us tossing and turning into a sleepless nation

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S . D E P A R T M E N T O F H E A L T H A N D H U M A N S E R V I C E S

a t i o n a l I n s t i t u t e s o f H e a l t h

a t i o n a l H e a r t , L u n g , a n d B l o o d I n s t i t u t e

National Center on Sleep Disorders Research

2003

NATIONAL

SLEEP DISORDERS

RESEARCH PLAN


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2003

NATIONAL

SLEEP DISORDERS

RESEARCH PLAN

U.S. DEPARTMENT OF HEALTH

AND HUMAN SERVICES

National Institutes of Health

National Heart, Lung, and Blood Institute

National Center on Sleep Disorders Research

Trans-NIH Sleep Research Coordinating Commit

NIH Publication No. 03-5209

July 2003


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FOREWORD iii

Much has changed since 1996. Stimulated in

significant part by the 1996 Plan, sleep research

funding by NIH has doubled. New research

and new knowledge have vastly expanded

the array of questions to be addressed, and

new technologies have yielded new toolsand mechanisms for a highly interdiscipli-

nary broad-based approach to sleep research.

It is in this context that revision of the 1996

National Sleep Disorders Research Plan was

deemed necessary. The 2003 Revision sum-

marizes the specific sleep research achieve-

ments since the 1996 Plan, identifies present

gaps in our knowledge and understanding,

and concludes with prioritized recommenda-

tions for future research. As with the 1996

Plan, the 2003 Plan is envisioned not as a

blueprint, but as a dynamic springboard for

the creativity of individual scientists, whose

insights and initiative underlie research

progress. We are confident that these

recommendations will contribute in sub-

stantial ways to advancing the frontiers of

biomedical knowledge related to sleep, enabl-

ing timely diagnosis and effective treatment,

and improving the health of our Nation

through community-based public health

education and intervention programs.

Elias Zerhouni, M.D.

Director, National Institutes of Health

FOREWORD

The National Center on Sleep Disorders

Research (NCSDR) was established

within the National Heart, Lung, and

Blood Institute (NHLBI) via a provision of the

National Institutes of Health (NIH) Revitalization

Act of 1993. The NCSDR was mandated to:

Conduct and support research, training,

health information dissemination, and

other activities with respect to a basic

understanding of sleep and sleep dis-

orders, including research on biological

and circadian rhythms, chronobiology,

and other sleep-related topics.

Coordinate NCSDR activities with similar

activities of other Federal agencies,including other components of the

NIH, and similar activities of other

public and nonprofit entities.

The legislation further provided for establish-

ment of a Sleep Disorders Research Advisory

Board and for development of a National

Sleep Disorders Research Plan. The Plan

called for strengthening existing sleep

research programs, creating new programsto address important research gaps and

opportunities, applying state-of-the-art

techniques and technologies to the study

of sleep, and developing strategies for

better understanding daytime sleepiness

and reducing its negative impact on society.


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PREFACE v

The 1996 National Sleep Disorders

Research Plan, developed under

the leadership of the NCSDR and

the Trans-NIH Sleep Research Coordinating

Committee (SRCC), has been an important

resource and stimulus for progressive expan-

sion of sleep-related programs within NHLBI

and NIH (see Appendix C). Indeed, since

1996 sleep-related initiatives totaling more

than $110 million have been funded, and

the total for all sleep-related research

grants within NIH has doubled.

To build on the achievements of the past

6 years and identify new opportunities for

progress, we embarked on a comprehensive

revision of the 1996 Plan, reviewing accom-

plishments, remaining knowledge gaps,

promising new scientific directions, and

unforeseen new challenges. A Task Force,

consisting of 14 basic science and clinical

research scientists representing a broad

interdisciplinary range of biomedical

expertise, was appointed to undertake

this task. Its members are:

David P. White, M.D., ChairThomas Balkin, Ph.D.

Gene Block, Ph.D.*

Daniel Buysse, M.D.

David F. Dinges, Ph.D.

David Gozal, M.D.

Steve Henriksen, Ph.D.

Hannah C. Kinney, M.D.

Carol A. Landis, D.NSc., R.N.*

Emmanuel Mignot, M.D., Ph.D.*

Judith A. Owens, M.D.

Jerry M. Siegel, Ph.D.

Esther Sternberg, M.D.

Debra E. Weese-Mayer, M.D.

*Member, 2002 Sleep Disorders Research Advisory Board

The 2003 Revised Sleep Disorders Research

Plan, submitted by this Task Force and

approved by the Sleep Disorders Research

Advisory Board (SDRAB), summarizes the

dramatic expansion in interdisciplinary

sleep-related research and resulting newknowledge achieved since the original 1996

Plan. The sleep research recommendations

should serve as a valuable stimulus and

guide to researchers in many disciplines

for prioritizing and planning future research

directions that will lead to expanding knowl-

edge of the interrelationships between sleep,

health maintenance, and disease prevention.

Claude Lenfant, M.D.

Director

National Heart, Lung, and Blood Institute

PREFACE


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INTRODUCTION vii

Sleep-related problems affect 50 to70 million Americans of all ages.Sleep-related problems have the same

clinical relevance in women as men, andsome sleep problems are more common inwomen. Important disparities in prevalence

and severity of individual sleep disorders havebeen identified in racial and ethnic minoritiesand underserved populations. Sleep problemsand disorders have major impacts on society,but have not received sufficient attention inclinical practice, in the education of healthcare providers and future biomedicalresearchers, or in public health educationand intervention programs.

The three broad categories of sleepproblems include:

Sleep Restriction: This results fromimposed or self-imposed lifestylesand work schedules. Many children,adolescents, and adults regularly failto get sufficient sleep to functioneffectively during waking hours.

Primary Sleep Disorders: More than70 types of sleep disorders chronicallyaffect people of all ages. Fifty percent ormore of patients remain undiagnosed

and therefore untreated. Secondary Sleep Disorders: People having

a chronic disease associated with pain orinfection, a neurological or psychiatricdisorder, or an alcohol or substanceabuse disorder often experience poor sleepquality and excessive daytime sleepiness.

The end result can be exacerbationof the primary medical condition andfurther impairment in health and safety,mood and behavior, and quality of life.

As part of the authorizing legislation estab-

lishing the National Center on Sleep DisordersResearch (NCSDR) within the National Heart,Lung, and Blood Institute, a Sleep DisordersResearch Advisory Board (SDRAB) was estab-lished to provide a primary source of adviceon matters related to planning, conduct,support, and evaluation of research in sleepand sleep disorders. The SDRAB consists of12 non-Federal members appointed by theDirector, NIH, 8 of whom are representativesof health and scientific disciplines related tosleep disorders and 4 of whom represent the

interests of individuals with a sleep disorder(see Appendix B). The Director, NCSDR,serves as Executive Secretary of the SDRAB.

The Trans-NIH Sleep Research CoordinatingCommittee (SRCC) was established in 1986by the Director of NIH for the purpose offacilitating interchange of information onsleep and sleep-related research. When theNCSDR was established in 1993, responsi-bility for the Trans-NIH SRCC was transferredto the NCSDR and its Director serves as Chair

of the Trans-NIH SRCC. The Trans-NIH SRCCin 1993 was comprised of only five NIHInstitute representatives, but membershiphas progressively increased in parallel withincreasing interdisciplinary scope of sleepresearch and especially since release of thefirst Sleep Disorders Research Plan in 1996.

INTRODUCTION


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viii 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Ten NIH Institutes/Centers are now membersof the Trans-NIH SRCC:

Heart, Lung, and Blood (NHLBI)Carl E. Hunt, M.D.; Michael Twery, Ph.D.

Aging (NIA)Andrew Monjan, Ph.D., M.P.H.

Arthritis, Musculoskeletal, and SkinDiseases (NIAMS)

Deborah Ader, Ph.D.Alcohol Abuse and Alcoholism (NIAAA)

Ellen Witt, Ph.D.Child Health and Human Development (NICHD)

Marian Willinger, Ph.D.Drug Abuse (NIDA)

Harold Gordon, Ph.D.Mental Health (NIMH)

Israel Lederhendler, Ph.D.Neurological Disorders and Stroke (NINDS)

Merrill M. Mitler, Ph.D.Nursing Research (NINR)

Mary Leveck, Ph.D., R.N.Complementary and AlternativeMedicine (NCCAM)

Nancy Pearson, Ph.D.

The Task Force appointed to revise the SleepDisorders Research Plan was assisted by the

NCSDR and the Trans-NIH SRCC. A draft ofthe updated plan was broadly circulated tosolicit comments from biomedical professionalsinvolved in sleep-related research and clinicalpractice, and from relevant professional andpublic organizations representing individualscientific disciplines and sleep disorders.

Many comments were received and werecarefully considered by the Task Force incompleting the 2003 National SleepDisorders Research Plan.

This Plan fully represents the deliberationsand recommendations of the Task Force,summarizes the dramatic advances inknowledge since 1996, and identifiescurrent gaps in our knowledge base. Therecommendations for future research willnot only guide prioritization of future sleepresearch within NIH and other Federal andnon-Federal entities, but should also behelpful in identifying opportunities fornew investigators from an ever-increasingdiversity of scientific and clinical disciplines.The recommendations regarding trainingof sleep research scientists, the educationof health care professionals, and community-based public education programs shouldalso stimulate much-needed progress inthese areas.

Carl E. Hunt, M.D.DirectorNational Center on Sleep Disorders ResearchNational Heart, Lung, and Blood InstituteNCSDR e-mail: [email protected] Web site: http://www.nhlbi.nih.gov/sleep


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EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

SECTION IBASIC SLEEP SCIENCE

Circadian Biology . . . . . . . . . . . . . . . . . . . . . . . . . .13

Sleep Neurobiology . . . . . . . . . . . . . . . . . . . . . . . . .16

Pharmacology and Pharmacogenetics ofSleep and Waking . . . . . . . . . . . . . . . . . . . . . . . . . .19

SECTION IIRESTRICTED SLEEP:

NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS

Sleep Deprivation in Adults . . . . . . . . . . . . . . . . . . .25

Sleep Deprivation in Children and Adolescents . . . . .28

SECTION IIIENABLING TECHNOLOGY

Analysis of Sleep-Wake States . . . . . . . . . . . . . . . . .33

Genetics and Proteomics: Phenotype Issuesand Methodological Approaches . . . . . . . . . . . . . . .35

Functional Neuroimaging of Sleep andWake States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38

Post Mortem Brain Analysis inSleep Disorder Patients . . . . . . . . . . . . . . . . . . . . . .41

SECTION IVSLEEP AND HEALTH

Normal Sleep, Sleep Restriction, andHealth Consequences . . . . . . . . . . . . . . . . . . . . . . .47

Sleep, Sex Differences, and Womens Health . . . . . .52

Racial and Ethnic Disparities . . . . . . . . . . . . . . . . . .57

Sleep and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . .60

Sleep and Safety . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Sleep in Medical Conditions . . . . . . . . . . . . . . . . . .67

SECTION VSLEEP DISORDERS

Immunomodulation, Neuroendocrinology,and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Sleep-Disordered Breathing . . . . . . . . . . . . . . . . . . .76

Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80

Narcolepsy and Other Hypersomnias . . . . . . . . . . . .84

Restless Legs Syndrome/Periodic LimbMovement Disorder . . . . . . . . . . . . . . . . . . . . . . . .87

Sleep in Other Neurological Disorders . . . . . . . . . . .90

Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92

Sleep in Psychiatric, Alcohol, andSubstance Use Disorders . . . . . . . . . . . . . . . . . . . . .95

SECTION VIPEDIATRICS

Sleep and Early Brain Development and Plasticity . .101

Adolescent Sleep . . . . . . . . . . . . . . . . . . . . . . . . .104

Sleep in Medical Disorders . . . . . . . . . . . . . . . . . . .106

Neuropsychiatric Disorders in Childhoodand Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109

SECTION VIIEDUCATION AND TRAINING

Scientific Training . . . . . . . . . . . . . . . . . . . . . . . . .113

Clinical Education and Training . . . . . . . . . . . . . . .115

Public and Patient Education . . . . . . . . . . . . . . . . .118

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121

APPENDICES

Appendix A: National Sleep Disorders ResearchPlan Revision Task Force . . . . . . . . . . . . . . . . . . . .127

Appendix B: National Sleep Disorders ResearchAdvisory Board . . . . . . . . . . . . . . . . . . . . . . . . . .129

Appendix C: NIH Sleep-Related Initiatives,1996 to 2002 . . . . . . . . . . . . . . . . . . . . . . . . . . . .133

CONTENTS

CONTENTS ix


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EXECUTIVE SUMMARY 1

PROCEDURE

The first National Sleep Disorders ResearchPlan was released by the National Institutes ofHealth (NIH) in 1996. Considerable scientificand clinical growth of the field has occurred

since then, necessitating a reassessment andupdate of research opportunities and recom-mendations. This 2003 revision of the NationalSleep Disorders Research Plan summarizesthe new knowledge acquired since the 1996Plan and provides an updated and expandedguide for scientific research on sleep andits disorders.

The sections selected for inclusion in thisrevised Plan provide a broad perspectiveon the field of sleep and sleep disorders,

and highlight the crosscutting and highlyinterdisciplinary evolution of this field.Each section provides:

A brief overview of the topic.

The major research accomplishmentssince release of the 1996 National SleepDisorders Research Plan.

The research recommendations for thefuture, including a listing of the two toprecommendations, in italics, followed by a

listing of any additional recommendations.

This executive summary presents the TaskForces highest recommendations for futureresearch.All the recommendations highlight-ed in this Executive Summary are considered

relatively equal in importance and are there-fore not listed in any prioritized order.

Several specifics of the overall process ofthe Task Force merit further comment. First,there was considerable discussion on how

to address pediatric sleep science, sincesome developmental processes are onlyencountered in infants and children, whileothers represent a continuum from infancyto old age. Reflecting this continuum, theadult and pediatric sections were combinedwhenever possible (e.g., insomnia, sleep, andbreathing). Separate sections focusing onlyon pediatric science were developed wherethere was no direct adult relevance.

Second, there was considerable discussion

of how sleep and its disorders relative towomens health should be addressed in thisdocument. It was decided to both createa specific section on sex differences andwomens health in sleep, to emphasizescientific content unique to women, andto include in other sections, wherever appro-priate, information as to how a particulardisorder or physiologic process might differ-entially affect women and men. In this way,there would be adequate emphasis of allthe diverse ways in which sleep concerns

impact on maintenance of health and pre-vention of disease in women. Similarly,there is a separate section in this revisedPlan devoted exclusively to racial and ethnicdisparities in sleep and health, and relevantcontent is also included in other sectionswherever appropriate.

EXECUTIVE SUMMARY


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2 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

PROGRESS SINCE THE 1996 NATIONALSLEEP DISORDERS RESEARCH PLAN

The years since release of the original NationalSleep Disorders Research Plan in 1996 have

been remarkably eventful not only in termsof progress in the sleep sciences but also interms of lifestyle and activities of daily lifethat impact on sleep habits and behaviors.America is increasingly becoming a 24-hourper day society with constantly escalatingexpectations for around-the-clock services,information, and entertainment. After theevents of September 11, 2001, we havealso become a much more vigilant society.All these lifestyle changes directly impactnot only the number of hours Americanssleep each day but also when during the24 hours that sleep occurs.

We are now beginning to understand theimpact of chronic sleep loss or sleeping atadverse circadian times on our ability tofunction optimally and on our physical andmental health. How sleep loss, sleep displace-ment (e.g., shift work, jet lag), and a widerange of sleep disorders affect ones abilityto maintain health and healthy functioning,

however, remains relatively poorly understood.Thus, despite the scientific progress madesince 1996 in both clinical and basic sciencerelated to sleep and its disorders, thereremains the challenge and the need to dis-cover the functions of sleep, to understandand develop better treatments for the manydisorders affecting sleep, and to explain thenature of human physiology during wake-fulness and the individual stages of sleep.Without progress in these areas, countlessmillions will continue to suffer the conse-

quences of dysfunction and abuse of thismost basic regulatory process. Progress inevery area cannot be included in this Execu-tive Summary, but the most important gainsin knowledge and understanding will be dis-cussed to provide a context for the researchrecommendations that follow.

Sleep Neurobiology: The discovery in 1998 to1999 of hypocretin/orexin and its role in thedevelopment of narcolepsy in animal modelsand in humans revolutionized our understand-ing of this debilitating disorder and promises

import ant advances in the diagnosis andtherapy of human narcolepsy. Discovery ofthe neuromodulatory role of hypocretin/orexinalso greatly improved our understanding ofthe basic neurobiologic processes that con-trol sleep and wakefulness. Anatomic areaspromoting sleep, such as the ventrolateralpreoptic (VLPO) area of the hypothalamus,have also been characterized. New anatomi-cal and physiological approaches have led toadvances in our understanding of the locationand interconnections between hypothalamicand brainstem circuits controlling rapid eyemovement (REM) sleep, non REM sleep, andwake states. Factors regulating the activity ofthese sleep-controlling neurons have beenidentified. Circuitry and neurotransmittermechanisms controlling muscle tone acrossthe sleep cycle, of relevance to numeroussleep pathologies, have also been identified.

Circadian Biology: A growing number ofclock genes have been identified since

1996 that play a critical role in mammaliancircadian timing. In addition, there is clearevidence that non-suprachiasmatic nucleus(SCN) tissues have clock genes and candemonstrate circadian rhythms. Thus,circadian modulation is now established tooccur both centrally and peripherally, furtheremphasizing the importance of circadianchronobiology in the timing of sleep andwaking as well as a wide variety of physio-logic functions. Now these genetic studiesare also being applied to humans, in particular

patients with advanced sleep phase syndrome.

Sleep-Disordered Breathing (SDB): The con-sequences of SDB (obstructive sleep apnea,sleep apnea) in both adults and childrenhave become increasingly clear over the lastfew years. In adults, the contribution of sleep


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EXECUTIVE SUMMARY 3

apnea to the development of systemichypertension is becoming more evident, anddata are accumulating that other adversecardiovascular outcomes (stroke, congestiveheart failure, myocardial infarction) may result

from this disorder. In children, there is increas-ing evidence that sleep apnea may contributeto behavioral problems as well as learningand cognitive deficits. Thus, the diagnosis andtreatment of this disorder is important from avariety of perspectives and across all ages.

Pediatrics: The recognition that having infantssleep supine (on their back) can substantiallyreduce the incidence of Sudden Infant DeathSyndrome (SIDS) is now appreciated as a pro-foundly important early infant interventionthat has saved thousands of lives. Recentresearch regarding the physiologic, psycho-logical, and developmental aspects of sleepin infants, children, and adolescents hascontributed to an increased understandingof the unique aspects of sleep and develop-ment. The study of pediatric disorders such asCongenital Central Hypoventilation Syndromeand Rett Syndrome has led to a better basicunderstanding of autonomic regulation andrespiratory control. Recent findings regarding

the complex relationship between sleep pat-terns and hormonal changes in adolescencehave broadened our understanding of puber-tal influences on sleep and circadian biology.The extent of sleep restriction and sleep dis-turbances among children and adolescentsis now recognized to be much greater thanpreviously believed, and the consequentimpact on mood, neurobehavioral andacademic functioning, safety, and healthis considerable. Recognition of the linkbetween sleep disturbances and neurobe-

havioral disorders in childhood, such asattention deficit hyperactivity disorder(ADHD), has profound public health impli-cations for both the treatment and pre-vention of psychiatric comorbidity.

Insomnia: The high prevalence, risk factors,and consequences of insomnia have been

increasingly recognized since 1996. Insomniahas been identified as a risk factor for theonset of subsequent depression, anxiety,and substance use disorders. In addition,the efficacy and durability of behavioral

therapies for insomnia have been demon-strated in controlled clinical trials.

Sleep Deprivation: Although previous studieshave demonstrated many of the ill effects oftotal sleep deprivation, the impact of chronicpartial sleep deprivation (restriction) had notbeen extensively investigated even thoughit is a much more common phenomenon.However, recent studies indicate that 4 to 6hours of sleep per night yields a progressive,cumulative deterioration in neurobehavioralfunction including vigilance, neurocognitiveperformance, and mood. This reduction inperformance is also associated with changesin cerebral activation during cognitive tasks.Physiologic changes (insulin resistance andincreased sympathetic activation) appear tooccur as well. Both the neurocognitive andphysiologic effects of chronic sleep losssuggest there is optimal sleep duration andthat there is a cost for failing to achieve it.However, the exact duration of sleep required

at different periods of life remains poorlyunderstood, as do the mechanisms drivingthese neural and metabolic processes.

Sleep Education: There is now broad recogni-tion of the curriculum inadequacies regardingsleep and its disorders within most medicalschools and residency training programs.A Sleep Academic Award Program wasestablished by NIH in 1996 to address theseeducational gaps, and this program has ledto the development of undergraduate and

postgraduate sleep curricula, educationaltools, and methods to enhance sleep knowl-edge. The awardees, working with nationalprofessional societies, have also begun toaddress sleep and fatigue in medical training.There have also been several public healtheducation initiatives, including an effort toestablish lifelong healthy sleep habits in


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school-age children begun in 2001 withGarfield, the Star Sleeper as thespokescatfor healthy sleep. A high school biology cur-riculum on sleep, sleep disorders, and biologi-cal rhythms has also been created, as have

programs to combat drowsy driving. Thus,a variety of educational activities haverecently been implemented that may havesubstantial impact on knowledge and publichealth behaviors.

We need to consolidate and extend theresearch progress made to date and totranslate new knowledge and discoveriesinto effective therapies and improved lifestylebehaviors for all Americans (as describedin the Department of Health and HumanServices Healthy People 2010 initiative).Sleep-related research must continue acrossthe full spectrum from basic science to clinicalinvestigation to community-based translationalprograms in order to apply what is known toimprove public health and quality of humanlife. The scientific areas most important inextending and translating the research gainsmade to date are summarized in the followingparagraphs. The order in which they are listeddoes not reflect any prioritization; indeed,

these individual recommendations are allimportant and of equivalent high priority.

RESEARCH RECOMMENDATIONS

An improved understanding of all aspects

of the neurobiology and functions of sleep

is needed. These aspects include:

The neurocircuitry whereby the previouslydescribed and yet-to-be-identified cellularsystems that modulate state are connected

to each other and to other neural systemsneeds to be characterized. In addition, theneuropharmacology and neuromodulatorsthat mediate neural signaling in sleep andwakefulness, and their hierarchy in thisprocess, need to be better understood.The genetic and proteomic mechanismsinvolved in the generation of sleep and

wakefulness also need elucidation. Finally,the phylogeny of sleep needs to be furtherinvestigated to help define the functionsof sleep.

The neurobiologic basis of the two-processsleep system (homeostatic and circadian)needs to be better characterized regardingthe anatomical, physiological, and function-al links between the two systems and thecontribution of each to altered sleep qualityand timing.

Further research is needed to better under-stand how developmental maturation fromthe fetus to the adult influences all of theneurobiologic processes described above.

This would include studies addressing howsleep itself influences neural developmentand how such development affects sleepat the neurobiologic level.

Investigation is needed of the neurobio-logical function of sleep as a whole andthe independent functions of NREM andREM sleep. Without some grasp of thefunctional role of sleep in the behaviorand survival of an organism, it remainsvery difficult to understand the develop-

ment, neurobiology, and importanceof sleep to physiologic function.

Enhance our understanding of the impact of

reduced or restricted sleep on behavior, and

neurobiologic and physiologic functions across

the age spectrum from childhood through

old age. Studies in this area should address:

The neurobiologic processes mediatingsleepiness, state instability, and decre-ments in specific aspects of neurocognitiveperformance and alertness: this includesidentification of brain structures, proteins,and genes that mediate the neural basisof sleepiness and the neurocognitive per-formance changes resulting from sleeploss. Also, the neurobiologic processesmediating the restoration of stablewakefulness, alertness, and perform-ance require further investigation.


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EXECUTIVE SUMMARY 5

A systematic delineation is needed of theprocesses involved in, the mechanismsunderlying, and the developmentalaspects of acute and chronic sleepdeprivation on non-neural systems.

These systems include endocrine,cardiovascular, immune, hematopoietic,renal, gastrointestinal and muscle.

The effects of sleep loss on behaviors thatdiminish the safety of both the individualand society in general need to be studied.This includes but is not limited to the trans-portation industry, the armed services, thespace industry, health care, law enforce-ment, and at-risk jobs in the construction,manufacturing, and service sectors.

Improve our understanding of the processes

that lead to specific sleep disorders in children

and adults. The following disorders are included

in this summary due to both their prevalence

and their impact on afflicted patients:

Insomnia, defined as difficulty initiating ormaintaining sleep: Studies should includethe development of animal models ofinsomnia, the study of specific insomniaphenotypes, and the application of neuro-

physiologic, neurochemical, neuroanatomic,and functional neuroimaging approachesto the study of insomnia in humans.Understanding why women are at higherrisk for insomnia should also be a goal.Finally, genetic, genomic, and proteomicstudies are also needed.

Restless Legs Syndrome (RLS) and PeriodicLimb Movement Disorder (PLMD): Studiesshould address the role of altered centraldopaminergic mechanisms and abnormal

iron metabolism in the pathogenesis ofthese conditions. Further development,refinement, and validation of animalmodels of RLS and PLMD are also needed.The use of neuropathologic techniquesin the evaluation of brains and spinalcords of affected patients is also likelyto be useful.

Sleep-Disordered Breathing (SDB),including sleep apnea and disorders ofventilatory control: Studies should addressthe processes that control both upper air-way patency and ventilation itself with a

particular focus on the influence of sleepon these biologic processes. The neuralconnections, neuromodulators, andmolecular events mediating these state-dependent processes affecting respirationduring sleep need to be studied.

Primary disorders leading to hypersom-nolence: The neural mechanisms leadingto hypersomnolence in conditions suchas narcolepsy or primary central nervoussystem hypersomnolence need to be

investigated. The focus of these studiesshould be how the neurobiologic causes ofhypersomnolence differ from or resemblethe effects of sleep loss.

An assessment of normal human sleep

phenotypes and the normal range of vari-

ation in this phenotype in adults and children

(including racial and ethnic differences) is need-

ed, not only to establish normative standards

but also to serve as a model for recommended

sleep behaviors. This assessment should include

sleep duration, sleep stage distribution, sleeptiming, sleep disruption, sleep quality, and

other variables by which sleep and sleepi-

ness can be quantitatively evaluated.

Once normal sleep phenotypes are de-fined, the associated genotypes shouldbe fully evaluated.

Abnormal sleep phenotypes should subse-quently be recognizable, and genotypingof these individuals should then be pursued

to define the genetic underpinning ofabnormal sleep or altered circadian rhythmprofiles. The impact of single nucleotidepolymorphisms (SNPs) on normal sleepphenotypes should be testable as well.


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The phenotype of patients with specificsleep disorders should be carefully definedin order to set the stage for subsequentgenetic testing.

Methods to define normal and abnormalphenotypes through questionnaires orsimple non-invasive testing should be agoal. Population surveillance and assess-ment of associated morbidities will thenbe possible on a large scale.

New treatments for sleep disorders are needed.

Adapting these therapies to individual patients,

using pharmacogenetic and other approaches,

is an important research priority. The outcomes

of such treatments, including complementary

and alternative medicine (CAM) therapies,need to be assessed at all levels including

adherence, effectiveness, morbidity, quality of

life, health care costs, safety, and performance/

productivity. Such studies will likely require

carefully designed and appropriately powered

clinical trials in order to yield evidence-based

guidelines for improved management and

treatment of sleep disorders and hence

substantial public health benefit:

Sleep-Disordered Breathing (SDB)Adult

and Pediatric: Continuous positive airwaypressure (CPAP) devices have improvedsubstantially and remain an effective formof therapy for adult SDB. However, theyare cumbersome and have achieved onlymoderate acceptance by patients. Otherapproaches, such as oral appliances andupper airway surgery, have relatively limitedsuccess rates for more than mild to moder-ate SDB. Therefore, current forms oftherapy need to be improved, and noveltherapies need to be developed. In children,

the indications for surgical interventionneed to be better defined. In addition,new surgical and nonsurgical treatmentsfor SDB in children are also needed, includ-ing those that address major risk factorssuch as overweight and obesity.

Insomnia: Although the efficacy anddurability of behavioral therapies havebeen demonstrated for primary insomnia,long-term trials evaluating the efficacyand safety of hypnotic medications

have not been conducted and are ahigh priority. The development of novelpharmacologic and nonpharmacologictherapies, as well as complementary andalternative medicine therapies, for insomniaof all types (including insomnia in high-riskpopulations) remains a priority as well.Finally, the effectiveness of behavioral,psychological, and popular mind-bodyapproaches and treatments should beevaluated in routine care settings.

Narcolepsy: The neurobiology of narco-lepsy is now better understood, and therole of hypocretin is well recognized.Exciting possibilities for new researchworthy of exploration include therapiesinvolving hypocretin peptide supplemen-tation, the development of hypocretinreceptor agonists, cell transplantation,and gene therapy.

Restless Legs Syndrome (RLS): Withouta better understanding of the etiology,

pathogenesis, and neurophysiology ofRLS, treatment strategies are limitedand not effective in all patients. RLSand Periodic Limb Movement Disorder(PLMD) can have profound negativeimpacts on quality of life includingdaytime functioning, work performance,and social and family life. Therefore,methods to determine the extent ofnocturnal sleep disturbance and day-time sleepiness both in children andadults with RLS can potentially enhance

opportunities to develop novel andeffective treatments.


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EXECUTIVE SUMMARY 7

Further investigation is needed into the

relationship between the processes of sleep

and the development and progression of

diseases of both neural and non-neural tissues.

How sleep and its disorders contribute to the

development of disease processes and altertheir natural history is minimally understood.

Conversely, the impact of various diseases on

sleep should also be studied. The interaction

between sleep and a variety of disease pro-

cesses therefore needs to be studied at the

epidemiologic, behavioral, physiologic and

basic neurobiologic levels. Examples of these

potential interactions include:

Medical Conditions: Many medical dis-orders can impair sleep quality and can,

in turn, be adversely affected by poorsleep. Common examples include conges-tive heart failure, pain, and obstructivelung disease. Congestive heart failure, forexample, can lead to a cycling respiratorypattern resulting in sleep fragmentationand decrements in both quality of life andperformance. The recurrent arousal fromsleep secondary to the intermittent hypoxiaassociated with this respiratory pattern canpotentially lead to a progression of heartfailure and hence to reduced survival.

Neurological Disorders: Neurological condi-tions such as neurodegenerative disorders(Alzheimers disease, Parkinsons disease),head trauma, encephalitis, stroke, andepilepsy are associated with insomnia,somnolence, motor activity during sleep,and/or breathing abnormalities duringsleep. Studies should evaluate whethersleep disorders predispose to specificneurological conditions, whether neuro-logical conditions can produce sleep dis-

orders, and whether sleep disorders impairrecovery for selected neurological disorders.

Psychiatric, Alcohol and Substance UseDisorders: The complex relationships andcausal pathways linking insomnia and sleepdeprivation to these disorders requirefurther investigation. The impact of sleep

disturbances on treatment outcomes andrecurrence risk is also significant. Specificexamples include the risk for subsequentdepression among individuals with insom-nia, the importance of sleep and dreamdisturbances in the development of post-traumatic stress disorder, and the role ofinsomnia and sleep deprivation in increas-ing risk for relapse to alcoholism anddrug addiction.

Pediatric Genetic and Neurodevelopmental

Disorders: Several genetic and neurodevel-opmental disorders have associated sleepand/or SDB abnormalities. These includeboth rare syndromes and more frequentconditions such as Attention DeficitHyperactivity Disorder (ADHD). Specificareas for further investigation include:(1) understanding the pathophysiologyof autonomic nervous system (ANS) dys-regulation in order to better understandmaturation of the ANS and the abnormali-ties that occur in SDB; (2) investigatingthe anatomical contributions of theupper airway to the obstruction foundin children with craniofacial malformationin order to better understand etiology ofthe more common causes of SDB; and(3) understanding how genetic disordersproduce primary insomnia, daytime som-nolence, or movement disorders duringsleep. Rare genetic disorders associatedwith sleep abnormalities provide uniquemodels that may facilitate exploration of

novel pathophysiologic mechanisms andthe discovery of new sleep-related genesthat may be relevant to other, morecommon sleep disorders.


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The education of health care providers and

the public about the role of healthy sleep

habits as an important lifestyle behavior

and about sleep disorders is important.

Current evidence suggests minimal learning

opportunities at all levels (undergraduate,postgraduate, and continuing education).

The development and implementation

of sleep educational programs needs to

encompass all relevant health profession-

als, including physicians, nurses, dentists,

pharmacists, nutritionists, psychologists

and other mental health practitioners).

Furthermore, since many individuals

use dietary supplements and other natural

products as sleep aids, research findings

regarding the effectiveness and safety

of such products should be widely dis-

seminated to health care providers and

the public. In addition, a rigorous evalu-

ation of the impact of these educational

programs is needed to assess their

efficacy in changing:

Professional knowledge, attitudes,skills and behavior

Clinical practice

Patient and health care providershealth and quality of life

Public education programs about healthysleep and sleep disorders should continuewith an emphasis on culturally, ethnicallyand racially appropriate materials. Theseefforts should include school-based pro-grams for both elementary and highschool students as well as adult educa-tional programs. An assessment of theimpact of these programs on knowledge,

attitudes, and sleep practices of childrenand adults should be a component ofthis process.

Recent scientific advances have led to the

development of new technologies and

methodologies, but these new approaches

have not been systematically applied to the

sleep sciences. In addition, new methods and

approaches not currently available are neededin the sleep field to answer scientific ques-

tions and to better diagnose and manage

patients. Prominent examples include:

Mechanisms needed to study the neuro-biology of a variety of sleep disorders,possibly including the development ofrelevant human brain banks. Examplesinclude SDB and RLS/PLMD, sleepdisorders in which little is knownneuropathologically.

Animal models of normal sleep as wellas individual sleep disorders would behighly useful in understanding not onlynormal sleep physiology, but also thepathogenesis of a variety of disordersand their behavioral and physiologicconsequences.

Functional neuroimaging techniques(e.g., PET, fMRI, MRS, MEG, NIR, SPECT)are increasingly available to study sleep,

sleep deprivation, and sleep disorders,thereby providing insights into thepatterns of regional brain activity thatcharacterize both normal and abnormalsleep/wake states. Application of thesetechniques to the study of sleep andsleepiness should be continued andexpanded as further improvementsand refinements become available.

Sleep monitoring in rodents, althoughcurrently utilized in a few laboratories,

needs to be standardized and then mademore broadly available so that mouse/ratsleep phenotypes can be easily definedin genetically altered animals.


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EXECUTIVE SUMMARY 9

New methods to measure and quantifythe structure of sleep in humans aregreatly needed. Such methods shouldbe outcome focused, such that whatis measured predicts not only the res-

torative processes of sleep but also theconsequences of disrupting this process.Methods to relatively easily definecircadian phase are also needed.

Effective new measures and methodsto quantify sleep and other relevantphysiological signals (such as respiration)in the home are greatly needed tofacilitate both large epidemiologic investi-gations and the broader evaluation ofpatients with potential sleep disorders.

Quantifiable, noninvasive, relatively rapidmethods to measure sleepiness in childrenand adults are greatly needed to scientifical-ly understand its causes and consequences,and to predict performance such that thesafety of the individual and society canbe protected.

Informatics can be directly applied toclinical, neurophysiologic, imaging, andgenetic questions as they apply to sleep

and its disorders, but are not currentlywidely utilized in this field. Thus. the useof these methods should be expanded.

Women, from adolescence to post menopause,

are underrepresented in studies of sleep and

its disorders. Enhanced efforts are needed to

better understand the neurophysiology of

sleep and the neuropathology of sleep disor-

ders in women. These efforts should include:

Basic and clinical studies to establishhow sex-related differences in sleepand its regulation influence the risk for,and mechanisms of, sleep disorders.

Longitudinal studies in women includ-ing both subjective and objective sleepindicators before and during menarche,in women of childbearing age includ-ing pregnancy and the postpartum

period, and in women during themenopausal transition.

Studies of how sleep disturbance inpregnancy affects fetal development

and health both acutely and postnatally. Racial and ethnic minorities have significant

health disparities. Improved data are needed

to develop and implement effective prevention,

intervention, treatment, and other sleep-related

programs and services for racial and ethnic

minorities. Elimination of disparities in sleep

disorder outcomes should address not only

social and environmental factors, such as

education and access to health care, but also

relevant gene-environment interactions.

Relevant studies should include:

Identifying the neurophysiologicaland neuroanatomical correlates andgene-environment interactions contri-buting to racial and ethnic disparitiesin prevalence and severity of individualsleep disorders.

Developing effective strategies toreach racial and ethnic minorities inpublic health education programsfor sleep-related conditions.

RESEARCH TRAINING

Although clinical activities and opportunitiesin the sleep field are expanding, a larger andmore interdisciplinary scientific work force isneeded if we are to fully address the scientificquestions discussed above. Attracting newbasic and clinical investigators to this fieldrepresents a major challenge for the field ifwe are to meet the expanding research

needs and opportunities. Some of thepotential barriers include:

The perceived difficulty of definingsleep phenotypes in mice/rats, therebymaking molecular and genetic studiesmore difficult.


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The perceived difficulty of studying astate in very reduced preparationsor cell lines.

The challenges posed to clinical research

by the need for objective measurementof sleep-wake physiology and behavior,using cumbersome and expensivetechnology, and the need to control awide range of factors, limit effectivemeasurement of sleep-wake processesin naturalistic environments.

Sleep science does not have Divisionor Departmental status at most medicalcenters. As a consequence, designatedspace, faculty positions, access to

graduate students, and potential forcollaboration are all limited.

Novel strategies to increase the numberand scope of sleep investigators need tobe identified and implemented. There is anacute need for additional dedicated SleepMedicine training programs and for investi-gators in other training programs (e.g.,neurobiology, genetics, aging, pulmonology,neurology, psychiatry, pediatrics, and neu-ropathology) to train sleep scientists. Sleep is

a highly interdisciplinary field, and successfulsleep centers therefore require scientific andclinical expertise from multiple disciplines,with a sufficient critical mass of investigatorsfocused on sleep in order to achieve scientificprogress. The association between basic sleepinvestigators and clinical scientists at thesesleep centers also promotes translationalresearch that can yield results more immedi-ately applicable to patient care and publichealth interventions. Due to a lack of acritical mass of sleep investigators at most

medical centers, this goal may demand amore regional or national approach than isneeded for most other disciplines. This mayalso require an iterative process by whichintegrated, multidisciplinary sleep centersare carefully developed with substantialtraining programs and the increasing dis-persal of well-trained program graduates

can then contribute to development ofnew sleep centers.

In addition to attracting new investigatorsto the sleep field, there is a need to expand

the number of trained scientists from otherrelevant disciplines electing to focus onsleep-related research. These disciplinesinclude informatics, epidemiology andgenetic epidemiology, clinical trials, functionalimaging, genetics, and molecular biology.Without collaborators demonstrating thesespecific skills, sleep science will not be ableto utilize currently available technologiesand methodologies and hence will havediminished potential for progress. Ongoingtraining and expanded collaborative oppor-tunities are needed, as is a comprehensiveplan to attract, train and retain new scien-tists, and to continue expanding the skillsof current investigators.

CONCLUSION

Considerable progress has been madesince release of the original National SleepDisorders Research Plan in 1996. Resourcesexpended by the National Institutes of Health

(NIH) to study sleep and its disorders havesteadily increased (see Appendix C). Newscientific techniques that facilitate researchdiscovery are being applied to sleep questions,and have led to an improved understanding ofnormal sleep physiology and the pathogenesisof a variety of sleep disorders. As a result, bothaccess to care for patients with sleep disordersand the quality of care are substantially better.However, many research questions remainunanswered, and new questions need tobe addressed; therapy for a number of sleepdisorders remains suboptimal; and the researchworkforce addressing sleep science is inade-quate. This Revised National Sleep DisordersResearch Plan presents a comprehensivesummary of focused research, training, andeducation recommendations that addressesthese opportunities and needs.


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SECTION I

BASIC SLEEP SCIENCE

Circadian Biology

Sleep Neurobiology

Pharmacology and Pharmacogeneticsof Sleep and Waking


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SECTION IBASIC SLEEP SCIENCE 13

BACKGROUND

Circadian oscillators are critically involvedin the regulation of the sleep/wakefulnesscycles, although the relationship is complexand not fully understood. It is generally

recognized that the sleep/wakefulnessrhythm is not driven directly by the circadianclock, but rather emerges from an interac-tion of the circadian clock located within thesuprachiasmatic nucleus (SCN), and a distinctsleep-wake homeostatic process (e.g., thesleep homeostat) in which the drive orneed for sleep depends upon the prioramount of wakefulness and sleep. Sleepdisorders may arise from dysfunction atseveral levels within these two timing systems.Alterations in the circadian pacemaker within

the SCN, changes in the sleep homeostat, andalterations in the coupling between the twotiming systems may each be causal in sleepdisturbances. A complete understanding ofhe origins of normal and abnormal sleep willrequire a detailed understanding of both thecircadian and sleep/wakefulness systems.

PROGRESS IN THE LAST 5 YEARS

Identification of the first mammalian

clock genes. Within the past 5 years,eight clock genes have been identifiedthat play a critical role in mammalian cir-cadian timing. A recent study indicatesthat alterations in the hPer2 gene areassociated with advanced sleep phasesyndrome. In addition, mutations of

the murine clock gene affect both sleepduration and the response to sleep loss,indicating that some genes may beinvolved in both the timing andpressure to sleep.

Confirmation of the multi-oscillatory,

distributed nature of the mammaliantiming system: Dynamic measurementsof molecular rhythms from several clockgenes reveal that many organs and non-SCN regions of the brain express circadianrhythms, although not as robust as therhythm generated by the SCN. Theseobservations raise issues about the roleof non-SCN rhythm generators in thecontrol of the sleep/wakefulness cycleand the development of sleep disorders.

Discovery of temporal complexity withinthe SCN. Recent experiments revealregional specialization in the capacityto express circadian rhythms. It is evidentthat not all SCN neurons enjoy the samephase relationship to one another.Molecular rhythms of the right and leftSCN appear out of phase in behaviorallysplit animals, and phase differences amongSCN neurons may be responsible for en-coding day-length information.

Discovery that circadian photoreceptionis functionally and anatomically separatefrom vision and that this nonvisual systemmay affect many physiological and behav-ioral systems. These findings are importantbecause sleep/wake rhythms are regulated

CIRCADIAN BIOLOGY


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by photoreception via the SCN, and thesleep/wakefulness cycle can influencephotoreception (e.g., eye closure duringsleep). These photoreceptors may belinked directly to sleep centers in the

brain, since there are retinal afferents ofunknown functions that project directlyto these centers.

Discovery of new neurotransmittersystems and anatomical areas of thebrain, especially the hypothalamus, andin particular discovery of the orexins/hypocretins in the regulation of rapideye movement (REM) sleep. These ana-tomical and neurochemical targets arelinked to the SCN and provide new

avenues for studying the interactionsof the circadian clock and sleep-wakingtiming systems.

Discovery that chronic partial sleep lossfor as little as 1 week can lead to meta-bolic and endocrine changes that areprecursors for specific disease states(e.g., obesity and diabetes) and are alsorelevant to aging. Decreased total sleeptime is often associated with circadiandysfunction either on a voluntary basis

(e.g., shift work) or involuntary basis(e.g., aging), making it imperative todetermine the importance of circadianfactors that lead to decreased sleep andthe health consequences associated withchronic sleep loss.

Discovery that the rest phase of the rest-activity cycle of the fruit fly shares manybehavioral and pharmacological featuresassociated with sleep. This should allowthis model organism to be used to

further explore the molecular and geneticbasis of sleep and the adverse effects ofsleep deprivation.


Recognition of the importance of theneurobiological basis of the two-process

sleep system and these two separate tim-

ing processes controlling sleep rhythmicitywill continue to provide an importantconceptual framework for the dissectionof altered sleep regulation. The anatomical,

physiological, and functional links betweenthe two systems are virtually unknown.The search for the neurobiological basis ofthese two processes and their interaction

should remain at the center of basicresearch in this area. A more completecharacterization of the contribution ofthese two processes to altered sleeptiming and quality, particularly in relationto development and aging, is important.

The circadian physiology of sleep disordersand the pathophysiology of certain disor-ders of the timing of sleep remain to befully characterized and understood at afundamental level. Circadian desynchronyis considered to be at the core of certaindisorders that involve both insomnia and

sleepiness (e.g., delayed sleep phase syn-drome; shift work sleep disorder). Giventhe number of people affected by thesedisorders and the behavioral debilitation,it is important to determine whether anyof the key circadian parameters (e.g., free-running period [tau], phase-response curve[PRC], light sensitivity, internal couplingbetween sleep and other circadian-mediated physiology, etc.) are altered inthese disorders. It will also be importantto search for linkages between circadianrhythms and sleep disorders not normally

associated with circadian timing (e.g.,Restless Legs Syndrome).


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The availability of clock gene mutations inmammals will allow study of the effectsof alterations of the circadian pacemakeron the sleep/wakefulness rhythm. In addi-tion, these genes may have effects on

sleep that are independent of the SCN.It will be important to determine howthese genes act to regulate sleep, inde-pendent of the central pacemaker, andto assess the effects of circadian period,phase, and amplitude on the sleep/wake-fulness rhythm.

Although the free-running period (tau)of the human circadian rhythm may notchange during aging, animal studiessuggest an impact on other circadian

parameters (e.g., amplitude). It will beimportant to explore the effects of agingon central and peripheral circadian gene-rators and how age-related changes incircadian function affect sleep.

How circadian dysregulation and sleeploss interact to affect health is an impor-tant but poorly understood topic. Thisissue is of particular importance to theaged and to disadvantaged populations.Multiple jobs and unusual work cycles

can lead to circadian disruption. It willalso be important to understand thelong-term effects of chronic sleep lossin adolescents. Good model systemsand more sophisticated long-term datacollection will be essential.

Development of a methodology fornon-invasive in vivo measurement ofhuman circadian phase is needed. Thismay require the identification of newmarkers and/or the development of

novel detection systems.

Quantitative modeling of a mammaliancircadian clock is needed. The molecularprocesses and interactions that appearto generate rhythmicity will need to bedescribed in a mathematically rigorous

fashion. The central clock mechanism hasgrown in complexity with an attendant lossof conceptual clarity. Modeling may allowfor a better focus on critical processes.

Although it is clear that there are significantsleep problems associated with adjustmentto shift work and transmeridian flight, ourunderstanding about entrainment kineticsis very limited. In particular, little is knownabout entrainment kinetics in older individu-als who have more difficulty in maintaining

stably entrained biological rhythms. Recentresearch indicating that different circadianrhythm generators within the brain andother organs reset with different kineticssuggests that the physiology of internaland external synchronization is important.Molecular and neurophysiological toolsare now available in several animal modelsystems to address these problems.

Animal research indicates that circadianphotoreception enjoys distinct photore-

ceptors within the retina and specializedneural pathways. A full functional andmolecular characterization of this systemin humans is required.


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SLEEP NEUROBIOLOGY


Molecular biological approaches havecontributed to understanding sleepcontrol mechanisms. These approacheshave led to one of the greatest achieve-

ments of sleep research since the discoveryof REM sleep; the identification of thehypocretin (orexin) system and its centralrole in narcolepsy and behavioral control.

Genetic expression studies of sleep indrosophila (fruit flies) have producedimportant discoveries about the geneticbasis of sleep. Moreover, they have estab-lished this species, with its well-documentedand readily manipulated genome as a validmodel of sleep genetics, making furtherrapid progress likely. Studies of murinemutants have progressed along the samelines. A better understanding of the popu-lations of genes activated by sleep, waking,and sleep deprivation, and the time courseof this activation has been made possibleby the application of recent developmentsin simultaneous assessment of the activityof large numbers of genes.

Studies using polymer-encapsulatedsuprachiasmatic nuclei (SCN) and relatedstudies of diffusible factors released by theSCN have identified some of the majormediators of circadian-sleep relations.

Less progress has been made in elucidating,at a molecular level, the phenomenon ofsleep debt. The functional and biochemicalregulation of changes in sleep time, REM

BACKGROUND

Sleep time is defended by an accumulationof sleep debtthe need for more sleepthat results from sleep restriction. Recentstudy findings in animals and humans

suggest that a complete and sustained lossof sleep can result in death. It is likely thatan understanding of the effects of sleep losswill reveal basic principles of brain functionrelevant to a broad spectrum of neurologicaland behavioral disorders. Sleep is knownto strongly affect the activity of mostbrain neurons.

Modern sleep neurobiology research has notyet achieved consensus as to the function ofsleep. What determines the brains memory

for sleep loss? What is the neurological defi-ciency being regulated by the sleep debtmemory? Does rapid eye movement (REM)sleep have different functions than non-REM(NREM) sleep?

Functional significance of the marked dif-ferences in the amount of sleep within theanimal kingdom is unknown. Similarly, theconsiderable variation in the duration of thesleep cycle (Wake-NREM-REM) in differentspecies of mammals from a high of 2 hours

to as little as 15 minutes is poorly understood,as are the determinants and health signifi-cance of the variations of sleep durationwithin the human population.


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and NREM amounts, and sleep morphology(e.g., delta power, eye movement intensity)with development remains mysterious,although some progress has been madein characterizing the neurophysiology and

neurochemistry of sleep changes acrossthe lifespan.

Progress has been made in the electro-physiology of sleep at the neuronal level.The mechanisms responsible for generat-ing and synchronizing rhythmic neuronalactivity in NREM sleep have been localizedto thalamic regions, and the ionic currentsmediating rhythmic discharge have beenidentified. Cell groups in the hypothalamusand basal forebrain critical in the control of

NREM and REM sleep have been identifiedwith anatomical and electrophysiologicaltechniques. Some recent evidence suggeststhat localized brain mechanisms may medi-ate sleep debt.

Important roles of amino acid andmonoamine mechanisms in regulatingmuscle tone at the motor-neuronal levelacross the sleep cycle have been demon-strated. The circuitry controlling neuro-transmitter release has been clarified.

These advances are important in under-standing numerous sleep disorders,including Sleep-Disordered Breathing(SDB), cataplexy, REM sleep behaviordisorder (RBD), and other parasomnias.

The neurochemical phenotypes of majorgroups of neurons contributing to REMand NREM sleep regulation have beenidentified. Previously appreciated mono-aminergic (serotonin, norepinephrine,epinephrine, dopamine, histamine)

mechanisms have been shown to inter-act with amino acid (glutamate, GABA,glycine) neurotransmitter systems at fore-brain and brainstem levels. Anatomicalconnections between the neurons criticalto REM and NREM sleep have been traced.Hypocretin/orexin has been identified asan important modulator of activity in

sleep-control systems. Other peptidesimportant in the control of sleep stateshave been described and localizedto brainstem and forebrain sleepcontrol regions.

Limited progress has been made inunderstanding the phylogeny of sleep.REM sleep has been found in primitivemammals. Some birds may show inter-hemispheric asymmetry during sleepbased on electroencephalogram (EEG)recordings. Unihemispheric sleep andunihemispheric sleep debt have beenfound in marine mammals.


Determine the function of sleep as awhole and of the differential roles ofREM and NREM sleep. It will be helpfulto study genetic mutant murine andinvertebrate models with unusual sleep

properties. A resource that can be betterutilized is the variation in sleep time andquality in the animal kingdom. As the costof sequencing continues to be reduced,it becomes practical to sequence the

genomes of diverse species to determinethe genetic basis of these differences.

Advances in technology have made itpractical to better record and character-ize the great differences in sleep durationand quality between species. Recent workdemonstrates that sleep is present uni-hemispherically in some mammals. In otheranimals, REM sleep appears to occur with-out the low-voltage activity seen in mostmammals. In still other mammals, blood

pressure, heart rate, respiratory changes,

eye movements, erections, and other phe-nomena characteristic of human sleep donot occur. These variations in mammalianand in nonmammalian species, particularlyif understood in an ecological context andat the cellular level, can provide a majorinsight into the functions of sleep.


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Bridge the gap between what is nowknown about the anatomy and neuro-chemistry of sleep, wake and wakingarousal-generating systems, and thenature of the information processing

that occurs at the synapses within thesesystems. Identification of the functionalrole played by each neurochemical linkand the analysis of neurotransmitterinteractions would, for example, facili-tate the development of drugs to controlmuscle tone over the sleep-wake cycle.

The pathophysiology and neurochemistryof sleep disorders needs to be better under-stood. How abnormal operation of sleepregulatory systems results in sleep disorders

needs to be clarified. The anatomical andpathophysiologic causes of RBD, SDB,periodic limb movements during sleep,and parasomnias are poorly understood.Although major advances have occurredin our understanding of narcolepsy (seeSection V), further work is needed toclarify the cause of narcolepsy withoutcataplexy, and how disorders of thehypocretin/orexin system and othersystems produce the multiple symptomsof narcolepsy. Studies in this area repre-sent a great opportunity for clarifyingbasic issues of sleep control andsleep pathology.

An understanding of sleep debt at thebiochemical and genetic level is needed,building on the new knowledge of sleepcontrol at the neuronal level. The bio-chemical and genetic substrates of

waking and arousal during wakingand of REM sleep and NREM sleepdebt need to be understood.

Interactions between sleep states andthermoregulatory, metabolic, cardio-vascular, and respiratory regulationat all levels of the neuroaxis need tobe better described and understood.The roles of sex, sex hormones, sexualmaturity, pregnancy, and lactation insleep control need to be investigated

at a mechanistic level.


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BACKGROUND

The use of sedative/hypnotic and psycho-stimulant drugs to treat medical conditionssuch as Attention Deficit HyperactivityDisorder (ADHD), insomnia, heart disease,

narcolepsy, Restless Legs Syndrome (RLS),and other medical disorders (see Section V)can result in profound effects on normalsleep/wake architecture and perceived sleepquality. In addition, over-the-counter andherbal remedy markets exist to cater tothe need to either stay awake or to fallasleep. The two most common substancesemployed in this capacity are caffeineand ethanol.

Self-medication can lead to dose-related

impairments in sleep/wake architecture andin other physiological parameters that in-directly impair sleep/wake quality. The useand misuse of other prescription and recre-ational drugsincluding psychostimulants(methamphetamine, cocaine), sedative/hypnotics (barbiturates, benzodiazepines),opiates (heroin, oxycodone), androgenicsteroids, and so-called club drugs (e.g.,MDMA)can be accompanied by adversephysiological consequences, including sig-nificant alterations in circadian rhythms

and sleep/wake architecture.

In addition to these drug-induced effectson normal sleep/wake rhythms, individualdifferences (including important gender andage factors) in the pharmacological responseto drugs are also important. In addition togender and age effects, these differences

also result from genetic differences inpharmacodynamic effects and drugmetabolism. However, a wide gap stillexists in understanding the potential rolethese diverse factors play in sleep/wakepharmacology. Future insights into the

pharmacology of arousal states mustinclude greater focus on pharmacogenetic-based studies, both in humans and inappropriate animal models of sleep/wakeand circadian rhythm disorders.


The original 1996 Sleep Disorders ResearchPlan provided no explicit recommendationsregarding the specific investigation of thepharmacology and pharmacogenetics ofsleep and arousal. Implicit in the recom-mendations, however, was an appreciationof the impact and scope that drugs haveon normal sleep/wake processes. Conversely,both primary and secondary sleep disorderphenotypes can be triggers for prescriptionand nonprescription drug use that may, as aside effect, exacerbate disturbances in sleep.Building on existing knowledge regardingthe effects of a wide spectrum of drugs onsleep and waking behavior, the 1996 Plan

has resulted in important, incrementalprogress in several relevant areas.

The increase in the number of investigator-initiated applications and responses toNIH-sponsored initiatives has led to fundedresearch bearing directly on pharmacologicperturbations of the sleep/wake cycle.

PHARMACOLOGY AND PHARMACOGENETICSOF SLEEP AND WAKING


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Relevant areas of research have included:(1) efficacy of caffeine on sleep inertiaand cognitive performance, (2) pharma-cotherapy for sleep/wake disorders inaging, (3) rational pharmacotherapy

of primary insomnia, (4) treatment ofhypnotic dependence, and (5) the effectsof hormone replacement therapy onsleep measures in postmenopausalwomen. Results from these and otherstudies have led to a better understand-ing of drug efficacy in several medicalconditions as well as the extent of indi-vidual differences in drug effects onsleep/wake measures.

We now have a better understanding

of the effects of prenatal and postnatalcigarette smoke exposure in Sudden InfantDeath Syndrome (SIDS) (see Section VI),the effects of opioids on rapid eye move-ment (REM) sleep suppression, the effectsof leptin on ventilatory and respiratorycontrol, and the effects of psychopharma-cological therapy on sleep in the majormental disorders. Furthermore, therehave been important advances in ourunderstanding of the effects of the majordrug classes on sleep disorders in animalmodels and the brain circuits where thesedrugs are believed to act.

Preclinical neuroscience research hasprovided new insights into the complexcircuitry, neurotransmitters, and neuromod-ulatory substances involved in sleep/wakeregulation and their interaction with braincircuits involved in circadian rhythm control.Findings from research in fruit flies, animals,and humans have added considerably toour knowledge of the complex regulation

of behavioral state. Because of these find-ings, greater opportunity exists to betterunderstand the actions of drugs on thebrain, and also to investigate novel classesof drugs that have nontraditional mecha-nisms of action on receptor systems withinthese newly refined brain circuits.

Research has delineated the molecularbasis of narcolepsy and circadian rhythmdisorders (see Section V). Genes responsiblefor these disorders have been positionallycloned and found to code for specific

proteins, some of which are receptors forother small molecules that could be targetsfor chemically synthesized drugs. Thesemight be effective for sleep/wake pharma-cology. Indeed, the clinical utility of drugssuch as modafinil and gammahydroxybu-tyrate (GHB) for narcolepsy, and selectivedopamine receptor agonists for treatmentof RLS, has been demonstrated. In addition,while short-term pharmacologic treatmentfor insomnia has been demonstrated to beefficacious, most Insomnia is chronic, notshort-term. No carefully conducted studieshave examined the longer-term pharma-cologic treatment of insomnia, includingissues such as efficacy, safety, or therelative advantages of different agents.

Genome screening and single nucleotidepolymorphism (SNP) analysis have beeninitiated in Sleep-Disordered Breathing(SDB), RLS, Alzheimers disease, and fatalfamilial insomnia (see Section V). Thesediseases have major sleep/wake disruptionsand are potentially subject to new formsof pharmacotherapy. Individual differencesin the response to such treatments mayrelate to genetic differences.

New knowledge has been achievedregarding the pharmacotherapy ofinsomnia in alcoholics, the physiologicalcorrelates of chronic alcohol ingestion inboth basic and clinical studies, and theinteractions between adolescent sleep,life-style and alcohol use. In addition,

sleep and the effects of alcohol inalcohol-dependent subjects are nowbetter understood, although more workneeds to be done. Alcohol has beenshown to alter circadian clock functionwhen exposure takes place in the earlypostnatal period in rat pups. Studieson selectively bred mice and rats have


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demonstrated both ethanol-related meta-bolic variations as well as wide variationsin ethanol-induced narcosis, indicatingstrong genetic regulation of ethanolpharmacology. Ethanol appears to have

sensitive, pharmacological actions primarilyon brain NMDA (N-methyl-D-aspartate)and GABA (gamma-aminobutyric acid)receptor subtypes, offering the possibilityof novel pharmacotherapy. In human stud-ies, virtually every type of sleep problemhas been observed in alcohol-dependentpatients. Their sleep patterns are fragment-ed and typical encephalographic (EEG)rhythms are altered. Sleep changes persistfor months or even years of abstinence,and alterations in sleep architecture appearto be predictive of relapse to alcoholism.Other studies indicate that alcohol aggra-vates SDB and further increases the decre-ments in cognitive performance resultingfrom sleep deprivation. Both gender andethnic differences in the response toethanol and other abused drugs havebeen studied, but additional research isneeded. Future studies should includestudies of sleep/wake measures duringdrug withdrawal and during relapse to

drug taking. Morphine and similar opioid drugs cause

selective decreases in REM sleep throughactions on brainstem cholinergic neurons,neurons known to participate in theinitiation of this sleep state. This mayhave relevance for the treatment of painas well as for understanding treatmentefficacy of opioids in RLS.

Sleep effects of therapeutic psychostimu-lant treatment in ADHD in both adolescents

and adults have received some attention,but results are so far inconsistent. Also,gender differences have not been ade-quately studied. Particularly in adults,underlying sleep/wake abnormalitieshave been reported in ADHD patientsthat can be exacerbated with medication,particularly dextroamphetamine.


Consolidate the recent gains made in thedescriptive anatomy and neurochemistryof sleep/wake generating systems by

investigating the hierarchies of neuro-transmitter interactions within these com-

plex circuits. These studies would facilitatethe development of drugs to treat sleepand waking disorders and also lead to abetter understanding of the neuropharma-cology of behavioral states.

Encourage studies of the relative efficacy,safety, and long-term effects of psycho-stimulants (e.g., methylphenidate, d-amphetamine, modafinil, and caffeine),

and hypnotics (particularly benzodiazepinereceptor agonists and antidepressants)related to sleep/wake measures in animalmodels and humans, including appropriate

patient populations. These pharmacologicalassessments should also be assessed withregard to potential interactions and efficacyof behavioral and hormonal therapies.

In both basic and clinical populations,study interindividual, gender, racial/ethnic,and age-related differences in baseline

sleep, circadian physiology, and responsesto both prescription and nonprescriptionpharmacological agents.

Investigate acute and long-term sleep/wake consequences of all classes ofabused drugs (including ethanol) asunique, self-administered pharmacologi-cal agents. Both clinical and basic studiesare needed.

Encourage pharmacological studies

of genetically/molecularly engineeredanimal models for sleep disorders. Exist-ing genome databases can be used toelucidate sleep/wake-related responseto drug effects and to facilitate thediscovery of new targets for sleep/wakedisorder medications.


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Encourage development of state-of-theart technologies to measure the effects ofdrugs on sleep, circadian physiology, andalertness in animal models and humansubjects (e.g., genomics, expression

arrays, proteomics, neurochemical,chemical, imaging, encephalographicanalysis, etc.).

Evaluate whether the identificationand treatment of sleep disturbances canimprove the clinical course of patientswith alcoholism and other substanceuse disorders.


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SECTION II

RESTRICTED SLEEP:

NEUROBIOBEHAVIORAL AND

PHYSIOLOGICAL EFFECTS

Sleep Deprivation in Adults

Sleep Deprivation in Children and Adolescents


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SECTION IIRESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 25

BACKGROUND

Studies on the effects of sleep loss onneurobehavioral functions, especially neu-rocognitive performance, have two primaryemphases: (1) specification of the properties

of tasks (e.g., cognitive versus physical; longversus short duration) that make them sensi-tive to sleep loss; and (2) specification of theaspects of performance (e.g., cognitive pro-cessing speed versus accuracy, declarativeversus implicit memory processes) that areimpacted by sleep loss. There has been con-troversy regarding the likely nature of sleeploss-induced performance deficits (e.g.,whether they reflect true deficits in physio-logical function of the brain, a motivationaleffect reflecting reprioritization of the rein-

forcement hierarchy, an initiation of sleeponset mechanisms in the face of wakingperformance, or some combination of theseprocesses). This controversy remains unre-solved due to lack of understanding of thefunction(s) of sleep, the physiological pro-cesses affecting recuperation during sleep,and the neurobiology of sleepiness.

Implicit in this research has been the assump-tion that total and partial sleep deprivationproduce qualitatively similar decrements in

brain function and/or motivation levels thatdiffer only in degree. As a result, the over-whelming majority of studies in which therelationship between sleep and performancehas been explored have utilized the more effi-cient total sleep deprivation procedures, andvery few studies have examined the effectsof chronic sleep restriction. Furthermore, of

these few studies only a very small subsethave included adequate and objectiveverification of compliance with the sleeprestriction regimen being studied.

Nevertheless, partial sleep deprivation is

more pervasive than total sleep deprivation.Epidemiological studies suggest that meansleep duration has decreased substantially asproportionally more people are awake moreof the time. These decreases are due, in part,to expanded possibilities for nighttime activi-ties that accompanied the introduction ofelectric light and other technologies and tothe more recent trend toward expansion ofboth manufacturing and service sectors to24-hour-per-day operations. Sleep restrictionappears to be an almost inevitable conse-

quence of nighttime shift work.

Because of the scarcity of chronic sleeprestriction experiments despite a wealth oftotal sleep deprivation/performance studies,theoretical and practical questions remain:

What are the physiological processesmediating neurobehavioral performancedeficits resulting from sleep loss?

What accounts for the wide individualdifferences that emerge in the ability tomaintain performance during sleep loss?

Do the physiological and neurobehavioralresponses to chronic partial sleep loss differfrom those resulting from total sleep loss?

Relative to the adverse neurocognitiveand physiological effects of sleep loss,

SLEEP DEPRIVATION IN ADULTS


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is there habituation/adaptation orpotentiation/sensitization to repeatedexposure to sleep loss?

Are there physiological and/or behavioral

adaptations or dysfunctions in sleep orcircadian physiology in response to chronicsleep restriction (e.g., a change in sleepitself or the brains recovery response tochronically inadequate sleep)?

Are the neurobehavioral and physiologicaleffects of chronic partial sleep loss differentat different circadian phases?

What are the physiological processes thataffect restoration of cognitive performancecapacity during recovery sleep, and arethese processes reflected in any currentlymeasured sleep parameters?

How much recovery sleep is requiredfollowing chronic partial sleep loss versustotal sleep deprivation?

What are the effects on neurobehavioralfunctions of long-term (weeks, months,years) exposure to a typical work or schoolschedule of 5 or more days of sleep restric-tion followed by 2 days of recovery?

Research on sleep loss countermeasures inhealthy adults, including pharmacologicaland nonpharmacological interventions, suchas napping strategies, has practical andtheoretical relevance. Studies on the efficacy,long-term effectiveness, and safety ofrepeated use of traditional stimulants (e.g.,caffeine, d-amphetamine, methylphenidate)and novel wake-promoting agents (e.g.,modafinil) for maintenance of performancein healthy adults engaged in emergencyand/or continuous operations are needed.Complementary studies of sleep-inducingand/or phase-shifting drugs (e.g., benzodi-azepine agonists, melatonin) to enhancesleep and subsequent alertness/performance(e.g., shift work, transmeridian travel, orrecovery from continuous operations) will

also continue to expand from the clinicalto the operational realm.

Napping strategies and sleep schedulingwill constitute at least part of any compre-

hensive strategy to maintain alertness andperformance during extended continuousoperations. Cell phones, beepers, and othercommunication devices can put someworkers in a perpetual on-call status inwhich sleep might be interrupted by needfor rapid decisions and/or other duty-relatedtasks. Studies of sleep inertia (and sleep in-ertia countermeasures), therefore, will be ofincreasing relevance and importance. Finally,exploration into the physiological effects ofacute and chronic sleep loss in vital organsystems other than the brain has only

just begun.


Functional brain imaging studies andelectroencephalographic (EEG) brain-mapping studies show that the patternsof functional connectivity between brainregions, evident during performance ofspecific cognitive tasks, are altered by

sleep loss. This suggests that maintenanceof performance during sleep loss maydepend upon regional functional plasticity.

Recent experiments have documentedprecise dose-response effects of chronicsleep restriction on waking neurobehavioraland physiological functions, suggesting thatthe cumulative waking neurocognitivedeficits and state instability that developfrom chronic sleep loss have a basis in aneurobiological process that can integrate

homeostatic pressure for sleep across days.

There have been increased efforts todetermine the roles of rapid eye move-ment (REM) sleep and non-rapid eyemovement (NREM) sleep in memory con-solidation, although definitive evidencefor such relationships remains elusive.


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SECTION IIRESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 27

Plasticity in visual cortices during a criticalperiod in some animal studies is NREMsleep-dependent. This suggests that onefunction of sleep is to facilitate the func-tional organization of the brain, and that

there are sleep-dependent aspects of puta-tively related processes such as long-termpotentiation (LTP) and DNA repair.

Genetic array techniques have identifiedthe patterns of gene expression thatcharacterize and differentiate sleep andwakefulness. This information will helpin understanding the most basic cellularprocesses mediating performance andalertness deficits following sleep loss, andthe restoration of performance capacity

and alertness during subsequent sleep.

Studies have identified those aspects ofperformance that are most susceptible tosleep inertia, their differential time courses,and have begun to identify sleep inertiacountermeasures (e.g., caffeine).


Determine the physiological and behavioralprocesses mediating the state instability(manifested as increased variability in alert-ness and neurobehavioral performance)that result from acute versus chronic sleeploss. Compare these processes with thosemediating the alertness and performancedeficits that characterize pathologies

such as narcolepsy, Sleep-DisorderedBreathing (SDB) (see Section V), andclosed head injury.

Identify the full range of psychological,behavioral, and physiological (e.g.,endocrine, immune, cardiovascular, liver,muscle, etc.) consequences of long-termcumulative partial sleep deprivation andtheir underlying mechanisms.

Discover the physiological processesmediating restoration/recovery of alertnessand performance by sleep. This includeselucidation of the basic mechanisms thatcontribute to the time course of recovery

within and between days, as well asdetermining whether there are longer-duration time constants for reversal of thecumulative neurobehavioral deficits

us tossing and turning into a sleepless nation

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