Annual Report
of the
Trans-NIH Sleep Research Coordinating Committee
FISCAL YEAR 2001

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 Child Health and Human Development
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


NCSDR Home Page
Sleep Disorders Information
Scientific Information and Resources

INTRODUCTION

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

National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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)

In addition, three other Institutes/Centers also have a sleep-related portfolio and this information is included in the attached grant listing and budget tables. These three are: National Center for Research Resources (NCRR), National Center for Complementary and Alternative Medicine (NCCAM), and National Human Genome Research Institute (NHGRI).

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

FY 2001 (ending September 30, 2001) has been a busy year for the NCSDR. We have participated in a number of workshops, new initiatives, and public education programs that are briefly described below. New activities initiated in FY 2001 include appointment of a Task Force to revise the Research Plan and of a Working Group to develop an outcomes evaluation related to our sleep education programs.

Recent Initiatives
Restless Leg Syndrome and Periodic Limb Movement Disorders (PA)
Sponsors: NINDS,NHLBI, NIA, NIMH
Objectives:
To enhance our understanding of the pathogenesis of RLS and PLMD in order to develop more effective treatment strategies. Studies in both humans and animal models are encouraged.

Sleep & Sleep Disorders in Children (RFA): $12.4 million
Sponsors: NHLBI,NIMH, NINR, NICHD
Objectives:
To stimulate research on the need for sleep in school-age children, and the mechanisms by which sleep deprivation and sleep disorders affect their cardiopulmonary, hematological, immunological, mental, and behavioral health
Applications under review

Interrelationship Between Sleep and Other Disorders (RFA): $12 million
Sponsors: NHLBI and NIDA
Objectives:
Identify measurable characteristics of sleep useful for study of sleep and sleep disorders, related to diagnosis, severity, or effectiveness of treatment
Applications under review

Interactions of Genes & Environment in Shaping Risk Factors for Heart, Lung, Blood, or Sleep Disorders (RFA): $36 million
Sponsors: NHLBI
Objectives:
Identify novel genes that interact with specific environmental exposures to modify risk factors for heart, lung, blood and sleep disorders using short-term focused interventions in families; identify subgroups based on genotype that are most likely to benefit from targeted environmental interventions to reduce development or progression of heart, lung, blood, or sleep diseases
Applications due March, 2002

Sleep-Related Workshops In FY 2001
Bioinformatics in Neuroscience and Sleep Research
Sponsors: American Academy of Sleep Medicine (AASM); Sleep Research Society (SRS); NHLBI
Objective:
Explore opportunities for bioinformatic approaches to sleep/circadian research

Implications for Insomnia
Sponsors: NSDR (NHLBI), NIMH, NIA, NIDA, NIAAA
Objective:
Review basic mechanisms for sleep in relation to insomnia; identify gaps in understanding of basic mechanisms of insomnia; summarize basic science knowledge required for clinical studies or trials

Sleep-Related Workshops Planned For FY 2002
Sleep, Fatigue, and Medical Training: Optimizing Learning and the Patient Care Environment
Sponsors: American Academy of Sleep Medicine; AMA Council on Medical Education; NCSDR (NHLBI); Sleep Research Society
October, 2001

Perspectives on the Role of Sleep in Memory
Sponsors: NIMH, NCSDR
December, 2001

Cardiovascular & Sleep-Related Consequences of Temporomandibular Disorders (TMD)
Sponsors: NHLBI (NCSDR, Division of Heart and Vascular Disease)
December 2001

Revision Of Sleep Disorders Research Plan
The scope of the original Plan signed by Dr. Varmus in March 1996 included basic science studies on the regulation and function of sleep and studies on sleep disorders, including basic research, clinical epidemiology, genetics, effects and cost of treatment. The Research Plan also addressed training needs for the field of sleep medicine.

Implementation of recommendations from this Research Plan led to substantial growth in research funding by NIH, with a 62% increase in total grant dollars in FY 00 compared to 1995-96 and a 21% increase from FY 00 to FY 01. The Research Plan also provided direction for extensive public health education and intervention programs related to sleep and sleep disorders. The Research Plan is now more than 5 years old, however, and advances in many disciplines applicable to sleep research have occurred since it was written (e.g. genetics, bioinformatics).

Implementation of recommendations from this Research Plan led to substantial growth in research funding by NIH, with a 62% increase in total grant dollars in FY 00 compared to 1995-96 and a 21% increase from FY 00 to FY 01. The Research Plan also provided direction for extensive public health education and intervention programs related to sleep and sleep disorders. The Research Plan is now more than 5 years old, however, and advances in many disciplines applicable to sleep research have occurred since it was written (e.g. genetics, bioinformatics).

It is now timely to revise and update the Research Plan. Using the 1996 Plan as a template, this process will include a review of accomplishments since 1996 and identification of objectives not yet achieved, knowledge gaps and new needs/opportunities. The charge to the Task Force is to develop a five-year research plan with prioritized recommendations related to sleep and sleep disorders.

Chair:
Dr. David White

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

The Task Force will meet twice in FY 02. A semi-final draft of the revised research plan will be widely distributed for comments by sleep research scientists, other sleep-related professional organizations, and the public. A two-hour session at the 2002 APSS annual meeting will provide opportunity for public input. The Trans-NIH Sleep Research Coordinating Committee and the Sleep Disorders Research Advisory Board will be actively involved in development of the new plan and will be responsible for approval of the revised plan by the end of FY 2002.

Other Activities Scheduled For FY 2002
Working Group on Sleepiness & Adolescents/Young Adults
Age range 13-22
Goals:
- Review normal sleep patterns and consequences of sleep deprivation
- Determine the causes of sleepiness in adolescents and young adults
- Develop continuing education strategies for pediatricians and other pediatric health care providers
Plans:
- Special Session at Fall, 2002 annual meeting of American Academy of Pediatrics
- Consider development of a Position Statement in partnership with the American Academy of Pediatrics related to sleep health in this age group

Working GroupMembers:
Co-Chairs:
Dr. David Kaplan
Dr. Richard Millman

Members:
Dr. Mary Carskadon
Dr. Ronald Dahl
Dr. Barbara Howard
Dr. Judy Owens
Dr. Allan Pack
Dr. Suzanne Riggs
Dr. Naomi Rogers
Dr. Stephen Sheldon
Dr. Amy Wolfson
Tammy Hurley - Manager, AAP Committee on Adolescence

Feasibility Study for Outcome Evaluation of Sleep Education Program:
Goals:
- To determine which program(s) will be most appropriate and feasible for cost-effective outcome assessment
- To determine the target audiences, how to measure baseline knowledge and behavior regarding healthy sleep, and how to measure the extent of program impact and its sustainability

Working Group Members:
Chair:
Dr. Tom Lasater

Members:
Dr. Neil Bracht
Dr. Mary Carskadon
Dr. Bruce Fuchs
Dr. Mel Hovell
David W. Kaplan
Dr. Barry Portnoy
Dr. Amelie Ramirez
Dr. Kingman Strohl
Dr. Clare Von Secker

Publications During FY 2001
Twery M, Hunt CE. Meet the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute: Research Opportunities in Sleep Medicine. Sleep and Breathing 2001;5:149-152.

Hunt CE. Sudden infant death syndrome and other causes of infant mortality: Diagnosis, mechanisms and risk for recurrence in siblings. Am J Resp Crit Care Med 2001;164:346-357.
- Gene-environment interactions; relationships to other sleep disorders

Hunt CE. Commentary:Familial small upper airways and sleep-disordered breathing: Relationship to idiopathic apparent life-threatening events. Pediatr Res 2001:50:3-5.
- Familial relationships between sleep-disordered breathing, SIDS, and apparent life-threatening events

Summary of Public Communications
NCSDR receives queries from or about patients with a sleep disorder, and from health care professionals, students or writers regarding sleep problems and sleep disorders. In FY 2001, 30% of all NCSDR inquiries were sent by e-mail. The NCSDR has extensive media contacts related to newspapers, professional and lay publications, radio, 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 receives public inquiries regarding sleep. These public communications are summarized below.

NCSDR Contacts By Primary Symptom Identified
(annualized totals based on data collected March-Sept 2001)

E-Mail
Snoring/Breathing/Apnea..................................... 60
Insomnia............................................................. 45
Narcolepsy......................................................... 45
Restless Legs Syndrome...................................... 19
Other Sleep Problem or General Information.......139
Total E-Mail..................................................... 308


Letters/Phone/Fax
Snoring/Breathing/Apnea................................... 219
Insomnia........................................................... 146
Narcolepsy......................................................... 50
Restless Legs Syndrome...................................... 43
Other Sleep Problem or General Information.......252
Total Letters/Phone/Fax.................................. 710

NCSDR (Annualized) TOTAL .................... 1,018
Percent E-MAIL 30%

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Press Office (NHLBI/OD) Media Contacts

Electronic Media (Internet, E-Mail)....................... 9
Live (Radio, TV Interviews)................................ 11
Print Media ........................................................ 42
Total ................................................................. 62

Health Information Network, OPEC Contacts (Cy 2001)

Number of Inquires ........................................................ 1,735
Number Of Sleep-Related Publications Distributed ....... 25,968

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III ACTIVITIES OF TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE MEMBER INSTITUTES

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

Scientific Research and Initiatives

NHLBI sleep research program covers a wide spectrum ranging from neuroscience, genetics, and circadian rhythm to anatomy, physiology, behavioral science, epidemiology, clinical research, and sleep/health education. The program is aimed at understanding themolecular, genetic, and physiological regulation of sleep and the relationshipof sleep disorders to cardiopulmonary disease.  NHLBI is a major supporter of investigator-initiated sleep research at the NIH. The Institute jointly sponsors program announcements on Basic and Clinical Research on Sleep and Wakefulness (PA-95-014) and on Biobehavioral Research for Effective Sleep (PA-00-046). The Institute also sponsors requests for applications (RFA) on the Obstructive Sleep Apnea in Children (RFA HL-98-004), Phenotypic Characterization of Sleep in Mice (RFA HL-99-001), Development of Mouse Phenotypic Screens (RFA HL-99-010), and Oxygen Sensing During Intermittent Hypoxia (RFA HL-00-004).

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. Another program, Ancillary Studies in Heart, Lung, and Blood Disease Trials (RFA HL-00-012) invites mechanistic studies using ongoing heart, lung and blood related clinical trial cohorts to investigate sleep-related pathophysiology including the pathogenesis of cardiopulmonary disease, diabetes, coagulation factors, vascular reactivity, and inflammation.

A new initiative on Sleep and Sleep Disorders in Children (RFA HL-01-006) will stimulate research on the need for sleep in school-age children and the mechanisms through which sleep deprivation and sleep disorders affect their cardiopulmonary, hematological, immunological, mental, and behavioral health. Another initiative to be awarded in fiscal year 2002 addresses the Interrelationship Between Sleep and Heart, Lung, and Blood Diseases (RFA HL-01-009) and is designed to identify measurable characteristics that have the potential to improve our understanding of these relationships and facilitate basic, clinical, and epidemiological studies of sleep and sleep disorders.

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 research with clinical investigations on the etiology and pathogenesis of sleep disorders particularly sleep apnea.  In addition, the ongoing multi-center Sleep Heart Health Study is employing clinical and epidemiological approaches to examine whether subjects with high blood pressure have sleep apnea; whether sleep apnea is a contributing risk factor for the development of cardiovascular and cerebrovascular disease; and how age, gender, and ethnicity influence the association between apnea, hypertension, and stroke.  Innovative biomedical technologies are being developed to improve diagnostic and treatment approaches for sleep-disordered breathing under the Small Business Innovation Research (SBIR) Program.

The Institute is also enhancing the awareness of medical students, physicians, and other health care professionals about sleep and sleep disorder diagnosis through the Sleep Academic Award program established in twenty medical schools. Sleep Academic Awardees have published over 35 reports on sleep medicine education since the program began in 1997. A website established by the American Academy of Sleep Medicine (http://www.aasmnet.org/MEDSleep/Home.htm) is facilitating electronic distribution of medical education resources developed under the Sleep Academic Award program

NHLBI also supports programs to train students, scientists, and physicians in basic and clinical research in sleep, pulmonary physiology, and medicine. Important new findings in the NHLBI sleep program include research in the epidemiology of sleep apnea and cardiovascular disease, and in sleep disordered breathing in children.

Sleep Apnea (Sleep Disordered Breathing) and Cardiovascular Disease

Sleep apnea is a common disorder characterized by interruptions in breathing with potentially serious effects on cardiopulmonary health and diminished quality of life due to excessive daytime sleepiness. Sleep apnea is also highly associated with increased cardiovascular disease risk independent of age, gender, ethnicity, and HDL cholesterol level. New findings obtained from over 6,000 middle age adults in the Sleep Heart Health Study (SHHS) indicate that sleep apnea increases the risk of heart failure 140%, the risk of stroke 60%, and the risk of coronary heart disease 30%.The SHHS and findings from other studies indicate that the greatest increase in cardiovascular disease risk is associated with minimal sleep apnea, commonly considered to be subclinical. Sleep apnea produces intermittent blood oxygen desaturation (hypoxemia) and episodes of brain activation (arousal) associated with abrupt increases in systemic blood pressure. Recent findings suggest that the cardiovascular risks associated with sleep apnea may correlate most closely with the duration of the hypoxemia and not the number of arousals.

New information is also becoming available on the molecular and genomic factors that may underlie pathophysiological relationships between sleep apnea and cardiovascular diseases. Patients with ischemic stroke and sleep apnea exhibit elevated plasma fibrinogen levels implicating blood-clotting mechanisms in the increased risk of stroke in sleep apnea. The level of endothelin-1 is a potent vasoconstrictor peptide that increases with intermittent hypoxia-induced hypertension in rats and appears to be elevated in patients with sleep apnea. On the other hand, the vascular response to bradykinin, a vasodilator, is blunted in sleep apnea.

Recent population study findings indicate that apolipoprotein E (APOe4), a genetic marker previously linked to cardiovascular disease risk, is associated with a two-fold increased risk of sleep apnea, and a 35% increase in the severity of apnea symptoms. The association between APOe4 marker, cardiovascular diseases, and sleep apnea indicates a possible common pathophysiological pathway involving lipid metabolism. Another new link between sleep apnea and lipid metabolism comes from studies indicating that the frequency of diabetes, a major risk factor for cardiovascular disease, increases with sleep apnea severity. Sleep apnea has been found to elevate circulating levels of an inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), that stimulates the breakdown of fat, and causes marked insulin resistance. TNF-alpha is also known to stimulate the secretion of a fat cell regulating hormone, leptin, which is closely correlated with the degree of obesity-related insulin resistance. Other new findings indicate that partial sleep deprivation of otherwise healthy control subjects produces a level of insulin resistance similar to that of diabetics. Sleep deprivation associated with sleep apnea could be a primary mediator of increased diabetic and cardiovascular disease risks.

Since sleep apnea of mild to moderate severity is not uncommon in the general population, the elucidation of these health risks may have considerable public health implications. The fact that even minimal sleep apnea and snoring are significant risk factors for hypertension suggests that sleep disordered breathing may play a pivotal role in the early development of high blood pressure and cardiovascular diseases. These new findings should help to identify sleep apnea patients at greatest risk and contribute to the development of management approaches that will reduce the risk of comorbid cardiovascular disease and daytime impairment associated with sleep apnea.

Sleep Disordered Breathing in Children

Little is known about the specific risks associated with difficulty breathing during sleep in children. The importance of ascertaining these risks has been highlighted by recent findings indicating that middle school children (ages 13-14) with lower academic performance are more likely to have snored during early childhood (ages 2-6) and to have required surgical treatment for snoring compared with better performing schoolmates. The study included over 1500 seventh and eighth grade public school children matched for age, gender, sex, school, and area of residence. Middle school children in the bottom 25% of their class were 2.5 times more likely to have exhibited frequent and loud snoring during early childhood than children in the top 25% of their class. Children with poor middle school performance were also 3 times more likely to have had their tonsils and adenoids removed for snoring during early childhood than top performing children in the same class. Previous studies of the relationship between sleep apnea and school performance have shown that there is also an unusually high prevalence of sleep apnea symptoms among elementary school students with academic difficulty.

These findings suggest that sleep disordered breathing during a period of childhood associated with major brain and cognitive development may have lasting or irreversible effects hampering subsequent academic achievement. Whether the developing brain suffers from sleep disturbances, alveolar hypoventilation causing episodic blood oxygen desaturation (hypoxemia) and hypercarbia, or metabolic abnormalities associated with sleep-disordered breathing is not clear. In contrast to the excessive daytime sleepiness typically associated with sleep-disordered breathing (sleep apnea) in adults, children with sleep-disordered breathing tend to have behavioral problems not unlike those in children with hyperactivity. Several new lines of evidence indicate that the retention of learning skills and the process of memory consolidation are dependent on the occurrence of sleep the first night after training, and that sustaining performance on learning tasks following partial sleep deprivation produces a significantly greater degree of cerebral activation in functional magnetic resonance imaging stressing the function of cortical synapses. Other lines of evidence obtained in rat hippocampus have revealed memory deficits associated with cholinergic pathway abnormalities following sleep deprivation, and specific molecular, anatomical, and neurophysiologic correlates of impaired maze learning produced by exposure to brief episodes of intermittent hypoxia in as little as 2-14 days.

Extrapolating from findings in adults, children with sleep-disordered breathing may also be predisposed to infectious/inflammatory diseases. Although long-term data are limited, sleep disordered breathing in children may also be associated with cerebrovascular and cardiovascular complications including hypertension, especially if there is persistence of sleep disordered breathing after adenotonsillectomy. Since sleep apnea occurs in 1-3% of preschool children, it will be important to determine the extent to which sleep disordered breathing persists after adenotonsillectomy and how to treat these children in order to reverse acute symptoms and to prevent long-term adverse neurocognitive and cardiovascular consequences.

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

Problems with sleep are common with advancing years, and occur in over half of those people age 65 years and more. It has been estimated that insomnia affects about a third of the older population in this country. This inability to have restful sleep at night also results in excessive daytime sleepiness, attention and memory problems, depressed mood, and lowered quality of life. Other factors associated with aging, such as disease, changes in environment, or concurrent age-related processes also may contribute to problems of sleep on older persons. It now is evident that disturbance in sleep can also lead to changes in other body systems, especially the production of appropriate levels of hormones and proper metabolic functioning.

Program Activities

Program growth in the NIA Sleep portfolio has grown to $14.5 million in FY2001. NIA cosponsored the workshop "Neurobiology of Sleep and Waking" held September 10-11, 2001. NIA also is represented on the Trans-NIH Sleep Research Coordinating Committee and on the Sleep Disorders Research Advisory Board of the National Center on Sleep Disorders Research, NHLBI.

Research Advances

Immediate early genes, such as c-fos, are induced in response to wakefulness. The c-Fos protein must bind to the DNA binding site, AP-1. Baseline levels of c-Fos and AP-1 were similar in young (3.5 months) and old (21.5 months) Sprague-Dawley rats. However, in response to 6 or 12 hours of sleep deprivation, old rats have significantly less c-Fos and AP-1 activity than young rats. This decline in molecular activity could be the basis of the decline in sleep that occurs with age. 

Studies over the last few years have shown the important sleep regulatory functions of a hypothalamic circuit involving the ventral lateral preoptic nucleus (VLPO). The effect of prolonged wakefulness in rats on the expression of c-fos (as a marker of cellular activation) and galanin mRNA (as a marker for the neurotransmitter synthesis) in VLPO neurons of older and younger rats resulted in no differences in the numbers of cells with age. Nor were there any differences in levels of adenosine A1 receptor mRNA. However, effects of caffeine, an adenosine antagonist (0, 10 mg/kg, 20 mg/kg, ip) administered at the start of the sleep period were dose and age dependent; older rats stayed awake longer, had less SWS and REM sleep. These data might indicate that there was a change in adenosine receptor function, rather than number, with age. While the SCN functions normally, target cells downstream are losing function with age, and the entrainment signal is not getting through.

The distribution of hypocretin (HCRT) receptors was mapped in the rat pons. Only HCRT-R1 was present in the locus coeruleus, but both subtypes were found in other pontine neurons responsible for mastication and bladder control A toxin was developed that lesions hypocretin-containing cells. Hypersomnia resulted in rats with deletion of HCRT neurons in lateral hypothalamus. This hypersomnia was manifested as increased sleep during the night that produced a loss of the diurnal rhythm of sleep.

The brainstem pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei play a critical role in REM sleep and wakefulness. Cholinergic and GABAergic neurons coexist in the LDT and PPT of cats. About 50% of cells with cholinergic profiles receive GABAergic input. ACh and GABA are co-localized in a subpopulation of axon terminals. In the LDT nucleus both the number and size of ChAT-positive neurons were significantly reduced during aging. In the PPT, there was no reduction in numbers, only in size with aging. Such alterations may account for REM sleep changes that occur with age. In old age, there was a clear decrease in the immunoreactivity of the medium-molecular weight subunit of neurofilaments in sensory and motor neurons in the cat brainstem. The distribution of HCRT-1 immunoreactive neurons in cats was located principally in the lateral hypothalamic area; the majority of these neurons were located dorsal and lateral to the fornix, and a small number of HCRT-ir neurons were also present in the dorsal and posterior hypothalamus. HCRT-ir fibers with varicose terminals were located throughout the hypothalamus, especially in the infundibular nucleus, the supra- and pre-mammillary nuclei, the SCN and the tuberomamillary nucleus. The uses of the cat as a model for age-related changes in sleep shows changes similar to those found in rodents.

There are significant effects of CLOCK mutation and of age on several variables, including activity onset precision, free-running period, and circadian amplitude. There are no significant interactions effects (genotype X age), however, suggesting that these effects are additive and independent. The presence of a CLOCK mutation does not exacerbate the effects of aging on the expression of circadian rhythms. Age affects the expression of the circadian gene BMAL-1; the circadian rhythm of its mRNA is lower in amplitude in old Golden hamsters (>18m) than in young controls (3m). BMAL-1 is a dimmer of the CLOCK gene. Of the other circadian genes, Per1 is not affected by age, while there may be a reduction of Per2 expression. Repeat studies are being done to confirm these associations. The null allele of aCamKII alters circadian rhythmicity, but age does not alter this effect.

The molecular processes underlying the role of sleep in the consolidation of long-term memory were examined using specific CREB-mutant mice. Results indicate that like sleep deprivation, inhibition of 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 when tested at 24 hours or 12 days after training. This does not occur with retention of cured-fear training, a hippocampus-independent task. Preliminary data indicate that training increases wakefulness immediately following training for 1 hour and increases sleep between 2 and 3 hours after training. Phosphorylated cyclic AMP-responsive element binding protein (CREB) levels within forebrain are higher in waking than in sleep, and levels of CRE-mediated transcription oscillate in the SCN in a circadian fashion. CREB mutant mice 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. Thus sleep may preferentially affect hippocampus-dependent and not amygdala-dependent memory consolidation, in fashion similar to that of the PKA signaling pathway

A study of data from healthy men, aged 16 to 83 years, looked at 24-hour profiles of plasma growth hormone (GH) and the stress hormone cortisol, and sleep using polysomnographic sleep recordings (measurements of brain activity, movements, and breathing during sleep). It was found that the decrease in SWS, i.e. the deepest most recuperative stage of sleep, from early adulthood to later life was paralleled by a decrease in GH secretion. Association of sleep with cortisol concentrations, on the other hand, was independent of age and became significant only after the age of 50 years when sleep became more fragmented and REM sleep, i.e. the sleep that is associated with dreaming and memory storage, declined. The strong and robust relationship between SWS and GH secretion has led to the proposal that they both are under the control of similar types of neurons that may be located in different areas of the brain, and they have shown that drugs that increase one of the functions also increase the other. It also has been proposed that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. Carbohydrate metabolism, endocrine function, and gastrointestinal balance in young, healthy adults were studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bed-time period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance and insulin sensitivity, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo-pituitary-adrenal function were qualitatively and quantitatively similar to those observed in normal aging. Thus, it appears that, in healthy men, that there are distinct changes in sleep quality that occur through the adult age span, and these changes also mark specific alterations in hormonal systems that are essential for metabolic regulation. In addition, these results indicate that sleep loss can increase the stress load, possibly facilitating the development of chronic conditions such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups. Development of drugs that affect common mechanisms in sleep and GH production may help alleviate some of these problems.

Sleep in women during the menopausal transition often is reported to be disturbed. In one large epidemiological study utilizing polysomnography, it was found that the likelihood of increased sleep-disordered breathing (SDB) over six months was significantly greater for women with peri and post, compared to pre-menopausal status. There was an independent risk of SDB (AHI>15) for menopausal compared to pre-menopausal women (OR=3.4) and peri- to pre-menopausal women (OR=1.4), independent of age or Body Mass Index. In addition, peri- and post- menopausal women using hormone replacement therapy (HRT) had lower and not statistically significant risks of SDB. This association is being further investigated to control for the differences in health and health behaviors of women on HRT. Relative to stable weight, a 10% weight gain predicted an approximate 32% increase in AHI. A 10% weight loss predicted a 26% significant decrease in AHI. A 10% increase in weight predicted a 6.0-fold increase in the odds of developing moderate-to-severe SDB over a four-year interval among 690 randomly selected participants in the study. This excluded participants with weight change in excess of 20% of baseline weight, since the model indicated a plateau of the relation with greater weight change. Menopausal status, independent of symptoms such as hot flashes, did not predict sleep problems or depression. Women with >10 nights with flashes per month had on average five more nights of restless sleep and four more nights of difficulty maintaining sleep and one more night of difficulty initiating sleep, than did women reporting no nighttime hot flashes; having <10 nighttime hot flashes was not strongly related to sleep complaints. The association between age and these complaints was slight, and menstrual status was not related to sleep complaints or depression.

Another large epidemiological longitudinal study of older men (mean age of 76.6 years, range 71 to 93) investigated the association between sleep disturbances (insomnia and daytime sleepiness) and the incidence of dementia and cognitive decline. It was found that there was a significant association between the self-report of excessive daytime sleepiness, found in 8% of the cohort, and diagnosis of incident dementia three years later. The risk was two-fold (O.R.= 2.2) as compared to those not reporting daytime sleepiness, after adjusting for age and other factors. Incident cognitive decline also was significantly associated with excessive daytime sleepiness (O.R. = 1.4). In contrast, insomnia, found in 31% of the cohort, was not associated with either incident cognitive decline or dementia.

A double-blind placebo-controlled clinical trial of melatonin was conducted on a group of older individuals (age 50 and older) with and a group without insomnia. Self-reports of insomnia were confirmed by actigraphy (measurements of body movements through the night period at home) as well as by polysomnography (measurements of brain activity, movements, and breathing during sleep) in the sleep laboratory. In addition to a placebo, each participant received different doses of melatonin (0.1, 0.3, and 3.0 mg) orally one-half hour before usual bedtime for one week in a random order, each followed by a one-week washout period. The highest dose (3.0 mg) is the dose commonly found in over-the-counter preparations and results in blood levels 10 to 20 times the normal physiological levels produced by the lower doses. The most effective dose for improving the quality of sleep, measured as sleep efficiency or the proportion of time in bed actually sleeping, was 0.3 mg. The highest dose, like the lowest dose, also improved sleep efficiency, although to a lesser extent. However, the 3 mg dose also significantly reduced nighttime body temperature and increased daytime melatonin levels.There was no relation found between a subject’s own endogenous melatonin levels and sleep efficiency. Individuals with normal sleep were unaffected by any dose of melatonin. Studies in young adults in a similar protocol indicate that when endogenous melatonin levels are high, exogenous melatonin (0.3 or 5.0 mg) has little effect. However, when exogenous melatonin is administered at circadian phases when endogenous melatonin is low, then there is a significant shortening of sleep latency and a significant increase in sleep efficiency. The results of this study demonstrate that low doses of melatonin that raise blood levels of melatonin to the normal nighttime range can significantly improve the quality of sleep in older people suffering from age-related insomnia, while not influencing the sleep of older people in whom sleep is normal.

Future Directions

Although there is a growing body of research on the aging circadian system, relatively little exists on the aging sleep homeostatic mechanisms. The brain mechanisms underlying age-dependent changes in the sleep homeostatic mechanisms are beginning to be understood. New studies are pursuing leads into the genetics of sleep. The relevance of the genetics of sleep to the problems of the older individual needs further stimulation. Similar to other recent findings that neuronal loss is not an inevitable consequence of aging, these data indicate that there is little evidence of an age-related loss of neurons that have been identified as playing a key role in the maintenance of sleep homeostasis. Thus, the age-related alterations in the control of sleep appear to not be due to loss of critical neurons but to subtle changes within the cells and in their interactions with other brain cells involved in the control of sleep and alertness. The elucidation of these factors, such as the role played by adenosine in the induction of sleep, should lead to the development of more effective and targeted pharmacological approaches to alleviate some of the problems of sleep that afflict over half of our older population.

Melatonin treatment is being tested for its sleep-inducing effects. However, it appears to be most effective at physiological doses in dealing with circadian desynchrony. Data from a clinical trial indicate that melatonin is not soporific in older people without insomnia. Research also needs to be directed at the development of new and more effective therapeutic modalities that are targeted at correcting the underlying pathological mechanisms of sleep disorders rather than treating them symptomatically. Until that time, however, clinical trials on the safety and efficacy of hypnotic and somnolent agents are needed

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

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

In FY2001, NIAAA awarded seven new applications that were submitted in response to a Request for Applications (RFA) on alcohol and sleep. The research areas supported under this new initiative include 1) the neural mechanisms of alcohol-induced sleep disturbances; 2) persistent poor sleep as a risk marker for development of alcoholism in adolescents; 3) the effects of prenatal alcohol exposure on development of circadian clock function; 4) medications for the treatment of sleep disorders in recovering alcoholic patients; 5) sleep and immune function in African Americans; and 6) alcohol abuse liability in insomniacs.As a result of this RFA, the NIAAA sleep research budget will almost triple between FY 2000 and FY 2002.

In addition to the newly funded grants, NIAAA continues to support sleep-related research in the following areas: 1) the effects of alcohol exposure through breast milk on the development of neural systems associated with sleep and arousal; 2) sleep disturbances in recovering alcoholics; 3) the relationship between alcohol consumption, sleep deficits, and serotonergic system function in nonhuman primates; 4) pharmacotherapy of alcoholism and comorbid insomnia; 5) adolescent sleep/arousal patterns as a pathway to alcoholism in early adulthood; and 6) animal models of alcohol’s effects on sleep. Published research highlights from currently funded projects are summarized below:

Sleep Disturbances after Exposure to Alcohol in Breast Milk

This study replicates and expands previous research demonstrating that sleep is disrupted during the 24 hr period following exposure to alcohol in mothers’ milk. In the current study, infants exposed to small amounts of alcohol through their mothers’ milk spent less time in active sleep and tended to be less active when they were awake than breast-fed infants not exposed to alcohol. These changes in sleep activity patterns were most evident in the three and a half hour period immediately following alcohol exposure. Of particular interest is that the infants compensated for the loss of active sleep by increasing the amount of active sleep during the following 20 hours when the mothers refrained from drinking. Although the mechanisms of this reduction in active sleep remain to be elucidated, this research has important practical significance for providing mothers and health professionals with information about the safety of drinking alcohol, especially in the hours immediately preceding breast-feeding. This study, which expands on previous research, indicates that short-term exposure to small amounts of alcohol produces distinctive changes in infants’ sleep-wake patterns, and that nursing women should time their breast-feeding in relation to drinking.

Insomnia, Self-Medication, and Relation to Alcoholism Relapse

It is well known that insomnia is a frequent complaint of recovering alcoholics. However, this is the first study to investigate the occurrence of insomnia and drinking to self-medicate insomnia in alcoholic patients, as well as the relationship of these two factors to alcoholism relapse. Based on eight items from the Sleep Disorders Questionnaire, 61% of alcoholics in treatment report high levels of insomnia 6 months prior to treatment. Compared to patients without insomnia, patients with insomnia are twice as likely to report using alcohol to get to sleep (55% vs. 28%), have worse polysomnographic measures of sleep continuity, and have more severe alcohol dependence and depression. Furthermore, symptoms of chronic insomnia, but not a history of self-medicating insomnia, are predictive of relapse to drinking during a 5-month follow-up period. These results suggest that patients at risk for relapse are easily identifiable by routine questions about sleep.

Interactive Effects of Age and Alcoholism on Sleep

Although both aging and alcoholism are associated with an increase in sleep disturbances, few studies have examined the combined effects of alcohol and aging on sleep. A recent study investigated whether older adults with alcoholism would exhibit more severe disturbances of sleep across a variety of objective sleep measures. Young and old recently abstinent alcoholic patients were compared with age-matched nonalcoholic controls. Although recently abstinent alcoholics and older adults have decreased total sleep time, increases in light sleep (Stage 1), respiratory distress, and periodic limb movements, older alcoholics have the most disturbances. Older alcoholics have the lowest sleep efficiency, percent of delta sleep, and rapid eye movement (REM) sleep latency and the highest sleep latency when compared to younger alcoholics and nonalcoholics of both age groups. These results indicate that age and alcoholism do interact to produce more severe sleep problems in older alcoholics and that it may be important to screen for sleep problems in this population.

Sleep Deprivation in Primary Alcoholics

Sleep disturbances are one of the most common problems reported by recovering alcoholics. EEG sleep studies reveal a reduction of total sleep time, fragmentation of sleep, losses of Stages 3 & 4 (delta) sleep, and less robust changes in REM sleep in alcoholics compared to controls. These sleep deficits are even more pronounced in African American alcoholics as compared with Euro-Americans. In healthy adults, sleep deprivation potentiates sleep continuity and enhances slow wave sleep. A recent study examined the effects of partial sleep deprivation in alcoholics to investigate reversibility of abnormal sleep in these patients. It was found that alcohol dependence interferes with the augmentation of slow wave sleep and delta power seen in healthy adults following sleep deprivation, but not does not impair increases in sleep continuity. The failure of sleep deprivation to ameliorate the loss of slow wave sleep and delta power is similar in Euro-American and African American patients. These results suggest a defect in regulation or plasticity of slow wave sleep in alcoholic individuals that could have implications for their health outcomes.

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

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

Targeting Sudden Infant Death Syndrome (SIDS): A Strategic Plan

In 1999, recognizing that substantial progress had been achieved, Congress recommended that the Institute develop a third five-year plan. At that time, the NICHD was engaged in Institute-wide strategic planning and thus had the opportunity to integrate the future goals and objectives of the SIDS program with those of other research agendas being developed by the Institute.

To formulate the plan, the NICHD convened a working group comprised of distinguished scientists and health care professionals from around the country. In collaboration with NICHD staff, the working group identified research objectives and strategies designed to achieve these goals. The working group drew on previous and ongoing planning efforts, conferences, workshops, and research findings to develop a strategic plan for a SIDS research and public health agenda that would guide the Institute over the next five years. The draft plan was placed on the web for public comment. The final plan was published on the NICHD website in the summer of 2001. It is available as a pdf file at: http://www.nichd.nih.gov/strategicplan/cells/

The following is an excerpt from the introduction.

“The purpose of the strategic plan is to outline a comprehensive research and public health agenda that builds on past successes and forges new paths of discovery. The recommendations go beyond deaths labeled as SIDS by medical examiners and coroners to include all sudden deaths occurring from late fetal life through infancy and early childhood. The plan defines strategies aimed at improving maternal as well as infant health. It encompasses both basic infant care practices and research based on the latest molecular genetic technologies. This framework will provide researchers with the knowledge and resources needed to illuminate the etiology of SIDS and, ultimately, to eliminate these needless deaths.”

The plan is divided into four sections: Etiology and Pathogenesis; Prognostics and Diagnostics; Prevention; and Health Disparities. Each section contains a statement of the problem, background information, and specific recommendations designed to address gaps in our current state of knowledge or intervention activities and to correct deficiencies in our basic scientific infrastructure.

Etiology and Pathogenesis: Knowledge acquired during the past decade supports the general hypothesis that infants who die from SIDS have abnormalities at birth that render them vulnerable to potentially life-threatening challenges during infancy. The recommendations in this section are targeted toward understanding:

- how the neural abnormalities observable in SIDS infants develop;
- how these neural abnormalities affect infant health and development before and after birth;
- whether there are genetic factors that predispose infants to sudden death;
- and finally, how specific characteristics of the fetal and postnatal environment either contribute to the pathological process or serve to protect infants

We know that SIDS is a developmental disorder: it originates during fetal development and occurs within a distinct developmental window. Ongoing research into the basic mechanisms governing normal development, utilizing the latest technologies, will provide us with an essential basis for understanding how developmental processes go awry in SIDS infants. This approach is founded on the basic principle that understanding normal developmental processes is an essential prerequisite for understanding derangements in development, a principle which is strongly emphasized in yet another of the Institute’s strategic plans, Developmental Biology: Understanding Normal and Abnormal Development. We also know that the health of the fetus determines the health of the infant—another fundamental principle reiterated in several current NICHD strategic plans, most notably Genetics and Fetal Antecedents of Disease Susceptibility and Biobehavioral Development. The biological continuum linking fetal and infant health or disease will be carefully explored throughout this SIDS strategic plan.

Prognostics and Diagnostics: The development of fetal and neonatal screening tools to identify fetuses and infants at high risk of sudden death depends upon knowing—or, at least, having a strong indication of—the functional abnormalities that are responsible for death. Such knowledge is also necessary for the development of effective therapies for at-risk infants. Advances in the realm of prognostics and diagnostics are likely to create new opportunities for refining ongoing investigations into the etiology and pathogenesis of SIDS. Although a slow process, as one knowledge base grows, so does the other. The recommendations in this section address:

- the assessment of neural maturity;
- the development and predictive value of screening tools

Prevention: As often happens in public health, it is possible to intervene successfully in the disease pathway and to reduce morbidity or mortality without a full understanding of the pathologic mechanism(s) involved. During the next five years, we wish not only to bolster the success of the “Back to Sleep” campaign, but also to diminish the prevalence of other SIDS risk factors.

The recommendations in this section emphasize the need for:

- strong community partnerships;
- knowledge of cultural variations
- rigorous evaluations of interventions and feedback from the lay community;
- comprehensive and consistent assessments of fetal and infant deaths;
- and finally, an understanding of how multiple risk factors may interact

The need to build and maintain viable collaborative partnerships with communities is a central theme of another of the Institute’s strategic plans, Health Disparities, Bridging the Gap. A recognition of the essential value of collaborations between the lay and scientific communities informs not only this section of the SIDS strategic plan, but also the following section as well.

Health Disparities: Although SIDS rates have declined in all populations throughout the U.S. during the last decade, disparities in SIDS rates and in the prevalence of risk factors remain evident in certain groups. On a national level, SIDS rates are highest among American Indians, Alaskan Natives, and African Americans, and lowest among Asians, Pacific Islanders, and Hispanics. However, heterogeneity in prevalence rates is also evident according to socioeconomic criteria or among subpopulations within the more general categories of race and ethnicity.

The recommendations in this section emphasize:

- the creation and maintenance of strong community resources for research and intervention;
- the investigation of both protective and adverse forces operating within and across populations;
- and finally, the investigation of both macro and micro (e.g., genetic predisposition) forces operating within and across populations.

Research Highlights

The Collaborative Home Infant Monitoring Evaluation (CHIME) Study, a multicenter cooperative study of home monitoring of high risk infants has been completed and analyses are in progress. Almost 1200 infants were enrolled in the following subject groups: healthy term infants, preterm infants <1750 grams, siblings of SIDS and babies experiencing an idiopathic apparent life-threatening event. The objectives of the study are to: determine whether home apnea monitors employing event recordings are effective in identifying episodes that are dangerous to the infant's health; determine the conditions that optimize the use of apnea monitors in high risk infants; correlate physiological markers, health status, and behavior with the propensity for life-threatening events; and provide important information on the maturation of heart and respiratory function in sleeping infants. The NICHD, CHIME investigators, and industry collaborated in the development of a new monitoring technology, which is being tested for its potential to detect and record life-threatening cardiorespiratory episodes. The technology incorporates new advanced computer capabilities, inductance plethysmography, ECG, pulse oximetry, and an accelerometer to detect motion and infant sleep position. In addition to home monitor event recording, which captures the physiology for a period before, during and post-event, the monitor is programmed to store continuous R-R intervals from the ECG, continuous breath-breath intervals, and normative 3 minute epochs at hourly intervals. A major study published in FY 2001 (JAMA 2001; 2852199-2207) showed that cardiorespiratory events (apnea and bradycardia) meeting conventional alarm thresholds are quite common, even in healthy term infants. More severe events were common only in preterm infants, and their timing suggests that they are not likely immediate precursors to SIDS. In addition, it is likely that conventional monitoring techniques would miss most of the cardiorespiratory events that were detected in the study subjects as they contained a high frequency of obstructed breathing.

Investigators have observed deficits in kainate, acetylchoine and serotonin receptors in the arcuate nucleus of the ventral medulla in infants who die with a diagnosis of SIDS. In Fiscal Year 1998, NICHD funded a program project grant, which is developing a piglet model to study the role of this and related brainstem regions in cardiorespiratory and cardiovascular responses to potentially life-threatening environmental stimuli during sleep. The investigative team has been focusing on arcuate nucleus homologues in the rostral ventral medulla (RVM). In FY 2001, two studies were published that may shed light on the mechanism of SIDS. When the RVM is inhibited using muscimol, which stimulates GABA receptors, the breathing response to elevated carbon dioxide was inhibited while the animals were awake and asleep (JAP 2001;90:971-980). The effect of muscimol was greatest during sleep. These data provide evidence that the RVM contains neurons, which are critical to the organism’s response to elevated carbon dioxide. In addition, the investigators obtained the first evidence that the RVM also contains neurons that are involved in the regulation of sleep architecture (Sleep 2001;24:514-527). When the RVM was exposed to muscimol, sleep cycling was abolished in some experimental animals, in others there was a decrease in low frequency eeg and delta power. Resting respiration, blood pressure, heart rate or ventilation and their modulation by state were unaffected.

Adenotonsillectomy (AT) is one of the most common surgical procedures performed in children for a variety of indications including suspected obstructive sleep-disordered breathing (SDB) and sometimes for inattention and hyperactivity, thought to be possible consequences of SDB. The goals of one research project are (1) to investigate the hypothesis that SDB is a cause of inattention, hyperactivity, and related behaviors in some children; (2) better define whether inattention and hyperactivity are frequent among children who undergo AT, (3) identify measures and levels of SDB that are indicative of these behaviors, (4) test whether improvement in SDB after AT is associated with improvement in behavior. Children ages 5 through 12 years are being recruited after they have been scheduled by their physicians for AT or hernia repair. A battery of well-validated behavioral assessment tools, cognitive tests, and structured psychiatric interviews will be used before surgery to define what behaviors are more prominent in the children scheduled for AT rather than hernia repair. All children will undergo preoperative polysomnography that will allow the determination of which polysomnographic findings are associated with well-defined adverse behavioral outcomes. Preoperative and postoperative testing in these subjects will provide a controlled non-randomized trial of AT for SDB, demonstrate whether SDB-associated abnormal behaviors improve after AT, and provide strong evidence for whether SDB is a cause of these behaviors.

The "Back to Sleep" National Public Health Education Campaign

Based on growing epidemiological evidence that sleeping on the stomach (prone) increases the risk for SIDS, the American Academy of Pediatrics (AAP) recommended in the spring of 1992 that healthy infants be placed to sleep on their side or back (supine) to reduce the risk of SIDS. In spring of 1994, the "Back to Sleep" coalition was formed between the U.S. PHS, the AAP, the Association of SIDS Program Professionals, and the SIDS Alliance, for the planning, development, and implementation of the "Back to Sleep" national public education campaign. In June of 1994, the campaign was launched. In 1996, the AAP revised the sleep position statement to recommend that back sleep position is preferred over side. Epidemiological studies have shown that side sleeping confers about twice the risk for SIDS relative to back, probably because babies roll from their side to their stomachs. The "Back to Sleep" campaign materials were revised to reflect this change. The campaign was in its fifth year of operation in FY 1999. The NICHD has taken the lead in activities of the "Back to Sleep" campaign with support and participation from the Bureau of Maternal and Child Health, HRSA, and the National Center on Sleep Disorders Research, NHLBI.

In FY 2001, outreach activities continued to focus on underserved minorities. In 1999, The National Black Child Development Institute (NBCDI) joined with the NICHD, the Back to Sleep campaign sponsors, and several other organizations in an outreach initiative to reduce SIDS in African American babies by urging parents and care givers to place healthy infants on their backs to sleep. The NBCDI and other organizations including the Alpha Kappa Alpha Sorority, Inc., Women in the NAACP, and National Coalition of 100 Black Women play a major role in promoting SIDS risk reduction activities throughout the U.S. To help these organizations initiate SIDS risk reduction programs in communities, the NICHD, Maternal and Child Health Bureau (MCHB) of HRSA , SIDS Alliance and partner organizations developed a Resource Kit for Reducing the Risk of Sudden Infant Death Syndrome (SIDS) in African American Communities. The Kit contains culturally appropriate materials such as fact sheets, brochures, magnets, a video, and a leader’s guide to encourage people to lead discussion groups in various community settings on ways to reduce the risk of SIDS. This kit was released at the beginning of FY 2001.

The first national training workshop on SIDS risk reduction was held on January 27, 2001 in Atlanta, GA. Approximately 50 participants from the Alpha Kappa Alpha Sorority, Inc., Women in the NAACP, and National Coalition of 100 Black Women convened to learn about SIDS, ways to reduce the risk, how to use the Resource Kit and what each organization can do to get the message out for local communities. Since then, the three organizations trained in Atlanta have utilized their regional meetings to train members of individual chapters and affiliates across the country on how to use the Resource Kit most effectively in their local serving communities. Over 40 train-the–trainer sessions have been completed and 1,050 individuals trained. Once trained, each chapter representative returned to their region to train other individuals on SIDS and the Resource Kit.Approximately 10,000 regional chapter or affiliate members have been trained to date.

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

Benzodiazapenes

Support by NIDA for sleep and circadian rhythm research includes both human and animal studies of brain circuitry underlying sleep architecture and, in particular, how psychoactive substances affect these circuits and associated biological rhythms. Among the most important are studies of sedative/hypnotic agents, notably benzodiazepines, designed to alleviate insomnia. These studies are important because the understanding of how these agents work will also provide insight into the causes of insomnia. Also, because these substances have abuse potential, the studies will provide clues to brain circuitry contributing to addiction.< yes">  In a recently published review [Mendelson WB (2001). J Clin Psychiatry 62 Suppl 10:5-8] it is noted that the most common benzodiazepine recognition site is associated with the gamma-aminobutyric acid A- [GABA(A)] benzodiazepine receptor complex. For example, the sleep-inducing effect of the intravenous anesthetic propofol (when injected into the medial preoptic area of the rat [Tung A, Bluhm B, Mendelson WB (2002). Life Sci 69(7):855-62]) was blocked for low doses by a GABA(A) antagonist [Tung A, Bluhm B, Mendelson WB (2001). Brain Res 908(2):155-60].

Oleamide

Oleamide, an endogenous unsaturated fatty acid amide, also has sleep promoting effects and has been shown to be associated with the GABA(A) receptor complex as evidenced by loss of its sleep-inducing effect in genetic knockout mice who lack the critical subunit of the receptor [Laposky AD, Homanics GE, Basile A, Mendelson WB (2001). Neuroreport 12(18):4143-7]. However, it was shown that the increase in slow-wave sleep in normals was not associated with concomitant changes in blood pressure, heart rate, or body temperature [Huitron-Resendiz S, Gombart L, Cravatt BF, Henriksen SJ (2001). Exp Neurol 172(1):235-43]. Currently-funded studies are focused on the fatty acid amide hydrolase enzyme in an attempt to understand the underlying physiological process en route to developing therapeutic interventions involving pain, sleep, and other disorders. Part of NIDA’s interest is driven by inclusion of this lipid signaling group of the endocannabinoid, anandamide.

Dopamine

While the role of dopamine is unclear in the various interacting mechanisms of circadian sleep/wake cycles and sleep architecture, its importance is becoming increasingly clearer. Wake-promoting compounds such as modafinil and, more generally, amphetamines seem to work by blocking the dopamine transporters. In genetic knock-out mice with the dopamine transporter absent, non-rapid eye movement sleep was reduced and wakefulness consolidation increased while methamphetamine had no effect [Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001). J Neurosci 21(5):1787-94]. Currently-funded research will focus on the effects of cocaine on the dopamine transporter and its effect on wakefulness as well as on sleep homeostasis, hypothesized to be decoupled. It is also hypothesized by the Mignot group that cocaine and methamphetamine operate on the dopamine terminals in the nucleus basalis. The lasting effects of cocaine on sleep and other cognitive functions are also being investigated in human cocaine addicts by Hobson and collaborators.

Genetics

Genetic studies are enthusiastically supported by National Institute on Drug Abuse in search of those genes underlying the mechanisms of drugs of abuse. Accordingly, these same mechanisms are observed in maintenance of circadian rhythms and the sleep architecture. The funded research ranges from work in Drosophila assessing how various circadian genes (e.g., Per) modulate the sensitivity of cocaine to investigations in different strains of mice to determine if there is a genetic basis to the differences in responses to drugs of abuse following sleep-deprivation.  The effects of sleep deprivation on the effects of alcohol and marijuana will also be investigated in humans.   This is important because sleepiness is often associated with traffic accidents involving these drugs; no systematic study has been conducted. The joint study of sleep and drugs of abuse is also important because sleep is disturbed in drug abusers whether they use cocaine, methamphetamine [Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Rischman MW (2001). Psychopharmacology 155(4):397-404], or marijuana [Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW (2001). Psychopharmacology 155(2):171-9]. Stimulants, especially methamphetamine, may be abused by those who have daytime sleepiness. Many of these studies are recently under way. NIDA hopes increasing studies in this area will shed light on the underlying mechanisms.

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

Training Future Generations: The Dement Fellows

In FY 2001, an innovative NIMH-supported program was implemented that involved 16 apprentices from 10 U.S. educational institutions. The apprentices, called Dement Fellows in honor of William C. Dement, M.D., Ph.D., took part in a 13-week program while enrolled in Psychology 0106 at Brown University. The intensive 3.5-week program included working with adolescent research participants and training in human sleep and circadian rhythms, behavioral and physiological research techniques, ethics of human research, and speech and communications. As part of the intensive program, each fellow received support to attend a rich academic experience at the annual scientific meeting of the Associated Professional Sleep Societies (APSS) in Chicago. Fellows crafted a selection of meeting events focused on content themes chosen by them and then explored further through the abstract book and preliminary program. Nine weeks of hands-on work on an adjunct NIMH-funded research project ("Adolescent Sleep: Circadian and Homeostatic Processes") followed. The apprenticeship program culminated in a two-day retreat that included each apprentice's brief oral presentation, career- and research-oriented presentations by the young investigators, and opportunities for fellowship.

Sleep In Children And Adolescents

Studies of adults over long periods of time have reported finding insomnia to be a significant predictor of the onset of substance abuse. Research supported by NIMH pursued the association between sleep problems and substance use among adolescents in the context of psychiatric problems. Data came from the US National Household Survey on Drug Abuse 1994-1996 that included 13,831 adolescents. In adolescents, use of cigarettes, alcohol, and illicit drugs were each associated with reports of frequent sleep problems. Adjusting for other problems such as depression, anxiety, deviance, and aggression reduced the associations between sleep problems and use of these substances, suggesting that part of the association is attributable to psychiatric problems. The part of the association not attributable to psychiatric problems was limited to the associations between sleep problems and use of illicit drugs. These results suggest that psychiatric problems are critical when considering the relationship between sleep problems and drug use/abuse. More specific measures of sleep problems may provide information on the relationship of sleep problems to the immediate health and well being of adolescents, as well as how successfully they progress into adulthood.

Important features of how the brain functions can be revealed by EEG measures such as “coherence”. Coherence is a measure of patterns of coordinated, periodic, and synchronous activity recorded in the brain. EEG studies in adults have shown high measures of coherence during sleep. The data have also indicated that EEG coherence measures are stable within individuals; that is, they showed high test-retest reliability and sensitivity to disruption by mood disorders including depression. NIMH-supported investigators have been trying to establish whether low values of inter- and intra- hemispheric coherence in EEG recordings are a reliable feature of childhood and adolescent depression. They hope that by identifying reliable biological features of depression they will be able to distinguish depression from other disorders and to select more appropriate treatments. The data to date suggest that low EEG coherence during sleep is indeed a biological marker for depression in children and adolescents.

Temporal coherence of EEG rhythms during sleep was different in adolescents with major depressive disorder compared to controls. Depressed children and adolescents both had lower intrahemispheric coherence, whereas interhemispheric coherence was lower only in depressed adolescents in comparison with controls. Interestingly, gender differences were evident in adolescents, but not in children (interhemispheric coherence was lowest in depressed adolescent girls). These findings are in keeping with increased risk for depression in females beginning at adolescence and extending throughout adulthood. Polysomnographic measures may also be predictors of the recurrence of major depressive disorder in children and adolescents. Subjects with a subsequent recurrence of major depressive disorder had decreased sleep efficiency and delayed sleep onset.

Circadian Rhythms: The Role Of The Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN) of the hypothalamus is believed to contain the “clock” that drives circadian oscillations permitting the entrainment of the daily activity of organisms to the external patterns of changing light and dark. A number of genes, such as Per1, have been identified that regulate these oscillations within SCN neurons. Some of these genes are not exclusive to the SCN or even to brain, but have been found in peripheral tissue like the gut and liver. One of the questions that this evidence opens up is the role played by the SCN. Current dogma holds that the SCN is the seat of the clock. Some investigators have begun to explore the view that the circadian system is a system of the whole animal that comprises multiple oscillators, including the SCN, perhaps as a master integrator.

NIMH-supported investigators began this line of questioning to examine how multiple rhythms may be coupled to form a coherent system. Their approach was to examine the effects of cycles of food availability on the rhythms of gene expression in the liver, lung, and SCN. Although food cycles are not commonly used in studies of circadian entrainment they do in fact exert powerful entraining effects on behavior. Taking advantage of a transgenically modified rat strain, investigators can continuously monitor rhythmic expression of the Per1 gene by measuring fluorescent light emissions from the tissues whenever the gene was active. They found that while the rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver cells, shifting its rhythm by 10 hours within 2 days. This indicates that feeding cycles entrain the liver independently of the SCN.

In another study neural tissues cultured from rats carrying the same genetic modifications were used to monitor the intrinsic Per1 expression patterns in different brain areas and, at the same time, their response to changes in the light cycle were measured. Fourteen of 27 brain areas expressing Per genes were rhythmic. The pineal and pituitary glands both expressed rhythms that persisted for .3 days in vitro, with peak expression during the subjective night. Nuclei in the olfactory bulb and the ventral hypothalamus expressed rhythmicity with peak expression at night, whereas other brain areas were either arrhythmic or weakly rhythmic and peaked at night. After a 6 hr advance or delay in the light cycle, the pineal, paraventricular nucleus of the hypothalamus, and arcuate nucleus each adjusted the phase of their rhythmicity with different kinetics. Thus the brain seems to contain multiple, damped circadian oscillators outside the SCN. The phase relationships of these oscillators to one another may play a critical role in coordinating brain activity and its adjustment to changes in the light cycle.

These results suggest that it may be important to reexamine the mammalian circadian hierarchy. Furthermore, the coordination of some peripheral circadian oscillations with light-dark cycles may occur primarily through rhythmic behaviors, such as feeding, rather than through intricate neural or hormonal connections linking the peripheral nervous system with the brain.

The progress of the circadian biology researchers in identifying the parts of the molecular machinery that operate the clock in the SCN has been a major neuroscience success story. In spite of important strides related to understanding the intracellular machinery, however, little is understood about how the signal produced by the clock controls certain rhythmic behaviors. A number of SCN secreting factors have been reported, and NIMH-supported investigators reasoned that some of them should control daily activity rhythms as measured by wheel running in hamsters, the standard and well-established measure. By systematically screening candidate molecules, they found that local infusions of TGF-alpha completely stopped wheel running, without any other motor impairments. Furthermore, levels of TGF-alpha were high in the SCN during the day when wheel running was inhibited and low at night.  The TGF-alpha signal from the SCN acted on another hypothalamic brain region outside the SCN called the subparaventricular zone that is known to control daily rhythms of running activity. These findings suggest that, at least for wheel running, light and the internal clock use the same molecular signals to inhibit running.

Seasonal Affective Disorder: Biological Substrates

Complaints of recurrent episodes of winter depression (seasonal affective disorder, or SAD) are a common and significant problem for people in temperate and boreal regions. Many of the symptoms are similar to seasonal changes seen with other mammals. These symptoms include changes in body fat, increased sleep drive, and reduced sexual motivation. We know that in animals these changes are associated with changes in day length. Reduced day length in winter increases the duration of nocturnal melatonin secretion. NIMH investigators hypothesized that perhaps the reduced day length acted as a signal for biological alterations in patients with seasonal affective disorder. By measuring the duration of melatonin secretion under constant conditions in winter and summer in both SAD patients and matched healthy volunteers, they found that in SAD patients the duration of the nocturnal period of active melatonin secretion was longer in winter than in summer. No changes in melatonin secretion were found in healthy volunteers. It is therefore possible, that the neural and hormonal systems mediating the effects of day length on mammalian behavior are similarly involved in patients with SAD.

Orexin/hypocretin Regulation of Behavioral State

The finding that narcolepsy is caused by abnormalities in the neuropeptide orexin directs attention to the role it plays in the control of sleep, wakefulness, and arousal. Endogenous orexin may suppress REM sleep and promote wakefulness. Thus, investigations pursuing the molecular mechanisms mediating orexinergic control of sleep are crucial. NIMH-supported studies of this system have found that perfusion of Orexin-A in the rat basal forebrain (cholinergic region of the horizontal limb of the diagonal band of Broca, and substantia inominata) increased wakefulness in a dose-dependent manner. Studies have shown that mice strains with mutations causing absence of orexin neurons exhibit narcolepsy and hypophagia with severe obesity. This finding suggests that orexin neurons are also involved in feeding behavior and body fat regulation. Nearly all neurons expressing pre-pro orexin mRNA also expressed prodynorphin mRNA and the reverse was also true. Dynorphin is known to influence feeding. Furthermore, within the lateral hypothalamus dynorphin expression is restricted to the orexin neurons.

The distribution and localization of these neurotransmitters in diurnal animals is not well known, but studies in the brain of a diurnal rodent, Arvicanthus niloticus, have also identified the localized presence of orexin in the lateral and dorsomedial hypothalamus, and in the perifornical area which is known to play a role in mammalian sleep and feeding systems. Dense staining of fibers was observed in paraventricular thalamus, locus coeruleus, and the brain stem raphe nuclei. While the distribution of orexinergic cells and fibers in this diurnal species is similar to nocturnal species such as rats and mice, it remains to be seen if the arousal functions of this system are also similar.

Sleep and Memory

NIMH investigators have made important strides in establishing that sleep affects memory, and learning influences sleep. Sleep researchers have led the way in showing how the brain undergoes profound changes in neurochemistry and neurophysiology throughout the wake-sleep cycle. They have also demonstrated that these changes are accompanied by alterations in cognitive processing. Indeed, some forms of learning may have a critical requirement for post-training sleep.

Visual perception and motor skill studies have shown important links between sleep and memory. For a visual texture discrimination task, consolidation of learning requires 6 hours of sleep on the night following training. Slow wave sleep appears necessary during the first two hours of sleep and REM sleep after the sixth hour of sleep. When subjects are totally sleep- deprived the night after training, no improvement is seen even after two nights of recovery sleep. These data suggest an important role for human sleep in off-line (non waking) memory reprocessing.

On the behavioral level, NIMH investigators have used the conditioned fear model of anticipatory anxiety to examine the effects of emotional stimuli on sleep. Both shock training and the subsequent presentation of fear-conditioned cues produce strong and relatively selective suppressing effects on rapid eye movement (REM) sleep in rats and mice. The REM-suppressing and sleep altering effects vary among inbred strains of mice that differ on behavioral tests of anxiety, with more “anxious” mice showing the greatest REM suppression. Some strains also show decreases in total sleep. The central nucleus of the amygdala (CNA), given its role in conditioned fear and REM regulation, may be a key region for regulating sleep in fearful and anxiety-producing situations. The formation of learned associations between shock and cue occurs in conjunction with marked decreases in REM sleep. BALB/cJ mice show reduced REM for up to four hours after shock training. In these mice, Fos gene expression, which marks activity in neurons, is high in the basolateral amygdala (BLA), and virtually absent in CAN at two and four hours after shock training. BLA is most linked to memory formation, whereas CNA is linked to REM control. Fos patterns in these mice indicate that REM suppression does not prevent activation of regions implicated in memory formation. Interestingly, increases in Fos in CNA have been reported at one hour after shock training.

It is clear that the regulation of brain plasticity during sleep will not be an easy process to understand. NIMH-funded investigators have shown that the expression of P-CREB, Arc, and BDNF, three genes whose induction is often associated with synaptic plasticity and the acquisition of new memories, is high during wakefulness and low during sleep. Furthermore, the induction of these genes during wakefulness depends on the activity of the noradrenergic system that is high in wakefulness and low in sleep. A critical question for future investigations is whether prolonged sleep deprivation may lead to disruption of plasticity because of specific cellular alterations. Moreover, it is becoming possible to ask, in molecular terms, whether sleep may be important for other aspects of memory. For example, is sleep involved in the selective consolidation of recently acquired memories, or is it instead involved in the maintenance of old memories through an ongoing, indiscriminate activation of neural circuits?

Disrupted Sleep And Event-Recall Following Trauma

Post-Traumatic Stress Disorder (PTSD) can be a chronic and debilitating disorder that develops in some people exposed to severely threatening trauma. Insomnia and non-restorative sleep are a widely recognized symptom. In addition, nightmares related to the trauma are also a cardinal symptom of PTSD. Dreams associated with trauma appear to be very different from normal dreams. Normally dreams are logically sequenced and do not appear to correspond to reality. In PTSD dream content appears to replicate the episodic quality of the experience. This repetition of features of the traumatic event during sleep has been proposed to contribute to a kind of hyper-consolidation of the associated memories. In a recent NIMH-supported study, injured patients (aged 18-54 yrs) were assessed six weeks following a life-threatening event and with follow-up assessments six weeks later in 39 participants. In 21 dream reports collected and rated from morning diaries, ten described events similar to the recent traumatic event. The participants reporting these distressing trauma dreams had more severe concurrent PTSD symptoms than those reporting other categories of dreams and had more severe initial and follow-up PTSD than those without dream recall. These findings, along with preliminary longitudinal observations relating changes in dream patterns to outcome, suggest a relationship of dream characteristics and early adaptive vs. maladaptive patterns of processing traumatic memory. Although the weight of data currently seems to favor a REM based origin for nightmares, more physiological measures of sleep such as REM density are needed. The potential for animal models to examine physiological indicators of memory recall following trauma has not been sufficiently explored in the context of sleep.

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

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

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% of RLS patients also have periodic limb movement disorder (PLMD), or nocturnal myoclonus, which is characterized by repetitive stereotyped movements of the limbs, primarily the legs, during sleep. In order to increase the amount of research in RLS and PLMD, NINDS, the National Institute on Aging (NIA), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Mental Health (NIMH) issued a Program Announcement in FY 2001 encouraging applications that would enhance our understanding of the pathogenesis of these disorders and develop more effective treatment strategies (also see Director’s Report, NCSDR).

In an ongoing RLS grant funded by the NINDS, Guy Rouleau and his colleagues in Montreal recently reported the results of a genome-wide scan in a large French-Canadian family. Significant linkage to chromosome 12q was found, with suggestion of an autosomal recessive mode of inheritance. Although there had been previous suggestions of familial associations in RLS, this study is the first identification of a major genetic locus for the RLS phenotype. Studies are continuing to locate and characterize the specific gene involved.

NINDS continues to support studies of the cause and treatment of narcolepsy, a neurological disorder characterized by excessive daytime sleepiness, an inability to move shortly after awakening, and sudden episodes of muscle weakness. Two years ago, researchers at the NINDS-supported Center for Narcolepsy and Related Disorders at Stanford University, led by Emmanuel Mignot, first reported the discovery of a gene that causes narcolepsy in a canine model. The gene carries instructions for making a nerve cell receptor for a brain-signaling molecule, called hypocretin or orexin. Last year, it was found that humans with narcolepsy did not have the same genetic defect, but they did have abnormally low brain levels of the hypocretin molecule. Dr. Mignot and colleagues have now cloned the canine narcolepsy gene (Hcrtr2) and are now developing transgenic mouse models of the disease.

Another study from the Mignot laboratory found an interesting association between apolipoproteinE and sleep apnea. Individuals with the z4 allele of the protein had an increased frequency of sleep-disordered breathing. ApoEz4 is also a well-known risk factor for Alzheimer disease and cardiovascular disease. Sleep-disordered breathing is common in Alzheimer patients and increases the risk for cardiovascular disease. Although these studies do not indicate a causal relationship, they do suggest that there is a complex interaction among sleep, brain pathology, and cardiovascular disease in ApoE4 carriers.

In an NINDS-supported study of sleep disturbances and associated complications, Ronald Chervin at the University of Michigan Medical Center found an increased frequency of attention-deficit/hyperactivity disorder (ADHD) among children with sleep-disordered breathing. Symptoms suggestive of a variety of sleep disorders, including periodic limb movement disorder, insomnia, sleep-disordered breathing, and excessive daytime sleepiness were present with high frequencies in children surveyed at two general pediatric clinics. An extensive chart review indicated that these symptoms were rarely discussed, diagnosed, or treated during these office visits.

The NINDS supports both animal and human studies in the area of circadian biology. One new grant in FY 2001 was submitted in response to a Program Announcement, sponsored by the National Institute on Aging (NIA) and co-sponsored by the NINDS, Earth Based Research Relevant to the Space Environment. In this grant, Charles Czeisler, of Brigham and Women’s Hospital, Boston, will determine the extent to which the intrinsic period of the human circadian pacemaker can be influenced by prior entrainment to non-24 hour day lengths. A manned exploration to Mars is scheduled for 2018, and astronauts will need to adapt to the 24.65 hour Martian day. The ability of astronauts to sustain a high level of performance during missions to Mars will be critically dependent upon the ability of the human circadian pacemaker to adapt to such non-24-hour day lengths. These studies will help answer fundamental questions on the mechanisms underlying circadian entrainment in humans and lead to the development of space flight countermeasures such as pre-adaptation of astronauts to non-24-hour days prior to space flight.

The NINDS, in collaboration with the National Center on Minority Health and Health Disparities (NCMHD), the National Center for Research Resources (NCRR), and the National Institute of Mental Health (NIMH) has initiated a new funding mechanism, the Specialized Neuroscience Research Program (SNRP) at Minority Institutions. One goal of the program is to foster innovative and effective partnerships and collaboration between minority institutions and established neuroscience laboratories at federal and non-federal research institutions. Of the ten programs established through a 1999 initiative, three are conducting research related to sleep and circadian rhythm.

At the Howard University SNRP (“Neuronal and Chemical Control of Breathing and Airway Function”), Musa Haxhiu is examining how CNS sites that regulate REM and non-REM sleep might exert a differential control on respiratory related skeletal and airway smooth muscles. David Gdovin, one of the investigators at the SNRP at the University of Texas at San Antonio, is studying an amphibian tadpole model to understand the development of respiratory oscillators and pacemakers. His results could be relevant to sudden infant death syndrome in humans. At the Alaska Basic Neuroscience Program, Dr. Abel Bult, in consultation with Dr. Rae Silver at Columbia University, is examining the role of the superchiasmatic nucleus in behavioral adaptation to extreme environments. It is hoped that these specialized programs will help develop and sustain viable neuroscience programs in these institutions.

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NATIONAL INSTITUTE OF NURSING RESEARCH
Karin Helmers PhD
NINR Representative to the Trans-NIH Sleep Research Coordinating Committee

NINR’s research portfolio consists of three general areas: 1) the impact of sleep deprivation across the lifespan in healthy populations; 2) sleep related problems in patients with chronic illnesses; and 3) the management of sleep disturbances. The following are some examples of these research studies.

Sleep Deprivation in Healthy Populations

Partial sleep deprivation is found among shift workers, medical workers, parents of small children, and as a result of lifestyle choices. An NINR-funded study will determine the amount and timing of chronic partial sleep deprivation at which alertness and waking functions are compromised. Another NINR funded study is testing an intervention on how to adjust to jet lag. Jet lag impairs judgment and performance of businessmen and women, diplomats and the military. Information on the effects of sleep deprivation and how to treat individuals who are forced to sleep at the wrong phase of the circadian cycle will be useful for shift workers and for others forced to deal with changing time and altered sleep schedules.

New parents often experience sleep disruption after the birth of their first infant. Sleep deprivation can lead to significant psychosocial morbidity including marital unhappiness, reduced quality of life, depression, and potential for child abuse. A recently funded NINR study will test an environmental-behavioral intervention to minimize the sleep disruption and fatigue experienced by new parents. In another study on infants, electrophysiological monitoring will evaluate whether skin-to-skin contact between premature infants and their mothers compared to sleeping in an incubator will promotes quiet sleep, which is necessary for brain development.

Sleep Disruption in the Chronically Ill

There are many chronic health conditions that interfere with sleep. Sleep disturbances are associated with Alzheimer’s disease, dementia, rheumatoid arthritis, fibromyalgia, AIDS, asthma and urinary incontinence. Sleep disturbance is exacerbated by pain and by conditions that require hospitalization. This sleep disturbance can exacerbate secondary conditions such as depression in chronically ill individuals. A recent study on pregnant women found that 23% reported restless leg syndrome (RLS), a sleep disturbance involving an unpleasant sensation in the legs (also see NINDS report). In comparison to other pregnant women, pregnant women with RLS had lower serum levels of folate and a more depressed mood state.

A majority of patients on hemodialysis report difficulty sleeping. It is known that daytime sleep affects nighttime sleep patterns, and recent research demonstrated that the hemodialysis procedure might induce daytime sleepiness as it alters core body temperature and triggers the production of sleep-inducing substances such as interleukin-1. A recent study co-funded by NINR and several other institutes found that end-stage renal patients who received hemodialysis in the morning had longer survival rates than those who received hemodialysis in the afternoon. A randomized clinical trial that varies the time of day at which hemodialysis is administered was recommended by the investigators.

NINR supports research on a variety of chronic disorders. These include the characterization of sleep patterns and their relationship to age and gender in coronary artery bypass patients; examining the neuroendocrine disruption of cortisol and serotonin and the autonomic imbalances that may account for the poor quality of sleep found in women with Irritable Bowel Syndrome (IBS) in comparison to non-IBS women; a study to identify which patients with narcolepsy are less likely to respond to stimulant medications, which will allow clinicians to concentrate their efforts on improving treatment regimes for these patients; and determining if a simple and inexpensive technique, pupillometry, can assess daytime sleepiness and several sleep disorders including sleep-disordered breathing (sleep apnea) and narcolepsy.

Management of Sleep Disturbance

The prevalence of sleep disturbance is highest in women, older adults, and patients with medical or psychiatric disorders. A researcher will be evaluating the normal non-linear changes that occur in sleep as one ages and will compare these changes in men and women. This research will help to determine normal sleep pattern changes and hence to identify abnormal changes. In another study, a new investigator is using behavioral treatments to improve sleep in the elderly. Older community dwelling adults frequently experience insomnia. Sleep difficulties can affect daytime physical and social functioning, and have been associated with an increased incidence of depression.

Agitation is a common problem experienced by people with dementia, and sleep disturbances have been associated with increased agitation. Nurse researchers are testing innovative strategies to improve nighttime sleep in institutionalized patients with Alzheimer’s disease. In addition, as a result of the nighttime activities of patients with Alzheimer’s disease, the sleep of their caregivers is also disrupted. A nurse researcher is developing a night alarm prompt system to reliably identify unsafe patient nighttime activity and hence alert caregivers. The decreased agitation in Alzheimer’s disease individuals and the reduced worry and increased sleep experienced by caregivers may delay or reduce the need for institutionalization of the demented patient.

Other examples of studies in the portfolio are determining whether melatonin is effective in alleviating the sleep disturbance found in Parkinson’s disease patients and evaluating an innovative intervention using the Internet to improve adherence with the continuous positive airway pressure (CPAP) ventilation in patients with obstructive sleep apnea.

Training and Career Development

NINR is committed to the training and career development of new investigators in the area of sleep research. NINR supports two mentored research scientist development awards related to sleep. The research focus of these mentored awards is the characterization of sleep in coronary artery bypass patients; studying the relationships among stress, immune function and sleep quality in persons with HIV; and exploring the relationships between maternal and infant circadian rhythms during early infant life. NINR also supports two pre-doctoral fellowships, one on an intervention using neurofeedback for treatment of insomnia and the other on examining sleep patterns of women at risk for preterm labor. In addition, NINR funds two post-doctoral positions in an institutional training grant on sleep and its disorders.

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FINANCIAL REPORT
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE

FY 2001 Sleep Disorders Research Funding
(Dollars in thousands)
1995 Actual 1996
Actual
1997 Actual 1998 Actual 1999 Actual 2000 Actual 2001 Actual 2002
Estimate
2003
Estimate

NHLBI

13,674

16,450

19,219

22,932

31,845

35,128

37,579

41,337 44,230

NINDS

8,018

9,453

11,598

13,639

15,231

12,495*

17,603

19,108 20,393

NICHD

6,627

7,368

7,217

9,131

7,116

6,797

7,084

8,100 8,800

NIA

7,847

7,800

9,179

11,818

13,296

13,034

14,533

16,500 17,900

NIMH

29,721

27,231

28,601

34,027§

39,219

40,667

50,742

57,438 62,243

NIDA

1,084

1,201

1,042

1,586

2,163

2,533

2,517

2,800 3,000

NIAAA

793

551

728

766

736

1,132

1,681

1,807 1,897

NINR

2,107

2,842

3,565

3,394

3,503

4,635

5,375

5,913 6,268

NCRR

2,944

3,247

3,570

5,542

6,637

7,117

7,193

8,906 9,764
NCCAM n/a n/a n/a n/a n/a n/a

177

210 250
NHGRI n/a n/a n/a n/a n/a n/a

599

679 740

Total

72,815

76,143

84,719

102,835§

119,746

123,558

145,083

162,798 175,485

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

§ Revised from Trans-NIH Annual Report for fiscal year 1998

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

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The complete FY 2001 grant listing can be viewed online in two formats:
Grants List in HTML [257K]
Grants List in PDF [135K]
(More information on PDF and the required reader is available.)

Printed copies of 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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