Annual Report
of the
Trans-NIH Sleep Research Coordinating Committee
FISCAL YEAR 1999

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
NIH Sleep Research FY 1999 (Grants List) [300 K]

NHLBI Home Page
Sleep Disorders Information  Scientific Information and Resources

I.  INTRODUCTION - Trans-NIH Annual Report, Fiscal Year 1999

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 basis of sleep and associated cardiopulmonary disorders. 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). Newly announced 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 twenty-eight 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 disorder characterized by interruptions in breathing and disturbed sleep. New epidemiological data suggests that sleep apnea may be a significant factor in the development of cardiovascular disease. An ongoing NHLBI study of over 6000 middle aged subjects has found that sleep apnea is common in middle age and older populations, and is associated with sustained increases in blood pressure and increasing odds of hypertension independent of age, gender and body weight. These studies also indicate that sleep apnea is modestly associated with all cause cardiovascular disease and stroke.

A study of over 800 middle aged subjects (The Wisconsin Sleep Cohort), recruited since 1989, are providing the population base for a series of investigations into risk factors associated with sleep disorders including sleep apnea. These investigations have provided the first prospective evidence that even minimal sleep apnea places people at significant risk of hypertension. These results suggest that hypertension attributable to sleep apnea may be greater than previously suspected and that apnea could be a significant risk factor during early development of hypertensive disease.

Sleep Apnea in Children

Recent studies indicate that the etiology of childhood apnea may be different from that in adults. Children with sleep apnea are 3-4 fold less sensitive to airway obstruction during deep sleep (REM sleep) than children without apnea. This finding suggests that children with apnea may have a generalized arousal deficit compared to normal children. Children with an arousal deficit and apnea maybe less prone to experience sleep disturbances resulting from the pauses in breathing, but the restoration of breathing may be slower and expose the affected child to longer periods of airway obstruction and hypoventilation. In contrast, arousal in adults is responsible for terminating airway obstruction, and recovery is faster at the expense of fragmented sleep.

Deep sleep is thought to facilitate growth and maturation, and the preservation of sleep patterns in children are believed to be developmentally important. Whether sleep disturbance in childhood and hypoxia associated with sleep apnea influences childhood development is an area of investigation. Hypoxia developing from inadequate ventilation during early development has been associated with SIDS, and may increase the risk of cardiorespiratory diseases later in life. Recent findings indicate that sleep apnea can cause high blood pressure in children as young as two years of age. This study which included 67 children found that elevated diastolic blood pressure was associated with both mild sleep apnea and snoring. However, the rise in diastolic blood pressure was significantly higher in the children with sleep apnea than in children who only snored. Elevated blood pressure in apneic children was present during both sleep and wakefulness. Also, the blood pressure increases associated with apnea were unrelated to the effects of obesity, which is associated with increases in both systolic and diastolic blood pressures.

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 Disturbance and Excessive Daytime Sleepiness

Sleep apnea disrupts the normal pattern of sleep and is a well recognized cause of excessive daytime sleepiness. However, the effect of sleep-disordered breathing (SDB) milder than sleep apnea on sleepiness is uncertain. A study of 1,824 community-dwelling adults has found that those with minimal to mild SDB are 33% more likely to have excessive sleepiness. The degree of sleepiness increased with SDB severity in this study and was independent of other factors such as age, sex, and body mass index. This study also suggests that about half of the middle aged and older adult population may have SDB levels producing excess sleepiness and associated risks such as occupational injury, poor job performance, traffic accidents, and reduced quality of life. Another NHLBI study of over 5,800 subjects has found that there is a strong association between daytime sleepiness in the elderly and cardiovascular disease-related morbidity and mortality, myocardial infarction, and congestive heart failure. This association is stronger in women than men, and independent of age and other factors. Together, these new research findings points to a potential role of sleep disturbances as a cardiovascular disease risk factor.

Sleep Disorders

Prolonged wakefulness significantly impairs human performance and creates a powerful drive to sleep. The Institute supports basic research to investigate how timekeeping oscillations of the biological clock are transmitted to other gene-regulating proteins, to study the rhythmicity of physiological and behavioral patterns, to identify the specific factors that generate the sleep drive, and to study the causes and consequences of sleep disorders. A study of how sleep loss impairs the basic ability to ward off infection has examined the time course and pathogenic sequelae of sleep deprivation. 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.

Other NHLBI supported studies examining the genetic basis of narcolepsy have identified 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 novel neuropeptide hypocretin (orexin). Other studies have confirmed these narcoleptic abnormalities using mice lacking either the hypocretin gene or the hypocretin receptor gene. More recently, human studies of hypocretin showed that hypocretin neurotransmission is deficient in some narcoleptics. This new knowledge has already provided clues to explain the effectiveness of an anti-narcoleptic drug recently approved by the FDA (modafinil/provigil). Studies in mice indicate that the drug acts by stimulating hypocretin-containing neurons regulating sleep and wakefulness. Together, these studies provide strong evidence for the role of the hypocretin system 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.

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NATIONAL INSTITUTE ON AGING

A. Monjan, Ph.D., M.P.H

Sleep and Circadian Rhythm Research

Sleep is a state that occupies about a third of our lives. Researchers have discovered that disturbances of normal patterns of sleep can exert a significant impact on the quality of life and, in some cases, can be life threatening. Unfortunately, relatively little more is known of the function or of the role sleep plays in health and disease. Sleep disturbances afflict a majority of the older population in the U.S., contributing to personal discomfort and illness, to care giver burden, and to overall health care costs. 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.

Program Activities

Program growth in the Sleep portfolio has been from $2 million in fiscal year 1988 to about $12.3 million in fiscal year 1999 that has been accomplished primarily through individual programming efforts.

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 comorbidities common in late life that affect sleep.

It has been reported previously that over half of a study population that included 9,000 elderly people had some chronic sleep complaint, and 28.7 percent had chronic insomnia, as defined by a chronic complaint of "trouble falling asleep" and/or "awaking too early". This population, however, was primarily Caucasian (C), although a small urban African-American (AA) cohort from New Haven, CT, was represented. This latter group reported fewer chronic sleep complaints than did their C counterparts. Their small numbers precluded any further detailed analyses. A larger AA cohort was developed within the five counties in the North Central Piedmont of North Carolina. The differences between the races in this larger sample duplicated the differences found in the New Haven group. The largest differences were in waking during the night wherein the prevalence of wakeful sleep among the AA was almost 60 percent that of the C. The percent prevalence of insomnia for the former group also was significantly lower (19.8% vs. 23.6%, respectively; p<0.05). The overall prevalence of insomnia for the C in rural North Carolina was similar to that found in predominantly rural Iowa (23.2%), as were the gender specific rates (20.4% and 25.5% for men and women, respectively, in North Carolina, versus 19.5% and 25.4% for the men and women, respectively, of rural Iowa). In contrast, the gender specific rates for the North Carolina AA (16.4% and 21.8% for the men and women, respectively) were both significantly (p<0.04) lower than those of their C counterparts.

The overall three-year incidence (15%) and remission (46.8%) rates for insomnia in the North Carolina study are similar to those in the primarily C groups studied in East Boston, New Haven, and Iowa (14.5% and 47.9%, respectively). However, the race and gender specific analyses indicated that only the AA women had a significantly higher incidence rate for insomnia. C males and females did not differ in their risks to develop insomnia. The apparently high remission rate for the AA males was not significantly different from the C males, reflecting the small numbers in each group. However, males had significantly higher remission rates than did the females. The increased likelihood of maintaining insomnia leads to the greater observed prevalence of insomnia in women, and AA women face the additional burden of a higher incidence rate.

Factors associated with incident insomnia were determined using a logistic regression risk model established for the larger cohort. Maintained or incident depressed mood was strongly associated with insomnia in both racial groups. This is a factor that is common across many studies. Maintained fair or poor health and of physical difficulties, also were associated with incident insomnia in, but not among the AA, who, on the other hand, showed an association between incident insomnia and incident development of the perception of fair or poor health. Overall, this risk model did not reflect the same significant factors as were found in the other cohort. The frequencies of poor health measures generally were greater in that cohort as a whole than in the North Carolina group. On the other hand, the rural Iowa cohort appeared to be more similar in these indices to this rural group. Thus, many of the differences between the two populations may be attributable to life-style factors. Factors related to the remission of insomnia weighted heavily on an improved perception of health within the C; resolution of depression was not a significant factor for the resolution of insomnia.

The natural history of sleep apnea is being studied in 70 AA with mean age 73.7 yrs and range of 65-88, and 70 C with mean age of 73.5 yrs and range of 65-93. The data so far suggest that for many older AA with hypertension, blood pressure does not fall the expected amount at night, and that this non-dipping is associated with more severe sleep disordered breathing (SDB). In fact, the respiratory distress index (RDI) was related to BP among non-dippers but not among dippers. Non-dippers with high systolic blood pressure (SBP) during the day or high SBP or diastolic blood pressure (DBP) during the night were more likely to have higher RDI. These results suggest that AA patients who are non-dippers need to be screened for SDB, and those AA patients who are prone to SDB and who are non-dippers might benefit from continuous positive air pressure treatment during their sleep periods. AA, but not C, with MMSE scores less than 27 had significantly more desaturations and spent more percent time at less than 90% saturation, suggesting that oxygenation may be related to cognitive impairment for some groups of elderly.

Interviews and in-home polysomnography have been conducted on Hmong people in La Crosse and Madison WI to collect data on sleep disorders, particularly sleep apnea, in this ethnic group at high risk for Sudden Unexpected Nocturnal Death Syndrome. Analysis of the interview data ;on sleep problems in Hmong men and women has indicated potentially important differences between Hmong and Caucasians in the correlates of self-reported breathing disturbances during sleep. Most notably, in the Hmong, nightmares and episodes of sleep paralysis occur relatively frequently and are strong predictors of snoring and breathing pauses. The relationships do not appear to be explained by adherence to traditional Hmong beliefs in nocturnal spirits and Shamanism. These sleep problems, measured with the same instruments on the larger Wisconsin population cohort, appear not to be related to SDB. In the subsample of Hmong studied by in-home polysomnography, an unusually high prevalence of SDB was found. Studies of heart rate abnormalities in conjunction with apnea and hypopnea are underway.

Mechanisms

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.

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.

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. It suggests that the new findings of the molecular and genetic mechanisms regulating the circadian clock of other species also may apply to humans.

This study changes some fundamental assumptions about the causes of sleeplessness among the elderly. Poor sleep is not a function of being old by itself. 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. Furthermore, the stability of the circadian clock across adult ages indicates that precise circadian timing is vital to the health and well being of humans. Finally, the similarity of circadian periods across the animal kingdom suggests that the findings of basic cellular and molecular mechanisms in these model systems will be applicable to solving the problems of sleep and wakefulness in humans.

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.

A recently described cluster of cells in the ventral lateral preoptic (VPLO) area of the hypothalamus exhibits c-Fos protein only during sleep. The number of c-Fos-immunoreactive neurons in the VLPO was correlated with the amount of sleep, independent of circadian phase. These cells project to the histaminergic tuberomammillary nucleus (TMN), primarily through GABA and galanin inhibitory projections. The TMN is the major source of histaminergic innervation of cortex and thus plays an important role in regulating wake-sleep states. The VLPO, furthermore, innervates other monoaminergic cell groups that provide diffuse cortical projections: the dopaminergic ventral tegmental area, the serotonergic dorsal and median raphe nuclei, and the noradrenergic locus coeruleus. Because the VPLO neurons are active during sleep, they can regulate the sleep-wake cycle by simultaneously hyperpolarizing the monoaminergic components of the ascending arousal system. Old rats have a decline in delta power and compensatory sleep following prolonged wakefulness. No differences were found from young rats in the numbers of c-Fos labeled cell in the VLPO. Caffeine significantly reduced sleep parameters in middle-aged (10 mos.) and old (21 mos.), but not young (2 mos.) rats. These data indicate that the decline in sleep in old rats cannot be attributed to loss of neurons implicated in sleep in VLPO since they had the same numbers of c-Fos labeled sleep-active cells in VLPO. However the caffeine data suggest that there is a change in the sensitivity and/or number of adenosine receptors with aging.

An interesting recently discovered molecule is 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. Its 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. Its link to the aging nervous system remains to be established.

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.

Passive body heating (PBH), or a warm bath, has been compared to a pharmacologic (zolpidem) as treatment for insomnia in older women. Zolpidem was used either as a 2.5 or 5.0 mg, PBH was bath at water temperature of 40-40.5 C, and placebo. Analysis of preliminary data with 5 subjects per group indicated that improvements were substantial with PBH, and that zolpidem at both doses showed modest improvement in objective sleep parameters but inconsistent subjective changes. No obvious differences between groups were seen in daytime MSLT. Daytime cognitive performance was similar for all treatment groups.

Melatonin treatment is being tested for its sleep-inducing effects. However, 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. Primarily as the result of several popularized books, melatonin has become available over the counter as a dietary supplement and presented as a natural hormone that can produce a number of outcomes, ranging from improving sleep to extending life span. These conclusions are based upon data that melatonin levels decline in older persons. However, other recent data question this premise since no differences were found in plasma melatonin levels when comparing healthy subjects free of sleep complaints and use of medication whether prescription or nonprescription. In the study, 34 healthy older people, both men and women ranging in age from 65 to 81, had nighttime melatonin levels that did not differ significantly from those of 98 younger men whose age ranged from 18 to 30. Study participants spent three days and three nights isolated under carefully controlled conditions in a sleep laboratory and maintained their normal sleep schedules. There were no statistically significant differences in nighttime melatonin concentrations between the young and older subjects, although the study does not address whether melatonin levels change after the eighth decade.

In ground-based studies supported jointly with NASA, a protocol was developed that would induce a disruption between the homeostatic sleep/wake and the circadian rhythm cycles in order to assess how these two processes interact, how normal neurobehavioral functions may be altered, and to obtain a dose-time-response curve for melatonin to alleviate these perturbations. When the homeostatic sleep/wake cycle and the circadian system were out of synchrony, there was maximal impairment in neuropsychological performance. Awareness of this relationship between the sleep processes and the circadian pacemaker should alert us to the potential of impaired functioning of individuals in jobs that require high levels of attention and decision making when their sleep/wake cycles or other than the usual patterns. These protocols and findings in healthy young adults now are being adapted to healthy older adults in order to quantify age-related changes in the impact of circadian cycles on sleep, the ability of older adults to tolerate and function with misalignment of the sleep/wake and circadian cycles, and to test the effectiveness of small doses of melatonin to alleviate the disturbances and promote sleep. Based upon this 20-hr forced desynchrony data from young adults, the protocol for the older adults is modified to be a within subjects design using melatonin at 0.3, 5.0 mg and placebo treatments. The study with the younger adults indicated that 0.3 mg was most effective at significantly shortening sleep latency and increasing sleep efficiency when sleep was at adverse circadian phases. Also, it was found that there appeared to be a greater benefit of exogenous melatonin administration on the sleep of females than in males.

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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 supported 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 interaction of alcohol, aging, and sleep; f) the relationship between alcohol consumption, sleep deficits, and serotonergic system function in nonhuman primates.

Highlights from several of these research areas are summarized below:

Sleep Effects of Exposure to Alcohol During Breast Feeding

Recent research has found that acute exposure to alcohol in mothers' milk alters the infants' sleep-wake patterning. Infants tended to fall asleep sooner, but sleep for significantly shorter periods of time, immediately after consuming alcohol through mothers' milk. This reduction is due, in part, to a shortening in the amount of time the infants spend in active sleep. In addition, infants tend to be more active during wakefulness after consuming alcohol through mothers' milk. In summary, although the mechanisms underlying the reduction in sleep remains to be elucidated, short-term exposure to small amounts of alcohol in mothers' milk produces distinctive changes in the infants' sleep-wake patterning.

Ethanol Abuse Liability in Insomniacs

Chronic insomniacs often self-medicate using over-the-counter medications and alcohol, with 67% of them using alcohol and reporting it is effective. Recent research has focused on whether ethanol use before sleep by insomniacs may lead to sustained ethanol intake extending beyond the therapeutic context and then become associated with "mood altering" effects. To date, research suggests that insomniacs are more likely to self-administer ethanol before bedtime than are non-insomniacs. Furthermore, a low dose of ethanol appears to make some subtle improvements in the insomniacs' sleep without disturbing their sleep in the second half of the night. Furthermore, mood changes in insomniacs consuming ethanol before sleep (tension and depression reductions and concentration increases) may function to reinforce its use as a hypnotic.

Sleep Disturbances, Mood, and Relapse Tendency in Alcoholics

EEG techniques are being utilized to predict relapses in recovering alcoholics. Since many alcoholics also show evidence of secondary depression early in the course of abstinence, the ability to differentiate the contribution of alcoholism and mood disorder to relapse is important. Research has shown that baseline "REM pressure" in primary non-depressed alcoholics is associated with 3-month relapse. In addition, increased REM density and decreased total sleep time at about 2-4 weeks of abstinence predict relapse by 3 months in depressed alcoholics. More recently, it was found that alcoholism affected polysomnography more than depression. The ability to identify alcoholics with a poor prognosis (i.e., relapse within three months of discharge) could have important prevention and treatment implications.

Alcohol, Aging, and Sleep Disordered Breathing

Recent studies have shown that among alcoholics, sleep disordered breathing was present in 3% of 91 subjects under 40, 17% of 83 subjects age 40 to 59, and 50% of 14 subjects age 60 or over. Subjects with sleep disordered breathing were more likely to be male and had more severe sleep disruption and nocturnal hypoxemia and more complaints related to daytime sleepiness than subjects without sleep disordered breathing. Analysis showed that age and body mass index were greater predictors of sleep disordered breathing than smoking or duration of heavy drinking. These findings suggest that sleep disordered breathing contributes significantly to sleep disturbance in a substantial proportion of older alcoholics, and that sleep disordered breathing increases with age in alcoholics. Sleep-disordered breathing, when combined with existing cardiovascular risk factors, may contribute to adverse health consequences in alcoholics.

Risk Markers for Alcoholism: The Relationship between low CSF 5-HIAA and Sleep Deficits in Nonhuman Primates

The ability to identify neuropharmacological, behavioral, and physiological risk markers for excessive alcohol consumption has been investigated using a nonhuman primate model. Cerebrospinal fluid concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were used as a measure of serotonin function. Low 5-HIAA concentrations in infancy predicted excessive alcohol consumption in adolescence. In addition, subjects with low 5-HIAA concentrations exhibited impaired impulse control, infrequent and inept social behaviors, low social status, social isolation, and early mortality rates. These findings were consistent with predictions from Cloninger's type II model of excessive alcohol consumption among men who exhibit impaired impulse control and violent antisocial behaviors.

A recent study investigated the relationship between serotonergic activity (5-HIAA concentrations) and sleep/wakefulness behavior in socially housed juvenile monkeys. Results showed a negative correlation between latency to fall asleep and 5-HIAA levels (i.e, subjects with low 5-HIAA concentrations were unlikely to fall asleep early). Subjects with low CSF 5-HIAA also showed more total activity, more frequent periods of activity, and longer mean durations of activity. This suggests that low CNS serotonin turnover is associated with higher nighttime activity, less overall sleep periods, and shorter mean periods of sleep. Thus, the serotonergic system may play a role in sleep onset and possibly in the regulation of diurnal activity rhythms in nonhuman primates.

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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.

In the past year, the information regarding the autonomic nervous system abnormalities in infants who succumb to SIDS has been significantly expanded. Previously, researchers had observed decreased binding of acetylcholine and kainate to receptors in the arcuate nucleus of SIDS infants, suggesting that the number of these neurotransmitter receptors was decreased. The arcuate is a region on the ventral brainstem believed to control chemoreception, and cardiorespiratory and cardiovascular responses. It is linked to other regions in the brain controlling arousal from sleep. It has been hypothesized the SIDS infants lack the ability to respond to life-threatening hypercapnic, hypoxic, hyperthermic and/or cardiovascular episodes during sleep. This year these researchers reported deficiencies in the serotinergic receptors in the arcuate nucleus as well as the n. raphe obscurus, inferior olive, n.paragigantocellularis, and the n. gigantocellularis. The deficits were not observed in brainstems of infants dying from other causes. These results suggest that the scope of the neurochemical abnormalities in SIDS infants is larger than previously expected and involves several functionally-related nuclei derived from the rhombic lip. These regions develop from the rhombic lip in early gestation, providing strong evidence for altered development of protective pathways during fetal in infants who later succumb to SIDS.

Infants are between 3 and 9 times greater risk of dying of SIDS if they are put to sleep on their stomachs. The mechanism of the risk associated with infant sleep position has been the subject of intense investigation. Studies are revealing differences in autonomic control in the prone and supine position of preterm, low birthweight infants. These infants exhibit higher heart rates, lower hear rate variability and higher respiratory rate in the prone compared with the supine position in both active and quiet sleep. With increasing postconceptional age, the differences in autonomic function between the prone and supine position increased. The observed variations in autonomic control in the prone position are similar to those recorded in term newborns who later died of SIDS. The more rigid autonomic control, and the observation by these investigators that infants sleeping prone spend more time in quiet (deep) sleep than supine infants, may lead to a compromised response to cardiorespiratory or cardiovascular challenges.

There are several studies in progress to identify physiologic markers of risk for life-threatening cardiorespiratory events and SIDS. One longitudinal prospective study is correlating cardiovascular, respiratory and arousal function in the fetus and infant with maternal medical and behavioral risks, SIDS, and poor developmental outcome. It is being conducted in a low risk population in New York City and a high risk population in the Aberdeen Area of the Indian Health Service. Since it has been shown that SIDS infants have reduced heart rate variability during sleep in the first few weeks of life compared with normal infants, the investigators have developed a test for the baroreceptor reflex, which controls heart rate in response to changes in blood pressure. Studies of newborn infants show that the reflex is already present during deep sleep in the first few days of life. In addition, the magnitude of the heart rate response is proportional to the baseline heart rate variability of the infant. In longitudinal studies, a change is observed at 2-4 months of age, the peak age range for SIDS. The heart rate response to a head up tilt, while present a birth is absent by this time and suggests a vulnerability to compensate for decreases in blood pressure. Studies are now in progress to investigate cardiovascular and respiratory control longitudinally from fetal life in the low and high risk groups and to correlate the responses with toxic exposures in utero such as cigarette smoke and alcohol.

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. A study of oxygen saturation during sleep in healthy term infants from birth through 24 weeks of age has provided important information. Healthy term infants generally have baseline SpO2 levels >95%, but transient acute desaturations do occur. The probability of having a transient acute decrease in blood oxygen was positively correlated with younger age, periodic breathing, and apnea, and appear to be part of normal breathing and oxygenation behavior.

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 1999, outreach activities continued to focus on underserved minorities and day care providers.

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. In 1998, half of the nighttime caregivers ere placing their infants to sleep on their backs and less than 20% on their stomachs. In addition, more than 90% of the survey population had received the message to place the baby on the back from at least one source, with the nurse in the newborn nursery or reading materials such as newspapers and magazines being the most common source.

Multiple logistic regression analyses of the cross-sectional and longitudinal surveys show that African Americans are twice as likely to place infants on their stomach. This may partially explain why the SIDS rate among blacks, while declining, remains about 2.2 times that of whites. It is likely that the routes of message dissemination and the cultural context influence behavioral change among African Americans. The NICHD is currently supporting a contract to obtain information on baseline knowledge of SIDS risk factors, how knowledge was obtained, perception of SIDS risk, cultural influences affecting infant care practices related to SIDS risk, and perception of a variety of SIDS educational materials within African American communities across the country. In addition, the NICHD in partnership with the National Black Child Development Institute and the Pampers Parenting Institute are working with leading African American organizations to develop targeted campaign materials and strategies to reduce the incidence of SIDS in this population.

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NATIONAL INSTITUTE ON DRUG ABUSE

H. Gordon, Ph.D.

Many researchers of sleep cycles and biological rhythms may be studying the same mechanisms involved in drug abuse and biological reward systems. An excellent example of this is a recently-funded study whereby circadian genes of the fruit fly, Drosophila melanogaster, are seen to play a role in sensitization to cocaine. These flies sensitize to repeated doses of cocaine just as in humans and in animal models. However, the sensitization process is eliminated in flies lacking either the period, clock, cycle, or doubletime gene (but not the timeless gene). The roles for these genes have not been fully explained, but it is believed that they function as regulators of tyrosine decarboxylase. [Report published by Andretic, R., Chaney, S., & Hirsh, J. (1999) Science, 285(5430):1066-8.] Circadian rhythm is also associated with nicotine and nicotinic acetylcholine receptors; the alpha-7 subunit is the most abundant in the suprachiasmatic nucleus. It was reported last year that nicotine appears to cause phase delays in the early subjective night and phase advances in the late subjective night in rats [O'Hara, B.F., Edgar, D.M., Cao, V.H., Wiler, S.W., Heller, H.C., Kilduff, T.S., & Miller, J.D. (1998) Psychoneurendocrinology, 23(2): 161-73]. Further work in the past year has characterized the development of the subunits and transcription factors in the suprachiasmatic nucleus and other brain structures (e.g., medial habenula) suggesting differential effects of nicotine on these structures and associated functions. [See O'Hara, B.F., Macdonald, E., Clegg, D., Wiler, S.W., Andretic, R., Cao, V.H., Miller J.D., Heller H.C., & Kilduff, T.S. (1999) Brain Res Mol Brain Res, 66(1-2):71-82.]

The laboratory of Wallace Mendelson at the University of Chicago has been investigating the effect of hypnotics on sleep regulation. An unsaturated acid amide, oleamide, has been observed to accumulate during sleep deprivation, but it induces sleep as well as increases motor activity in the open field when administered intracerebroventricularly in rats. While the mechanisms are not clear, it was recently shown that the cannabinioid-1 receptor antagonist SR141716 prevents the sleep-inducing effects of oleamide, suggesting that the cannabinoid receptor is involved. [See reports: Basile, A.S., Hanus, L., & Mendelson, W.B. (1999) Neuroreport, 10(5):947-51, and Mendelson, W.B., & Basile, A.S. (1999) Neuroreport, 10(15):3237-9]

Other laboratories are investigating the effects of drugs of abuse on the sleep architecture. Methylphenidate increased scores on the multiple sleep latency test and fatigue scales and was selected for use by subjects who had reduced time in bed, presumably to reduce fatigue [Roehrs, T., Papineau, K., Rosenthal, L., & Roth, T. (1999) Exp Clin Psychopharmacol, 7(2):145-50]. Subjects using the recreational drug, (+/-)3,4-methylenedioxymethamphetamine (MDMA), known as "ecstasy," had less sleep, especially Non-REM sleep (only Stage 2) which may be due to the effect on the serotonergic system [Allen, R.P., McCann, U.D., & Ricaurte, G.A. (1999) Sleep, 16(6):560-4].

Finally, it should be reported that a recently funded project will combine the forces of the major sleep research group led by J. Allan Hobson and a major cocaine research group led by Marian Fischman to study the phenomenon that monoaminergic drugs of abuse, such as cocaine, first potentiate but then later impair the neuromodulatory dynamics of the wake-sleep cycle. The hope is that the example of this collaboration will be emulated by others who recognize the similarity of the brain systems studied by both sleep researchers and drug abuse researchers and will result in future-funded, joint projects

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NATIONAL INSTITUTE OF MENTAL HEALTH

I. Lederhendler, Ph.D.

Psychobiology of Sleep and Depression in Children and Adolescents

There are two principal alterations of sleep-wake patterns during adolescence. The first is timing of sleep, which is strongly influenced by psychosocial factors, but influenced as well by changes in biological sleep and circadian timing systems. The second change is the pattern of adolescent sleep deprivation, which is influenced by both the delay of sleep and by the necessity to terminate sleep prematurely to attend school. The focus of continuing NIMH research is on implications of sleep-wake patterns for emotional regulation and depression. In addition sleep patterns may provide important and needed early indicators of vulnerability for mood disturbance and depression in childhood and adolescence.

A significant feature of major depression in adult patients is the disruption of circadian rhythms, or the balance between sleep and wake time. Important changes in sleep and circadian rhythms in adolescence have been documented to include phase delay for sleep onset, late offset of melatonin secretion, and daytime sleepiness. The neuroendocrine mechanisms are not yet understood, but adolescent habits related to bedtimes and sleep onset times interact with maturational changes in sleep and circadian rhythms to increase risk for mood disturbance and depression in this vulnerable group.

Survey data accumulated over the past two decades indicate that older teenagers have later bedtimes and sleep less than younger teenagers, even though the need for sleep does not decrease. Older teenagers also are likely to have earlier rise times, as in many school districts the school day starts progressively earlier as children proceed from grade school to middle school or junior high school and high school. Younger adolescents are more likely than older adolescents to wake spontaneously; older teenagers increasingly rely on external assistance (parents, alarm clock). With age, teenagers show an increasingly larger discrepancy between school night and weekend sleep schedules. Teenagers who work 20 or more hours per week report later bedtimes, sleep fewer hours per night, and are more likely to oversleep and fall asleep in school than teenagers who work less than 20 hours per week.

The sleep homeostatic system strongly influences the distribution and patterning of sleeping and waking. In adolescents, this phenomenon was observed in discrepancies between school night and weekend sleep schedules. Recent findings indicate a developmental decline in the strength of homeostatic control during adolescence: reduced slow wave sleep and, even given an adequate amount of sleep, increased daytime sleepiness. Studies focusing on neurophysiological responses to insufficient sleep in the waking brain (sleepiness) and the sleeping brain (slow wave sleep) are provide evidence of a link between acute sleep restriction and negative emotionality.

The circadian rhythm or timing system affects sleep architecture as well as timing of sleep and waking behavior. The timing of sleep onset, the length of sleep, and the timing of rapid eye movement (REM) sleep vary with phase of the circadian timing system marked by core body temperature. Core body temperature typically rises across the day to late afternoon or early evening and then falls across the night, rising again in the early morning hours. The circadian timing system also controls the secretion of melatonin, a hormone secreted by the pineal gland during nocturnal hours. Ongoing NIMH-supported research is showing that a phase delay in the circadian timing system occurs in association with pubertal development and that the offset phase of melatonin secretion is correlated with age as well as pubertal stage. Adolescents studied before and after transition to high school with earlier start times were more likely after transition to exhibit REM sleep in multiple sleep latency tests conducted across morning hours, indicating that their circadian rhythms continue in nocturnal mode. Morning REM also was related to later dim light controlled melatonin onset, or circadian phase delay. Along with strong psychosocial influences, changes in bioregulatory systems controlling sleep appear to limit adolescents' capacity to make adequate adjustments to an early school schedule.

Most of the research examining sleep processes in adolescents has focused on the macroarchitecture of sleep. Sleep dysregulation (short REM latency, a drop in slow wave sleep, increased arousal, sleep fragmentation, and prolonged sleep latency) is one of the most consistent biological markers in adult major depression. In adolescent major depression, there is significantly shorter REM latency. In childhood depression, interactions between REM latency and cholinergic pharmacology suggest that sleep dysregulation may be subthreshold. Recently, one team of researchers has begun to examine the microarchitecture of sleep in depressed adolescents, focusing on the temporal organization of sleep during the entire night of sleep: Their analysis of quantitative sleep EEG for intra- and interhemispheric coherence in children and adolescents with and without a major depressive disorder is showing that these coherence measures differentiate both children and adolescents with major depression from normal controls. Their findings suggest that intrahemispheric coherence does not depend on complete brain development, but that interhemispheric coherence shows a maturational decline with brain development and may be useful in identifying individuals with major depression in early adolescence.

Sleep deprivation also has major effects on everyday functioning in adolescents. Recent research shows that the ability to perform two different tasks simultaneously is particularly sensitive to the effects of sleep deprivation. In one study, adolescents' postural balance was impaired by sleep deprivation only while performing a cognitive task. In another study requiring, sleep deprivation impaired adolescents' ability to perform tasks requiring simultaneous emotional and cognitive processing. These tasks represent real world challenges facing adolescents: the need to think and control emotions at the same time. Social competence requires similar skills of cognitive processing under conditions of emotional challenge. Given that we have data on very high rates for sleep deprivation among adolescents, these findings also raise important questions about pathways to affect dysregulation and affective disorders.

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NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

F. J. Brinley, Jr., M.D., Ph.D.
C. McCutchen, M.D.

Exciting progress has been made in the neurology and neuroscience of sleep in FY99. Program officials of the NINDS continue to participate in the activities of the National Center for Sleep Disorders Research (NCSDR) at the National Heart Lung and Blood Institute, and in the Trans NIH Sleep Research Coordinating Committee, chaired by the NCSDR Director.

While we as yet know neither the function nor all of the molecular mechanisms underlying sleep, public interest in the clinical and scientific relevance of sleep related issues has grown significantly. This increasing public awareness is reflected in congressional language encouraging NINDS and NIH efforts on behalf of basic and clinical research into the function and neurobiology of sleep.

The following areas represent some of the high points of sleep and circadian neuroscience research supported by NINDS in fiscal year 1999 :

Basic Neurobiology of Sleep

The Sleep Medicine and Circadian Neuroscience Program at NINDS has fostered the development of basic neuroscience programs which promise to unlock the secrets of sleep and circadian rhythms. One NINDS investigator, James Krueger, has such original ideas that occasionally study sections indicate that his work is too risky. One such idea was that the immune system had a major role in sleep regulation, an idea that his work has proved to be true. His research has developed such that he was eventually lauded by study sections for "creating a whole new paradigm for understanding sleep regulation" by the immune system. NINDS was recently able to honor him with the Jacob Javits award , NINDS' highest award for excellence in neuroscience. Another investigator who received the Javits award this year is Jerry Siegel of UCLA. His work holds the promise of our being able to intervene during a crucial period in neurodevelopment to prevent neural destruction by the immune system which decades later results in symptoms of the neurodegenerative disease narcolepsy. The applicability of this paradigm for other neurodegenerative diseases such as Parkinsonism, ALS, and Alzheimer's Disease is an exciting prospect. Teaming up with investigators who cloned the mammalian circadian gene CLOCK, NINDS investigator Dr. Emmanuel Mignot of Stanford University found that a mutation on this Chromosome 4 gene helps determine preference for morning or night activity. Thus "morning" people and "night" people may have genetic reason for their differences.

Neurological Disorders and Sleep Research

The Sleep Medicine and Circadian Neuroscience Program at NINDS fosters the development of the neurological component of the Sleep Medicine field, by mentoring young neurologists interested in the area, and identifying and supporting promising programs in academic neurology departments throughout the nation. This is particularly important for improving neurological and neuroscientific input into the sleep field, and to insure that neurological sleep disorders such as narcolepsy and Restless Legs Syndrome receive an adequate share of expert scientific and medical attention. The Restless Legs Syndrome Foundation supported a fellowship at NINDS which trained the first clinical neurologist from the NINDS program to devote his scientific explorations to Restless Legs Syndrome, Dr. William Bara. The first Sleep Fellow to graduate from the intramural Sleep Research Program, Dr. Beth Malow, has been awarded two career development awards from NINDS, and has inaugurated a Sleep and Epilepsy Interest Group within the American Epilepsy Society. Another NINDS Sleep Fellow, Dr. Heidi Siegel, developed and presented the revolutionary ultrasound diagnostic technique for obstructive sleep apnea, and is now an Assistant Professor of Neurology at Mt. Sinai Medical Center. Through site visits and personal communications, the Program is currently encouraging the development of sleep medicine programs which will look at the genetics of human circadian rhythms, circadian mechanisms in epilepsy, and movement disorders and sleep.

Narcolepsy Research

Narcolepsy is a disorder involving the brain where patients suffer from attacks of irresistible sleepiness, sudden loss of muscle tone with resultant paralysis, and dream-like hallucinations. Often beginning in adolescence, its diagnosis may be delayed for a decade or more. With a prevalence estimated at one in 1000, it is not a common disorder, but it can be devastating for those afflicted. Typically, education, employment, and daily activities such as driving are severely adversely affected. Since little was known about the mechanisms underlying the symptomatology, treatment of the excessive sleepiness was limited to symptomatic treatment with general central nervous system stimulants. The attacks of impaired muscle tone, known as cataplexy, were even more disabling and difficult to control in many patients, and often necessitated empirical therapeutic trials of a variety of agents.

Scientific investigation of this lifelong and incurable familial disorder has been facilitated by the formation of a national Narcolepsy patient registry, under the Direction of Dr. Michael Thorpy of Montifiore Medical Center in New York, chaired by the NINDS Program Director for Sleep and Circadian Neuroscience, Dr. Charlotte McCutchen. The Registry now boasts of a substantial database, which is being utilized increasingly by investigators. Also in 1999, the FDA approved PROVIGIL (modafinil), the first effective new therapy for Narcolepsy in several decades, with significant contributions to the development of the drug by NINDS-supported investigators. One of these investigators is Dr. Emmanuel Mignot of Stanford University's Center for Narcolepsy and his collaborators , who this year presented the world with the gene responsible for narcolepsy. After more than a decade of support from NINDS, and using sophisticated genetic techniques, the group worked with a canine model of narcolepsy which closely mimics the disease in humans to identify the gene . The gene, hypocretin receptor 2, codes for a protein that acts as a receptor on the neuron for the peptide "hypocretin", also known as "orexin" which is important in sleep regulation. When abnormal, the gene apparently codes for a receptor that cannot properly recognize signals involving hypocretin, leading to the symptoms characteristic of narcolepsy. The paper announcing the discovery was published in the journal Cell, and is titled : The Sleep Disorder Canine Narcolepsy is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene. Ironically, another group of investigators under Dr. Yanigasawa at the University of Texas, while looking for appetite suppression in orexin knock-out rodents, found that they appeared to be having attacks of cataplexy. That laboratory's paper describing the possibility that these mice may have narcolepsy was published in the next volume of the same journal where Dr. Mignot's paper created a sensation. This is our first gene for a complex neurological behavior, and one responsible for a faulty receptor which provides a direct target for therapeutics development. Dr. Mignot has more recently published the results of a study where he found that 7 out of 9 patients with narcolepsy had undetectable levels of hypocretin in their spinal fluid when compared to normal subjects. He envisions a day when patients with narcolepsy can be treated by replacing the substance, hypocretin, that their bodies are missing, much the way diabetics are treated with insulin. Dr Mignot received the Jacob Javits award from NINDS for excellence in neuroscience this year.

The discovery of the narcolepsy gene holds the promise of allowing development of specific therapies to address the disorder, perhaps even obviating the need for controlled drugs as treatment. Another very important and novel development that may have implications for future research into the causes of narcolepsy is the finding by Dr. Jerry Siegel at UCLA that neuronal degeneration can be detected in the brains of narcoleptic humans and canines. This degeneration was seen in areas of the amygdala, septal nuclei, and basal forebrain, and he is currently conducting experiments to determine how these degenerative changes produce the symptoms of narcolepsy, including cataplexy. The next step will be to determine how these degenerative changes take place, possibly leading to preventive therapies for this debilitating disorder. The future may see susceptible individuals being identified with genetic testing, and treated with preventive therapies in such a way that the symptoms as well as the neural substrate for the disease never develop.

The discovery of the narcolepsy gene also opens up the possibility that elucidation of the relationship between the gene and the mechanism of neurodegeneration may lead to a better understanding of neurodegenerative processes in general. This discovery may also lead to an increase in our understanding of other sleep disorders, and of the role of sleep itself in our lives.

Reference:

Ling, L., Faraco, J., Li, R., Kadotani, H., Rogers, W. , Lin, X., Qiu, X., deJong, P., Nishino, S., and Mignot, E., (1999) The Sleep Disorder Canine Narcolepsy is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene. Cell. 98, 365-376.

Grant Numbers :

2R01 NS33797-06 Emmanuel Mignot, P.I. "Molecular Genetics of Human Narcolepsy"
2P01 NS23724-09 Emmanuel Mignot, P.I. "Center for Narcolepsy and Related Disorders"
2R01 NS27710-09 Emmanuel Mignot, P.I. "Neuropharmacology of Human and Canine Narcolepsy"

Small Business Innovative Research in Sleep

The funds for this program are specifically designated for small business firms , with the intent of fostering the involvement of small business in biomedical research. The program has potential for being a means of supporting first-rate applied systems neuroscience. The Sleep Medicine and Circadian Neuroscience Program at NINDS, to assure that this money is spent on high quality research, has actively sought out top investigators in industry and academia, and encouraged them to team up to produce novel, high quality applications. With such applicants using both the grant and contract mechanisms, the results have been gratifying . More successful phase II applications than in the history of the program have been approved for funding. A substantial number of these have specifically addressed sleep-related topics advertised by the Institute, such as :

1) Novel therapies for sleep disorders
2) New methods for quantifying optimal alertness
3) Models of Neurological sleep disorders
4) Novel applications of evoked potentials to sleep neuroscience
5) Portable devices for cost-effective and user-friendly sleep disorder monitoring

The large multi-million dollar contract portfolio of Small Business Innovative Research (SBIR) proposals seeks to improve diagnostic and therapeutic possibilities for sleep medicine , and apply advances in technology to clinical neurophysiology. Funded proposals include : the development of convenient patch and suppository formulations of drugs for treating patients with poor oral or venous access who have sleep disorders; the development of "passive" methods of detecting drowsiness that can be part of the instrument panel of motor vehicles to prevent drowsy driving; brain physiology monitoring capability in electrically difficult situations where the brain is at risk if therapy is delayed, such as ambulances, intensive care units, emergency and operating rooms ; methods of objectively quantifying the need for stimulant therapy for patients with narcolepsy, using new applications of evoked potentials and electroencephalography ; methods of objectively quantifying the cognitive toxicity of neuroactive drugs such as anticonvulsants ; development of cheaper, more efficient methods of electophysiologically detecting and following sleep disorders in at-risk populations; development of the best paradigms for using light to treat circadian disorders such as jet lag.

Intramural Sleep Neuroscience Research

The intramural Sleep Research Program at NINDS participated in the development of a revolutionary but simple and cost-effective method of determining the site of obstruction in patients with obstructive sleep apnea, using ultrasound. Prior to our introduction of this technique at the American Academy of Neurology meeting in Toronto in April, 1999, patients with this disorder who underwent the surgical procedure that is most often used to correct it (uvulopalatopharyngeoplasty) had as much as a 40% failure rate. We demonstrated that visualization of the obstruction using our non-invasive technique during natural sleep can allow the surgical approach to more efficiently address the specific anatomic defect responsible for the obstruction in such patients. Our paper describing this work has been accepted for publication in the journal Neurology.

The intramural sleep research program also continues to investigate the interaction between sleep and neurological disorders to gain mechanistic insights into both. Careful evaluation of physiological parameters recorded by polysomnography resulted in the discovery of a fixed relationship between physiological events at the onset of Rapid Eye Movement Sleep (REMS). The relationship between the onset of muscle tone reduction, appearance of EEG "sawtooth" waves, and the first rapid eye movements of REM sleep appears to be so mathematically precise that the ratios of the intervals may represent a new way of gauging quality of function of the brainstem tegmentum, perhaps the reticular formation. After publishing these findings in the Journal of Electroencephalography and Clinical Neurophysiology in December 1997, the research team tested this hypothesis further by evaluating these physiological relationships in patients affected by the post-polio syndrome. These data , presented at the American Academy of Neurology in April 1998, support the hypothesis by showing that those subjects with a history of bulbar involvement had an alteration of the mathematical relationships between these events , while those subjects without brainstem involvement resembled normal subjects. This same relationship is also altered by selected anticonvulsant compounds, as presented at the American Epilepsy Society Meeting December 1998, and this may have implications for the understanding of brainstem actions of these compounds. Additional studies are characterizing the contribution of neurological problems to the development of obstructive sleep apnea. A paper describing obstructive sleep apnea in the post-polio syndrome was published in the journal "Neurology", and represented collaboration among several of the NINDS intramural programs.

Workshop: The Dopamine Connection in Restless Legs Syndrome, Periodic Limb Movement Disorder, Parkinsonism and Narcolepsy: Toward a Better Understanding of Common Mechanisms in Uncommon Disorders

Dr. Charlotte McCutchen, liaison to the NCSDR for NINDS, organized, directed, and participated in a unique international workshop on dopaminergic mechanisms in neurologic disorders and sleep. The workshop was lauded for bringing clinicians and basic scientists together in an unusual format to identify scientific opportunities, as well as clinical and research priorities. The workshop was described by Dr. Bruce Alberts, President of the National Academy of Sciences, as a prototype for generating progress in needed areas. It was also hailed by Harold Varmus, Director of NIH, for its bringing together "basic and clinical experts in divergent but complementary fields" which "can refocus and catalyze research and lead both to new opportunities and to unprecedented advances." The workshop, which was developed with the help of both the Restless Legs Syndrome Foundation and the NIH Office of Rare Diseases, as well as members of the academic community, was supported by several NIH institutes, including the National Institute on Aging, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Center on Sleep Disorders Research of the National Heart, Lung, and Blood Institute. An executive summary of the workshop is available at the following web site: http://www.ninds.nih.gov/neuroscience/workshopsumm/dopamine.htm

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NATIONAL INSTITUTE OF NURSING RESEARCH

K. Helmers, Ph.D.

Sleep deprivation 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 from illness, aging, pain, depression, and lifestyle. A majority of U.S. adults have experienced a sleep problem and sleepiness has been associated with accidents at work or 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.

During the past year, NINR has focused on three general areas of sleep-related research: 1) the impact of sleep deprivation across the lifespan in healthy populations; 2) sleep related problems found in those with chronic illnesses; and 3) the management of sleep disturbance.

Sleep Deprivation 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 or 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, 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 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 effect of 72 hours of sleep loss on immunity and disease susceptibility in a rat model.

Research is needed on the problem of sleepiness in elementary and high school children and its relationship to possible effects on learning and behavior problems. The 1999 National Sleep Foundation Omnibus found that 15% of children have fallen asleep at least once during the school year. Excessive daytime sleepiness may lead to decreased cognitive functioning, mood and performance and may be a risk factor for poor behavioral adjustment in children. However, the developmental stage may alter the consequences of sleep deprivation. For example sleep deprivation in children may result in overactivity and behavioral problems, whereas in adolescents it may lead to lethargy and sleepiness. An NINR funded study is one of the first to examine carefully the impact of sleep restriction on childrens' and adolescents' behavior and emotional control. This study will provide further information that is relevant to the current debate on opening times for elementary, middle and high schools.

Sleep Disruption in 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.

NINR supported research is examining the association between sleep deprivation and the chronic condition of fibromyalgia. Fibromyalgia syndrome (FMS) affects about 5% of all Americans, is more common in women, and occurs primarily between the ages of 40-60 years. FMS is characterized by end organ and tissue peripheral changes, particularly in muscle and immune/inflammatory system, that give rise to fatigue, non-restorative sleep, muscle pain, somatic and psychological distress and immune changes. A nurse researcher recently reported that disrupted sleep may play an important role in the pathophysiology of symptoms in fibromyalgia. Sleep disruption for several consecutive nights in healthy women resulted in FMS signs and symptoms of a decreased pain threshold, increased discomfort, fatigue and the inflammatory flare response in the skin. Further work will examine the circadian rhythms, and neuroendocrine and immune changes found in women with FMS.

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 the cancer patients' caregivers experience their own fatigue and sleep disturbance. Efforts to understand the physiological and psychological mechanisms by which these three symptoms interact and influence one another within patients and between patients will provide important information to plan intervention studies for patients who are undergoing radiation therapy.

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 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 effects 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 will help to focus the future development of sleep-promoting interventions.

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 in some patients, but up to one-third 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.

Management of Sleep Disturbance

The prevalence of sleep disturbance is highest in women, older adults, and patients with medical or psychiatric disorders. There is a need to find innovative strategies to manage sleep disturbance as medical therapies are not always effective and can have side effects. Nurse researchers are evaluating non-pharmacological interventions for sleep maintenance in community dwelling older adults with insomnia. Insomnia is a frequent complaint of older adults and is associated with an increased incidence of depression.

Agitation is a common problem experienced by people with dementia. and sleep disturbances are 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. Further research is needed in these specialized groups to find simple, effective interventions to improve the quality of sleep and overall quality of life.

Sleep disturbance is also commonly found in patients with Parkinson's disease. Between 70-90% of Parkinson's disease patients have sleep disturbance. NINR funded research is examining whether melatonin may be effective in alleviating the sleep disturbance. The findings of this study may provide support for the broad use of melatonin as a sleep aid.

Training and Career Development

NINR is committed to the training and career development of new investigators in the area of sleep research. NINR supports three mentored research scientist development awards in the areas of sleep in coronary artery bypass patients, the examination of the autonomic nervous system during sleep in heart failure patients, and exploration of some of the biochemical mechanisms that occur during obstructive sleep apnea that may contribute to the incidence of nocturia in the elderly.

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FINANCIAL REPORT
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE

Sleep Disorders Research
(Dollars in thousands)

1995

1996

1997

1998

1999

2000

2001

Actual

Actual

Actual

Actual

Actual

Estimate

Estimate

NHLBI

13,674

16,450

19,219

22,932

31,845

33,701

35,735

NINDS

8,018

9,453

11,598

13,639

15,231

16,908

17,213

NICHD

6,627

7,368

7,217

9,131

7,116

8,100

8,500

NIA

7,847

7,800

9,179

11,818

13,296

15,290

16,131

NIMH

29,721

27,231

28,601

34,027§

39,219

44,751

47,353

NIDA

1,084

1,201

1,042

1,586

2,163

2,400

2,500

NIAAA

793

551

728

766

736

1,000

1,250

NCRR*

2,944

3,247

3,570

5,542

6,637

6,960

7,479

NINR

2,107

2,842

3,565

3,394

3,503

4,200

5,040

Total

72,815

76,143

84,719

102,835§

119,746

133,310

141,201

* Not included on the Trans-NIH Sleep Research Coordinating Committee
§ Revised from Trans-NIH Annual Report for fiscal year 1998

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