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Annual Report of the Trans-NIH Sleep Research Coordinating Committee

Fiscal Year 2004


Table of Contents

Introduction
National Center on Sleep Disorders Research
National Heart, Lung, and Blood Institute
National Institute on Aging
National Institute on Alcohol Abuse and Alcoholism
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Cancer Institute
National Institute of Child Health and Human Development
National Center for Complementary and Alternative Medicine
National Institute on Drug Abuse
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
National Institute of Nursing Research
Office of Research on Womens' Health
Financial Report of the Trans-NIH Sleep Research Coordinating Committee


NCSDR Home Page
Sleep Disorders Information
NHLBI Workshop and Meeting Summaries, and Other Scientific Reports

Annual Report Archive (Current and Past Four Reports)

INTRODUCTION

The Trans-NIH Sleep Research Coordinating Committee (SRCC) was 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. The SRCC meets every 2-3 months to discuss ongoing activities in NIH sleep-related programs and to develop new programs. In conjunction with the creation of NCSDR, the Director of NIH transferred responsibility for the Trans-NIH SRCC to the NCSDR, and the NCSDR Director serves as Chair of the Trans-NIH SRCC. The SRCC membership in Fiscal Year 2004 included the following NIH Institutes and Centers:

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 Cancer Institute (NCI) *
National Institute of Child Health and Human Development (NICHD)
National Center for Complementary and Alternative Medicine (NCCAM)
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)
Office for Research on Women's' Health (ORWH) *

* New SRCC Member

In addition, the National Center for Research Resources (NCRR), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the National Institute of Environmental Health Sciences (NIEHS), the National Institute of Dental and Craniofacial Research (NIDCR) and the National Center on Minority Health and Health Disparities (NCMHD) each has a sleep-related portfolio in Fiscal Year 2004 and this information is included in the Financial Summary and Grant Listings at the end of this Report.

The National Center on Sleep Disorders Research (NCSDR) was established within The National Heart, Lung, and Blood Institute (NHLBI) in 1993. As an advocacy and coordinating center, it is responsible for supporting and facilitating basic and clinical research, research training, health information dissemination, and other activities related to sleep disorders. The NCSDR also coordinates sleep-related programs within NIH and with other federal agencies and public organizations. The NCSDR maintains a complete file of Trans-NIH SRCC Annual Reports from the initiation of the SRCC in 1986

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

Al Golden, MPH, Program Analyst

The NCSDR has participated in the planning and conduct of workshops, new initiatives, and public awareness programs during Fiscal Year 2004.

New Initiatives Released in Fiscal Year 2004

RFA-HL-04-010: Inter-Relationships of Sleep, Fatigue, and HIV/AIDS ($2.5 million)

Sponsors: NHLBI; NIMH
Release Date: October, 2003

Objectives: Elucidate the etiology of sleep disturbances and fatigue associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency disease syndrome (AIDS). An improved understanding of this etiology will help in the development of approaches to improve the sleep and quality of life of HIV-infected patients and improve our fundamental understanding of the relationship between sleep and chronic infections in particular and chronic diseases in general.

Workshops/Conferences Conducted in Fiscal Year 2004

Frontiers of Knowledge in Sleep and Sleep Disorders: Opportunities for Improving Health and Quality Of Life: March 29 - 30, 2004, NIH Campus, Bethesda MD

Federal Sponsors: NHLBI (NCSDR), NIAAA, NIA, NIAMS, NICHD, NIDA, NIMH, NINDS, NINR, NCCAM, Office of Rare Diseases (NIH)

Co-Sponsors: American Academy of Sleep Medicine, American Insomnia Association, American Sleep Apnea Association, Narcolepsy Network, National Sleep Foundation, Restless Legs Syndrome Foundation, Sleep Research Society

Outcome: The conference brought together over 300 health care providers, public health and education experts, policy makers, patient advocacy organizations, sleep medicine specialists, and other stakeholders. The central focus was the question "How can current knowledge about sleep and sleep disorders be translated into cost-effective strategies for (1) improving individual knowledge, attitudes and sleep-related behaviors, (2) improving rates of diagnosis and treatment of sleep disorders, (3) reducing health care costs due to untreated sleep disorders, and (4) improving public health and quality of life?"

Dr. Richard Carmona, the U.S. Surgeon General, provided opening remarks. The full text of his remarks has been published in J Clinical Sleep Medicine, January, 2005. They can also be viewed online here (in .pdf format). At the close of the conference, recommendations were developed for enhancing public awareness activities to enhance sleep literacy with the potential to positively impact public health.

Additional information, including the Conference Summary can be accessed online here.

2003 National Sleep Disorders Research Plan

The National Sleep Disorders Research Plan continues to be a state-of-the-art resource that summarizes the dramatic advances in knowledge since 1996, identifies current gaps in our knowledge base, and provides a broad range of recommendations for future sleep research. These recommendations not only guide prioritization of sleep research within NIH and other Federal and non-Federal entities, but are also helpful in identifying opportunities for new investigators from diverse scientific and clinical disciplines. The recommendations regarding training of sleep research scientists, the education of health care professionals, and community-based public education programs are also intended to help stimulate much needed progress in these areas.

The complete 2003 National Sleep Disorders Research Plan can be accessed online (in html and pdf versions) here.
Printed copies of the Plan can be obtained by contacting the NCSDR.

Other Fiscal Year 2004 Activities

National Health and Nutrition Examination Survey (NHANES)
- Large national, population-based sample of subjects 16 years and older
- 2005-2007 Household Questionnaire expanded to include 23 questions related to sleep duration, sleep problems, and sleep disorders.

Institute of Medicine (IOM) Study - Development of Strategies and Recommendations for Enhanced Support of Sleep Medicine and Sleep Research in Academic Health Centers

Federal Sponsors: NCSDR/NHLBI, and the Trans-NIH Sleep Research Coordinating Committee. Funded in part by an Fiscal Year 2004 Evaluation 1% Set-Aside award, Office of Evaluation, Office of Science Education, NIH

Co-Sponsors: American Academy of Sleep Medicine; National Sleep Foundation; Sleep Research Society

The purpose is to develop strategies and recommendations leading to new interdisciplinary programs for the training of future sleep researchers, educators, and sleep medicine clinicians, to address the fragmentation of sleep-related research and clinical care currently present in most academic institutions. This 18-month study began toward the end of Fiscal Year 2004 and the final results will be released in early 2006.

Sleep medicine and sleep research have been growing exponentially during the last 20 years. By 2002, over 2,000 specialized sleep centers existed in the United States. The growth of the field has been fueled by the needs of a large patient population. Although clinical practice related to sleep problems and sleep disorders has been expanding rapidly in the last few years, scientific research is not keeping pace. Insomnia and Restless Legs Syndrome are two examples of very common disorders about which we know very little neurobiologically. Treatments for sleep apnea (e.g., Continuous Positive Airway Pressure) have made a huge difference in the lives of many patients, yet they are still fairly intrusive and not universally accepted by patients.

The field of sleep medicine is multidisciplinary, cutting across multiple Institutes and Centers of the National Institutes of Health (NIH). Sleep research is not limited to very young and old patients--sleep disorders reach across all ages and ethnicities. A pressing need recognized by the 2003 Sleep Disorders Research Plan was training and coordination of sleep medicine and sleep research in existing academic health centers. There are now an estimated 4,500 clinical professionals in the American Academy of Sleep Medicine, yet fewer than 100 basic research faculty members spend the majority of their time in sleep research. To remedy this situation, there is a need to develop new programs for the training of future sleep researchers and sleep medicine clinicians.

The Institute of Medicine (IOM) will convene an ad hoc committee of experts in public health, academic and medical administration, and health sciences research that will:

1. Review and quantify the public health significance of sleep health, sleep loss, and sleep disorders based on current knowledge. This task will include assessments of the contribution of sleep disorders to poor health, reduced quality of life, and early mortality, and the economic consequences of sleep loss and sleep disorders, including lost wages and productivity. Target populations will be segmented as children, adults, and the elderly.

2. Identify gaps in the public health system relating to the understanding, management, and treatment of sleep loss and sleep disorders, and assess the adequacy of the current resources and infrastructures for addressing the gaps. The committee, however, will not be responsible for making any budgetary recommendations.

3. Identify barriers to and opportunities for improving and stimulating multidisciplinary research, education, and training in sleep medicine. Delineate fiscal and academic organizational models that promote and facilitate: sleep research in the basic sciences; cooperative research efforts between basic science disciplines and clinical practice specialties; and multidisciplinary efforts in education and training of practitioners in sleep health, sleep disorders, and sleep research.

4. Develop a comprehensive plan for enhancing sleep medicine and sleep research, as appropriate, for improving the public's health. This will include interdisciplinary initiatives for research, medical education, training, clinical practice, and health policy.

The results of the study will be described in a report that will be made available to the public.

Sleep Apnea and Cardiovascular Disease
- Scientific Statement in preparation, sponsored by the American Heart Association
- Authors: Somers VK, White DP, Abraham WT, Amin R, Costa F, Culebras A, Floras JS, Hunt CE, Pickering TG, Russell R, Woo M, Young T.

Time for Kids (TFK)

NCSDR and the NHLBI Office for Prevention, Education, and Control (OPEC) partnered with Time for Kids (TFK), a Time Inc. subsidiary for educational materials, to produce and distribute materials on sleep to the approximately 30,000 third-grade teachers who subscribe to TFK, and to their 750,000 students.

A 4-page color magazine for students and a 4-page teacher's guide with suggested classroom activities were distributed in March 2004 in association with National Sleep Awareness Week. A follow-up TFK survey indicated that 90 percent of the teachers used these materials in their classroom. Of these, 90 percent reported their students liked the materials "very much," and 80 percent of students were "very satisfied" with the materials. Another 15 percent of students said they were either "extremely" or "somewhat" satisfied. The materials will be distributed to the same group of teachers and their new 3rd graders in March 2005.

High School Biology Curriculum Supplement

In 2004, the NCSDR and OPEC, in partnership with the NIH Office of Science Education (OSE), completed a high school biology supplemental curriculum, "Sleep, Sleep Disorders, and Biological Rhythms". The 5-day curriculum, introduced in the 2004/2005 school year, addresses the biology of sleep and its relationship to health, the importance of obtaining adequate sleep, and the dangers of sleep deprivation. Print copies are distributed at no cost through the OSE to high school teachers, and can also be downloaded from the OSE Web site. To date, the OSE has distributed approximately 12,000 copies of the curriculum, primarily to high school teachers. In addition, more than 2,000 students have accessed the Web site database portion of the curriculum.

Future Conferences

State of the Science Conference: Manifestations and Management of Chronic Insomnia in Adults

Coordinating Agency: NIH Office of Medical Applications and Research (OMAR)

Date: June 13-15, 2005 Location: Natcher Center, NIH

NIH Sponsors: NIMH (Lead Institute), NCSDR/NHLBI, NCCAM, NIA, NIAAA, NIDA, NINDS, NINR, ORWH
Other Federal Sponsors VA; FDA; Federal Railroad Administration, DOT; Agency for Healthcare Research and Quality (AHRQ)
Consensus Panel Chair: Alan I. Leshner, PhD

Objectives: Review the science of insomnia and its treatments in order to respond to the following questions:

1. How is chronic insomnia defined, diagnosed, and classified, and what is known about its etiology?

2. What are the prevalence, natural history, incidence, and risk factors for chronic insomnia?

3. What are the consequences, morbidities, comorbidities, and public health burden associated with chronic insomnia?

4. What treatments are used for the management of chronic insomnia and what is the evidence regarding their safety, efficacy, and effectiveness?

5. What are important future directions for insomnia-related research?

Neuroimaging in Sleep Disorders (FY 2006)

Date: March, 2006 Location: NIH

NIH Sponsors: NCSDR/NHLBI, NIA, NIAAA, NICHD, NIDA, NINDS, NIDCD

Objectives: Review opportunities for neuroimaging applications in sleep-related research, neuroimaging results in sleep deprivation and sleep disorders, and current state-of-the-art in neuroimaging approaches. Recommendations will be developed regarding potential needs to stimulate new research related to neuroimaging to fill gaps in knowledge.

Publications

Frontiers of Knowledge in Sleep and Sleep Disorders: Opportunities for Improving Health and Quality of Life Conference - Text of Opening Remarks - Dr Richard Carmona, U.S. Surgeon General, J Clinical Sleep Medicine 2005;1:83-84.

In preparation: Nature Insight: Nature will publish an Insight entitled "Sleep and Sleep Disorders as a supplement to an October, 2005 issue. This supplement is sponsored by NCSDR/NHLBI, NIMH, NINDS, and ORWH.

Communications

Public Contacts:

NCSDR receives inquiries from the general public, health care professionals, and from other individuals regarding sleep problems and sleep disorders. In Fiscal Year 2004, 40% of these public inquiries to NCSDR were received and answered by e-mail. Public contacts received and responded to during Fiscal Year 2004 by primary symptom(s) or concerns are summarized as follows:

Snoring/Breathing/Apnea
202
Insomnia
127
Narcolepsy
75
Parasomnias
67
Restless Legs Syndrome
61
General Sleep Problem or General Information
256
TOTAL
788

Media Interviews:

NCSDR also has significant media contact with newspapers, professional and lay publications, radio, the Internet, and television that are coordinated by the Press Office [NHLBI and Office of the Director (OD)]. A total of 63 media inquiries related to sleep problems and sleep disorders were received that resulted in an NCSDR interview in Fiscal Year 2004. These include the following requests for information and interviews:

Newspaper/Wire Service
16
World Wide Web
3
Magazines
26
Radio
13
TV
2
Other (Book, Newsletter, etc.)
3
TOTAL
63

Media Monitoring:

1. NHLBI News Release: First National Sleep Conference March 29-30 Explores Sleep's Role in Public Health-Surgeon General, Leading Experts to Discuss Current Evidence, Future Initiatives, March 25, 2004

Wire Coverage

- Reuters (Maggie Fox) - "American Kids, Parents Lack Sleep, Survey Finds"-March 30, 2004
- UPI - "Panel: Sleep disorder education needed"- March 29, 2004
- Health Behavior Service News Service (Aaron Levin) - "Driving is the biggest danger for sleepyheads" - March 29, 2004

Print Coverage

- JAMA (Lynne Lamberg: Medical News & Perspectives: Promoting Adequate Sleep Finds a Place on the Public Health Agenda - May 26, 2004 (Vol 291, no. 20).

- Psychiatric News (Lynne Lamberg): Clinical & Research News: Don't Let Your Patients Lose Sleep Over Insomnia - May 7, 2004 (Volume 39 Number 9). Excerpt: Participants at an NIH conference translate findings from sleep studies into practical advice to improve public health and quality of life.

- US News And World Report, May 17, 2004 (Nell Boyce and Susan Brink):
"The Secrets of Sleep (It's a mystery, but it clearly makes us smarter and healthier)" Quotes Drs. Ruth Benca and Virend Somers Excerpt (p. 6 of Web article): The National Heart, Lung, and Blood Institute last year included sleep apnea as an identifiable cause of high blood pressure, but the medical community has been slow to embrace the idea.;
"How to Get a Good Sleep" (Susan Brink) Quotes Drs. Meir Kryger (mentions board member of the National Sleep Foundation") and David Dinges; "A Nation's Wake-Up Call" (Lack of sleep becoming a new epidemic?) (Bernadine Healy, M.D.) Excerpt (last paragraph): What's still wanting, however, is a public-health rally like the ones that brought attention to the ravages of tobacco, the dangers of obesity, and the need for daily exercise. Let's face it: We arise every morning and do our jobs, but for want of sleep, not always as healthily or as safely as we could. It's time for a wake-up call to nudge our sleepy nation.

- Newsday (Earl Lane, Washington Bureau): The Nation's Need for ZZZZs -- A culture that sometimes touts sleep loss has a health problem, April 13, 2004

- Miami Herald- (Shari Rudavsky): "When counting sheep fails", March 30, 2004

- Health Magazine (Jancee Dunn) -(interview for October issue)

Wire Pickup

- UPI - "Panel: Sleep disorder education needed"; Washington Times

- Reuters (Maggie Fox) - "American Kids, Parents Lack Sleep, Survey Finds" Macon Area Online; ;Reuters AlertNet, UK; Reuters, United States; Reuters, UK; Yahoo News

Online Coverage

- Medscape (Todd Zwillich) - "Physicians May Be Missing Sleep Problems: Poll"
- WebMD (Todd Zwillich) - "Kids not Getting Enough Sleep"

2. NHLBI News Release: NIH Offers New Resources to Better Understand Sleep, June 21, 2004

Wire Coverage

- Reuters (Maggie Fox) - "American Kids, Parents Lack Sleep, Survey Finds"-March 30, 2004
- Sleep-e Times (newsletter) -- Summer 2004

Sleep RFA-L Listserv

The Sleep RFA-Listserv, established by NCSDR in 1998, provides information about federal agency initiatives and activities of potential interest to the sleep and circadian research community. As the chart below demonstrates, there has been significant growth in the Sleep RFA Listserv membership since its inception. Listserv archives and additional information about joining the Listserv can be found at: http://list.nih.gov/archives/sleeprfa-l.html

Link to data table of RFA Listserv Subscription 1998-2004

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ACTIVITIES OF TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE MEMBER INSTITUTES AND CENTERS

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. A major focus is sleep disordered breathing as a potential risk factor for cardiopulmonary disease, stroke, and weight gain. The NHLBI is a major supporter of investigator-initiated sleep research at NIH. The Institute initiated requests for applications (RFA) on the Role of Sleep and Sleep-Disordered Breathing in Metabolic Syndrome (RFA HL-03-008) and the Inter relationships of Sleep, Fatigue, and HIV/AIDS (RFA HL-04-010). Sleep research was also solicited in conjunction with the NHLBI initiatives for Overweight and Obesity Control at Worksites (RFA HL-04-006), the Pulmonary Complications of Sickle Cell Disease (RFA-HL-04-015), and the Cultural Competence and Health Disparities Academic Award (RFA-HL-04-012).

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 (SHHS) 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. A prospective longitudinal study launched in 2003 is investigating the significance of sleep disorders as a risk factor for decline in cognition, impaired physical functioning, morbidity, and mortality in men (MrOS). This investigation complements a similar NIH study of women already underway (SOF). Recruitment is also underway for two new blinded sham-controlled multi-center clinical trials to assess continuous positive airway pressure (CPAP) as a treatment for sleep disordered breathing. The "Apnea Positive Pressure Long-term Efficacy Study" (APPLES) will assess the effectiveness of CPAP for the treatment of sleepiness and cognitive deficits associated with moderate to severe obstructive sleep apnea. The "Impact of CPAP On Functional Outcomes In Milder Obstructive Sleep Apnea" (CATNAP) trial is focused on investigating the threshold severity at which therapy should be initiated.

The highlights of new research findings from the NHLBI sleep program include the effects of short sleep duration on cardiovascular disease risk, irregular heart rhythm associated with Sleep Disordered Breathing (SDB), and the effects of SDB on appetite, metabolism, and behavior.

Excessive Sleepiness and Short Sleep Duration in Women

New evidence links both too little and too much sleep to an increased risk of mortality and morbidity. A new prospective four year study of over 3,000 women demonstrates that the risk of death is three times greater among those who sleep more or less than the average of 6 8 hours per night. Daytime sleepiness also appears linked to mortality. The results suggest that each hour of napping is associated with a 6% increased risk of mortality. Women reporting daily naps also walk slower and exhibit weaker hand grip strength. Difficulty sleeping or functioning due to poor sleep (34% of women at baseline) was associated with a two times greater risk of depressive symptoms at follow up.

Other new findings indicate that sleep duration is associated with an increased risk of coronary events independent of physiological factors such as age, obesity, 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 over ten years found that 70% slept less than eight hours per night. Sleep durations of seven, six, or less than five hours per 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.

Irregular Heart Rhythm Linked With Sleep Disordered Breathing (SDB)

Increasing evidence indicates that SDB including loud snoring and recurring episodes of airway obstruction is a chronic disease associated with increased cardiovascular disease risk. SDB shares many risk factors with irregular heart rhythm (arrhythmia), including male gender, hypertension, congestive heart failure, and coronary artery disease. A study of 460 patients has established that patients with an irregular heart rhythm are more than twice as likely to have SDB compared to other cardiology patients. The association of SDB with irregular heart rhythm was greater than the association of OSA with other previously reported SDB risk factors such as body mass index, neck circumference, diabetes, and hypertension. The study confirms that cardiovascular diseases previously associated with SDB, such as coronary artery disease and congestive heart failure, are accompanied by a high prevalence of SDB. The results suggest that the prevalence of SDB in patients with irregular heart rhythm is substantially greater than the prevalence of SDB in patients with established cardiovascular disease and no diagnosis of irregular heart rhythm.

Irregular heart rhythm is a growing public health concern given that the age adjusted prevalence of irregular heart rhythm in the United States has tripled from 1960 to 1990. Irregular heart rhythm in patients with congestive heart failure is more common in patients with sleep apnea, and the presence of sleep apnea is predictive of heart rhythm irregularities after coronary bypass surgery. Since treatment of SDB lowers the risk of an irregular heart rhythm, determining the prevalence of SDB in cardiology patients is clinically important.

Sleep and the Regulation of Appetite, Metabolism, and Behavior

Insufficient sleep related to lifestyle, shift work, depression, and untreated sleep disorders influences behaviors contributing to cardiovascular health and stress. New findings from a study of over 1,000 adults demonstrates that a lack of exercise is associated with increased severity of SDB independent of body weight, gender, age, and other factors. The average severity of SDB ranged from 6 events per hour in those reporting no weekly exercise to 2 events per hour in those reporting more than 7 hours of exercise weekly. The causal mechanism in this relationship is unclear. Sleep disturbance associated with relatively mild SDB can lead to excessive daytime sleepiness and hormonal abnormalities that may disincline persons to be physically active. Sleep-related growth hormone secretion represents 70% of daily hormone production. Decreased energy level and fatigue reported by growth hormone deficient individuals is associated with disturbed sleep and sleep apnea.

SDB is also an independent risk factor for insulin resistance, a condition associated with an increased risk of diabetes. Continuous positive airway pressure (CPAP) treatment of SDB improves insulin sensitivity. Weight gain as a function of appetite regulation may also be influenced by SDB. Recent findings from a study of 130 adults links SDB with abnormalities in leptin, an inflammation producing cytokine that influences appetite. The results suggest that SDB is associated with an exaggerated suppression of leptin during sleep and secretion of leptin during the day independent of age, gender, and ethnicity. This pattern may contribute to the pathogenesis of elevated leptin levels and a state of leptin resistance that is characteristic of human obesity. New findings indicate that overall leptin levels decrease with long term CPAP therapy independent of body weight changes. While further research is needed to elucidate the mechanisms for these associations, the new findings suggest that treatments to improve sleep quality may enhance healthy behavior by influencing physical activity, appetite, and metabolism.

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

Significance of Program Activity

Problems with sleep are common with advancing years and occur in over 50% of adults age 65 and older. 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 results in excessive daytime sleepiness and 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 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 geriatric population due to the associated co-morbidities common in later life. Disturbance in sleep can also lead to adverse changes in functioning of a number of body systems.

The NIA Sleep portfolio totaled almost $16.5 million in Fiscal Year 2004, down from a total of approximately $18.2 million in FY 2003. In addition to the Trans-NIH Sleep Research Coordinating Committee, NIA is also represented on the Sleep Disorders Research Advisory Board. NIA worked with the National Sleep Foundation (NSF) to develop their first Leadership Congress on Sleep, Health and Aging, held March 31-April 1, 2003. The journal Geriatrics" included a series of three issues starting in January 2004 with articles on sleep medicine for CME credit, based upon presentations from this meeting. A report of the meeting was published in JAMA (July 16, 2003 Volume 290 (3) 319-323), and a report on the final recommendations from this meeting is in preparation. A new section of the NIH SeniorHealth website on sleep and aging is in preparation. In addition, two trans-NIH PAs on sleep are being reissued for FY 2005: "Research on Sleep and Sleep Disorders" and "Restless Legs Syndrome and Periodic Limb Movement Disorder". The NIA also was a co-sponsor of a major conference "Frontiers of Knowledge in Sleep and Sleep Disorders: Opportunities for Improving Health and Quality of Life" that was held at NIH on March 29-30, 2004. NIA is co-sponsoring the State-of-the-Science Conference on Chronic Insomnia being held June 13-15, 2005.

Health Disparities-Related Research

Ethnic differences in post-menopausal women were studied in San Diego in an ancillary study to the Women's Health Initiative. African-American women and Hispanic women slept less than Caucasian women (5.25 hours, 5.83 hours, and 6.15 hours, respectively), based upon wrist actigraphy. Thus, objective sleep time was significantly related to ethnicity (p <0.001) when controlled for covariates of illumination, age, education, and depression score. These objective actigraphy data differ from earlier studies based on self-reported sleep durations indicating that sleep problems tend to be lower amongst African-Americans than Caucasian groups in the North Central Piedmont of North Carolina), a biracial community study in Brooklyn, New York), and the Studies of Women Across the Nation (SWAN). These self-report data suggested that complaints of difficulty sleeping were more frequent among the Caucasian women than in the other groups, and likelihood of psychological distress was significantly higher for Caucasians than for the other racial/ethnic groups. These differences in perception of sleep quality and objective data confirm other studies showing such differences and may result from people under-reporting their wake time after sleep onset, as well as from social factors and expectations.

Basic Research

The use of neuroimaging technologies to study sleep is relatively new. Drummond, et al., have reviewed the literature and found only 19 papers in the last 14 years that have used neuroimaging methods (PET, SPECT, and fMRI) to view brain activity during normal NREM and REM sleep. In general, these studies have found that there is a global decrease in brain activity, especially the thalamus and the frontal and parietal cortices, during NREM sleep, suggesting a down-regulation of the central nervous system (CNS) with deepening sleep. During REM sleep, however, there appears to be an increase in metabolic activity within the limbic system, the pons, basal ganglia, and the auditory and occipital cortices, which could be linked to the dream activity that is concentrated during REM sleep. Nofzinger, et al., have recently reported that patients with insomnia show greater global glucose cerebral metabolism during sleep and while awake than do normal sleepers, and that there is a smaller decline in the metabolism of the wake-promoting regions of the brain during the transition from wake to sleep, suggesting that the disturbed sleep of insomnia is associated with a failure of arousal mechanisms to decrease activity while transitioning to sleep. Furthermore, they found that there was reduced daytime metabolic activity in the prefrontal cortex resulting from the insomnia.

The use of Drosophila in circadian cycle research has been well established. More recently, the rest behavior of fruit flies has been successfully modeled as sleep, opening the Drosophila genome and molecular biology to elucidate sleep mechanisms. Using Drosophila, it has been established that a null mutation (cyc01) in a clock gene, cycle, is related to a deficient rest phenotype; rest was specifically and significantly reduced without marked effects on locomotor activity. The animals were not generally hyperactive but rested less while having normal or slightly decreased locomotor activity. After rest deprivation, males exhibited a decrease and females an increase in duration of rebound, with males having a shortened lifespan. Cycle is clock-independent (period and timeless did not change or show rest rebound) while Clock mutants have a modest effect similar to cycle, possibly implicating that the CLOCK: CYCLE dimer is involved in regulating rest. Modafinil was found to produce a small but significant rebound, and flies given chronic modafinil had shortened lifespan. Microarray studies showed that sleep deprivation increased genes related to metabolism, immune function, and stress (including oxidative stress and endoplasmic reticulum (ER) stress). Relatively few genes were increased during rest rebound, but one important gene that repairs oxidative damages - methionine sulfoxide reductase A (msrA) was increased. A putative serotonin receptor gene (most closely related to mammalian 5HT2B) appears to modulate the effects of light on the circadian rhythm.

Microarray studies in rodents have shown that different functional categories of genes are selectively expressed during wake and sleep states. Wakefulness tends to be associated with genes that code for energy metabolism, stress proteins, synthesis of excitatory neurotransmitters, and neural plasticity and long-term potentiation. Sleep is associated with protein synthesis, membrane trafficking and maintenance, and neural plasticity.

Our current understanding of the regulation of the human sleep-wake cycle indicates that sleep and wake behaviors are generated by a complex interaction of sleep homeostatic and endogenous circadian processes, as well as environmental factors. The sensation of sleepiness, propensity to fall asleep and depth of sleep are hallmarks of the compensatory response to sleep loss. This drive toward sleep and the tendency to sleep longer and more deeply after sleep deprivation is referred to as "sleep homeostatic process". The sleep homeostatic process regulates the amount of slow wave sleep and depth of sleep. It has been postulated that the sleep homeostatic process is regulated by sleep factors that increase during wakefulness and decline during sleep.

Recent studies suggest that adenosine may play an important role in this physiological drive toward sleep. With increased wakefulness, brain energy stores decrease and adenosine accumulates, resulting in increased neuronal membrane depolarization and inhibition of neuronal transmission. In support of the hypothesis that sleep is required for the restoration of brain energy metabolism, levels of brain glycogen decreased by about 40% in brains of rats deprived of sleep for 12 or 24 hours while recovery sleep of 15 hours duration after 12 hours sleep deprivation reversed the decreases in glycogen. The glycogen was found to be concentrated in white matter (predominantly localized to glial fibrillary acidic protein (GFAP) positive astrocytes), but also found in gray matter. No changes specifically related to sleep deprivation were found in the activity of any of the major metabolic adenosine enzymes in any brain region, although they were generally higher during periods of activity. In rats, levels of glycogen in brain areas do increase with age, decrease with sleep deprivation, and rebound to higher than normal levels with recovery sleep. All adenosine metabolic enzymes exhibited diurnal variations in activity, but not in all brain regions, while no changes were found specifically related to sleep deprivation. Thus, changes in adenosine with sleep deprivation are not a consequence of alterations in adenosine enzyme activity. While adenosine does increase with prolonged wakefulness in the rat, old rats appear to have a reduction in the sensitivity of the adenosine receptor and do not transduce the adenosine signal to the same degree as in young rats, possibly contributing to the decline in sleep drive common in the elderly. These data suggest that sleep deprivation produces a gradual depletion of brain ATP and higher adenosine levels in some brain regions (striatum and hippocampus) and that different regulatory mechanisms control adenosine levels in these areas compared to the cortex. The effects of sleep deprivation however, are not uniform in all strains of mice, indicating that brain glycogen level per se is dependent upon genetic factors.

Future Directions

Although there is a growing body of research on the aging circadian system, relatively few data exist 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 to better define the basis of age-related sleep changes. New studies are addressing the genetics of sleep, and the relevance of sleep genetics 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 studies indicate that there is little evidence of an age-related loss of neurons that have been identified as playing a key role in the maintenance of sleep homeostasis. Thus, the age-related alterations in the control of sleep appear to not be due to loss of critical neurons but to subtle changes within neurons and to 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 50% of our older population

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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 2004, The National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded regular Research Project Grants, Postdoctoral and Career Development Awards, and Cooperative Agreement components on the topic of alcohol and sleep. The specific areas of sleep-related research supported during the past year 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 and the relationship of prenatal alcohol exposure to the incidence of sudden infant death syndrome (SIDS); 4) assessment and treatment of sleep disturbances in recovering alcoholics; 5) pharmacotherapy of alcoholism and comorbid insomnia; 6) sleep and immune function in African Americans; and 7) effects of acute alcohol intake on performance and alcohol abuse liability in insomniacs.

Published research highlights during Fiscal Year 2004 from currently funded projects are summarized below:

Sleep Problems in Early Childhood as a Risk Marker for Early Onset of Alcohol Abuse

It is well documented that sleep problems, primarily insomnia, are associated with the onset of alcohol problems among some adults and predict relapse in adult alcoholics in remission. In contrast, there are only a few studies in adolescents that have found a positive correlation between sleep disturbances and the presence of alcohol and other drug problems. Furthermore, because these studies in adolescents were cross-sectional and not prospective, it could not be determined whether sleep problems are the cause or consequence of drinking. However, a recent study has used a longitudinal prospective design to examine the etiological relationship between sleep problems in early childhood and the onset of alcohol and other drug use in early adolescence. In this study, mothers' ratings of their children's sleep problems at ages 3 to 5 years significantly predicted an early onset of any use of alcohol, marijuana, and illicit drugs, as well as an early onset of cigarette use by age 12 to 14. Although sleep problems in early childhood also predicted attention problems and anxiety/depression in later childhood, these disorders did not mediate the relationship between sleep problems and the onset of alcohol and other drug use. This is the first study to demonstrate that early childhood sleep problems may be a robust marker for increased risk of later alcohol and drug use disorders.

Neonatal Alcohol Exposure May Permanently Disrupt Circadian Rhythms

The internal biological clock responsible for the generation of circadian rhythms is located in a region of the brain referred to as the suprachiasmatic nucleus (SCN). In addition to its timekeeping function, the SCN also mediates the entrainment or synchronization of mammalian circadian rhythms to light/dark cycles. Because clinical sleep-wake disturbances have been observed in human infants, children, and adolescents following prenatal alcohol exposure, studies were conducted in rats to determine whether early alcohol exposure produces long-term changes in the circadian time-keeping function of the SCN. Two recent studies found that early postnatal (equivalent to third trimester in humans) ethanol exposure in rats tested as adults produces increased phase-shifting responses to light and alters the circadian rhythm of brain-derived neurotrophic factor, an important rhythmic output from the SCN. These findings, coupled with the changes in circadian period and light/dark entrainment in adult rats prenatally treated with ethanol, suggest that developmental ethanol exposure may permanently alter the clock mechanism in the SCN and its regulation of circadian behavior.

Effects of Sleep Loss and Ethanol on Performance and Risk-Taking Behavior

Sleepiness and ethanol ingestion alone and in combination have documented detrimental effects on memory, attention, and psychomotor performance. Up to now, however, no studies had compared variable "doses" of sleep loss to multiple doses of ethanol on performance measures. In a recent study, subjects were exposed to 0, 2, 4, and 8 hours of sleep loss or ingested 0, 0.3, 0.6, or 0.9 g/kg ethanol and were then tested on a battery of memory, psychomotor, vigilance and divided attention tasks. At the studied "doses," sleep loss was more potent than ethanol in its sedative effects, but comparable to ethanol in its effects on psychomotor performance. Ethanol produced greater memory impairments than sleep loss, and ethanol-exposed participants were less aware of their overall performance impairment at low and medium doses. This finding is consistent with traffic safety data that show ethanol-related traffic accidents in individuals with relatively low blood alcohol concentration, possibly due to their poor perception of impairment. Another study examined whether sleepiness and ethanol degrade psychomotor speed and risky choice and whether caffeine attenuates these effects. Individuals who were sufficiently well-rested made less risky choices on a laboratory model of risk-taking choice behavior and were more aware of the consequences of their actions than sleep-deprived subjects. Under conditions where risk-taking depends on responding rapidly, alcohol may also influence risky choice and caffeine may attenuate this effect. These studies also have important public health implications, since both impaired performance and risky choice behaviors may contribute to increased risk of automobile crashes.

Mechanisms of Impaired Sleep Loss in African American Alcoholics

Research has demonstrated an inter-relationship between sleep and immune functioning. For example, animal studies provide evidence that sleep is involved with three classes of cellular hormones, referred to as cytokines, which regulate immune system activity: T helper 1 (Th1, e.g., interferon), anti-inflammatory/Th2 (e.g., interleukin 10), and pro-inflammatory (IL-6) cytokines. In humans, it appears that sleep onset, duration, and depth are correlated with levels of the pro-inflammatory cytokine, IL-6. Since previous studies have shown that African American alcoholics show more severe disturbances of sleep and immune function compared to their Euro-American counterparts, a recent study investigated whether elevated circulating levels of proinflammatory IL-6 and tumor necrosis factor alpha (TNF) are associated with disordered sleep in alcoholdependent African American subjects. Compared to controls, abstinent alcohol-dependent subjects had increased nocturnal levels of IL-6 and TNF, which also occured following sleep deprivation. In addition, experimental sleep deprivation produces abnormal elevations of IL-6 and TNF in African-American alcoholics, and elevated levels of circulating IL-6 prior to sleep onset predicted a delay in the time to fall asleep. Taken together, these findings indicate that circulating levels pro-inflammatory cytokines may have a negative influence on sleep initiation.

Abnormal Melatonin Secretion and Disordered Sleep in Alcoholics

Melatonin is thought to affect sleep by resetting the internal biological clock. In alcoholics, the relationship between melatonin and disordered sleep is unknown. Therefore, a recent study examined the association between decreases and/or delays in melatonin secretion and abnormalities of sleep in abstinent alcoholics. Compared to controls, alcoholics showed abnormal secretion of the circadian-dependent hormones, melatonin and cortisol, and a delay in the nocturnal rise of melatonin. Coupled with the delay of nocturnal melatonin secretion, alcoholics show a prolonged sleep latency which correlates with later onset of the nocturnal plateau of melatonin. This association between delayed onset of sleep and night-time melatonin secretion supports the notion that abnormally low melatonin levels or a delay in melatonin release during the night might contribute to disordered sleep in alcoholics. This finding has implications for the use of melatonin in the treatment of insomnia in recovering alcoholics.

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NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Deborah Ader, PhD
NIAMS Representative To The Trans-NIH Sleep Research Coordinating Committee

The NIAMS funded 5 grants in sleep-related research in Fiscal Year 2004 in the areas of fibromyalgia (FM), rheumatoid arthritis, and bone fracture. One study examines sleep and stress as predictors of pain, fatigue, and distressed mood in FM. One study is investigating behavioral treatments for rheumatoid arthritis, with sleep quality as one of the outcome variables. Another study es investigates the role of impaired sleep as a major cause of fractures, disability and cognitive decline in older women. Finally, a conference on the role of fatigue in rheumatic diseases was held in September, 2004.

The NIAMS has no sleep-specific initiatives active in FY 2005.

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NATIONAL CANCER INSTITUTE
Ann O'Mara, PhD
NCI Representative To The Trans-NIH Sleep Research Coordinating Committee

NCI supports a variety of sleep-related research in patients diagnosed with cancer. Sleep disturbances can occur at any point in the cancer trajectory, from diagnosis through survivorship to end of life. Often the problem occurs in conjunction with other symptoms, most notably pain and fatigue. It may be the result of treatment for the disease or for one or more symptoms, such as pain. During Fiscal Year 2004, the NCI supported 14 investigator-initiated projects (R03, R21, R01), one clinical trial (U10) and two conferences (R13) in sleep -related research.

Three investigator-initiated projects are exploring the onset, severity, and relationships of sleep and fatigue in patients undergoing chemotherapy and radiotherapy. One study is testing an intervention to ameliorate fatigue and, secondarily, sleep problems. Hot flashes and resultant sleep disturbances are particularly problematic in the breast cancer population and two studies are testing hypnosis and acupuncture to relieve hot flashes and possibly the associated sleep problems. Cancer survivors have reported sleep disturbances, long after their treatments have ended. Three studies are testing interventions to relieve or reduce insomnia in cancer survivors. The remaining five studies are exploring biological mechanisms of insomnia and related sleep disorders in patients undergoing therapy and in cancer survivors. In addition to investigator-initiated projects, the NCI also supports a large clinical trials network for preventing and treating cancer, and for managing associated symptoms. Currently, NCI is supporting a phase III trial to test the efficacy of valerian to improve sleep in patients undergoing adjuvant therapy.

The Institute is also supporting two conference grants. Of increasing importance is the impact of caring for a family member with cancer and one conference was devoted to synthesizing existing knowledge in order to chart future directions for scientists in order to reduce the distress associated with sleep disturbances, particularly insomnia, in adults and children with cancer and their caregivers. The other conference focused on recent developments in cell biology that are important in identifying mechanisms underlying genetic diseases and providing insights into methods for prevention, diagnosis and therapy of human diseases. A basic knowledge of cell biology will be required to understand the defects in cell function that cause human diseases, including many cancers, cardiovascular pathologies, defective immune responses, sleep disorders, hypertension, diabetes, and neurodegenerative disorders.

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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 National Institute of Child Health and Human Development (NICHD) supports and promotes sleep research in infants, children, adults, 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, and changes across the lifespan in reproductive health. Highlights from a few of the projects follow.

Research Highlights

Sleeping on the stomach increases the risk for SIDS. It has been proposed that stomach sleep position increases the likelihood that the infant will rebreathe expired air, which is low in oxygen (hypoxia). In addition, stomach sleep position increases the likelihood that an infant will have their face and/or head covered and overheat (hyperthermia). In order to understand how these environmental conditions influence autoresuscitation, mice were exposed to either condition or combination of the two and the ability of the animals to autoresuscitate was examined. While neither hyperthermia nor hypoxia alone affected autoresuscitation, there was an increasing frequency of failure to autoresuscitate to the first exposure to hypoxia as the temperature increased. In addition, there was decreased ability to recover from multiple exposures to hypoxia when the temperature was increased. These studies suggest that both hypoxia and hyperthermia in combination may contribute to the increased SIDS risk posed by stomach sleep position and the head covered by bedding (J Appl Physiol 2004;97:669-674).

The Collaborative Home Infant Monitoring Evaluation (CHIME) Study, a multicenter cooperative study of home monitoring of high risk infants has been completed. Almost 1200 infants were enrolled in the following subject groups: healthy term infants, preterm infants less than 1750 grams, siblings of SIDS and babies experiencing an idiopathic apparent life-threatening event. The objectives of the study were to: determine whether home apnea monitors employing event recordings are effective in identifying episodes that are dangerous to the infant's health; determine the conditions that optimize the use of apnea monitors in high risk infants; correlate physiological markers, health status, and behavior with the propensity for life-threatening events; and provide important information on the maturation of heart and respiratory function in sleeping infants. The NICHD, CHIME investigators, and industry collaborated in the development of a new monitoring technology, which was tested for its potential to detect and record life-threatening cardiorespiratory episodes.

In 2001, a major study from CHIME showed that cardiorespiratory events (apnea and bradycardia) meeting conventional alarm thresholds are quite common, even in healthy term infants. More severe events were common only in preterm infants, and their timing suggests that they are not likely immediate precursors to SIDS. The information from this study was used by the Committee on Fetus and Newborn, American Academy of Pediatrics in the drafting of their policy statement, Apnea, Sudden Infant Death Syndrome, and Home Monitoring, which was published in 2003. This policy statement recommended that home cardiorespiratory monitoring should not be prescribed to prevent SIDS and that parents should be advised that these monitors have not been proven to prevent unexpected deaths in infants. Home monitoring may be warranted for a limited time for premature infants at high risk for recurrent cardiorespiratory episodes after discharge from the hospital (Pediatrics 2003;111:914-917).

In January 2004, the entire CHIME database, which includes all raw physiological records and study forms became accessible to researchers at the following website: http://dccwww.bumc.bu.edu/ChimeNisp/. In Fiscal Year 2004 the NICHD awarded a grant to use the CHIME database to examine spontaneous arousal from the polysomnograms that were done on the infants enrolled in CHIME. This grant is testing automated analysis to standardize the definitions of arousal and will examine shifts in autonomic activity associated with these arousals using measures of heart rate variability. In addition, An "Atlas of Infant Polysomnography" was published by the CHIME Study and is a valuable resource for researchers and clinicians.

It can be hazardous for an infant to sleep on an adult bed alone or with another person because it has the potential to lead to entrapment, overlay, and suffocation. While bed sharing with other children increases SIDS risk, there is controversy regarding the risk associated with sharing a bed with a parent. The Infant Care Practices Study, which was a longitudinal prospective study of over 15,000 mother-infant dyads enrolled at birth in Massachusetts and Ohio from 1995-1998, obtained information on bed sharing practices in the United States. The proportion of women who reported bed sharing for most of the past night decreased from 22% when the infant was one month of age to 13% and 14% at 3 and 6 months of age respectively. At all ages, breastfeeding was a strong predictor of bed sharing, primarily among white and Asian women. In addition, the probability of bed sharing was high among Black women and their infants independent of breastfeeding (J Dev Behav Pediatr 2004;25:141-149). More research is needed to understand the motivation, and potential benefits or hazards.

Sleep-disordered breathing (SDB) affects 1-3 percent of children and can have associated morbidities including inattentive and hyperactive behavior, disruptive behavior disorders, cognitive deficits, and excessive daytime sleepiness. The goal of this project is to study and improve methods for the identification of childhood SDB that carries reversible morbidity. Children scheduled for adenotonsillectomy, hernia repair, and other minimally invasive procedures are enrolled and compared to a group of healthy control children by assessments of behavior, psychiatric status, cognition, and sleepiness. Neuropsychological and psychiatric testing, overnight polysomnography, and daytime Multiple Sleep Latency Tests are performed at baseline and the neuropsychological testing is repeated at 3 and 12 months post surgery. Early results, comparing physical findings with polysomnographic findings, suggest that tonsillar size may be the most reliable predictor of sleep-disordered breathing (SDB) severity. SDB severity, as measured by polysomnography, showed only limited association with behavioral outcomes. Rates of periodic limb movements during sleep also predicted behavioral outcomes. Behavioral morbidity among children scheduled for adenotonsillectomy was notably high and included both disruptive behavior disorders and attention deficit/hyperactivity disorders. Follow-up data after treatment for SDB and in control children will help to demonstrate if SDB causes behavioral problems. This study will also provide valuable sleep and sleep-related data on normal children. The data could enhance bedside and laboratory identification of optimal candidates for adenotonsillectomy, improve clinicians' diagnostic accuracy in cases of SDB, and expand knowledge of how sleep, breathing, and daytime behavior are intimately related in children.

Prenatal Alcohol in SIDS and Stillbirth Network (PASS)

In Fiscal Year 2003, the NICHD and NIAAA funded four cooperative agreements to create a network for the development of community-linked studies to investigate the role of prenatal alcohol exposure in the risk for sudden infant death syndrome (SIDS) and adverse pregnancy outcomes such as stillbirth and fetal alcohol syndrome (FAS), and how they may be inter-related. The network is composed of two Comprehensive Clinical Sites, a Developmental Biology and Pathology Center, and a Data Coordinating and Analysis Center. The comprehensive Clinical sites will be working with Northern Plains Indian communities and populations in the Western Cape of South Africa. The investigators will work collaboratively with NICHD and NIAAA over a three-year period to plan and pilot multidisciplinary investigations using common protocols, within communities at high risk for prenatal maternal alcohol consumption. The long-term goals of this initiative are to decrease fetal and infant mortality and improve child health in these communities. In Fiscal Year 2004, the network has made great strides in developing a study design that will combine prospective and retrospective data collection. It incorporates the use of methodologies in epidemiology, physiology, pathology, and the neurosciences to decipher the complex relationship between alcohol use and abuse during pregnancy and their effect on the developing fetus and infant.

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.

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

Since 1999 the NICHD has been working with affected communities to develop specific campaign initiatives.

- African American Outreach Initiative

In January 2004, the NICHD, CJ Foundation for SIDS, and the National Black Reproductive and Child Health Institute sponsored a training event in Jacksonville, Florida. The event was hosted by the Bold City Chapter of The Links, Inc. and provided an opportunity for participants to learn how to use the Resource Kit for Reducing the Risk of SIDS in African American Communities and conduct SIDS education in local community settings.

During April 2004, the NICHD again joined forces with The Links, Inc. - the Prince George's County Chapter in Maryland. This local group sponsors an annual Black Family Symposium, which includes educational workshops, health screenings, and healthy activities for children. Several NICHD research staff presented on various topics including SIDS and health issues during infancy.

During October 2004, which is SIDS Awareness Month, the NICHD ran public service announcements on radio stations around the country and displayed ads on buses in the Washington, D.C. area to remind African American parents, grandparents, and caregivers about reducing the risk of SIDS. Also, specific public education activities occurred in the Mississippi Delta region. Woman to Woman, a Mississippi state-wide television show, aired PSAs throughout the month and into early November. The Mississippi Head Start Association partnered with the State Day Care Licensing division and sent SIDS information to 28,000 child care providers across the state. Over 250 pastors in Mississippi, Louisiana, and Arkansas received information about SIDS Sunday, in which they were asked to pick a Sunday in October to talk to their church members about SIDS risk reduction. Mississippi First! Health Partner members conducted a variety of outreach activities. They held SIDS poster contests at the Boys and Girls Club; conducted a SIDS workshop for 1,000 people; provided information to a newborn nursery; gave out SIDS risk reduction materials at a local mall; and worked with the Delta Health Partners in developing a SIDS curriculum.

- American Indian/Alaska Native Outreach Initiative

In the summer of 2004, NICHD organized a meeting with several work group members from each region that served as site coordinators along with their discussion group leaders to report the findings from the discussion groups. The findings were constructive to proceed to the next phase in developing adaptable materials and support material for diverse American Indian and Alaska Native communities. The work group and partners will be involved throughout the development of the plan and will continue to provide guidance and feedback at various stages

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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. For example, approximately 1.6 million adults (3.1% of all adults who used CAM in 2002) used CAM specifically for sleep problems. These CAM therapies include dietary supplements such as melatonin and valerian, mind/body approaches such as meditation, and therapies such as acupuncture and yoga that are part of non-western traditional medical systems. 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 summarized below.

Insomnia

Chronic insomnia is a significant health problem for many individuals and is often difficult to treat. Furthermore, conventional therapies 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 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 study is to establish whether a regimen of yoga practice will improve sleep onset latency measured by both subjective and objective criteria. In addition, NCCAM funds an ongoing trial of melatonin for insomnia in the elderly. A significant percentage of elderly individuals with insomnia have low endogenous levels of melatonin, which is a normally occurring neurohormone as well as a popular dietary supplement used for various sleep disorders. This clinical study will investigate whether melatonin will relieve insomnia in these individuals.

Sleep Deprivation Related to Neurodegenerative Diseases

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) are often accompanied by sleep disturbances due to pain and/or neurological changes related to disease progression. NCCAM supports a clinical study investigating the efficacy and safety of valerian for the treatment of sleep disturbances in PD. 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 advertised as having hypnotic properties effective in treating sleep disorders. However, 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 PD, 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 PD patients.

In addition, NCCAM supports a study on the use of high intensity light therapy for AD patients in nursing homes. The long term care of AD 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 lights installed in nursing home common rooms and used for various periods of time will contribute to a lessening of these problems. If results are positive, this could provide a low-risk alternative and relatively inexpensive treatment.

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, as part of an initiative in 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 drugs. This includes interactions between drugs used to treat sleep disorders and dietary supplements such as valerian and melatonin.

Circadian Biology

Perturbations of the biological sleep-wake regulatory cycle may cause sleep disturbances. Light, neurohormones such as melatonin (produced in the pineal gland), and other substances affect this cycle. In 2004, NCCAM co-sponsored a conference on Pineal Cell Biology that brought together experts in the field of circadian biology to summarize new research findings in this area and to consider future directions. The NCCAM also support a study investigating the effect of blue light on sleep-wake regulatory cycle in humans.

Systematic Reviews

Because of the wide use of the dietary supplement, melatonin, for sleep disorders, NCCAM commissioned the Agency for Healthcare Research and Quality (AHRQ) to conduct a systematic review of published research on this subject to determine the strength of scientific evidence supporting the efficacy of melatonin for sleep disorders. . This systematic review published in 2004 found that melatonin appears to be safe, butit may not be effective for treating most primary sleep disorders. However, melatonin may be effective in treating delayed sleep phase syndrome. Finally, the report suggests that the mechanism by which melatonin produces sleepiness in humans is still not well understood. More information is needed about how melatonin is absorbed, distributed, and metabolized in humans. The information from this systematic review should help guide future research.

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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) has a primary research goal to understand brain systems affected by psychoactive drugs of abuse. Sleep disturbances both during and following withdrawal from use of such drugs among individuals who are addicted strongly support the need for NIDA-supported sleep research. Current studies focus on the neurobiology associated with sleep, sleep and circadian cycles, and sleep architecture. Indeed, sleep disturbances often outlast other withdrawal symptoms and are often a cause for relapse. This suggests that the neural systems involved in the addiction process are many of the same ones also involved in sleep architecture. In addition, it is important to study how sleepiness and, conversely, insomnia contribute to drug abuse and to relapse following withdrawal.

Several sleep studies of interest to NIDA are at the molecular level. Fatty acid amide hydrolase (FAAH) is an enzyme that degrades fatty acid amides (FAAs) such as the endocannabinoid anandamide and the sleep-inducing substance oleamide. FAAs are implicated in several biologic functions including sleep. For example, oleamide has been isolated from the cerebral fluid of sleep-deprived cats. A newly funded study will focus on N-arachidonylglycine (NAGly), an endogenous constituent of many tissues, which has a potent inhibitory effect on FAAH. Studies of these mechanisms will provide insight into the cannabinoid system as well as their interactions in the brain. To this end, Boger and colleagues examined several sulfoxide and sulfone inhibitors of FAAH (Du et al., 2005 Bioorganic & Medicinal Chemistry Letters, 15, 1003-106.) Also, in the laboratory of Cravatt, characterization of the sleep-wake patterns in FAAH knock-out mice demonstrated increased slow-wave sleep and more intense episodes of slow-wave sleep than control littermates, supporting a role of FAA as possible modulators of sleep (Huitron-Resendiz. Sleep 2004; 27(5):857-865). Finally, it should be noted that study of these amides and metabolites also determines their role in nociceptive pathways (Cravatt & Lichtman. J Neurobiol 2004; 61(1):149-160) which are important influences in drug abuse research.

NIDA supports several studies that focus on benzodiazepines and non-benzodiazepine hypnotics, most of which are concerned with mechanisms of action and potential for abuse. For example, one such study on zolpidem demonstrated an improvement in sleep quality and next-day performance but worsened mood compared to placebo (Hart et al. Exp Clin Psychopharm 2003;11(4):259-268).

Because of overlap in the neural systems involved in sleep and drug abuse, there is reason to hypothesize that treatments for sleep disorders may prove effective in the treatment of drug abuse as well. For example, Modafinil, a drug approved for the treatment of narcolepsy, is now being investigated as a possible atypical agonist replacement for cocaine. Trials are being conducted to determine if it will reduce the "high" or drug effect of cocaine and if it, together with cognitive behavior therapy, can be an effective treatment. The first steps in these investigations of modafinil are to determine pharmacokinetic properties. For example, one study showed that d-enantiomer was eliminated from human serum quicker than the l-enantiomer (Donovan et al. Ther Drug Monit 2003; 25(2):197-202). Continued studies will determine the effectiveness of the drug.

Finally, a major thrust of research results just starting to be reported is the effect of drugs of abuse on sleep architecture. How do drugs affect sleep cycles and sleep efficiency? And importantly, are the effects on sleep following drug withdrawal part of the cause of relapse? Studies of sleep quality for marijuana are underway as are studies of magnetic resonance imaging on brain changes. The most comprehensive study to date characterizes sleep quality in chronic cocaine users (Pace-Schott et al. Psychopharm 2005). Volunteer cocaine users resided on an inpatient unit while studied with three days of baseline abstinence, three days of (monitored) binge cocaine use, and 15 days of abstinence. During this period, sleep duration, efficiency, and onset latency worsened while subjective reports remained constant. It is concluded that this dissociation between objective and subjective sleep quality is related to disruption of the sleep homeostat and may be contributory to relapse. Therapeutic intervention might take these data into consideration. Continuing studies in these areas may to lead to better understanding on biological mechanisms underlying drug abuse vulnerability as related to sleep architecture.

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NATIONAL INSTITUTE OF MENTAL HEALTH
Regina Dolan-Sewell, PhD
NIMH Representative to the Trans-NIH Sleep Research Coordinating Committee

Sleep disorders and sleep disruption associated with mental illness account for significant impairment in many children and adults and present a notable challenge to mental health. NIMH supports a wide variety of sleep-related research including genetics, cellular and molecular mechanisms of circadian systems, nosology and epidemiology of sleep disorders, the relationship of sleep disruption to mental illness, and the development of treatments for sleep disorders. The NIMH sleep portfolio spans the basic and applied neuroscience areas, and includes research program and career development grants.

Freeing Older Adults with Insomnia from Chronic Dependence on Sleep Medications

Older adults suffer disproportionately from chronic insomnia, which is associated with a variety of functional impairments, reduced quality of life, and increased risk for depression. Commonly treated with benzodiazepine (BZD) sleep medications, such individuals frequently exceed the recommended short-term use of these drugs and experience iatrogenic exacerbations of their sleep disturbance, including altered sleep structure, medication tolerance and dependence, withdrawal symptoms, rebound insomnia, and other hypnotic-dependent sleep problems. Once caught in this vicious cycle, patients typically become long-term BZD users and experience great difficulty in discontinuing these medications. Moreover, with prolonged use in older adults, BZD medications tend to lead to or increase the risks of experiencing multiple health-threatening consequences, including impairments in cognitive functioning, falls and fractures, and even mortality. Research is thus needed to identify more effective intervention strategies for helping older adults with chronic insomnia on two interlinked fronts, i.e., how to reduce or discontinue reliance on BZD medications while also alleviating the sleep disturbance that led to hypnotic medication use in the first place.

In a randomized clinical trial, Morin et al. compared the relative effectiveness of a supervised regimen for BZD tapering, cognitive-behavioral therapy (CBT) for insomnia, and the combination of the two. These approaches were tested over a 10-week intervention period in 76 older adult outpatients with chronic insomnia and prolonged BZD use. Follow-up assessments were conducted at 3 and 12 months with respect to changes in levels of BZD use, sleep indices, and symptoms of depression and anxiety. The results showed that all three interventions produced significant reductions in BZD use; patients reduced their overall usage by 90 percent in quantity and 80 percent in frequency, with 63 percent of patients becoming drug-free within an average of 7 weeks. The combined treatment approach was more effective than either component alone in helping patients achieve drug-free status by the end of active treatment, but its degree of superiority fell off considerably at the follow-up points. Meanwhile, CBT, alone or in combination with tapering, was effective in alleviating some aspects of participants' insomnia, though improvements often became obvious only after patients stayed off BZDs for several months. With gradual and structured tapering of the BZDs, however, even the patients assigned to the tapering condition alone experienced few withdrawal symptoms and little rebound insomnia. The study findings document the efficacy of clinical procedures for facilitating BZD discontinuation while also minimizing negative consequences on sleep patterns, and even improving these over time. Future research advances may come from identifying the essential therapeutic components of these or similar procedures.

Morin, C. M., Bastien, C., Guay, B., Radouco-Thomas, M., Leblanc, J., & Vallieres, A. Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. American Journal of Psychiaty 2004;161:332-342.

Progress in Understanding the Relationship of Anxiety and Learning to Sleep

Behavioral and physiological studies support the theory that anxiety interferes with rapid eye movement (REM) sleep and that REM sleep is a very favorable state for the consolidation and integration of memories. Investigators have used the open-field test to test the relationships between sleep, anxiety, and learning in rodents. The open-field test is a well-established tool for the assessment of rodent behavior and induces anxiety-like behaviors in rodents (who naturally avoid open spaces). When rodents are placed in this condition the novelty or "threat" of the open space serves as a stressor, and fear-conditioned mice show decreases in REM sleep after exposure to this fearful cue or context. In contrast, some forms of non-fear learning (such as maze exposure/learning) result in increases in REM sleep post- exposure. Despite these robust findings, however, why and how anxiety and learning are related to sleep remains poorly understood.

In order to determine how anxiety and exploration in the open-field could influence sleep, Tang et al recorded sleep after time in the open-field in strains of mice bred for various levels of anxiety behaviors. All strains of mice showed immediate decreases in REM sleep - consistent with the hypothesis that the open-field is stressful. However, the time course and amount of REM decrease, as well as subsequent increases in REM sleep varied among the strains of mice, with the mice bred to be the most anxious having greater decreases in REM sleep and a longer interval before return to baseline levels of REM sleep. Additionally, greater open-field activity (thought to be indicative of exploratory learning) was positively related to REM increases after time in the open field. Mice bred to be less anxious showed the greatest amount of activity and the greatest increases in REM sleep.

The results suggest that anxiety may induce initial REM suppression and exploratory learning may be associated with REM increase. The relative changes in REM sleep (depending on strain of mice) after time in the open field may result from the interaction between emotionality (i.e., anxious behavior) and learning (i.e., exploration) experiences during wakefulness. Future research should help determine if this is true and should further clarify the nature of the relationships among anxiety, learning and sleep.

Tang, X, Xiao J., Liu X & Sanford L.D. Strain differences in the influence of open field exposure on sleep in mice. Behavioral Brain Research 2004;154:137-147.

Neuropeptide with Arousal-Promoting and Anxiolytic-Like Effects Identified

Sleep and anxiety disorders are significant public health concerns affecting millions of people. Although research has provided clues to the origins of these disorders, the identification of treatment targets continues to pose challenges to investigators. Arousal (i.e., sleep/wake state) regulation involves multiple neurochemical compounds and complex neurocircuitries including neurotransmitters such as noradrenaline, acetycholine, serotonin, glutamate, and GABA and neuropeptides such as hypocretin/orexin and neuropeptide Y. Some of these same circuits and signaling molecules have also been implicated in anxiety disorders, suggesting the existence of some shared brain regulatory components for arousal and anxiety.

While many brain systems regulating arousal and anxiety have been identified, it is likely that additional compounds and systems have yet to be discovered. Novel neurotransmitters or modulators can be found through studies of Orphan G-Protein Coupled Receptors (GPCRs). GPCRs are cloned receptor proteins whose endogenous ligands have not yet been identified. Xu et al describe physiological functions of such a newly de-orphanized GPCR system, neuropeptide S (NPS), and its cognate GPCR. The NPS receptors were localized to several brain regions including a population of neurons that are adjacent to the norepinephrine cells of the locus coeruleus, an area recognized for its role in arousal regulation. Rats injected (icv) with NPS spent more time in wakefulness during the first hour post-NPS injection followed by a rebound in the amount of non-REM sleep in the second hour. In a second study, mice injected icv with NPS displayed increased motor activity (behavioral arousal) independent of novel or stressful conditions. Finally, mice injected with NPS displayed increased exploratory behavior similar to mice injected with known anxiety-reducing compounds. Results revealed that NPS is a novel neuropeptide that potently modulates arousal and possibly sleep-wake behavior. Together, these data show that NPS can promote arousal, might be involved in the induction of wakefulness or suppression of sleep, and may regulate anxiety. Future studies of this neurotransmitter system might further our understanding of sleep disorders and pathological anxiety, facilitate the identification of novel treatment targets, and promote the development of more effective treatments for sleep and anxiety disorders.

Xu Y-L, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher, FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, and Civelli O. Neuropeptide S, a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 2004;43:487-497.

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NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Merrill Mitler, PhD
NINDS Representative to the Trans-NIH Sleep Research Coordinating Committee

The NINDS has a long-standing interest in central nervous system homeostatic mechanisms such as sleep and circadian rhythms. The NINDS supports basic and clinical research on the neuroscience of sleep including studies of fundamental mechanisms of sleep, sleep disorders and associated complications. As listed in this report, NINDS' financial support of extramural sleep disorders research projects totaled almost $25 million in Fiscal Year 2004. Basic and clinical research projects have yielded important homeostatic mechanisms in the brainstem that further our understanding of sleep, certain sleep disorders, and the relationship between sleep and energy balance. The following are some of the most notable scientific advances made by NINDS-funded investigators in Fiscal Year 2004.

The NINDS portfolio includes a number of studies which focus on the central mechanisms involved in the regulation of sleep and wakefulness. One recent study showed that neurons that synthesize melanin-concentrating hormone may modulate arousal and energy homeostasis. NINDS-funded researchers have developed a viral approach for selective long-term reporter gene expression in such neurons, allowing the study of their cellular physiology in hypothalamic slices and showing that neurons containing melanin-concentrating hormone may integrate information within the arousal system in support of energy conservation. A second study provided evidence to suggest that histaminergic neurons promote wakefulness. Histaminergic neurons are found exclusively in the tuberomammillary nucleus (TMN), and electrolytic lesions of the posterior hypothalamus, where the TMN resides, produce intense hypersomnolence, or excessive sleepiness. It is important to determine the limits of histaminergic involvement in wakefulness. Electrolytic lesion studies have demonstrated that extensive loss of histaminergic neurons in this brain region is not critical for spontaneous periods of wakefulness, even though histamine probably has a role in sustaining wakefulness.

The NINDS also supports research on sleep disruption and its consequences. Animal and human studies of sleep and learning have demonstrated that training on various tasks increases subsequent rapid eye movement (REM) sleep, followed by improvement in performance on the learned task. Experiments have demonstrated that experimental activation of a certain REM sleep mechanism, the P-wave, enhances the physiological process of memory. On the other hand, REM sleep deprivation after training blocks the expected performance improvement. NINDS-funded investigators showed that activation of the P-wave generator in rats through the administration of a drug prevented the memory-impairing effects of REM sleep deprivation on learning and memory.

Detailed understanding of circadian timing mechanisms, the body's "clock" on which the sleep-wake cycle depends, is critical for sleep disorders research. Circadian clocks comprise a cyclic series of dynamic cellular states, characterized by the changing availability of substrates that alter clock time when activated. NINDS-supported investigators are trying to determine the molecular signals which are responsible for circadian timing. One recent study showed that chronic inhibition of protein kinase G type II disrupted electrical activity rhythms and tonically increased Bmal1 mRNA, a key component of circadian control mechanisms. Protein kinase G type II activation may define a critical control point for temporal progression into the daytime domain by acting on the positive arm of the transcriptional/translational feedback loop.

When the body's circadian clock is disrupted, sleep disorders such as insomnia may result. One therapeutic approach to insomnia associated with difficulty sleeping through the night is exposure to bright light. It has been shown in animal studies that exposure to brief pulses of bright light can phase shift the circadian pacemaker and that the resetting action of light is most efficient during the first minutes of light exposure. In humans, multiple consecutive days of exposure to brief bright light pulses have been shown to phase shift the circadian pacemaker. NINDS-supported investigators have recently shown that a single sequence of intermittent bright light pulses can delay the human circadian pacemaker and that intermittent pulses have a greater resetting efficacy on a per minute basis than does continuous exposure.

The NINDS portfolio also includes studies to understand sleep disordered breathing (sleep apnea), which can produce intermittent hypoxia on a nightly basis associated with substantial cortico-hippocampal damage leading to impairments of neurocognitive, respiratory and cardiovascular functions. NINDS-supported investigators have developed a mouse model of sleep apnea to study the molecular causes and consequences of the disorder. New findings indicate that the increased production of reactive oxygen species and oxidative stress propagation contribute, at least partially, to the cortical neuronal cell death and neurocognitive dysfunction associated with intermittent hypoxia.

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NATIONAL INSTITUTE OF NURSING RESEARCH
Kathy Mann Koepke, PhD
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

Previous study (Dinges R01NR4281; Sleep 2003;2:117-126) has suggested that it is not the total amount of lost time from sleep, but rather the total time of wakefulness that results in declining concentration and cognitive performance. These investigators have now demonstrated that both acute total and short-term partial sleep deprivation resulted in elevated high-sensitivity C-Reactive Protein concentrations, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity (JAmCollCardiol 2004;43:678-83). Sleep loss may be one of the ways that inflammatory processes are activated and contribute to the association of sleep complaints, short sleep duration, and cardiovascular morbidity observed in epidemiologic surveys.

Parents of newborn babies experience more sleep disruption at night during the postpartum period as compared to the last month of pregnancy. Compared to fathers, with their stable 24-hour sleep patterns over time, mothers had less sleep at night and more sleep during the day after the baby was born, but there was no gender difference in ratings of fatigue (Lee R01NR5345; Biological Research for Nursing 2004;5:311-318).

Often thought to be the result of lifestyle choices, sleep deprivation appears especially common in adolescence. Wake times imposed by school schedules oppose the maturational tendency toward later bedtimes. A recent study suggests that this shift toward later bedtimes may be in part the result of shifting underlying biology rather than behavioral choices (Carskadon R01NR8381; Annals New York Academy of Sciences 2004;1021:276-291).

Sleep Disturbance in the Chronically Ill

Sleep disturbances significantly contribute to the burden of illness in many chronic health conditions. In addition to the effects of pain disturbing sleep, changes in physiologic processes may interfere with normal sleep patterns. For example, Alzheimer's disease, dementia, rheumatoid arthritis, fibromyalgia, AIDS, asthma, and urinary incontinence are all accompanied by sleep disruptions.

In cardiac surgery patients, sleep contributes to both physical functional and emotional well-being following surgery. Almost half of the patients who had cardiac surgery were still reporting sleep disturbances at 8 weeks post surgery, and these sleep disturbances were related to both physical function and emotional well-being (Redeker R01NR8022; Nursing Research 2004;53;154-16). Sleep was most disturbed during the first postoperative week and improved at fourth and eighth postoperative week. Preoperative sleep variables predicted the sleep variance postoperatively; i.e., the presence of sleep disturbance preoperatively predicts the longer maintenance of sleep disturbances during the postoperative period (Redeker R01NR8022; Research in Nursing & Health, 2004, 27, 217-22).

The symptoms of fibromyalgia, a common rheumatic condition in women between the ages of 40 and 60, include fatigue and non-restorative sleep. Women with fibromyalgia had lower pain thresholds, more psychological distress, higher depression scores, and reduced subjective and objective sleep quality when compared to women without fibromyalgia. However, pain, mood, and sleep symptoms are not associated with changes in the enumeration of peripheral lymphocytes or function (i.e., immune response markers) in fibromyalgia (Landis R01NR8136; Brain, Behavior, and Immunity 2004;18:304-313).

Because fatigue and sleep disturbances are common in patients with chronic disorders, it is important to be able to quickly, but accurately measure alertness/fatigue in patients who may be suffering from pain and other discomforts. In a study to assess whether axillary or thoracic skin temperatures could be used to replace the standard rectal temperature measurement of circadian timing, neither axillary and skin temperatures served as an adequate substitute in adult women (Thomas K01NR7649 [last funded in FY03, active in FY04]; Biological Research for Nursing 2004;5:187-194). In contrast, a study of narcoleptic and obstructive sleep apnea patients found pupillometric Alertness Level Test (ALT) scores of sleepiness were consistent with EEG records and self-report measures (Merritt R01NR4959 [last funded in FY 2003, active in Fiscal Year 2004]; International Journal of Psychophysiology 2004;52: 97-112). The ALT is convenient, easily repeatable and less technically demanding than EEG sleepiness measures.

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. For example, one intervention in rural older adults with obstructive sleep apnea seeks to increase adherence to CPAP via self-directed, focus counseling provided via an interactive internet connection (Smith R01NR4828). Another study is evaluating whether melatonin and behavioral techniques are an effective intervention for jet lag that has been found to impair judgment and performance (Eastman R01NR7677). In another, a new nurse investigator is using behavioral treatments to improve sleep in community dwelling elders who frequently experience insomnia secondary to chronic pain (Perlis R21NR9080). An individualized behavioral intervention to promote nighttime sleep by maximizing daytime activity in breast cancer patients undergoing chemotherapy is ongoing (Berger R01NR7762). Similarly, menopausal women are prompted to increase their daily exercise in order to improve nighttime sleep (Davis R01NR8024).

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. Both patients with dementia and their caregivers experience significant sleep deprivation. Researchers are testing innovative strategies (e.g., melatonin, light, nighttime alarm systems [Rowe R42NR4952]) 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 (9 in Fiscal Year 2004), mentored research scientist development awards, and institutional training grants (3 in Fiscal Year 2004) focusing on sleep research. The research foci of these awards include studying the relationships among sleep, hormonal regulation, immune function, and disease (e.g., in estrogen-related disorders and in respiratory infection); the dysregulation of sleep in disease (e.g., in cancer and cancer therapy; in premature infant chronic lung disease; and in heart disease), and perceptions of sleep hygiene and intervention in adults (e.g., sleep intervention in long-haul truckers and perceptions of CPAP in African Americans).

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OFFICE OF RESEARCH ON WOMEN'S HEALTH
Eleanor Hanna, PhD
ORWH Representative to the Trans-NIH Sleep Research Coordinating Committee

The Office of Research on Women's Health (ORWH) supported projects within the National Institute of Mental Health and the National Institute of Nursing Research related to sleep disorders in which sleep disruption is a factor, changes in relevant symptoms across the fluctuating hormonal cycle in women, and changes in relevant symptoms or other basic factors across the natural age span in men and women. Since the ORWH has no direct funding authority; the Institutes to which these dollars have been assigned are noted in the summaries that follow, and funding details can be found in the respective ICs' grant listings.

5R01MH059919-05 Menopausal Depressions: Chronobiological Basis University of California, San Diego, Barbara L Parry (NIMH)

The effects of estradiol and progesterone administration on circadian rhythms in humans will be tested in healthy postmenopausal women. It is hypothesized that estrogen advances the amplitude and synchrony of biological rhythms as measured by melatonin, sleep, and activity and that progesterone antagonizes these effects. This study further extends study of this hypothesis in a controlled design and should yield important information about the possible mechanisms mediating the effects of hormones on mood and behavior

5R01NR004142-07 Nursing Management of IBS: Improving Outcomes University of Washington. Margaret M. Heitkemper (NINR)

The investigator will further test the effectiveness of comprehensive self-management (CSM) treatment for Irritable Bowel Syndrome (IBS) by comparing face-to-face intervention with a telephone version relative to a usual-care group of men and women with IBS. Outcome measures will be HRQOL, GI symptoms, sleep disturbance, psychological distress, and sickness impact. The second aim of the study will be to examine the relationship between GI symptom improvement and decrease in psychological stress using self report measures as well as physiological arousal as measures by catecholamine and cortisol levels in men and women. Results will help define the underlying pathology, the possible effects of sex and gender, and provide information on the potential role of serotonin processing in IBS.

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FINANCIAL REPORT
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE

NIH Sleep Research Funding 1996-2004
(Dollars in thousands)

 
1996
1997
1998
1999
2000
2001
2002
2003
2004
NHLBI
16,450
19,219
22,932
31,845
35,128
37,579
45,155
50,328
53,085
NINDS
9,453
11,598
16,369
15,231
*12,495
17,603
22,918
24,588
24,952
NICHD
7,368
7,217
9,131
7,116
6,797
7,084
7,344
7,367
7,506
NIA
7,800
9,179
11,818
13,296
13,034
14,533
14,600
18,178
16,492
NIMH
27,231
28,601
^34,027
39,219
40,667
50,742
56,647
63,222
59,785
NIDA
1,201
1,042
1,586
2,163
2,553
2,517
3,235
2,988
3,126
NIAAA
551
728
766
736
1,132
1,681
4,342
4,553
4,857
NINR
2,842
3,565
3,394
3,503
4,635
5,375
8,091
11,030
10,025
NCRR
3,247
3,570
5,542
6,637
7,117
7,193
11,490
13,204
14,648
NIAMS
N/A
N/A
N/A
N/A
N/A
N/A
300
248
161
NCCAM
N/A
N/A
N/A
N/A
N/A
177
900
1,121
1,062
NHGRI
N/A
N/A
N/A
N/A
N/A
599
0
0
0
NIBIB
N/A
N/A
N/A
N/A
N/A
N/A
N/A
258
243
NCI
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
**N/A
ORWH
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
**N/A
NIEHS
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
190
NIDCR
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
99
NCMHD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
7
                   
TOTAL
76,143
84,719
102,835
119,746
123,558
145,083
175,022
197,085+
196,239

^ 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

+ 159% increase over 1996

** Grant and funding data not included in NIH FY 2004 sleep total. Please refer to respective narrative sections for details.

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The grant list and funding detail for Fiscal Year 2004 can be viewed online as a separate .pdf document

PDF fileGrants List in PDF [192K]

The complete Trans NIH Report for Fiscal Year 2004, including the complete grand and funding lists and Appendices, can be viewed online as a separate .pdf document
PDF file Complete Trans-NIH Sleep Research Coordinating Committee Report-Fiscal Year 2004

More information on PDF and the required reader is available.

Printed copies of the Grants List and the complete Annual 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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