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Trans-NIH Sleep Research Coordinating Committee
FISCAL YEAR 2005
Table of Contents
The Trans-NIH Sleep Research Coordinating Committee (SRCC) was established in 1986 by the Director, National Institutes of Health (NIH) for the purpose of facilitating interchange of information on sleep and sleep-related research. The SRCC meets every 2-3 months to discuss ongoing activities in NIH sleep-related programs and to develop new programs. In conjunction with the creation of National Center on Sleep Disorders Research (NCSDR) in 1993, the Director of NIH transferred responsibility for the Trans-NIH SRCC to the NCSDR, and the NCSDR Director serves as Chair of the Trans-NIH SRCC. The SRCC membership in Fiscal Year 2005 included the following NIH Institutes and Centers:
National Heart, Lung, and Blood Institute (NHLBI)
* New SRCC Member in FY 2005
In addition, the National Center for Research Resources (NCRR), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the National Institute of Environmental Health Sciences (NIEHS), the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institutes of Health RoadMap each has a sleep-related portfolio in Fiscal Year 2005 and this information is included in the Financial Summary and Grant Listings at the end of this Report. The NCSDR is a component of the National Heart, Lung, and Blood Institute (NHLBI) and is charged with the conduct and support of research, training, health information dissemination, and other activities with respect to sleep disorders, including biological and circadian rhythm research, basic understanding of sleep, chronobiological and other sleep related research. The NCSDR also coordinates the activities of the Center with similar activities of other Federal agencies, including the other agencies of the NIH, and similar activities of other public and nonprofit entities. Community input is obtained through a Sleep Disorders Research Advisory Board which meets twice a year. A list of selected coordination activities and programs in which NCSDR participated during Fiscal Year 2005 is outlined below.
NATIONAL CENTER ON SLEEP DISORDERS RESEARCH
Fiscal Year 2005 Initiatives, Conferences and Reports
PA-05-046: Research on Sleep and Sleep Disorders
Sponsors: NHLBI; NIA; NIAAA; NIAMS; NCI; NICHD; NCCAM; NIDA; NIMH; NINDS; NINR; ORWH/OD
Release Date: February, 2005
Objectives: Encourage research to advance biomedical knowledge related to sleep or sleep disorders, improve understanding of the neurobiology or functions of sleep over the life-span, enhance timely diagnosis and effective treatment for individuals affected by sleep-related disorders, or implement and evaluate innovative community-based public health education and intervention programs.
State of the Science Conference: Manifestations and Management of Chronic Insomnia in Adults
Coordinating Agency: NIH Office of Medical Applications and Research (OMAR)
Date: June 13-15, 2005
NIH Sponsors NIMH (Lead Institute), NCSDR, NCCAM, NIA, NIAAA, NIDA, NINDS, NINR, ORWH
Other Federal Sponsors Veterans Administration; Food and Drug Administration (FDA); Federal Railroad Administration, Department of Transportation (DOT); Agency for Healthcare Research and Quality (AHRQ
Outcome: The two day Conference on the Manifestations and Management of Chronic Insomnia in Adults included an analysis of existing evidence in the medical literature, and expert presentations on the latest scientific knowledge about chronic insomnia and available treatments. An independent panel prepared and presented conference statement that addressed questions listed below.
1. How is chronic insomnia defined, diagnosed, and classified, and what is known about its etiology?
2. What are the prevalence, natural history, incidence, and risk factors for chronic insomnia?
3. What are the consequences, morbidities, comorbidities, and public health burden associated with chronic insomnia?
4. What treatments are used for the management of chronic insomnia, and what is the evidence regarding their safety, efficacy, and effectiveness?
5. What are important future directions for insomnia-related research?
Online access to the Final Statement, the literature review, the Program and Abstract book, and the archived videocast of the conference is at http://consensus.nih.gov/PREVIOUSSTATEMENTS.htm
State of the Science Conference Related Publications
• National Institutes of Health. State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005 Sep 1;28(9):1049-57.
• Buscemi N, et al., Manifestations and Management of Chronic Insomnia in Adults. Evidence Report/Technology Assessment No. 125. (Prepared by the University of Alberta Evidencebased Practice Center, under Contract No. C400000021.) AHRQ Publication No. 05-E021- 2. Rockville, MD: Agency for Healthcare Research and Quality. June 2005.
State of the Science Conference Related Commentaries
• NIH State-of-the-Science Conference on Chronic Insomnia. Regina T. Dolan-Sewell, Ph.D.; William T. Riley, Ph.D.; Carl E. Hunt, M.D. J Clin Sleep Med. 2005;1(4): 233-4
• Insomnia State of the Science: An Evolutionary, Evidence-Based Assessment. Daniel J. Buysse, MD. Sleep, Vol. 28, No. 9, 2005: 1045-6.
• The Diagnosis and Treatment of Chronic Insomnia in Adults. Alexandros N. Vgontzas, MD. Sleep, Vol. 28, No. 9, 2005: 1047-8.
Development of Strategies and Recommendations for Enhanced Support of Sleep Medicine and Sleep Research in Academic Health Centers (Institute of Medicine (IOM) Study http://www.iom.edu/?id=23160
Sponsors: NIH Office of Evaluation, American Academy of Sleep Medicine, Sleep Research Society, National Sleep Foundation
In follow-up to recommendations put forward by the Sleep Disorders Research Advisory Board, the NIH, NCSDR, members of the Trans-NIH Sleep Research Coordinating Committee, and other public, nonprofit entities commissioned an IOM study to develop strategies and recommendations addressing the fragmentation of sleep-related research and clinical care currently typical of academia. This 18-month study brought together experts in public health, academic and medical administration, and health sciences research for a series of public and closed session discussions that began in Fiscal Year 2005. The committee report is expected in April 2006.
2003 National Sleep Disorders Research Plan http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html
The National Sleep Disorders Research Plan continues to serve as a resource that summarizes advances in knowledge since 1996, current gaps in knowledge, and a broad range of recommendations for future sleep research. The 2003 National Sleep Disorders Research Plan can be accessed online (in html and pdf versions) at the website listed above. Printed copies of the Plan can be obtained by contacting the NCSDR.
Community Outreach, Education, and Coordination
NCSDR maintains a website (http://www.nhlbi.nih.gov/sleep) with information on sleep disorders for patients and health care providers. A special area of emphasis is educating youth. The NCSDR Sleep Well, Do Well, Star Sleeper Campaign (http://www.nhlbi.nih.gov/health/public /sleep/starslp/) was launched in 2001 and continues to educate America's children – and their parents, educators, and healthcare providers – about the importance of adequate night time sleep. Another innovative development is the high school curriculum module on Sleep, Sleep Disorders, and Biological Rhythms produced in partnership with the NIH Office of Science Education (http://science.education.nih.gov/customers.nsf/HSSleep). The module includes a teacher’s study guide, suggested student activities, and web-based simulations available from the NIH at no cost to high school educators.
Following-up on public interest in sleep is another major NCSDR activity. In Fiscal Year 2005, the NCSDR prepared over a thousand responses to individual queries from the public, health care professionals, and lay publications (newspapers, internet, radio, and television). In the spirit of coordination, the NCSDR partners with professional organizations such as the American Academy of Pediatrics (AAP) which published guidelines on Sleepiness in Adolescents and Young Adults in June 2005.
In addition, the NCSDR convened two meetings of the Sleep Disorders Research Advisory Board including representatives from other Federal agencies in Fiscal Year 2005 to discuss the status of sleep disorders research. These meetings are videocast live and accessible in an online archive at http://www.videocast.nih.gov/PastEvents.asp?c=26
Selected NIH News Releases concerning Sleep and Sleep Disorders in Fiscal Year 2005
Panel Calls for a New Look at Treatments Commonly Used for Chronic Insomnia - NIH Stateof- the-Science Panel Also Recommends Broader Use of Cognitive and Behavioral Therapies http://www.nih.gov/news/pr/jun2005/od-15.htm
Breathing Problems During Sleep May Affect Mental Development in Infants and Young Children (jointly prepared by NHLBI and NICHD) http://www.nhlbi.nih.gov/new/press/04-10-07.htm
Study Finds Possible Mechanism for Link Between Sleep Disturbances and Metabolic Syndrome (jointly prepared by NIA, NHLBI, NIDDK) http://www.nhlbi.nih.gov/new/press/05-04-21.htm
News Release: Sleep Apnea and Risk for Stroke and Death http://www.nhlbi.nih.gov/new/press/05-11-09.htm
ACTIVITIES OF TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE MEMBER INSTITUTES AND CENTERS
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
The NHLBI sleep research program covers a spectrum of sleep research related to heart, lung, and blood diseases. The research programs are aimed at understanding the molecular, genetic, and physiological underpinnings of sleep and sleep disorders through basic, clinical, and epidemiological research. A major focus is sleep disordered breathing (SDB) as a potential risk factor for cardiopulmonary disease, stroke, and weight gain. NHLBI is a major supporter of investigator-initiated sleep research at NIH.
Mounting evidence indicates that SDB is a chronic disease condition associated with serious cardiovascular outcomes. Evidence suggests that SDB is relatively common affecting at least 3% of children, 2% of middle-aged women, 4% of middle-aged men, and 10-20% of the elderly. The incidence of new sleep disordered breathing cases has been estimated to be 3-6%. However, less than 10% of adult SDB cases are diagnosed. If left untreated, SDB predisposes to an increased risk of new hypertension and heart attack through sympathetic activation, hyperleptinemia, insulin resistance, elevated C reactive protein (CRP) levels, and oxidative stress. Since the treatment of SDB may ameliorate the severity of cardiovascular disease risk factors, studies of the relationship between SDB and cardiovascular outcomes are clinically important.
New findings from two independent studies associate SDB with a 2-4 fold increased frequency of stroke in middle age adults. A 3 year prospective clinical study of 1,000 middle age adults found that the frequency of stroke and all-cause mortality was doubled among participants diagnosed with moderate to severe sleep apnea. The association was independent of common risk factors including age, sex, race, smoking status, body-mass index (BMI), and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension. This is the first longitudinal study indicating that the relationship of sleep apnea severity to stroke and allcause mortality is independent of common cardiovascular and cerebrovascular risk factors.
A cross sectional community based study of 1,500 participants associated a diagnosis of moderate-severe apnea with a 4 fold increased frequency of stroke. A prospective sub study of 1,200 participants in the same community also indicated that the frequency of first time stroke over four years was 4 fold greater if initially diagnosed with moderate to severe apnea, but was dependent on BMI. These findings are the first evidence that sleep disordered breathing precedes stroke and may, in fact, contribute to the development of stroke.
Left Ventricular Function in Children
A recent study evaluated heart function in a sequential sample of 60 children (ages 5-18) referred to a pediatric sleep clinic using echocardiographic imaging and blood pressure at rest. Left ventricular (LV) diastolic function was decreased in apneic children (apnea hypopnea index > 5) compared to children with very mild sleep disordered breathing (snoring). The decrease in LV function was proportional to apnea severity and independent of age, gender, race, and blood pressure. Follow-up of 10 children in which the apnea was treated and managed for one year (tonsillectomy, uvulopalatopharyngoplasty, or CPAP dictated by standard of care) revealed an 18% improvement in LV function. Follow-up of 9 untreated snoring children revealed a trend toward decreased LV function at one year which did not reach significance.
Short Sleep Duration, Metabolism Impairment, and Elevated Risk of Obesity
New findings from a study of 1,500 participants in the Sleep Heart Health Study indicate that sleep duration of 6 hours or less is associated with an increased frequency of diabetes and impaired glucose tolerance (IGT). At 5 hours of sleep or less, the odds ratio for diabetes presence increased to 2.5, and with 6 hours of sleep the odds ratio for diabetes presence increased to 1.6 compared to those with 7-8 hours of sleep. The association between sleep duration and IGT and diabetes persists after excluding insomnia and adjusting for girth, demographic factors, caffeine, and cardiovascular disease risk factors. Sleep duration longer than 9 hours per night was also associated with a greater risk of poor glycemic control.
New findings in a mutant mouse model link insufficient sleep to abnormalities in the regulation of hunger, satiety, and metabolism. Mice with a mutation in the Clock gene sleep less, expend less energy, consume more calories, and gain as much weight on a regular diet as normal mice fed a high-fat diet. Overall daily activity levels in mutant and normal mice are similar. Short sleeping mutant mice fed a high-fat diet gained about 50 % more weight than normal mice on this diet. Weight gain in short sleeping mutants fed a regular diet was associated with a 65% increase in lean mass and a 35% increase in fat mass, whereas mutants fed the high-fat diet exhibited a 25% increase in lean mass and a 75% increase in fat mass relative to normal mice. The adult short sleeping mutant mice had high levels of blood cholesterol, triglycerides, and glucose, and insulin resistance indicative of metabolic disease. High leptin blood levels and reduced levels of ghrelin and orexin in brain indicate that abnormalities in signaling satiety and hunger to brain are associated with weight gain in the short sleeping mutant mice.
Clinical Trials, Observational Studies, and Specialized Centers of Research
A diverse program of clinical trials and observational studies is underway to elucidate the specific cardiopulmonary risks and excessive sleepiness associated with sleep disordered breathing. The Apnea Positive Pressure Long-Term Efficacy Study (APPLES) seeks to determine whether using a continuous positive airway pressure (CPAP) device during sleep decreases excessive daytime sleepiness and improves daytime cognition and performance. The Sleep Heart Health Study (SHHS) is investigating how sleep disordered breathing affects the risk of heart attack, stroke, hypertension, and total mortality over a 14 year period. A substudy of the LookAhead clinical trial is characterizing sleep disordered breathing severity in a population with pre-existing obesity and diabetic conditions. Sleep disorders and cardiovascular outcomes are also being evaluated in children and elderly populations. Other ongoing studies are focused on elucidating genetic risk factors and gene-environment relationships coupled to the occurrence of sleep disordered breathing. An ongoing NHLBI Specialized Centers of Research (SCOR) program brings together a critical mass of multidisciplinary sleep expertise at three centers that has led to many fundamental discoveries and translational findings.
Voluntary sleep curtailment (habitual short sleep duration) is a pervasive lifestyle and untreated sleep disorders are also common. Average sleep duration in adults has declined from 8.5 to less than 7 hours/night over the last 40 years. Typical sleep durations of six hours are now common and the proportion of young adults sleeping less than seven hours has increased from 16 to 37%. Declines in sleep duration have occurred concurrent with an upward trend in obesity prevalence, but only recently have sufficient data emerged to suggest that these two epidemics may have mechanistic interrelationships. Studies are needed to elucidate cause-and-effect relationships and mechanisms to explain associations between short sleep duration and increased risk of obesity or overweight due to altered metabolism, appetite, or inflammation. Recent advances using genomic analyses have also led to the discovery that the genetic program comprising the molecular clock mechanism in brain is regulating genomic expression and cellular function in peripheral tissues associated with heart, lung, and blood diseases. Studies are needed to elucidate the specific molecular pathways through which the genetic program of the biological clock influences peripheral tissue function, and how mutations in the molecular clock components contribute to heart, lung, and blood disease, as well as sleep disorder related health consequences.
NATIONAL INSTITUTE ON AGING
Significance of Program Activity
Sleep is essential to well-being and occupies about a third of our lives. Without enough sleep, fatigue, clouded thinking, possible metabolic dysregulation leading to diabetes and obesity, and diminished quality of life can occur. For older people, these symptoms can be more than a matter of discomfort; they can lead to more serious complications. Falls resulting from fatigue and confusion, for example, can result in debilitating, costly injuries in this vulnerable population. The importance of recognizing and treating age-associated health problems, such as sleep disorders, takes on new dimension as the Nation's elderly population grows to record numbers. In the next fifty years, the aged will make up a progressively greater proportion of the general population. Many older people are very healthy and have normal sleep. Many people believe that poor sleep is a normal part of aging, but it is not. In fact, many healthy older adults report few or no sleep problems. Sleep patterns change as we age, but disturbed sleep and waking up tired everyday are not part of normal aging. However, many older adults have sleep problems, which are often linked to underlying medical conditions. Abnormal sleep can cause disease; but diseases can cause abnormal sleep. 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.
The NIA Sleep portfolio was about $16.3 million for 50 grants in Fiscal Year 2005, compared with 38 grants totaling about $16.4 million in Fiscal Year 2004. 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. A new section of the NIH SeniorHealth web-site on sleep and aging was issued in the spring of 2005. In addition, two trans-NIH PAs on sleep were reissued for Fiscal Year 2005: "Research on Sleep and Sleep Disorders" and “Restless Legs Syndrome and Periodic Limb Movement Disorder”. The NIA also was a co-sponsor of a State-of-the-Science Conference “Manifestations and Management of Chronic Insomnia in Adults”, with NIMH as the lead, which was held June 13-15, 2005 in Bethesda. In conjunction with the Trans-NIH Sleep Research Coordinating Committee, a workshop on Neuroimaging in Sleep Deprivation and Sleep Disorders is planned for March 29- 30, 2006 in Bethesda. Planning assistance also has been provided to the International Longevity Center-USA in the development of a “Sleep and Healthy Aging Scientific Consensus Conference” that took place in New York City on November 2-4, 2005.
Highlights of Research Advances
Health Disparities Related Research
Sleep disordered breathing (SDB) is a highly prevalent sleep disorder in older persons. It is known to be associated with reductions in cognitive function. As part of a larger study examining SDB in African-Americans and Caucasians, it was examined whether racial background. Community-dwelling African-American and Caucasian elderly at high risk for SDB were tested at two time points. During each visit, subjects were interviewed in their homes about their sleep and medical condition. The Mini-Mental Status Examination (MMSE) was used to assess cognitive function. Objective sleep studies were recorded in the subjects' homes and scored for sleep, apneic events, and oxygen saturation levels. Night-to-night variability of sleep and respiratory parameters did not differ between African-Americans and Whites. Increases in respiratory disturbance index (RDI) were associated with decreases in cognitive performance over time, after controlling for gender and education level. There were no differential effects of race on this relationship. There was no relationship between declining cognitive function and hypoxemia. Analyses of the data confirm that declining cognitive function in older persons with mild to moderate SDB is related to the amount of respiratory disturbances occurring at night, and suggest that the effect of SDB on cognitive decline is unrelated to race and measured hypoxemia. The large number of community-dwelling elderly with mild to moderate SDB may accrue considerable benefits (both cognitively and medically) from the treatment of SDB, even if they are not markedly hypoxemic.
Differences in SDB between hypertensives with or without a family history of hypertension were studied in African Americans who were referred to the clinic because of a sleep complaint; 91% of the patients received an SDB diagnosis. Of these patients, 25% were hypertensives without a family history, 20% were hypertensives with a family history, and 55% were normotensives. Increasing weight was accompanied by increasing severity of SDB. Hypertensives with a family history are likely to show a profile of greater blood pressure, higher BMI, and more severe SDB, which are more common among African Americans.
The likelihood of insomnia and insomnia-related health consequences among individuals of different socioeconomic status in individuals of lower individual and household education were significantly more likely to experience insomnia even after controlling for ethnicity, gender, and age. Additionally, individuals with fewer years of education, particularly those who had dropped out of high school, experienced greater subjective impairment because of their insomnia.
The use of neuroimaging technologies to study sleep is relatively new. A review of the literature found only 19 papers in the last 14 years that have used neuroimaging methods (PET, SPECT, and fMRI) to view brain activity during normal NREM and REM sleep. In general, these studies have found that there is a global decrease in brain activity, especially the thalamus and the frontal and parietal cortices, during NREM sleep, suggesting a down-regulation of the CNS with deepening sleep. During REM sleep, however, there appears to be an increase in metabolic activity within the limbic system, the pons, basal ganglia, and the auditory and occipital cortices, which could be linked to the dream activity that is concentrated during REM sleep. Using PET technology, it has recently been reported that patients with insomnia show greater global glucose cerebral metabolism during sleep and while awake, than do normal sleepers, and that there is a smaller decline in the metabolism of the wake-promoting regions of the brain during the transition from wake to sleep, suggesting that the disturbed sleep of insomnia is associated with a failure of arousal mechanisms to decrease sufficiently while transitioning to sleep. Furthermore, there was reduced daytime metabolic activity in the prefrontal cortex resulting from the insomnia.
Some sleep disorders have been linked to hypertension, but few studies have examined the relationship between daytime sleepiness and blood pressure (BP). A recent study determined that scores on a short questionnaire assessing daytime sleepiness (Epworth Sleepiness Scale - ESS) were associated with BP and could be used to predict hypertension after 5 years in healthy older adults, men and women 55 to 80 years of age, who had not previously been diagnosed with hypertension. Compared to individuals with low ESS sores, those scoring high had increased casual and sleep BP as well as higher systolic BP levels and diastolic BP variability during waking hours, and reported higher levels of anger, depression, anxiety, and intensity of psychological symptoms as well as lower defensiveness. Individuals with high ESS scores were more likely to be diagnosed with hypertension 5 years later. Groups with high and low ESS scores did not differ significantly on any other variables. The ESS, a simple measure of daytime sleepiness, identified individuals at risk for hypertension. Future studies should investigate the possibility that diagnosis and treatment of daytime sleepiness could aid in BP reduction and ultimately in decreased morbidity and mortality from cardiovascular disorders. Reduction of sleep times may lead to metabolic dysfunctions leading to obesity, hypertension, insulin resistance, and a diabetic phenotype.
Leptin and ghrelin are two hormones that provide the brain information about energy balance. Leptin, produced by adipocytes (fat cells), rapidly increases when there is an excess of caloric intake and decreases appetite. In contrast, ghrelin, produced primarily in the stomach, stimulates appetite. In experimental studies carbohydrate metabolism, endocrine function, and gastrointestinal balance in young, healthy adults were studied after restricting sleep to 4 hours per night for 6 nights as compared to a fully rested condition. Leptin levels were decreased, ghrelin levels were increased, and there was an increase in hunger and appetite under the short sleep condition with levels of activity and caloric intake the same for both conditions. This was associated with decreased glucose tolerance and insulin sensitivity and elevated evening cortisol levels. These alterations were qualitatively and quantitatively similar to those observed in normal aging.
Similar findings were found in a population-based longitudinal study of over a 1,000 participants now between 45 and 75 years of age. In those who slept less than 8 hours per night (about 75% of the sample), body mass index increased as sleep time decreased. Short sleep also was associated with reduced leptin and elevated ghrelin levels in the blood.
A study using mice with a mutation that disrupts their circadian rhythms and produces fragmented sleep found a link between sleep disturbances and metabolic syndrome, a cluster of conditions shown to increase risk of heart attack, stroke, and diabetes, suggesting that the brain system controlling the sleep-wake cycle might play a role in regulating appetite and metabolism. The mice, with this mutation, when fed a regular diet gained about as much weight as normal mice that were fed a high-fat diet, and showed even greater weight gain and changes in metabolism when fed a high-fat diet. This study in mice has brought to light the importance of the circadian clock on the regulation of processes regulating body weight and metabolism. As has been found in human studies, it shows that disruptions of the normal sleep-wake cycle alter the body’s ability to regulate its energy balance, especially when there is an overloading of fat in the diet.
There has been an increasing trend towards shorter sleep times over the last century, and this has been mirrored by an increasing trend of obesity in the U.S. Studies now are showing that chronic sleep restriction is associated with hormonal and metabolic changes leading to the possible development of chronic conditions, such as obesity, diabetes, and hypertension, leading to increased cardiovascular disease morbidity and mortality. It now is clear that maintenance of proper sleep habits is necessary for the maintenance of health.
Other factors associated with aging, such as disease, changes in environment, or concurrent age-related processes may contribute to problems of sleep in older persons. 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; light of indoor intensity can have a significant phase-shifting effect on the circadian pacemaker, and can suppress plasma melatonin secretion . Therefore, awakening early in the morning, such as when associated with nocturia (nighttime voiding), and turning on a lamp, may lead to an earlier entrainment of the circadian clock and contribute to the early morning awakenings of older individuals.
Older adults with dementia often have disruptions in circadian rhythms, including disruptions of the rest-activity rhythm. Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. The circadian variation of core-body temperature and motor activity was studied in institutionalized patients with dementia (AD or DLB) prior to death and the dementia confirmed by neuropathology. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that the consequences of the disease processes may mediate the circadian disturbances in AD and DLB. The differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar, and differed significantly from non-demented agematched institutionalized controls. These disruptions are a product of internal neuronal activity and external environmental influences, both of which are deficient in dementia. However, the consequences of disturbed rhythms are unknown. Another study examined the relationship between rest-activity rhythms and death in patients with dementia and found that although restactivity rhythms as a whole were not related to survival, the timing of the rhythm was. Patients with dementia appear to develop an abnormal timing of their rhythms, which is predictive of shorter survival.
An interesting recently discovered molecule is hypocretin (Hcrt), a hypothalamus-specific peptide that 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 brain cells that secrete the hypocretins 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 sleepwake cycle. In young rats and monkeys, levels of Hcrt1 are highest at the end of the wakeactive period and lowest toward the end of the sleep period. The effects of age on the diurnal rhythm of Hcrt1 levels in the cerebrospinal fluid (CSF) were determined by radioimmunoassay. In old rats there was a 10% decline in CSF Hcrt1 over the 24-hour period, compared to young adult rats. Functionally, if there was less Hcrt1, and there also was a decline in Hcrt receptor mRNA, as had been previously found. The overall consequence in aging would be diminished action of Hcrt at target sites. This would diminish the waking drive, which in the elderly could contribute to the increased tendency to fall asleep during the normal wake period.
Little is known about the molecular mechanisms underlying sleep. Recently, it has been shown that the induction of key regulatory proteins in a cellular protective pathway involves the unfolded protein response (UPR). Using C57/B6 male mice maintained on a 12:12 light/dark cycle, it was found that, in cerebral cortex, the protein expression of BiP/GRP78, a chaperone and classical UPR marker, increased with increasing durations of sleep deprivation. UPR helps the endoplasmic reticulum (ER) restore function in response to cellular stress by up-regulating the expression of chaperones and promoting preventing the aggregation of misfolded proteins and helping to properly fold the protein. PERK, the transmembrane kinase responsible for attenuating protein synthesis, which is negatively regulated by binding to BiP/GRP78, was activated by dissociation from BiP/GRP78 and by autophosphorylation. There was phosphorylation of the elongation initiation factor 2á and alteration in ribosomal function, all components of the UPR. These changes are first observed after 6 hours of sleep deprivation following the onset of the dark cycle when the mice normally would sleep. The longer the length of sleep deprivation (up to 12 hours), the greater was the expression of BiP/GRP78. Thus, prolonging wakefulness induced the UPR indicating that extending wakefulness produces ER stress .
Sleep disturbances and decline in neuropsychological performance are common in older adults. Reduced social and physical activity, commonly seen in nursing homes and assisted care facilities, is likely a contributing factor for these age-related changes in sleep and cognition. A pilot study determined whether a single daily morning or evening activity session (sessions consisted of stretching, low-impact aerobics, and game playing) for 2 weeks would also improve sleep and neuropsychological function and whether these effects were dependent on the timing of the activity sessions. Twelve older men and women participated in 14 days of structured activity sessions in the morning or evening. Exposure to either morning or evening activity significantly improved performance on a neuropsychological test battery over baseline levels. Subjective sleep-quality ratings, measured by the Pittsburgh Sleep Quality Index, improved following activity sessions in either the morning or the evening, although objective measures of sleep did not improve when measured by actigraphy or polysomnography. Similar findings were seen in a larger nursing home study of 118 residents randomized to a multidimensional, nonpharmacological intervention versus usual care. A significant decrease was found in daytime sleeping compared to usual care controls, which may translate to an improvement in quality of life. These results suggest that short-term exposure to either morning or evening social and physical activity improves objective measures of neuropsychological performance and subjective sleep quality in the elderly. Increasing exposure to social and physical activity may be a useful intervention to improve sleep quality and daytime function in older adults
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 agedependent changes in the sleep homeostatic mechanisms are beginning to be understood. New studies are pursuing leads into the genetics of sleep. The relevance of the genetics of sleep to the problems of the older individual needs further stimulation. Similar to other recent findings that neuronal loss is not an inevitable consequence of aging, these data indicate that there is little evidence of an age-related loss of neurons that have been identified as playing a key role in the maintenance of sleep homeostasis. Thus, the age-related alterations in the control of sleep appear to not be due to loss of critical neurons but to subtle changes within the cells and in their interactions with other brain cells involved in the control of sleep and alertness.
The elucidation of these factors, such as the role played by adenosine in the induction of sleep, 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.
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.
Research needs to further elucidate how the state of sleep debt is associated with decreased glucose tolerance and insulin sensitivity, elevated evening cortisol levels, and increased sympathetic activity. It appears that there are distinct changes in sleep quality that occur through the adult age span, and these changes also mark specific alterations in hormonal systems that are essential for metabolic regulation. Sleep loss may increase the stress load, possibly facilitating the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low socio-economic groups.
Another exciting area of newly developing research is the understanding of the relationships between sleep and cognitive functioning. This may be especially important in the older individual, given the increased risks for disturbed sleep and disturbed cognition. This is an exciting window of opportunity as research on the relationships between sleep, cognition, aging, and the neurophysiologic and molecular mechanisms is just beginning to coalesce.
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
In Fiscal Year 2005, The National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded a total of 15 research projects, including regular Research Project Grants and Career Development Awards, and Cooperative Agreement components, on the topic of alcohol and sleep. The specific areas of sleep-related research supported by NIAAA during the past year include: 1) the neural mechanisms of alcohol-induced sleep disturbances; 2) adolescent sleep/arousal patterns as a pathway to alcoholism in early adulthood; 3) the effects of prenatal and adult alcohol exposure on circadian clock function; 5) assessment and treatment of sleep disturbances in recovering alcoholics; 6) pharmacotherapy of alcoholism and comorbid insomnia; 7) sleep and immune function in African Americans; and 8) effects of acute alcohol intake on performance and alcohol abuse liability in insomniacs.
Published research highlights during Fiscal Year 2005 from currently funded projects are summarized below:
Alcohol Consumption and the Circadian Clock Function
Circadian clocks are mechanisms by which an organism synchronizes its internal and external environments. These circadian rhythms oscillate within a 24-hour cycle and provide a temporal framework by which an organism can program its physiological tasks and optimize survival. At the molecular level, circadian rhythms are originated by genetic elements known as clock genes. At the systems level, circadian oscillations in mammalian tissues are synchronized by a central pacemaker in the brain, referred to as the suprachiasmatic nucleus (SCN) of the hypothalamus. This master clock is entrained or synchronized by external cues, the most critical being light stimulation. However, the SCN also can be entrained through internal signal such as the hormone, melatonin. Normal circadian rhythmicity is critical for health, and disruption in circadian rhythms is associated with abnormalities in several processes, including sleep. Alcohol consumption and abuse leads to problems falling asleep, decrease in total sleep time, and disruptions in other biological rhythms. Recent research has investigated the effects of prenatal and adult alcohol exposure on circadian rhythmic output and the mechanisms underlying these changes.
Effects of Alcohol on Circadian Activity Rhythms
Two studies examined the effects of chronic alcohol consumption and alcohol withdrawal on circadian rhythms of free-running activity and light responsiveness of the circadian pacemaker in adult rats. In one study, free-running circadian activity was monitored for several weeks before, during and after exposure to either 10% or 20% concentrations of alcohol. Individual differences in response to alcohol concentrations were found -- both lengthening and shortening of the free running period was observed. Furthermore, following termination of alcohol, animals receiving the 10% concentration of alcohol returned to their normal circadian running cycle, while animals consuming 20% alcohol displayed an exacerbation of alcohol’s effect on circadian activity. These results indicate that both chronic alcohol intake and alcohol withdrawal may produce changes in a fundamental parameter of the circadian pacemaker and its free-running period.
In addition to their effects on circadian free-running activity, chronic treatment with alcohol may also affect the response of the circadian pacemaker to light signals. Male rats were given 24 hour periods of constant darkness interspersed with a brief 15 minute light pulse. The brief light pulses shortened the running periods for normal animals, but not those exposed to alcohol. Recent research has shown that prenatal exposure to alcohol (on postnatal days 4-9) produces permanent changes in circadian regulation of rat activity rhythm and entrainment to light/dark cycles.
Alcohol Effects on Central Clocks Controlling Neuroendocrine Function
Endogenous opioids are small proteins molecules, referred to as peptides, that are produced primarily in the pituitary gland and in the brain. These peptides are involved in a variety of physiological processes, including the rewarding and reinforcing effects alcohol. The protein proopiomelanocortin (POMC) is a precursor to the opioid peptide, â-endorphin. Recent studies have show that alcohol consumption affects the circadian functions of endorphin-containing neurons that are involved in control of reward and reinforcement in alcohol drinking. Chronic alcohol administration to rats abolishes the circadian rhythm of POMC mRNA expression in â-endorphin neurons and circadian expression of the clock-governing Period genes (rPer1 and rPer2) in the arcuate nucleus of the hypothalamus. Alcohol consumption also disrupts the circadian rhythms of the rPer2 and rPer3 gene expression in the SCN, suggesting a deficit in the function of the central pacemaker. The POMC system is integrated with the hypothalamicpituitary- adrenal axis and the mesolimbic dopamine system, which have important roles in mediating the behavioral, neuroendocrine and pathologic responses to alcohol. Thus, chronic alcohol exposure causes major alterations in the central and internal clocks governing neuroendocrine functions, and may have significant pathological consequences.
Clock Genes and Alcohol
Recent research in mice has found a link between the clock gene mPer2 and responses to acute and chronic alcohol intake. It was found that mPer2 mutant mice, e.g., animals with a deficit in function of the Per2 gene, exhibit enhanced alcohol intake and preference. Furthermore, mPer2 mutant mice show a deficit in removal of the neurotransmitter, glutamate, from the brain due to a down regulation of the glutamate transporter GLAST. The resulting elevation in glutamate levels leads to a “hyperglutamatergic” state. Acamprosate, a drug thought to act by dampening a hyperglutamatergic state in the alcohol dependent brain, reduces alcohol consumption and normalizes extracellular glutamate levels in mPer2 mutant mice. In humans, variations in the hPer2 gene are associated with regulation of alcohol intake. These findings taken together support a relationship among abnormal functioning of the circadian clock gene Per2, glutamate, and increased alcohol intake.
Sleep Disturbance, Alcoholism Risk, and Remission
Two recent prospective epidemiological studies, using data from a community sample, investigated the association of sleep disturbance with the following: 1) risk for alcohol-related problems, and 2) chronic dependence or remission of alcohol dependence. In the first study, it was found that individuals who report sleep disturbances because of worry are at increased risk of developing alcohol-related problems after an extended interval (median 12.6 years later). Risk is highest among those with a history of anxiety disorders or mood symptoms. The exact pathway between sleep disturbances and alcohol-related problems is unknown. However, these findings emphasize the need to assess and treat sleep disturbances in those with psychiatric disorders, because of the potential to increase alcohol intake for self-medication of sleep problems.
In the second study, it was found that alcohol dependent individuals who reside in the community are twice as likely to self-report insomnia compared to those without a history of dependence. In addition, remission of alcohol dependence in this community sample is associated with a lower risk of sleep disturbance that is similar to those who have never been dependent on alcohol. These findings underscore the importance for evaluation and treatment of sleep disturbances in individuals with persistent alcohol dependence, since sleep difficulties may be an important factor in relapse to drinking.
Sleep Deprivation and Cardiovascular Problems in Abstinent Alcoholics
Alcohol dependence is a major risk factor for cardiovascular disease, with alcoholic men showing an increased prevalence of hypertension and cardiac arrhythmias. Increased sympathetic activity in response to stress is a potential mechanism for these harmful cardiovascular effects. Therefore, a recent study measured cardiovascular responses and levels of two sympathetic hormones, norepinephrine and epinephrine, in response to a behavioral stressor, sleep deprivation, in abstinent male alcoholic patients. Sleep deprivation induces elevated heart rate and levels of epinephrine and norepinephrine in male alcoholdependent patients compared to healthy nonalcoholic individuals. These elevations in heart rate and sympathetic hormone levels do not recover even after a full night of recovery sleep. Abstinent alcoholic individuals show an extended course of sleep problems that can persist for months or years. Therefore, increased sympathetic nervous system activity that occurs along with habitual sleep loss could play a role in tremor, anxiety, hypertension, and cardiac arrhythmias of abstinent alcoholic subjects.
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
NIAMS funded 5 grants in sleep or sleep-related research in Fiscal Year 2005 in the areas of fibromyalgia (FM), rheumatoid arthritis, and bone fracture. One investigator’s 3-year high-risk (R21) grant found cognitive-behavioral insomnia therapy (CBT) to be a promising intervention for reducing sleep difficulties and other key symptoms in FM sufferers. Post-hoc analyses of these data suggested that addition of sleep hygiene (SH), education regarding CBT strategies might enhance treatment efficacy, and pilot regression analyses suggested the usefulness of sleep disturbance measures as mediators and moderators of FM pain improvement. In Fiscal Year 2005, funding was awarded via an R01 grant to confirm and extend these findings in a moderately large FM sample. In addition to evaluating the CBT/SH intervention, this study will analyze additional measures to identify sleep-based mediators and moderators of improvements in key non-sleep FM symptoms (e.g., pain, fatigue). Results of this trial should provide insights into the pathophysiology and management of FM.
In addition, NIAMS is funding an ongoing study investigating behavioral treatments for rheumatoid arthritis, with sleep quality as one of the outcome variables, and research investigating the role of impaired sleep as a major cause of fractures, disability and cognitive decline in older women.
NIAMS has no sleep-specific initiatives active at this time.
NATIONAL CANCER INSTITUTE
NCI supports a variety of sleep-related research in patients diagnosed with cancer. Sleep disturbances in this population can occur at any point in the cancer trajectory, from diagnosis through survivorship to end of life. Often, the problem occurs in conjunction with other symptoms, most notably pain and fatigue and may be the result of treatment for the disease or for one or more symptoms, such as pain. During Fiscal Year 2005, the NCI supported 61 investigator-initiative projects (R03, R21, R01, and R43), four cooperative agreements (U10, U54, U56) and two conferences (R13) in sleep or sleep-related research. Projects include longitudinal studies aimed at capturing incidence and prevalence of the problem; clinical trials testing behavioral interventions, pharmacologic agents, and complementary and alternative approaches; studies investigating underlying mechanisms; and studies testing new approaches to measuring sleep disturbances. Some examples of research that NCI currently supports in these areas are summarized below.
Sleep Disturbances across the Cancer Continuum
The majority of investigator initiated projects are exploring sleep disturbances as a co-occurring symptom with pain, fatigue, hot flashes, and depression. Patients and their caregivers are often reluctant to communicate their symptoms to clinicians and a number of studies are underway that are testing interventions to help patients and their caregivers communicate their sleep disturbances to clinicians, as well as assist clinicians in routinely assessing these symptoms. Family and informal caregivers are assuming increasing responsibilities for the care of their loved ones with cancer. NCI is supporting several studies investigating how the burden of caregiving, such as sleep disturbances, is affecting informal caregivers.
Complementary and Alternative Approaches
Currently, NCI is supporting research projects that are testing hypnosis, acupuncture, exercise, meditation, massage, yoga, and healing touch to relieve the primary symptom of insomnia or to relieve co-occurring symptoms, which may, in turn, alleviate sleep disturbances.
There is increasing attention on understanding the underlying biological mechanisms, e.g., cytokines, underlying cancer- and treatment-related symptoms, such as sleep disorders. One example of this is an exploratory study of the role of cytokines in pancreatic cancer patients experiencing depression. Although depression is the primary symptom under investigation, it is well known that other symptoms (sleep disorders, pain, and anxiety) co-exist within this population and an analysis of these symptoms is included in the study.
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
NICHD supports and promotes sleep research in infants, children, adults, and in animals with early development resembling that of humans. These studies are designed to gain an understanding of the processes that may be involved in the normal development of behavioral state and physiologic control during sleep, as well as those that accompany Sudden Infant Death Syndrome (SIDS), learning deficits, and mental retardation, and changes across the lifespan in reproductive health. Highlights from a few of the projects follow.
The pathogenic process that leads to SIDS has been under investigation for many years. One major theory is that infants who are vulnerable to SIDS do not respond appropriately during sleep to low oxygen levels and high carbon dioxide levels in the air during sleep. In animal models, these asphyxiating conditions result in a rapid decrease of oxidative metabolism in tissues. This leads to slow heart rate (bradycardia), episodes of prolonged cessation of breathing (apnea), and hypoxic coma.
NICHD supports studies of how the brain controls breathing during sleep, in animal models and in human Congenital Central Hypoventilation Syndrome. In Fiscal Year 2005, a program project grant studying SIDS pathogenesis in animal models examined the role of the neurotransmitter serotonin in the regulation of breathing responses to high carbon dioxide. Researchers found that if serotonin levels are raised in the medullary raphe, an area of the brain that has been shown to have deficits in serotonin receptors in SIDS infants, the breathing response to elevated carbon dioxide is augmented. In addition, inhibition of serotonergic neurons in the medullary raphe caused a decrease in the breathing response to high carbon dioxide, but not to low oxygen. Inhibiting these neurons also decreased body temperature and increased the time the animal spent awake model, Therefore, neurons in the medullary raphe that are activated by serotonin, are involved in the brain’s control of breathing in response to elevated carbon dioxide, and the brain’s controls of body temperature and arousal. All of these control mechanism have been implicated in SIDS pathogenesis.
Patients with Congenital Central Hypoventilation Syndrome (CCHS) have a reduced drive to breathe during sleep, a reduced breathing response to elevated carbon dioxide, and impaired autonomic nervous system regulation, such as control of the cardiovascular and respiratory systems. By comparing the biology of CCHS patients with healthy subjects, we learn about the parts of the brain involved in these functions. Functional magnetic resonance imaging techniques provide researchers with tools to examine the activation of brain areas in response to particular stimuli. When breathing low oxygen, certain brain areas were activated in normal subjects but not in CCHS patients. These include the midbrain, where the medullary raphe is located, as well as thalamic, limbic and cerebellar structures. The participation of the limbic areas has not been previously observed in animal models and suggest future lines of research.
Sleeping on the stomach increases the risk for SIDS. Babies are at much higher risk if they sleep on the back and are placed to sleep on the stomach, without the experience of stomach sleeping. It has been proposed that stomach sleep position increases the likelihood that the infant will become face down in the bedding and rebreathe expired air, which is low in oxygen (hypoxia) and rich in carbon dioxide. Researchers examined the protective behaviors of babies who were either experienced in sleeping on their stomachs or inexperienced. The infants were placed to sleep face down in bedding and as a result began breathing in expired air, and all of the infants aroused. If the babies lifted and turned their head, then the carbon dioxide they breathed in dropped more for a longer time than if the just moved their head and nuzzled the bedding. Infants with experience in stomach sleeping had the best protective responses, with more head lifting and turning. In addition, the inexperienced stomach sleepers spent more time with their face down in the bedding. These studies suggest that protective behaviors are learned, and support the theory that some SIDS infants die because they do not acquire the ability to learn protective behaviors. This could be due to a deficit in the nervous system substrate for learning, or to a deficit in the ability to sense carbon dioxide that does not allow them to develop a learned response to elevated carbon dioxide. The latter is consistent with findings by researchers studying brains from SIDS babies, of unique abnormalities in a network of nerve cells that use serotonin as a transmitter and are responsible for sensing carbon dioxide.
Another theory of SIDS is that some babies have a problem with arousal mechanisms during sleep and don’t wake up in response to life-threatening stimuli. Sleep has two main components, active sleep or REM and quiet sleep, which is a deep sleep. Scientists have found that infants who sleep on the stomach spend more time in quiet sleep than infants who sleep on their back. Also, babies take longer to wake up to arousing stimuli in the stomach position compared to the back. In Fiscal Year 2005, researchers extended this finding by showing that even when the babies who sleep on their stomachs are in active sleep, the brain wave activity is slower in frequency that babies who sleep on their backs. The active sleep in stomach sleepers shows more resemblance to quiet sleep. This may explain the increased arousal thresholds observed in babies who sleep in their stomachs.
Prenatal Alcohol in SIDS and Stillbirth Network (PASS)
In Fiscal Year 2003, NICHD and NIAAA funded four cooperative agreements to create a network for the development of community-linked studies to investigate the role of prenatal alcohol exposure in the risk for SIDS and adverse pregnancy outcomes such as stillbirth and fetal alcohol syndrome (FAS), and how they may be inter-related. The network is composed of two Comprehensive Clinical Sites, a Developmental Biology and Pathology Center and a Data Coordinating and Analysis Center. The Comprehensive Clinical sites are working in the Northern Plains, including American Indian communities, and in the Western Cape of South Africa. The investigators are working collaboratively with NICHD and NIAAA over a three-year period to plan and pilot multidisciplinary investigations using common protocols, within communities at high risk for prenatal maternal alcohol consumption. The long-term goals of this initiative are to decrease fetal and infant mortality and improve child health in these communities.
The network has developed a study design that will combine prospective and retrospective data collection in order to meet these objectives. In order to firmly establish and understand the role of prenatal alcohol in SIDS and stillbirth, prospective collection of behavioral and clinical data during pregnancy is necessary. In addition, in order to understand how fetal development is affected, fetal physiological measurements must be done. The mothers and babies will be followed through birth and through year one, with continuity in physiological and clinical assessments. In addition, specific genetic studies, biochemical and structural studies of the placenta, and neurochemical studies of the brain are planned to link alcohol exposure and genetic predisposition, with structural and functional development. The PASS Network began enrolling pregnant women phase 1 protocols in Fiscal Year 2005, and developed the study design for a large prospective cohort in phase 2.
NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE
Many individuals use complementary and alternative medicine (CAM) therapies to treat sleep disorders. For example, it has been estimated that approximately 1.6 million adults (3.1% of all adults who used CAM) used CAM specifically for sleep problems in 2002. These CAM therapies include the use of dietary supplements such as melatonin and valerian; mind/body approaches such as meditation, and therapies that are part of non-western traditional medical systems, such as acupuncture and yoga. NCCAM’s mission is to investigate CAM therapies and train CAM researchers in the context of rigorous science. As part of this mission, we support research and research training related to the use of CAM therapies for sleep disorders. Some examples of research that NCCAM currently supports in this area are given below.
Chronic insomnia is a significant health problem for many individuals, is often difficult to treat, and can last for years. Furthermore, conventional therapeutics can produce unwanted side effects. As a result, many individuals have turned to alternative therapies in search of more effective treatments with lesser side effects. NCCAM is interested in determining whether or not these alternative treatments, which are already in the public domain, are effective. Currently, NCCAM supports a study using yoga as a treatment for insomnia. Although yoga has been recommended for treatment of insomnia by yoga practitioners, its effectiveness has not been scientifically established. The main goal of this ongoing clinical study is to establish whether a regimen of yoga practice will improve sleep onset latency measured by both subjective and objective criteria. In addition, NCCAM funds an ongoing trial on melatonin for insomnia in the elderly. A significant portion of elderly individuals with insomnia have low endogenous levels of melatonin, which is a normally occurring neurohormone as well as a popular dietary supplement sold to treat a variety of sleep disorders. This clinical study will investigate whether dietary supplements of melatonin will relieve insomnia in these individuals.
Another dietary supplement often used for insomnia and other sleep disorders in valerian. Valerian is derived from the root of the plant Valeriana officinalis and is commonly sold as a dietary supplement in the United States and Europe. It is often advertised as having hypnotic properties effective in treating sleep disorders. However, insufficient scientific data exists to determine its true effectiveness. NCCAM is currently supporting a study to evaluate its efficacy for insomnia in healthy older adults.
Finally, NCCAM has recently funded a study to investigate whether homeopathic remedies for insomnia are effective. While quite controversial, homeopathy is widely used to treat a variety of conditions in many countries throughout the world, including Great Britain, Germany, France, Belgium, India, and Mexico. A major aim of this study is to determine whether homeopathic treatments for insomnia, compared to placebo, actually have a physiological effect on stages of sleep using polysomnography and sleep electroencephalography.
Sleep Deprivation Related to other Diseases
Neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, are often accompanied by sleep disturbances due to pain and/or neurological changes related to the progression of the disease. NCCAM currently supports an ongoing clinical study investigating the efficacy and safety of valerian for the treatment of sleep disturbances in Parkinson’s disease. Some evidence does exist in a mouse model to suggest that valerian reduces spontaneous locomotor activity, which is a problem in Parkinson’s disease, where excessive nocturnal motor activity is related to sleep deprivation. The results of this study should clarify whether valerian is effective in treating sleep disturbances in Parkinson’s disease patients.
In addition, NCCAM supports a study on the use of high intensity light therapy for Alzheimer’s disease patients in nursing homes. The long term care of Alzheimer’s disease patients and patients with other dementias is a growing public health issue and economic burden. Among the most difficult long term care management issues for these patients are treatment of sleep/wake disorders, depressive symptoms, and agitation. This study will investigate whether high intensity lights installed in nursing home common rooms for various periods of time will contribute to a lessening of these problems. If results are positive this could provide a low-risk alternative treatment that is relatively inexpensive once the lighting is installed.
Finally, NCCAM has recently funded an investigation of the effect of valerian root on sleep disturbances for individuals with rheumatoid arthritis. This clinical study will investigate whether valerian taken an hour before bedtime will improve sleep outcomes.
Basic Science Research
NCCAM supports basic science research aimed at understanding the underlying biological mechanisms of CAM therapeutic modalities including those used to treat sleep disorders. For example, as part of an initiative in Basic and Preclinical Research on Complementary and Alternative Medicine (PA-05-141), NCCAM continues to encourage and solicit research on interactions between CAM and conventional therapeutics, including but not limited to interactions between dietary supplements and drugs. This would include the interactions between drugs used to treat sleep disorders and dietary supplements such as valerian and melatonin. In addition, NCCAM currently supports a study to investigate whether the active constituents of hops modulate a lipid signaling pathway believed to induce sleep in mammals.
Perturbations of the biological sleep-wake regulatory cycle may cause sleep disturbances. Light, neurohormones, such as melatonin, produced in the pineal gland, and other substances affect this cycle. NCCAM supports a study investigating the effect of blue light on sleep-wake regulatory cycles in humans. In addition, we recently funded research to determine the effect of vitamin B12 on the human circadian pacemaker.
NATIONAL INSTITUTE ON DRUG ABUSE
NIDA has a primary research goal to understand brain systems affected by psychoactive drugs of abuse. Sleep disturbances both during use of, and following withdrawal from, such drugs among individuals who are addicted strongly suggest the value of sleep studies for the Institute. Indeed, sleep disturbances often outlast other withdrawal symptoms and may be a cause for relapse. NIDA supports sleep studies’ focus on the neurobiology associated with sleep, sleep and circadian cycles, and sleep architecture because some of the neural systems involved in the addiction process are also involved in the sleep architecture. In addition, it is important to study how sleepiness on the one hand and insomnia on the other contribute to drug abuse and to relapse following withdrawal.
Several sleep studies of interest to NIDA are at the molecular level. Fatty acid amide hydrolase (FAAH) is an enzyme that degrades fatty acid amides (FAAs) such as the endocannabinoid, anandamide, and the sleep-inducing substance oleamide. FAAs are implicated in several functions including sleep. For example, oleamide has been isolated from the cerebral fluid of sleep-deprived cats. In addition, FAAH knock-out mice demonstrate increased behavioral responses to administered anandamide and oleamide, including hypomotility, catalepsy, and analgesia, as well as increased endogenous brain levels of FAA. These results suggest that discovery of FAAH inhibitors may be used therapeutically for analgesic effects as well as sleep treatments. In Fiscal Year 2005 NIDA grantees continued to study the structure and function of FAAH, and reported on the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors.
NIDA supports several studies that focus on benzodiazepines and non-benzodiazepine hypnotics, most of which are concerned with mechanisms of action and the potential for abuse. One of these, flunitrazepam, is marketed internationally (but not in the U.S.) for treating insomnia and inducing anesthesia. Unfortunately, it has also become popular as the club drug rohypnol, sometimes referred to as a “date-rape” drug. In a double-blind, placebo-controlled trial comparing flunitrazepam to the standard hypnotic triazolam, NIDA funded researchers found that users’ self-reported they liked flunitrazepam significantly more than even high doses of triazolam thus confirming a high abuse potential and therefore a more risky treatment for insomnia.
Because of the overlap in the neural systems involved in sleep and drug abuse, there is reason to hypothesize that sleep disturbances influence efforts to treat drug abuse or conversely, that drug abuse induces sleep disturbances that exacerbate other health problems. Accordingly, it is possible that treatments for sleep disorders may prove effective in the treatment of drug abuse as well. The relationship between sleep disturbances and elevated inflammatory markers (notably IL-6) was reported this year in patients with depression. The Investigator is now conducting an ongoing study assessing the relationship between increased cytokines in abstinent cocaine abusers and sleep disturbances. Sleep disturbances are also reported by smokers withdrawing from nicotine.
Significantly, treatments for those wishing to quit smoking, bupropion and/or the nicotine patch also cause sleep disturbances. Accordingly, the Investigator is currently administering a project to formally assess the impact of state-of-the-art treatments including either or both medical and behavioral techniques on sleep quality and daytime sleepiness.
A major thrust of research is how using drugs of abuse and withdrawing from drugs of abuse affect sleep cycles and sleep efficiency; how cognitive efficiency is affected either by drugs themselves, or loss of sleep because of drugs; and importantly, are the effects on sleep following drug withdrawal part of the cause in cases of relapse? In a study of cocaine abusers residing on an inpatient unit, sleep duration, efficiency, and onset latency worsened across three days of binge use followed by 15 days of abstinence. By contrast, the patients did not report subjective differences in sleep quality. In this study it was concluded that this dissociation between objective and subjective sleep quality is related to disruption of the sleep homeostat and may be contributory to relapse. An ongoing, polysomnographic study of sleep quality following abstinence of marijuana abuse is also being carried out where reported sleep disturbances are systematically documented in heavy users. Finally, a study using phosphorous magnetic resonance spectroscopic imaging following sleep deprivation in withdrawing cocaine or heroin abusers seeks to determine metabolic changes in the anterior cerebrum compared to sleep deprivation in non-users. Continuing studies in these areas promise to inform on biological mechanisms underlying drug abuse vulnerability as related to sleep architecture.
NATIONAL INSTITUTE OF MENTAL HEALTH
Sleep disorders and sleep disruption associated with various mental disorders produce significant distress and impairment, contributing to the burden of mental illness in our society. As a result, NIMH supports a rich portfolio of sleep-related research that spans the basic to clinical research continuum and includes research in sleep disturbances of children, adults, and the elderly. Sleep-related research supported by NIMH includes cellular and molecular mechanisms of circadian and sleep-wake systems, effects of sleep on learning and memory, nosology and epidemiology of sleep disorders, the relationship of sleep disruption to mental illness, and development and evaluation of treatments for sleep disorders. NIMH also provides career development grants to increase both the number and scope of sleep researchers. A few recently published studies supported by NIMH are highlighted below.
Restricted Sleep Reduces Hippocampal Cell Survival and Neurogenesis
A body of current research indicates that sleep helps consolidate memories by providing a brain state conducive to structural and functional neural changes, or brain plasticity. A recent study shows that the impact of sleep on memory depends upon the type of memory and the brain structures involved. Laboratory rats were trained in one of two water maze tasks. In the nonspatial or hippocampus-independent task, a visible platform was moved to a different quadrant of the maze after every four trials. In the spatial or hippocampus-dependent task, a submerged or hidden platform remained in the same location throughout all trials. Half of the animals in each learning task were sleep restricted. As expected, sleep restriction impaired spatial or hippocampus-dependent learning and resulted in reduced cell survival and neurogenesis in the hippocampus. In the nonspatial or hippocampus-independent task, however, sleep restriction actually improved performance. Further analysis revealed that rested animals used a spatial strategy regardless of the task demands and that this preferred spatial or hippocampus-dependent strategy actually interfered with performance on the nonspatial task.
These findings provide further support for the role of sleep in brain plasticity and memory consolidation, but they also suggest that sleep restriction differentially affects certain memory and performance tasks. The more the hippocampus is activated in learning a task, the more neurogenesis occurs in this region and the more severe the effects of sleep loss are on neurogenesis and hippocampus-dependent learning. The study results further our understanding of the functions of sleep and highlight the complexity of assessing the effects of sleep deprivation on various types of memory and performance.
A Clock Gene Essential for Circadian Rhythms also Regulates Long-Term Memory
Circadian rhythms are cyclic daily patterns of physiological and behavioral activity critical to a normal sleep-wake cycle. Investigators have identified clock period genes that are essential for establishing circadian rhythm and have determined the importance of CREB (cAMP-responsive element-binding protein) in maintaining the normal expression of these clock genes. CREB protein synthesis is also critical to long-term memory. Therefore, these researchers hypothesize that long-term memory may be regulated by the same clock genes that regulate circadian rhythms.
In a study funded in part by NIMH and recently published in the Proceedings of the National Academy of Sciences (PNAS), investigators studied the effects of clock gene mutations on long27 term memory performance of fruit flies (Drosophila melangaster). The genes of fruit flies can be easily manipulated to rapidly produce generations of flies with the specific genetic mutation, providing a powerful model system for understanding the role that genes play on regulating basic biological and behavioral processes. In this study, various mutations of fruit flies were trained or conditioned to reduce courtship behaviors in response to specific environmental cues and later observed to assess the effects of the genetic mutations on the long-term memory to this conditioning. The researchers found that fruit flies with a defective copy of only one specific clock gene, per, were unable to form and retain this learned conditioning over long periods of time. In addition, the over-activation of the per gene resulted in enhanced long-term memory. The findings of this study show that a clock gene, per, originally identified as essential to the regulation of circadian rhythms, appears to also be important for long-term memory. This research provides promising new directions for understanding and eventually treating deficits in long-term memory associated with numerous psychiatric and neurological conditions.
Differences in PET Scans of Depressed Patients During Wake and Non-REM Sleep
Sleep disturbance is common in depression and is an important risk factor for depression onset and relapse. Depression is also associated with disrupted sleep patterns including alterations in Non-Rapid Eye Movement (NREM) sleep. To better understand the brain functions associated with sleep disturbance in depressed patients, researchers performed regional cerebral glucose metabolism assessments (e.g., PET scans) of depressed and healthy participants during wake and NREM sleep.
Compared to healthy controls, depressed patients showed a smaller decrease in metabolism from wake to NREM sleep in broad regions of the brain (e.g., thalamus and frontal, parietal, and temporal cortex). These smaller decreases from wake to NREM sleep, however, appeared to be due primarily to lower metabolism, particularly in prefrontal regions of the brain, during waking periods in depressed patients. Prefrontal hypometabolism may be fundamentally altered in depressed patients or may be the result of sleep disturbance in these patients.
In contrast, depressed patients showed larger decreases in metabolism from wake to sleep in ventral and posterior brain structures including the left amygdala, anterior cingulated cortex, cerebellum, parahippocampal cortex, fusiform gyrus, and occipital cortex compared to healthy controls. These larger decreases from wake to NREM sleep, however, appeared to be due primarily to increased metabolism in these brain areas during waking periods in depressed patients. The hypermetabolism in these regions is consistent with increased arousal that may interfere with sleep onset and maintenance.
The findings from this study offer intriguing possibilities for the complex relationship at the neurobiological level between depression and sleep disturbance. In the ventral and posterior regions of the brain, depressed patients show increased activity compared to healthy controls, both during wake and sleep states, and this hyperarousal may contribute to the sleep disturbance commonly associated with depression. In the prefrontal regions of the brain, depressed patients show decreased activity compared to healthy controls during waking periods, and sleep deprivation may contribute to the altered prefrontal cortex function consistently observed in depressed patients. Additional neuroimaging research in sleep and related disorders could further elucidate the relationship of sleep disturbance and mental disorders such as depression.
A Longitudinal Study of Young Children’s Sleep Patterns
During the first five years of life, as many as a third of children have some type of sleep disturbance, yet little is known about the nature, course, or possible risk factors for these sleep disturbances. An NIMH-sponsored study assessed sleep behavior, including video observations of sleep, in 68 families of infants over four years. About a third of the infants were classified as “stable non-self-soothers” who were unable at ages six and nine months to calm themselves back to sleep after awakening. These infants were more likely to have sleep onset problems and to be sleeping with a parent at age two. During the first two years of life, 19% of children had sleep difficulties based on stringent classification criteria. Over time, problems with nighttime awakenings (e.g., sleep maintenance) diminished, but sleep onset problems persisted.
Approximately half of children at 2 years of age required parental presence to fall asleep. A quarter of the children slept with their parent(s), but only a third of these parents reported this behavior to be a problem. Intermittent sleeping with parents was not associated with sleep problems at later time points, but a subgroup of parents (9%) consistently slept with their children up to age four, which may reflect difficulty having the child sleep independently once sleeping with the parent(s) becomes routine.
This study documents the considerable sleep difficulties among young children and the impact on their families. Additional research is needed to better understand the sleep difficulties of young children and how parents should respond to minimize long-term sleep problems and reduce the impact of these difficulties on the family.
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
NINDS has a long-standing interest in homeostatic mechanisms of the central nervous system including sleep and circadian rhythms. NINDS supports basic and clinical research on the neuroscience of sleep, including studies of fundamental mechanisms of sleep, sleep disorders and associated complications. As listed in this report for Fiscal Year 2005, NINDS funded 88 sleep disorders and circadian rhythms research projects, with support totaling $20.7 million. The following are some of the significant scientific advances made by NINDS-funded investigators in Fiscal Year 2005.
For most species of mammals, newborns and young spend more of the 24-hour day resting and sleeping than do their elders. Sleep time gradually decreases approaching adulthood. While sleep appears to be essential for life, NINDS supported investigators found some striking exception to this developmental sleep pattern. Unlike terrestrial mammals, baby killer-whales and bottlenose-dolphins as well as their mothers show little or no typical sleep behavior for the first postpartum month, avoiding obstacles and remaining mobile for 24 hours a day. Over the several months after birth, babies and mothers gradually increase the amount of time they spend resting to normal adult levels, but never exceed these levels. These findings indicate either that sleep may not have the developmental and life-sustaining functions attributed to it, or that whales and dolphins somehow accomplish the important functions of sleep without actually sleeping.
Studies on the relationship between sleep and the immune system continue to provide fundamental insights into the reason we sleep and the adverse consequences of not sleeping. We feel sleepy when we have a cold and sick when we have not slept enough. Two substances, tumor necrosis factor alpha and interleukin-1 beta, increase their concentration in the brain after neuronal activity. These substances are proinflammatory and promote immune reactions to clear the brain of themselves along with other unwanted molecules. Tumor necrosis factor alpha and interleukin-1 beta have also been shown to regulate sleep. Recent studies supported by NINDS indicate that these substances are produced in response to activation of brain cells and can cause sleep-like slowing of brain waves, even when they are administered to small areas of the brain. Tumor necrosis factor alpha and interleukin-1 beta are also involved in neuronal growth and plasticity. Since the intense neuronal activity of wakefulness causes the release of these immune system substances, many researchers think that sleep is initiated by the immune system and that sleep's purpose is to: regulate the growth of connections between brain cells, clear the brain of substances produced during previous wakefulness, and prepare the brain to function properly during subsequent periods of wakefulness.
A detailed understanding of circadian timing mechanisms, the body’s “clock” on which the sleepwake cycle depends, is critical for sleep disorders research. Normal functioning of this clock requires a complex interplay of several genes and the neuropeptides these genes produce. Rapid progress understanding the clock has come from studies of the fruit fly in part because it is possible to breed and study large numbers of flies with various genetic make-ups. Two NINDS-funded studies published in 2005 have identified one neuropeptide, pigment dispersing factor, as key in coordinating the circadian clock of the fruit fly. Abnormalities in the gene that produces pigment dispersing factor disrupt the smooth function of the clock and disrupt behavior. Because mammals have a closely related peptide which may have similar functions in the mammalian circadian clock, these findings have implications for insomnia and related sleep problems in humans.
Narcolepsy is a disabling sleep disorder affecting about 200,000 Americans. NINDS supported research on narcolepsy has established the importance of the neurotransmitter, hypocretin, in regulating wakefulness and sleep. Losses and defects in neurons that contain hypocretin cause narcolepsy in humans and animals. However, the mechanisms and extent of damage to hypocretin neurons in narcolepsy is not understood. By conducting post-mortem studies, NINDS-funded investigators found that two neuronal regulating molecules, neuronal activityregulated pentraxin and prodynorphin, which are normally found in the same neurons as hypocretin, were greatly reduced in patients with narcolepsy compared to normal controls. This finding also indicates that loss of neuronal activity-regulated pentraxin and prodynorphin function contributes to the symptoms of narcolepsy. Studies of this kind may lead to new avenues of therapy that target molecules that are found in hypocretin neurons.
NATIONAL INSTITUTE OF NURSING RESEARCH
NINR supports sleep research in several areas, including sleep disturbances in people with chronic illness, the effects of sleep deprivation on development and function, and how to manage sleep disturbances in a variety of healthcare settings. NINR-funded scientists are studying sleep-related topics such as: designing behavioral interventions to help people improve their sleep habits; studying the effects of sleep/wake cycle disruptions on premature infant development; and investigating the effects of chemotherapy-related sleep disturbances on the quality of life of cancer patients. The following are a few examples of recent sleep research findings by NINR-funded investigators and currently funded NINR sleep-related research projects.
Recent NINR-Funded Advances in Sleep Research
Getting a Good Night’s Sleep May Lead to Easier Labors and Deliveries for Pregnant Women
Women often complain of fatigue and difficulty sleeping during pregnancy, especially as they approach delivery. Researchers studied women who slept less than 6 hours per night or who experienced frequent sleep disturbances during their pregnancy. These women had significantly longer labors and were 3-4 times more likely to have a cesarean delivery than women who slept 7-8 hours a night with fewer disruptions. These results suggest a need for women to get adequate sleep during their pregnancy, and a need for care providers to communicate the benefits of better sleep during pregnancy to their patients.
Promoting Sleep Regulation Helps Reduce Irritability and Crying in Colicky Infants
Infants with colic may cry inconsolably for several hours each day, frustrating both parents and health care providers. New theories link colic to the immaturity of the infant’s sleep/wake state regulation. In a controlled trial, NINR-funded scientists tested an intervention that used a program of home visits from nurses to help families cope with infant irritability and promote the development of sleep/wake regulation in the infant. Parents were taught over a 2 week period to establish routine daily activity patterns; provide holding, rocking and other soothing contacts; and establish a period of quiet for themselves to promote rest and recovery. Eight weeks after the intervention began, parents reported that crying had fallen from an average of 5-6 hours to less than 1 hour per day. In the control group, which received standard care, crying was only reduced to 4 hours per day. These results demonstrate that interventions which establish an infant’s sleep/wake cycle and educate parents in caring for their colicky infant may help families improve their quality of life.
Bright-Light Treatment of Alzheimer’s Patients May Improve Circadian Rhythm
Erratic sleep/wake cycles are a major disabling symptom of Alzheimer’s disease sufferers. Light levels in long-term care facilities are often low and may affect the circadian clock of residents with Alzheimer’s. In a randomized clinical trial, NINR-funded researchers tested the effect of one hour of bright light exposure on the quality of sleep and wakefulness, and rest/activity cycles, of institutionalized Alzheimer’s patients. Bright light exposure significantly improved rest/activity rhythms in these patients, but had no effect on quality of nighttime sleep or daytime wakefulness. This study suggests that timed bright light exposure may help to adjust the circadian rhythms of Alzheimer’s patients to a normal 24-hour day.
Current NINR Sleep Research Activity
Improving the Sleep/Wake Cycle of Hemodialysis Patients
The majority of patients with end-stage renal disease undergoing hemodialysis (HD) have problems with sleep that affect their quality of life. Sleep/wake cycles are influenced by body temperature (BT), with relatively low BTs occurring prior to the onset of sleep. HD often causes slight elevations in a patient’s BT. Because of these two factors, NINR-funded scientists are currently testing the effects of using cool dialysate during HD instead of the warm dialysate normally used in an effort to lower BT and promote sleep. Dialysate is the cleansing solution composed of salts and glucose used during dialysis. Researchers will monitor the sleep/wake cycles of patients receiving the intervention, as well as patients’ behavioral and physiological functioning. Findings from this research may assist care providers in improving the quality of life of patients undergoing HD.
Using Social Activity and Resistance Training to Improve Sleep in Persons with Dementia
Persons with cognitive disorders often suffer from sleep disturbances, especially those in longterm care facilities. Drug treatments often prove ineffective at combating these sleep problems. In a randomized controlled trial, NINR-funded scientists are testing a behavioral intervention for its ability to improve the sleep quality of nursing home residents. The treatment will involve social activities such as listening to music or playing games, progressive resistance training of the hips and arms, or both. A control group will receive usual treatment. Sleep and wake quality will be measured after seven weeks. This intervention may inform clinicians of the usefulness of innovative behavioral interventions in improving the sleep quality and quality of life of patients with dementia.
Recovery of Neurobehavioral Functioning Following Sleep Deprivation
Chronic sleep loss due to medical conditions or other factors is known to affect normal daily functioning and cause health problems. NINR-funded researchers are currently determining the amount and types of sleep (e.g. REM sleep) necessary to recover normal behavioral and physiological function following sleep deprivation. These scientists are testing a group of healthy subjects who have been kept awake and then allowed to sleep, both for varying amounts of time. The investigators are monitoring behavioral and physiological functioning while the subjects are awake and are measuring physiological states while the subjects are asleep. Findings from this research could lead to an improved theoretical understanding of the relationship between sleep and neurobehavioral function, and lead to the development of better interventions and guidelines for the public regarding sleep and health.
OFFICE OF RESEARCH ON WOMEN'S HEALTH
ORWH supported three projects with total costs of $500,000, that were related to sleep research through their foci on disorders in which sleep disruption is a factor, changes in relevant symptoms across the fluctuating hormonal cycle in women, and changes in relevant symptoms across the natural age span in men and women or studies of relevant basic factors. ORWH also contributed funds for the special Nature Insight Review on Sleep and was actively involved in sponsorship of the State of the Science (SOS) Conference on Insomnia. ORWH has no direct funding authority; therefore, the Institutes to which these dollars have been assigned are noted in the summaries that follow.
1R01DE016212-02 Hormonal Cycles in Women: Effects on TMD Pain & Symptoms
This project studies the interaction of mind and body in pain conditions affecting the temporomandibular joint and muscles of mastication. These pain problems are twice as common in women as in men and prevalence peaks in the reproductive years. Two related studies will investigate the cyclic nature of this pain. Study one assesses the relationship of pain to salivary levels of reproductive hormones and psychological stress across two consecutive menstrual cycles of TMD patients with normal menstrual cycles compared with normal cycling woman with episodic headache pain and with normally cycling women free of all chronic pain problems. Study two will compare the effects among these groups of a continuous oral contraceptive to stabilize the hormonal environment and eliminate menses, a self management intervention focused on and timed to the chronobiology of the TMD symptoms across the menstrual cycle, and usual self management intervention. It is expected that these studies will shed light on the mechanisms underlying the cyclic nature of TMD pain as well as determine which treatment modality yields greatest improvement.
1R01AG021487-03 Health, Illness, and Social Life at Older Ages: National Social Life, Health and Aging Project
An interdisciplinary team of social and medical scientists are conducting a nationally representative longitudinal survey to assess the physical, psychological and social implications of sexual health and behavior in a probability sample of 3,000 independent and assistedcommunity living men and women aged 55-88. In addition to the information collected in the 2 hour, in home interview, biomarkers will also be collected. These data will be examined in terms of The Interactive Biopsychosocial Model, an extension of Engel’s biopsychosocial model and permits examination of both cross-sectional and longitudinal hypotheses. In addition to establishing a baseline description of older Americans with respect to health, illness, social life, etc., the study will also examine the relationship of older adult sexuality to (1) quality of life and health behaviors including physical activity, nutrition, sleep, substance use and preventive health behaviors, (20 the expression of physical illness, disability, pain, and medication use, (3) important life stages, and (4) social embeddedness. This study will build a foundation for medical, psychological and social interventions aimed at maintaining or improving health and independence among older Americans.
5R01NR004142-08 Nursing Management of IBS: Improving Outcomes
This study will further test the effectiveness of comprehensive self-management (CSM) treatment for IBS by comparing the face-to-face intervention with a telephone version relative to a usual care group of men and women with IBS. Outcome measures will be HRQOL, GI symptoms, sleep disturbance, psychological distress, and sickness impact. The second aim of the study will be to examine the relationship between GI symptom improvement and decrease in psychological stress using self report measures as well as physiological arousal as measures by catecholamine and cortisol levels in men and women. Results will help define the underlying pathology, the possible effects of sex and gender, and provide information on the potential role of serotonin processing in IBS.
TRANS-NIH SLEEP RESEARCH COORDINATING COMMITTEE
NIH Sleep Research Funding 1996-2005
^ Revised from Trans-NIH Annual Report for fiscal year 1998
* This reduction in FY 2000 funding compared to FY 1999 was due to a one-time change in the method of identifying sleep-related grants
** Grant and funding data not included in NIH FY 2005 sleep total. Please refer to respective narrative sections for details.
The grant list and funding detail for Fiscal Year 2005 can be viewed online as a separate .pdf document
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