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 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
Financial Report of the Trans-NIH Sleep Research Coordinating Committee

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 3 to 4 months to discuss ongoing activities in NIH sleep-related programs and to develop new programs. The SRCC membership in Fiscal Year 2003 included the following NIH Institutes and Centers:

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

In addition, the National Center for Research Resources (NCRR) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) each has a sleep-related portfolio 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 a research, advocacy and coordinating center, it is responsible for conducting and supporting research, training, health information dissemination, and other activities related to sleep disorders, and coordinating sleep-related programs with other NIH components, Federal agencies, and public entities. In conjunction with the creation of NCSDR, the Director of NIH transferred responsibility for the Trans-NIH SRCC to the NCSDR. The NCSDR maintains a complete file of annual reports from the initiation of the Committee in 1986.

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

The NCSDR has participated in the planning and conduct of workshops, new initiatives, and public education programs during Fiscal Year 2003. The 2003 National Sleep Disorders Research Plan, the first major revision of the 1996 Sleep Disorders Research Plan, was released by NIH in Fiscal Year 2003 and summarizes the specific sleep research achievements since 1996, identifies present gaps in our knowledge and understanding, and concludes with prioritized recommendations for future research.

New Initiatives Released in Fiscal Year 2003

RFA-HL-03-008: Role of Sleep and Sleep-Disordered Breathing in Metabolic Syndrome ($3.4 Million)
Sponsors: NHLBI; NIA. Release Date: October, 2002

Objectives:
Elucidate the relationship of sleep deprivation and sleep-disordered breathing (SDB) to characteristics of the metabolic syndrome including obesity, high blood pressure, dyslipidemia, insulin resistance, and vascular inflammation. Specific objectives include identifying the pathophysiological mechanisms and genetic risk factors linking sleep deprivation and SDB to these characteristics.

Outcomes:
Twelve grants have been funded under this RFA at over $4 Million total direct costs per year for 4 years. Four applications address sleep and sleep restriction, one is related to polycystic ovary syndrome, and the remaining seven pertain to sleep disordered breathing.

PAS-03-131: Sleep Disturbance in Parkinson's Disease and Parkinson-Like Conditions
Sponsors: NINDS; NHLBI. Release Date: June 2, 2003

Objectives:
To stimulate and support research on sleep disorders in Parkinson's disease (PD) and Parkinson's related neurological conditions (PRNC).

Workshops Conducted in Fiscal Year 2003

Effects of Sleep Disorders and Sleep Restriction on Adherence to Cardiovascular and Other Disease Treatment Regimens (March 11-12, 2003)
Sponsors: NHLBI (NCSDR, Division of Lung Diseases, Division of Epidemiology and Clinical Applications, Division of Heart and Vascular Diseases, Division of Blood Diseases and Resources); NINDS

Outcome:
This workshop resulted in a range of recommended new directions for research required to better understand the pathophysiologic mechanisms underlying the relationship between SDB and cardiovascular diseases and the extent of this association from an epidemiologic perspective. The final report is posted on the NCSDR web site and can be accessed here

Congress on Sleep, Health and Aging (March 30-31, 2003)
Sponsors: National Sleep Foundation (NSF), in cooperation with NIA, NIMH, NCSDR (NHLBI), The Association of American Medical Colleges, Canadian Institutes of Health Research

Outcome:
(1) Reviewed the knowledge base about sleep and its disorders and their impact on health for those with chronic and age-related diseases, and (2) Developed strategies to bridge the gap between science and the bedside.

A conference summary has been published in JAMA: Lamberg L. Illness, Not Age Itself, Most Often the Trigger of Sleep Problems in Older Adults. JAMA 2003;290:319-323.

A four-part series from the Conference is being published in Geriatrics. These articles (Geriatrics vol 59) can be accessed at: http://www.geri.com/geriatrics/

The January, 2004 issue includes an introduction: Meir Kryger, MD, Andrew Monjan, PhD, MPH, Donald Bliwise, PhD, Sonia Ancoli-Israel, PhD. Sleep, Health, and Aging - Bridging the Gap Between Science and Clinical Practice. Geriatrics. 2004;59:24-30.

The February, 2004 issue includes a second article from the conference: Daniel J. Buysse, MD. Insomnia, depression, and aging Assessing sleep and mood interactions in older adults. Geriatrics. 2004;59:47-51. This article can be accessed at: http://www.geri.com/geriatrics/

The third in the series of CME articles is in the March, 2004 issue: Quan SF, Zee P. Evaluating the effects of medical disorders on sleep in the older patient. Geriatrics 2004;59:37-44. This article can be accessed at: http://www.geri.com/geriatrics/

Neuro-Immune Mechanisms and Chronic Fatigue Syndrome (CFS). Will Understanding Central Mechanisms Enhance the Search for the Causes, Consequences, and Treatment of CFS (June 12-13, 2003)
Sponsors: Office of Research on Women's Health; Trans-NIH Working Group for Research on Chronic Fatigue Syndrome (CFS) - (NCSDR/NHLBI is represented on this Working Group)

Outcome:
(1) Elucidated the scientific understanding of CFS by examining the interface between the brain, immune system, and symptoms of CFS and related disorders. (2) Explored the mechanisms by which hormones, cytokines, and other mediators act as intermediaries between the brain and other body systems. (3) Explored how new methodologies used in the study of these mediators and their central and peripheral actions could be applied to CFS and related disorders. A final workshop report is in preparation.

Revision Of Sleep Disorders Research Plan

The scope of the original National Sleep Disorders Research Plan released by NIH in1996 included basic research, clinical epidemiology, genetics, and effects and cost of treatment related to sleep disorders. The 1996 Plan also addressed training needs for the field of sleep medicine, and provided direction for public health education and intervention programs related to sleep and sleep disorders. Implementation of recommendations from this 1996 Plan led to substantial growth in sleep research funding by NIH, from $76.1 million in Fiscal Year 1996 to $197.1 million in Fiscal Year 2003, representing a 159% increase.

The 2003 National Sleep Disorders Research Plan summarizes the dramatic advances in knowledge since 1996, identifies current gaps in our knowledge base, and provides a broad range of recommendations. The recommendations for future research are intended to not only guide prioritization of future sleep research within NIH and other Federal and non-Federal entities, but also to be helpful in identifying opportunities for new investigators from an ever-increasing diversity of scientific and clinical disciplines. The recommendations regarding training of sleep research scientists, the education of health care professionals, and community-based public education programs 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 2003 Activities

National Children's Study:
The NCSDR continues to participate in protocol development for this proposed study of 100,000 children age 0-21. Additional information about this study is available on-line at http://nationalchildrensstudy.gov/ A core set of sleep-related data has been proposed that should be collected in all enrolled mother-child pairs.

Sleep Apnea and Cardiovascular Disease:
- American Heart Association Council on High Blood Pressure, Professional & Public Education Committee
- Scientific Statement in preparation

NHLBI Long Term Plan for Research & Translation in Hypertension for Enhancing Public Health:
- This Plan is in the final draft stage, and includes a new section on "Sleep Problems"

NHLBI Working Group Report on High Blood Pressure in Children & Adolescents:
- This Report is in the final draft stage, and includes for the first time specific content related to sleep problems and sleep disorders in children

Future Conferences Planned

2004
Frontiers of Knowledge in Sleep and Sleep Disorders: Opportunities for Improving Health and Quality of Life (March 29-30, 2004):
NIH, in collaboration with co-sponsoring organizations, will assemble health care providers, public health and education experts, policy makers, patient advocacy organizations, and sleep medicine specialists from across the country to develop an innovative and interactive action plan to improve public health and overall quality of life. The key questions to be addressed at this conference will be "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.

2005
State of the Science Conference - Chronic Insomnia: Manifestations and Management:
The planning is being coordinated by NIH's Office of Medical Applications and Research (OMAR). The Consensus Panel will be chaired by Dr. Alan I. Leshner, CEO, AAAS, and formerly Director, NIDA

Lead Institute: NIMH. Co- Sponsors: NHLBI ; NCSDR, NIA, NIDA, NINR, NIAAA, NINDS, ORW, VA, FDA; FRA (DOT)

The key questions to be addressed are:
- What defines chronic insomnia and what is its morbidity and natural history?
- What is the extent and magnitude of the public health burden associated with chronic insomnia?
- Who is at risk and should be treated for chronic insomnia?
- What are the benefits and harmful effects of available treatments alone or in combination?
- What are important future directions for insomnia-related research?

Publications

Quan SF, Gersh BJ. Cardiovascular Consequences of Sleep-Disordered Breathing--Past, Present and Future: Report of a Workshop from the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute. Circulation 2004;109:951-957.

Golden A, Twery M, Hunt CE. National Center on Sleep Disorders Research. Sleep Medicine 5 (2004) 83-85.

Hunt CE. Medical and public health impact of sleep problems. Sleep and Biol Rhythms 2004;2:62-63.

Hunt CE. Recent progress in sleep research: Biological, clinical and public health impact. Sleep and Biol Rhythms 2004;2:9-10.

Working Group on Sleepiness in Adolescence/Young Adults. Excessive sleepiness in adolescents. Pediatrics, in press.

Hunt CE, Buysse DJ, Germain A, Hall M, Landis, CA, Lee KA, Mignot E, Phillips B. Sleep Problems and Sleep Disorders in Women, in Clinical Updates in Women's Health Care, ed. by M Stenchever, American College of Obstetrics and Gynecologists. Vol. III, No. 2, April, 2004.

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 2003, 46% of these public inquiries to NCSDR were received and answered by e-mail. Public contacts received and responded to during Fiscal Year 2003 by primary symptom identified are summarized as follows:

Snoring/Breathing/Apnea	127
Insomnia	72
Narcolepsy	36
Parasomnias	49
Restless Legs Syndrome	37
General Sleep Problem or General Information	273
TOTAL-NCSDR	594

Media Contacts:

NCSDR also has extensive media contacts from newspapers, professional and lay publications, radio, the Internet and television that are coordinated by the Press Office [NHLBI, Office of the Director (OD)]. The Health Information Network [NHLBI, Office of Prevention, Education and Control (OPEC)] also coordinates media campaigns and activities regarding sleep information. These communications are summarized in the following sections.

Office of Prevention, Education, and Control

Fiscal Year 2003 was a busy year for media coverage of the "Sleep Well. Do Well. Star Sleeper Campaign" with Garfield as the NCSDR "spokescat" for healthy sleep among children. A school assembly and press conference in January, 2003 resulted in print media coverage in 22 newspapers across the country, including the Wall Street Journal, Los Angeles Times, Washington Post, Philadelphia Inquirer, Associated Press Newswires, and the Miami Herald. There was also coverage by 13 online news services, including CNN.com, CBS News, and AP Online.

The Garfield program was also highlighted in 45 TV news programs across the country including Fox News Live, ABC 7 News, and local coverage in Boston, New York City, San Francisco, Washington DC, Detroit, and Chicago.

A feature article released at the time of the 2003 "Back to School" public education campaign for children in September, 2003 was distributed to 10,000 small and medium daily and weekly newspapers across the country. This feature article ran in over 350 newspapers in 31 different states with a total readership of approximately 18 million.

Press Office (NHLBI)

A total of 153 media inquiries related to sleep problems and sleep disorders were received in Fiscal Year 2003. These include the following general types of requests and primary responses from the Press Office and NCSDR:

Background and other resource information provided	65
Unable to provide requested information, or not relevant to NCSDR	11
Request forwarded to extramural sleep expert	19
NCSDR telephone interviews	52
NCSDR taped or live interviews for TV or Radio	6
TOTAL-Press Office	153

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ACTIVITIES OF TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE MEMBER INSTITUTES

Scientific Research and Initiatives

The NHLBI sleep research program covers a wide spectrum ranging from neuroscience, genetics, and circadian rhythm to anatomy, physiology, behavioral science, epidemiology, clinical research, and health education. The program is aimed at understanding the molecular, genetic, and physiological regulation of sleep and the relationship of sleep disorders to cardiopulmonary disease. NHLBI is a major supporter of investigator-initiated sleep research at NIH. The Institute initiated requests for applications (RFA) on the Interrelationship Between Sleep and Heart, Lung, and Blood Diseases (RFA HL-01-009) and the Role of Sleep and Sleep-Disordered Breathing in Metabolic Syndrome (RFA HL-03-008). 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).

The Program on Genomic Applications for Heart, Lung, and Blood Research (HL-99-024) is identifying new animal models of sleep disorders, training sleep researchers in functional genomic approaches, and collaborating with sleep researchers in new studies of sleep disorder genetic epidemiology. An Innovative Research Grant Program (RFA HL-03-015) and a program for Ancillary Pharmacogenetics Studies in Heart, Lung, Blood, and Sleep Disorders (RFA HL-03-001) encourage the addition of sleep research questions to ongoing investigations of heart, lung, and blood diseases. A new initiative to be awarded in Fiscal Year 2004 on the Inter-Relationships of Sleep, Fatigue, and HIV/AIDS (RFA HL-04-01) invites new proposals to study the etiology of sleep disturbances and fatigue associated with human immunodeficiency virus (HIV) infection and improve our fundamental understanding of the relationship between sleep and chronic infections.

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.

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 has started to investigate the significance of sleep disorders as a risk factor for decline in cognition, impaired physical functioning, morbidity, and mortality in men. This investigation complements a similar NIH study of women already underway. 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.

New findings in the NHLBI sleep program in Fiscal Year 2003 are highlighted by findings related to the epidemiology of sleep disordered breathing (SDB) and risks for cardiovascular disease, and the effects of SDB on children.

SDB Diagnosis and Treatment

Sleep disordered breathing has been associated with an increased risk of cardiovascular disease. New findings from a community-based study of 1,037 adults in the SHHS indicate that one link between SDB and cardiovascular disease may involve abnormal blood vessel function. The data suggest that, based on arterial diameter and arterial response to blood flow, vascular health decreases as SDB severity increases; this decrease is independent of other cardiovascular risk factors such as obesity. The cause for this vascular abnormality in SDB patients is not well understood. Decreases in blood oxygen during SDB (intermittent hypoxia) stimulates the nervous system to constrict blood vessels, and increases the circulating level of adhesion molecules, reactive oxygen species, and other factors that have been associated with changes in blood vessel structure and vascular disease in other studies.

New findings also indicate that the effects of SDB on cardiovascular health may be difficult to recognize. An analysis of medical disorders, symptoms of sleep disorders, and cardiovascular risk factors gathered from 15,699 individuals in 5 communities suggests that SDB is widely under-diagnosed in the U.S. The prevalence of primary symptoms (frequent snoring and daytime sleepiness) is estimated to be 3 times higher than the number of patients reporting a physician diagnosis of SDB and 7 times higher than the number of patients diagnosed and treated for SDB. Men with clinical symptoms are twice as likely as women to be diagnosed and 5 times more likely to be treated. The significance of gender bias in the diagnosis of SDB is underscored by a five year study that found women to have a 2 fold greater risk than men of more severe SDB at follow-up. The overall five year incidence of new SDB cases (men and women) was 8%. The findings suggest that research is needed to identify the thresholds of SDB severity at which treatment will reduce cardiovascular morbidity, and to eliminate gender bias in primary care strategies for SDB detection.

Future strategies to diagnose and treatment SDB may be enhanced by understanding the relative contribution of genetic and environmental factors in the development of this disorder. A new community-based analysis has found that SDB tends to occur within family groups and in individuals carrying genetic risk factors for obesity. The findings suggest that the interrelationship of OSA and obesity may be partially explained by one or more genes that contribute to the risk of both diseases. The nature of this inter-relationship is not well understood. While obesity is a risk factor for SDB, the sleep disturbance associated with SDB may also contribute to the risk of obesity through impaired metabolism, and reduced physical activity. Psychobiological factors may also play a role in successful treatment of SDB. A study of patient adherence to CPAP therapy recommendations suggests that those who were least vigilant at baseline were more likely to comply with treatment and experience greater improvements in attention, psychomotor speed, executive functioning and nonverbal delayed recall.

Sleep Disordered Breathing in Children

Adequate sleep is essential for health and survival, but the etiology of sleep disorders and the benefits of treatment are not well understood. Inadequate sleep and unhealthy sleep practices are common, especially among adolescents and young adults. Recent population-based findings indicate that the prevalence of SDB is 2-5% among children ages 8 to 11 years old. SDB is 4-6 times more likely in black children compared with white children, and 3 to 5 times more likely in children who were preterm. There may thus be opportunities for anticipatory screening of SDB in children who are otherwise at high risk for developmental delays and who may be more vulnerable to the adverse effects of SDB if left untreated. Obesity may also be a risk factor for SDB in children but this risk appears smaller than that associated with preterm birth status and race. Limited data are available on the health outcomes associated with SDB in children. Problems with attention are a frequent presenting symptom in children with SDB but the etiology of this relationship is not well understood. New findings from a prospective study of SDB in 149 children ages 6 to 12 years indicate that SDB increases the overall time spent in the shallower stages of sleep and impairs cognitive function. The results link sleep disturbance associated with SDB to impaired learning and memory, and low blood oxygen associated with SDB to decreased nonverbal skills. Extrapolating from data in adults, CPAP therapy may be able to at least partially reverse the adverse cognitive effects of SDB, but further research is needed to determine what approaches might be most beneficial.

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

Significance of Program Activity

More than half of all people aged 65 and older experience sleep problems. Insomnia affects approximately one-third of older Americans and can result in excessive daytime sleepiness, attention and memory problems, depressed mood, falls, and a lower quality of life. Other factors associated with aging may also contribute to sleep problems. These include disease, changes in environment, or concurrent age-related processes. However, the old dogma that poor sleep is a natural part of aging has been disproved. Data indicate that age itself does not predict insomnia, even in the presence of a decrease in sleep efficiency and decreased proportion of slow-wave sleep. Rather, the prevalence of insomnia and other sleep disorders is high in the population due to a variety of factors common in late life.

Program Activities

Program growth in the NIA Sleep portfolio increased to $18.1 million in Fiscal Year 2003 from $14.6 million in Fiscal Year 2002. NIA is represented on the Trans-NIH Sleep Research Coordinating Committee and the Sleep Disorders Research Advisory Board of the National Center on Sleep Disorders Research, NHLBI, and participated in the revision of the 1996 National Sleep Disorders Research Plan. NIA collaborated 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" will include a series of four issues starting in January 2004 based upon presentations from this meeting (see page 3 for references). In conjunction with this meeting, the NSF conducted a national survey of sleep in older adults. NIA staff also were represented at a "Sleep, Health and Longevity Workshop" sponsored by the International Longevity Center-USA on October 3-6, 2002. A report of this workshop is pending.

Research Advances

- Sleep-Disordered Breathing

Sleep Disordered Breathing (SDB) encompasses obstructive sleep apnea, hypopnea (shallow breaths), and upper airway resistance syndrome. Patients with obstructive sleep apnea (OSA) or hypopnea may have frequent and repetitive episodes of oxygen desaturation, and all SDB patients have frequent arousals from sleep and resultant sleep deprivation. The clinical symptoms include loud snoring and excessive daytime sleepiness. The intermittent hypoxemia and episodes of brain activation (arousal) are associated with abrupt increases in systemic blood pressure, and SDB patients do not demonstrate the expected nocturnal dip in blood pressure. It has been observed that older African-Americans (AA) have at least a two-fold greater risk of clinically undiagnosed SDB than do Caucasians (C), independent of age, gender, or body mass index (BMI). The prevalence of hypertension, which is higher in AA than C, is associated with SDB, and severe SDB is associated with a significant increase in cardiovascular events. For many older individuals with hypertension, blood pressure does not fall (dip) the expected amount at night. This non-dipping is more frequent in AA than C, and cannot be explained by BMI, gender, mean arterial blood pressure, or SDB. Thus non-dipping specifically was not a result of SDB, but independently related to race. In both races, however, non-dipping was most likely in those older individuals with SDB and hypertension, and the SDB was significantly more likely to be severe among AA with hypertension. These results suggest that AA who are hypertensive and who are non-dippers should be screened for SDB.

The most important risk factor for SDB is overweight and obesity, suggesting that its incidence is likely to increase dramatically with the continuing epidemic of overweight and obesity. The association is well established in clinic populations and every population-based study conducted to date has shown strong correlations of any measure of increased body mass with SDB. A recent prospective study from the Wisconsin Sleep Cohort documented the role of weight gain in increasing incidence and progression of SDB, and the role of weight loss in slowing progression. Previous studies of weight loss and SDB have been in samples of morbidly obese patients; the importance of this study lies in demonstrating that even modest body weight changes affect SDB, and the findings offer hope for prevention and reduction of SDB. For chronic diseases (not immediately fatal and with no "cure"), prevalence escalates with aging. The most effective treatment for SDB (continuous positive air pressure or CPAP) is palliative and not curative. Consequently, we can expect the high prevalence of SDB in middle-aged populations to increase in later life unless it directly contributes to higher mortality. Many studies indeed suggest that prevalence is very high in people ages 65 and older, but interestingly there does not appear to be a distinct linear increase after that.

The breathing pauses of SDB clearly cause acute cardiovascular abnormalities; the uncertainty lies only in whether these events cause sustained, chronic disease. Apnea and hypopnea episodes during sleep cause acute, transient blood pressure perturbations, inducing elevations of 30 mmHg or more in mean arterial pressure, fluctuations in heart rate and rhythm, increased sympathetic nerve activity, arousal and sleep fragmentation, and swings in intrathoracic pressure. Several cross-sectional and one prospective population-based study have reported positive associations between polysomnographically-assessed number of apneas (breathing cessation for at least 10 seconds) and hypopneas, or decrease in blood oxygen by at least 4 percent per hour (the apnea/hypopnea index, AHI) and hypertension while controlling for multiple potential confounding variables including, minimally, age, sex and BMI. A study in Spain (n=455) showed that subjects with an AHI of less than 5 events/hour but more than zero had an increased odds of hypertension (odds ratio=2.5) compared to those with an AHI of zero. The Sleep Heart Health Study (SHHS) reported odds ratios of 1.2, 1.3, and 1.4 for AHI categories of 5 - 15, 15 - 30, and >30, respectively, vs. AHI <1.5.

While these studies have had compatible results, because of their cross-sectional design, none has been able to demonstrate that SDB pre-dated hypertension. This issue was addressed in a prospective analysis from the Wisconsin Sleep Cohort. Even minimally elevated AHI at baseline was associated with a 42% increased odds of developing hypertension over a 4-year period. A dose-response relation was observed, with an odds ratio of 2.9 for AHI>15 vs. AHI=0 events/hour.

Thus far, a population-based prospective study of SDB and incident cardiovascular disease has not been reported. However, several clinic-based studies and a cross-sectional analysis of self-reported cardiovascular disease in the SHHS support a significant association. In the SHHS, those in the upper quartile of AHI (>11.0 events/hour) had a 42% (95% CI: 13 to 78%) greater odds of prevalent CVD (including coronary heart disease, stroke, and congestive heart failure) compared with participants in the lowest quartile (AHI<1.3 events/hour), after adjusting for multiple potential confounders. Additional analyses examining the association of SDB and CVD along the entire spectrum of SDB severity suggested that most of the elevation in risk of CVD occurs as the AHI rises from 0 to10 events/hour. The analysis included adjustment for hypertension, suggesting that hypertension is not the only mechanism by which the risk of cardiovascular sequelae is heightened in persons with SDB. The SHHS found a stronger association between stroke and SDB than between total CVD and SDB; the odds ratio of prevalent stroke in persons in the upper SDB quartile compared to those in the lowest quartile, adjusted for several possible confounding factors was 1.58 (95% CI: 1.02 to 2.46).

SDB has been linked with considerable behavioral morbidity (including excessive daytime sleepiness, decreased cognitive function, motor vehicle accidents, depression) and decreased quality of life. Excessive daytime sleepiness is a cardinal feature of clinically recognized SDB. Clinic patients are unrepresentative of subjects with elevated AHI in the general population, as asymptomatic individuals are less likely to be evaluated for the presence of SDB than are those who complain of sleepiness. However, in the Wisconsin Sleep Cohort, 23% of women and 16% of men with AHI 5 reported frequent occurrence of 3 manifestations of sleepiness compared with only 10% of women and 3% of men with AHI<5. In the SHHS, there was a significant, progressive increase in Epworth Sleepiness Scale (ESS) score with increasing AHI, from a mean of 7.2 in subjects with AHI<5 to 9.3 in subjects with AHI 30. The percentage of subjects with excessive sleepiness, defined as an ESS score 11, increased from 21% in subjects with AHI<5 to 35% in those with AHI 30.

Population-based studies of the effect of SDB on cognitive function are few and the existing findings are somewhat weaker than results from clinic-based studies. This is not surprising because of selective referral In the Wisconsin Sleep Cohort Study AHI was significantly but weakly related to diminished psychomotor efficiency, a factor reflecting the coordination of fine motor control with sustained attention and concentration. SDB was not related to the memory factor. Extrapolating the regression findings, the effect of an increase in AHI of 15 was approximately equivalent to the effect of 5 years of aging on psychomotor function. Weak but significant associations of SDB and neuropsychological function were also found in a study of 100 self-reported snorers recruited from public advertisements and clinic referrals, screened to exclude comorbidity related to cognitive function. In a study to assess the association between sleep-disordered breathing and cognitive functioning in an elderly cohort of Japanese-American men between 79 and 97 years of age, less than 30% of the men had no sleep-disordered breathing (AHI < 5) and nearly one-fifth (19%) had severe sleep-disordered breathing (AHI > or = 30). Severe sleep-disordered breathing was associated with higher body mass index, habitual snoring, and daytime drowsiness, but no association was found between sleep-disordered breathing and cognitive functioning, including measures of memory function, concentration, and attention.

- Insomnia

Insomnia is a subjective complaint of insufficient or non-restorative sleep, which can generally be divided into two different types of complaints depending upon the duration of the sleep difficulty. Insomnia may be either short-term (transient/acute) or chronic. In the elderly, transient insomnia may be caused by bereavement, adjustment to medical difficulties and physical limitations. Transient insomnia will generally improve without intervention or with short-term hypnotic medication. Chronic insomnia, however, can have serious impact on daily functioning and can result in impaired functioning and reduced quality of life in older adults. Telephone interviews in 1,000 randomly selected U.S. adults revealed that the prevalence of occasional insomnia did not change with age; however, the prevalence of chronic insomnia was highest (20%) in adults age 65 and over. This suggests that, although occasional sleep complaints may not be associated with age, older adults experience chronic sleep difficulties more often than younger adults. A similar poll of 1500 older Americans (aged 55+) found that 67% reported trouble sleeping and that only 1 in 8 had discussed these problems with their physicians.

While there is agreement that total sleep loss is harmful to our health, the field of sleep research is not unanimous in whether small decreases of the sleep period have an effect on the human brain and body. Some researchers divide sleep into "core sleep" which is the slow wave sleep and "optional" or "buffer" sleep that consists of stage 2 sleep and some REM sleep. Furthermore, recently published epidemiological studies have suggested that insomnia, paradoxically, is associated with prolonged life.

Insomnia appears not only to affect mental health, since it is a significant risk factor for depression, but also to be associated with physical problems such as hypertension. The increasing prevalence of insomnia in midlife (ages 40-50 years) appears to some extent to be secondary to weakening sleep mechanisms such as loss of slow wave sleep associated with the aging process. Furthermore, insomnia appears to be associated with hypercortisolemia and a daytime shift of IL-6 and TNFa secretory patterns, conditions that may lead to multiple health problems including visceral obesity, insulin resistance, hypertension, and osteoporosis that, in turn, may affect longevity.

Insomnia in older adults is not benign. Cross-sectional and longitudinal studies have shown that insomnia has a negative impact on cognitive functioning and quality of life. Insomnia patients were found to have slower reaction time, poorer balance, and were more likely to forget numbers in the digit span test than carefully matched controls. Furthermore, these deficits were seen even after the insomnia patients spontaneously experienced a subjectively good night of sleep. Individuals with insomnia complaints were found to have overall poorer quality of life than individuals without insomnia and individuals with insomnia had more symptoms of depression and anxiety. It is, therefore, unclear whether depression and anxiety lead to both sleep disturbance and impaired life quality, or whether the sleep disruption leads to the impaired quality of life and psychiatric difficulties. However, few studies have addressed the effect of insomnia on quality of life in older adults. In one of the few such studies, older adults with secondary insomnia had worse quality of life than those with primary insomnia, while another study examined poor sleep in older adults and found that poor sleepers reported more difficulty functioning during the day and experienced more tension and depression. In a cohort of non-depressed and non-demented older adults, self-reported excessive daytime sleepiness was associated with moderate impairments in daily functions, such as housework, sports, and general activity levels.

Self-reported sleep problems tend to be lower amongst African-Americans (AA) than Caucasian (C) groups. This has been found previously in a large AA cohort developed within the five counties in the North Central Piedmont of North Carolina. The largest differences were in waking during the night; the prevalence of wakeful sleep among AA was only 60 percent that of the C. Similar results were found in a biracial community study in Brooklyn, New York, although the prevalence rates for each race were higher in Brooklyn than in North Carolina. Further analysis of this population for within- ethnic group differences showed that English-speaking Caribbean-born AA reported fewer sleep complaints than did U.S.-born AA, and Haitian-born AA were intermediate between these two groups..

Analysis of data from the Studies of Women Across the Nation (SWAN) indicates an association between psychological distress and natural menopause in a community sample of African American, White, Chinese, Hispanic, and Japanese women aged 40 to 55. Psychological distress was defined as feeling tense, depressed, and irritable in the previous 2 weeks, and was highest in early peri-menopause (28.9%) and lowest in pre-menopause (20.9%) and post menopause (22%). In comparison with pre-menopausal women, early peri-menopausal women were at a greater risk of distress, with and without adjustment for vasomotor and sleep symptoms and covariates. Complaints of difficulty sleeping were more frequent among the White women than in the other groups, and likelihood of psychological distress was significantly higher for Whites than for the other racial/ethnic groups. More recent cross-sectional analyses of the SWAN data indicate that difficulty sleeping was reported overall by 38% of the women, but that the age-adjusted rates were highest amongst the peri-menopausal (45.4%) and surgically menopausal (47.6%) groups.

Restless Legs Syndrome (RLS) is a sensori-motor disorder characterized by an unremitting urge to move the legs during periods of rest, especially during bed time that interferes with sleep onset and disrupts sleep. It is estimated to occur in 10% of adults, increasing in prevalence with increasing age. A workshop was held in May, 2002, to evaluate the diagnostic and epidemiological criteria for RLS and to develop standardized criteria for diagnosis in cognitively impaired elders. A report of this meeting and these new diagnostic criteria has been published (see NCSDR web site). Clinical interventions for RLS have focused upon dopaminergic agonist therapies. However, it appears that RLS patients have an underlying deficiency in serum and cerebrospinal fluid (CSF) ferritin levels resulting in a problem of iron utilization. Dopamine synaptic integrity is dependent upon Thy-l, a glycoprotein that is expressed on T-cells and highly expressed in the brain. Thy-1 mRNA is modulated by iron, and Thy-1 protein levels are markedly decreased in RLS brains. Neuropathological examination of brains from RLS patients revealed no histopathological abnormalities, but did show that iron, ferritin, and transferrin receptor staining all were markedly decreased in substania nigra cells, while transferrin staining was increased and tyrosine hydroxylase was present at normal levels, suggesting that RLS may be a functional disorder of iron processing in these neuromelanin cells that impairs the dopaminergic system.

Although many older adults, unfortunately, see poor sleep quality as a part of normal aging this is likely not the case. Although sleep does change across the life span, complaints about sleep by older adults should not be discounted. The underlying causes of sleep complaints may be risk factors for other health complications. The effects of poor sleep on quality of life should not be ignored. Sleep and Cognition

Cross-sectional and longitudinal studies have shown that disturbed sleep has a negative impact on cognitive functioning and quality of life. The Established Populations for Epidemiologic Studies of the Elderly (EPESE) data set examines whether self-reported symptoms of insomnia independently increase risk of cognitive decline in older adults. Among non-depressed men, those reporting symptoms of chronic insomnia had an adjusted odds ratio (OR) of 1.49 (95% CI = 1.03-2.14) for cognitive decline relative to those with no insomnia. Men with incident insomnia were not at increased risk (OR = 1.16, 95% CI = 0.82-1.65). These relationships were not found in women. Therefore, while chronic insomnia independently predicted incident cognitive decline in older men, no associations between insomnia and cognitive decline were found in women.

There is a large and increasing research literature on the cognitive deficits associated with sleep disordered breathing (SDB). Cross-sectional studies of normal populations have typically found small or no relationship between SDB and cognitive functioning; in a Sleep Heart Health Study sub-study in which participants were generally older adults and many had SDB, deficits in attention, manual dexterity, psychomotor efficiency, and executive functioning were found. However, in the Honolulu-Asia Aging Study of Sleep Apnea, where 70% of the men had SDB (AHI 5 or more) and nearly one-fifth (19%) had severe sleep-disordered breathing (AHI 30 or more), severe SDB was associated with higher body mass index, habitual snoring, and daytime drowsiness. No association was found between SDB and cognitive functioning, including measures of memory function, concentration, and attention on standardized cognitive tests used to screen for Alzheimer disease and other dementias. Because a healthy-participant effect may have contributed to this finding, more extensive cognitive testing may be necessary to reveal more subtle deficits resulting from sleep-disordered breathing

The molecular processes underlying the role of sleep in consolidating long-term memory are being examined using specific phosphorylated cAMP-responsive element binding protein (CREB)-mutant mice. Like sleep deprivation, inhibition of protein kinase A (PKA) or protein synthesis disrupts memory consolidation only at discrete times following training and these times vary depending upon the strength of the training protocol. Total sleep deprivation in mice from 0-5 hours, but not 5-10 hours, after training impairs retention of contextual fear conditioning (in which an animal learns to fear a new environment), a hippocampus-dependent task when tested at 24 hours or 12 days after training. This does not occur with retention of cued-fear training (when an animal learns an association between a cue, such as a tone, and a shock), a hippocampus-independent but amygdala-dependent task. Levels of cAMP response element (CRE)-mediated transcription oscillate in the SCN in a circadian fashion; CREB levels within forebrain are higher in waking than in sleep. CREB ") mutant mice (lacking the " and ) isoforms of CREB) had increased levels of sleep parameters (NREM, REM, total sleep time, less time awake) and normal circadian period than wild type, indicating that CREB protein contributes to the mechanisms by which wakefulness is maintained. CREB mutants also do not have the induction of CRE-mediated gene expression in the hippocampus following sleep deprivation, indicating the critical role played by CREB in its induction following sleep deprivation. Protein-dependent processes are necessary components of the incorporation of memories into long-term storage. Thus sleep may preferentially affect hippocampus-dependent and not amygdala-dependent memory consolidation, in a fashion similar to that of the PKA signaling pathway that is crucial for long-term memory storage.

Changes in Sleep and Circadian Rhythms with Age

Aging is characterized by changes in both sleep and circadian rhythms. Complaints of non-specific sleep disturbances and awakenings during the night, daytime sleepiness, and the use of hypnotic medications increase significantly with age. Several factors have been implicated to produce sleep fragmentation in the elderly, including sleep disorders, compensation for lost sleep, and increased total time in bed, lack of social constraints and disruption of the circadian system. Sleep disorders such as sleep disordered breathing, restless legs, and periodic limb movement disorder increase in prevalence with age. Increasing evidence also suggests that medical conditions such as diabetes, nocturia, cardiovascular disease, respiratory disorders and chronic pain contribute to poor sleep in the elderly.

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. 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 model that sleep is required for the restoration of brain energy metabolism, levels of brain glycogen decreased significantly by about 40% in brains of rats deprived of sleep for 12 or 24 hr while recovery sleep of 15 hr duration after 12 hr sleep deprivation reversed the decreases in glycogen. The glycogen was found to be concentrated in white matter (predominantly localized to GFAP-positive astrocytes), but also found in gray matter. No changes specifically related to sleep deprivation was 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. Thus, changes in adenosine with sleep deprivation are not a consequence of alterations in adenosine enzyme activity. 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.

With age, circadian rhythms are advanced or shifted earlier relative to clock time. This can result in the internally driven sleep period moving earlier than the desired sleep period. Older adults commonly report that they can hardly stay awake until bedtime, but are awake before the sun rises in the morning. The fact that older adults are likely to complain of sleep difficulties in the latter half of the night suggests that the endogenous timing of the sleep/wake cycle may contribute to the sleep difficulties. The relationship between sleep timing and the timing of the circadian rhythm of plasma melatonin secretion was investigated in a group of healthy young and older subjects without sleep complaints. The timing of sleep and the phase of the circadian melatonin rhythm were earlier in the older subjects, although the duration of sleep was similar. Consequently, the older subjects were waking at a time when they had higher relative melatonin levels, in contrast with younger subjects, whose melatonin levels were relatively lower by wake time. This cannot be explained by a shortening of the circadian period, since it has been reported that the free running period of young and very health elderly subjects did not differ (24 hr 11 min) and that circadian rhythm amplitude can be well preserved in the "super healthy" older person. However, while the relationship between the circadian period and wake time is significantly correlated in younger healthy persons, this relationship is absent in healthy older adults. These findings indicate that aging is associated not only with an advance of sleep timing and the timing of circadian rhythms but also with a change in the internal phase relationship between the sleep-wake cycle and the output of the circadian pacemaker.

At the cellular and molecular level, it has been shown that there are age-associated changes in afferent and efferent pathways of the suprachiasmatic nucleus (SCN), the biological clock that controls the circadian patterning of many neural, endocrine, and behavioral functions. The clock mechanism of the SCN depends upon several genes and their associated protein products that work together through a transcriptional and translational feedback loop to circadian signal. The first mammalian clock gene (the Clock gene of mice) was been identified and cloned in 1994. It recently has been reported that the encoded factor CLOCK and another factor BMAL1 are two members of bHLH-PAS-containing family of transcription factors that represent the positive elements of circadian autoregulatory feedback loop that activate transcription of other circadian rhythm genes, period (per) and cryptochrome (CRY) that code other circadian proteins. Age alters the 24-h expression profile of CLOCK and its binding partner BMAL1 in the hamster SCN, but there is no effect of age on the 24-h profile of either Per1 or Per2 proteins when hamsters are housed in constant darkness. Light pulses, which induce smaller phase shifts in old animals than in young, lead to decreased induction of Per1, but not of Per2, in the SCN of old hamsters. The only difference between SCN rhythmicity in young and old rats is a small but significant age-related shortening of the free-running period.

Circadian rhythmicity is not limited to the SCN, but also is found in other tissues, such as the liver. To investigate the organization of a mammalian circadian system, a transgenic rat line was constructed in which luciferase was rhythmically expressed under the control of the mouse Per1 promoter. Light emission from cultured suprachiasmatic nuclei (SCN) of these rats was invariably and robustly rhythmic and persisted for up to 32 days in vitro. Liver, lung, and skeletal muscle also expressed circadian rhythms, which damped after two to seven cycles in vitro. Circadian rhythmicity in some peripheral tissues was unaffected by aging, whereas rhythmicity in other tissues was either phase advanced relative to the light cycle or absent. Those tissues that were arrhythmic could be induced to oscillate by application of forskolin, a compound that activates cyclic adenosine monophosphate (cAMP) activity independent of the membrane receptors, suggesting that they retained the capacity to oscillate but were not being appropriately driven in vivo. Aging seems to affect rhythms in some but not in all tissues and may act primarily on interactions among circadian oscillators, perhaps attenuating the ability of the SCN to drive damped oscillators in the periphery.

Using Drosophila, it has been established that a null mutation (cyc01) in a clock gene, cycle, as well as for the Jerk mutant of Clock, is related to a deficient rest phenotype; rest was specifically and significantly reduced without marked effects on locomotor activity. That is, the animals were not generally hyperactive but rested less while having normal or slightly decreased locomotor activity. In preliminary microarray studies, the cycle mutants had reduced ability to respond to oxidative stress (a normal response in sleep-deprived flies), and were significantly short-lived compared to their wild type background, suggesting that a mechanism links sleep abnormalities and shortened lifespan. Similarly, it was found that modafinil, a drug that reduces rest, also leads to early mortality. Long-lived methuselah flies did not show the same decrease in sleep rebound after deprivation with age that is seen in wild type flies, suggesting that long-lived mutants may have abnormally robust homeostatic mechanisms.

Future Directions

The NIA, in conjunction with the Trans-NIH Sleep Research Coordinating Committee, is developing a national sleep conference "Frontiers of Knowledge in Sleep & Sleep Disorders: Opportunities for Improving Health & Quality of Life" to be held in Bethesda on March 29-30, 2004. A State-of-the-Science Conference on Insomnia is also being planned for Fiscal Year 2005.

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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 2003, The NIAAA funded a total of 20 research projects, including 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); 5) assessment and treatment of sleep disturbances in recovering alcoholics; 6) pharmacotherapy of alcoholism and comorbid insomnia; 7) sleep and immune function in African Americans; and 8) effects of acute alcohol intake on performance and alcohol abuse liability in insomniacs.

Published research highlights from currently funded projects are summarized below:

Effects of Alcoholism on Auditory Evoked K-complexes during Sleep

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

Treatment for Alcohol-Induced Sleep Disturbance

Alcohol-dependent individuals commonly experience sleep disturbances following periods of heavy drinking and during abstinence. Further, insomnia in these patients may be a major contributor to relapse. Little is known, however, about management of insomnia in recovering alcoholics. A survey of addiction medicine physicians to examine medical management of sleep disturbances among patients in early recovery from alcoholism showed that although two thirds of these physicians might offer pharmacological treatment on occasion, fewer than a quarter offer medication to more than half of sleep-disordered patients. When they do prescribe, the most widely used medications are trazadone, other sedating antidepressants, and antihistamines, despite limited evidence for or against these medications. Thus, although the treatment of sleep disorders in alcoholic patients in early recovery may be warranted to prevent relapse, controlled studies of these sleep agents are needed.

To date, there have been few studies on effective treatments for sleep disturbances associated with alcohol dependence. One recent pilot study examined the effectiveness of trazadone vs. gabapentin in treating insomnia in alcohol-dependent outpatients. Trazadone is a sedating antidepressant that has been used to treat alcoholism. Gabapentin is an antiepileptic drug that has also been used to treat alcohol-related disorders because of its anticonvulsant, sedative, and anxiolytic effects. Although both medications improved insomnia, as measured by the Sleep Problem Questionnaire, patients on gabapentin improved significantly more than did patients on trazadone. While these studies offer promise for medications that treat sleep disorders in alcoholic patients as well as prevent relapse, the results are preliminary and more rigorous clinical trials are needed.

Sleep EGG as a Measure of Risk in Depressed Children with a Family History of Alcohol Abuse

One method to identify potential risk factors for alcohol use disorders is to study potential risk markers in individuals with a family history (FH) of alcoholism, but who have not yet developed the disorder. Although numerous studies have found abnormalities in electrophysiological activity (EEG, ERP) of high-risk children of alcoholics, relatively few have examined sleep EEG measures or used children younger than 18 years of age. One group that may be at high risk for development of alcohol and other substance use disorders is depressed children and adolescents. Therefore, a study was conducted to determine if there is an association between family history of alcohol use disorders and EEG measures during sleep and waking in a sample of adolescents with depression. Power-spectral analyses revealed that an association between high alpha activity (7.5-11 Hz and 11-12.25 Hz) and FH of alcoholism, but only in males. Furthermore, increased alpha power is found both during the awake period of the night and during several periods of sleep. These findings are consistent with previous findings that alpha power is positively associated with family history of alcohol use disorders.

Mechanisms Underlying Alcohol's Effects on Sleep

Despite the established relationship between alcohol and sleep disturbances, the biological basis for alcohol's effects on sleep is not understood. Experiments using rats as a model to study mechanisms of alcohol-induced sleep impairments have found that, to a large extent, alcohol's effects on sleep in this species parallel those observed in humans. However, most of these studies have examined relatively short durations of sleep time (e.g., 1 hr) and do not report time of day for alcohol's effects, even though this may be a significant factor in sensitivity to alcohol. Therefore, a recent study investigated the diurnal effects of acute and chronic alcohol administration on sleep. Differences were found in the effects of acute alcohol on sleep parameters, including EEG spectra, depending on whether alcohol was given at the onset of the active period (dark) or sleep (light) period. Acute alcohol extends non-rapid eye movement sleep (NREMS) time, but the depth of sleep is reduced. These effects are much more obvious during the dark period. With chronic alcohol administration (3 weeks), normal circadian variation in REMS time is reduced because of both decreases in REMS during the sleep (light) period and increases in REMS time during the dark (active) period. Furthermore, there is a dramatic rebound effect in REM sleep 1 week after withdrawal, which corresponds with the increased "REM pressure" observed in human alcoholics during withdrawal. These results demonstrate that there are differences in the effect of acute and chronic alcohol depending on time of administration and that alterations in circadian sleep patterns are induced by chronic treatments in as little as three weeks.

The thalamus is an integral component of sleep wake cycles and sleep wave spindles that occur during Stage II sleep. This form of sleep is enhanced in response to acute alcohol and reduced in alcoholics. A key mediator of thalamic spindle wave activity is low calcium T-type current. Thus, the effect of low and high concentrations of ethanol on T-type current was examined using whole cell electrophysiological recordings in slices of the thalamus. It was found that low concentrations of ethanol enhance T-type current, whereas higher concentrations of ethanol decrease T-type current. A more detailed assessment of these dose-dependent relationships will determine more precisely how ethanol interacts with the T-type channel. However, the ability of ethanol to perturb calcium currents in thalamic relay cells implicates voltage-gated ion channels in the disruption of sleep/wake behavior in ethanol-exposed individuals, providing a potential therapeutic target to address alcohol-induced sleep disturbances

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

The NIAMS funded 7 grants in sleep or sleep-related research in FY 2003. Two studies involve examining sleep in the context of fibromyalgia (FM), a syndrome characterized by widespread, chronic muscle pain, fatigue, cognitive disturbance, and impaired sleep. One study is examining the relationship between disrupted sleep patterns and night-time secretion of ACTH, cortisol, and cytokines, and one study is investigating, among other things, sleep and stress as predictors of pain, fatigue, distressed mood in FM. Two studies involve examining sleep in the context of arthritis. A new grant funded in 2003 is investigating behavioral treatments for rheumatoid arthritis, with sleep quality as one of the outcome variables. An ongoing study, using a murine model of arthritis, experimentally induces partial chronic sleep deprivation to investigate the relationships between sleep fragmentation and immune- and non-immune-mediated arthritic processes.

Additional funded research involves investigating the role of impaired sleep as a major cause of fractures, disability and cognitive decline in older women. Finally, a conference grant on the role of fatigue in rheumatic diseases was funded in 2003, with the conference scheduled for autumn 2004.

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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 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

The pathogenic process that leads to SIDS has been under investigation for many years. One major theory is that infants who are vulnerable to SIDS do not respond appropriately during sleep to low oxygen levels. Studies of animals that are deprived of oxygen show that the low blood oxygen concentration results in a rapid decrease of oxidative metabolism in tissues. This leads to bradycardia, apnea and hypoxic coma. The animals initiate a gasping (large breaths) response. If the gasp provides enough oxygen to the heart and lungs the cardiovascular function rapidly improves and "autoresustication" and rapid recovery takes place. Researchers analyzing home monitor recordings of infants who died of SIDS and from other causes showed that hypoxic gasping takes place immediately before death. Most of the non-SIDS cases showed evidence of return of cardiovascular function and partial or complete autoresuscitation prior to death. SIDS infants were distinct in that they had more double and triple gasps. Importantly, among the SIDS cases, only one showed a transient increase in heart rate following a gasp and none had evidence of complete resuscitation. These results suggest that SIDS infants may have a deficit in the circulatory or other components of the autoresuscitation mechanism (Pediatr Pulmon 2003;36:113-122).

Northern Plain Indians have the highest rates of SIDS in the nation. The Aberdeen Area Infant Mortality Study (AAIMS), was conducted in collaboration with Aberdeen Area Tribal Chairman's Health Board and funded by NICHD, the Indian Health Service (IHS), and the Centers for Disease Control and Prevention (CDC). In Fiscal Year 2002, we reported on the unique risk factors for SIDS in this population. In Fiscal Year 2003, the Aberdeen Area Infant Mortality Study was the first study to link epidemiological findings with neurochemical deficits in the developing human brain. Previously it was reported that SIDS infants have a unique deficit in a network of neurons in the brainstem that use serotonin as a transmitter. In this study, it was observed that binding abnormalities to serotinergic receptors in the medullary regions of the SIDS cases in AAIMS were similar to those observed in SIDS cases from other populations. In addition the serotonin receptor abnormalities in the arcuate nucleus were associated with exposure to adverse prenatal exposures, i.e., cigarette smoking (p=0.011) and alcohol (p=0.075), during the periconceptional period or throughout pregnancy. Prenatal exposure to cigarette smoke and/or alcohol may contribute to abnormal fetal medullary 5-HT development in SIDS infants (J Neuropathol Expt Neurol 2003; 62:1166-1177).

It can be hazardous for an infant to sleep on an adult bed alone or with another person due to the potential for 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 National Infant Sleep Position Study (NISP) has provided the opportunity to study infant care practices in the sleep environment that may influence SIDS risk. Almost half of infants in the survey population spent at least some time at night on an adult bed in the last 2 weeks. Between 1993 and 2000, the proportion of infants usually sharing an adult bed at night increased from 5.5% to 12.8%. Among the factors that independently increased the probability of usual bed sharing are: young maternal age, maternal race reported as black or as Asian/other, household income <$20,000, and infant age <8 weeks. The NISP study also found that bed sharing infants were almost twice as likely to be covered by a quilt or comforter as infants who did not share an adult bed. A quilt or comforter in the bed sharing environment is a potential hazard for SIDS if the baby's face or head gets covered (Arch Pediatr Adolesc Med 2003;157:43-49). More research is needed to understand the range of bed sharing practices, 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 with 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 after surgery. Early results, comparing physical findings with polysomnographic findings, suggest that tonsillar size may be the most reliable predictor of 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.

This year the NICHD initiated support of a small grant to examine sleep dysfunction in adults who are mentally retarded as well as those who have autism in combination with varying degrees of mental retardation. The purpose of this study is to obtain a more precise estimate of the sleep problems in these populations using appropriate technology to assess sleep architecture.

The "Back to Sleep" National Public Health Education Campaign

Based on strong 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 American Academy of Pediatrics (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.

In countries with successful SIDS risk reduction campaigns, the contribution of risk factors to SIDS changed between the pre-and post-intervention periods. The NICHD conducted a population-based case-control study in eleven counties in California from May 1997 through April 2000 to evaluate risk since initiation of "Back to Sleep". This study provided critical evidence to support the recommendation that "back is best" for all sleep periods and should be used consistently by all caregivers. Infants last placed on their sides for sleep were twice as likely to die of SIDS as were infants last placed on their backs.

In addition, the risk of SIDS was significantly increased if infants turned from their sides to their stomachs during sleep. While the reason isn't clear, the instability of the side position makes it more likely for babies who are placed to sleep in this position to roll over onto their stomachs. A pattern also emerged when the researchers looked specifically at the position in which an infant was last placed to sleep, compared to their usual sleeping position. If an infant who was usually placed to sleep in the low-risk position -- on the back -- was then placed to sleep in a high-risk position (the stomach or side), his or her SIDS risk was seven to eight times greater than that of an infant who was always placed to sleep on his or her back (AJE 2003;157:446-455). The "Back to Sleep" campaign materials have been revised to reflect that the back sleep position confers the least risk. While the decline in SIDS rates has occurred in all segments of the population, the decline has been less in American Indian communities. Today, American Indian infants are more than twice as likely to die from SIDS as white infants.

The NICHD hosted a second meeting in January 2003 with members from the American Indian community to discuss infant mortality and SIDS in the Northwest and the Northern Plains. The goal of this meeting was to identify and develop community driven strategies for increasing SIDS awareness and reducing the number of infant deaths in American Indian (AI) and Alaska Native (AN) communities. Participants from various disciplines and community based programs discussed ways to reach people with risk reduction messages while preserving cultural traditions. As a result, the NICHD is working with the small work group established to develop a communications outreach plan: "American Indian Infant Mortality: Community Driven Strategies." Our objective is to translate the information captured in the report into a communications and outreach plan, which will determine the most effective approaches to reach the regional AI/AN communities with the SIDS risk reduction messages.

African American Outreach Initiative

Despite a 50% decline in the rate of SIDS among African Americans since 1992, African American infants are still more than twice as likely to die of SIDS as white infants. The Partnerships for Reducing the Risk of SIDS in African American Communities is a project with the Alpha Kappa Alpha Sorority, Inc. (AKA), the National Coalition of 100 Black Women (NCBW), and the Women in the NAACP (WIN). The leaders of these three organizations have committed to hosting three summits featuring the NICHD SIDS risk reduction campaign information and materials. Leaders and members of the AKA, NCBW, and WIN participated in all three regional summits. Each organization took the lead responsibility to organize and host one of the three regional meetings and continues to serve as the catalyst for activity in that region. The goals for the summit meetings were to encourage a significant regional population to engage in SIDS risk reduction activities, build alliances within communities to assist in SIDS risk reduction activities, educate those with the power to make a change in policy or behavior, and create sustaining collaborative models and resources.

Suitably named, the Journey for Our Children summits traveled to three regions of the U.S. which have both high rates of SIDS and large African American populations. The NICHD and Partners used a review of national data on SIDS rates and census data on the African American/Black population as the basis for a discussion of the locations of the three summits.

The following is a list of the summit locations:

NCBW as Host: Tuskegee, Alabama (January 31 - February 1, 2003) WIN as Host: Los Angeles, California (March 14-15, 2003) AKA as Host: Detroit, Michigan (May 30-31, 2003)

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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) used CAM specifically for sleep problems in 2002. These CAM therapies include the use of dietary supplements such as melatonin and valerian; mind/body approaches such as meditation, and therapies that are part of non-western traditional medical systems, such as acupuncture and yoga. NCCAM's mission is to investigate CAM therapies and train CAM researchers in the context of rigorous science. As part of this mission, we support research and research training related to the use of CAM therapies for sleep disorders. Some examples of research that NCCAM currently supports in this area are given below.

Insomnia

Chronic insomnia is a significant health problem for many individuals, but is often difficult to treat. Furthermore, conventional therapeutics can produce unwanted side effects. As a result, many individuals have turned to alternative therapies in search of more effective treatments with less side effects. NCCAM is interested in determining whether or not these alternative treatments, which are already in the public domain, are effective. Currently, NCCAM supports a study using yoga as a treatment for insomnia. Although yoga has been recommended for treatment of insomnia by yoga practitioners, its effectiveness has not been scientifically established. The main goal of this ongoing clinical study is to establish whether a regimen of yoga practice will improve sleep onset latency measured by both subjective and objective criteria. In addition, NCCAM has recently funded a trial on melatonin for insomnia in the elderly. A significant portion of elderly individuals with insomnia have low endogenous levels of melatonin, a normally occurring neurohormone as well as a popular dietary supplement sold to treat a variety of sleep disorders. This clinical study will investigate whether dietary supplements of melatonin will relieve insomnia in these individuals.

Sleep Deprivation Related to Neurodegenerative Diseases

Neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease are often accompanied by sleep disturbances due to pain and/or neurological changes related to the progression of the disease. NCCAM currently supports an ongoing clinical study investigating the efficacy and safety of valerian for the treatment of sleep disturbances in Parkinson's disease. Valerian is derived from the root of the plant Valeriana officinalis and is commonly sold as a dietary supplement in the United States and Europe; 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 Parkinson's disease, where excessive nocturnal motor activity is related to sleep deprivation. The results of this study should clarify whether valerian is effective in treating sleep disturbances in Parkinson's disease patients.

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

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. Valerian is sold as a dietary supplement for sleep disorders. An NCCAM-supported project completed in 2002 performed a detailed pharmacokinetic study of a complex botanical derived from valerian root. In addition, as part of an initiative on Basic and Preclinical Research on Complementary and Alternative Medicine (PA-02-124), NCCAM continues to encourage and solicit research on interactions between CAM and conventional therapeutics, including but not limited to interactions between dietary supplements and drugs. This would include the interactions between drugs used to treat sleep disorders and dietary supplements such as valerian and melatonin.

Systematic Reviews

Because of the wide use of the dietary supplement, melatonin, for sleep disorders, NCCAM has commissioned the Agency for Healthcare Research and Quality to conduct a systematic review of published research on this subject to determine how strong the scientific evidence is to support the efficacy of melatonin for sleep disorders and to guide future research in this area.

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

The NIDA has several new grants in its portfolio involving sleep studies with the aim of understanding the brain systems affected by psychoactive drugs of abuse. There are wide-spread sleep disturbances both during use of, and following withdrawal from, these drugs among individuals who are addicted. Indeed, sleep disturbances often outlast other withdrawal symptoms and are often a cause for relapse. This means that the neural systems involved in the addiction process are many of the same ones also involved in the sleep architecture. Sleep researchers and drug abuse researchers are likely studying the same neural systems perhaps without realizing it.

Recent research is focusing on individuals taking the drug, MDMA ("ecstasy"), who have sleep disturbances likely due to MDMA's effects on the serotonergic system in the brain. Toxicology studies in animals and human subjects are attempting to determine what permanent and temporary damage results from its use. Studies focus on both serotonergic and other neural systems and on the consequent behavioral disturbances, including sleep. In addition to sleep disturbances, MDMA may have an effect on neuroendocrine function which will be studied along with effects on the sleep architecture. These studies are relatively new and definitive results are absent. The expectation is that sleep disturbances will help inform the neural mechanisms of action of MDMA and associated consequences to shared brain systems.

While marijuana may not have the severe toxicity as is being described for MDMA, it nevertheless causes lasting sleep disturbances in abstinent heavy users. There are no objective polysomnographic measures validating subject reports. These will be obtained in studies initiated this year. Also initiated this year are polysomnographic and (phosphorous) magnetic resonance imaging studies of differential sleep disturbances experienced by cocaine-dependent and opiate-dependent individuals. Since sleep disturbances include sleeplessness, similar studies on sleep-deprived healthy individuals will be used for comparison. Preliminary studies in healthy subjects indicate increases in �-nucleoside triphosphate and decreases in phospholipid catabolism, as measured by an increase in the concentration of glycerylphosphorylcholine. [Dorsey, C.M., Lukas, S.E., Moore, C.M., et al., 2003. Sleep, 26(5), pp. 573.577.]

NIDA also supports several studies on the effect of cocaine on sleep in a naturalistic setting. That is, how is the normal sleep architecture affected during use and subsequent withdrawal from cocaine? Also, since the serotonergic system is affected, how do medications that affect the serotonergic system, such as selective serotonin reuptake inhibitors, interact in these individuals? The first studies on non-treatment-seeking crack cocaine users in a 22-day protocol that included 1) washout, 2) (laboratory-controlled) binge cocaine use, and 3) abstinence demonstrated a significant decline in sleep duration, REM latency, and sleep efficiency with an increase in sleep onset latency over the course of the protocol. Behavioral tests associated with these sleep changes included declines in recognition memory, vigilance reaction time and psychomotor speed. [Pace-Schott, E.F., Stickgold, R., et al., 2003. Sleep, 26 (Abstract supplement), pp. A379-380.]

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

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NATIONAL INSTITUTE OF MENTAL HEALTH
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 genetic, cellular and molecular mechanisms of circadian systems, nosology and epidemiology of sleep disorders, relationship of sleep disruption to mental illness, and treatments for sleep disorders. In Fiscal Year 2003, the NIMH sleep portfolio grew to nearly 200 grants, spanning the basic neuroscience and applied science areas, and including research program and career development grants.

Sleep Deprivation Reduces Cell Proliferation in the Rat Hippocampus

Adult neurogenesis, or the creation of neurons from progenitor cells, has been shown to occur in several species, including rodents, non-human primates, and humans. The dentate gyrus (DG) of the adult hippocampus (among other brain structures) gives rise to progenitor cells that ultimately develop into neurons. Numerous factors affect neurogenesis. For example, several growth factors (e.g., brain-derived neurotophic factor), living in an enriched environment, exercise, and the administration of anti-depressant medication increase neurogenesis, whereas environmental or psychosocial stress and glucocorticoid administration decrease neurogenesis. Reductions in hippocampal volume, possibly reflecting impaired neurogenesis, have been documented in humans with clinical depression. While many of the modulators of neurogenesis are also known to affect sleep quality and quantity, to date it has not been known whether sleep or sleep loss has any effect on cell proliferation, or neurogenesis.

The aim of the Guzman-Marin et al. study was to determine the effect of sleep loss on cell proliferation in the DG of adult male rats. Male rats were implanted for polysomnographic recording, and divided into one of three groups: treadmill sleep-deprived, treadmill control and cage control groups. Stereological analysis showed that the number of proliferating cells in the DG of the dorsal hippocampus was reduced by 54% in the sleep-deprived group in comparison with the treadmill control and by 68% in comparison with the cage control group.

Guzman-Marin, R., Suntsova, N., Stewart, D.R., Gong, H., Szymusiak, R., & McGinty, D. (2003). Sleep deprivation reduces proliferation of cells in dentate gyrus of the hippocampus in rats. Journal of Physiology, 429 (2) 563-571.

Quality of Sleep Predicts Recurrence of Depression in Children and Adolescents.

Polysomnographic abnormalities are prevalent in adults with major depressive disorders (MDD). For example, common sleep abnormalities in adults with depression include difficulty initiating and maintaining sleep, abnormal timing or distribution of rapid eye movement, and decreased restorative, slow-wave sleep. To date, though, findings regarding the macroarchitecture of sleep in children and adolescents with and without depression have been more equivocal. Several recent studies, however, have suggested that adults and children and adolescents with depression may share similar finer-tuned (or microarchitectural) sleep patterns (specifically, temporal incoherence between beta and delta EEG activity).

The Armitage study (Armitage R et al. Sleep microarchitecture as a predictor of recurrence in children and adolescence with depression. International J Neuropsychopharmacology 2002;5:217-228) used standard sleep measures and temporal coherence of sleep electroencephalogram (EEG) rhythms to predict recovery and recurrence in a 1-year naturalistic follow-up in 47 children and adolescents 8 to 18 years of age with MDD. Although standard sleep measures did not predict clinical course, temporal coherence measures discriminated between those who recovered from depression, recovered but had a recurrence of depression, and those who did not recover from the index episode. Specifically, coherence between �, ? and d EEG activity recorded in the right hemisphere was significantly lower in the no-recovery group. In addition, temporal coherence was strongly associated with both time to recovery and recurrence. Those with the lowest coherence were less likely to recover or experienced a recurrence of depression. While true for both boys and girls, the findings were strongest for boys. This study supports the use of quantitative sleep EEG measures as a predictor of clinical course in depression.

Development of PTSD Symptoms After Traumatic Injury Associated with Fragmented REM Sleep

Post-traumatic stress disorder (PTSD) often becomes chronic and treatment-resistant if not ameliorated in the earliest stages of illness. Thus, understanding the early pathogenesis of PTSD is critical for the development of effective strategies for the prevention of chronicity. PTSD is characterized, in part, by difficulty in arousal regulation and memory consolidation, which are aspects of sleep functions. Sleep findings from patients with chronic PTSD are complex and somewhat contradictory, and data from the acute phase are quite limited. In the present study, the investigators used polysomnographic recordings during the acute period after subjects were exposed to life threatening situations and injury. The primary aim of the study was to relate measures of sleep duration and maintenance, along with the timing, intensity, and continuity of REM sleep, to the early development of PTSD.

Post-injury patients meeting study criteria received at least one polysomnographic recording close to the time of medical/surgical stabilization and within a month of injury. PTSD symptoms were assessed concurrently and 6 weeks later. Sleep measures were compared among patients with and without significant PTSD symptoms at follow-up, as well as in ten non-injured control subjects, and were also correlated with PTSD severity. Findings indicate that trauma-exposed patients had more wake time after the onset of sleep than did non-injured control subjects, irrespective of whether they showed PTSD symptoms at follow-up. The group that developed PTSD symptoms was distinguished by findings suggesting a more fragmented pattern of REM sleep (e.g., shorter average duration of REM sleep before a stage change and more periods of REM sleep). This study suggests that the adaptive functions of REM sleep after trauma may depend on the duration of REM sleep that occurs without disruption.

Mellman, T, Bustamante, V., Fins, A., Pigeon, W., Nolan, B. (2002). REM Sleep and the Early Development of Posttraumatic Stress Disorder. American Journal of Psychiatry (159)1696-1701.

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

NINDS supports basic and clinical research on the neuroscience of sleep, including studies of fundamental mechanisms of sleep, sleep disorders and associated complications, and circadian biology. In 2003, NINDS-funded investigators made several noteworthy advances in these areas.

Elucidation of central mechanisms involved in the regulation of sleep and wakefulness as well as the control of physiological patterns during sleep, is an important NINDS focus. Numerous studies have suggested that sleep is essential for optimal immune response, and excessive sleepiness and fatigue are common symptoms of many infectious diseases. Mice respond to viral challenge, such as infection with the influenza virus, with strong stimulation of sleep mechanisms, including increases in non-rapid eye movement (NREM) sleep. To understand the molecular basis of this response, NINDS researchers studied the effects of influenza infection on NREM sleep in mice lacking the growth hormone-releasing hormone receptor gene (GHRH receptor). Since the GHRH protein has previously been shown to be important in the regulation of sleep, this study tested if the GHRH pathway is also involved in the sleep response to viral infection. Using electrophysiological measures, they found that following influenza infection, mice lacking a functional GHRH receptor did not produce the characteristic increase in NREM sleep as did controls. Control mice spent more time in normal NREM sleep and their NREM sleep was more intense than mice lacking the GHRH receptor. Mice lacking the GHRH receptor also had a higher death rate after influenza infection than the controls. This study points to a role of GHRH signaling in the sleep response to infection. Further study is needed to determine the precise relationship between infection, disruption of sleep, and progression of disease symptoms.

The NINDS portfolio also includes studies to understand the basis of various sleep disorders. Restless legs syndrome (RLS) is a common neurological disorder characterized by unpleasant sensations of the legs and an urge to move them for relief. Because symptoms are intensified by inactivity and lying down, RLS patients often have difficulty falling asleep and staying asleep. Left untreated, RLS causes exhaustion and fatigue, which can affect occupational performance, social activities, and family life. It has been estimated that about 80 percent of RLS patients also have periodic limb movement disorder (PLMD), or nocturnal myoclonus, which is characterized by repetitive stereotyped movements of the limbs, primarily the legs, during sleep.

This year, NINDS-funded researchers conducted the first ever autopsy study of brains from people with RLS. In this important study, the researchers compared autopsied brain tissue from seven RLS patients to five autopsied brains from people with no history of neurological disease. Since a number of previous studies have linked RLS to deficiencies in iron and dopamine, the researchers examined a region of the brain characterized by a concentration of dopaminergic neurons, the substantia nigra, for levels of iron and iron-related proteins. The amount of iron in cells of the substantia nigra was extremely low, and that there were very few receptors for transferrin, a protein that binds to iron and transports it into cells. Levels of several other proteins linked to iron storage and transport were also low. The study suggests that iron transport is altered in people with RLS. Further research is needed to determine how deficits in iron acquisition affect brain cells and particularly, the potential effect of low iron on dopaminergic function.

NINDS supports studies on the cause and treatment of narcolepsy, a neurological disorder associated with a defect in the hypocretin/orexin neurotransmitter system characterized by excessive daytime sleepiness, an inability to move shortly after awakening, and sudden episodes of muscle weakness. Aspects of narcolepsy include sleep attacks that involve both REM and NREM sleep, sudden transitions from wakefulness to REM sleep, and episodes of cataplexy (sudden loss of postural muscle tone). However, the molecular mechanisms underlying transitions from wakefulness to REM sleep and wakefulness to NREM sleep are not known. Using transgenic mouse models, researchers have now uncovered some of the molecular mechanisms behind these sleep regulatory processes. Researchers compared mice lacking the orexin receptor, OX2R (OX2R-/- mice) with mice lacking an orexin peptide (orexin -/- mice). The orexins, also referred to as hypocretins, are peptides involved in the regulation of feeding, energy homeostasis, and sleep/wakefulness states; a reduction in orexin neurons is associated with narcolepsy.

Using behavioral criteria, the researchers found differences between the two groups in REM sleep control and manifestations of REM sleep. Orexin -/- mice were more likely to exhibit cataplectic-like episodes characterized by abrupt cessation of motor activity and sustained postural collapse than were the OX2R-/- mice. Electrophysiological and pharmacological measures showed that these abrupt transitions were accompanied by a rapid transition from wakefulness to REM sleep, or premature transitions from NREM to REM sleep. This study suggests that hypocretin/orexin signaling may have several actions. Acting through the OX2R receptor, the neurotransmitters appear to regulate the gating of transitions from wakefulness to NREM sleep and play a predominant role in preventing the emergence of sleepiness and sleep attacks. In contrast, OXR2- independent mechanisms (possibly regulated through another orexin receptor, the OXR-1 receptor) may regulate other aspects of narcolepsy including cataplexy and abrupt transition to REM sleep states. Understanding the molecular basis of this disease will help in identifying potential therapeutic targets.

NINDS supports both basic and clinical research in circadian biology. Studies in animal models have identified genes responsible for the regulation of circadian rhythms, the body's "clock" on which the sleep-wake cycle is dependent. These genes work in concert in an autoregulatory feedback loop to generate circadian rhythmicity. This year, two important NINDS-funded studies have further dissected the molecular mechanisms underlying circadian oscillation. In the first study, the investigators used the Drosophila circadian clock mutant Andante, which has abnormally long circadian periods, to show that a regulatory protein, casein kinase 2, plays a role in determining period length. They found that casein kinase 2 is important for the regulation of two known clock proteins, Period and Timeless, and suggests that casein kinase 2 may have an important role in the regulation of the circadian period. This study points to the need to pursue this work in other species. In the second study, NINDS-funded researchers showed that the mammalian homolog of Timeless (mTim) is required for circadian rhythmicity, and that Timeless was required for regulating rhythmic activity in cells of the suprachiasmatic nucleus, the site of the master circadian clock in mammals. As in Drosophila, Timeless is associated with another clock component, Period, in these cells. The findings prompt further study of the molecular workings of the mammalian clock.

NINDS also participates in initiatives relevant to sleep mechanisms and sleep disorders. In Fiscal Year 2003, NINDS and NHLBI issued a Program Announcement with set-aside funds (PAS) entitled "Sleep Disturbance in Parkinson's Disease and Parkinson-like Conditions," to stimulate and support research on sleep disorders in the context of these neurological conditions. In addition, NINDS participated in a program announcement on "Diet Composition and Energy Balance," which invites applications for research addressing the impact of diet on energy expenditure and energy balance and the relationship between diet and sleep loss.

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NATIONAL INSTITUTE OF NURSING RESEARCH
Kathy Mann Koepke, RN
NINR Representative to the Trans-NIH Sleep Research Coordinating Committee

The NINR 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

For some time, sleep researchers have thought that sleep regulation could be modeled by two factors: homeostasis, or the drive to return to the middle, even biologic state, and a circadian process, a cycling much like a 24-hour clock. These two processes were thought to interact in a linear or simple additive way. However, some research results conflict with this model. A recent study suggests that either homeostatic or circadian processes interact in a non-linear way during sleep deprivation, or there is a third factor that must yet be defined that also interacts.

A related study suggests 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 findings help us better predict when humans are most vulnerable to poor performance and thereby increased injury. For example, addressing long worker hours may be more important than the number of lost sleep hours in addressing shift workers safety and medical worker performance. Further, study participants were uniformly poor in judging their own performance decline, with little association between perceived sleepiness and cognitive decline. That is, even very mildly sleepy subjects demonstrated significant cognitive decline. This again suggests that long working hours may be especially dangerous for workers who need to assess their own performance and the safety of others, such as long-haul drivers, air pilots, and medical workers.

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.

In contrast, jet lag results in a misalignment of circadian processes and the local destination clock. An intervention to advance the circadian clock of travelers, in anticipation of misalignment with local time, resulted in partial success with a two-hour phase advance for eastward travelers. This modest phase shift may facilitate further phase adjustment for long-distance travelers and suggests further research to lengthen the possible phase shift and potentially eliminate the effect of jet lag.

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.

Sleep disorders, such as sleep apnea and restless legs syndrome, frequently co-occur with some chronic illnesses. Up to 80% of dialysis patients report sleep complaints ranging from excessive daytime sleepiness to periodic limb movement disorder (PLMD, a sleep disturbance characterized by unpleasant sensations in the limbs). Although sleep apnea and PLMD undoubtedly contribute to excessive daytime sleepiness in these patients, a recent study suggests that another, as yet unidentified, factor plays an important role in their sleepiness. New research to better predict or evaluate daytime sleepiness would allow clinicians to target interventions to the patients mostly likely to benefit.

Improved development and health in preterm infants who experience cycling light and darkness in the neonatal intensive care unit (NICU) suggest that circadian processes may play a hitherto unrecognized role in fetal development. Surprisingly, neonates kept in near darkness (thought to be more like the in utero sensory experience) developed more visual disorders than did those kept in either cycling light-darkness or continuous light. These findings may lead to improved lighting strategies in the NICU.

A recent study found that women with irritable bowel syndrome (IBS) report significantly more sleep disturbances than women without IBS. Use of oral contraceptives had no impact on sleep in these women, nor did IBS symptom pattern. The extent to which sleep interventions to improve sleep can lessen IBS symptoms is unknown.

The subjective experience of sleep in women who are HIV-positive reveals substantial decline in sleep quality. Women articulated several strategies to enhance their sleep quality, including creating sleep habits, choosing sleep-inducing activities when sleep is difficult, accepting lack of control over sleep loss, and planning for and self-monitoring daytime behaviors that enhance night-time sleepiness. The use of physical activity to enhance sleep was a reoccurring theme that resonates with prior research of better sleep quality in active individuals and suggests an important intervention strategy.

Management of Sleep Disturbances

Multiple studies examine sleep disorders and interventions to improve sleep. For example, older adults with sleep apnea have more fragmented sleep and greater declines in cerebral oxygenation during sleep. Previous studies in older adults have demonstrated that low cerebral oxygenation is associated with cognitive decline. Further, older adults report increases of mild-to-moderate levels of sleep disturbance and memory decline. In one study, severity of reported sleep disturbance was correlated to reported severity of memory decline, suggesting that interventions to enhance sleep might reduce memory decline.

A study investigating the effects of an individualized behavioral intervention on manifestations of insomnia (i.e., sleep onset latency and time spent awake after sleep onset), severity of insomnia, symptoms associated with insomnia (e.g., fatigue), functional status, and absenteeism from work has been initiated. This study will also determine which patients are most likely to benefit from the intervention.

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

Training and Career Development

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

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NIH Sleep Research Funding 1996-2003 (and 2004 estimate)
(Dollars in thousands)

	1996	1997	1998	1999	2000	2001	2002	2003	2004 (estimate)
NHLBI	16,450	19,219	22,932	31,845	35,128	37,579	45,155	50,328	51,737
NINDS	9,453	11,598	16,369	15,231	*12,495	17,603	22,918	24,588	25,195
NICHD	7,368	7,217	9,131	7,116	6,797	7,084	7,344	7,367	7,700
NIA	7,800	9,179	11,818	13,296	13,034	14,533	14,600	18,178	18,800
NIMH	27,231	28,601	^34,027	39,219	40,667	50,742	56,647	63,222	65,205
NIDA	1,201	1,042	1,586	2,163	2,553	2,517	3,235	2,988	3,078
NIAAA	551	728	766	736	1,132	1,681	4,342	4,553	4,700
NINR	2,842	3,565	3,394	3,503	4,635	5,375	8,091	11,030	11,251
NCRR	3,247	3,570	5,542	6,637	7,117	7,193	11,490	13,204	13,649
NIAMS	N/A	N/A	N/A	N/A	N/A	N/A	300	248	255
NCCAM	N/A	N/A	N/A	N/A	N/A	177	900	1,121	1,155
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	266
TOTAL	76,143	84,719	102,835	119,746	123,558	145,083	175,022	+197,085	202,991

^ 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

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The complete Fiscal Year 2003 grant listing can be viewed online as a .pdf document

Grants List in PDF [259K]

More information on PDF and the required reader is available.

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

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