Phyllis C. Zee, MD, PhD - US grants

DESCRIPTION (Adapted from the Applicant's Abstract) The goal of this application is to integrate teaching about sleep and sleep medicine into mainstream undergraduate medical school education, graduate house staff training, and relevant subspecialty training. The diagnosis and management of sleep disorders is conceived as a common and essential primary care skill and is emphasized. An interdisciplinary approach to medical student and resident teaching will be used. First and second year teaching will be expanded to six didactic lectures; conventional as well as interactive electronic problem-based learning sessions will be used. Computer-assisted case studies will be created. Third year medicine and primary care clerks will receive core lectures in sleep disorders for the first time. Extensive teaching about sleep in the required neurology clerkship will be continued. A fourth year elective in sleep medicine will be developed. At the graduate level, medicine residents will receive regular core teaching in sleep medicine and will have the opportunity to rotate in the sleep clinic. Sleep medicine topics will be added to their weekly case conferences. Family practice and pediatrics residents will receive core teaching. Rehabilitation medicine residents will receive teaching in the form of core lectures. Sleep-related training of pulmonary and geriatrics fellows will be integrated with a sleep fellowship training program. Connections between basic and clinical researchers have been established. Existing links to community programs and organizations, and to media resources, will be used to enhance community awareness. Through the Illinois Academy of Family Medicine, a day long course in sleep medicine for primary care physicians will be developed.

It is estimated that approximately 50% of Americans over the age of 65 have sleep disturbances. Sleep disruption and nocturnal wandering is the second most common problem which precipitates nursing home institutionalization, and with the aging of the American population, it is expected that the number of elderly who require nursing home care will increase dramatically over the next decade. Our long term goal is to understand the basis of and develop effective therapies for chronic sleep disturbances in older adults. Research in both humans and animals has suggested that age-related changes in the endogenous circadian pacemaker, combined with reduced exposure to light during the day, contribute to disruptions of sleep/wake rhythms in the elderly. Timed exposure to bright light can improve sleep efficiency and daytime performance in older adults. However, recent results in animal models of aging suggest that the effectiveness of light therapy for the treatment of sleep disorders may be limited by reduced responsiveness of the aging clock to light. In addition, animal studies indicate that the reduction in responsiveness to light by the aging pacemaker may be due to impaired regulation of calcium homeostasis. Treatments that decrease intracellular calcium levels, such as the calcium channel antagonist nimodipine, have been shown to exhibit neuroprotective effects, improve neural plasticity and reverse aging-associated declines in motor and cognitive performance. Recent results indicate that calcium channel antagonists can also increase the responsiveness of the clock to light, since nimodipine increases the magnitude of phase shifts of circadian activity rhythms following exposure to light in both young and old mice. The goal of this proposal is to test the hypothesis that nimodipine will increase responsiveness of the human circadian system to light. This will be tested by assessing the effect of nimodipine on light-induced suppression of nocturnal melatonin levels. The results from this pilot study will provide the basis for a comprehensive study to determine whether nimodipine can enhance the effectiveness of light therapy for the treatment of sleep/wake disorders in the elderly.

Our long term goal is to understand the basis of and develop effective therapies for chronic sleep disturbances in older adults. Age-related changes in the endogenous circadian pacemaker, combined with reduced exposure to light during the day, may contribute to disruptions of sleep/wake rhythms in the elderly. Timed exposure to bright light can improve sleep efficiency and daytime performance in older adults. However, recent results in animal models of aging suggest that the effectiveness of light therapy for the treatment of sleep disorders may be limited by reduced responsiveness of the aging clock to light. While the circadian timing system of old rodents shows reductions in responsiveness to light, it is not known whether the human clock exhibits similar changes with age. The hypothesis is that the responsiveness to light is decreased in the elderly will be tested by assessing the light-induced suppression of nocturnal melatonin levels and phase shifts of the circadian temperature and melatonin rhythms in young and old subjects. In addition, animal studies indicate that the reduction of responsiveness to light by the aging pacemaker may be due to impaired regulation of calcium homeostasis. Treatments that decrease intracellular calcium levels, such as the calcium channel antagonist nimodipine, have been shown to exhibit neuroprotective effects, improve neural plasticity and reverse aging-associated declines in motor and cognitive performance. Preliminary results indicate that calcium channel antagonists can also restore the responsiveness of the clock to light, since nimodipine increases the magnitude of phase shifts of circadian activity rhythms following exposure to light in old mice. Therefore, the results from this study, in combination with results from ongoing studies in rodents, will suggest whether nimodipine might also enhance the effectiveness of light on phase shifts of circadian rhythms in older adults. These studies will advance the long term goal of this project, which is to determine whether nimodipine can enhance the effectiveness of light therapy for the treatment of sleep/wake disorders in the elderly.

This Mentored Medical Student Clinical Research Program is being submitted on behalf of Mr. Samir Bangalore, an outstanding third year medical student at Northwestern University Medical School who is interested in pursuing a career in biomedical research. The proposed clinical and research training program for Mr. Bangalore will provide interdisciplinary training in the areas of aging, sleep and circadian rhythms research and sleep medicine. The mentors in this training program have a long and productive history of collaboration in research and educational projects in the areas of gerontology, neurobiology, genetics, cognition/behavior and circadian rhythms. Mr. Bangalore will be exposed to an excellent training environment with activities that are integrated across disciplines. As the director Sleep Disorders Center and principal investigator of GCRC based studies, I will serve as Mr. Bangalore's lead mentor, Dr. Fred W. Turek and Dr. Susan Benloucif will serve as co-mentors in this training program. Dr. Turek is a world renowned leader in the field of circadian biology and sleep. Dr. Benloucif has extensive experience in linking basic research in sleep and circadian rhythms to clinical applications. She is involved in several of the General Clinical Research Center (GCRC) based projects and will provide supervision for Mr. Banaglore's research study. The proposed training program is designed to provide Mr. Bangalore with a strong knowledge base of the essential elements of biomedical research and to stimulate his interest in clinical research. The core training curriculum will have three major components: 1) direct participation in a GCRC based clinical study, 2) didactic teaching in the form of courses in biostatistics and epidemiology and seminars, and 3) additional involvement in other clinical research studies in the areas of aging, sleep and circadian rhythms.

DESCRIPTION (provided by applicant): Tremendous progress in the past few years has led to the identification of several circadian clock genes. This now makes it possible to determine how alterations of human circadian clock genes, and their expression, could lead to differences in circadian and sleep/wake cycle phenotypes. Of particular interest for understanding genetics of the human circadian system are individuals with sleep phase disorders, such as delayed sleep phase syndrome (DSPS) and advanced sleep phase syndrome (ASPS), because recent studies indicate a genetic basis for these disorders. While it is assumed that both ASPS and DSPS are disorders of circadian timing, little is known about how the circadian clock system, or its interaction with sleep processes, are affected in these individuals. Therefore, one of the overall objectives of the proposed studies is to determine the properties (e.g., phase, amplitude, and period) of circadian rhythms under entrained and constant routine conditions in familial ASPS or DSPS. A second objective is to test hypotheses that could explain the mechanisms (i.e., response to light, alterations in period) that underlie the phase disturbance in these conditions. Although it is commonly assumed that sleep per se is normal in the circadian sleep phase disorders, there is some evidence to suggest that the regulation of sleep homeostasis may be altered in DSPS. Therefore, a third specific aim of the proposed studies is to define the sleep-wake characteristics via EEG/polysomnography in DSPS and ASPS subjects during baseline sleep and recovery sleep following sleep deprivation in which the subjects are allowed to begin recovery sleep at a normal or an abnormal circadian time. The approach of studying familial DSPS and ASPS provides a unique opportunity to clearly define circadian and sleep phenotypes in individuals whose sleep/wake cycle is due to intrinsic biological changes and not merely a result of environmental influences and societal pressures. The results of these studies are expected to not only lead to new insights into the regulation of sleep and circadian rhythms in humans, but also to new therapeutic approaches for the treatment of sleep/wake cycle disorders.

nimodipine; human therapy evaluation; phototherapy; circadian rhythms; aging; sleep disorders; wakefulness; body temperature regulation; hormone regulation /control mechanism; melatonin; patient oriented research; human subject; clinical research;

DESCRIPTION (provided by investigator): With increase in life expectancy, there has also been a parallel increase in chronic co- morbidities that impair functional status and quality of life in older age. Converging lines of evidence link sleep quality and quantity with cardiovascular health. A considerable body of literature demonstrates that short sleep duration (<7 hours) is associated with increased levels of cardiovascular disease (CVD) risk factors including obesity, hypertension, and diabetes in population-based studies. Further, evidence suggests that poor health status also increases the prevalence of sleep disorders. This relationship may be particularly prominent in older adults, who often have the burden of both sleep disturbances and medical co-morbidities. The proposed study is uniquely able to examine these matters cross-sectionally (in older people), and prospectively -- in particular the relation of early adult CVD risk factor levels to sleep quality and sleep disorders in older age by examining a pre-assembled cohort of the Chicago Heart Association Study with CVD risk status characterized approximately 40 years ago. The specific aims are to: a) determine the relationship between CVD risk status, especially low risk (LR), at ages 25-44 with subsequent sleep quality, levels of daytime sleepiness, and sleep apnea in older age (65-79);b) assess whether change in risk factor status from ages 25-44 to older age relates to sleep quality, daytime sleepiness, sleep apnea, neuropsychological performance, and cardiovascular health status in older age, and c) explore relationships among current CVD risk factors, CVD, sleep quality, sleepiness, sleep apnea, daytime neuropsychological performance, and other variables in older age. Both objective and subjective measures of sleep are to be used in conjunction with measures of CVD risk (BMI, blood pressure, lipids, glucose, smoking, C-reactive protein), clinical and subclinical CVD (coronary artery calcium, ankle brachial index), obtained by the recently funded parent grant (R01 HL081141;Principal Investigator, Martha L. Daviglus). 1,380 participants, identified at baseline as LR for CVD or not LR for CVD, are to undergo subjective and objective sleep measures (questionnaires and actigraphy). A subset of 150 participants (50 LR who do not become high risk by older age, 50 LR who became high risk, and 50 high risk at baseline who remain so in older age) are to attend the laboratory for more detailed physiological studies of sleep. By leveraging resources of the parent grant, this ancillary study is uniquely positioned to study these multiple relationships among CVD risk at ages 25-44, sleep variables, and other traits in older age. Results of this study can have important implications theoretical and practical, e.g., for prevention and treatment of sleep disorders and CVD in later life. PUBLIC HEALTH RELEVANCE: Recent studies indicate a strong link between sleep and sleep disorders, such as sleep apnea with cardiovascular health. A considerable body of evidence clearly demonstrates that short sleep duration disrupts metabolic and cardiovascular function and has been associated with increased levels of cardiovascular risk factors, such as C-reactive protein, BMI, blood pressure, lipids, coronary artery calcium, ankle brachial index, glucose, and smoking. Therefore, an improved understanding of the relationship between sleep and cardiovascular health will lead to preventive approaches and treatment strategies to improve function, health, and overall quality of life in the growing population of older adults.

DESCRIPTION (provided by applicant): Sleep disturbances are common in the general population, and women are a population at particular risk. Recent studies indicate a link between short sleep duration and sleep disturbances with adverse health risks. Evidence from physiological and epidemiological studies demonstrate an association between short sleep duration and an increased risk of obesity, diabetes, hypertension, and mortality. In addition, specific sleep disorders, in particular sleep disordered breathing have been linked with cardiovascular and metabolic disorders. Despite the emerging evidence of the importance of sleep for health and data that sleep disturbances are common among pregnant women, there is a paucity of research on the potentially important link between sleep and maternal/ fetal outcomes, particularly metabolic and cardiovascular complications of pregnancy. Specifically, there is limited data on how insufficient sleep and sleep disorders may contribute to the development of gestational diabetes, gestational hypertension, and preeclampsia. We have identified a unique and timely opportunity to leverage the resources of the recently established Nulliparous Research Network of 10,000 pregnant women to address the relationship between sleep abnormalities (short sleep duration, poor sleep quality and common sleep disorders) and pregnancy outcomes. The overall hypothesis to be tested is that sleep disturbances are associated with an increase risk for cardiometabolic disorders during pregnancy. Specifically this application proposes to evaluate self-reported and objective sleep/wake characteristics in a large cohort of pregnant women from whom detailed cardiovascular and metabolic pregnancy outcomes will be measured from the first trimester to delivery. The specific aims are: 1) To systematically characterize sleep patterns using survey and actigraphy in a large cohort of pregnant women; 2) To determine the relationships between abnormal sleep patterns (sleep quality and sleep disorders) and cardiovascular and metabolic disorders of pregnancy (gestational hypertension, preeclampsia, gestational diabetes); 3) To determine concordance between self-reported measures of sleep and objectively derived sleep measures (using actigraphy) in a pregnant population. This application will provide the first large scale longitudinal assessment of sleep in a pregnant population and determine the relationship between sleep characteristics and disorders with pregnancy outcomes. The results of this study have the potential to inform and change clinical care to improve pregnancy outcomes. PUBLIC HEALTH RELEVANCE: Disturbed sleep is common among pregnant women and few studies have evaluated sleep in pregnancy or examined maternal and fetal outcomes in women with sleep disturbances. Given the link between sleep disturbances and metabolic and cardiovascular complications, of which pregnant women are at particular risk, there is a great need for such a study. The current application will seize the unique opportunity to leverage the resources of the recently established Nulliparous Research Network to study the relationship between sleep abnormalities and pregnancy outcomes; specifically this application proposes to evaluate self-reported and objective sleep/wake characteristics in a large cohort of pregnant women from whom detailed cardiovascular and metabolic pregnancy outcomes will be measured. This study will form the basis for future studies to determine whether screening for and treatment of sleep disturbances during pregnancy is an effective strategy to improve pregnancy outcomes.

Decreased amplitude and stability of rhythmic behaviors, including the prominent fragmentation of sleep are hallmarks of aging in humans. It is now established from both laboratory and field studies that disrupted circadian function represents a significant risk factor for cardiometabolic disease (CMD) in humans. The exciting evidence of the ubiquity of circadian clocks in all tissues, and their critical role in metabolism, not only opens up new avenues for exploring the mechanistic interactions between central and peripheral clocks in cardiometabolic aging, but also to develop therapeutic interventions to re-establish synchrony between central and peripheral clocks with each other and with the external physical and social environments. Feeding has been shown to synchronize clocks in peripheral tissues and animal studies have demonstrated that restricting feeding to the active period decreases CMD risk, while in humans decreased caloric intake in the evening is associated with a lower body mass index (BMI). The amplitude of melatonin (typically decreased with advancing age), can be considered a marker of robustness of central circadian function, but melatonin also has physiological effects beyond circadian regulation throughout the body. Recent observations have demonstrated low melatonin levels are a risk factor for incident diabetes and hypertension independent of sleep duration. Together, this data suggests that strategies aimed at synchronizing feeding behavior and enhancing the nocturnal melatonin signal can positively impact cardiometabolic function in older adults. We propose to take an innovative approach that combines the recent data on the role of feed/fast patterns on clock regulated metabolic activity and the reemergence of scientific interest of the central and peripheral effects of melatonin on cardiometabolic function to improve metabolic health in late middle to old age. The primary aim of this project is develop translatable circadian based interventions that enhance synchronization of central and peripheral rhythms, to ultimately improve cardiometabolic function and sleep quality in older adults. This project will enroll 100 older adults (55-75 years) to participate in a parallel (4 arm intervention) placebo controlled study to determine whether a 6 week program of extended overnight fasting (EOF) of 12-14 hours and/or low dose (3 mg) melatonin administration will enhance circadian amplitude and improve cardiometabolic function, as well as to evaluate the potential beneficial effects of a regimen that combines both treatments. The results from this study will demonstrate novel circadian based clinically applicable approaches for maintaining circadian-metabolic health in older age. In addition, the similarity of the baseline characteristics in Project 1 and Project 2, and the complementary physiological and molecular measures and analyses of clock genes and NAD+ regulatory pathways across all 3 projects will allow us to study the links between aging, circadian rhythms, sleep and metabolism that would not be possible without the program project grant as a whole.

The primary function of the Administrative Core (Core A) is to provide the overall coordination of logistical and financial components of the Program Project, as well as to serve as an administrative structure that initiates and facilitates harmonization between the three projects and their supporting Cores. To serve these two interrelated functions, Core A has the following objectives: 1. Facilitate the complex interdepartmental and inter-institutional coordination of the various aspects of research administration. Core A will serve as the central liaison with departmental, administrative, and institutional oversight offices of both participating universities. 2. Ensure appropriate fiscal management of the Program Project by maintaining the records and accounting for all expenditures, maintain personnel records, prepare all required narrative and fiscal reports to ensure transparency of expenditures, communicate changes in fiscal matters in a timely manner to the Project and Core PIs and their respective units as required. 3. Prepare the annual Progress Report and applications supplemental funding for the Program project when appropriate. 4. Organize the bimonthly meetings of the Project leaders, co-investigators and internal Steering Committee, monthly teleconferences and quarterly meetings of the study coordinators (projects and cores), the annual meetings of the External Review Committee, the visits of external consultants, and bimonthly seminars that will include other collaborators and trainees associated with the Program Project. 5. Coordinate recruitment efforts of the human participants for Projects 1 and 2. 6. Promote intellectual discourse among the Projects, and facilitate the interaction with other funded programs within and outside of our institutions in order to maximize the impact of the Program Project to the scientific community. Overall, Core A will ensure that the scientific output of the Program Project is greater than the sum of the contributions of the individual projects.

PROJECT SUMMARY There is a growing body of evidence from both laboratory and field studies that disrupted circadian function, particularly decreased amplitude and stability of rhythmic behaviors represent significant risk factors for cardiometabolic disease (CMD) in humans. The exciting evidence of the ubiquity of circadian clocks in all tissues and their critical role in metabolism, not only opens up new avenues for understanding the mechanistic interactions between central and peripheral clocks in cardiometabolic disease pathogenesis, but also to develop therapeutic interventions to re-establish synchrony between central and peripheral clocks with each other and with the external physical and social environments. Feeding has been shown to synchronize clocks in peripheral tissues. Animal studies have demonstrated that restricting feeding to the active period decreases CMD risk, while in humans decreased caloric intake in the evening is associated with a lower body mass index (BMI). The amplitude of melatonin can be considered a marker of robustness of central circadian function, but melatonin also has physiological effects beyond circadian regulation throughout the body. Recent observations have demonstrated that having a low melatonin level is a risk factor for incident diabetes and hypertension independent of sleep duration. Together, the evidence suggests that strategies aimed at synchronizing feeding behavior and enhancing the nocturnal melatonin signal can positively impact cardiometabolic function. We propose to take an innovative approach that combines the recent data on the role of feed/fast patterns on clock regulated metabolic activity and the reemergence of scientific interest of the central and peripheral effects of melatonin on cardiometabolic function to elucidate the physiological and molecular mechanisms that underlie the relationship between circadian dysregulation and obesity associated CMD risk. This will be accomplished by strengthening the amplitude of circadian metabolic signals via extended overnight fasting (EOF) and enhancement of nocturnal circadian signaling with exogenous melatonin in overweight and obese middle aged and older adults. In addition, this study will provide crucial information regarding the importance of circadian timing for the design of future clinical trials on CMD in overweight and obese adults. This is a critical time in the lifespan when circadian based strategies for prevention and treatment are most likely to have the greatest impact on CMD risk. This project will enroll 100 adults (40-65 years) to participate in a parallel (4 arm intervention) placebo controlled study to determine whether a six- week program of extended overnight fasting (EOF) of 12- 14 hours and/or low dose (3 mg) melatonin administration will enhance circadian amplitude and enhance cardiometabolic function, as well as to evaluate the potential beneficial effects of a regimen that combines both approaches. The results from this study will demonstrate novel mechanistically based approaches for maintaining and improving circadian-metabolic health during a critical time in the lifespan when there is a rapid increase in the prevalence of CMD.

Circadian organization of behavior and physiology is often challenged by individual choices, social/societal pressures and pathology, leading to circadian misalignment, sleep deficiency and ultimately, adverse health outcomes. Just in the past decade, advances in the scientific knowledge of circadian biology in animal model systems, as well as in humans, coupled with the evidence of circadian disruption with aging, indicate the transformative potential of circadian based strategies for maximizing healthy aging. In this Program Project application, we propose to seize this opportunity by capitalizing on our history of successful collaborations and collective and complementary expertise and experience, as well as in circadian biology, aging and clinical research to advance our understanding of the interaction between centrally regulated circadian rhythms, sleep and peripheral tissue clocks in cardiometabolic aging. Our mechanistic approach will be complemented by interventions that increase circadian synchrony to improve cardio-metabolic health in middle age and older adults. Our multi-disciplinary and multi-institutional (Northwestern and U of Chicago) approach combines novel translational, clinical (Projects 1 & 2) and basic (Project 3) studies and is uniquely poised to achieve the scientific aims of each of the three projects. Specifically, the Program will define the role and mechanisms of interplay between central and peripheral clocks in aging and dissect the contribution of age-related changes in the circadian clock system, as measured by amplitude and phase alignment, in cardiometabolic aging. Project #1 (Zee, PI) has as its primary aim to develop translatable circadian based interventions to enhance synchronization of central and peripheral rhythms through increased amplitude, and ultimately to improve cardio- metabolic function and sleep quality in older adults. Project #2 (Van Cauter and Knutson, PIs) focuses on the impact of dietary alignment of peripheral oscillators on cardio-metabolic risk, sleep quality and the overall synchronization of the circadian system. Project #3 (Bass and Turek, PIs) will use mouse models to test circadian phase-restricted feeding as a life- and health-span extending intervention and explore molecular, physiological, and behavioral mechanisms by which phase-restricted feeding may enhance circadian robustness, metabolic function, and sleep. These projects are thematically unified by the overall Program focus on the role of aging on central and peripheral clock interactions in the regulation of cardiometabolic function at the molecular, cellular and physiological levels, and the three projects will be supported by the innovative metabolic measures and analyses proposed in the Cores. In addition, the rich, molecular data and extensive and novel physiological/metabolic data (from mice and humans) will be used to explore common mechanistic hypotheses across the entire program in order to greatly enhance our understanding of the importance of chronobiology-sleep-metabolism concepts for successful aging.

Project Summary/Abstract This is a renewal application of an established NHLBI- sponsored T32, ?Training Grant in Circadian and Sleep Research?, to train predoctoral and postdoctoral students and fellows at Northwestern University. The integration of circadian biology and sleep research has been the cornerstone of this Training Program from its inception in 1998. Dr. Fred Turek will be one of the Program Directors of this T32 Program, which he has been for 20 years. Dr. Phyllis Zee will also be one of the two Program Directors (Multiple PI), in order to provide leadership for increasing clinical research training in Circadian Biology and Sleep Research for Fellows and residents at the Northwestern University Feinberg School of Medicine (FSM) who will become leading physician scientists as their careers develop. The T32 Program will involve 15 Primary Training Faculty who have their primary appointments in either basic science or clinical departments. The proposed Training Program will offer predoctoral and postdoctoral students interdisciplinary and multidisciplinary training in a wide range of scientific disciplines that are highly relevant to understanding the function, regulation and health implications of sleep and circadian rhythmicity. Central to this Program is the training of students in modern basic science, translational research as well as patient oriented research. Multiple research perspectives have fueled for more than 2 decades the productive interactions and cross-fertilization that have developed between the preceptors in this Program. As our nation is facing unprecedented epidemics of obesity, diabetes and their cardiovascular consequences, the Training Program proposed in the present application is uniquely positioned to train an interdisciplinary workforce of academic and industry investigators, as well as government decision makers, to address the roles of sleep disturbances and circadian dysfunction in these public health challenges. A key feature of our Training Program is the inclusion of 7 Collaborating Faculty with additional clinical, scientific and/or educational expertise that greatly enhances our training environment. Our Program will enable trainees to integrate cutting edge approaches and techniques in the areas of genetics, genomics, microbiomics, endocrinology, metabolism, pharmacology, neurobiology, pulmonology, cognitive neuroscience, gerontology, and gastroenterology into their training in sleep and circadian research. Because the preceptors are actively involved in research at the molecular, cellular, systems, behavioral, and epidemiological levels, trainees will be trained in a rich environment of research activities that are integrated to study of the basic mechanisms of sleep and circadian function at all levels of biological organization. We are requesting support from this T32 renewal for 4 predoctoral students and 4 postdoctoral fellows for each of the five years. We anticipate the training period will be 2-3 years for each student/fellow, although it may be less if a trainee obtains individual support through other funding sources. It should be noted that the NU graduate school will provide support for an additional 2 predoctoral students for each of the next 5 years of this Training Program.

PROJECT SUMMARY Narcolepsy is a serious and debilitating condition involving persistent and excessive sleepiness that affects 1 in 2000 Americans and 3 million people worldwide. Although wake-promoting pharmacotherapy can reduce sleepiness there is no cure and people with narcolepsy experience significantly poor health-related quality of life, particularly in the domains of mental and social health. New preliminary data reveals that current practices within the traditional health care system are not adequate for addressing the psychosocial needs of people with narcolepsy. Therefore, the overarching goal of this research is to test the effectiveness of a mindfulness-based intervention (MBI) for improving health-related quality of life as a complementary practice to standard care for narcolepsy. This project builds upon our preliminary work by conducting a feasibility trial to determine the optimal parameters for adapting and delivering MBI to people with narcolepsy. The specific aims are to: 1) Determine the feasibility and acceptability of MBI delivered using videoconferencing for the purpose of improving psychosocial functioning in people with narcolepsy and 2) Determine the feasibility of recruitment and assessment methods for delivering MBI using videoconferencing. We plan to carry out these aims in two phases. Phase I features the completion of the study protocol and training of MBI providers to work with narcolepsy patients. Phase II features a feasibility trial in which 60 adults with narcolepsy will be randomized to receive either a 4-week (short), 8-week (standard), or 12-week (extended) MBI. Each MBI will be similar in content, which includes mindfulness practices and group discussions with adaptations for working with narcolepsy symptoms. All MBIs will be delivered in small groups using a live videoconferencing platform to enhance accessibility. If the findings of this project support the feasibility of further testing, the next project would be aimed at enhancing rigor and reproducibility (e.g., designing appropriate control, refining outcome measures and eligibility criteria) in preparation for a large-scale pragmatic trial. We have a team armed with experience in mindfulness, sleep disorders, and treatment development, and a rich environment with the infrastructure and resources to carry out this project. The overall significance of this research is to develop a scalable mind-body intervention that addresses a major research gap on improving psychosocial functioning in people with narcolepsy.