1985 — 1993 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
An Indispensable Resource For the Study of Narcolepsy
This proposal seeks continuation of support for maintenance of an indispensable national resource--a colony of dogs which provides the only existing animal model of the human disease of narcolepsy. These animals manifest the identical pathognomonic signs found in human narcolepsy (namely, sleep onset REM periods and bouts of cataplexy) and genetically transmit this trait. Recent research investigations have identified specific neurochemical defects in the brains of affected animals that may reflect the underlying neural basis of this disease. We plan to maintain a breeding colony of 25 dogs with heritable narcolepsy for five years and a research colony of 80 narcoleptic dogs/year reared to 100 days of age. The dog breeds that will be maintained are Doberman pinschers, Labrador retrievers, and Labrador-Doberman mixtures, all of which transmit the narcoleptic trait genetically. The narcoleptic dog colony is a necessary resource for current and future projects for both Stanford and extra-Stanford investigators. It is the only colony of narcoleptic animals in the world. The research projects made possible by the existence of this colony will elucidate the neurochemical and genetic causes of narcolepsy, clarify the mechanisms of symptoms, such as excessive sleepiness and hallucinations, present in other human illnesses, and provide insights into the basic mechanisms of sleep.
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0.958 |
1985 |
Dement, William C |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Sleep and Its Disorders in the Elderly
This is a program project proposal. It requests support for nine individual projects. Each project will address some aspect of sleep and sleep disorders as a function of the aging process. Two large projects involving clinical sleep disorders form the core of the program. The first includes a precise, comprehensive assessment of the prevalence of sleep-wake disorders in discrete populations of elderly individuals. The core project involves a broad-based longitudinal assessment of elderly persons with sleep apnea syndromes and matched control subjects. The longitudinal study will evaluate mortality, morbidity, cardiovascular-respiratory function, cognition, behavioral function, and daytime alertness. Essential to the efficient progress of the two core projects are the installation and refinement of a sleep disorders information system and a series of microcomputer-based ammbulatory monitors. Another clinical project involves two key issues in hypnotic safety and efficacy in elderly patients; the effect of sleeping pills in individuals with sleep apnea, and the effect of sleeping pills on daytime alertness. Four additional projects will address basic research issues concerning sleep and aging. Circadian rhythms and aging will be evaluated using life span recordings of sleep-wake and activity-inactivity in mice. Nocturnal determinants of daytime alertness in elderly humans will be evaluated in a series of sleep restriction, sleep loss, and napping studies. The precise relationship of respiratory function during sleep to aging will be evaluated using sophisticated invasive procedures in cats. Finally, the fourth project will focus on neurochemical processes during sleep in the aging brain, with in vivo studies of young and old cats and dogs. A planning group, including epidemiologists, statisticians, gerontologists, and others will direct the project and integrate the research findings.
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0.958 |
1985 — 1996 |
Dement, William C |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Sleep and Its Disorders
Clinical research on the pathologies of sleep and basic research on the pathologies of sleep form the heart of the proposed research program. The major prongs of the program are as follows: Research on Normal and Pathological Sleepiness/Alertness. A theoretical optimal adjustment to the 24-hour environment is to be very alert and energetic in the daytime and very sleepy, or soundly asleep, at night. The most predictable and pervasive interaction of sleep and wakefulness is through the induction of sleepiness in response to various schedules of sleep loss. At the present time, a very broad program has evolved with in-depth studies of the basic nature of the sleepiness/alertness dimension and its major determinants; amount an quality of sleep at night, circadian phase, age, drugs, and various pathologies. We will also investigate the role of this dimension in human performance. Narcolepsy Research. Prior efforts have led to the development of a pure, reliably reproducing strain of Doberman pinscher narcolepsy. The availability of an unlimited supply of animals constitutes a breakthrough and opens up the problem of narcolepsy to a variety of decisive investigations. We will carry out a series of biochemical studies capitalizing on prior research which documents specific CNS abnormalities in canine narcolepsy. Sleep-Related Respiratory Disturbance and Aging. We are investigating the relationship of sleep apnea and hypopnea to a variety of other functions in elderly populations. We emphasize longitudinal studies and cognitive studies. Other areas are cardiovascular factors and daytime sleepiness. We are also developing research programs in chronobiology, cellular neurophysiology, sleep and wakefulness in the teaching nursing home and a suitable animal model for research on sleep in the aged organism.
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0.958 |
1985 — 1986 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sleep and Aging--Basic Research
The proposed research will examine the role of environmental and constitutional factors in the regulation of sleep behavior and sleep-influenced physiological variables in the aged cat. Longitudinal changes in EEG state-pattern characteristics and breathing parameters will be assessed as will the effects on sleep of exercise, environmental temperature, and partial and total sleep deprivation. The overall aims of this work are: i) to broaden an understanding of sleep mechanisms and sleep-related pathology in senescence and ii) to identify safe and effective means of improving sleep efficiency in the elderly. Young adult (2-4 years) and old (greater than 11 years) cats will be surgically prepared with indwelling electrodes for chronic recording of EEG, EOG, and EMG, and lateral geniculate activity. Respiratory variables will be measured using both inductive plethysmography and pneumotachography. Data will be evaluated by visual inspection and computer analyses.
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0.958 |
1985 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Narcolepsy Basic Research
This project will address the problem of narcolepsy by conducting research on an animal model of the illness. The model consists of Doberman pinschers in which the sleep disorder is genetically transmitted by an autosomal recessive gene. Preliminary neurochemical evidence supports the hypothesis that a neurochemical defect is involved. We will pursue further elucidation of the pathological mechanisms in canine narcolepsy by carrying out studies in three areas. We will conduct regional assays of biogenic amines and their metabolites as well as measurement of binding sites and binding properties of dopaminergic, cholinergic, serotonergic, and adrenergic receptors. Other neurochemical studies will involve push-pull cannula approaches with assay of neurotransmitters and metabolites in perfusage. We also propose functional neuroanatomical mapping of cataplexy and REM sleep by 2-deoxyglucose techniques. Finally, we will investigate the neurophysiological substrates of narcolepsy be recording discharge patterns of single units in specific brainstem areas related to REM sleep control.
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0.958 |
1985 — 1986 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Model of Depression: Theta Eeg Circadian Rhythm
disease /disorder model; electroencephalography; circadian rhythms; chordate locomotion; antidepressants; wakefulness; imipramine; hippocampus; lithium; REM sleep; implant; telemetry;
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0.958 |
1985 |
Dement, William C |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Effects of Hypnotic Drugs On Respiration in the Aged Cat
We submit this proposal as established investigators needing prompt support for a pilot project to maintain research momentum and productivity and to exploit the current existence of a research colony of aged cats. These cats will eventually die and no cats of comparable age are available afterwards. This study will evaluate the effects of benzodiazepines (triazolam, diazepam, and flurazepam) and barbiturates (pentobarbital and secobarbital) on sleep and respiratory variables in the aged cat. Young adult and old (greater than 11 years) animals will be implanted with electrodes to record EEG, EOG, EMG, and lateral geniculate activity. Respiratory air flow and end-tidal pCO2 will be measured via a tracheostomy. Respiratory measurements will be determined by on-line analysis with a laboratory PDP-11/34 computer. Hypercapnic and hypnoxic rebreathing tests will be conducted to assess respiratory chemoresponses. The purpose of this pilot study is to determine whether selected benzodiazepines and barbiturate hypnotics induce significant respiratory impairment in the aged animal.
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0.958 |
1985 — 1988 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adolescent Development: Sleeping and Waking Behavior
Adolescence is a time of great susceptibility to sleep problems. A three-part approach to the assessment of sleeping and waking behavior in adolescents is planned with the following goals: to assess the mcehanisms of sleep function and the role of nocturnal sleep in achieving optimal alertness in adolescents; to evaluate the impact of daytime sleepiness on education and to investigate the efficacy of intervention; to achieve an estimate of the prevalence of specific sleep disorders in adolescents and to evaluate therapeutic interventions, as well as to begin the search for a biochemical marker of narcolepsy in adolescents "at risk" for the disorder. Mechanisms of sleep function and the role of nocturnal sleep in adolescents will be assessed in a number of sleep laboratory studies. These studies include an evaluation of the role of slow wave sleep in young and older adolescents, assessment of the relevance of sleep continuity, the effects of sleep length, napping, and the role of circadian rhythms. Educational impact will be determined from survey data and primarily from remote video observational studies in the classroom. In addition, one experiment is designed to assess the effectiveness of an educational program in junior high school students. The final series of project will include polysomnographic verification of sleep complaints, nonpharmacologic treatment of specific sleep disorders, and a longitudinal assessment of children "at risk" to develop narcolepsy.
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0.958 |
1986 — 1994 |
Dement, William C |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Center For Narcolepsy and Related Disorders
This is a proposal to establish a research center on narcolepsy and related disorders. Its purpose is to bring together a multidisciplinary group of investigators who will conduct research into the etiology, pathogenesis, diagnosis, prevention, and treatment of narcolepsy -- a neurogenetic disorder of sleep processes afflicting more than 250,000 persons in the United States. Disorders of excessive daytime sleepiness which do not fit the exact criteria for narcolepsy and afflict an additional large group of individuals, will also be at issue. The initiating concept is that scientific methodologies now routinely available for research on other medical and neurological problems will be brought to bear simultaneously and cooperatively in one place on a primary sleep pathology. The Center will have core facilities and research projects: For the latter, we propose a molecular genetic study of human and canine narcolepsy utilizng restriction fragment length polymorphism studies and DNA sequencing. Another project proposes experiments to test the autoimmune basis for narcolepsy. An autoimmune mechanism is strongly suggested by the high association of HLA-DR2 antigen and the narcolepsy phenotype, an association which is present in many other autoimmune diseases. A third project involves neurochemistry and rests on the foundation of prior findings showing regional abnormalities in catecholamines and neurotransmitter receptors in the central nervous system of the narcoleptic dog. The fourth project involves the refinement of the diagnosis of non-respiratory disorders of excessive daytime sleepiness, of which narcolepsy and CNS hypersomnia are the major categories. It will study the role of the HLA system through typing studies coupled with clinical evaluation and family studies. The fifth major project involves observations on sleep/wake behavior during adolescence in high-risk children, e.g. children who have a parent with narcolepsy. Finally, in order to accelerate research on narcolepsy and related disorders, we propose four special pilot projects in several promising new areas.
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0.958 |
1986 — 1995 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Sleep, Exercise, Aging and the Circadian System |
0.958 |
1987 — 1991 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Follow-Up of Elderly Patients With Sleep Apnea
This is a longitudinal study proposing to follow elderly individuals over time to determine the morbidity and mortality associated with sleep-related respiratory disturbance (SRRD). SRRD shows a strong age-related prevalence and indirect evidence suggests that SRRD could be associated with higher mortality. Likewise some studies have suggested associations between SRRD and morbidity (impairment in psychological and cardiovascular function), but the findings to date have been inconclusive. For cardiovascular function in particular, studies have not employed epidemiological definitions of cardiovascular disease. In this study, two samples of aged individuals will be followed over time: 1) a group of 150 elderly former sleep clinic patients with documented SRRD at entry and 2) a group of 100 non-clinic elderly research subjects studied biennially. Respiration in sleep will be recorded for 2 nights with in-lab polysomnography in sample 1 and with ambulatory monitors for 2 nights in sample 2. All individuals will also undergo a psychological evaluation (consisting of measures of depression, psychological symptoms, neurological impairment, and a newly-validated inventory of self-reported daytime sleep tendency) and a cardiovascular evaluation (consisting of 12-lead electrocardiography, and standardized measurements of myocardial enzymes, angina and hypertension). Primary analyses will focus on prediction of putative outcomes through use survival analysis in a proportional hazards model. Follow-up interval and other measures at entry (SRRD, age, sex, obesity) will serve as risk factors. By using previously acquired data, the proposed study is a cost- effective means to investigate the progression of SRRD over time. If associations between SRRD and morbidity outcomes can be demonstrated here, full-scale prospective epidemiological studies of SRRD in groups more representative of the general population would be implicated.
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0.958 |
1988 — 1998 |
Dement, William C |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Research Training in Geriatric Sleep Disorders Medicine |
0.958 |
1989 — 1992 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Indispensable Resource For the Study of Narcolepsy
The goal of the Center for Narcolepsy research is to unravel the cause of narcolepsy, a genetic disorder of REM sleep affecting approximately 250,000 Americans. Since 1973, the Stanford University Canine Narcolepsy Colony has been a indispensable resource in the study of this disorder. The specific aim of this competitive renewal is to maintain and optimate the use of this resource, the only existing animal model of the human disorder. To implement this goal, we will: . maintain a breeding colony of 88 control and genetically narcoleptic dogs . continue to supply animals and tissue to our research teams and to collaborating laboratories . construct a DNA tissue bank from all animals in the colony . continue to develop and expand the Canine Narcolepsy Colony computerized database. This canine colony has been funded by NIH for the past decade. The current level of funding of this grant has become inadequate for maintaining a colony of sufficient size and quality to ensure humane care of the animals and to supply animals for expansion of the colony to 88 animals; improved veterinary care and housing required by law, necessitating increased per diems and involvement of key personnel to optimize the specialized breeding program. The colony is a key resource to study narcolepsy. The main research directions of our approved and funded program project using this resource are: . To investigate the effects of new pharmacological compounds selective for receptor subtypes on canine cataplexy. We expect that the results of these investigations will allow us to elaborate new therapeutic strategies for human narcolepsy. . To determine the regional changes in neurotransmitter and receptor levels underlying canine narcolepsy. . To evaluate the functional significance of these neurochemical abnormalities using local in vivo pharmacology. . To conduct detailed observations of the natural evolution of canine narcolepsy combined with neurochemical/pharmacological testing. . To identify neuronal cells involved in the regulation of canine cataplexy and study their physiological role in relationship with REM sleep and the pathophysiology of the disorder. . To determine the basic genetic defect underlying canine and human narcolepsy. The increased size of the colony and the breeding possibilities will facilitate genetic studies directed toward the isolation of the gene responsible for narcolepsy. In the current funding period we have identified a candidate marker probably linked with narcolepsy and will be pursuing this exciting aspect of the research to the fullest capacity by increasing the breeding program. The existence of this canine colony will also allow us to explore any relationship between narcolepsy and other inherited disorders in Dobermans (e.g., von Willebrand Disease, hypothyroidism, familial glomerulonephropathy). In summary, the canine narcolepsy colony represents a unique opportunity to unravel the pathophysiology of this disorder through a multidisciplinary approach of pharmacology, neurochemistry, physiology, and genetics.
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0.958 |
1989 — 1991 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuropharmcology of Human Narcolepsy
The Stanford University Sleep Disorders Center has established a colony of dogs affected with a genetically transmitted form of narcolepsy. We now propose extensive in vivo and in vitro pharmacological investigations utilizing this animal model in order to further understand the neurotransmitter defects in narcolepsy and to elaborate new therapeutic strategies for human narcolepsy. The specific aims of this project are: * To study the effects of monoaminergic and muscarinic agonists and antagonists selective for receptor subtypes on canine cataplexy. * To study the binding properties of these agents in vitro and to correlate these properties with in vivo effects on canine cataplexy. * To study the influence of nighttime sleep on daytime canine cataplexy. Nighttime sleep will be manipulated by various alerting and hypnogenic drugs (especially those increasing REM sleep). A key variable will be the intensity of cataplexy on the following day. * To study the effect of prazosin (an alpha 1 antagonist) and yohimbine (an alpha 2 antagonist) on human narcoleptic patients.
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0.958 |
1990 — 1993 |
Dement, William C |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Sleep &Its Disorders
Basic and clinical research on sleep and its pathologies form the heart of a proposed research program. The major components of the program are as follows: *Research on the etiologies of human and canine narcolepsy This program will utilize in vivo and in vitro investigation methods in both canines and humans to answer genetic and neurochemical questions about narcolepsy with the long range goal of the development of new clinical therapeutic strategies. This program is housed in an environment which has a large population of narcoleptic patients in a computerized clinical database, and a well established colony of dogs affected with a genetically transmitted form of narcolepsy. *Research on the circadian control of sleep and wakefulness This program seeks to understand the role of circadian timing systems in manifestations of sleep and wakefulness. Utilizing a sophisticated automatic scoring system with the capacity to record 128 animals simultaneously, we are studying long term circadian sleep/wake manifestations as they relate to a host of manipulations including activity feedback to the clock, several neurochemical studies, and the interaction of sleep loss and circadian timing. *Research on the homeostatic aspects of human sleep and sleepiness/alertness This research is based on the theoretical construct that the circadian regulation of sleep and the homeostatic regulation of sleep are two independent and isolated processes. The research will test homeostatic regulation in two groups of patients with normal circadian timing. One group is the "alert" insomniac who experiences optimal daytime alertness even when experiencing the effects of reduced and disturbed sleep at night. The other group is the patient with narcolepsy where, in the face of profound sleepiness, there is no evidence of appropriate associated changes in sleep parameters. It is hypothesized in both groups that deprivation and satiation procedures will yield results which are the opposite of normal. In the upcoming award period, there will also be the further development of a comprehensive multidisciplinary basic sleep research program.
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0.958 |
1991 — 1992 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sundown Syndrome in a Skilled Nursing Facility
Nocturnal agitation is a major management problem in Alzheimer's Disease and other dementias. This descriptive study will use systematic, intensive, 24-hour behavioral observations and measurements of illumination and body temperature to investigate a physiological basis for such sundowning in demented patients in a skilled care nursing facility. Our overall hypothesis is that sundowning is physiologically based in decrements in the circadian timing systems of aged, demented patients. Agitation will be defined through use of a well-developed, highly reliable rating scale used by research assistants 96 times per day to determine both verbal and physical components of agitation. Sundowning will be defined operationally as occurring when over 50% of a given patient's agitated behavior observations occur between sunset and sunrise. Observations will be made continuously 24-hours a day over 3 weeks for a total of 1440 observations per patient. Patients will be studied under conditions of both relatively high illumination (summer) and relatively low illumination (winter) with order counterbalanced to control for terminal decline. On the bases of these observations we will: 1) determine the prevalence of sundowning; 2) fully describe the temporal pattern of agitated behavior over the 24 hour day; 3) study apparent seasonal variation in agitation in dementia (more agitation under lower illumination); 4) determine whether some demented patients may become more agitated by bright light exposure. Pilot data to date suggest high statistical power (>.90) for projected sample size. These results will map directly into non-pharmacological, behaviorally based treatments for sundowning in dementia.
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0.958 |
1992 — 1994 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuropharmacology of Human Narcolepsy
Human narcolepsy is a disabling disorder of sleep and wakefulness that affects 0.1% of the general population. The singular objective of this project is to dissect the neurochemical control of normal and pathological sleep processes using a pharmacological approach and to utilize this new knowledge in the development of new treatments for human narcolepsy. Understanding narcolepsy should not only help narcoleptic patients but also provide critical information on the neurochemical mechanisms that generate normal sleep, with possible applications that extend to other areas of sleep medicine. Research is greatly facilitated by the use of an animal model of the human disorder (autosomal recessive narcolepsy) which is independently funded for an additional two years. This project is a competitive renewal of an R01 grant that has been funded for three years. In the past funding period, we have demonstrated that cataplexy, a pathological model of REM sleep atonia, is mainly controlled by two neurochemical systems, the cholinergic and the noradrenergic systems. We have also identified a number of receptor subtypes that mediate these neurochemical effects: muscarinic M2, alpha-lb adrenergic, and D2/alpha-2 receptor subtypes. In the next period of funding, we will (1) further our identification of monoaminergic and cholinergic receptor subtypes involved in the control of cataplexy and REM sleep atonia. Coadministration studies of compounds acting on monoaminergic and cholinergic systems will also be performed to examine how these systems interact synergistically. (2) Assess the role of key non-cholinergic, non-monoaminergic systems by studying the effects of intracerebroventricular infusion of candidate peptides. (3) Characterize compound effects on sleep and wakefulness in narcoleptic canines using electroencephalographic (EEG) recording techniques. One compound from each pharmacological class that modified cataplexy in our previous studies will be explored. This will include studying the effects of these compounds on sleep-wake patterns, EEG spectral analysis, and alertness using a canine version of the Multiple Sleep Latency Test. (4) Determine the site of action of pharmacologically active compounds by local pharmacological injections and studies of immediate early gene expression. (5) Use antidepressant compounds that selectively block monoamine uptake to investigate the hypothesis that the effect of current treatments of narcoleptic patients is mediated via an activation of noradrenergic systems.
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0.958 |
1993 — 1996 |
Dement, William C |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Circadian and Homeostatic Determinants of Sleep in Aging
The Stanford University Sleep Disorders and Research Center has established a multi-disciplinary research program dedicated to understanding the phenomena and elucidating the basic mechanisms of age- related disorders of sleep, wakefulness and circadian timekeeping. Reduced day-time alertness, night-time sleep fragmentation, and early morning awakenings are common complaints of older people. Age-related sleep disorders also pose significant health and safety risks as well as diminish the quality of life in this expanding portion of the population. A well focused multi-disciplinary research effort toward elucidating the basic mechanisms of circadian timing and control, and the homeostatic regulation of sleep are essential to progress on the problems of age- related sleep disorders. We have an established team of specialists and collaborators in the fields of sleep and circadian neurobiology with sufficiently diverse expertise to advance our knowledge in the area and build on significant advances made in the last few years. The proposed work is divided into 6 different but inter-related scientific projects: Project C - The aging of Circadian and Homeostatic Processes Controlling Sleep, Project D - Sleep, Circadian Timekeeping, and Aging in the Tau Mutant Hamster, Project E - The Aging Circadian Clock In Vitro, Project F - Homeostatic Determinants of Sleep Maintenance in Aging, Project G - Zeitgeber Transduction and the Aged Circadian System. The objectives of each project are based on a unifying conceptual theme -- that diminished alertness in aging can be due to age-related deterioration of the clock, impaired function of the sleep homeostatic process, or both. this research theme is founded in our Opponent Process Model of sleep/wake regulation which we believe offers a new and valuable conceptual framework for investigations into the mechanisms of sleep/wake cycle regulation in aging. The growing realization of the enormous personal and societal consequences resulting directly or indirectly from age- related sleep disorders mandate a concerted multi-disciplinary effort.
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0.958 |
2001 — 2002 |
Dement, William C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Determinants of Compensatory Sleep Phenotype in Mice
Increased NonREM sleep time, sleep episode duration, and EEG delta power reflect normal compensatory sleep responses (CSR) to extended wakefulness and constitute a central tenet of sleep physiology- that sleep is homeostatically regulated. In rats, catecholamine releasing stimulants (e.g., methamphetamine) also potently induce CSR. Wakefulness induced by selective dopamine reuptake blockers (e.g., GBR12909), however, produces no CSR, suggesting dopamine transporter involvement in sleep homeostatic mechanisms. To further investigate this possibility we will first confirm that these phenomena generalize to mice. We will then investigate stimulant interactions with sleep homeostasis in mice with null mutations of the dopamine transporter allele and in Cast/Ei mice. Our preliminary data show that Cast/Ei mice have less sleep time and attenuated compensatory sleep responses to sleep deprivation and methamphetamine-induced wakefulness relative to C57BL/6 mice. Using high throughput automated sleep scoring technology, we will investigate the involvement of the dopamine transporter in sleep homeostasis, and will begin to identify the genetic underpinnings of sleep regulatory variation between C57BL/6 and Cast/Ei mice. Four interrelated specific aims will test the hypotheses that: (1) mice (C57BL/6J) exhibit compensatory sleep responses to behavioral SD or methamphetamine-induced wakefulness, but do not exhibit compensatory sleep responses to wakefulness induced by the selective dopamine reuptake blocker GBR12909 or adenosine receptor antagonists, akin to that observed in laboratory rats; (2) the cell membrane dopamine transporter is necessary for the wakefulness-promoting effects of GBR12909, methamphetamine, caffeine and cyclopentyltheophylline.; (3) the cell membrane dopamine transporter is a functional constituent of sleep homeostasis and is therefore necessary for compensatory sleep responses to sleep deprivation (SD). We will also test the hypothesis that (4) three sleep phenotypes that differ between C57BL/6 mice and Cast/Ei mice - i.) total sleep time, ii.) compensatory sleep response to behavioral SD, and iii.) compensatory sleep response to wakefulness induced by methamphetamine treatment-- are not regulated by distinct genetic loci. Finally, we propose a set of pilot studies that will test if the cell membrane serotonin transporter is necessary for compensatory sleep responses to sleep deprivation and wakefulness induced by methamphetamine. The proposed research will advance our understanding of dopaminergic stimulant interactions with sleep homeostasis, CSR mechanisms, and genetic determinants of phenotypic variation in sleep homeostasis.
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0.958 |
2001 |
Dement, William C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurochemical Basis of Sleep Homeostasis
DESCRIPTION (adapted from applicant's abstract): Compensatory sleep responses (CSR) following extended prior waking constitute a central tenet of sleep physiology-- that sleep is "homeostatically" regulated. NonREM sleep time, sleep episode duration, and EEG delta power normally increase proportional to prior wake duration. Waking from stimulants (methamphetamine and methylphenidate) also induce CSR. However, waking induced by pemoline or selective dopamine reuptake blockers (DARBs) produces no CSR, suggesting that dopamine-induced wakefulness can uncouple the sleep homeostatic mechanism. The cholinergic neurons in the nucleus basalis (NBM) and adjacent basal forebrain regions that diffusely project to the cerebral cortex have been extensively characterized in promotion of wakefulness. Because the NBM receives dopaminergic input directly from the ventral tegmental area (VTA), wakefulness produced by DARBs is likely to be mediated directly in this region. Given the hypothetical role of adenosine as an endogenous sleep factor, it is possible that adenosine levels in this region may interact with dopaminergic influences on the NBM. The research proposed investigates dopaminergic interaction with sleep homeostasis in terms of its generality, involvement of the basal forebrain, DA receptor subtypes involved, interaction with sleep deprivation, and interaction with adenosinergic mechanisms that also modulate sleep-wakefulness. Six interrelated specific aims will examine the role of DA in sleep homeostasis using computerized sleep recording, microinjection, and in vivo dialysis techniques in rats. The experiments will test the hypotheses that: 1.) Wakefulness induced by selective increase in DA neurotransmission is uncoupled from the sleep homeostatic process; 2.) Direct VTA dopaminergic projections to the NBM mediate DA waking without subsequent compensatory sleep; 3.) Specific DA receptor subtypes mediate the ability of DARBs to promote waking without subsequent compensatory hypersomnolence; 4.) DA-induced basal forebrain waking counteracts compensatory sleep drive following sleep deprivation; 5.) Elevated adenosine levels mediate hypersomnolence following sleep deprivation or waking induced by classic psychomotor stimulants (methamphetamine, methylphenidate); 6.) Adenosinergic agonists in the NBM can restore CSR after pemoline or DARB-induced wakefulness. Excessive sleepiness undermines the health and quality of life in millions of people including the elderly, sleep apnea sufferers, narcoleptics, and shift-workers. Sleep regulation is also highly disturbed in patients with abnormal DA production, such as in Parkinson's Disease. The proposed studies will advance our basic understanding of central mechanisms underlying compensatory sleep, with the hope that this basic knowledge will lead to better long-term treatments for excessive sleepiness.
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0.958 |
2002 — 2005 |
Dement, William C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Apples: Apnea Positive Pressure Long-Term Efficacy Study
DESCRIPTION (provided by applicant): Nasal continuous positive airway pressure (CPAP) therapy is in widespread use as the primary treatment for the obstructive sleep apnea syndrome (OSAS), a sleep-related breathing disorder affecting more than 15 million Americans. The therapeutic effectiveness of CPAP in providing significant, stable, and long-term neurocognitive or other functional benefits to patients with OSAS has not been systematically investigated. The revised proposed study is a randomized, blinded, sham-controlled, multi-center trial of CPAP therapy. The principal aims of the study are: 1) to assess the long-term effectiveness of CPAP therapy on neurocognitive function, mood, sleepiness, and quality of life by administering tests of these indices to subjects randomly assigned to active or sham CPAP; 2) to identify specific neurocognitive deficits associated with OSAS in a large, heterogeneous subject population; 3) to determine which deficits in neurocognitive function in OSAS subjects are reversible and most sensitive to the effects of CPAP; 4) to develop a composite multivariate outcome measure from the results of this study that can be used to assess the clinical effectiveness of CPAP in improving neurocognitive function, mood, sleepiness, and quality of life; and 5) to use functional magnetic resonance imaging to compare cortical activation before and after CPAP therapy, and to assess whether this change is associated with improvement in specific neurocognitive task performance. The primary endpoint of this proposed study is the effect of 6 months of CPAP treatment on neurocognitive function. A total of 1050 subjects (525 per treatment group) will be enrolled from the patient populations at five sites (Stanford; U of Arizona; Harvard; St. Luke's Hospital, MO; St. Mary's Hospital, WA). This study will advance our knowledge of the major, most debilitating, clinically relevant OSAS-associated conditions, and, by scientifically establishing the effectiveness of CPAP therapy, should greatly improve access for the countless victims now denied treatment.
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0.958 |