 32% increase in the AHI and a 6-fold increase in the odds of developing moderate-to-severe SDB while a 10% weight loss predicted a 26% decrease in the AHI. These data indicate that clinical and public health programs that result in even modest weight control are likely to be effective in reducing SDB severity and reducing new occurrence of SDB.

Emerging data implicate SDB as a risk factor for hallmarks of diabetes such as insulin resistance and impaired glucose tolerance. In addition, sleep deprivation and SDB may activate the sympathetic nervous system and proinflammatory cytokines, with cardiovascular impact. Moreover, SDB may be linked to abnormal lipid metabolism. Thus, SDB and sleep deprivation may play a significant role in the metabolic syndrome, defined as a clustering of three or more of the following risk determinants in an individual: abdominal obesity, elevated triglycerides, low level of high density lipoprotein cholesterol, high blood pressure, and high serum glucose. Using 2002 census data, the Third National Health and Nutrition Examination Survey yielded an estimate that that 47 million U.S. residents (24%) have the metabolic syndrome. Persons with the metabolic syndrome are at increased risk for developing diabetes mellitus (type 2 diabetes) and cardiovascular diseases. Metabolic syndrome also is associated with central obesity, and the increasing trends for obesity (BMI 30 or more) in the U.S. (NHANES, 1999-2000) show that the greatest prevalence (35.8% and 39.6% for men and women, respectively) and largest increase (12.0% and 11.0% for men and women, respectively) is in the 60-74 age groups.

However, SDB independent of obesity also is associated with the metabolic syndrome. Middle-aged men with sleep apnea, when compared to age- and BMI-matched non-apneic controls, were found to have higher levels of plasma leptin, TNF-alpha, and IL-6, and increased insulin resistance indices (increased fasting plasma glucose and insulin). In a community-based sample of 150 individuals who were minimally obese (120-160% of ideal body weight) with average age of 58.7 years, 46% were overweight (BMI 25 to 29.9) and 54% obese (BMI 30.0 or more). 62% had significant sleep apnea (AHI 5+), and 36% with AHI 20+. This SDB was associated with impaired glucose tolerance and insulin resistance independent of obesity.

A study of data from healthy men aged 16 to 83 years looked at 24-hour profiles of plasma growth hormone (GH) and the stress hormone cortisol, and sleep using polysomnographic sleep recordings including brain activity, movements, and breathing. It was found that the decrease in SWS, e.g., the deepest most recuperative stage of sleep, from early adulthood to later life was paralleled by a decrease in GH secretion. Association of sleep with cortisol concentrations, on the other hand, were independent of age and became significant only after the age of 50 years when sleep became more fragmented and REM sleep, e.g. the sleep that is associated with dreaming and memory storage, declined. The strong and robust relationship between SWS and GH secretion has led to the proposal that they both are under the control of similar types of neurons that may be located in different areas of the brain. Researchers have shown that drugs that increase one of the functions also increase the other. These data suggest that life-style behaviors and schedules resulting in chronic sleep restriction may increase susceptibility to the metabolic syndrome independent of SDB or other sleep disorders. Development of drugs that affect common mechanisms in sleep and GH production may help alleviate some of these problems.

Sleep disturbances can also lead to changes in other physiological systems, especially the production of appropriate levels of hormones and proper metabolic functioning. Studies of sleep deprivation in healthy adults provide additional data indicating potentially important effects on risk for insulin resistance and its association with obesity and hypertension (disorders included in the metabolic syndrome). Partial sleep deprivation of otherwise healthy control subjects produces a level of insulin resistance similar to that of diabetics. Carbohydrate metabolism, endocrine function, and gastrointestinal balance in young, healthy adults were studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bed-time period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance and insulin sensitivity, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo-pituitary-adrenal function were qualitatively and quantitatively similar to those observed in normal aging. It appears that, in healthy men, that there are distinct changes in sleep quality that occur through the adult age span, and these changes also mark specific alterations in hormonal systems that are essential for metabolic regulation.

It also has been proposed that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. In addition, data indicate that sleep loss can increase the stress load, possibly facilitating the development of chronic conditions which have an increased prevalence in low SES groups, such as obesity, diabetes, and hypertension.

Recent studies are investigating the associations between peri- and post-menopause and sleep problems. Four applications, parts of an Interactive Research Project Grant (IRPG), recently were funded to characterize the relationship between menopausal characteristics and sleep in a sample of 430 women, drawn from participants in the ongoing Study of Women's Health Across the Nation (SWAN) that will consist of 200 Caucasians, 150 African-Americans, and 80 Chinese Americans. This IRPG will recruit a sample of pre- and peri-menopausal women from the SWAN cohort, conduct ambulatory polysomnography at home and collect sleep diary data as well as data on menopausal characteristics (bleeding patterns, vasomotor symptoms, hormone levels, and related psychosocial and biological data) from the five years of SWAN core data. The specific aims are: (1) characterize sleep problems in a large multi-ethnic sample of mid-life women, (2) characterize relationships between menopausal characteristics and sleep problems, (3) evaluate the influence of relevant psychobiological and psychosocial factors on sleep problems during the early menopausal transition, and (4) establish baseline data on menopausal-related sleep problems for future longitudinal study.

Although sleep disruptions, insomnia, and the incidence of sleep disordered breathing increase in mid-life women, little is known about the relationship between menopause and sleep. The few data that now exist suggest that the sleep-menopause relationship is not one merely of age, but that a variety of relevant psychobiological factors contribute. Sleep in women during the menopausal transition often is reported to be disturbed. In one large epidemiological study utilizing polysomnography it was found that the likelihood of increased SDB over six months was significantly greater for women with peri- and post-, compared to pre-menopausal status. There was an independent risk of SDB (AHI>15) for menopausal compared to pre-menopausal women (OR=3.4) and peri- to pre-menopausal women (OR=1.4), independent of age or BMI. In addition, peri- and post- menopausal women using hormone replacement therapy (HRT) had a trend toward lower risk for SDB. Menopausal status, independent of symptoms such as hot flashes, did not predict sleep problems or depression. The association between age and these complaints was slight. Similarly, another study found that the prevalence of sleep apnea was low in pre-menopausal women (0.6%) as well as post-menopausal women with HRT (0.5%). However, post-menopausal women without HRT had significantly higher prevalence (2.6%), similar to the prevalence found in men (3.9%). In this study, sleep apnea was strongly associated with BMI 32.3 or more. These associations need further investigation to control for the differences in health and health behaviors of women on HRT.

A number of cross-sectional and longitudinal research studies have shown that disturbed sleep has a negative impact on cognitive functioning and quality of life. A large epidemiological longitudinal study (HAAS) of older men (mean age of 76.6 years, range 71-93) investigated the association between sleep disturbances (insomnia and daytime sleepiness) and the incidence of dementia and cognitive decline. A significant association was found between the self-report of excessive daytime sleepiness, found in 8% of the cohort, and diagnosis of incident dementia three years later. The risk was two-fold (O.R. = 2.2) as compared to those not reporting daytime sleepiness, after adjusting for age and other factors. Incident cognitive decline also was significantly associated with excessive daytime sleepiness (O.R. = 1.4). In contrast, insomnia, found in 31% of the cohort, was not associated with either incident cognitive decline or dementia. APOE4, a risk factor for Alzheimer's disease, was reported to be strongly associated (O.R. = 2.0) with sleep apnea in a sample of middle-aged (30 to 60 years) adults in the Wisconsin longitudinal cohort study of sleep, independent of age, sex, BMI, and ethnicity. These data suggest that this relationship to SDB might be due to the elevated levels of LDL-cholesterol and triglycerides found with this allele. Such an association between SDB and APOE4 was not found in a much older (79-97 years of age) Japanese-American cohort, most likely reflecting differences in age, ethnic, and BMI factors. However, these finding do suggest that it might be warranted to search for common genetic factors affecting sleep disturbances such as SDB and cognitive decline.

Few studies have addressed the effect of insomnia on quality of life, specifically in older adults. In one of the few such studies, older adults with secondary insomnia had worse quality of life than those with primary insomnia. Health-related quality of life (HRQOL) was measured in a sample of elderly African-Americans screened for snoring and daytime sleepiness and found to be associated with sleep apnea after controlling for medical conditions, suggesting that sleep disturbances may impact upon daily living and health as much as other medical conditions such as depression and chronic obstructive pulmonary disease. In a population based study, it was found that sleep duration did not correlate with a Quality of Well-Being scale, although greater sleep satisfaction, younger age, less obesity, non-Hispanic white ethnicity, and higher levels of daytime illumination were associated.

Several therapeutic strategies, especially phototherapy and melatonin administration, are likely to become effective treatments for some of the insomnias associated with aging. The use of bright light therapy for phase disorders is now more commonplace. Behavioral modifications such as stimulus control and sleep restriction appear to be effective techniques for shortening the sleep latency and wake-after-sleep-onset times.

The relationship between sleep timing and timing of the circadian rhythm of plasma melatonin secretion was investigated in a group of healthy young and older subjects without sleep complaints. The timing of sleep and the phase of the circadian melatonin rhythm were earlier in the older subjects, although the duration of sleep was similar. Consequently, the older subjects were waking at a time when they had higher relative melatonin levels, in contrast with younger subjects, whose melatonin levels were relatively lower by wake time. These findings indicate that aging is associated not only with an advance of sleep timing and the timing of circadian rhythms but also with a change in the internal phase relationship between the sleep-wake cycle and output of the circadian pacemaker.

Melatonin treatment is being tested for its sleep-inducing effects. A double-blind placebo-controlled clinical trial o f melatonin was conducted in groups of older individuals (age 50 and older) with and without insomnia. Self-reports of insomnia were confirmed by actigraphy (measurements of body movements through the night period) at home as well as by polysomnography (measurements of brain activity, movements, and breathing) in the sleep laboratory. In addition to a placebo, each participant received different doses of melatonin (0.1, 0.3, and 3.0 mg) orally one-half hour before usual bedtime for one week in a random order, each followed by a one-week washout period. The highest dose (3.0 mg) is the dose commonly found in over-the-counter preparations and results in blood levels 10-20 times the normal physiological levels produced by the lower doses. The most effective dose for improving sleep quality, measured as sleep efficiency or the proportion of time in bed actually sleeping, was 0.3 mg. The highest dose, like the lowest dose, also improved sleep efficiency, although to a lesser extent. However, the 3 mg dose also significantly reduced nighttime body temperature and increased daytime melatonin levels. There was no relation between endogenous melatonin levels and sleep efficiency. Individuals with normal sleep were unaffected by any dose of melatonin.

There is an increasing experimental base defining the relationships between sleep deprivation and cognitive functioning. It now appears that sleep, both slow wave sleep early in the sleep period and REM sleep late in the sleep period are necessary for memory consolidation. Research at the molecular level examing the processes underlying the role of sleep in the consolidation of long-term memory is being conducted using specific phosphorylated cyclic AMP-responsive element binding protein (CREB)-mutant mice. Results indicate that like sleep deprivation, inhibition of protein kinase A (PKA) or protein synthesis disrupts memory consolidation only at discrete times following training and these times vary depending upon the strength of the training protocol. Total sleep deprivation in mice 0-5 hours but not 5-10 hours after training impairs retention of contextual fear conditioning (in which an animal learns to fear a new environment), a hippocampus-dependent task when tested at 24 hours or 12 days after training. This does not occur with retention of cured-fear (when an animal learns an association between a cue, such as a tone, and a shock) training, a hippocampus-independent but amygdala-dependent task. CREB levels within forebrain are higher in waking than in sleep, and levels of camp response element (CRE)-mediated transcription oscillate in the SCN in a circadian fashion. CREB alpha-delta mutant mice (lacking the alpha and delta isoforms of CREB) had increased durations of sleep (NREM, REM, total sleep time), less time awake, and normal circadian period than wild type, indicating that CREB protein contributes to the mechanisms by which wakefulness is maintained. CREB mutants also do not have the induction of CRE-mediated gene expression in the hippocampus following sleep deprivation, indicating the critical role played by CREB in its induction following sleep deprivation. Thus sleep may preferentially affect hippocampus-dependent and not amygdala-dependent memory consolidation, in a fashion similar to that of the PKA signaling pathway that is crucial for long-term memory storage.

Immediate early genes, such as c-fos, are induced in response to wakefulness. The c-Fos protein must bind to the transcription factor AP-1. Baseline levels of c-Fos and AP-1 binding activity were similar in young (3.5 months) and old (21.5 months) Sprague-Dawley rats. However, in response to 6 or 12 hours of sleep deprivation, old rats have significantly less c-Fos and AP-1 binding activity than young rats. This decline in molecular activity could be the basis of the decline in sleep that occurs with age. Studies over the last few years have shown the important sleep regulatory functions of a hypothalamic circuit involving the ventral lateral preoptic nucleus (VLPO). The effect of prolonged wakefulness in rats on the expression of c-fos (as a marker of cellular activation) and galanin mRNA (as a marker for neurotransmitter synthesis) in VLPO neurons of older and younger rats resulted in no differences in the numbers of cells with age.

Future Directions

Although there is a growing body of research on the aging circadian system, relatively little exists on the aging sleep homeostatic mechanisms. The brain mechanisms underlying age-dependent changes in the sleep homeostatic mechanisms are beginning to be understood. More consistently applied neuroscience methods (e.g., neurophysiology, neuroanatomy, neuroimaging, and neuropharmacology) in animal and human aging studies are needed in order to better define the basis of age-related sleep changes. New studies are exploring the genetics of sleep. The relevance of the genetics of sleep to the problems of the older individual needs further stimulation. Similar to other recent findings that neuronal loss is not an inevitable consequence of aging, these data indicate that there is little evidence of an age-related loss of neurons that play a key role in the maintenance of sleep homeostasis. Thus, the age-related alterations in the control of sleep appear not to be due to loss of critical neurons but to subtle changes within the cells and in their interactions with other brain cells involved in the control of sleep and alertness. The elucidation of these factors, such as the role played by adenosine in the induction of sleep, can lead to the development of more effective and targeted pharmacological approaches to alleviate some of the problems of sleep that afflict over half of our older population.

The apparent distinct changes in sleep quality that occur through the adult age span and associated specific alterations in hormonal systems that are essential for metabolic regulation represent exciting areas of research that need to be pursued. In addition, these results indicate that sleep loss can increase the stress load, possibly facilitating the development of chronic conditions which have an increased prevalence in low SES groups, including obesity, diabetes, and hypertension,. A recent RFA, issued in collaboration with NHLBI will target these issues. Development of drugs that affect common mechanisms in sleep and GH production may help alleviate some of these problems.

Another exciting area of newly developing research is the understanding of the relationships between sleep and cognitive functioning. This may be especially important in the older individual, given the increased risks for disturbed sleep and disturbed cognition. This is an exciting window of opportunity as research on the relationships between sleep, cognition, aging, and the neurophysiological and molecular mechanisms is just beginning to coalesce.

Development of novel, safe, efficacious treatments for sleep disturbances in the elderly is an important goal. This may include the development of novel behavioral, pharmacological, hormonal, and physical (e.g., light) treatments for conditions such as insomnia and sleep-wake disruptions in dementia. Melatonin treatment is being tested for its sleep-inducing effects. However, it appears to be most effective at physiological doses in dealing with circadian dysynchrony. Data from a small clinical trial indicate that melatonin is not soporific in older people without insomnia. Further replications with larger groups with objectively defined sleep problems with a broader range of medical co-morbidities are needed. Research also needs to be directed at the development of new and more effective therapeutic modalities that are targeted at correcting the underlying pathological mechanisms of sleep disorders rather than treating them symptomatically. However, until that time, clinical trials on the safety and efficacy of hypnotic and somnolent agents are needed.

The boundaries of normal and abnormal age-related sleep changes, as well as guidelines for intervention, need better definition. Examples include defining when SDB or periodic limb movements during sleep require intervention.

A large proportion of older nursing home residents have problems in nighttime sleep and daytime wakefulness. They often are treated for their sleep problems with hypnotic agents that may put them at risk for falls and for confusion. Behavioral and environmental approaches may be more effective at dealing with these sleep problems. In addition, undiagnosed SDB may underlie some of these problems.

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NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
Ellen Witt, PhD
NIAAA Representative to the Trans-NIH Sleep Research Coordinating Committee

In Fiscal Year 2002, The National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded a total of 15 research projects related to alcohol and sleep, including regular Research Project Grants, Career Development Awards, and Center components. The specific areas of sleep-related research supported by NIAAA include: (1) the neural mechanisms of alcohol-induced sleep disturbances; (2) adolescent sleep/arousal patterns as a pathway to alcoholism in early adulthood; (3) the effects of prenatal alcohol exposure on development of circadian clock function; (4) the effects of alcohol exposure through breast milk on the development of neural systems associated with sleep and arousal; (5) assessment and medications for sleep disturbances in recovering alcoholics; (6) pharmacotherapy of alcoholism and comorbid insomnia; (7) sleep and immune function in African Americans; and (8) alcohol abuse liability in insomniacs.

Published research highlights during Fiscal Year 2002 from currently funded projects are summarized below:

Effects of Medication during Alcohol Detoxification on Mood and Sleep Disturbance

Outpatient treatment of alcohol withdrawal has received little attention, even though this may be the major setting for treatment of alcohol withdrawal. Furthermore, given that medical/ psychiatric outcomes are subject to much less control in an outpatient setting, the choice of medication may be more critical in determining effective outcomes for outpatient detoxification than inpatient treatment. Therefore, the present study evaluates the differential effects of an anticonvulsant, carbamazepine, and a benzodiazepine, lorazepam, on several psychiatric and psychosocial domains (including sleep quality) in outpatient subjects with and without multiple prior detoxifications. It was found that carbamazepine is superior to lorazepam in ameliorating anxiety and sleep problems in patients with mild to moderate withdrawal. Both medications improve subjective evaluation of ability to return to work. However, individuals with multiple detoxifications have higher levels of self-reported anxiety and poorer self-reported sleep quality, and are less inclined to return to work. This study has important implications for improved models of outpatient detoxification. Future studies should focus on comparing anticonvulsant agents to longer acting benzodiazepines over extended periods to determine the impact on sleep and anxiety outcomes and to better understand how persistence of symptoms may predispose to relapse.

Alcohol and Insomnia

Two recent studies examined aspects of alcohol use by insomniacs. One study investigated whether insomniacs are self-treating their sleep problems and if so, how and with what substances, for how long, and with what risks. In a survey of a representative sample of adults aged 18-65 in the Detroit Metropolitan area, exclusive past-year use of alcohol for sleep was reported by 10%, prescription medications by 8%, and over the counter (OTC) medications by 10%. In this study, prescription drug users were older, had more severe insomnia, medicated for a longer duration, and had greater disability, neuroticism, and daytime fatigue than the other two groups. In contrast, the alcohol users had greater daytime sleepiness than the others. In this sample, insomnia of self-treating insomniacs (e.g., alcohol and OTC users) is less severe than those receiving medical treatment, but is still associated with some risks.

A second study evaluated whether zaleplon, a new selective gamma-aminobutyric acid (GABA) agonist hypnotic used to treat insomnia, would impair performance and cognition or potentiate the disruptive effects of ethanol. The performance-impairing and ethanol-potentiating effects of zaleplon were compared with those of triazolam, another drug used to treat insomnia. In absolute terms, zaleplon produced less performance impairment and shorter periods of ethanol-potentiated effects on cognition than triazolam. These results may have important implications for administration of hypnotics for treatment of insomnia.

Disordered Sleep, Nocturnal Cytokines, and Immunity in African American Alcoholics

Studies have shown an inter-relationship between sleep and three classes of cellular hormones, referred to as cytokines, that regulate immune system activity: T helper 1 (Th1, e.g. interferon), anti-inflammatory/Th2 (e.g., interleukin 10), and pro-inflammatory (IL-6) cytokines. For example, in humans, sleep onset, duration, and depth are correlated with levels of the pro-inflammatory cytokine, IL-6. In addition, levels of IL-2 and interferon gamma (INF) increase during sleep and decline with sleep loss. Substantial evidence now exists that African American alcoholics are at increased risk for infectious illnesses and also suffer from severe sleep disturbances marked by loss of sleep continuity and depth. Therefore, a recent study evaluated whether secretory patterns of cytokines and natural killer (NK) cell activity are altered in African American alcoholics to produce coincident changes in sleep and immunity. Coupled with losses of delta sleep and increases in REM sleep, alcoholics show lower levels of IL-6, suppression of the IL-6/IL-10 ratio, and reduction of NK activity. In addition, levels of IL-10 measured prior to sleep predict subsequent amounts of delta sleep. These results suggest that disordered sleep contributes to immune alterations in alcoholics. Moreover, the association between awake levels of the anti-inflammatory/Th2 cytokine, IL-10, and subsequent amounts of delta sleep support the possibility of a bi-directional interplay between cytokines and sleep in humans.

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NATIONAL INSTITUTE ON ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Deborah Ader, PhD
NIAMS Representative to the Trans-NIH Sleep Research Coordinating Committee

The NIAMS funded 7 grants in sleep-related research in Fiscal Year 2002. Three studies examine sleep in the context of fibromyalgia (FM), a syndrome characterized by widespread, chronic muscle pain, fatigue, cognitive disturbance, and impaired sleep. One of these studies is a cognitive-behavioral intervention for insomnia in FM patients. The second study examines the relationship between disrupted sleep patterns and night-time secretion of ACTH, cortisol, and cytokines. The third study investigates sleep and stress as predictors of pain, fatigue, distressed mood in FM.

Additional funded research investigates the role of impaired sleep as a major cause of fractures, disability and decline in cognition in older women. Finally, a newly funded study, using a murine model of arthritis, will experimentally induce partial chronic sleep deprivation to investigate the relationships between sleep fragmentation and immune- and non-immune-mediated arthritic processes.

Although the National Institute Of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has no sleep-specific initiatives active at this time, disturbances of sleep and their relationship to disease process, symptoms, and disability in rheumatic diseases is identified as an area of interest in RFA 02-011, Multidisciplinary Biobehavioral Rheumatic Diseases Workshops.

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NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
Marian Willinger, PhD
NICHD Representative to the Trans-NIH Sleep Research Coordinating Committee

The Center for Research for Mothers and Children of the National Institute of Child Health and Human Development (NICHD) supports and promotes sleep research in infants, children, and in animals with early development resembling that of humans. These studies are designed to gain an understanding of the processes that may be involved in the normal development of behavioral state and physiologic control during sleep, as well as those that accompany Sudden Infant Death Syndrome (SIDS), learning deficits, and mental retardation. Highlights of progress from a few of the projects follow.

Research Highlights

One group of researchers at Stanford University is investigating the physiological basis for the restorative function of sleep. Glycogen is a natural starch in the body that serves as storage for energy. When the body needs energy for metabolism, the glycogen stores in tissues are converted to glucose, which is then used to generate energy. The investigators theorized that one of the restorative functions of sleep might be to build glycogen stores back up to so they can be used during wakefulness. After an animal is sleep deprived, there is a restorative sleep rebound. Glycogen stores are increased during quiet sleep, a stage that characterizes rebound sleep. The investigators found that during sleep deprivation, glycogen stores are depleted in those parts of the brain that are very metabolically active during sleep deprivation (Am J Physiol RICP2002; 283:R54-59). The investigators are now examining how stress may affect the mobilization of glycogen stores during sleep deprivation.

Sleeping on the stomach increases the risk of SIDS. Public education campaigns in the United States (see below) and several countries have led to large reductions in the proportion of infants placed to sleep on their stomach, and declines in the rate of SIDS of 50% or more. There are many theories as to why sleeping on the stomach increases the risk of SIDS and why back sleep position is protective. One theory relates to sleep state. Infants sleeping on the stomach spend more time in quiet sleep and less time in active sleep compared with those who sleep on their backs. Quiet sleep is a deep sleep. Compared with active sleep, quiet sleep is characterized by fewer awakenings and the arousal threshold is increased. Researchers at Columbia University have found that after a feeding (the post-prandial period) infants enter a period of quiet sleep. In infants who sleep on their stomach the duration of this quiet sleep period increases with the carbohydrate in the diet (Pediatr Res 2002; 52:399-404). The growing infant expends a lot of energy during the absorption of nutrients during the post- prandial period. The energy expenditure may be increased by the nutrients in the diet, like carbohydrate, and by stomach sleep position, which puts a demand on thermoregulation and cardiovascular regulation. The increase in quiet sleep in the prone position after a feed may be a restorative response to metabolic demand as theorized by the researchers at Stanford (see above).

In Fiscal Year 2002, the NICHD awarded a Research Career Development Award to an investigator at the University of Pennsylvania who is planning a career focusing on patient oriented research in sleep medicine and epidemiology. The research project associated with this award is investigating the hypothesis that pregnancy is a period of accelerated sleep disordered breathing. Little is known about sleep disorders in pregnancy. Sleep disordered breathing could have potentially have adverse effects on the health of the pregnant woman, such as pregnancy induced hypertension, and on the developing fetus, such as growth restriction.

The "Back to Sleep" National Public Health Education Campaign

Based on growing epidemiological evidence that sleeping on the stomach increases the risk for SIDS, the American Academy of Pediatrics (AAP) recommended in spring of 1992 that healthy infants be placed to sleep on their side or back to reduce the risk of SIDS. In spring of 1994, the "Back to Sleep" coalition was formed between the U.S. PHS, the AAP, the Association of SIDS Program Professionals, and the SIDS Alliance, for the planning, development, and implementation of the "Back to Sleep" national public education campaign. In June of 1994, the campaign was launched. In 1996, the AAP revised the sleep position statement to recommend that back sleep position is preferred over side. Epidemiological studies have shown that side sleeping confers about twice the risk for SIDS relative to back, probably because babies roll from their side to their stomachs. The "Back to Sleep" campaign materials were revised to reflect this change. The NICHD has taken the lead in activities of the "Back to Sleep" campaign with support and participation from the Bureau of Maternal and Child Health, HRSA, and the National Center on Sleep Disorders Research, NHLBI.

In 1999, The National Black Child Development Institute (NBCDI) joined with the NICHD, the Back to Sleep campaign sponsors, and several other organizations in an outreach initiative to reduce SIDS in African American babies by urging parents and care givers to place healthy infants on their backs to sleep. The NBCDI and other organizations including the Alpha Kappa Alpha Sorority (AKA), Inc., Women in the NAACP (WIN), and National Coalition of 100 Black Women (NCBW) play a major role in promoting SIDS risk reduction activities throughout the U.S. To help these organizations initiate SIDS risk reduction programs in communities, the NICHD, Maternal and Child Health Bureau (MCHB) of HRSA , SIDS Alliance and partner organizations developed a Resource Kit for Reducing the Risk of Sudden Infant Death Syndrome (SIDS) in African American Communities. The Kit contains culturally appropriate materials such as fact sheets, brochures, magnets, a video, and a leader's guide to encourage people to lead discussion groups in various community settings on ways to reduce the risk of SIDS.

In fiscal year 2002, outreach activities continued to focus on underserved minorities. The leaders of these three organizations have committed to hosting three summits featuring the NICHD SIDS risk reduction campaign information and materials. Leaders and members of the AKA, NCBW, and WIN will participate in all three regional summits. Each organization will take the lead responsibility to organize and host one of the three regional meetings and will continue to serve as the catalyst for activity in that region. At a Partners' planning forum held in June 2002, the Partners established goals for the summit meetings such as to encourage a significant regional population to engage in SIDS risk reduction activities, build alliances within communities to assist in SIDS risk reduction activities, educate those with the power to make a change in policy or behavior, and create collaborative models and resources that can remain within communities.

While the decline in SIDS rates has occurred in all segments of the population, the decline has been less in American Indian communities. Today, American Indian infants are more than twice as likely to die from SIDS as white infants.

The Aberdeen Area Infant Mortality Study, a study of Northern Plains Indians, found that infants were less likely to die of Sudden Infant Death Syndrome (SIDS) if their mothers received visits from public health nurses before and after giving birth. This study was funded by three agencies of the Department of Health and Human Services: the Indian Health Service (IHS), NICHD, and the Centers for Disease Control and Prevention (CDC). The Aberdeen study found that binge drinking (five or more drinks at a time) during the mother's first trimester of pregnancy made it eight times more likely that her infant would die of SIDS. Any maternal alcohol use during the periconceptional period (three months before pregnancy or during the first trimester) was associated with a six-fold increased risk of SIDS. The study also found that infants were more likely to die of SIDS if they wore two or more layers of clothing while they slept (JAMA 2002;288:2717-2723).

The NICHD has begun to work with American Indian tribal communities to develop SIDS risk reduction strategies. The NICHD hosted a meeting in June of 2002 with members from the American Indian community to discuss infant mortality and SIDS in the Northwest and the Northern Plains. The group was presented with general information on SIDS, statistics illustrating the racial disparities in incidence and prevalence rates of SIDS, and descriptions and examples of existing programs and materials that have been implemented successfully. In addition, participants had the opportunity to interact with each other and to discuss the information presented. That meeting brought together individuals representing American Indian communities in four areas of Indian country - Aberdeen, Bemidji, Billings, Portland- that have the highest rates of SIDS. Participating were representatives from various American Indian organizations and federal agencies, including the Aberdeen Area Tribal Chairmen's Health Board, the Northwest Portland Area Indian Health Board, the Bemidji Area Indian Health Board, the Billings Area Indian Health Service, the Aberdeen Area Indian Health Service, the Inter-tribal Council of Michigan, the Minnesota State Department of Health, the Association of American Indian Physicians, the American Indian Research and Policy Center Institute, the Red Lake Tribal Council, the CDC, National Indian Women's Health Resource Center, and American Indian Education Programs.

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NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE
Nancy Pearson, PhD
NCCAM Representative to the Trans-NIH Sleep Research Coordinating Committee

Many individuals use complementary and alternative medicine (CAM) therapies to treat sleep disorders. These CAM therapies include the use of dietary supplements such as melatonin and valerian; mind/body approaches such as meditation, and therapies that are part of non-western traditional medical systems, such as acupuncture and yoga. Part of NCCAM's mission is to investigate CAM therapies and train CAM researchers in the context of rigorous science. As part of this mission, we support research and research training related to the use of CAM therapies for sleep disorders. Some examples of research that NCCAM currently supports in this area are given below.

Insomnia

Chronic insomnia is a significant health problem for many individuals, is often difficult to treat, and can last for years. Furthermore, pharmacological treatments can produce unwanted side effects. As a result, many individuals have turned to alternative therapies in search of more effective treatments and fewer side effects. NCCAM is interested in determining whether or not these alternative treatments, which are already in the public domain, are effective. Currently, NCCAM supports a study using yoga as a treatment for insomnia. Although yoga has been recommended for treatment of insomnia by yoga practitioners, its effectiveness has not been scientifically established. The main goal of this ongoing clinical study is to establish whether a regimen of yoga practice will improve sleep onset latency measured by both subjective and objective criteria.

Sleep Deprivation Related to Neurodegenerative Diseases

Neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease are often accompanied by sleep disturbances due to pain and/or neurological changes related to the progression of the disease. NCCAM currently supports an ongoing clinical study investigating the efficacy and safety of valerian for the treatment of sleep disturbances in Parkinson's disease. Valerian is derived from the root of the plant Valeriana officinalis and is commonly sold as a dietary supplement in the United States and Europe. Although it is advertised as having hypnotic properties effective in treating sleep disorders, insufficient scientific data exist to determine its true effectiveness. Some evidence does exist in a mouse model to suggest that it reduces spontaneous locomotor activity, which is a problem in Parkinson's disease, where excessive nocturnal motor activity is related to sleep deprivation. The results of this study should clarify whether valerian is effective in treating sleep disturbances in Parkinson's disease patients.

In addition, NCCAM supports a study on the use of high intensity light therapy for Alzheimer's disease patients in nursing homes. The long term care of Alzheimer's disease patients and patients with other dementias is a growing public health issue and economic burden. Among the most difficult long term care management issues for these patients are treatment of sleep/wake disorders, depressive symptoms, and agitation. This study will investigate whether high intensity light installed in nursing home common rooms for various periods of time will contribute to a lessening of these problems. If results are positive this could provide a low-risk alternative treatment that is relatively inexpensive once the lighting is installed.

Basic Science Research

NCCAM supports basic science research aimed at understanding the underlying biological mechanisms of CAM therapeutic modalities including those used to treat sleep disorders. For example, an NCCAM-supported project completed in 2002 performed a detailed pharmacokinetic study of a complex botanical derived from valerian root. As mentioned above, valerian is sold as a dietary supplement for sleep disorders. In addition, as part of an initiative on Basic and Preclinical Research on Complementary and Alternative Medicine (PA-02-124), NCCAM continues to encourage and solicit research on interactions between CAM and conventional therapeutics, including but not limited to interactions between dietary supplements and pharmacological drugs. Desired areas of future research also include the interactions between pharmacological drugs used to treat sleep disorders and dietary supplements such as valerian and melatonin.

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NATIONAL INSTITUTE ON DRUG ABUSE
Harold Gordon, PhD
NIDA Representative to the Trans-NIH Sleep Research Coordinating Committee

The National Institute on Drug Abuse (NIDA) is continuing to expand its portfolio on sleep studies. There are widespread sleep disturbances both during and following withdrawal from the use of psychoactive drugs among addicted individuals. Indeed, sleep disturbances often outlast other withdrawal symptoms and are often a cause for relapse. It is clear that the neural systems involved in the addiction process are also involved in sleep. Sleep researchers and drug abuse researchers are likely studying the same neural systems perhaps without realizing it.

Recent research is focusing on individuals taking the drug MDMA ("ecstasy"), which has sleep disturbances likely due to its effect on the serotonergic brain. Toxicology studies in animals and human subjects are attempting to determine what permanent and temporary damage results from its use. Studies focus on both serotonergic and dopaminergic systems and several consequent behaviors including sleep disturbances. The studies are relatively new and definitive results are still pending. The expectation is that sleep disturbances will help inform the neural mechanisms of action of MDMA and associated consequences to these brain systems.

NIDA also has been supporting several studies of the effect of cocaine on sleep in a naturalistic setting. That is, how is the normal sleep architecture affected during use and subsequent withdrawal from cocaine? And also, since the serotonergic system is affected, how do medications that affect the serotonergic system, such as selective serotonin reuptake inhibitors, interact in these individuals?

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is being studied by using stimulant drugs by Mignot and colleagues. In one study, dopamine measurements in narcoleptic dogs revealed that amphetamine increased extracellular dopamine. However, in mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines. Studies are on-going to determine the effect on wakefulness by acute administration of cocaine and of methamphetamine. [Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM, 2001. J Neurosci 21(5):1787-94.]

Among the effects of marijuana and withdrawal from marijuana are mood alterations and sleep disturbances. Haney, Foltin and colleagues at Columbia University have been attempting to determine pharmacological treatments for marijuana withdrawal. Symptoms of marijuana withdrawal include increased irritability, depression and anxiety, as well as decreased sleep quality. Nefazodone, an antidepressant with sedative properties, only attenuated some symptoms of marijuana withdrawal (e.g., anxiety) but did not reduce irritability or disturbances of sleep. Buproprion was also tried because it relieves similar symptoms in nicotine withdrawal. In fact, buproprion increased mood and sleep disturbances. These studies contribute to our knowledge of which neural systems are affected by psychoactive drugs. Future studies will focus on the effects of marijuana in HIV positive individuals. [Haney M, Hart CL, Ward AS, Foltin RW, Psychopharmacology 2002; Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW, Psychopharmacology 2001, 155(2):171-179]

At the molecular level, studies are being carried out on fatty acid amides, which are lipids involved in signaling and which include the endocannabinoid, anandamide, and the sleep-inducing substance, oleamide. They are implicated in several functions including sleep. For example, oleamide has been isolated from the cerebral fluid of sleep-deprived cats and anandamide binds to the cannabinoid receptor. Oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase and inhibiting the degradation of endogenous anandamide. In addition, these substances affect opioid systems and modulate pain. Studies of these mechanisms will provide insight into the effects of the cannabinoid and opioid systems as well as their interactions in the brain.

New studies supported by NIDA are being initiated and developed. For example, Irwin and colleagues at UCLA will be studying cytokines because of the connection between cocaine addiction and risk of infectious disease. Cytokines are associated with the immune response to infection and are known to affect sleep architecture. The study will evaluate the reciprocal relationship between sleep and cytokine expression. The advent of more powerful imaging techniques, such as larger magnets for magnetic resonance imaging and better analysis techniques, will lead to enhanced studies of brain function and sleep. For example, one can compare the brain function following sleep deprivation in non-users of drugs to sleep deprivation that results from drug taking. Studies such as these are mutually informative-of sleep and its brain mechanisms on the one hand, and of drug-affected neural systems, on the other.

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NATIONAL INSTITUTE OF MENTAL HEALTH
Israel Lederhendler, PhD
NIMH Representative to the Trans-NIH Sleep Research Coordinating Committee

Treating Insomnia

In any year, insomnia affects approximately 30% of the adult population. In about 10-15% of the population, insomnia constitutes a clinical disorder characterized by significant distress or functional impairment. Well-controlled epidemiological studies show that insomnia follows a chronic course for 50-80% of those affected. Insomnia thus represents a significant health burden on American society through increased health care costs, increased rates of serious accidents, and measurable decreases in occupational functioning.

Insomnia is a problem of special interest to NIMH since it is a significant risk factor for the later development of depressive and anxiety disorders. At least six independent studies have demonstrated this relationship in young and older adults with follow-up periods of 1 to 35 years. The effective treatment of insomnia would significantly help Americans who suffer physical and emotional trauma. In the absence of information about the long-term use of hypnotics, psychotherapeutic/behavioral treatments for chronic insomnia are often recommended.

Persistent primary insomnia (PPI) is a subset of chronic insomnia that affects about 5% of the general population and 20% of patients who present clinically for treatment of sleep-related complaints. It is a disorder of middle-stage sleep maintenance that is predictive of the development of clinical depression and associated with increased use of health care services. Behavioral interventions designed to correct habits that disrupt sleep and perpetuate insomnia have proven both effective and durable over a six-month follow-up period. But results with PPI patients have been mixed. Several studies have suggested that combining cognitive therapy (which addresses attitudes and education about sleep) with standard behavioral techniques is a more comprehensive approach that is effective with both sleep-onset and sleep-maintenance problems, and that has more durable effects than medications.

A study of seventy-five patients with PPI were assigned randomly to 6 weeks of treatment with a) a hybrid Cognitive Behavioral Therapy (CBT) involving sleep education, stimulus control methods, and time-in-bed restrictions; b) progressive muscle relaxation training; or c) a quasi-desensitization approach that constituted a behavioral placebo treatment relative to PPI. Patients were assessed on multiple sleep outcome measures, and followed up 6 months after completion of treatment. The results indicated that CBT led to more improvement on most sleep measures, and a greater normalization of sleep and subjective symptoms. For example, the extent of reduction in (middle and terminal stage) wake time after sleep onset (WASO) averaged 54% for patients treated with CBT compared to 16% for those receiving relaxation training and 12% for those in the behavioral placebo condition. In addition, the CBT-treated patients in this trial showed larger improvements in dysfunctional attitudes toward sleep, as measured on an attitudinal questionnaire measure. Even when compared with less specific or less comprehensive kinds of psychotherapeutic approach, CBT led to clinically meaningful sleep improvements within 6 weeks, and the improvements appeared to endure through the following 6 months.

A sleep-oriented CBT thus appears to be a promising intervention for Persistent Primary Insomnia. However, since chronic insomnia is often a lifelong complaint it remains important to develop safe, rapidly acting, long-term treatments. There is a pressing need to evaluate how many and which groups of patients can best be helped by these behavioral methods and whether combination therapy with appropriate medication provides additional benefit.

Disaster survivors: Findings from a variety of studies tell us that estimates of post disaster mental illness vary and that in nearly half of the studies, 25% or more of the samples suffered from criterion-level psychopathology The possibility that a simple sleep treatment program can lead to improvements in the psychological health of survivors stems from research with fire evacuees in Los Alamos, NM, following the Cerro Grande Fire of May 2000. The study was initiated 8 months after the devastating Fire in 66 men and women who suffered from moderate to severe insomnia and post-traumatic stress disorder (PTSD) symptoms. One third of the group also reported chronic nightmares. Nearly 50% of these individuals had previously sought various treatments for sleep and PTSD symptoms soon after the fire, but most had not received any formal therapy or been prescribed medications prior to enrolling in this study. Forty-nine participants reported improvement in insomnia and 53 reported improvement in PTSD symptoms after treatment.

The program consisted of six weekly 90-minute sessions in a large group format. The program diverged from traditional PTSD treatment approaches by not discussing traumatic events and by not having patients "re-live" their traumatic experiences. Instead, the program integrated several standard evidence-based techniques and clinical sleep medicine instructions that teach people how to "stop losing sleep over losing sleep." As in many insomnia management efforts, trauma survivors were encouraged to examine and improve sleep quality and not to focus on sleep quantity. In addition, nightmare sufferers learned imagery rehearsal therapy to treat their disturbing dreams. The results showed that insomnia improvement correlated in a statistically significant manner with improvements in PTSD, anxiety, and depression symptoms during every stage of the treatment. The findings show promise that insomnia treatments within 8 months of some forms of trauma will reduce PTSD symptoms. They strongly encourage further studies where those victims who developed symptoms of PTSD are directly compared to those who did not.

Insomnia in the Elderly: Poor sleep quality is a salient feature of the physiological and psychological changes seen with advancing age, increasingly referred to as "the somatopause". In two large samples including 3,000 elderly individuals, careful health screening reduced the percent of subjects with sleep complaints or disorders to 2.3% in contrast to the commonly cited figure for significant sleep complaint of 50% in the general older population. These findings support the emerging epidemiological literature that most sleep complaints that increase in prevalence with advancing age, are probably secondary to associated medical, psychiatric and health-related burdens.

Furthermore, healthy older individuals did not complain of significantly disturbed sleep despite the fact that their objectively measured sleep was significantly more disturbed than that of younger non-complaining adults. This indicates that many healthy older individuals appear to adapt their perception of what is "acceptable" sleep and therefore do not necessarily complain of the disturbed sleep they may typically experience. These findings suggest that even declines in objective sleep quality that can reasonably be related as primary to aging per se, do not necessarily result in complaints of poor subjective sleep quality in older men and women. Rather, much of the sleep disturbance seen with advancing age is the result of primary sleep disorders or to effects that are secondary to other health burdens. Even the changes in sleep that seem to be "age-dependent", that is, the result of "non-pathological aging", need not necessarily be perceived as significant disturbances of sleep.

Hypocretin/Orexin

The neuropeptide Hypocretin/Orexin (HCRT) has received intense attention in the sleep research community since the discovery of the connection between the genes responsible for their expression and symptoms of narcolepsy. Studies using molecular genetics in mice and dogs, as well as histopathological analyses of human disease, lead to the conclusion that narcolepsy is indeed caused by failure of signaling mediated by these molecules. The HCRT system, originating in the hypothalamus, is widespread throughout many brain regions and is therefore likely to influence a number of systems. In fact, the original discovery of these neurons was connected to feeding. Thus in addition to its critical role in sleep/wake regulation HCRT may link energy homeostasis to the modulation of sleep/wake cycles and other behavioral states. One attractive hypothesis is that the orexin system may modulate wakefulness in response to internal energy homeostasis in order to support various drives emanating from the hypothalamus. Fasting, mating, or nesting, for example, may initially increase arousal. HCRT neurons may also participate in high-arousal processes such as those associated with stress. However, recent findings suggest that some HCRT neurotransmission may vary across the circadian cycle and that waking per se is not associated with increased HCRT neurotransmission. The effects on wakefulness may be exerted through the diurnal rhythms.

HCRT and Arousal: The dependence of HCRT neurotransmission on the state or degree of neuronal activity was determined by measuring electrical activity within both HCRT-synthesizing neurons and neurons expressing HCRT-1 receptor across several conditions. These conditions were associated with varying levels of waking (diurnal sleeping, spontaneous diurnal waking, spontaneous nocturnal waking, or diurnal novelty stress). The immediate early gene product Fos, and either prepro-HCRT or HCRT1-receptors were visualized with double-labeling procedures in locus coeruleus, or basal forebrain - regions associated with arousal. Relative to diurnal sleeping, nocturnal waking and stress increased Fos expression within HCRT-synthesizing neurons. But within HCRT1-receptor-bearing neurons, only stress increased Fos expression. Thus HCRT neurotransmission may be a signal indicating level of arousal.

Antipsychotic Drugs and Weight Gain: The side effects of some antipsychotic drugs (APDs) include sleep disturbance and weight gain. Since one of the homeostatic contributions of the HCRT system is energy balance, the interactions among APDs, sleep, and eating may be related to the activation of orexin neurons. In recent animal studies, APDs with significant weight gain liability were compared to those with low or absent weight gain liability. High liability APDs increased Fos expression in orexin neurons, but APDs with low or absent weight gain liability did not. The weight gain liability of APDs was correlated with the degree of Fos induction in orexin neurons of the lateral hypothalamus. In contrast, amphetamine, which causes weight loss, increased Fos expression in orexin neurons of the medial but not lateral hypothalamus. The effects of amphetamine and clozapine were then compared on orexin neurons innervating the prefrontal cortex. Clozapine, an APD with weight gain liability, induced Fos in 75% of the orexin neurons that project to the cortex, but amphetamine induced Fos in less than a third of these cells. These data suggest that APD-induced weight gain is associated with activation of distinct orexin neurons and emphasize the presence of anatomically and functionally heterogeneous populations of orexin neurons. Some of the interactions among sleep disturbance and other aspects of arousal and energy regulation may thus need to be understood as a disrupted neurobehavioral system involving altered levels of expression of HCRT.

Circadian Rhythms

Melanopsin: A Circadian Photopigment?: Animals have an internal biological clock in a region of the brain called the suprachiasmatic nucleus (SCN). This structure is important for the regulation of behavior and physiology. Cycles of sleeping and waking, body temperature, eating, and levels of arousal, connect to this clock and are reset daily by daylight. Photoreceptors in the eye detect the light and signal the clock, but the identities of the photoreceptors and the light-reactive photopigment have remained elusive. Several independent groups have now discovered a class of Retinal Ganglion Cells (RGC) that contain a molecule, melanopsin and send information to the circadian clock. Most RGCs project to brain areas involved in vision. But about 1% or 2% of those in the rodent retina go to other parts of the brain, including the SCN; melanopsin is now a leading candidate to be a circadian photopigment. This light-detection system is suited to respond to the level of illumination rather than to images. It is entirely independent from the rods and cones, and sends information to multiple brain regions including the SCN. Such a system may have an important impact on general well-being since light levels (among other functions) can modulate mood, activity, and performance.

Oscillators Outside the Suprachiasmatic Nucleus (SCN): The SCN in mammals is frequently referred to as the master circadian pacemaker driving daily rhythms. This has been the dominant view in chronobiology for many years. However, this view is changing somewhat as evidence for the presence of circadian oscillators outside the mammalian SCN is increasing. Recent studies in rats, using cultured neural tissues from different brain areas, monitored the intrinsic Per1 expression patterns in these tissues and their response to changes in the light cycle. Per1 is one of a number of genes that have been found in the last five years to be involved in the production of oscillations from SCN cells. In culture, many brain areas that expressed the Per gene were arrhythmic but 14 of 27 brain areas examined were rhythmic. The pineal and pituitary glands both expressed rhythms that persisted for eight hours in vitro, with peak expression during the subjective night. Nuclei in the olfactory bulb and the ventral hypothalamus expressed rhythmicity with peak expression at night, whereas other brain areas were either weakly rhythmic and peaked at night, or arrhythmic. After a 6 hr advance or delay in the light cycle, the pineal, paraventricular nucleus of the hypothalamus, and arcuate nucleus each adjusted the phase of their rhythmicity suggesting the presence of mechanisms enabling entrainment, although the kinetics of each region seemed to be different. These results indicate that the brain contains multiple, damped circadian oscillators outside the SCN. The phasing of these oscillators to one another may play a more general role in the coordination of brain activity than previously suspected.

New Approaches to the Functions of Sleep and Rhythms

Replay of Birdsong During Sleep: One of the possible functions of sleep that has received attention recently is its role in normal waking cognition, including memory. One specific aspect of this function is the hypothesis that waking experience is replayed during sleep, thereby strengthening or fine- tuning neural connections. Songbirds such as the zebra finch have become a fascinating partner in this research that has previously studied primarily rodents and humans. The zebra finch brings well-understood neural circuitry supporting highly quantifiable behavior to the problem. The high vocal center (HVC) is a nucleus that sends neural signals for song production to the muscles of the vocal organ and receives auditory input. Auditory responses within this pathway are greatly enhanced under anesthesia or in sleep, highlighting the scientific potential in this system for exploring the process of signal replay during sleep, and suggest the presence of a gating mechanism that controls auditory input in relation to various physiological states. The initial avian studies used observational methods to determine the state of the organism. Two important issues required further attention: one concerns the definition of relevant physiological states, the other concerns the primary site of the gate. Recent progress has demonstrated the feasibility of using electroencephalography (EEG) to identify the wake/sleep state in zebra finches. These measurements have shown that HVC auditory responses do indeed change with physiological states, and that the HVC response to auditory stimuli is greatest during slow-wave sleep.

The bird's own song (BOS) is a critical feature of the process by which birds acquire their unique vocalization. It is interesting that during slow-wave sleep, but not during wakefulness, multiunit extracellular HVC recordings showed preferential responding to the BOS compared to nonspecific song, or BOS played in reverse. HVC response to BOS changed within milliseconds as one physiological state replaced the other. Abrupt changes in the EEG occurred when the bird fell asleep, awoke spontaneously, or was awakened by the experimenter. Concomitant with these changes, the BOS response of HVC increased with sleep and decreased with waking. A robust decrease in HVC firing that was correlated with waking occurred within 750 ms of light onset. The response of HVC neurons to the BOS occurred only during sleep and ceased upon waking. Similar changes in the downstream follower nucleus, RA, were reported previously, without EEG measures, but they were not found in this study. Thus, auditory gating in HVC is associated with sleep but the sleep-related gating properties of nucleus RA are less clear. The activity of the song system during sleep may be a form of replay of learned information. Since it appears that auditory input (BOS) also triggers this activity, the replay of information may also include the bird's well-established, crystallized, adult song. Perhaps this system makes use of similar mechanisms of memory consolidation to maintain as well as acquire behaviors.

Circadian Modulation of Learning: One commonly ignored connection between sleep, circadian rhythms, and daily functioning, is their connection to the perception of time. In fact, one important feature of the circadian clock is to allow temporal coordination of the organism with the external world and the sleep/wake cycle. The dominant cue that may be used for this purpose is the daily cycle of light and dark. Animals and humans certainly associate time of day and food availability. Vigilance and performance are modulated by circadian phase, and this may influence learning abilities. In fact, SCN lesions were reported to eliminate a 24-h rhythm in performance on a passive avoidance task, and rats subjected to desynchronization of the circadian light-dark cycle experienced impaired recall of a spatial task. The magnitude of long-term potentiation (LTP) in the hippocampus has also been reported to vary with circadian phase. And finally, hippocampal synaptic activity in rats was highest in the middle of the dark phase and lowest in the middle of the light phase while the opposite effect was reported in diurnal squirrel monkeys.

A recent investigation of the relationship of circadian phase to learning and memory demonstrated that different aspects of memory, namely acquisition, recall and long-term extinction for simple associative memory in mice are modulated by the circadian system. Mice were trained in the day or night using either tone conditioning or context fear conditioning. When comparing the performance of animals during the day and night, the mice generally acquired the conditioning faster in the day than in the night. Recall for context and tone consistently peaked during the day for at least 3 days after training, irrespective of the time of training. Finally, extinction exhibited sensitivity to circadian phase in that mice trained at night exhibited a greater degree of extinction than mice trained during the day. The finding that the mice learned this task better in the day, when they are normally inactive, than at night is contrary to the expectation that performance would be best during the night when nocturnal organisms are normally active. Greater daytime efficacy for acquisition and recall may be a feature of aversive conditioning tasks since, for nocturnal animals, daytime may induce additional fearfulness that may enhance performance. Extinction however, may benefit from an opposite relationship to emotional state. Furthermore, different neural substrates supporting different forms of learning conditioning may be differently influenced by time of day. Since time is a critical parameter of the environment, it would seem adaptive for organisms to use time as a variable in learning. Associating certain times of day with either rewarding stimuli or potential dangers may thus be beneficial.

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NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Paul Nichols PhD
NINDS Representative to the Trans-NIH Sleep Research Coordinating Committee

The NINDS supports a wide variety of research on the neurological and neuroscience aspects of sleep, including studies of basic mechanisms, sleep disorders, associated complications, circadian biology, and instrumentation.

The NINDS is active in the support of studies of the cause and treatment of narcolepsy, a neurological disorder characterized by excessive daytime sleepiness, an inability to move shortly after awakening, and sudden episodes of muscle weakness. Researchers at the NINDS-supported Center for Narcolepsy and Related Disorders at Stanford University, led by Dr. Emmanuel Mignot, were first to report the discovery of a gene that causes narcolepsy in a canine model of the disease. The gene carries instructions for making a receptor by which nerve cells respond to a brain-signaling molecule called hypocretin or orexin. Although narcolepsy in humans is not caused by a single gene (identical twins are usually discordant), the animal studies still offer clues to the etiology. Human narcolepsy is related to low levels of hypocretin-containing neurons in the hypothalamus. Dr. Mignot and colleagues have cloned the canine narcolepsy gene (Hcrtr2) and are now developing transgenic mouse models of the disease.

An increase in MHC-II antigens has been linked to symptom onset in the narcoleptic canines, suggesting that development of symptoms resulting from a mutation of the hypocretin receptor-2 gene may involve the immune system. Investigators in the laboratory of Dr. Jerome Siegel at UCLA administered immunosuppressive and anti-inflammatory drugs to narcoleptic dogs. They found that oral administration of these drugs delayed disease onset and prevented the development of severe symptoms. Most human narcoleptics share an MHC-II haplotype, suggesting that immune-related factors may play a role in causing human narcolepsy as well. This treatment was the first shown to affect symptom development in animal narcolepsy, and may be an important step in the development of treatment regimes for human narcolepsy.

Restless Legs Syndrome (RLS) is a common neurological disorder characterized by unpleasant sensations of the legs and an urge to move them for relief. Because symptoms are intensified by inactivity and lying down, RLS patients often have difficulty falling asleep and staying asleep. Untreated RLS causes exhaustion and fatigue, which can affect occupational performance, social activities, and family life. It has been estimated that about 80% of RLS patients also have periodic limb movement disorder (PLMD), or nocturnal myoclonus, which is characterized by repetitive stereotyped movements of the limbs, primarily the legs, during sleep. In order to increase the amount of research in RLS and PLMD, the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Mental Health (NIMH) issued a Program Announcement in 2001 encouraging applications that would enhance our understanding of the pathogenesis of these disorders and develop more effective treatment strategies.

The genetics of RLS are complex. Several studies have shown familial associations, and Dr. Guy Rouleau and his colleagues at Montreal General Hospital reported significant linkage to chromosome 12q in a large French-Canadian RLS pedigree. Studies are continuing to locate and characterize the specific gene involved. This result has not been confirmed in other studies, suggesting genetic heterogeneity.

Central dopamine mechanisms are thought to be involved in the etiology of several sleep disorders, including RLS, PLMD, and narcolepsy, as well as Parkinson's disease. Dopaminergic agents have been used, with varying degrees of success, to treat all of these disorders. NINDS grantee Dr. David Rye at Emory University is studying possible mechanisms by which dopamine affects behaviors including arousal in rodent and nonhuman primate models. He has described a previously unknown mesothalamic dopamine system in which the thalamus receives dopaminergic projections from the same dopaminergic cells as those that degenerate in Parkinson's disease. These results suggest a new and direct pathogenic mechanism of action of dopamine that may be acting in the etiology of RLS and PLMD.

In another study showing the dopamine connection between periodic limb movements and narcolepsy, Dr. Mignot and his colleagues have observed PLMD-like movements in their narcoleptic canines. Dopamine agonists that are selective for the D2 and D3 receptor subtypes have been effective in humans for the treatment of PLMD, and Dr. Mignot found that this same class of drugs alleviated the abnormal leg movements in the narcoleptic canines. At the same time, cataplectic symptoms were aggravated, leading to the hypothesis that the dopamine system is involved in both sleep-related motor inhibition (cataplexy) and activation (PLMD). These dogs may prove to be the first animal model of PLMD.

A recent report from the laboratory of Dr. Christopher Early at The Johns Hopkins Bayview Medical Center suggests that the hypocretin system may be affected in RLS as well as narcolepsy. Unlike narcolepsy, patients with RLS had slightly increased CSF levels of hypocretin. The increase was found only among early-onset RLS patients, the subgroup for which genetics seems to play a larger role. These results suggest that excessive daytime sleepiness in these RLS patients may be prevented by the higher than normal levels of hypocretin.

The NINDS supports both basic and clinical research in the area of circadian biology. Studies in a variety of animal models have identified genes responsible for the regulation of the circadian clock. One of the clinical studies being supported was submitted in response to a Program Announcement sponsored by the National Institute on Aging (NIA) and co-sponsored by NINDS, "Earth Based Research Relevant to the Space Environment." In this grant, Dr. Charles Czeisler, of Brigham and Women's Hospital, Boston, will determine the extent to which the intrinsic period of the human circadian pacemaker can be influenced by prior entrainment to non-24 hour day lengths. A manned exploration to Mars is scheduled for 2018, and astronauts will need to adapt to the 24.65 hour Martian day.

In another clinical study, Dr. Scott Rivkees at Yale University is testing the hypothesis that early cycled lighting in preterm nurseries can help establish circadian patterns and will lead to earlier establishment of rest-activity cycles, and improve infant growth, behavior, and parent-infant interactions. Preliminary results suggest that preterm infants in the cycled lighting group immediately show day-night differences in rest and activity patterns, while similar patterns are not observed in control infants until after 3 weeks at home.

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NATIONAL INSTITUTE OF NURSING RESEARCH
Mary Leveck, PhD, RN
NINR Representative to the Trans-NIH Sleep Research Coordinating Committee

NINR's sleep research portfolio consists of three general areas: (1) the impact of sleep deprivation across the lifespan in healthy populations; (2) the impact of sleep disturbance in patients with chronic illnesses; and (3) the management of sleep disturbances. The following are examples of the research studies funded by NINR.

Sleep Deprivation in Healthy Populations

The most pervasive form of sleep loss is partial sleep deprivation. Partial sleep deprivation is found among shift workers, medical workers, and as a result of lifestyle choices. An NINR funded study will determine the amount and timing of chronic partial sleep deprivation at which alertness and waking functions are compromised.

Another group that experiences sleep deprivation is new parents after the birth of their first infant. Sleep deprivation can lead to significant psychosocial morbidity including marital unhappiness, reduced quality of life, depression, and child abuse. A recently funded study will test an environmental-behavioral intervention to minimize the sleep disruption and fatigue experienced by new parents.

Recent findings from an NINR funded meta-analysis on sleep changes across the lifespan indicate that as one ages, one goes to bed and gets up earlier but takes longer to fall asleep and experiences more frequent and longer awakenings. Thus, less time is spent sleeping. A significant amount of the age related changes are due to the health status of the individual. These changes are linear. This investigator is now evaluating the normal non-linear changes that occur in sleep with increasing age. This research will help to determine normal and abnormal sleep patterns in men and women as they age.

Sleep Disturbance in the Chronically Ill

There are many chronic health conditions that interfere with sleep. Sleep disturbances are associated with Alzheimer's disease, dementia, rheumatoid arthritis, fibromyalgia, AIDS, asthma, and urinary incontinence. Sleep disturbance is exacerbated by pain and by conditions requiring hospitalization.

In a recent study, 23% of pregnant women reported Restless Legs Syndrome (RLS), a sleep disturbance characterized by unpleasant sensations in the legs. In comparison to other pregnant women, these women with RLS had lower serum levels of folate and a more depressed mood state.

Fibromyalgia (FM) is a common rheumatic condition in women between the ages of 40 and 60, and the symptoms include fatigue, non-restorative sleep, chronic pain, and distress. Preliminary findings from a study of healthy women indicate that sleep disruption results in a reduced pain threshold, and increased discomfort and fatigue. These symptoms are similar to those of FM, and suggest there may be a complicated interrelationship between sleep and FM.

A majority of patients on hemodialysis report difficulty sleeping. It is known that daytime sleep affects nighttime sleep patterns, and recent research has demonstrated that the hemodialysis procedure might induce daytime sleepiness as it alters the core body temperature and triggers the production of sleep-inducing substances such as interlukin-1. Further, a recent study co-funded by several NIH Institutes found that end-stage renal patients who receive hemodialysis in the morning had longer survival rates than those who received hemodialysis in the afternoon. Possible explanations for differential survival in association with morning vs. afternoon dialysis include salutary effects of sleep in the morning.

Fatigue, pain, and sleep disturbance are common problems encountered by patients receiving radiation therapy. Studies are underway to determine the patterns of change in sleep disturbance, fatigue, and pain over the course of radiation therapy, and to examine the relationship between opioid use, pain, and sleep in oncology patients.

Management of Sleep Disturbances

NINR funds a variety of different interventions to improve sleep. Sleep difficulties can affect daytime physical and social functioning, and have been associated with an increased incidence of depression. One study is evaluating whether melatonin and behavioral techniques are an effective intervention for jet lag that has been found to impair judgment and performance. In another study, a new nurse investigator is using behavioral treatments to improve sleep in community dwelling elders who frequently experience insomnia.

Disturbed sleep with nighttime wandering is common in patients with Alzheimer's disease, and has been cited as the most frequent cause for nursing home placement. Researchers are testing innovative strategies (e.g., melatonin, light, nighttime alarm systems) to improve nighttime sleep in these individuals. The improved sleep may decrease the agitation commonly found in individuals with Alzheimer's disease. In addition, the improved sleep in patients with Alzheimer's disease may also increase the sleep experienced by caregivers, and subsequently may delay or reduce the need for institutionalization of the demented patient.

Training and Career Development

NINR is committed to the training and career development of new investigators in the area of sleep research. NINR supports pre-doctoral fellowships, mentored research scientist development awards, and institutional training grants focusing on sleep research. The research foci of these awards include studying the relationships among sleep, stress, and immune function in persons with HIV; exploring the relationships between maternal and infant circadian rhythms during early life; developing an intervention using neurofeedback for treatment of insomnia; and examining sleep patterns of women at risk for preterm labor.

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FINANCIAL REPORT
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE

Fiscal Year 2002 Sleep Disorders Research Funding
(Dollars in thousands)

1995
Actual 1996
Actual 1997
Actual 1998
Actual 1999
Actual 2000
Actual 2001
Actual 2002
Actual 2003
Estimate

NHLBI

13,674

16,450

19,219

22,932

31,845

35,128

37,579
45,155 48,090

NINDS

8,018

9,453

11,598

13,639

15,231

12,495*

17,603
22,918 24,537

NICHD

6,627

7,368

7,217

9,131

7,116

6,797

7,084
7,344 7,900

NIA

7,847

7,800

9,179

11,818

13,296

13,034

14,533
14,600 15,700

NIMH

29,721

27,231

28,601

34,027^�

39,219

40,667

50,742
56,647 61,161

NIDA

1,084

1,201

1,042

1,586

2,163

2,533

2,517
3,235 3,500

NIAAA

793

551

728

766

736

1,132

1,681
4,342 4,560

NINR

2,107

2,842

3,565

3,394

3,503

4,635

5,375
8,091 8,415

NCRR

2,944

3,247

3,570

5,542

6,637

7,117

7,193
11,490 12,794

NIAMS

NA

NA

NA

NA

NA

NA

NA
300 330

NCCAM NA NA NA NA NA NA
177
900 970

NHGRI NA NA NA NA NA NA
599
679 740

Total
72,815

76,143

84,719

102,835^�

119,746

123,558

145,083
175,022 187,957

	1995 Actual	1996 Actual	1997 Actual	1998 Actual	1999 Actual	2000 Actual	2001 Actual	2002 Actual	2003 Estimate
NHLBI	13,674	16,450	19,219	22,932	31,845	35,128	37,579	45,155	48,090
NINDS	8,018	9,453	11,598	13,639	15,231	12,495*	17,603	22,918	24,537
NICHD	6,627	7,368	7,217	9,131	7,116	6,797	7,084	7,344	7,900
NIA	7,847	7,800	9,179	11,818	13,296	13,034	14,533	14,600	15,700
NIMH	29,721	27,231	28,601	34,027^�	39,219	40,667	50,742	56,647	61,161
NIDA	1,084	1,201	1,042	1,586	2,163	2,533	2,517	3,235	3,500
NIAAA	793	551	728	766	736	1,132	1,681	4,342	4,560
NINR	2,107	2,842	3,565	3,394	3,503	4,635	5,375	8,091	8,415
NCRR	2,944	3,247	3,570	5,542	6,637	7,117	7,193	11,490	12,794
NIAMS	NA	NA	NA	NA	NA	NA	NA	300	330
NCCAM	NA	NA	NA	NA	NA	NA	177	900	970
NHGRI	NA	NA	NA	NA	NA	NA	599	679	740

Total	72,815	76,143	84,719	102,835^�	119,746	123,558	145,083	175,022	187,957

** FY2001 Trans-NIH Sleep Research Coordinating Committee Member Institute

^� Revised from Trans-NIH Annual Report for fiscal year 1998

* This reduction in FY 2000 funding compared to FY 1999 was due to a one-time change in the method of identifying sleep-related grants

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The complete Fiscal Year 2002 grant listing can be viewed online as a .pdf document

Grants List in PDF [239K]

More information on PDF and the required reader is available.

Printed copies of the Grants List and the complete Report can also be obtained by contacting the National Center on Sleep Disorders Research by calling 301-435-0199 or via e-mail at ncsdr@nih.gov

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PUBLIC NCSDR CONTACTS (E-Mail, Phone, Letters)
Snoring/Breathing/Apnea	197
Insomnia	109
Narcolepsy	86
Restless Legs Syndrome	71
General Sleep Problem or General Information	401
TOTAL PUBLIC CONTACTS-NCSDR	864

PRESS OFFICE (NHLBI/OD) MEDIA CONTACTS
Electronic Media (Internet, E-Mail)	8
Live (Radio, TV, Telephone Interviews)	25
Print Media	16
TOTAL-PRESS OFFICE MEDIA CONTACTS	49

MEDIA COVERAGE, OPEC AUDIENCE IMPRESSIONS (CY 2002)
Parents Magazine	500,000
Washington Parents	100,000
CBS Early Show	6,000,000
Sleep Savvy	100,000
San Antonio Express News	600,000
Baltimore Sun	800,000
Parade Magazine	93,000,000
Yahoo! News	9,000,000
Medscape.com	2,900,000
Intelihealth	1,800,000
Boston Herald	600,000
Los Angeles Times	1,000,000