Annual Report
of the
Trans-NIH Sleep Research Coordinating Committee
FISCAL YEAR 2000

Table of Contents

Introduction
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
Complete List of Sleep Research Grants, FY 2000 (Grants List)
    Grants List in HTML [270 K]
    Grants List in PDF [167 K] (More information on PDF and the required reader is available.)


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Sleep Disorders Information Scientific Information and Resources

I.  INTRODUCTION - Trans-NIH Annual Report, Fiscal Year 2000

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, the sleep-related portfolio of the National Center for Research Resources is included in the attached budget table.

The NHLBI was mandated to establish the National Center on Sleep Disorders Research (NCSDR) in 1993. In conjunction with this mandate, the Director, NIH, transferred responsibility for the Trans-NIH Sleep Research Coordinating Committee to the NCSDR, the main coordinating unit within the NIH. The NCSDR maintains a complete file of annual reports from the initiation of the Committee in 1986.

II. Sleep Related Research Activities of Institutes Comprising the Trans-NIH Sleep Research Coordinating Committee

THE NATIONAL CENTER ON SLEEP DISORDERS RESEARCH (NCSDR)

M. Twery, Ph.D.

The NCSDR continues to facilitate the development of research, training, and educational programs across NIH and other federal agencies including the following initiatives, workshops, symposia, and meetings:

Collaborative Activities

Trans-NIH and federal agency collaborative projects included:

Education Activities: In addition, the Center continues to work with the Sleep Disorders Research Advisory Board, other federal agencies, and professional and voluntary organizations in a wide range of collaborative projects including federal accounting of sleep research, opportunities for implementing and monitoring the National Sleep Disorders Research Plan, dissemination of educational materials, and medical education on sleep.

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NATIONAL HEART, LUNG AND BLOOD INSTITUTE
M. Twery, Ph.D.

Scientific Research and Initiatives

The NHLBI sleep research program covers a wide spectrum of fields ranging from neuroscience, genetics, and circadian rhythm to anatomy, physiology, behavioral science, epidemiology, clinical research, and health education.  The program is aimed at understanding the molecular, genetic, and physiological regulation of sleep and the relationship of sleep disorders to cardiopulmonary disease.  NHLBI is a major supporter of investigator-initiated sleep research at 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); and requests for applications (RFA) on the Molecular Biology and Genetics of Sleep and Sleep Disorders (RFA HL-97-015), Obstructive Sleep Apnea in Children (RFA HL-98-004), and Phenotypic Characterization of Sleep in Mice (RFA HL-99-001).  New initiatives on the Development of Mouse Phenotypic Screens (RFA HL-99-010), Oxygen Sensing During Intermittent Hypoxia (RFA HL-00-004), and Genomic Applications for Heart, Lung, and Blood Research (HL-99-024) will stimulate research on new models related to the study of 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 control with clinical investigations on the etiology and pathogenesis of sleep disorders particularly sleep apnea.  In addition, the ongoing multi-center Sleep Heart Health Study is employing clinical and epidemiological approaches to examine whether subjects with high blood pressure have sleep apnea; whether sleep apnea is a contributing risk factor for the development of cardiovascular and cerebrovascular disease; and how age, gender, and ethnicity influence the association between apnea, hypertension, and stroke.  Innovative biomedical technologies are being developed to improve diagnostic and treatment approaches for sleep-disordered breathing under the Small Business Innovation Research (SBIR) Program.

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 30 reports on sleep medicine education since the program began in 1997.  NHLBI also supports programs to train students, scientists, and physicians in basic and clinical research in sleep, pulmonary physiology, and medicine.  A number of new findings in the NHLBI sleep program are highlighted by research into the epidemiology of sleep apnea and cardiovascular disease; sleep apnea and children; and sleep disorders.

Sleep Apnea 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.  Recent studies provided new evidence that the risk of cardiovascular disease associated with sleep apnea may be much greater than previously suspected.  New findings indicate that minimal sleep apnea (intermittent blockage of breathing during sleep) and even snoring are associated with a 1.5 fold increased risk of hypertension.  The association of moderate to severe sleep apnea with hypertension is strongest in young adults even when they are of normal weight.  Although the prevalence of sleep apnea is 2-3 times greater in men, the risk of hypertension in men and women with sleep apnea is similar.  A correlation also exists between severity of sleep apnea at baseline and the presence of hypertension four years later, independent of other risk factors such as body weight and gender.  In older age groups, an association has been found between sleep apnea and hypertension, heart failure, stroke, and all cause cardiovascular disease.  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.

The effects of sleep apnea that lead to cardiovascular disease are incompletely understood.  Repetitive episodes of apnea have been previously shown to produce sustained increases in the nervous system signals that constrict blood vessels.  New findings suggest that sleep apnea may also impair the ability of blood vessels to dilate and respond to the weight-reducing hormone, leptin.  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 Apnea in Children

Recent studies indicate that the etiology of childhood apnea may be different from that in adults. Previous studies have shown that children with sleep apnea are less sensitive to airway obstruction than children without apnea.  New findings indicate that apnea occurs primarily during episodes of deep (REM) sleep in children and that the severity of apnea increases over the course of the night.  However, apnea does not appear to affect the regular pattern of REM sleep episodes in children.  In contrast, arousal in adults is responsible for terminating airway obstruction but produces fragmented sleep.  Normal children have a relatively narrow upper airway, but maintain airway patency during sleep because of increased airway muscle tone and an increased drive to breath.  The findings indicate that children with apnea may be less easily aroused by interruptions in breathing compared to normal children and suggest that the worsening of apnea at night may be secondary to factors such as airway muscle fatigue and abnormal control of airway muscles.

REM sleep is thought to facilitate growth and maturation and the preservation of sleep patterns in children are believed to be developmentally important.  Studies are underway to determine whether intermittent hypoxia is associated with sleep apnea and influences childhood development.  Hypoxia developing from inadequate ventilation during early development has been associated with SIDS, and may increase the risk of cardiorespiratory diseases later in life.  Extrapolating from findings in adults, unrecognized apnea may also be expected to predispose children to cerebrovascular disease, pulmonary hypertension, and performance deficits.  Since sleep apnea occurs in 1-3% of preschool children, it will be important to understand why sleep disordered breathing leads to hypertension in children and how to treat children at risk.

Sleep Disorders

Prolonged wakefulness significantly impairs human performance and is associated with a greater risk of motor vehicle accidents.  A recent study investigated the vulnerability of patients with untreated sleep apnea and narcolepsy in safe driving performance.  The findings indicate that the ability of patients to maintain attention over time-on-task decreased 24 fold in patients with apnea and 100 fold in narcoleptics.  The brain wave patterns exhibited by sleep apnea patients during driving simulation suggest that poorer driving performance can be attributed to both attention lapses and sleep.  A new study of 50 sleep apnea patients has shown that successful treatment with continuous positive airway pressure (CPAP) improves driving simulator performance and decreases risk of motor vehicle accident..

Human susceptibility to narcolepsy, a sleep disorder characterized by episodes of sleepiness and sudden losses of muscle tone, has been associated with several genetic markers.  New research into the genetic basis of narcolepsy led to the discovery of a mutation on dog chromosome 12 that produces symptoms resembling those of human narcolepsy.  This gene for canine narcolepsy encodes a defective receptor for the potential neurochemical signaling substance in the brain called hypocretin (orexin).  Other studies have confirmed these narcoleptic abnormalities using genetically engineered mice lacking either the hypocretin gene or the hypocretin receptor gene.   Recently, the level of hypocretin in human tissue has been investigated and found to be deficient in many narcoleptics.  Human brain tissue from narcoleptic patients has also been examined and there is evidence that hypocretin-producing cells have been damaged or destroyed.

Chronic or intermittent sleep-related problems, such as sleep apnea, narcolepsy, and insomnia are associated with significant morbidity and dysfunction due to excessive sleepiness.  Together, these new studies provide strong evidence for the role of a specific neural pathway (hypocretin) in the pathophysiology of narcolepsy.  This discovery is important in that it not only links a gene to the disease, but paves the way to an improved understanding of the fundamental nature of sleep and its contribution to human health and well-being.  Mutations in the hypocretin receptor gene may be a factor in some, if not all, human narcolepsy cases and specific therapies to target and compensate for the failure of the hypocretin system in this and other sleep disorders can be designed.  The knowledge from these new studies also provided clues to explain the effectiveness of an anti-narcoleptic drug recently approved by the FDA (modafinil/provigil).  Studies in mice suggest that the drug may act by stimulating hypocretin-containing neurons regulating sleep and wakefulness.  This discovery is important in that it not only links a gene to the disease but paves the way to an improved understanding of the fundamental nature of sleep and its contribution to human health and well-being.

The Institute also supports basic research to investigate how sleep deprivation impairs the ability to ward off infection.  The results indicate that soon after the start of chronic sleep loss there is a proliferation of bacteria in the intestine and lymph nodes that precedes overt signs of illness.  The findings suggest that sleep loss causes an abnormality in the immune system allowing disease-causing bacteria to migrate into normally sterile tissues such as the liver, lung, and spleen.  The toxic effects of this bacterial invasion may further impair certain cardiopulmonary, endocrine, and metabolic processes.  Sleep quickly reverses these abnormalities implying that the restorative function of sleep may include maintenance of the immune system.

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NATIONAL INSTITUTE ON AGING
A. Monjan, Ph.D., M.P.H

Sleep and Circadian Rhythm Research

Changes in daily sleep patterns are some of the most prominent behavioral and symptomatic changes that occur with aging.  Understanding the age-related changes in the nervous system that underlie changes in sleep can lead to better means of primary and secondary prevention of these disorders and, thus, reduce the economic and social impacts of sleep disturbances in the older population.  Data indicate that in the elderly, age by itself does not predict incident complaints of insomnia, even in the presence of lowered sleep efficiency and decreased proportion of slow wave sleep.  Rather, the prevalence of insomnia and other sleep disorders is high in the older population due to their growing numbers and the associated co-morbidities common in late life that affect sleep.

Several therapeutic strategies, especially phototherapy and melatonin administration, are likely to become effective treatments for some of the insomnias associated with aging.  The use of bright light therapy for phase disorders is now more commonplace.  Behavioral modifications, such as stimulus control and sleep restriction appear to be effective techniques for shortening the sleep latency and wake after sleep onset times.  Melatonin treatment is being tested for its sleep-inducing effects; it appears to be effective at physiological doses in dealing with circadian desynchrony.  Research also needs to be directed at the development of new and more effective therapeutic modalities that are targeted at correcting the underlying pathological mechanisms of sleep disorders rather than treating them symptomatically.  However, until that time, clinical trials on the safety and efficacy of hypnotic and somnolent agents are needed.

At the cellular and molecular level, it has been shown that there are age-associated changes in afferent and efferent pathways of the suprachiasmatic nucleus (SCN), the biological clock that controls the circadian patterning of many neural, endocrine, and behavioral functions.  It is quite possible that disruption in the integrative neural systems could have serious deleterious effects in the function of other organ systems.  For example, shifts in biological clocks affect secretion and metabolism in a wide variety of neuroendocrine functions that influence not only the sleep-wake cycle but also metabolic functions and activities in organ systems.  Shifts in the phase or amount of compounds released by such cycling systems may influence such activities as drug metabolism, nutrient absorption, and other basic physiological functions essential to health.  It now appears that the intrinsic period of the endogenous human circadian pacemaker is not significantly different between healthy old and young adults, and is much closer to 24 hours than previously thought.  Thus, the deterioration in the SCN may represent a pathologic rather than a normal change.  This indicates that age-related changes of rhythm in vivo may be due to defects either upstream or downstream from the SCN.  The sleep-wake cycle appears to be controlled by two processes:  a circadian drive for wakefulness located in the SCN and a wake-dependent increase in sleep propensity probably situated within the classical pontine and thalamic sleep system, and more recently within the hypothalamic preoptic area.  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 not understood, primarily because of their complexities and relatively few ongoing investigations.

Program Activities

Program growth in the NIA Sleep portfolio quadrupled from FY1988 to over $13 million in FY2000.  The visibility of NIA's interests in this area have been enhanced through its role in a number of joint NIH initiatives, the latest being an RFA (HL-99-001) on the "Phenotypic Characterization of Sleep in Mice" cosponsored with NHLBI, NINDS, and NIMH; NIA made two awards.  NIA also cosponsored the workshop:  "Sleep and Host Defense Mechanisms."  In addition, NIA 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

Epidemiology

Data indicate that in the elderly age by itself does not predict incident complaints of insomnia, even in the presence of lowered sleep efficiency and decreased proportion of slow wave sleep.  Rather, the prevalence of insomnia and other sleep disorders is high in the older population due to their growing numbers and the associated co-morbidities common in late life that affect sleep.  Insomnia, in fact, is the most prevalent sleep problem reported not only among the older, but also across all population age groups within the industrialized countries of the world.  Restless legs syndrome (RLS) often is associated with a sleep complaint.  It has been estimated to afflict between 2% to 15% of the population.  Its prevalence in an older German population (age 65 years and greater) was found to be 9.6% overall (13.9% in women and 6.1% in men) with a decreasing trend with increasing age due to a marked decrease in prevalence with age in men.

A survey of the general population in five northern European countries assessed the prevalence of insomnia.  Severe self-reported insomnia (sleeping problems for a median of 2-6 years) ranged from 4% to 22%, was higher in women, and did not show a significant increase with age.  There was a clear relationship of the degree of poor quality of life with increasing severity of insomnia.  A much higher prevalence of insomnia was found in a representative sample of 2,398 community-living northern Italian elders (age 65 and older):  36% in men and 54% in women.  This cross-sectional study adopted the same series of questions and definitions used in the NIA EPESE study and identified similar associated risk factors (depressive symptomology, female, poor self-reported health, use of sleep medications, and no trend with age) although the prevalence rates for insomnia were much higher, suggesting that cultural differences in psychological factors might be related to the higher rates.

The first epidemiological study of insomnia among the Japanese general adult population found an overall prevalence rate of 21.4%.  However, amongst the older group (age 60 and over) the rate was 29.5% with an odds ratio, adjusted for a number of sociodemographic, lifestyle, and psychological factors, twofold greater than for younger adults (ages 20 to 39).  This prevalence rate is similar to the 28.7% reported for the NIA EPESE study and to the 33% found for a cohort of American older persons (mean age 72.8 years) from the NHLBI-supported Cardiovascular Health Study.  A cross-sectional study of elderly (mean age 78 years) Japanese-American men residing in Hawaii (NIA Honolulu-Asia Aging Study – HAAS) found a prevalence of insomnia of 32.6%.  A Japanese study of the prevalence of insomnia and the use of hypnotic medications found that while poor perceived quality of sleep was less associated with advancing age (OR about 0.56), the use of hypnotic medication was markedly associated with advancing age (OR about 9.7).  Use of hypnotic medication in the elderly also was found to be significantly prevalent in the NIA EPESE study as well as in a longitudinal study of Australians aged 75 or over.  While it has been estimated that close to two-thirds of hypnotic prescriptions in the U.S. go to chronic users, the proportion in Europe and other parts of the world may be even higher.  Unfortunately, in light of potential risks, the benefits of chronic use of hypnotics lack controlled studies.

Risk Factors

There are characteristic changes in sleep architecture with aging: increased proportion of Stage 1 (light) sleep and decreased proportion of Stages 3 and 4 (deep) slow wave sleep; increased EEG-arousals and reduced sleep efficiency; and phase advances of temperature nadir bed times and wake times by about an hour earlier than for younger adults.  However, epidemiological studies, such as those cited above, have consistently identified a constellation of medical and psychosocial factors significantly associated with insomnia complaints in the elderly:  physical disability, respiratory disorders, depressive symptomology, perception of poor health, psychological stress, use of hypnotic medications, suggesting that most of the insomnia is associated with these co- morbidities rather than age alone.

Neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have been associated with sleep disorders.  A study of a population-based sample of 205 AD patients found that 40% were sleeping more than usual, and 31% had early morning awakening.  Nighttime awakenings were less frequent (24%) but were most disturbing to the caregivers.  As in earlier reports the frequency of sleep problems increased with the patients’ cognitive and functional disturbances.  PD patients often complain of sleep problems, the most of which are REM sleep disorders, not uncommonly, but not necessarily, associated with hallucinations.  Pathological sleepiness (mean sleep latency < 5 minutes) and sleep-onset REM periods were also observed in a group of PD patients.  Although it has been suggested that dopaminergic therapy contributes to this problem, this study found little relationship with disease specific variables, such as level of disability, medication use.  Data from the NIA Honolulu-Asia Aging Study indicate that PD is a significant predictor of excessive daytime sleepiness (OR=1.9).

Sleep Disordered Breathing and Sleep Apnea

The prevalence of sleep disordered breathing, that is sleep apnea (at least 5 episodes of cessations of breathing exceeding two seconds) and hypopnea, jointly indicated by the apnea-hypoxia index (AHI), was assessed in an ongoing population of over 6,000 aged 40 or more years of age.  This Sleep Heart Health Study (SHHS), supported by NHLBI, is the largest study focused on the association of sleep disordered breathing (SDB) and hypertension.  Overall, the cross-sectional association with the highest category of AHI (30 or more per hour) and hypertension was a significant OR of 1.37, adjusted for age, BMI, and other related risk factors.  The data also show that 20% of the 2,800 persons 65 years of age and older had an AHI of 15 or more events per hour and nearly 7% had AHI of 30 or more.

The prevalence of SDB also increases as women age through the menopausal stages from pre- to peri- to post-menopause.  A small clinical trial of hormone replacement therapy (estradiol with or without progesterone) yielded positive results in the reduction of the signs of SDB in post-menopausal women.  Another trial, supported by NIA, is underway to study the effects of estrogen replacement on sleep and circadian rhythms in 80 healthy post-menopausal women.

Sleep apnea has been proposed as a cause of reversible dementia.  Excessive daytime sleepiness, a common sequelae of sleep apnea, has been significantly associated with cognitive impairment (OR=2.26) among older Japanese-American men in the HAAS cohort; 8% of 2,905 men reported being sleepy most of the day.  Cardiovascular disease also was significantly associated with excessive daytime sleepiness (OR=1.55) in this study as well as in the NHLBI Cardiovascular Health Study, a random sample cohort of 5,888 participants 65 years of age and older (ORmen = 1.35, ORwomen = 1.66).

Mechanisms

At the cellular and molecular level, it has been shown that there are age-associated changes in afferent and efferent pathways of the SCN, the biological clock that controls the circadian patterning of many neural, endocrine, and behavioral functions.  It is quite possible that disruption in the integrative neural systems could have serious deleterious effects in the function of other organ systems.  For example, shifts in biological clocks affect secretion and metabolism in a wide variety of neuroendocrine functions that influence not only the sleep-wake cycle but also metabolic functions and activities in organ systems.  Shifts in the phase or amount of compounds released by such cycling systems may influence such activities as drug metabolism, nutrient absorption, and other basic physiological functions essential to health.

The sleep-wake cycle appears to be controlled by two processes:  a circadian drive for wakefulness located in the SCN and a wake-dependent increase in sleep propensity probably situated within the classical pontine and thalamic sleep system, and more recently within the hypothalamic preoptic area.  Although there is a growing body of research on the aging circadian system, relatively little exists on the aging sleep homeostatic mechanisms.  Within the last several years, two important nuclei have been identified within the hypothalamus that are important for the control of sleep homeostasis.

The first is a cluster of cells in the ventral lateral preoptic (VPLO) area of the hypothalamus.  These VPLO cells exhibit activation, indicated by generation of c-Fos protein (a marker protein for activated cells), only during sleep, and independent of the circadian cycle, and are inhibited by noradrenaline, acetylcholine, and serotonin, neurotransmitters associated with the waking state.  Because the VPLO neurons are active only during sleep, it is proposed that they are central to the regulation of the sleep-wake cycle.  Cell-specific damage of these neurons result in significant decreases in NREM sleep and electroencephalogram delta power in a linear fashion, independent of circadian rhythmicity.  These cells project to and inhibit the systems that activate the cortical areas that play an important role in regulating wake-sleep states, and retrograde tracer studies indicate that the circadian regulation of the VLPO is likely controlled through multi-synaptic pathways rather than by direct axonal outputs from the SCN.  In older people, there is a reduced ability to fully and rapidly recover from prolonged wakefulness, i.e., during recovery from the stress of prolonged wakefulness the sleep has less slow wave sleep (SWS) and is of shorter duration, than found in younger adults.  In the first study of the VLPO on aged subjects, older rats (20 mos.) showed less sleep and SWS for a given amount of prior wakefulness than did young rats (2 mos.), similar to the situation in humans.  The less intense SWS rebound was not a function of fewer neurons in the VLPO, which has been implicated in sleep generation, since the numbers of c-Fos-containing cells in the VLPO were no different between the two ages of rats during normal sleep.  Under the usual sleep/wake cycle (absence of the maintained wakefulness), the c-Fos activation in those neurons as well as the amount of sleep was not different between young and old rats.  However, in response to 6 or 12 hrs. of prolonged sleep wakefulness, old rats had significantly fewer c-Fos induced cells and SWS, suggesting that in old rats the mechanism responsible for c-Fos induction in response to prolonged wakefulness is deficient .

The second recently discovery is that there are neurons in the dorsomedial hypothalamus that contain an interesting recently discovered molecule, hypocretin (Hcrt), a hypothalamus-specific peptide that shares substantial nucleic acid sequences with the gut hormone secretin.  Hcrt mRNA is a product of a gene on mouse chromosome 11.  Hcrt protein is restricted to neuronal cell bodies in the dorsal and lateral hypothalamic areas.  Two forms have been identified, Hcrt1 and Hcrt2, with the latter proposed as a peptide neurotransmitter.  The Hcrt receptor is in the class of G protein-coupled receptors.  The brain cells that contain them make connections with many of the brain regions involved in regulating the sleep-wake cycle.  The hypocretins may act as chemical signals involved in the mechanisms of homeostasis and alertness.  Their functions have been proposed as involved in coordination of autonomic functions and homeostasis, including feeding, blood pressure regulation, neuroendocrine regulation, thermoregulation, and the sleep-wake cycle.  Hcrt now appears to be the gene for narcolepsy.  Recently, it has been shown in autopsy brains from human narcoleptics that there is a 85% to 95% reduction in the numbers of Hcrt neurons, associated with gliosis indicative of a neurodegenerative process being the cause of the cell loss in narcolepsy.  Its link to the aging nervous system remains to be established.

It now has been reported that the human circadian clock has a period of close to 24 hours (24 hr 11 min), similar to other species, rather than about 25 hours as previously thought.  This study used a technique that controls the confounding effects of entrainment (resetting) of the circadian clock by light and other non-photic synchronizers.  This study found no difference in circadian period between healthy young and older individuals.  This counters the belief that the circadian clock speeds up (shortens in duration) as we age.  These findings indicate that the human circadian clock is as stable and precise as that of other animals.  Similar conclusions have been reported recently in animal studies that found that the circadian period does not shorten with age in Syrian hamsters.  These new findings suggest that the molecular and genetic mechanisms regulating the circadian clock of other species also may apply to humans.

However, healthy older individuals do tend to show a propensity to advance their sleep-wake timing.  It was found that the average wake time and endogenous circadian phase of healthy older subjects were earlier than that of young men.  The earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people.  Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups.  The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity, and that these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase.  This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.  Studies on young adults have shown that entrainment of the circadian timing system can be achieved with much lower light intensities than was previously estimated, as little as 8 lux of ambient light.  Light of indoor intensity can have a significant phase-shifting effect on the circadian pacemaker, and can suppress plasma melatonin secretion.  The phase-angle of entrainment between the habitual sleep-wake and the midpoint of the plasma melatonin secretion pattern is significantly shorter in older than younger adults (3.67 +/- 0.54 h vs. 4.23 +/- 0.96 h, p<.02).  This difference may be due to an altered phase angle of entrainment in older people due to reduced circadian sensitivity to light while maintaining the average intrinsic period of 24.2 h.

Thus, the deterioration in the SCN may represent a pathologic rather than a normal change.  This indicates that age-related changes of rhythm in vivo may be due to defects either upstream or downstream from the SCN.  Studies on rodents typically find that there is a shortening of the circadian period with age.  This age effect has been attributed to loss of cells with age within the SCN.  However, when the free running period of hamsters is continuously measured under dim light conditions longitudinally over the life of the animals, the average circadian periods did not change with age, suggesting that other environmental factors may play a role in the shortening period with age observed with maintenance under the usual light/dark cycles.  The brain mechanisms underlying age-dependent changes in the sleep homeostatic mechanisms are not understood, primarily because of their complexities and relatively few ongoing investigations.  One potential model proposes that reductions in cerebral metabolism induce increased synthesis of adenosine from AMP, resulting in more release of adenosine and the concomitant increased stimulation of neuronal adenosine receptors.

Other factors associated with aging, such as disease, changes in environment, or concurrent age-related processes may contribute to problems of sleep on older persons.  A study of data from healthy men, aged 16 to 83 years, looked at 24-hour profiles of plasma growth hormone (GH) and cortisol and polysomnographic sleep recordings and found that the decrease in SWS from early adulthood to later life was paralleled by a decrease in GH secretion.  Association of  sleep with cortisol concentrations, on the other hand, were independent of age and became significant only after the age of 50 years when sleep became more fragmented and REM sleep declined .

It 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 sympatho-vagal 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, 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.  These results indicate that sleep loss can increase the "allostatic load" and facilitate the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups.

Treatment Approaches

Several therapeutic strategies, especially phototherapy and melatonin administration, are likely to become effective treatments for some of the insomnias associated with aging.  The use of bright light therapy for phase disorders is now more commonplace.  Behavioral modifications, such as stimulus control and sleep restriction appear to be effective techniques for shortening the sleep latency and wake after sleep onset times.  Melatonin treatment is being tested for its sleep-inducing effects.  It appears to be effective at physiological doses in dealing with circadian desynchrony.  Melatonin is a hormone produced by the pineal gland, which signals the brain about the onset of subjective night and primes the organism to engage in nighttime activities.  For humans, and most other primates, this activity is sleep.  Administration of melatonin has recently been reported to entrain the circadian rhythms of most blind people who have free-running rhythms and the insomnia and daytime sleepiness associated with that circadian desynchrony.   This means that the about 200,000 totally blind people in the U.S. may have a curable sleep disorder.  Without light perception through the eyes, the body clocks of blind people run at a period slightly longer than 24 h, and the older one is, the more likely the legally blind will lose their ability to perceive any light at all, leading to the free-running condition.  It now is likely that most, if not all of these people, can have their underlying disorder treated by a daily dose of melatonin, which substitutes for the daily light cue available to sighted subjects.  Preliminary data also indicate that the dose can be reduced substantially to a dose that is so low that it produces  physiological levels found in sighted people.

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 not understood, primarily because of their complexities and relatively few ongoing investigations.  The workshop on Sleep and Host Defense Mechanisms demonstrated that a number of messenger molecules are common to sleep, stress, and the immune systems.  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.

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.  Preliminary 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.  However, until that time, 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 wake.  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.

Similar to other recent findings that neuronal loss is not an inevitable consequence of aging, these data indicate that there is no evidence of an age-related loss of neurons that have been identified as playing a key role in the maintenance of sleep homeostasis.  Furthermore, findings reported last year indicated that the circadian clock of healthy older persons functions as well as that of healthy younger individuals.  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, can lead to the development of more effective and targeted pharmacological approaches to alleviate some of the problems of sleep that afflict over half of our older population.

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NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

W. Hunt, Ph.D.
E. Witt, Ph.D.

During the past year, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has continued to support sleep-related research in the following areas:  a) the effects of alcohol exposure through breast milk on the development of neural systems associated with sleep and arousal; b) sleep and immune function in African Americans; c) alcohol abuse liability in insomniacs; d) sleep disturbances in recovering alcoholics; and  e) the relationship between alcohol consumption, sleep deficits, and serotonergic system function in nonhuman primates. In addition, new research areas were funded including pharmacotherapy of alcoholism and comorbid insomnia, adolescent sleep/arousal patterns as a pathway to alcoholism in early adulthood, and animal models of alcohol’s effects on sleep.

This year NIAAA developed a new initiative to stimulate research on alcohol and sleep.  It is well known that acute and chronic alcohol consumption cause sleep disturbances.  In individuals with alcoholism, continuing sleep problems may be a core factor in alcohol relapse. Despite the adverse effects of alcohol on sleep and the serious implications for alcoholism treatment, the topic of alcohol and sleep is currently an understudied area.  In an effort to build this program, NIAAA issued a Request for Applications (RFA) to stimulate research in areas that are of particular interest because of the potential contribution to our understanding of the etiology and treatment of alcoholism.  These research areas include the neural mechanisms of alcohol-induced sleep disturbances, persistent poor sleep as a risk marker for development of alcoholism in adolescents and non-alcoholic young adults, sleep disorders as predictor of relapse in abstinent alcoholics, and the health consequences of alcohol’s disruptive effects on sleep particularly the interaction with age, ethnicity, and gender.  The NIAAA plans to commit approximately $3 million in FY2001 to fund eight to ten new and/or competitive continuation grants in response to this RFA.

Research highlights from currently funded projects are summarized below:

Alcohol, African-American Ethnicity and Sleep

Sleep disturbance is one of the most common complaints in recovering alcoholic patients and may be a predictor of relapse.  Recent evidence indicates that ethnicity is also an important factor in the outcome of primary alcoholics.  Given the potential influence of both sleep disturbances and ethnicity on alcoholism recovery, a study was conducted to evaluate the effects of African American ethnicity and alcoholism on sleep EEG using polysomnographic and spectral analyses measures. Following two weeks of abstinence, African- American alcoholic patients showed more sleep abnormalities than Euro-American alcoholics as indicated by more prolonged sleep latency, shorter REM latency, and more  pronounced loss of delta sleep.  In the spectral analyses, delta and theta power were also lowest in the African American alcoholics.  In view of the possible relationship between relapse and poor sleep as well as the role of sleep in health, these data may have implications for treatment and morbidity outcomes in African-American alcoholics.

Effects of Chronic Alcohol Exposure on Sleep in Rats

Human clinical studies have found that abstinent alcoholics manifest numerous sleep abnormalities including prolonged sleep latency, reduced percentage of Stage 3 and 4 (Delta) sleep, and increased REM sleep.  Animal models provide more controlled studies of alcohol’s acute and chronic effects on sleep because they eliminate confounding factors such as co-morbid disorders, nutritional factors, and liver disease.  A recent study examined the sleep EEG using spectral analysis immediately following 6 weeks of chronic alcohol exposure and after 5 weeks of withdrawal.  Although decreases in the time spent in slow wave sleep were not found immediately after chronic ethanol exposure in this study, there was a reduction in spectral power including the delta, theta, and beta ranges, which was still evident following chronic withdrawal.  These findings of normal sleep duration and latency combined with persistent reductions in spectral power suggest that EEG spectral analysis may be a particularly sensitive measure of the chronic effects of alcohol on sleep.

Epidemiology of Insomnia and Alcoholism in the General Population

Insomnia is a prevalent problem in alcoholic patients with estimates ranging from 36% to 67%.  The prevalence of insomnia among alcoholics in the general population was recently studied in 7,717 people interviewed at two waves of the Epidemiological Catchment Area survey, including 288 (3.7%) with a current (past 6 mo) diagnosis of alcoholism.  Insomnia was assessed with the question “Have you ever had a period of two weeks or more when you had trouble falling asleep, staying asleep, or with waking up too early?” A total of 10.8% of the sample met these criteria for insomnia, including 18.1% of alcoholics and 10.5% of non-alcoholics.  Although insomnia rates were higher for females than males across both alcoholics (32.8% vs. 14.3%) and non-alcoholics (12.5% vs. 7.4%), female alcoholics had the highest rates of insomnia.  Similarly, insomnia rates were higher when an Axis I mental disorder was present vs. absent in alcoholics (53.2% vs. 11.2%) and non-alcoholics (39.6% vs. 9.0%).  Older age was not associated with more frequent insomnia than younger age, although this finding was reported previously using the ECA database.  In sum, insomnia was more prevalent in alcoholics than non-alcoholics in the general population, although some of this difference could be attributed to higher rates of mental disorders in alcoholics (16.3%) vs. non-alcoholics (4.6%).

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NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

C. Catz, M.D.
M. Willinger, Ph.D.

The Center for Research for Mothers and Children of the National Institute of Child Health and Human Development (NICHD) supports and promotes sleep research in infants 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) and mental retardation.  Highlights of progress from a few of the projects follow.

Fatigue, excess sleepiness, and sleep are symptoms in infectious diseases.  Respiratory and gastrointestinal infections have been implicated as co-factors in SIDS, either to potentiate risk when an infant is sleeping on the stomach or independently as triggers.  Their role in pathogenesis in not defined but one hypothesis is that they enhance sleep, particularly stage 3-4 sleep, thereby  increasing the arousal threshold when infants are confronted with a life-threatening stimulus.  One study supported by the NICHD is investigating the molecular mechanisms that are responsible for the changes in sleep patterns induced by influenza virus in an animal model.  Influenza virus activates the transcription factor, nuclear factor kappa B (NFkB).  Substances that inhibit sleep also inhibit the production of this factor.  The investigators examined the activation of the transcription factor over sleep-wake cycles and observed that activation exhibits a diurnal pattern with the highest levels during the day in the cerebral cortex.  In addition, sleep deprivation increased activation.  Inhibitors of NFkB activation inhibited sleep if administered during the light period and also inhibited interleukin-1b induced sleep and febrile responses.

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 position.  In addition to 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 study published this fiscal year in the American Journal of Respiratory and Critical Care Medicine (2000;162:471-480), showed that 80% of the apneas identified by the CHIME monitor to be obstructed were judged to be obstructed by either nasal end-tidal carbon dioxide measurements or nasal/oral thermistor measurements.  Therefore, the longitudinal monitoring records collected during sleep periods in the CHIME study provide an opportunity to analyze physiological events not previously recorded in the home.  The CHIME database, which includes all raw physiological records and study forms will be made available to the public on CD-ROM next fiscal year.

SIDS is associated with a sleep period.  Research has shown that factors in the sleep environment such as stomach sleep position, head covered by bedding and sleeping on soft bedding are associated with increased SIDS risk.  Several countries have documented that a change to back sleep position has led to a dramatic decrease in SIDS incidence.  Recent small cases histories suggested that infants who were “inexperienced’ with the stomach sleep position were at great risk of dying when placed in or rolling to the stomach position.  Several cases of infants dying within the first week in childcare were documented. This fiscal year, scientists reported a careful analysis of these phenomena from a large case-control study initiated before the public health campaigns (Arch Ped Adolesc Med 1999;153:1136-1141).  Twenty percent of all SIDS cases represented those who lacked experience with the prone position. Eight percent were usually placed non-prone but were placed prone on the night of death.  Their risk of death was 19 times that of those usually placed non-prone and placed non-prone on the night of death. Twelve percent of all cases were last placed non-prone but rolled to the prone position.  These data emphasize the need for consistency in infant sleep position among all caregivers and the use of back sleep position, which is more stable than side.  They also suggest that an infant’s competence to escape from the hazards of the stomach sleep position may be impaired by inexperience in that position.

The "Back to Sleep" National Public Health Education Campaign

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

In fiscal year 2000, outreach activities continued to focus on underserved minorities.  The District of Columbia Department of Health joined the campaign and a Metrobus poster targeted to African American communities was unveiled at the “Anacostia Gateway to Health and Wellness Fair.”  It is now displayed on buses throughout the city.  In addition, a resource kit, “Reducing the Risk of SIDS in African American Communities” was developed in collaboration with the National Black Child Development Institute and other Back to Sleep Campaign outreach partners.  This will placed into production in Fiscal Year 2001.

The NICHD has been evaluating the implementation and health impact of the AAP recommendation and the campaign since 1992.  In collaboration with Boston University three studies were initiated in the United States:  (1) annual telephone surveys of nighttime caregivers of infants <8 months of age in the 48 coterminous states to assess infant care practices and dissemination of the AAP recommendation; (2) periodic surveys of samples of the membership of the AAP, the American Academy of Family Practitioners, pediatric health providers in the National Association of Community Health Centers, and nurses in newborn nurseries to assess provider beliefs and practices regarding the AAP recommendation; and (3) a longitudinal survey of over 15,000 mother infant pairs in the metropolitan Boston and Toledo areas to assess the effect of the recommendation on infant care practices and health outcomes.

Analyses of the nighttime caregiver surveys from 1994-1998, published in the Journal of the American Medical Association (2000;283:2135-2142) showed that physician recommendation of “back not stomach” was the single strongest influence on caregiver choice of sleep position, independent of sociodemographic characteristics of the mother.  However, the strongest probability of a choice of back sleep position was observed when the caregivers reported exposure to the recommendation from multiple sources:  the hospital nurse, the baby’s physician, magazines and newspapers and radio and television.  By the spring of 2000, 14% of infants in the nighttime caregiver survey were being placed to sleep on their stomachs and 66% on their backs.

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NATIONAL INSTITUTE ON DRUG ABUSE

H. Gordon, Ph.D.

Support by the National Institute on Drug Abuse for sleep and circadian rhythms include human studies and animal models of neurosystems associated with brain mechanisms underlying sleep architecture and sleep disturbances.  For example, dopamine is a crucial transmitter to both circadian rhythms and to the reward circuitry affecting drug abuse.  In decapitated Drosophila dopamine receptors can be directly studied by applying drugs to the nerve cord.  A recent study (Andretic R., Hirsh, J. (2000) Proc. Natl. Acad. Sci. USA 97(4):1873-8) show that dopamine receptor responsiveness is under circadian control and depends on the normal function of the period gene.  Because of the similarity to humans of piglet postnatal development of respiration and sleep-wake behavior and of opioid receptor systems which affect these behaviors (Laferrier A., Liu, J.K., Moss, I.R. (1999) Brain Res Dev Brain Res, 112(1):1-9), these animals may used in studies to determine the effect of prenatal cocaine.  In one study (Liu, J.K., Laferrier, A., Moss, I.R. (2000) Brain Res Bull 51(5):419-24) prenatal cocaine exposure increased met-enkephalin immunoreactivity in the respiratory-related hypoglossal and solitary tract.

However, in humans, the effect of prenatal cocaine may be subtle.  There were no apparent effects on sleep architecture for infants of mothers who took cocaine during pregnancy (Scher, M.S., Richardson, G.A., Day, N.L. 2000) Pediat 105(1): 39-48.)  However, visual inspection of EEG patterns showed some abnormalities.  More striking was the effect of prenatal tobacco exposure that seemed to predict decreased active sleep, quiet sleep, and increased indeterminate sleep as well as body movements during active and quiet sleep.  Alcohol had similar effects; marijuana increased arousals during active sleep and may affect latency to fall asleep and latency to REM (Haney, M., Ward, A.S., Comer, S.D., Foltin, R.W., Fischman, M.W. (1999) Psychopharm 141(4):385-94).

Several reports on the study of brain mechanisms associated with drugs of abuse affecting sleep were issued from the laboratory of W. Mendelson.  The sleep-inducing effects of unsaturated fatty acid amides (e.g., oleamide) were blocked by an antagonist of a cannabinoid receptor suggesting some of the action of the amide is associated with the cannabinoid receptor (Mendelson, W.B., Basile, A.S. (1999) Neuroreport 10:3237-9).  In another investigation of how adenosine increases sleep at the medial preoptic site (Mendelson, W.B., (2000) Brain Res 852:479-481), adenosine was injected in rats together with a benzodiazepine receptor blocker, which prevented a large increase in total sleep that would have been induced.  These data suggest that adenosine is, for some of its action, modulated by the GABA-benzodiazepine receptor complex.  Finally, one more study (Mendelson, W.B. (1999) Life Sci 65(25):301-7) showed that one site where there was no pharmacological action of benzodiazepines was the ventrolateral preoptic area as assessed in rats.

There is continuing and developing interest at the National Institute on Drug Abuse for the combined study of mutual influence and brain mechanisms of psychoactive substances and sleep architecture.  We expect currently funded projects to yield information in the near future and hope that researchers in the brain mechanisms of the sleep architecture will apply their knowledge to the similar brain circuitry in drug abuse.

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NATIONAL INSTITUTE OF MENTAL HEALTH

I. Lederhendler, Ph.D.

Narcolepsy

Hypocretin/Orexin.  The molecules originally described as the hypocretins and subsequently as the orexins were initially implicated in the control of food intake.  Recent observations implicate this newly described neurotransmitter system in the sleep disorder narcolepsy and, potentially, in the regulation of normal sleep processes.  During the dark (active) period, null mutants of the prepro-orexin (prepro-hypocretin) gene have cataplectic attacks and increased levels of both rapid eye movement (REM) and non-REM (NREM) sleep.  Intracerebroventricular injection of one of the encoded neuropeptides, orexin-A, early in the light period increases wakefulness and reduces REM sleep in the rat, suggesting that this system may be involved in the normal regulation of sleep and wakefulness.  To further test this hypothesis, NIMH investigators measured hypocretin (hcrt) mRNA levels in mouse and rat hypothalamus after short-term (6 h) sleep deprivation (SD) and 2-4 hours after recovery from SD.  Although the procedures induced a sleep debt and increased c-fos mRNA expression in the cortex and hypothalamus as others described, this group found that hypocretin mRNA levels were not significantly changed after either SD or after recovery from SD.  If the hcrt system is involved in normal regulation of sleep and wakefulness, longer periods of SD may be necessary to affect hcrt mRNA levels or changes may occur at the protein rather than mRNA level.  Alternatively, it is possible that this system may also be involved in other functions that counteract the effects of SD-induced changes in hcrt mRNA levels.

Potential Translation of Basic Research to Treatment.   With the support of an NIMH-mentored career award (K01), Dr. Seigi Nishino collaborated with Dr. Emmanuel Mignot in a pharmacological approach to the dissection of the neurochemical mechanisms underlying the symptoms of narcolepsy.  Cataplexy  is a dysfunctional manifestation of REM sleep atonia.  It is commonly treated with antidepressants that also reduce physiological REM sleep and induce other sleep disturbances.  Recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy may be different from those producing REM sleep.  This stimulated a search for compounds that could act specifically on cataplexy without affecting REM sleep.  Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation.  Sulpiride, a D2/D3 antagonist, was found to reduce cataplexy, but not REM sleep.  An additional analysis of sleep architecture from numerous polygraphic recordings from narcoleptic and healthy dogs demonstrated that cataplexy and REM sleep are differentially regulated and that cataplexy and sleep fragmentation, but not abnormal REM sleep generation, are the primary symptoms of narcolepsy.  Furthermore, local perfusion of dopamine D3 agonists into the substantia nigra significantly aggravated cataplexy but did not modulate sleep in the narcoleptic dogs.  These findings taken together challenge the current notion that narcolepsy is primarily a disorder of REM sleep.  Furthermore, the findings indicate that REM sleep is regulated by mechanisms that are different from cataplexy and that in cataplexy dopaminergic mechanisms are specifically involved. The alternative view proposed by this group may hopefully lead to additional approaches and insights to the pharmacological treatment of narcolepsy.  These include results suggesting that a thyrotropin-releasing hormone analog could be a promising new form of treatment for human narcolepsy.

Sleep, Stress, and Mood

Melatonin.  In humans, the secretion of melatonin can be a subtle but extremely important determinant of normal functioning.   Shifts in melatonin secretion are known to contribute significantly to impaired functioning in many high school students.  Shifts in mood in adults have been associated with seasonal changes in length of day.  NIMH intramural investigators tested the idea that in patients with seasonal affective disorder (SAD) the suprachiasmatic nucleus (SCN) may not be registering seasonal changes in the duration of the natural photoperiod.  One outcome of this dysfunction could be expressed in the failure of patients with SAD to exhibit seasonal changes in the duration of nocturnal melatonin secretion.  In men with SAD, but not in healthy men or women with SAD, the intrinsic duration of nocturnal melatonin secretion was significantly longer in winter than in summer and largely attributable to winter-summer changes in the timing of morning offset of secretion rather than evening onset of secretion.

The Amygdala is Involved in Regulating Sleep and Wakefulness.  The amygdala is important in processing emotion and in the acquisition and expression of fear and anxiety.  NIMH-supported investigators have now found evidence that it also appears to be involved in the regulation of sleep and wakefulness.   In studies using rhesus macaques they found that animals without damage to the amygdala had sleep patterns characterized by frequent arousals.  Animals with large bilateral lesions of the amygdala showed very little sleep disruption.  These latter animals had more sleep overall and a higher proportion of rapid-eye-movement (REM) sleep than did either animals with smaller lesions or the animals with an intact amygdala.  It seems likely that, in the primate, the amygdala plays a role in sleep regulation and may be important in mediating the effects of emotions/stress on sleep.

Hypothalamic-pituitary-adrenal axis (HPA) and cytokines.  Evidence for the involvement of corticotropin-releasing hormone (CRH), a regulator of the HPA axis, in sleep-wake regulation has emerged from NIMH-supported research.  Studies have shown that the CRH receptor antagonist, astressin, after a delay of several hours, reduces waking and increases slow-wave sleep (SWS) in rats.  This delay suggests a cascade of events that begins with the HPA axis and culminates with actions on sleep regulatory systems in the central nervous system.  One candidate mediator in the brain for these actions is interleukin (IL)-1.  IL-1 promotes sleep and glucocorticoids inhibit IL-1 synthesis.  To determine directly whether IL-1 is involved in astressin-induced alterations in sleep-wake behavior, rats were pretreated with anti-IL-1beta antibodies before injecting astressin.  The increase in SWS and the reduction in waking that occur after astressin were abolished suggest that IL-1 is a mediator of astressin-induced alterations in sleep-wake behavior.

Consciousness and The Perception of Time

Research on sleep and wakefulness has long been seen as a unique opportunity for scientists and philosophers to understand features of consciousness.  A symposium at NIH, “Scientific Approaches to Consciousness: Reductionism Debated,” organized by Dr. Howard Kurtzman of NIMH, May 10, 2000, explored whether our sense of consciousness could ever be reduced to a set of neurons and molecular interactions.  Several leading approaches to this frontier of psychological and brain sciences were represented.  Molecular differences between waking and dreaming states and the anatomical regions that shift the brain through various states that include vigilance, daydreaming, relaxation, and drowsiness were the focus of the contribution from senior sleep researcher, Dr. Allan Hobson.  He argued that this could provide an empirical basis for studying how consciousness changes with brain states.  In many ways the speakers at the symposium reflected the view that the term “consciousness” remains an intriguing catchall for processes that also include aspects of memory, attention, and perception.  The perception of time is critical to the way humans navigate many of the changes associated with changing behavioral and brain states including how attentive children are in school, when people exercise, rest, or sleep, or how they travel and plan seasonal recreations.

In a landmark theoretical contribution, NIMH-supported scientists led the development of a fundamentally new conception of classical and operant conditioning that focuses on the ability of animals to compute the temporal intervals between events.  According to most current models of learning, representations of various stimulus, response, and reinforcement events are stored in memory.  Associative links among these representations are built up over the course of repeated experiences.  In practice, however, these associative models may provide an insufficient accounting of the properties of the events themselves and they may not directly account for the effects of manipulating the time intervals among events.  In the new approach, animals are seen as capable of automatically and continually recording in memory the time intervals among events and, furthermore, performing statistical analyses on this information.  By determining the rate at which an unconditioned stimulus co-occurs with a conditioned stimulus, as well as the rate at which it occurs without the conditioned stimulus, an animal reaches a point where it begins to respond to the conditioned stimulus alone.

Brain correlates of these important psychological regulators of information processing may ultimately have implications for the putative role of sleep in memory consolidation.  In particular, NIMH-supported studies of the spatiotemporal patterns of firing in neuronal networks found that spike sequences in rat hippocampus observed during wheel running were “replayed” at a faster timescale during sharp-wave bursts of slow-wave sleep.  The temporal compression of patterns of neural activity during sleep may relate to how information is stored and recalled subsequently.

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NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

Cheryl Kitt, Ph.D.

NINDS continues to support a wide variety of research on the neurological and neuroscience aspects of sleep.  This includes research on the molecular and cellular mechanisms underlying circadian rhythm generation, and the role of the endocrine and immune systems in modulating sleep activity, as well as studies aimed at understanding the genetic and physiological bases for sleep disorders such as sleep apnea, narcolepsy, and sleep related disorders such as restless legs syndrome (RLS).  NINDS-supported researchers are also investigating the role of sleep in other neurological disorders, including the relationship between sleep and seizure initiation in epilepsy, and sleep disturbances in Parkinson’s disease.

In addition, NINDS participates in trans-NIH sleep activities as a member of the Trans-NIH Sleep Research Coordinating Committee, and NINDS program staff work closely with staff of the National Center for Sleep Disorders Research (NCSDR) at the National Heart Lung and Blood Institute on initiatives of common interest.

A major highlight from the past year was the identification by NINDS-supported investigators of a possible cause for the sleep disorder narcolepsy in humans.  Narcolepsy is a serious brain disorder that affects sleep in a dramatic way.  Symptoms include extreme daytime sleepiness, a frightening inability to move shortly after awakening or dozing off, and sudden episodes of muscle weakness called cataplexy.  In 1999, Dr. Emmanuel Mignot and colleagues at the NINDS-supported Center for Narcolepsy and Related Disorders at Stanford University discovered a defective gene that causes narcolepsy in dogs, one of the few animals that exhibit this disorder.  The gene carries the instructions for making a receptor by which nerve cells respond to a brain-signaling molecule called hypocretin (also known as orexin).  Building on these animal findings, two NINDS- supported investigators (Dr. Mignot at Stanford and Dr. Jerome Siegel at UCLA) and colleagues demonstrated this past year that people with narcolepsy have abnormally low brain levels of the hypocretin molecule, due to the fact that the nerve cells that normally produce hypocretin either die or stop making the molecule.  This finding suggests the exciting possibility that supplying hypocretin, or drugs that mimic its actions, may help prevent or treat this disorder.

Other NINDS-supported investigators reported progress in understanding the pathophysiology of the sleep related disorder, restless legs syndrome.  Restless legs syndrome (RLS) is a movement disorder characterized by uncomfortable sensations in the legs, which are worse during periods of inactivity or rest.  Individuals affected with the disorder describe their symptoms as pulling, crawling, tingling, prickly, sometimes painful sensations that are usually accompanied by an overwhelming urge to move the legs.  Movement provides temporary relief from the discomfort.  Since it is usually worst during periods of inactivity, symptoms can oftentimes interfere with sleep onset.  During this past year, Dr. Christopher Earley, an NINDS-supported investigator at Johns Hopkins University, reported that patients with RLS had lower stores of iron in their brains, as compared to normal controls.  While this finding needs to be replicated in a larger sample, it suggests that RLS may be caused in part by a defect in iron transport or storage in the brain.

References:

Earley, C.J., Connor, J.R., Bear, J.L., Malecki, E.A., Epstein, D.K., Allen, R.P. (2000) Abnormalities in CSF concentrations of ferritin and transferrin in restless leg syndrome. Neurology, 54(8): 1698-1700.

Nishino, S., Ripley, B., Overeem, S., Lammers, G.J., & Mignot, E. (2000) Hypocretin(orexin) deficiency in human narcolepsy. The Lancet, 355:39-40.

Peyron, C. et al. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Medicine, 6(8):991-997.

Thannickal, T.C., Moore, R.Y., Nienhuis, R., Ramanathan, L. Gulyani, S., Aldrich, M., Comford, M., & Siegel, J.M. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27:469-474.

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NATIONAL INSTITUTE OF NURSING RESEARCH

K. Helmers, Ph.D.

Inadequate sleep occurs across the life span and is found among the healthy and the chronically ill.  The role of sleep is to maintain healthy, optimal waking functions and this is compromised by sleep loss related to illness, aging, pain and lifestyle.  Inadequate sleep has been associated with accidents at work and at home and dozing off at the wheel of an automobile.  As a consequence inadequate sleep has major implications for public health safety, productivity, and well being.

In FY 2000, NINR published a program announcement (PA) entitled “Biobehavioral Research for Effective Sleep” that encourages research in the area of behavioral, psychosocial and physiological consequences of acute and chronic partial sleep deprivation in either chronically ill or healthy individuals and to develop environmental, clinical management, and other interventions with the potential to reduce sleep disturbances and significantly improve the health of large numbers of people.  This PA encompasses the three general areas of sleep-related research found at NINR:  1) the impact of inadequate sleep across the lifespan in healthy populations; 2) sleep related problems found in patients with chronic illnesses; and 3) the management of sleep disturbances.

Inadequate Sleep in Healthy Populations

Inadequate sleep has major implications for public health safety, productivity, and well being.   It has been estimated that more than 60 million Americans, or approximately one in three adults, experience inadequate sleep that can interfere with daily activities.  Excess sleepiness has been associated with accidents at work and at home, and at least three percent of serious automobile accidents and fatalities are due to a fatigued driver.  These statistics have major implications for the public sector.

Insomnia is among the most frequent health complaints brought to the attention of primary care providers.  The single most pervasive form of sleep loss is partial sleep deprivation.  Partial sleep deprivation is found among shift workers, medical workers, and parents of small children and as a result of lifestyle choices.  A NINR-funded study will determine the amount and timing of chronic partial sleep deprivation at which alertness and waking function are compromised.  This research may help to set guidelines for the number of hours and consecutive days that are safe to work without incurring increased performance errors as may be found in certain occupational groups (i.e., truck drivers, air pilots, medical workers, etc.).

Sleep is believed to be restorative and inadequate sleep is thought to be associated with disease susceptibility. However, little is known about the relationship between sleep and immune function.  A nurse researcher is examining the effects of 72 hours of sleep loss on immunity and disease susceptibility in a rat model.

Babies born prematurely have a different sleep pattern than babies born at full term.  Quiet sleep is a very deep sleep, and infants seldom arouse in response to environmental stimuli when in this state.  Premature infants spend less time in quiet sleep and more time in active sleep when compared to full term babies even at the same chronological age.  Quiet sleep is necessary for brain development, the emergence of attentive and interactive neural capacities, and is restorative and anabolic in nature.  A nurse researcher, using electrophysiological monitoring, is evaluating whether skin-to-skin contact between premature infants and their mothers promotes more quiet sleep than sleep in an incubator.

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 NINR-funded research study will be the first to characterize the patterns of change in sleep disturbance, fatigue, and pain over the course of radiation therapy in four groups of oncology outpatients (breast, prostate and lung cancer and brain tumors) and their caregivers.  Fatigue, pain and sleep disturbance are common problems encountered by patients receiving radiation therapy, and there is evidence that cancer patients’ caregivers also experience fatigue and sleep disturbance.  Efforts to understand the physiological and psychological mechanisms by which these three symptoms interact and influence one another, both in patients and between patients and caregivers, will provide important information for the planning of intervention studies.

Other examples of patients who suffer from sleep problems are hemodialysis and coronary artery bypass surgery patients. 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 itself can induce daytime sleepiness as it alters core body temperature and triggers the production of sleep-inducing substances such as interleukin-1.  Nurse researchers will provide information on the sleep-wake cycles of hemodialysis patients, and whether the timing of the hemodialysis treatment affects quality of life and functional health status.

Coronary artery bypass surgery is among the most frequently performed surgical procedures in the United States, and many patients experience altered sleep patterns.  The characterization of sleep patterns and their relationships to age and gender, currently underway by an NINR-funded researcher, will help focus the future development of sleep-promoting interventions in coronary bypass patients.

NINR-supported research is also examining the quality of sleep in women with Irritable Bowel Syndrome (IBS) and non-IBS women.   IBS is a common chronic functional bowel disorder in which patients frequently report sleep problems including poor sleep quality, difficulty getting to sleep and frequent awakenings.  A nurse researcher is looking at the neuroendocrine disruption of cortisol and serotonin and the autonomic imbalances that may account for the poor quality of sleep found in women with IBS.

Narcolepsy, a chronic sleep disorder, is characterized by a sudden uncontrollable disposition to sleep that occurs at irregular intervals.  Many of the consequences of narcolepsy can be directly attributed to sleep attacks and excessive daytime sleepiness.  These uncontrollable sleep attacks make driving hazardous, affect the individual's ability to pursue a career, and often interfere with interpersonal relationships.  Current treatments for narcolepsy can improve symptoms, but up to one-third of patients obtain little or no benefit. NINR-funded research is underway to identify which patients are less likely to respond to stimulant medications, which will allow clinicians to concentrate their efforts on improving treatment regimes for these patients.

Testing for excessive daytime sleepiness is labor intensive, time consuming and receives limited health coverage.  A nurse researcher will determine if pupillometry can be used to measure excessive daytime sleepiness.  Pupillometry is based on the observation that as people become sleepy the pupils are decreased in size and oscillate widely.  This simple and inexpensive technique may be able to assess several sleep disorders including obstructive 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 nurse 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 what are normal sleep pattern changes and will be useful to identify abnormal changes.  Insomnia is frequently experienced by older community dwelling adults.  Sleep difficulties can affect daytime physical and social functioning and have been associated with an increased incidence of depression.  A nurse investigator is using behavioral treatments to improve sleep in the elderly.  Specifically, the researcher is testing stimulus control, sleep restriction and a combination of the two behavioral interventions.  This study may demonstrate practical behavioral strategies to improve sleep in the elderly found in the community as well as those in nursing homes and other communal residences.

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.  If the interventions are effective, these strategies may provide a means to reduce or delay the institutionalization of the Alzheimer’s disease patient and may decrease the intensity of afternoon delirium.  As a result of the nighttime activities of the Alzheimer’s’ disease patients, the sleep of caregivers of Alzheimer’s’ disease patients is also disrupted.  Exhaustion of the caregiver and caregiver fear for the safety of the patient are some of the most frequently cited reasons for the decision to institutionalize the patient with dementia.  A nurse researcher is developing a night alarm prompt system to reliably identify unsafe nighttime activity and alert caregivers of unsafe nighttime activity by the Alzheimer’s’ disease patient.  The reduced worry and increased sleep experienced by caregivers may delay the need for institutionalizing the demented patient.

Sleep disturbance is also commonly found in patients with Parkinson’s disease.  NINR funded research is examining whether melatonin is effective in alleviating the sleep disturbance.  The findings of this study may provide support for the broad use of melatonin as a sleep aid.

Obstructive Sleep Apnea (OSA) is associated with accidents and injuries, cardiovascular and neurocognitive consequences.  The treatment of choice for OSA is continuous positive airway pressure (CPAP) ventilation.  However, many patients have difficulties with adherence to the CPAP.  A nurse researcher is conducting an innovative intervention using the Internet to improve adherence with the CPAP in patients with Obstructive Sleep Apnea and to improve support by the family caregivers.  This study will ultimately improve patient and family caregiver quality of life and reduce patient and family caregivers’ morbidity.

Another NINR-funded study is testing an intervention on how to adjust to jet lag.  Jet lag is one of society’s most prevalent disorders and symptoms include insomnia, daytime sleepiness, fatigue, decreased alertness and loss of concentration.  Jet lag impairs judgment and performance of business men and women, diplomats and the military.  Information on how to treat individuals who are forced to sleep at the wrong phase of the circadian cycle will be useful not only for those with jet lag, but also for shift workers and others who must deal with changing time and altered sleep schedules.

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: the first is in the area of sleep in coronary artery bypass patients, and the second explores the relationships among stress, immune function and sleep quality in persons with HIV.  In addition, NINR supports a pre-doctoral fellow exploring an intervention using neurofeedback for treatment of insomnia, and co-funds two institutional training grant post-doctoral positions focused on the area of sleep and its disorders.

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FISCAL YEAR 2000 FINANCIAL REPORT
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE

Sleep Disorders Research
(Dollars in thousands)


 
1995 
Actual
1996 
Actual
1997 
Actual
1998 
Actual
1999 
Actual
2000 
Actual
2001
Estimate
NHLBI
 13,674
 16,450
19,219 
 22,932
 31,845
 35,128
 38,816
NINDS
 8,018
 9,453
 11,598
 13,639
 15,231
 12,495*
N/A 
NICHD
 6,627
 7,368
 7,217
 9,131
 7,116
 6,797
8,200
NIA
 7,847
 7,800
9,179
 11,818
 13,296
 13,034
13,295
NIMH
 29,721
 27,231
28,601
 34,027§
 39,219
 40,667
N/A 
NIDA
 1,084
 1,201
 1,042
 1,586
 2,163
 2,553
N/A 
NIAAA
 793
 551
 728
 766
 736
 1,132
N/A 
NCRR**
 2,944
 3,247
 3,570
 5,542
 6,637
 7,117
7,479 
NINR
 2,107
 2,842
 3,565
 3,394
 3,503
 4,635
5,099
TOTAL
72,815 
76,143
 84,719
 102,835§
 119,746
 123,558
  

*Due to implementation of a more rigorous procedure for identifying sleep-related grants during FY2000, the final total was reduced by 26 grants (29%) and by $2,161,000 (15%) compared to the preliminary total for FY2000.

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

** Not included on the Trans-NIH Sleep Research Coordinating Committee

The complete grant listing can be viewed online in two formats:
    Grants List in HTML [270 K]
    Grants List in PDF [167 K] (More information on PDF and the required reader is available.)

Copies 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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