U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Heart, Lung, and Blood Institute

National Center on Sleep Disorders Research

2003

NATIONAL

SLEEP DISORDERS

RESEARCH PLAN

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 Committee

NIH Publication No. 03-5209

July 2003

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 tools 

and mechanisms for a highly interdisciplinary 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 summarizes the specific sleep research achievements since the 1996 Plan, identifies present

gaps in our knowledge and understanding,

and concludes with prioritized recommendations 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 substantial ways to advancing the frontiers of 

biomedical knowledge related to sleep, enabling 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 disorders, 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 establishment 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 programs 

to 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.

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 expansion 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 accomplishments, 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., Chair

Thomas 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 new

knowledge 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 knowledge of the interrelationships between sleep,

health maintenance, and disease prevention. 

Claude Lenfant, M.D.

Director

National Heart, Lung, and Blood Institute

PREFACE

INTRODUCTION vii

Sleep-related problems affect 50 to 

70 million Americans of all ages. 

Sleep-related problems have the same

clinical relevance in women as men, and 

some sleep problems are more common in

women. Important disparities in prevalence

and severity of individual sleep disorders have

been identified in racial and ethnic minorities

and underserved populations. Sleep problems

and disorders have major impacts on society,

but have not received sufficient attention in

clinical practice, in the education of health

care providers and future biomedical

researchers, or in public health education

and intervention programs. 

The three broad categories of sleep 

problems include: 

• Sleep Restriction: This results from 

imposed or self-imposed lifestyles 

and work schedules. Many children, 

adolescents, and adults regularly fail 

to get sufficient sleep to function 

effectively during waking hours. 

• Primary Sleep Disorders: More than 

70 types of sleep disorders chronically 

affect people of all ages. Fifty percent or

more of patients remain undiagnosed 

and therefore untreated. 

• Secondary Sleep Disorders: People having 

a chronic disease associated with pain or

infection, a neurological or psychiatric

disorder, or an alcohol or substance 

abuse disorder often experience poor sleep

quality and excessive daytime sleepiness.

The end result can be exacerbation 

of the primary medical condition and 

further impairment in health and safety,

mood and behavior, and quality of life. 

As part of the authorizing legislation establishing the National Center on Sleep Disorders

Research (NCSDR) within the National Heart,

Lung, and Blood Institute, a Sleep Disorders

Research Advisory Board (SDRAB) was established to provide a primary source of advice 

on matters related to planning, conduct, 

support, and evaluation of research in sleep

and sleep disorders. The SDRAB consists of 

12 non-Federal members appointed by the

Director, NIH, 8 of whom are representatives

of health and scientific disciplines related to

sleep 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 Coordinating

Committee (SRCC) was established in 1986 

by the Director of NIH for the purpose of 

facilitating interchange of information on 

sleep and sleep-related research. When the

NCSDR was established in 1993, responsibility for the Trans-NIH SRCC was transferred

to the NCSDR and its Director serves as Chair

of the Trans-NIH SRCC. The Trans-NIH SRCC 

in 1993 was comprised of only five NIH

Institute representatives, but membership 

has progressively increased in parallel with

increasing interdisciplinary scope of sleep

research and especially since release of the 

first Sleep Disorders Research Plan in 1996. 

INTRODUCTION
viii 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Ten NIH Institutes/Centers are now members

of 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 Skin 

Diseases (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 Alternative 

Medicine (NCCAM)

Nancy Pearson, Ph.D.

The Task Force appointed to revise the Sleep

Disorders Research Plan was assisted by the

NCSDR and the Trans-NIH SRCC. A draft of

the updated plan was broadly circulated to

solicit comments from biomedical professionals

involved in sleep-related research and clinical

practice, and from relevant professional and

public organizations representing individual 

scientific disciplines and sleep disorders. 

Many comments were received and were 

carefully considered by the Task Force in 

completing the 2003 National Sleep 

Disorders Research Plan.

This Plan fully represents the deliberations 

and recommendations of the Task Force, 

summarizes the dramatic advances in 

knowledge since 1996, and identifies 

current gaps in our knowledge base. The 

recommendations for future research will 

not only guide prioritization of future sleep

research within NIH and other Federal and

non-Federal entities, but should also be 

helpful in identifying opportunities for 

new investigators from an ever-increasing

diversity of scientific and clinical disciplines.

The recommendations regarding training

of sleep research scientists, the education 

of health care professionals, and communitybased public education programs should 

also stimulate much-needed progress in 

these areas. 

Carl E. Hunt, M.D.

Director 

National Center on Sleep Disorders Research

National Heart, Lung, and Blood Institute

NCSDR e-mail: ncsdr@nih.gov

NCSDR Web site: http://www.nhlbi.nih.gov/sleep
EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

SECTION I—BASIC SLEEP SCIENCE

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

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

Pharmacology and Pharmacogenetics of 

Sleep and Waking . . . . . . . . . . . . . . . . . . . . . . . . . .19

SECTION II—RESTRICTED SLEEP: 

NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS

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

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

SECTION III—ENABLING TECHNOLOGY

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

Genetics and Proteomics: Phenotype Issues 

and Methodological Approaches . . . . . . . . . . . . . . .35

Functional Neuroimaging of Sleep and 

Wake States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38

Post Mortem Brain Analysis in 

Sleep Disorder Patients . . . . . . . . . . . . . . . . . . . . . .41

SECTION IV—SLEEP AND HEALTH

Normal Sleep, Sleep Restriction, and 

Health Consequences . . . . . . . . . . . . . . . . . . . . . . .47

Sleep, Sex Differences, and Women’s Health . . . . . .52

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

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

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

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

SECTION V—SLEEP DISORDERS

Immunomodulation, Neuroendocrinology, 

and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

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

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

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

Restless Legs Syndrome/Periodic Limb 

Movement Disorder . . . . . . . . . . . . . . . . . . . . . . . .87

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

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

Sleep in Psychiatric, Alcohol, and 

Substance Use Disorders . . . . . . . . . . . . . . . . . . . . .95

SECTION VI—PEDIATRICS

Sleep and Early Brain Development and Plasticity . .101

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

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

Neuropsychiatric Disorders in Childhood 

and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109

SECTION VII—EDUCATION 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 Research 

Plan Revision Task Force . . . . . . . . . . . . . . . . . . . .127 

Appendix B: National Sleep Disorders Research 

Advisory Board . . . . . . . . . . . . . . . . . . . . . . . . . .129 

Appendix C: NIH Sleep-Related Initiatives, 

1996 to 2002 . . . . . . . . . . . . . . . . . . . . . . . . . . . .133 

CONTENTS

CONTENTS ix

EXECUTIVE SUMMARY 1

PROCEDURE

The first National Sleep Disorders Research

Plan was released by the National Institutes of

Health (NIH) in 1996. Considerable scientific

and clinical growth of the field has occurred

since then, necessitating a reassessment and

update of research opportunities and recommendations. This 2003 revision of the National

Sleep Disorders Research Plan summarizes 

the new knowledge acquired since the 1996

Plan and provides an updated and expanded

guide for scientific research on sleep and 

its disorders.

The sections selected for inclusion in this

revised Plan provide a broad perspective 

on the field of sleep and sleep disorders, 

and highlight the crosscutting and highly 

interdisciplinary evolution of this field. 

Each section provides:

• A brief overview of the topic.

• The major research accomplishments 

since release of the 1996 National Sleep

Disorders Research Plan.

• The research recommendations for the 

future, including a listing of the two top 

recommendations, in italics, followed by a 

listing of any additional recommendations. 

This executive summary presents the Task

Force’s highest recommendations for future

research. All the recommendations highlighted in this Executive Summary are considered

relatively equal in importance and are therefore not listed in any prioritized order.

Several specifics of the overall process of 

the Task Force merit further comment. First,

there was considerable discussion on how 

to address pediatric sleep science, since 

some developmental processes are only

encountered in infants and children, while 

others represent a continuum from infancy 

to old age. Reflecting this continuum, the

adult and pediatric sections were combined

whenever possible (e.g., insomnia, sleep, and

breathing). Separate sections focusing only 

on pediatric science were developed where

there was no direct adult relevance.

Second, there was considerable discussion 

of how sleep and its disorders relative to

women’s health should be addressed in this

document. It was decided to both create 

a specific section on sex differences and

women’s health in sleep, to emphasize 

scientific content unique to women, and 

to include in other sections, wherever appropriate, information as to how a particular 

disorder or physiologic process might differentially affect women and men. In this way,

there would be adequate emphasis of all 

the diverse ways in which sleep concerns

impact on maintenance of health and prevention of disease in women. Similarly, 

there is a separate section in this revised 

Plan devoted exclusively to racial and ethnic

disparities in sleep and health, and relevant

content is also included in other sections 

wherever appropriate. 

EXECUTIVE SUMMARY
2 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

PROGRESS SINCE THE 1996 NATIONAL

SLEEP DISORDERS RESEARCH PLAN

The years since release of the original National

Sleep Disorders Research Plan in 1996 have

been remarkably eventful not only in terms 

of progress in the sleep sciences but also in

terms of lifestyle and activities of daily life 

that impact on sleep habits and behaviors.

America is increasingly becoming a 24-hour

per day society with constantly escalating

expectations for around-the-clock services,

information, and entertainment. After the

events of September 11, 2001, we have 

also become a much more vigilant society. 

All these lifestyle changes directly impact 

not only the number of hours Americans 

sleep each day but also when during the 

24 hours that sleep occurs. 

We are now beginning to understand the

impact of chronic sleep loss or sleeping at

adverse circadian times on our ability to 

function optimally and on our physical and

mental health. How sleep loss, sleep displacement (e.g., shift work, jet lag), and a wide

range of sleep disorders affect one’s ability 

to maintain health and healthy functioning,

however, remains relatively poorly understood.

Thus, despite the scientific progress made

since 1996 in both clinical and basic science

related to sleep and its disorders, there

remains the challenge and the need to discover the functions of sleep, to understand

and develop better treatments for the many

disorders affecting sleep, and to explain the

nature of human physiology during wakefulness and the individual stages of sleep.

Without progress in these areas, countless 

millions will continue to suffer the consequences of dysfunction and abuse of this 

most basic regulatory process. Progress in

every area cannot be included in this Executive Summary, but the most important gains 

in knowledge and understanding will be discussed to provide a context for the research

recommendations that follow.

Sleep Neurobiology: The discovery in 1998 to

1999 of hypocretin/orexin and its role in the

development of narcolepsy in animal models

and in humans revolutionized our understanding of this debilitating disorder and promises

import ant advances in the diagnosis and 

therapy of human narcolepsy. Discovery of 

the neuromodulatory role of hypocretin/orexin

also greatly improved our understanding of

the basic neurobiologic processes that control sleep and wakefulness. Anatomic areas

promoting sleep, such as the ventrolateral 

preoptic (VLPO) area of the hypothalamus,

have also been characterized. New anatomical and physiological approaches have led to

advances in our understanding of the location

and interconnections between hypothalamic

and brainstem circuits controlling rapid eye

movement (REM) sleep, non REM sleep, and

wake states. Factors regulating the activity of

these sleep-controlling neurons have been

identified. Circuitry and neurotransmitter

mechanisms controlling muscle tone across 

the sleep cycle, of relevance to numerous 

sleep pathologies, have also been identified.

Circadian Biology: A growing number of

“clock genes” have been identified since 

1996 that play a critical role in mammalian 

circadian timing. In addition, there is clear 

evidence that non-suprachiasmatic nucleus

(SCN) tissues have clock genes and can

demonstrate circadian rhythms. Thus, 

circadian modulation is now established to

occur both centrally and peripherally, further

emphasizing the importance of circadian

chronobiology in the timing of sleep and 

waking as well as a wide variety of physiologic functions. Now these genetic studies 

are also being applied to humans, in particular

patients with advanced sleep phase syndrome.

Sleep-Disordered Breathing (SDB): The consequences of SDB (obstructive sleep apnea, 

sleep apnea) in both adults and children 

have become increasingly clear over the last

few years. In adults, the contribution of sleep
EXECUTIVE SUMMARY 3

apnea to the development of systemic 

hypertension is becoming more evident, and

data are accumulating that other adverse 

cardiovascular outcomes (stroke, congestive

heart failure, myocardial infarction) may result

from this disorder. In children, there is increasing evidence that sleep apnea may contribute

to behavioral problems as well as learning 

and cognitive deficits. Thus, the diagnosis and

treatment of this disorder is important from a

variety of perspectives and across all ages.

Pediatrics: The recognition that having infants

sleep supine (on their back) can substantially

reduce the incidence of Sudden Infant Death

Syndrome (SIDS) is now appreciated as a profoundly important early infant intervention

that has saved thousands of lives. Recent

research regarding the physiologic, psychological, and developmental aspects of sleep 

in infants, children, and adolescents has 

contributed to an increased understanding 

of the unique aspects of sleep and development. The study of pediatric disorders such as

Congenital Central Hypoventilation Syndrome

and Rett Syndrome has led to a better basic

understanding of autonomic regulation and

respiratory control. Recent findings regarding

the complex relationship between sleep patterns and hormonal changes in adolescence

have broadened our understanding of pubertal influences on sleep and circadian biology.

The extent of sleep restriction and sleep disturbances among children and adolescents 

is now recognized to be much greater than

previously believed, and the consequent

impact on mood, neurobehavioral and 

academic functioning, safety, and health 

is considerable. Recognition of the link

between sleep disturbances and neurobehavioral disorders in childhood, such as 

attention deficit hyperactivity disorder

(ADHD), has profound public health implications for both the treatment and prevention of psychiatric comorbidity. 

Insomnia: The high prevalence, risk factors,

and consequences of insomnia have been

increasingly recognized since 1996. Insomnia

has been identified as a risk factor for the

onset of subsequent depression, anxiety, 

and substance use disorders. In addition, 

the efficacy and durability of behavioral 

therapies for insomnia have been demonstrated in controlled clinical trials. 

Sleep Deprivation: Although previous studies

have demonstrated many of the ill effects of

total sleep deprivation, the impact of chronic

partial sleep deprivation (restriction) had not

been extensively investigated even though 

it is a much more common phenomenon.

However, recent studies indicate that 4 to 6

hours of sleep per night yields a progressive,

cumulative deterioration in neurobehavioral

function including vigilance, neurocognitive

performance, and mood. This reduction in 

performance is also associated with changes 

in cerebral activation during cognitive tasks.

Physiologic changes (insulin resistance and

increased sympathetic activation) appear to

occur as well. Both the neurocognitive and

physiologic effects of chronic sleep loss 

suggest there is optimal sleep duration and

that there is a cost for failing to achieve it.

However, the exact duration of sleep required

at different periods of life remains poorly

understood, as do the mechanisms driving

these neural and metabolic processes.

Sleep Education: There is now broad recognition of the curriculum inadequacies regarding

sleep and its disorders within most medical

schools and residency training programs. 

A Sleep Academic Award Program was 

established by NIH in 1996 to address these

educational gaps, and this program has led 

to the development of undergraduate and

postgraduate sleep curricula, educational 

tools, and methods to enhance sleep knowledge. The awardees, working with national

professional societies, have also begun to

address sleep and fatigue in medical training.

There have also been several public health

education initiatives, including an effort to

establish lifelong healthy sleep habits in
4 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

school-age children begun in 2001 with

Garfield, the “Star Sleeper” as the“spokescat”

for healthy sleep. A high school biology curriculum on sleep, sleep disorders, and biological rhythms has also been created, as have

programs to combat drowsy driving. Thus, 

a variety of educational activities have 

recently been implemented that may have 

substantial impact on knowledge and public

health behaviors.

We need to consolidate and extend the

research progress made to date and to 

translate new knowledge and discoveries 

into effective therapies and improved lifestyle

behaviors for all Americans (as described 

in the Department of Health and Human

Services “Healthy People 2010” initiative).

Sleep-related research must continue across

the full spectrum from basic science to clinical

investigation to community-based translational

programs in order to apply what is known to

improve public health and quality of human

life. The scientific areas most important in

extending and translating the research gains

made to date are summarized in the following

paragraphs. The order in which they are listed

does not reflect any prioritization; indeed,

these individual recommendations are all

important 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 previously

described and yet-to-be-identified cellular 

systems that modulate state are connected 

to each other and to other neural systems

needs to be characterized. In addition, the

neuropharmacology and neuromodulators 

that mediate neural signaling in sleep and

wakefulness, and their hierarchy in this

process, need to be better understood. 

The genetic and proteomic mechanisms

involved in the generation of sleep and

wakefulness also need elucidation. Finally,

the phylogeny of sleep needs to be further

investigated to help define the functions 

of sleep.

The neurobiologic basis of the two-process

sleep system (homeostatic and circadian)

needs to be better characterized regarding 

the anatomical, physiological, and functional links between the two systems and the

contribution of each to altered sleep quality

and timing.

Further research is needed to better understand how developmental maturation from 

the fetus to the adult influences all of the 

neurobiologic processes described above. 

This would include studies addressing how

sleep itself influences neural development 

and how such development affects sleep 

at the neurobiologic level.

Investigation is needed of the neurobiological function of sleep as a whole and 

the independent functions of NREM and

REM sleep. Without some grasp of the

functional role of sleep in the behavior 

and survival of an organism, it remains 

very difficult to understand the development, neurobiology, and importance 

of 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 mediating

sleepiness, state instability, and decrements in specific aspects of neurocognitive

performance and alertness: this includes

identification of brain structures, proteins,

and genes that mediate the neural basis 

of sleepiness and the neurocognitive performance changes resulting from sleep 

loss. Also, the neurobiologic processes

mediating the restoration of stable 

wakefulness, alertness, and performance require further investigation.
EXECUTIVE SUMMARY 5

A systematic delineation is needed of the

processes involved in, the mechanisms

underlying, and the developmental 

aspects of acute and chronic sleep 

deprivation on non-neural systems. 

These systems include endocrine, 

cardiovascular, immune, hematopoietic, 

renal, gastrointestinal and muscle.

The effects of sleep loss on behaviors that

diminish the safety of both the individual 

and society in general need to be studied. 

This includes but is not limited to the transportation industry, the armed services, the

space industry, health care, law enforcement, 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 or

maintaining sleep: Studies should include

the development of animal models of

insomnia, the study of specific insomnia

phenotypes, and the application of neurophysiologic, neurochemical, neuroanatomic,

and functional neuroimaging approaches 

to the study of insomnia in humans.

Understanding why women are at higher

risk for insomnia should also be a goal.

Finally, genetic, genomic, and proteomic

studies are also needed.

Restless Legs Syndrome (RLS) and Periodic

Limb Movement Disorder (PLMD): Studies

should address the role of altered central

dopaminergic mechanisms and abnormal

iron metabolism in the pathogenesis of

these conditions. Further development,

refinement, and validation of animal 

models of RLS and PLMD are also needed.

The use of neuropathologic techniques 

in the evaluation of brains and spinal 

cords of affected patients is also likely 

to be useful.

Sleep-Disordered Breathing (SDB), 

including sleep apnea and disorders of 

ventilatory control: Studies should address

the processes that control both upper airway patency and ventilation itself with a

particular focus on the influence of sleep 

on these biologic processes. The neural 

connections, neuromodulators, and 

molecular events mediating these statedependent processes affecting respiration

during sleep need to be studied.

Primary disorders leading to hypersomnolence: The neural mechanisms leading 

to hypersomnolence in conditions such 

as narcolepsy or primary central nervous 

system hypersomnolence need to be 

investigated. The focus of these studies

should be how the neurobiologic causes of

hypersomnolence differ from or resemble

the effects of sleep loss.

 An assessment of normal human sleep 

phenotypes and the normal range of variation in this phenotype in adults and children

(including racial and ethnic differences) is needed, 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, sleep

timing, sleep disruption, sleep quality, and 

other variables by which sleep and sleepiness can be quantitatively evaluated.

Once normal sleep phenotypes are defined, the associated genotypes should 

be fully evaluated.

Abnormal sleep phenotypes should subsequently be recognizable, and genotyping 

of these individuals should then be pursued

to define the genetic underpinning of

abnormal sleep or altered circadian rhythm

profiles. The impact of single nucleotide

polymorphisms (SNPs) on normal sleep 

phenotypes should be testable as well.
6 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

The phenotype of patients with specific

sleep disorders should be carefully defined

in order to set the stage for subsequent

genetic testing.

Methods to define normal and abnormal

phenotypes through questionnaires or 

simple non-invasive testing should be a

goal. Population surveillance and assessment of associated morbidities will then 

be 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 airway

pressure (CPAP) devices have improved 

substantially and remain an effective form

of therapy for adult SDB. However, they 

are cumbersome and have achieved only

moderate acceptance by patients. Other

approaches, such as oral appliances and

upper airway surgery, have relatively limited

success rates for more than mild to moderate SDB. Therefore, current forms of 

therapy need to be improved, and novel

therapies need to be developed. In children,

the indications for surgical intervention 

need to be better defined. In addition, 

new surgical and nonsurgical treatments 

for SDB in children are also needed, including those that address major risk factors

such as overweight and obesity.

Insomnia: Although the efficacy and 

durability of behavioral therapies have 

been demonstrated for primary insomnia,

long-term trials evaluating the efficacy 

and safety of hypnotic medications 

have not been conducted and are a 

high priority. The development of novel 

pharmacologic and nonpharmacologic 

therapies, as well as complementary and

alternative medicine therapies, for insomnia

of all types (including insomnia in high-risk

populations) remains a priority as well.

Finally, the effectiveness of behavioral, 

psychological, and popular mind-body

approaches and treatments should be 

evaluated in routine care settings.

Narcolepsy: The neurobiology of narcolepsy is now better understood, and the 

role of hypocretin is well recognized.

Exciting possibilities for new research 

worthy of exploration include therapies

involving hypocretin peptide supplementation, the development of hypocretin

receptor agonists, cell transplantation, 

and gene therapy.

Restless Legs Syndrome (RLS): Without 

a better understanding of the etiology,

pathogenesis, and neurophysiology of 

RLS, treatment strategies are limited 

and not effective in all patients. RLS 

and Periodic Limb Movement Disorder

(PLMD) can have profound negative 

impacts on quality of life including 

daytime functioning, work performance,

and social and family life. Therefore, 

methods to determine the extent of 

nocturnal sleep disturbance and daytime sleepiness both in children and 

adults with RLS can potentially enhance 

opportunities to develop novel and 

effective treatments.
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 alter 

their 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 processes therefore needs to be studied at the 

epidemiologic, behavioral, physiologic and 

basic neurobiologic levels. Examples of these

potential interactions include:

Medical Conditions: Many medical disorders can impair sleep quality and can, 

in turn, be adversely affected by poor 

sleep. Common examples include congestive heart failure, pain, and obstructive 

lung disease. Congestive heart failure, for

example, can lead to a cycling respiratory

pattern resulting in sleep fragmentation 

and decrements in both quality of life and

performance. The recurrent arousal from

sleep secondary to the intermittent hypoxia

associated with this respiratory pattern can

potentially lead to a progression of heart

failure and hence to reduced survival.

Neurological Disorders: Neurological conditions such as neurodegenerative disorders

(Alzheimer’s disease, Parkinson’s disease),

head trauma, encephalitis, stroke, and

epilepsy are associated with insomnia, 

somnolence, motor activity during sleep,

and/or breathing abnormalities during 

sleep. Studies should evaluate whether

sleep disorders predispose to specific 

neurological conditions, whether neurological conditions can produce sleep disorders, and whether sleep disorders impair

recovery for selected neurological disorders.

Psychiatric, Alcohol and Substance Use

Disorders: The complex relationships and

causal pathways linking insomnia and sleep

deprivation to these disorders require 

further investigation. The impact of sleep

disturbances on treatment outcomes and

recurrence risk is also significant. Specific

examples include the risk for subsequent

depression among individuals with insomnia, the importance of sleep and dream 

disturbances in the development of posttraumatic stress disorder, and the role of

insomnia and sleep deprivation in increasing risk for relapse to alcoholism and 

drug addiction.

Pediatric Genetic and Neurodevelopmental

Disorders: Several genetic and neurodevelopmental disorders have associated sleep

and/or SDB abnormalities. These include

both rare syndromes and more frequent

conditions such as Attention Deficit

Hyperactivity Disorder (ADHD). Specific

areas for further investigation include: 

(1) understanding the pathophysiology 

of autonomic nervous system (ANS) dysregulation in order to better understand

maturation of the ANS and the abnormalities that occur in SDB; (2) investigating 

the anatomical contributions of the 

upper airway to the obstruction found 

in children with craniofacial malformation 

in order to better understand etiology of 

the more common causes of SDB; and 

(3) understanding how genetic disorders

produce primary insomnia, daytime somnolence, or movement disorders during

sleep. Rare genetic disorders associated 

with sleep abnormalities provide unique

models that may facilitate exploration of

novel pathophysiologic mechanisms and 

the discovery of new sleep-related genes

that may be relevant to other, more 

common sleep disorders.
8 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

 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 professionals, 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 disseminated to health care providers and 

the public. In addition, a rigorous evaluation 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 providers 

health and quality of life

Public education programs about healthy

sleep and sleep disorders should continue

with an emphasis on culturally, ethnically

and racially appropriate materials. These

efforts should include school-based programs for both elementary and high 

school students as well as adult educational programs. An assessment of the

impact of these programs on knowledge,

attitudes, and sleep practices of children

and adults should be a component of 

this 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 needed 

in the sleep field to answer scientific questions and to better diagnose and manage

patients. Prominent examples include:

Mechanisms needed to study the neurobiology of a variety of sleep disorders, 

possibly including the development of 

relevant human brain banks. Examples

include SDB and RLS/PLMD, sleep 

disorders in which little is known 

neuropathologically.

Animal models of normal sleep as well 

as individual sleep disorders would be 

highly useful in understanding not only 

normal sleep physiology, but also the 

pathogenesis of a variety of disorders 

and their behavioral and physiologic 

consequences.

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 the 

patterns of regional brain activity that 

characterize both normal and abnormal

sleep/wake states. Application of these

techniques to the study of sleep and 

sleepiness should be continued and 

expanded as further improvements 

and refinements become available.

Sleep monitoring in rodents, although 

currently utilized in a few laboratories,

needs to be standardized and then made

more broadly available so that mouse/rat

sleep phenotypes can be easily defined 

in genetically altered animals.
EXECUTIVE SUMMARY 9

New methods to measure and quantify 

the structure of sleep in humans are 

greatly needed. Such methods should 

be outcome focused, such that what 

is measured predicts not only the restorative processes of sleep but also the 

consequences of disrupting this process.

Methods to relatively easily define 

circadian phase are also needed.

Effective new measures and methods 

to quantify sleep and other relevant 

physiological signals (such as respiration) 

in the home are greatly needed to 

facilitate both large epidemiologic investigations and the broader evaluation of

patients with potential sleep disorders.

Quantifiable, noninvasive, relatively rapid

methods to measure sleepiness in children

and adults are greatly needed to scientifically understand its causes and consequences,

and to predict performance such that the

safety of the individual and society can 

be protected.

Informatics can be directly applied to 

clinical, neurophysiologic, imaging, and

genetic questions as they apply to sleep 

and its disorders, but are not currently 

widely utilized in this field. Thus. the use 

of 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 disorders in women. These efforts should include:

• Basic and clinical studies to establish 

how sex-related differences in sleep 

and its regulation influence the risk for,

and mechanisms of, sleep disorders.

• Longitudinal studies in women including both subjective and objective sleep

indicators before and during menarche,

in women of childbearing age including pregnancy and the postpartum 

period, and in women during the

menopausal transition.

• Studies of how sleep disturbance in 

pregnancy 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 neurophysiological 

and neuroanatomical correlates and

gene-environment interactions contributing to racial and ethnic disparities

in prevalence and severity of individual

sleep disorders.

• Developing effective strategies to 

reach racial and ethnic minorities in 

public health education programs 

for sleep-related conditions.

RESEARCH TRAINING

Although clinical activities and opportunities 

in the sleep field are expanding, a larger and

more interdisciplinary scientific work force is

needed if we are to fully address the scientific

questions discussed above. Attracting new

basic and clinical investigators to this field 

represents a major challenge for the field if 

we are to meet the expanding research 

needs and opportunities. Some of the 

potential barriers include:

• The perceived difficulty of defining 

sleep phenotypes in mice/rats, thereby 

making molecular and genetic studies 

more difficult.
10 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• The perceived difficulty of studying a

“state” in very reduced preparations 

or cell lines.

• The challenges posed to clinical research 

by the need for objective measurement 

of sleep-wake physiology and behavior,

using cumbersome and expensive 

technology, and the need to control a 

wide range of factors, limit effective 

measurement of sleep-wake processes 

in naturalistic environments. 

• “Sleep science” does not have Division 

or Departmental status at most medical

centers. As a consequence, designated

space, faculty positions, access to 

graduate students, and potential for 

collaboration are all limited.

Novel strategies to increase the number 

and scope of sleep investigators need to 

be identified and implemented. There is an

acute need for additional dedicated Sleep

Medicine training programs and for investigators in other training programs (e.g., 

neurobiology, genetics, aging, pulmonology,

neurology, psychiatry, pediatrics, and neuropathology) to train sleep scientists. Sleep is 

a highly interdisciplinary field, and successful

sleep centers therefore require scientific and

clinical expertise from multiple disciplines, 

with a sufficient critical mass of investigators

focused on sleep in order to achieve scientific

progress. The association between basic sleep

investigators and clinical scientists at these

sleep centers also promotes translational

research that can yield results more immediately applicable to patient care and public

health interventions. Due to a lack of a 

critical mass of sleep investigators at most

medical centers, this goal may demand a 

more regional or national approach than is

needed for most other disciplines. This may

also require an iterative process by which 

integrated, multidisciplinary sleep centers 

are carefully developed with substantial 

training programs and the increasing dispersal of well-trained program graduates 

can then contribute to development of 

new sleep centers. 

In addition to attracting new investigators 

to the sleep field, there is a need to expand

the number of trained scientists from other 

relevant disciplines electing to focus on 

sleep-related research. These disciplines 

include informatics, epidemiology and 

genetic epidemiology, clinical trials, functional

imaging, genetics, and molecular biology.

Without collaborators demonstrating these

specific skills, sleep science will not be able 

to utilize currently available technologies 

and methodologies and hence will have 

diminished potential for progress. Ongoing

training and expanded collaborative opportunities are needed, as is a comprehensive 

plan to attract, train and retain new scientists, and to continue expanding the skills 

of current investigators.

CONCLUSION

Considerable progress has been made 

since release of the original National Sleep

Disorders Research Plan in 1996. Resources

expended by the National Institutes of Health

(NIH) to study sleep and its disorders have

steadily increased (see Appendix C). New 

scientific techniques that facilitate research 

discovery are being applied to sleep questions,

and have led to an improved understanding of

normal sleep physiology and the pathogenesis

of a variety of sleep disorders. As a result, both

access to care for patients with sleep disorders

and the quality of care are substantially better.

However, many research questions remain

unanswered, and new questions need to 

be addressed; therapy for a number of sleep

disorders remains suboptimal; and the research

workforce addressing sleep science is inadequate. This Revised National Sleep Disorders

Research Plan presents a comprehensive 

summary of focused research, training, and

education recommendations that addresses

these opportunities and needs.
SECTION I

BASIC SLEEP SCIENCE

• Circadian Biology

• Sleep Neurobiology

• Pharmacology and Pharmacogenetics 

of Sleep and Waking

SECTION I—BASIC SLEEP SCIENCE 13

BACKGROUND

Circadian oscillators are critically involved 

in the regulation of the sleep/wakefulness

cycles, although the relationship is complex

and not fully understood. It is generally 

recognized that the sleep/wakefulness 

rhythm is not driven directly by the circadian

clock, but rather emerges from an interaction of the circadian clock located within the

suprachiasmatic nucleus (SCN), and a distinct

sleep-wake homeostatic process (e.g., the

“sleep homeostat”) in which the drive or 

need for sleep depends upon the prior 

amount of wakefulness and sleep. Sleep 

disorders may arise from dysfunction at 

several levels within these two timing systems.

Alterations in the circadian pacemaker within

the SCN, changes in the sleep homeostat, and

alterations in the coupling between the two

timing systems may each be causal in sleep

disturbances. A complete understanding of 

he origins of normal and abnormal sleep will

require a detailed understanding of both the

circadian 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 identified

that play a critical role in mammalian circadian timing. A recent study indicates 

that alterations in the hPer2 gene are 

associated with advanced sleep phase 

syndrome. In addition, mutations of 

the murine clock gene affect both sleep

duration and the response to sleep loss,

indicating that some genes may be 

involved in both the timing and 

pressure to sleep. 

• Confirmation of the multi-oscillatory, 

distributed nature of the mammalian 

timing system: Dynamic measurements 

of molecular rhythms from several clock

genes reveal that many organs and nonSCN regions of the brain express circadian

rhythms, although not as robust as the

rhythm generated by the SCN. These 

observations raise issues about the role 

of non-SCN rhythm generators in the 

control of the sleep/wakefulness cycle 

and the development of sleep disorders.

• Discovery of temporal complexity within 

the SCN. Recent experiments reveal 

regional specialization in the capacity 

to express circadian rhythms. It is evident

that not all SCN neurons enjoy the same

phase relationship to one another.

Molecular rhythms of the right and left 

SCN appear out of phase in behaviorally

split animals, and phase differences among

SCN neurons may be responsible for encoding day-length information. 

• Discovery that circadian photoreception 

is functionally and anatomically separate

from vision and that this nonvisual system

may affect many physiological and behavioral systems. These findings are important

because sleep/wake rhythms are regulated

CIRCADIAN BIOLOGY
14 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

by photoreception via the SCN, and the

sleep/wakefulness cycle can influence 

photoreception (e.g., eye closure during

sleep). These photoreceptors may be 

linked directly to sleep centers in the 

brain, since there are retinal afferents of

unknown functions that project directly 

to these centers. 

• Discovery of new neurotransmitter 

systems and anatomical areas of the 

brain, especially the hypothalamus, and 

in particular discovery of the orexins/

hypocretins in the regulation of rapid 

eye movement (REM) sleep. These anatomical and neurochemical targets are

linked to the SCN and provide new 

avenues for studying the interactions 

of the circadian clock and sleep-waking 

timing systems.

• Discovery that chronic partial sleep loss

for as little as 1 week can lead to metabolic and endocrine changes that are 

precursors for specific disease states 

(e.g., obesity and diabetes) and are also 

relevant to aging. Decreased total sleep

time is often associated with circadian

dysfunction either on a voluntary basis 

(e.g., shift work) or involuntary basis 

(e.g., aging), making it imperative to 

determine the importance of circadian

factors that lead to decreased sleep and 

the health consequences associated with

chronic sleep loss.

• Discovery that the rest phase of the restactivity cycle of the fruit fly shares many

behavioral and pharmacological features

associated with sleep. This should allow 

this model organism to be used to 

further explore the molecular and genetic

basis of sleep and the adverse effects of

sleep deprivation.

RESEARCH RECOMMENDATIONS

• Recognition of the importance of the 

neurobiological basis of the two-process

sleep system and these two separate timing processes controlling sleep rhythmicity

will continue to provide an important 

conceptual framework for the dissection 

of altered sleep regulation. The anatomical,

physiological, and functional links between

the two systems are virtually unknown. 

The search for the neurobiological basis of

these two processes and their interaction

should remain at the center of basic

research in this area. A more complete 

characterization of the contribution of 

these two processes to altered sleep 

timing and quality, particularly in relation 

to development and aging, is important.

• The circadian physiology of sleep disorders

and the pathophysiology of certain disorders of the timing of sleep remain to be

fully characterized and understood at a 

fundamental level. Circadian desynchrony 

is considered to be at the core of certain

disorders that involve both insomnia and

sleepiness (e.g., delayed sleep phase syndrome; shift work sleep disorder). Given 

the number of people affected by these 

disorders and the behavioral debilitation, 

it is important to determine whether any 

of the key circadian parameters (e.g., freerunning period [tau], phase-response curve

[PRC], light sensitivity, internal coupling

between sleep and other circadianmediated physiology, etc.) are altered in

these disorders. It will also be important 

to search for linkages between circadian

rhythms and sleep disorders not normally

associated with circadian timing (e.g.,

Restless Legs Syndrome).
SECTION I—BASIC SLEEP SCIENCE 15

• The availability of clock gene mutations in

mammals will allow study of the effects 

of alterations of the circadian pacemaker 

on the sleep/wakefulness rhythm. In addition, these genes may have effects on 

sleep that are independent of the SCN. 

It will be important to determine how 

these genes act to regulate sleep, independent of the central pacemaker, and 

to assess the effects of circadian period,

phase, and amplitude on the sleep/wakefulness rhythm.

• Although the free-running period (tau) 

of the human circadian rhythm may not

change during aging, animal studies 

suggest an impact on other circadian

parameters (e.g., amplitude). It will be

important to explore the effects of aging

on central and peripheral circadian generators and how age-related changes in 

circadian function affect sleep.

• How circadian dysregulation and sleep 

loss interact to affect health is an important but poorly understood topic. This 

issue is of particular importance to the 

aged and to disadvantaged populations.

Multiple jobs and unusual work cycles 

can lead to circadian disruption. It will 

also be important to understand the 

long-term effects of chronic sleep loss 

in adolescents. Good model systems 

and more sophisticated long-term data 

collection will be essential. 

• Development of a methodology for 

non-invasive in vivo measurement of 

human circadian phase is needed. This 

may require the identification of new 

markers and/or the development of 

novel detection systems. 

• Quantitative modeling of a mammalian 

circadian clock is needed. The molecular

processes and interactions that appear 

to generate rhythmicity will need to be

described in a mathematically rigorous 

fashion. The central clock mechanism has

grown in complexity with an attendant loss

of conceptual clarity. Modeling may allow

for a better focus on critical processes.

• Although it is clear that there are significant

sleep problems associated with adjustment

to shift work and transmeridian flight, our

understanding about entrainment kinetics 

is very limited. In particular, little is known

about entrainment kinetics in older individuals who have more difficulty in maintaining

stably entrained biological rhythms. Recent

research indicating that different circadian

rhythm generators within the brain and

other organs reset with different kinetics

suggests that the physiology of internal 

and external synchronization is important.

Molecular and neurophysiological tools 

are now available in several animal model

systems to address these problems.

• Animal research indicates that circadian

photoreception enjoys distinct photoreceptors within the retina and specialized

neural pathways. A full functional and 

molecular characterization of this system 

in humans is required.
16 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

SLEEP NEUROBIOLOGY

PROGRESS IN THE LAST 5 YEARS

• Molecular biological approaches have 

contributed to understanding sleep 

control mechanisms. These approaches 

have led to one of the greatest achievements of sleep research since the discovery

of REM sleep; the identification of the

hypocretin (orexin) system and its central

role in narcolepsy and behavioral control. 

• Genetic expression studies of sleep in

drosophila (fruit flies) have produced 

important discoveries about the genetic

basis of sleep. Moreover, they have established this species, with its well-documented

and readily manipulated genome as a valid

model of sleep genetics, making further

rapid progress likely. Studies of murine

mutants have progressed along the same

lines. A better understanding of the populations of genes activated by sleep, waking,

and sleep deprivation, and the time course

of this activation has been made possible 

by the application of recent developments

in simultaneous assessment of the activity 

of large numbers of genes. 

• Studies using polymer-encapsulated

suprachiasmatic nuclei (SCN) and related

studies of diffusible factors released by the

SCN have identified some of the major

mediators of circadian-sleep relations. 

• Less progress has been made in elucidating,

at a molecular level, the phenomenon of

sleep debt. The functional and biochemical

regulation of changes in sleep time, REM

BACKGROUND

Sleep time is defended by an accumulation 

of “sleep debt”—the need for more sleep 

that results from sleep restriction. Recent 

study findings in animals and humans 

suggest that a complete and sustained loss 

of sleep can result in death. It is likely that 

an understanding of the effects of sleep loss

will reveal basic principles of brain function 

relevant to a broad spectrum of neurological

and behavioral disorders. Sleep is known 

to strongly affect the activity of most 

brain neurons. 

Modern sleep neurobiology research has not

yet achieved consensus as to the function of

sleep. What determines the brain’s memory

for sleep loss? What is the neurological deficiency being regulated by the sleep debt

memory? Does rapid eye movement (REM)

sleep have different functions than non-REM

(NREM) sleep? 

Functional significance of the marked differences in the amount of sleep within the

animal kingdom is unknown. Similarly, the

considerable variation in the duration of the

sleep cycle (Wake-NREM-REM) in different

species of mammals from a high of 2 hours 

to as little as 15 minutes is poorly understood,

as are the determinants and health significance of the variations of sleep duration 

within the human population. 
SECTION I—BASIC SLEEP SCIENCE 17

and NREM amounts, and sleep morphology

(e.g., delta power, eye movement intensity)

with development remains mysterious,

although some progress has been made 

in characterizing the neurophysiology and

neurochemistry of sleep changes across 

the lifespan. 

• Progress has been made in the electrophysiology of sleep at the neuronal level.

The mechanisms responsible for generating and synchronizing rhythmic neuronal

activity in NREM sleep have been localized

to thalamic regions, and the ionic currents

mediating rhythmic discharge have been

identified. Cell groups in the hypothalamus

and basal forebrain critical in the control of

NREM and REM sleep have been identified

with anatomical and electrophysiological

techniques. Some recent evidence suggests

that localized brain mechanisms may mediate sleep debt. 

• Important roles of amino acid and

monoamine mechanisms in regulating 

muscle tone at the motor-neuronal level

across the sleep cycle have been demonstrated. The circuitry controlling neurotransmitter release has been clarified. 

These advances are important in understanding numerous sleep disorders, 

including Sleep-Disordered Breathing

(SDB), cataplexy, REM sleep behavior 

disorder (RBD), and other parasomnias. 

• The neurochemical phenotypes of major

groups of neurons contributing to REM 

and NREM sleep regulation have been 

identified. Previously appreciated monoaminergic (serotonin, norepinephrine, 

epinephrine, dopamine, histamine) 

mechanisms have been shown to interact with amino acid (glutamate, GABA,

glycine) neurotransmitter systems at forebrain and brainstem levels. Anatomical 

connections between the neurons critical 

to REM and NREM sleep have been traced.

Hypocretin/orexin has been identified as 

an important modulator of activity in 

sleep-control systems. Other peptides

important in the control of sleep states 

have been described and localized 

to brainstem and forebrain sleep 

control regions. 

• Limited progress has been made in 

understanding the phylogeny of sleep. 

REM sleep has been found in primitive

mammals. Some birds may show interhemispheric asymmetry during sleep 

based on electroencephalogram (EEG)

recordings. Unihemispheric sleep and 

unihemispheric sleep debt have been 

found in marine mammals. 

RESEARCH RECOMMENDATIONS

• Determine the function of sleep as a 

whole and of the differential roles of 

REM and NREM sleep. It will be helpful 

to study genetic mutant murine and 

invertebrate models with unusual sleep

properties. A resource that can be better

utilized is the variation in sleep time and

quality in the animal kingdom. As the cost

of sequencing continues to be reduced, 

it becomes practical to sequence the

genomes of diverse species to determine

the genetic basis of these differences.

Advances in technology have made it 

practical to better record and characterize the great differences in sleep duration

and quality between species. Recent work

demonstrates that sleep is present unihemispherically in some mammals. In other

animals, REM sleep appears to occur without the low-voltage activity seen in most

mammals. In still other mammals, blood

pressure, heart rate, respiratory changes,

eye movements, erections, and other phenomena characteristic of human sleep do

not occur. These variations in mammalian

and in nonmammalian species, particularly 

if understood in an ecological context and

at the cellular level, can provide a major

insight into the functions of sleep. 
18 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Bridge the gap between what is now

known about the anatomy and neurochemistry of sleep, wake and waking

arousal-generating systems, and the 

nature of the information processing 

that occurs at the synapses within these 

systems. Identification of the functional 

role played by each neurochemical link 

and the analysis of neurotransmitter 

interactions would, for example, facilitate the development of drugs to control

muscle tone over the sleep-wake cycle. 

• The pathophysiology and neurochemistry 

of sleep disorders needs to be better understood. How abnormal operation of sleep

regulatory systems results in sleep disorders

needs to be clarified. The anatomical and

pathophysiologic causes of RBD, SDB, 

periodic limb movements during sleep, 

and parasomnias are poorly understood.

Although major advances have occurred 

in our understanding of narcolepsy (see

Section V), further work is needed to 

clarify the cause of narcolepsy without 

cataplexy, and how disorders of the

hypocretin/orexin system and other 

systems produce the multiple symptoms 

of narcolepsy. Studies in this area represent a great opportunity for clarifying 

basic issues of sleep control and 

sleep pathology. 

• An understanding of sleep debt at the 

biochemical and genetic level is needed,

building on the new knowledge of sleep

control at the neuronal level. The biochemical and genetic substrates of 

waking and arousal during waking 

and of REM sleep and NREM sleep 

debt need to be understood. 

• Interactions between sleep states and 

thermoregulatory, metabolic, cardiovascular, and respiratory regulation 

at all levels of the neuroaxis need to 

be better described and understood. 

The roles of sex, sex hormones, sexual

maturity, pregnancy, and lactation in 

sleep control need to be investigated 

at a mechanistic level. 
SECTION I—BASIC SLEEP SCIENCE 19

BACKGROUND

The use of sedative/hypnotic and psychostimulant drugs to treat medical conditions

such as Attention Deficit Hyperactivity 

Disorder (ADHD), insomnia, heart disease, 

narcolepsy, Restless Legs Syndrome (RLS), 

and other medical disorders (see Section V)

can result in profound effects on normal

sleep/wake architecture and perceived sleep

quality. In addition, over-the-counter and

herbal remedy markets exist to cater to 

the need to either stay awake or to fall 

asleep. The two most common substances

employed in this capacity are caffeine

and ethanol. 

Self-medication can lead to dose-related

impairments in sleep/wake architecture and 

in other physiological parameters that indirectly impair sleep/wake quality. The use 

and misuse of other prescription and recreational drugs—including psychostimulants

(methamphetamine, cocaine), sedative/

hypnotics (barbiturates, benzodiazepines), 

opiates (heroin, oxycodone), androgenic

steroids, and so-called “club drugs” (e.g.,

MDMA)—can be accompanied by adverse

physiological consequences, including significant alterations in circadian rhythms 

and sleep/wake architecture. 

In addition to these drug-induced effects 

on normal sleep/wake rhythms, individual 

differences (including important gender and

age factors) in the pharmacological response

to drugs are also important. In addition to

gender and age effects, these differences 

also result from genetic differences in 

pharmacodynamic effects and drug 

metabolism. However, a wide gap still 

exists in understanding the potential role 

these diverse factors play in sleep/wake 

pharmacology. Future insights into the 

pharmacology of arousal states must 

include greater focus on pharmacogeneticbased studies, both in humans and in 

appropriate animal models of sleep/wake 

and circadian rhythm disorders.

PROGRESS IN THE LAST 5 YEARS

The original 1996 Sleep Disorders Research

Plan provided no explicit recommendations

regarding the specific investigation of the

pharmacology and pharmacogenetics of 

sleep and arousal. Implicit in the recommendations, however, was an appreciation 

of the impact and scope that drugs have 

on normal sleep/wake processes. Conversely,

both primary and secondary sleep disorder

phenotypes can be triggers for prescription

and nonprescription drug use that may, as a

side effect, exacerbate disturbances in sleep.

Building on existing knowledge regarding 

the effects of a wide spectrum of drugs on

sleep and waking behavior, the 1996 Plan 

has resulted in important, incremental 

progress in several relevant areas.

• The increase in the number of investigatorinitiated applications and responses to 

NIH-sponsored initiatives has led to funded

research bearing directly on pharmacologic

perturbations of the sleep/wake cycle.

PHARMACOLOGY AND PHARMACOGENETICS

OF SLEEP AND WAKING
20 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Relevant areas of research have included: 

(1) efficacy of caffeine on sleep inertia

and cognitive performance, (2) pharmacotherapy for sleep/wake disorders in 

aging, (3) rational pharmacotherapy 

of primary insomnia, (4) treatment of 

hypnotic dependence, and (5) the effects 

of hormone replacement therapy on 

sleep measures in postmenopausal 

women. Results from these and other 

studies have led to a better understanding of drug efficacy in several medical 

conditions as well as the extent of individual differences in drug effects on

sleep/wake measures. 

• We now have a better understanding 

of the effects of prenatal and postnatal 

cigarette smoke exposure in Sudden Infant

Death Syndrome (SIDS) (see Section VI), 

the effects of opioids on rapid eye movement (REM) sleep suppression, the effects 

of leptin on ventilatory and respiratory 

control, and the effects of psychopharmacological therapy on sleep in the major

mental disorders. Furthermore, there 

have been important advances in our

understanding of the effects of the major

drug classes on sleep disorders in animal

models and the brain circuits where these

drugs are believed to act.

• Preclinical neuroscience research has 

provided new insights into the complex 

circuitry, neurotransmitters, and neuromodulatory substances involved in sleep/wake

regulation and their interaction with brain

circuits involved in circadian rhythm control.

Findings from research in fruit flies, animals,

and humans have added considerably to

our knowledge of the complex regulation 

of behavioral state. Because of these findings, greater opportunity exists to better

understand the actions of drugs on the

brain, and also to investigate novel classes

of drugs that have nontraditional mechanisms of action on receptor systems within

these newly refined brain circuits.

• Research has delineated the molecular 

basis of narcolepsy and circadian rhythm

disorders (see Section V). Genes responsible

for these disorders have been positionally

cloned and found to code for specific 

proteins, some of which are receptors for 

other small molecules that could be targets

for chemically synthesized drugs. These

might be effective for sleep/wake pharmacology. Indeed, the clinical utility of drugs

such as modafinil and gammahydroxybutyrate (GHB) for narcolepsy, and selective

dopamine receptor agonists for treatment

of RLS, has been demonstrated. In addition,

while short-term pharmacologic treatment

for insomnia has been demonstrated to be

efficacious, most Insomnia is chronic, not

short-term. No carefully conducted studies

have examined the longer-term pharmacologic treatment of insomnia, including

issues such as efficacy, safety, or the 

relative advantages of different agents.

• Genome screening and single nucleotide

polymorphism (SNP) analysis have been 

initiated in Sleep-Disordered Breathing

(SDB), RLS, Alzheimer’s disease, and fatal

familial insomnia (see Section V). These 

diseases have major sleep/wake disruptions

and are potentially subject to new forms 

of pharmacotherapy. Individual differences

in the response to such treatments may

relate to genetic differences.

• New knowledge has been achieved 

regarding the pharmacotherapy of 

insomnia in alcoholics, the physiological 

correlates of chronic alcohol ingestion in

both basic and clinical studies, and the

interactions between adolescent sleep, 

life-style and alcohol use. In addition, 

sleep and the effects of alcohol in 

alcohol-dependent subjects are now 

better understood, although more work

needs to be done. Alcohol has been 

shown to alter circadian clock function

when exposure takes place in the early

postnatal period in rat pups. Studies 

on selectively bred mice and rats have
SECTION I—BASIC SLEEP SCIENCE 21

demonstrated both ethanol-related metabolic variations as well as wide variations 

in ethanol-induced narcosis, indicating

strong genetic regulation of ethanol

pharmacology. Ethanol appears to have 

sensitive, pharmacological actions primarily

on brain NMDA (N-methyl-D-aspartate) 

and GABA (gamma-aminobutyric acid)

receptor subtypes, offering the possibility 

of novel pharmacotherapy. In human studies, virtually every type of sleep problem 

has been observed in alcohol-dependent

patients. Their sleep patterns are fragmented and typical encephalographic (EEG)

rhythms are altered. Sleep changes persist

for months or even years of abstinence, 

and alterations in sleep architecture appear

to be predictive of relapse to alcoholism.

Other studies indicate that alcohol aggravates SDB and further increases the decrements in cognitive performance resulting

from sleep deprivation. Both gender and

ethnic differences in the response to 

ethanol and other abused drugs have 

been studied, but additional research is

needed. Future studies should include 

studies of sleep/wake measures during 

drug withdrawal and during relapse to 

drug taking.

• Morphine and similar opioid drugs cause

selective decreases in REM sleep through

actions on brainstem cholinergic neurons,

neurons known to participate in the 

initiation of this sleep state. This may 

have relevance for the treatment of pain

as well as for understanding treatment 

efficacy of opioids in RLS.

• Sleep effects of therapeutic psychostimulant treatment in ADHD in both adolescents

and adults have received some attention,

but results are so far inconsistent. Also, 

gender differences have not been adequately studied. Particularly in adults, 

underlying sleep/wake abnormalities 

have been reported in ADHD patients 

that can be exacerbated with medication,

particularly dextroamphetamine. 

RESEARCH RECOMMENDATIONS

• Consolidate the recent gains made in the

descriptive anatomy and neurochemistry 

of sleep/wake generating systems by 

investigating the hierarchies of neurotransmitter interactions within these complex circuits. These studies would facilitate

the development of drugs to treat sleep 

and waking disorders and also lead to a

better understanding of the neuropharmacology of behavioral states.

• Encourage studies of the relative efficacy,

safety, and long-term effects of psychostimulants (e.g., methylphenidate, damphetamine, modafinil, and caffeine), 

and hypnotics (particularly benzodiazepine

receptor agonists and antidepressants) 

related to sleep/wake measures in animal

models and humans, including appropriate

patient populations. These pharmacological

assessments should also be assessed with

regard to potential interactions and efficacy

of 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 responses 

to both prescription and nonprescription

pharmacological agents.

• Investigate acute and long-term sleep/

wake consequences of all classes of 

abused drugs (including ethanol) as 

unique, self-administered pharmacological agents. Both clinical and basic studies

are needed.

• Encourage pharmacological studies 

of genetically/molecularly engineered 

animal models for sleep disorders. Existing genome databases can be used to 

elucidate sleep/wake-related response 

to drug effects and to facilitate the 

discovery of new targets for sleep/wake 

disorder medications.
22 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Encourage development of state-of-the 

art technologies to measure the effects of

drugs on sleep, circadian physiology, and

alertness in animal models and human 

subjects (e.g., genomics, expression 

arrays, proteomics, neurochemical, 

chemical, imaging, encephalographic

analysis, etc.).

• Evaluate whether the identification 

and treatment of sleep disturbances can

improve the clinical course of patients 

with alcoholism and other substance 

use disorders.
SECTION II

RESTRICTED SLEEP: 

NEUROBIOBEHAVIORAL AND

PHYSIOLOGICAL EFFECTS

• Sleep Deprivation in Adults 

• Sleep Deprivation in Children and Adolescents

SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 25

BACKGROUND

Studies on the effects of sleep loss on 

neurobehavioral functions, especially neurocognitive performance, have two primary

emphases: (1) specification of the properties 

of tasks (e.g., cognitive versus physical; long

versus short duration) that make them sensitive to sleep loss; and (2) specification of the

aspects of performance (e.g., cognitive processing speed versus accuracy, declarative 

versus implicit memory processes) that are

impacted by sleep loss. There has been controversy regarding the likely nature of sleep

loss-induced performance deficits (e.g.,

whether they reflect true deficits in physiological function of the brain, a motivational

effect reflecting reprioritization of the reinforcement hierarchy, an initiation of sleep

onset mechanisms in the face of waking 

performance, or some combination of these

processes). This controversy remains unresolved due to lack of understanding of the

function(s) of sleep, the physiological processes affecting recuperation during sleep, 

and the neurobiology of sleepiness. 

Implicit in this research has been the assumption that total and partial sleep deprivation

produce qualitatively similar decrements in

brain function and/or motivation levels that

differ only in degree. As a result, the overwhelming majority of studies in which the 

relationship between sleep and performance

has been explored have utilized the more efficient total sleep deprivation procedures, and

very few studies have examined the effects 

of chronic sleep restriction. Furthermore, of

these few studies only a very small subset 

have included adequate and objective 

verification of compliance with the sleep

restriction regimen being studied. 

Nevertheless, partial sleep deprivation is 

more pervasive than total sleep deprivation.

Epidemiological studies suggest that mean

sleep duration has decreased substantially as

proportionally more people are awake more 

of the time. These decreases are due, in part,

to expanded possibilities for nighttime activities that accompanied the introduction of 

electric light and other technologies and to 

the more recent trend toward expansion of

both manufacturing and service sectors to 

24-hour-per-day operations. Sleep restriction

appears to be an almost inevitable consequence of nighttime shift work. 

Because of the scarcity of chronic sleep 

restriction experiments despite a wealth of

total sleep deprivation/performance studies,

theoretical and practical questions remain: 

• What are the physiological processes 

mediating neurobehavioral performance

deficits resulting from sleep loss? 

• What accounts for the wide individual 

differences that emerge in the ability to

maintain performance during sleep loss? 

• Do the physiological and neurobehavioral

responses to chronic partial sleep loss differ

from those resulting from total sleep loss?

• Relative to the adverse neurocognitive 

and physiological effects of sleep loss, 

SLEEP DEPRIVATION IN ADULTS
26 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

is there habituation/adaptation or 

potentiation/sensitization to repeated 

exposure to sleep loss? 

• Are there physiological and/or behavioral

adaptations or dysfunctions in sleep or 

circadian physiology in response to chronic

sleep restriction (e.g., a change in sleep

itself or the brain’s recovery response to

chronically inadequate sleep)? 

• Are the neurobehavioral and physiological

effects of chronic partial sleep loss different

at different circadian phases? 

• What are the physiological processes that

affect restoration of cognitive performance

capacity during recovery sleep, and are

these processes reflected in any currently

measured sleep parameters? 

• How much recovery sleep is required 

following chronic partial sleep loss versus 

total sleep deprivation? 

• What are the effects on neurobehavioral

functions of long-term (weeks, months,

years) exposure to a typical work or school

schedule of 5 or more days of sleep restriction followed by 2 days of recovery?

Research on sleep loss countermeasures in

healthy adults, including pharmacological 

and nonpharmacological interventions, such 

as napping strategies, has practical and 

theoretical relevance. Studies on the efficacy,

long-term effectiveness, and safety of 

repeated use of traditional stimulants (e.g.,

caffeine, d-amphetamine, methylphenidate)

and novel wake-promoting agents (e.g.,

modafinil) for maintenance of performance 

in healthy adults engaged in emergency

and/or continuous operations are needed.

Complementary studies of sleep-inducing

and/or phase-shifting drugs (e.g., benzodiazepine agonists, melatonin) to enhance 

sleep and subsequent alertness/performance

(e.g., shift work, transmeridian travel, or 

recovery from continuous operations) will 

also continue to expand from the clinical 

to the operational realm. 

Napping strategies and sleep scheduling 

will constitute at least part of any comprehensive strategy to maintain alertness and 

performance during extended continuous

operations. Cell phones, beepers, and other

communication devices can put some 

workers in a perpetual “on-call” status in

which sleep might be interrupted by need 

for rapid decisions and/or other duty-related

tasks. Studies of sleep inertia (and sleep inertia countermeasures), therefore, will be of

increasing relevance and importance. Finally,

exploration into the physiological effects of

acute and chronic sleep loss in vital organ 

systems other than the brain has only 

just begun.

PROGRESS IN THE LAST 5 YEARS

• Functional brain imaging studies and 

electroencephalographic (EEG) brainmapping studies show that the patterns 

of functional connectivity between brain

regions, evident during performance of 

specific cognitive tasks, are altered by 

sleep loss. This suggests that maintenance

of performance during sleep loss may

depend upon regional functional plasticity.

• Recent experiments have documented 

precise dose-response effects of chronic

sleep restriction on waking neurobehavioral

and physiological functions, suggesting that

the cumulative waking neurocognitive

deficits and state instability that develop

from chronic sleep loss have a basis in a

neurobiological process that can integrate

homeostatic pressure for sleep across days. 

• There have been increased efforts to 

determine the roles of rapid eye movement (REM) sleep and non-rapid eye 

movement (NREM) sleep in memory consolidation, although definitive evidence 

for such relationships remains elusive.
SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 27

• Plasticity in visual cortices during a critical

period in some animal studies is NREM

sleep-dependent. This suggests that one

function of sleep is to facilitate the functional organization of the brain, and that

there are sleep-dependent aspects of putatively related processes such as long-term

potentiation (LTP) and DNA repair. 

• Genetic array techniques have identified 

the patterns of gene expression that 

characterize and differentiate sleep and

wakefulness. This information will help 

in understanding the most basic cellular

processes mediating performance and 

alertness deficits following sleep loss, and

the restoration of performance capacity 

and alertness during subsequent sleep. 

• Studies have identified those aspects of 

performance that are most susceptible to

sleep inertia, their differential time courses,

and have begun to identify sleep inertia

countermeasures (e.g., caffeine). 

RESEARCH RECOMMENDATIONS

• Determine the physiological and behavioral

processes mediating the state instability

(manifested as increased variability in alertness and neurobehavioral performance) 

that result from acute versus chronic sleep

loss. Compare these processes with those

mediating the alertness and performance

deficits that characterize pathologies 

such as narcolepsy, Sleep-Disordered

Breathing (SDB) (see Section V), and 

closed head injury.

• Identify the full range of psychological,

behavioral, and physiological (e.g.,

endocrine, immune, cardiovascular, liver,

muscle, etc.) consequences of long-term

cumulative partial sleep deprivation and

their underlying mechanisms.

• Discover the physiological processes 

mediating restoration/recovery of alertness

and performance by sleep. This includes 

elucidation of the basic mechanisms that

contribute to the time course of recovery

within and between days, as well as 

determining whether there are longerduration time constants for reversal of the

cumulative neurobehavioral deficits that

accrue during chronically restricted sleep.

• Determine whether and how factors such 

as cognitive activity/workload and physical

activity/work modulate sleepiness.

• Identify factors accounting for individual 

differences in sleep need and in the 

apparent differential vulnerability among

people with similar sleep needs in their 

neurocognitive and physiological responses

to sleep deprivation. Once the stability and

reliability of these individual differences 

are established, a search for stable and 

reliable biological and behavioral predictors to establish a phenotype can then 

be investigated.

• Determine the physiological basis and

behavioral characterization of sleep 

inertia effects, and study the comparative effects of possible countermeasures 

for sleep inertia.

• Assess the physiological modulation 

of sleepiness by stimulant and wakepromoting pharmacological agents, 

focusing on their sustained efficacy and

safety for acute and chronic sleep deprivation, the impact of repeated dosing, 

and the effect of these agents on recovery sleep homeostasis and on the 

“recycle rate” (the speed with which 

full recovery from sleep loss is achieved,

preparing the individual for initiation of

another episode of sleep restriction/

deprivation).
28 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Many fundamental questions regarding 

basic physiologic processes mediating sleepiness and alertness and the neurobiological

processes underlying the cumulative neurobehavioral effects of chronic and intermittent

sleep restriction are important in understanding their effects on the developing brain. Very

little is known about the extent to which the

relative plasticity of neural systems in children

affects their vulnerability to adverse neurobehavioral, cognitive, emotional and physical

consequences of sleep loss, and how sleep

restriction affects a variety of neurodevelopmental processes.

Compared to adults, little is known about 

the magnitude and distribution, causes, 

consequences, and assessment of sleep loss

and sleepiness in children and adolescents.

Because the neurobehavioral manifestations 

of sleepiness in children may differ substantially from those of adults, the first challenge 

is to operationally define sleepiness in children. Objective, reliable, and cost-effective

measures of sleepiness and alertness in 

children are lacking—particularly measures

that could be applied to large epidemiological samples. In addition, subjective self-report

data regarding sleepiness are largely unavailable in children, and behavioral manifestations

of sleepiness not only vary with age and developmental level but also are often not reliably

interpreted by parents and other caretakers. 

Empirical studies involving both normal 

and sleep-deprived pediatric populations 

(e.g., children with sleep disorders, 

adolescents) have described the extent 

and consequences of inadequate or disrupted sleep in children. A few studies have

examined mood, behavior, and performance

changes resulting from acute sleep loss in 

children in experimental settings, but results

have been inconsistent. Profiles of neurobehavioral and cognitive deficits related to

chronic sleep loss and cumulative sleep debt

in children are even less well defined, and 

little is known about the functional impairments that can develop in “real world” 

activities such as school performance, 

social relationships, behavior at home, 

and extracurricular and safety-sensitive 

activities (e.g., sports, driving).

Furthermore, few studies have attempted 

to use neuroimaging or metabolic techniques in children and adolescents to 

correlate changes secondary to sleep loss 

with alterations in specific brain functions

known to occur in adults, e.g., complex 

tasks modu-lated by the prefrontal cortex.

Despite potentially important adverse effects

of sleep loss on neuroendocrine, metabolic,

immunologic, cardiovascular, and other 

physiologic systems in the developing 

organism, the relationship between sleepiness and these physiologic parameters in 

children is largely unexplored. 

SLEEP DEPRIVATION IN CHILDREN

AND ADOLESCENTS
SECTION II—RESTRICTED SLEEP: NEUROBEHAVIORAL AND PHYSIOLOGICAL EFFECTS 29

An additional challenge is to examine variables that may serve as relative risk-promoting

or protective factors for the effects of sleep

loss in children, including those that may be

genetically determined. These variables may

yield important information about the 

development of interindividual differences 

in vulnerabilities to sleep loss that extend 

into adulthood. In addition, understanding

these variables will allow definition of vulnerable populations, including racial and 

ethnic minorities and underserved children, 

in whom early intervention may be necessary

for maintenance of health and prevention of

long-term sequelae. 

PROGRESS IN THE LAST 5 YEARS

• Epidemiologic studies have begun to

explore selected relationships between

chronic partial sleep deprivation and 

sleep disruption related to primary sleep 

disorders, mood and performance deficits

in children and adolescents, and academic

failure. Studies of sleep in children with 

primary behavior and learning problems

have further supported an association

between sleep restriction and performance

impairments. Evidence indicates that children experience significant daytime sleepiness as a result of disturbed or inadequate

sleep, and most studies suggest a strong

link between sleep disturbance and 

behavioral problems.

• Studies delineating the neurobehavioral,

cognitive, and emotional effects of sleep

loss in experimental settings in adolescents and older school-aged children 

have broadened our understanding of 

the similarities and differences that exist

between adults and children and between

children of different ages. Decreased 

positive mood in association with sleep 

disturbance is a consistent finding.

Neuropsychological profiles of impairment

have been less consistent, however, with

more reliable effects on attention/response

inhibition, and variable effects on motor

skills, memory, verbal creativity, problem

solving, and general cognitive abilities.

RESEARCH RECOMMENDATIONS

• Establish the incidence and prevalence 

of chronic sleep loss and sleepiness in 

children using objective, standardized, 

and cost-effective methods of assessing

sleepiness and/or its functional consequences at all stages of maturational 

development. Specific vulnerable and 

at-risk populations for adverse consequences of sleep loss and sleepiness 

should be identified, as well as relative 

risks and protective factors for the expression of sleep-deprivation effects. 

The biological and behavioral factors 

that result in sleep loss in children and 

adolescents also need to be identified.

• Identify deficits in specific neuropsychological domains and patterns of impairment resulting from acute and chronic 

sleep loss in children at various developmental stages, including higher level 

cognitive processes, such as attention, 

motivation and emotional regulation.

Neuroimaging and other novel techniques should be utilized to examine 

the neurophysiologic effects of sleep 

loss on cognition and performance 

in the developing human.

• Examine the bidirectional effects of 

sleep loss and sleepiness on the immune,

neuroendocrinologic, metabolic, cardiovascular, and other physiologic systems, 

and identify developmentally appropriate biologic markers for the effects of 

sleep loss.

SECTION III

ENABLING TECHNOLOGY

• Analysis of Sleep-Wake States

• Genetics and Proteomics: Phenotype Issues 

and Methodological Approaches 

• Functional Neuroimaging of Sleep and 

Wake States

• Post Mortem Brain Analysis in Sleep 

Disorder Patients 

SECTION III—ENABLING TECHNOLOGY 33

ANALYSIS OF SLEEP-WAKE STATES

adverse outcomes such as neurocognitive

impairment or cardiovascular disease). 

As a result, new methods to both measure

and quantify SDB and its consequences 

are needed.

Currently utilized methods for recording 

sleep and breathing not only have the quantitative problems described above but are 

also cumbersome and expensive. They do not

allow for the evaluation of large populations

suspected of having potential sleep disorders

or for the completion of substantial epidemiologic evaluation of normal or at-risk populations. Simple, noninvasive methodologies to

directly or indirectly monitor sleep, respiration,

and other physiologic variables thus need 

to be developed both for the screening 

and diagnosis of sleep disorders and for 

epidemiologic investigation.

PROGRESS IN THE LAST 5 YEARS

• Meaningful standardization of the 

methods, equipment, and definitions 

for SDB and associated syndromes has 

been accomplished. 

• Numerous studies, ranging from a 

single signal (generally oximetry) to full

polysomnography, have investigated 

simplified systems to measure sleep 

and respiration in the home, but have 

yielded varied results. However, none of

these approaches has been sufficiently

effective to be commonly utilized in 

routine clinical practice.

BACKGROUND

The monitoring of sleep states is accomplished

using several electroencephalographic (EEG)

leads in combination with electrooculographic

(EOG) and submental electromyographic

(EMG) signals. These variables are scored in

combination using a system described by

Rechtschaffen and Kales (R and K) in the 

early 1960s to yield non rapid eye movement

(NREM) stages 1 to 4 sleep and rapid eye

movement (REM) sleep. Although this system

has been useful, it also has weaknesses. The

principal weakness is the inability to easily

detect and quantify microarousals or subtle

disruptions of sleep. Thus, the full impact of

many sleep disorders on sleep architecture

cannot be meaningfully quantified. In addition,

measures of sleep staging, sleep continuity,

and sleep disruption do not accurately predict 

subsequent performance. Although there 

are several possible explanations for this poor

relationship, the limitations of the R and K,

despite new definitions applied to it, preclude

measurement of sleep micro-architecture and

its disruptions. Therefore, new methods are

needed to monitor and quantify sleep.

The quantification of breathing abnormalities

during sleep also presents a unique challenge.

Until recently, there were no standard definitions of apneas, hypopneas, or the clinical 

syndromes associated with these events.

However, even after the standardization of

equipment, measurement techniques, and 

definitions, the current methods of assessment of Sleep-Disordered Breathing (SDB)

seem to predict little regarding associated
34 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• New assessments of EEG signals 

(primarily frequency analyses) and 

heart rate variability have provided 

new insight not only into sleep itself, 

but also into the consequences of 

sleep disruption.

RESEARCH RECOMMENDATIONS

• New methods are needed to measure 

and quantify the structure of sleep. 

These methods should be outcome 

focused such that what is measured 

predicts not only the restorative processes 

of sleep, but also the results of disrupting

this process. Sophisticated, computerbased signal-processing methodologies

should be applied, using both linear 

and nonlinear dynamic approaches. 

The result should be a quantitative 

assessment of both the macro and 

micro structure of sleep.

• New approaches are needed for the 

measurement, assessment, and quantification of physiologic/biologic variables 

during sleep. Such methods should be 

easily accomplished to permit broad 

applicability, quantitative, and predictive 

of the consequences of the sleep disorder

under assessment. The focus should be 

on novel, noninvasive approaches that 

do not require labor-intensive, expensive

scoring, perhaps including microtechnology, should be.

• Portable ambulatory systems to measure

sleep and other physiologic variables 

(respiration, leg movements, etc.) reliably 

in the home environment are needed. 

These systems should be inexpensive, 

easy to use both for screening and for 

diagnosis of sleep disorders, and be 

applicable for large-scale epidemiologic

studies. Furthermore, these systems 

should measure variables that are 

outcome-focused such that the 

results can be utilized to both predict 

consequences and define the need 

for therapy.

• New methods are needed to define 

circadian phase in the clinical setting 

such that the role of circadian abnormalities in disorders such as insomnia

can be determined. Such methods 

would also allow for more precise 

manipulation of circadian phase 

when appropriate.
SECTION III—ENABLING TECHNOLOGY 35

BACKGROUND

Sleep behavior is extremely variable across 

and within animal species, suggesting the

importance of genetically based differences.

Limited genetic epidemiological data indicate that many sleep disorders have a strong

genetic component. Advances in genetics 

and genomics have been spectacular and

include sequencing the genomes of various

organisms and high-throughput studies using

genetic arrays and polymorphic markers.

Animal models of sleep and circadian disorders with selected genetic alterations are

now being generated. Similar developments 

in the area of protein characterization and 

the more general field of proteomics are 

now rapidly developing. The field of sleep 

disorders medicine is now well-positioned to

take advantage of these new technologies.

A solid foundation in the area of phenotyping sleep and its disorders in both animals 

and humans is needed before proceeding 

with genetic analysis. The discovery of new

methods and improvements in existing sleep

recording techniques in humans are also 

needed. When performing genetic studies, 

it is important to consider potential study

design limitations. The strength and location

of linkage regions identified, for example,

depends on the strength and precise phenotype selected. Thus, linkage regions may 

not be identified if the power of the study 

is insufficient, and large numbers may be

required for such studies to be successfully

accomplished. Even if linkage regions are 

identified, these may be large and contain

many candidate genes. Sequencing of 

candidate genes may not yield mutations 

or may identify mutations that are not 

relevant to the phenotype. In this case, 

the use of complementary approaches such 

as DNA expression arrays and proteomics to

identify novel genes of interest may be a 

powerful approach to identify relevant 

candidate genes.

Molecular correlates of sleep and diurnal

rhythms would be important for a wide 

range of clinical studies. Much human 

research relies on blood samples, which 

are easily obtained, but often there is little

knowledge about chronobiologic variations 

in the parameters being measured, and no

regard for the time of day or the sleep 

history of the subject when the sample is

taken. The impact of sleep and diurnal 

variation on other systems is exemplified 

by blood coagulation and thrombotic tendencies. Myocardial infarctions or strokes 

occur more often in the morning, and blood

properties such as platelet aggregation may

change during the day. It would be useful 

to have molecular markers to assess chronobiologic and sleep history variability. 

PROGRESS IN THE LAST 5 YEARS

• There have been advances in technology

development in the area of sleep phenotyping in mice. In the clinical arena, sleep

recording devices have been made more

portable and easier to use. Similar progress

has been made in automated sleep scoring

GENETICS AND PROTEOMICS: PHENOTYPE ISSUES AND

METHODOLOGICAL APPROACHES
36 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

algorithms that utilize concepts such as

neural networks, fuzzy math, and wavelet

fitting, allowing for more rapid analysis 

and the possibility of high-throughput 

sleep phenotyping.

• Eight genes that significantly contribute 

to the generation of circadian periodicity

have been isolated in mammals. Recently,

studies in humans have shown, for the 

first time, a correspondence between

human and animal sleep phenotypes. 

Most strikingly, a mutation in the gene

HPER2—a gene known to be involved in

the regulation of circadian rhythmicity in

mammals—was demonstrated to cause

Familial Advanced Sleep Phase Syndrome

(FASPS) in a human family. Additionally a

polymorphism in CLOCK, another gene

involved in the generation of circadian

rhythmicity, was found to influence 

morningness-eveningness tendencies in

humans. These studies are likely to be

extended and lead to discovery of other

human mutations and polymorphisms

affecting circadian regulation. 

• Similar progress has been made using 

a genetic approach in narcolepsy (see

Section V). Using a positional cloning

approach, mutations in the hypocretin

receptor 2 gene) have been isolated in a

canine model of narcolepsy. The knockingout of preprohypocretin, a gene initially

believed to be involved in appetite regulation, led to the establishment of a murine

model of narcolepsy. These findings were

found to be directly applicable to human

narcolepsy-cataplexy, as it has been now

shown that most patients have a hypocretin deficiency. This last finding is 

remarkable as the disorder in humans is

genetically complex and HLA-associated.

These results demonstrate the importance

of careful phenotyping of human sleep 

disorders to reduce disease heterogeneity

and the importance of animal models.

• Genome screening and genetic association studies have been initiated in 

Sleep-Disordered Breathing (SDB) and

Restless Legs Syndrome (RLS) (see Section

V). Significant linkage results have been

reported and await confirmation. In the

candidate gene area, an association

between APOE e4 and sleep apnea

has been reported and will need to 

be replicated.

RESEARCH RECOMMENDATIONS

• Develop new methods to measure sleep, 

circadian physiology, and sleepiness in 

large numbers of animals and human 

subjects. One goal is to develop and 

validate surrogate measures. Another 

goal is to define normal sleep-pattern 

variation in the general human population.

Normative data will also be critical to define

and validate existing or novel sleep disorder

phenotypes. These data will be needed to

elucidate corresponding genetic factors.

• Continue the study of animal models, 

such as the fruit fly, zebra fish, and mice 

to enhance our understanding of physiology and circadian biology. Use of these

models to study sleep or the regulation 

of rest/activity should be a priority, as this

may lead to the discovery of novel sleepregulatory pathways. Powerful new 

genetic approaches, such as those used 

to discover circadian clock genes (e.g.,

mutagenesis screens), can be used to find

new genes that are involved in the homeostatic need to sleep and in interactions

between the circadian and sleep-wakefulness systems. Other approaches, such as

“quantitative trait loci,” should be considered insofar as true “sleep knockouts” 

may be not viable in mutagenesis screens.

• Identify new disease phenotypes, including

rare familial sleep disorders or subtypes of

current sleep disorders based on treatment
SECTION III—ENABLING TECHNOLOGY 37

response or other characteristics. The study

of multiplex families where sleep disorders

appear to be segregating as a single gene

could lead to the positional cloning of 

novel sleep disorder-related genes. This 

may facilitate our understanding of other,

more common sleep disorders, as well as

increase our understanding of the normal

physiology of sleep.

• Study interindividual differences in 

baseline sleep, circadian physiology and

response to sleep deprivation in a large

number of subjects to better define 

normal and pathological conditions. 

Recent results indicate large interindividual

differences in how people react to sleep

deprivation. Additionally, subjective sleepiness varies significantly in patients with

equivalent degrees of SDB and sleep 

fragmentation. The study of these interindividual differences has both clinical 

and basic research relevance.

• Twin prevalence and segregation analysis

studies need to be conducted for all sleep

disorders across various populations in 

order to estimate heritability and environmental contributions for each sleep 

disorder. This will help prioritization and

design of further genetic studies.

• Genome screening studies using classical

family design and candidate gene-based

research should be continued and extended. Since most sleep disorders are

genetically complex, large numbers will be

needed and there is a need to encourage

the blending of epidemiological and genetic

designs. Ethnic variation in the expression

and the genetic basis of various sleep disorders has been identified and will require

further exploration. Studies of SDB, RLS,

and other disorders such as hypersomnia

will benefit from this approach. 

• Genetic array and proteomic studies 

in selected tissue samples or proteinprotein interaction experiments should 

be encouraged. These new techniques 

can be extremely useful to discover 

novel components within a molecular 

or a disease pathway. 

• Mouse models are increasingly used 

in genetic and behavioral studies, and 

have been created but not yet widely 

utilized in narcolepsy. A large number of

mice with various genetic alterations are

being created in multiple laboratories but

are rarely tested for sleep abnormalities.

Finding sleep abnormalities in some of 

these models could lead to the discovery 

of novel sleep regulating pathways that 

may be involved in selected sleep disorders.

To remedy this situation, there is a need 

for developing and distributing genetically

determined animal models for sleep disorders. Collaborative efforts should be

explored to phenotype sleep in mice 

models for investigators that are working outside of the field of sleep research.
38 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Although the physiological and adaptive 

functions of sleep remain to be clarified, 

it is clear that sleep and wakefulness are 

neurologically mediated. Sleep researchers

have employed behavioral observations, 

clinicopathologic observations, correlative 

studies with polysomnographic measures, 

and extrapolations based on invasive research

in non human subjects in order to characterize

and understand the brain processes mediating

and constituting sleep and wakefulness. Each

of these approaches continues to yield new

knowledge about sleep and the brain, and

each provides a unique view, or “level of

analysis,” of sleep and brain functioning 

ranging from the behavior of single neurons 

to the behavior of the entire organism. The

ultimate result of this multifaceted approach 

is likely to be a comprehensive and coherent

understanding of sleep. 

Functional brain imaging techniques, such 

as positron emission tomography (PET), 

functional magnetic resonance imaging

(fMRI), Magnetic Resonance Spectroscopy

(MRS), single photon emission computed

tomography (SPECT), magnetoelectroencephalography (MEG), and near-infrared 

optical imaging (NIR) have enabled new 

and unique analyses in the study of sleep 

and waking. These techniques allow measurement of metabolic and neurochemical activity

throughout the brain, and can discern dynamic patterns of regional cerebral activity during

various brain states, including stages of sleep

and levels of alertness during wakefulness or

during functional challenge. Furthermore,

these techniques are likely to enhance 

identification of both normal and abnormal

sleep/wake processes. 

PROGRESS IN THE LAST 5 YEARS

• Functional neuroimaging techniques 

(primarily PET) reveal that non-rapid eye

movement (NREM) sleep is associated with

deactivation of centrencephalic regions

(brainstem, thalamus, basal ganglia) and

multimodal association cortices (e.g., 

prefrontal and superior temporal/inferior

parietal regions). Rapid eye movement

(REM) sleep is characterized by reactivation 

of all centrencephalic regions deactivated

during NREM sleep except the multimodal

association areas. Thus, deactivation of 

the multimodal association areas has 

been shown to be a defining characteristic of sleep.

• PET studies during sleep-deprived wakefulness reveal regional cerebral deactivations

that are especially prominent in prefrontal

and inferior parietal/superior temporal 

cortices, and in the thalamus. These 

patterns are similar to that found during 

NREM sleep, but the deactivations are of

lesser magnitude than during NREM sleep.

This pattern is consistent with, and helps

explain, the nature of cognitive performance deficits that occur during sleep loss.

Considered together with results of sleep

studies, this pattern suggests that NREM

sleep initiation and sleep-deprived wakefulness in healthy individuals are manifestations of related neurobiological processes. 

FUNCTIONAL NEUROIMAGING OF SLEEP

AND WAKE STATES
SECTION III—ENABLING TECHNOLOGY 39

• Relative activation/deactivation patterns

revealed by fMRI techniques during performance of cognitive tasks suggest that

maintenance of performance following

sleep loss may be a function of the extent

to which other cortical brain regions can 

be recruited for task performance in the

sleep-deprived state. This is one of a 

number of possible ways that individual 

differences may occur in the ability to 

maintain alertness and performance 

following sleep loss.

• PET, SPECT, and fMRI studies reveal 

that a subset of depressed patients 

show initially elevated activation in 

anterior cingulate and medial orbital cortices. In these patients, sleep deprivation

reduces this regional hyperactivation, and

improvements in mood are a function of

the extent to which this activity is reduced.

These studies suggest possible mechanisms

by which antidepressant drugs may exert

their effects.

• PET scans reveal that the midbrain reticular activating system remains relatively 

active during stage 2 sleep—a finding 

that may account for the relatively heightened arousability that characterizes this

stage of sleep. 

• PET scans taken at 5 versus 20 minutes 

after awakening suggest that reemergence

of conscious awareness upon awakening

occurs as a function of centrencephalic

reactivation, and reestablishment of a 

specific pattern of functional interconnectivity between brain regions. These data 

also suggest that restoration of alertness

(e.g., dissipation of sleep inertia effects)

occurs as a function of reactivation and

reestablishment of functional interconnectivity patterns involving prefrontal 

cortices. These findings could constitute 

an important first step toward specification

of the physiological basis of post-sleep 

waking cognitive capability. 

RESEARCH RECOMMENDATIONS

• Perform neuroimaging studies that 

measure absolute as well as relative 

changes in brain metabolic activity and 

neurotransmitter levels. Such studies are

needed to: (1) determine the effects of 

sensory and cognitive demands on subsequent levels and patterns of regional brain

activity during both sleep and wakefulness

and as a function of state changes, and 

(2) to establish the functional neuroanatomy of sleep, wakefulness, alertness,

and cognitive capability.

• Apply the enhanced capabilities afforded 

by improved functional neuroimaging,

including greater temporal and spatial 

resolution, to study sleep and sleep disorders. These applications will help to 

determine the physiological correlates of

phasic events like eye movements during

REM, sleep-dependent changes in activity

levels of specific thalamic nuclei, and brain

changes subserving microsleeps and lapses

of attention. 

• Utilize functional neuroimaging techniques

to determine the functional neuroanatomy

of REM sleep, NREM sleep, and waking in

patients in sleep disorders such as narcolepsy, REM behavior disorder, and Restless

Legs Syndrome. Such studies will yield

insight into the pathophysiology of these

disorders. Similar studies in patients with

other disorders known to impact sleep

processes (e.g., depression, chronic pain

conditions) will yield insight into the 

pathophysiology of these disorders.

• Determine the effects of sleep and alertness-promoting pharmacological agents 

on patterns of regional brain activation/

deactivation and on occupancy/activation 

at specific receptor sites. Such studies will

elucidate the mechanisms by which these

agents impact sleep/wake processes, and

will facilitate the development of new
40 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

agents that might more specifically target

sleep/wake-relevant sites and receptors. 

• Develop new approaches to obtain

polysomnographic measures and other

physiological signals during MRI scanning 

to facilitate the study of sleep and alertness

unaffected by electromagnetic interference

from the MRI scanner. 
SECTION III—ENABLING TECHNOLOGY 41

BACKGROUND

The post mortem study of brains of patients

with sleep disorders has significantly contributed to our understanding of human 

sleep regulation and its dysfunction. Human

brain analysis at autopsy in sleep disorders 

is important for two major reasons: (1) it 

generates hypotheses from observations

directly in human tissues about the cellular 

and molecular mechanisms of human disease

for testing in animal models, cell culture systems, and genetic models; and (2) it tests the

relevance to human disease of observations

made in animal models and cell culture 

systems by examining specific cellular and 

molecular markers in human tissue samples. 

Currently, human neuropathology involves

analysis at the structural, neurochemical, 

cellular, and molecular levels, and its modern

tools hold promise of much-needed insights

into central and autonomic mechanisms in

sleep disorders. A potentially revolutionary 

tool for human brain analysis is microarray

analysis of gene expression in autopsied 

tissues. The potential of this genomic technology in human neuropathology to uncover

critical molecular abnormalities is illustrated 

by its recent application to post mortem brain

analysis in schizophrenia. With cDNA microarrays, altered gene expression was found in 

the frontal cortex in schizophrenic patients

compared to autopsy controls. The most

changed gene, which was never before 

linked to schizophrenia, was a regulator 

of G-protein signaling 4, suggesting schizophrenia is a disease of the synapse and thus

providing an opportunity to better understand

a devastating disorder whose basic mechanism(s) has been elusive.

Sudden Infant Death Syndrome (SIDS) represents a sleep disorder in which neuropathologic examination with modern neurochemical

techniques suggests abnormalities in a specific

brainstem region and neurotransmitter system,

namely the medullary serotonergic system).

These findings from human infant brains will

generate hypotheses to be tested in animal

models. Narcolepsy, on the other hand, represents a sleep disorder in which seminal observations in genetic animal models resulted in

subsequent delineation of the neuropathology

in affected human patients, e.g., deficiencies

in the hypothalamic hypocretin system. 

These two examples underscore the critical

need to analyze the human brain at autopsy in

patients with sleep disorders. National autopsy

networks and brain tissue banks may be needed to collect brain tissues from patients with

common, rare, or non-lethal sleep disorders,

and to disseminate affected and control brain

samples to interested sleep researchers. Some

national, NIH-supported brain tissue banks are

well established, and have proven vital to the

success of human brain research in neurodegenerative disorders such as Alzheimer’s disease and genetic disorders such as Rett syndrome). An informal survey of national brain

tissue banks, however, reveals virtually no

accrual of brains from patients with any primary sleep disorders except SIDS. Specialized

training of neuropathologists in the neuroanatomy, neurochemistry, and neuropathology of sleep will be needed, however, to make

optimum use of this new research resource. 

POST MORTEM BRAIN ANALYSIS IN

SLEEP DISORDER PATIENTS
42 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

PROGRESS IN THE LAST 5 YEARS

• The neuropathologic post mortem evaluation of brains in patients with narcolepsy

confirmed observations from animal models

that the major lesion is in the hypocretin

neurons of the lateral hypothalamus. A

reduced number of hypocretin neurons,

associated with gliosis, was reported in 

the hypothalamus of human patients with

narcolepsy, as well as, in a separate study,

the absence of hypocretin mRNA in the

hypothalamus and lack of hcrt-1 and 

hcrt-2 levels in the cerebral cortex and 

pons (target sites).

• The neuropathologic post mortem evaluation of brains in patients with Fatal Familial

Insomnia (FFI), a prion disorder, established

that the major lesions are in certain subnuclei of the thalamus that are interrelated to

the limbic system, and suggested a specific

role for these thalamic regions in sleep and

autonomic control that can now be tested

in animal models.

• Neuropathologic insights from analysis 

of SIDS and control brains at autopsy

revealed that a substantial subset of SIDS

victims have abnormalities in serotonergic

receptor binding in regions of the medulla

involved in chemoreception, respiratory

drive, blood pressure responses, and 

upper airway control. Dysfunction of 

serotonergic neurotransmission in the

medulla in affected infants may put them 

at risk for sleep-related sudden death 

when stressed by hypoxia and/or hypercarbia in a critical developmental period.

• Neuropathologic post mortem analysis 

in patients with dementia and REM

Behavior Disorder (RBD) revealed an 

association between Lewy body dementia

and RBD. Lewy bodies were present in

affected patients in regions of the brainstem involved in arousal, REM sleep, and

autonomic control. 

RESEARCH RECOMMENDATIONS

• Utilize established national brain tissue

banks for increased accrual and dissemination of brain samples and associated 

histories from patients affected by both 

primary and secondary sleep disorders 

(see Section V). The spinal cord should 

be likewise stored in certain cases in which

spinal cord involvement is postulated, e.g.,

Restless Legs Syndrome. The accrual of 

central nervous system (CNS) samples 

from control cases without sleep 

disorders will also be needed.

• Establish a National Autopsy Network 

for Sleep Disorders, and perhaps Centers 

for individual sleep disorders, in order to

assure accrual of brains from patients with

sleep disorders, including those that are 

rare and/or non-lethal. Such a network, 

for example, would alert pathologists 

that the brain of an individual with SleepDisordered Breathing (SDB) or insomnia

dying of an unrelated cause is of interest 

to sleep scientists and should be obtained

and processed as needed for neuropathologic analysis. Blood, cerebrospinal fluid

(CSF), and brain and spinal cord tissues

should be collected in addition to a 

detailed sleep history. 

• Apply state-of-the-art neurochemical, 

cellular, and molecular markers to the 

study of sleep disorders in human brain 

tissue, especially those without a pathologic correlate at the light microscopic 

level. Techniques should include gene

expression microarray technology, protein analysis with mass spectroscopy, 

tissue receptor autoradiography, in situ

hybridization for mRNA in tissue sections,

immunocytochemistry with single and 

double labeling, stereological cell counting, and electron microscopy combined 

with immunological markers.
SECTION III—ENABLING TECHNOLOGY 43

• Apply state-of-the-art genomic approaches

to post mortem brain analysis for novel

gene discovery and gene expression profiling in sleep disorders. Possible approaches

include microarrays, quantitative real-time

PCR assays, and serial analysis of gene

expression (SAGE). These methods, among

many others, provide information about

normal and abnormal gene expression 

in a tissue or cell. Details must be refined

regarding applicability of this technology 

in human brain tissues with variable agonal

conditions (e.g., pH changes) and post

mortem intervals. The methods for relating

expression data to disease-model databases

and gene sequence databases (e.g., single

nucleotide databases) will also require

refinement. Multifactorial and multilevel

analyses will need to combine massive 

gene expression datasets with the clinical

diagnosis, medication, family history of the

illness, and genetic heritage of each subject.

• Ensure neuropathology limbs to large, 

multi-institutional studies of human sleep

disorders for analysis and storage of specimens (e.g., brain, CSF, blood), and for 

correlation of neurochemical, cellular, 

and/or genetic markers with clinical 

pathophysiology.

• Analyze the spatial and temporal profiles 

of sleep-related molecules across development including aging in relevant brain

regions (e.g., hypothalamus, basal forebrain, brainstem, thalamus, cerebral 

cortex) in human post mortem brain.

SECTION IV

SLEEP AND HEALTH

• Normal Sleep, Sleep Restriction, and 

Health Consequences

• Sleep, Sex Differences, and Women’s Health

• Racial and Ethnic Disparities

• Sleep and Aging

• Sleep and Safety

• Sleep in Medical Conditions

SECTION IV—SLEEP AND HEALTH 47

BACKGROUND

Government publications, such as “Healthy

People 2000” and its sequel “Healthy People

2010,” contain recommendations for adequate nutrition and physical fitness for healthy

functioning, but no recommendations or standards for normal sleep duration and quality.

Epidemiological data have never been

obtained defining normal sleep and wakefulness as measured systematically by both

subjective and objective indicators in infants,

children, adolescents, young adults, middleaged and older adults. Only limited electroencephalographic (EEG) sleep data as a

function of age and gender are available 

from laboratory studies published more than

25 years ago. Data used to describe “normal”

EEG sleep from infancy to old age were based

on 1 or 2 nights of sleep recordings in a small

number of subjects in a laboratory setting.

Most of these studies were conducted prior 

to the establishment of accepted sleep monitoring and scoring standards. In fact, the 

most widely used reference of “normal”

human EEG sleep is based on studies in 

which EMG recordings were not used in the

scoring of rapid eye movement (REM) sleep. 

Despite beliefs about the importance of 

sleep for health and normal growth and 

development, there are no standards of sleep

physiology based on current polysomnographic

criteria. Furthermore, there is no comprehensive database defining normal sleep-wake

behavioral patterns by age or sex across the

life span. Thus, health care providers have no

normative reference for comparison with an

individual’s sleep pattern alone or as it relates

to good health, and public health agencies

have no way of knowing whether there are

population shifts in the quality and quantity 

of sleep obtained by different age groups. 

Descriptions of sleep phenotypes and definitions of normal sleep patterns and requirements must incorporate the wide range of

normal developmental and physical maturational changes across the life span. Although

cross-sectional studies yield important information regarding sleep in discrete age groups,

they do not address the evolution and persistence of sleep/wake patterns across time.

There is a need to understand the complex

reciprocal relationship between sleep and 

cognitive/emotional development from the

prenatal period through adolescence and

through adulthood. Prospective longitudinal

studies utilizing validated screening and 

assessment tools are thus needed to delineate the development of sleep patterns and

behaviors and to generate predictive models.

PROGRESS IN THE LAST 5 YEARS

Sleep and Environment

• Sensory stimulation resulting from environmental noise, light, motion, temperature,

and even odors can produce activation 

at levels antithetical to the initiation and

maintenance of sleep. Thus, sleep environments in which sensory stimulation 

is minimal (e.g., dark, quiet, comfortable

temperature) tend to be preferred subjectively and tend to enhance sleep initiation

and maintenance. 

NORMAL SLEEP, SLEEP RESTRICTION, AND

HEALTH CONSEQUENCES
48 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Recent efforts by some hotels to offer

rooms that are especially conducive to

sleep, and by some transportation industries to improve the sleep environments 

of both customers and employees, reflect

recognition of the importance of sleep 

and a sleep-conducive environment.

• Despite knowledge of the importance of

environmental variables for sleep quality

and duration and of considerable variations in sleep environments across ethnic

and socioeconomic strata, there has been

little scientific investigation of environmental factors potentially critical for healthy

sleep and waking. Subjects requiring 

scientific investigation include:

– Cosleeping or bed-sharing (sleeping

with one or more other persons in

the bed): Although evidence suggests

that the somesthetic stimulation resulting

from bed-sharing can have a negative

effect on sleep continuity and architecture, the relative benefits and adverse

consequences of this practice have not

been adequately explored.

– Sleep location: Sleep at home versus

sleep in public places in which control

over environmental stimulation is minimal (e.g., on an airplane), or in the 

work environment (e.g., sleeper berths

on trucks, trains, and planes).

– Sleep position: This has been determined to be important in Sudden Infant

Death Syndrome (SIDS) and in modulating the severity of Sleep-Disordered

Breathing (SDB), but sleep position has

not been studied relative to the potential

for sleep fragmentation (e.g., sleeping

semi-recumbent versus fully recumbent).

– Sleep surface: Virtually ignored in sleep

science, many consider optimal sleep 

surface to be crucial to obtaining a 

good night’s sleep.

– Environmental noise/light: Ambient

noise and vibration have occasionally

been studied as factors improving or

impairing sleep quality, but little is 

known regarding the extent to which 

various types of noise and vibration 

affect sleep. A few experiments have

found that light at night can enhance

alertness, and that properly timed light

exposure can hasten phase shifts of 

circadian biology (e.g., shift workers).

There have been no studies, however, 

to determine whether turning on room

lights at night adversely affects sleep

quality or quantity.

– Health disparities and vulnerable 

populations: Socioeconomically disadvantaged populations may be more

likely to sleep in environments that are

hot, humid, cold, noisy, and/or crowded.

There has been no systematic study of

the effects of these factors on sleep 

quality and quantity either alone or in

combination, and no study of potential

effects of these factors on waking functions including school and work performance. Children and adolescents, the

elderly, and shift workers are populations who may be especially vulnerable 

to the adverse effects of environmental

variables on sleep quantity and quality.

It is important to determine the extent to

which each of these environmental factors

affect sleep quality and contribute to sleep

loss, sleep pathology, daytime sleepiness, 

and daytime functioning. Scientific data 

in these areas would be fundamental to

answer questions regarding the determinants of a good night’s (or day’s) sleep. 
SECTION IV—SLEEP AND HEALTH 49

Health Consequences of Insufficient 

Sleep and Chronic Sleep Debt

• Adequate sleep is essential for healthy 

functioning and survival. Inadequate sleep

and unhealthy sleep practices are common,

however, especially among adolescents and

young adults. In the 2002 National 

Sleep Foundation annual survey, nearly 

40 percent of adults ages 30 to 64, and 

44 percent of young adults ages18 to 29

reported that daytime sleepiness is so 

severe that it interferes with work and 

social functioning at least a few days each

month. Excessive daytime sleepiness is a

major public health problem associated 

with interference with daily activities, 

including cognitive problems, motor 

vehicle crashes (especially at night), poor 

job performance, and reduced productivity.

Optimum daytime performance with minimal sleepiness in adolescents and young

adults appears to require at least 8 to 9

hours of sleep at night with few interruptions. A majority of adolescents and

adults, however, report habitual sleep 

durations of fewer than 7 hours per night

during the week and fewer than 8 hours 

of sleep each night on weekends. 

• The beneficial effects of healthy sleep 

habits and the adverse consequences of

poor or insufficient sleep have not been 

well studied. Sleep is essential for survival,

yet only in the last decade has scientifically

credible, experimentally based data from

humans been gathered on dose-response

relationships between chronic restriction 

of sleep by 1 to 4 hours a night and accumulating daytime sleepiness and cognitive

impairments. Most individuals develop 

cognitive deficits from chronic sleep debt

after only a few nights of reduced sleep

quality or quantity, and new evidence suggests additional important health-related

consequences from sleep debt related, 

for example, to common viral illnesses, 

diabetes, obesity, heart disease, and 

depression. Findings from a recent study 

of young adult men placed on a restricted

sleep schedule of 4 hours each night for 6

consecutive nights showed altered metabolism of glucose with an insulin resistance

pattern similar to that observed in elderly

men. The implications from this study, 

if replicated, are that chronic sleep loss 

may contribute to obesity, diabetes, heart

disease, and other age-related chronic 

disorders. As promising as these data are 

for providing solid scientific evidence of the

health consequences of chronic insufficient

sleep, most people report habitual nighttime sleep in the range of 6 hours. Data 

are needed to determine the extent to

which habitual sleep durations of 6 to 

8 hours are associated with increased 

disease risk in men and in women. 

Sleep Duration and Quality: 

Relationship to Morbidity and Mortality

• The relationship between sleep (quantity

and quality) and estimates of morbidity 

and mortality remains controversial. Data

from epidemiological studies suggest that 

a habitual short sleep duration (less than 

6 hours of sleep per night) or long sleep

duration (more than 9 hours of sleep per

night) is associated with increased mortality. A recent epidemiological report found

that self-reported sleep duration averaging

either less or more than 7 hours of sleep

daily was associated with higher mortality. 

It is not clear how sleep duration increases

risk. Moreover, although such epidemiological studies have used very large convenience samples, they have relied on 

retrospective self-report, the least accurate index of sleep. 

• There have been no epidemiological

prospective studies examining the relationship between sleep and health outcomes

(morbidity and mortality) that included 
50 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

estimates of sleep based on both subjective and objective measures. Past practices

of adding questions about habitual sleep

duration to large epidemiological studies

designed to answer questions about, for

example, the relationship between nutrition and risk for heart disease or between

smoking and cancer risk are not sufficient.

Although studies of sleep patterns and

behavior would be prohibitively expensive

and require multiple sites with subjective

and objective measures of sleep in a very

large sample, important questions regarding the relationship between sleep duration

and quality and morbidity and mortality 

can only be addressed through such large

studies. Furthermore, recent studies have

shown that sleep duration of at least 8

hours is necessary for optimal performance

and to prevent physiological daytime sleepiness and the accumulation of ”sleep debt.“

Findings from these and other studies can

only be reconciled with data suggesting 

that habitual sleep durations of eight hours

are associated with higher mortality by a

large comprehensive study of the effects 

of sleep on health and risk for disease. 

Without knowledge of what needs sleep 

fulfills or what sleep patterns (duration and

quality) best predict health (or morbidity 

and mortality), it is very difficult for sleep

researchers and clinicians to answer questions such as: 

– What are normal sleep patterns?

– How much sleep is needed by infants,

children, teenagers, adults, and the 

elderly for healthy functioning?

– What is the minimum amount of 

sleep required for optimal functioning and for health?

– How much of the patterning of 

sleep is genetic and how much 

is environmental?

– How are patterns of growth and 

development from infancy to adolescence and from adolescence to 

adulthood negatively impacted by 

insufficient sleep?

– What is the influence of prematurity

on the development of sleep patterns?

Do infants considered “poor” or 

“problem” sleepers develop insomnia

as children and/or adults?

– What sleep patterns in young and 

middle-aged adults predict good 

quality sleep in the elderly? Is the 

amount of sleep more important than

the time of day when sleep occurs?

– Do daytime naps make up for lost 

sleep at night?

– What are the health consequences of

long-term exposure to chronic sleep

restriction such as those imposed by 

a typical work or school schedule 

of 5 or more days of sleep restriction

followed by 2 days of partial recovery?

– Does the duration of recovery sleep, or

the timing of recovery sleep in the daily

cycle, or both, determine the benefits 

of sleep for healthy functioning?

– How much recovery sleep is required 

following exposure to chronic sleep

restriction in order to restore physiological and neurobehavioral capability 

to baseline?

– Does habituation/adaptation in the 

body’s physiological systems develop 

to sleep loss or chronic sleep restriction

and at what cost to one’s health?

– How important are environmental 

variables, such as sleep surface and 

light, in affecting sleep quality

and quantity?
SECTION IV—SLEEP AND HEALTH 51

RESEARCH RECOMMENDATIONS

• Epidemiological longitudinal studies to

define normal sleep behavior (timing, 

duration, quality) and phenotypes using

state-of-the art objective and subjective

technologies. Such studies are needed

across the life span and especially in 

vulnerable populations, and should 

focus on the transition from infancy 

to adolescence, adolescence to middle 

age, and middle age to advanced age.

Prospective studies representing the 

diversity of human cultures are needed 

to define normal sleep phenotypes across

cultures and in different ethnic and socioeconomic groups.

• Epidemiological longitudinal studies to

prospectively assess the relationships 

among sleep duration (short and long),

sleep quality (good and poor), and health

outcomes (morbidity and mortality). There 

is a need to determine the incidence and

prevalence of “sleep debt” in vulnerable

populations including children, adolescents,

young adults, shift workers, new parents.

those exposed to prolonged work hours,

those of low socioeconomic status. There 

is also a need to determine the functional

and health-related consequences of sleep

debt on increased disease risk, such as 

related to depression, obesity, diabetes, 

and cardiopulmonary diseases. 

• The genetic, environmental, and psychosocial factors that impact children’s sleep,

and the relative contributions of each, 

need to be identified.

• Identify how sleep disturbances in early

childhood impact cognitive and social 

development, behavior and performance, 

as well as subsequent development of 

sleep disorders in adolescents and adults.

• Studies to identify and evaluate countermeasures and novel approaches to prevent

sleep deprivation in children and adults.

Countermeasures to improve the sleep 

of shift workers, especially daytime sleep

after the night shift, are needed. Practical

methods need to be developed to phase

shift circadian rhythms to align with 

daytime sleep. Factors in need of study

include: work and sleep schedule combinations, light exposure during night shifts

(intensity, timing, duration, wavelength),

and daylight exposure following completion of the night shift.

• The effects on sleep physiology and daytime functions of relevant environmental

variables (in isolation and combination)

need to be investigated, especially in 

vulnerable populations such as children,

adolescents, the elderly, the socioeconomically disadvantaged, and shift 

workers. Factors to study include sleeping alone versus sleeping with one or 

more other persons in the bed (including

children), sleep position, sleep surface, 

personal risk, and environmental stimuli

such as noise, vibration, light, temperature, and humidity.
52 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Women, from adolescence to postmenopause are underrepresented in studies of 

sleep and its disorders. Although sleep complaints are twice as prevalent in women, 75

percent of sleep research has been conducted

in men. More sleep studies in the past 5 years

have included women, but small sample sizes

prohibit meaningful sex comparisons. Thus,

sex differences in sleep and sleep disorder

characteristics, in responses to sleep deprivation, and in sleep-related physiology remain

unappreciated. Furthermore, findings from

studies based primarily in men are often 

considered to be representative of “normal”

even when it is recognized that there are

important sleep-related physiological differences in women, including timing of nocturnal

growth hormone secretion and differential

time course of delta activity across the night. 

Sexual dimorphism in the central nervous 

system has been well documented but the

functional implications of sex differences in 

the neurotransmitter and peptide systems 

that modulate sleep and wake are unknown.

There is a need to study sex differences in

sleep and homeostatic regulation across

species to more fully understand the role 

that sleep plays in normal development, 

maturation, adaptation, aging, and disease

propensity. Sex hormones influence sleep 

and circadian rhythms, and sleep affects 

neuroendocrine functioning, in particular 

the episodic secretion of gonadatropin hormones. There are potentially different effects

of endogenous sex hormone cycling on neuronal groups involved in regulating behavioral

states and circadian rhythms. It is important 

to understand how sex-related differences 

in sleep and its regulation influence the risk 

for and mechanisms of sleep disorders and

other diseases. 

Evidence from animal studies supports the

presence of sex-related differences throughout the lifespan in susceptibility to disease in

general and to sleep disorders in particular. 

As classic examples of sexual dimorphism,

both the long-term neurobehavioral consequences of sleep-associated intermittent

hypoxia, as occurs in Sleep-Disordered

Breathing (SDB), and the consequences

induced by early life maternal separation 

stress exposures, are reduced in female animals when compared to male littermates. 

The mechanistic roles of sex-related hormones and their receptors and signaling 

pathways in mediating the emerging sexdependent differences in susceptibility to 

specific neural insults are only now beginning to be explored, and the new insights

achieved should have major implications 

for the development of novel therapeutic

interventions.

Physiologic changes in neuroendocrine

hormones, body temperature, mood, and

emotional state during puberty, the menstrual cycle, pregnancy, and menopause

have profound effects on sleep quality, 

daytime functioning, and well-being 

in adolescent girls and adult women. 

It generally has been assumed that sleep 

prior to puberty is similar in girls and boys, 

and that sex differences first emerge during

this developmental transition. The validity of

SLEEP, SEX DIFFERENCES, AND WOMEN’S HEALTH
SECTION IV—SLEEP AND HEALTH 53

this assumption, however, and the extent of

sex differences in sleep and sleep disorders 

in children and adolescents are not known.

There have been no cross-sectional or longitudinal studies of subjective and objective

measures of sleep coupled with measures 

of neuroendocrine functioning during and

after puberty. Despite the propensity for 

mood disorders to emerge during adolescence

and the greater prevalence in girls compared

to boys, little is known about how changes 

in sleep, sex hormones, and sleep deprivation

affect mood and emotional problems in this

age group. 

Although being female is a risk factor for

insomnia, and insomnia is a risk factor 

for depression, little is known about how

changes in sex hormones during the menstrual cycle impact sleep physiology and mood

in adolescent girls and women. In fact, most

of what is known about sex hormones and

sleep is derived from studies of exogenous

hormones in adult rodents and humans. Little

is known about endogenous sex hormones,

changes in sleep physiology, and the development of dysphoric mood and dysmenorrhea

during the menstrual cycle. There have been

only a few sleep laboratory studies in small

samples of adult women during all phases 

of the menstrual cycle. Findings show wide

individual variation, with no consistent relationships between menstrual phase and

changes in sleep physiology. 

There are considerable methodological 

challenges in studying sleep across phases 

of the menstrual cycle. Without normative

data based on ovulating and nonovulating

women, however, neither the researcher nor

the clinician have reference points to aid in 

the interpretation of menstrual cycle effects 

on sleep or its disorders. Although not all

women of childbearing age experience premenstrual symptoms and secondary insomnia,

insomnia and related symptoms may occur

associated with onset of menses. Insomnia

related to menses may be related to a fall in

endogenous progesterone or a differential 

sensitivity to endogenous hormone fluctuations, but these hypotheses require further

testing. Potential health consequences or 

disease risk that are engendered by this 

repetitive “incident” insomnia that can occur

every month for 40 years of a woman’s life 

are not known. However, menstrual cycle

symptoms and premenstrual dysphoria 

correlate with excessive daytime sleepiness.

Women with significant dysmenorrhea may 

be at higher risk for developing insomnia

and depression.

Hormonal changes and physical discomfort 

are common during pregnancy, and both 

can affect sleep. Although nearly all pregnant women will experience disturbed sleep 

by the third trimester, there have been only

two longitudinal sleep studies of subjective

and objective sleep measures during pregnancy. There have been no reports of intervention

studies to improve sleep quality during pregnancy. Some have assumed that disturbed

sleep is a “natural” consequence of pregnancy, labor, delivery, and postpartum that

resolves over time, since few women seek

assistance to improve sleep. Research has not

shown a relationship between sleep quality

and quantity and any perinatal adverse outcome, length of labor, or type of delivery.

More studies are needed, however, to clarify

the extent to which sleep-related problems

during pregnancy may have adverse fetal, 

perinatal, or infant-related consequences. 

Very little is known about the effects of 

late stage pregnancy sleep disturbances 

on labor and delivery, emotional distress, or 

postpartum depression. However, nighttime

labor and a history of sleep disruption in late

stage pregnancy are related to a higher incidence of postpartum “blues.” Certain sleep

disorders, such as Restless Legs Syndrome

(RLS), Periodic Limb Movement Disorder

(PLMS), SDB, or insomnia, may emerge 

during pregnancy, and the extent to which

these disorders resolve or place women at

higher risk for sleep disorders later in life is 

not clear. Pregnancy induces changes in the
54 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

upper airway and in functional residual 

capacity that predispose women to snoring,

SDB, and reduced oxygen stores. Pregnant

women who snore may be at risk for preeclampsia and/or SDB. The number of pregnant women with SDB may be substantial, 

but the prevalence has not been defined 

in either uncomplicated or complicated 

pregnancy. Women with pre-eclampsia and

excessive weight gain during pregnancy are 

at greater risk for the development of SDB 

and pregnancy-induced hypertension, which

have been associated with adverse perinatal

outcomes, but few polysomnographic studies

have been done in these women. 

Many women during the menopausal 

transition (perimenopause, menopause, 

postmenopause) complain of sleep disturbances that are attributed to vasomotor 

symptoms (e.g., hot flushes and night sweats)

rather than to menopausal status. Estimates 

of self-reported menopausal-related insomnia

range from 33 to 51 percent, but the actual

prevalence of sleep disturbances in midlife

women, particularly as a function of race, 

ethnicity, and body size is not well defined.

Although there have been only a few sleep

studies with both subjective and objective

measures, a majority of midlife women with

self-reported poor sleep quality report high

psychological distress without objective evidence of poor sleep efficiency. Whether these

women are physiologically hyperaroused (e.g.,

increased hypothalamic-pituitary-adrenal axis

or sympathetic activity) without significant

impact on standard indices of laboratory 

sleep remains to be clarified. 

Data on changes in sleep physiology in 

women during the menopausal transition 

are sparse and no longitudinal sleep studies

have been conducted. Compared to placebo,

short-term hormone replacement therapy

(HRT) has shown beneficial effects on 

improving subjective and objective sleep 

quality in women with menopausal symptoms, but not all studies show the same

effects. Menopause may be a significant 

risk factor for SDB. It has been suggested 

that menopause-induced sex hormone deficiency might explain the increased prevalence

of SDB in post-menopausal women and that

women on HRT might be at lower risk. Given

concerns about disease risk, such as related 

to thromboembolic events, cardiovascular 

disease, and breast cancer) associated with

HRT for the treatment of menopausal symptoms, fewer women in the future may 

receive HRT. Hence, more women may 

experience menopause-related insomnia

or HRT withdrawal symptoms that could 

exacerbate insomnia. Alternative and established therapies for insomnia need to be 

systematically evaluated in women during 

and after menopause. 

In addition to perimenopausal and

menopausal effects on sleep in women, 

surveys show that more than 80 percent of

working women report fatigue and exhaustion, and half of them obtain inadequate

sleep. Women shift workers with altered 

sleep and circadian rhythms are at increased

risk for menstrual irregularities, infertility, 

miscarriage, and low birth weight infants.

Women remain the main caregivers for children and elderly family members. These

responsibilities may add a significant stress

burden and increased vulnerability for sleep

disturbances with negative impacts on health

and quality of life. In addition, significant life

events, such as spontaneous abortions, stillbirth, or death of a child or spouse, have 

been associated with development of posttraumatic symptoms, including sleep disturbances. Women who consume alcohol as 

a method of coping with work, family, and

social demands are at increased risk for 

alcohol-induced sleep disturbances. 

PROGRESS IN THE LAST 5 YEARS

Sleep and the Menstrual Cycle/

Premenstrual Syndrome

• Sleep architecture is unaffected by 

menstrual cycle phase. Body temperature
SECTION IV—SLEEP AND HEALTH 55

is elevated and circadian rhythm amplitude is reduced during sleep, however, in

the high progesterone phase (luteal) of 

the menstrual cycle, but the underlying 

mechanism is not known. Compared to

men, women have a blunted drop in body

temperature and an earlier nadir of the 

circadian body temperature rhythm.

• Women on oral contraceptives have

reduced slow wave sleep and REM 

latency. Body temperature throughout 

the menstrual cycle is similar to that of 

normal cycling women in the luteal phase. 

• Dysmenorrhea is associated with significantly disturbed sleep quality prior to

menses. Compared to control women,

women with dysmenorrhea had altered 

sex hormones, body temperature, and 

sleep throughout the menstrual cycle.

Sleep in Pregnancy and Postpartum

• Longitudinal studies indicate that age, 

combined with anemia, is related to first

trimester fatigue and that reduced sleep

time is related to fatigue during the third

trimester. Both reduced sleep time and 

anemia are related to fatigue postpartum.

Significant changes in sleep are evident 

in the first trimester of pregnancy, with

increased total sleep time coupled with

more awakenings, but postpartum sleep

efficiency is lower than in prepregnancy.

Slow wave sleep percentage is reduced

throughout pregnancy compared to

prepregnancy and postpartum. One study

found that REM sleep was reduced during

pregnancy, but was reduced in another 

longitudinal study, most notably during 

the third trimester.

• RLS occurs in about 20 percent of pregnant women and may be associated 

with reduced levels of folate.

• Thirty percent of pregnant women 

begin snoring for the first time during 

the second trimester. 

• Pre-eclamptic women show evidence 

of SDB associated with increased blood

pressure. Pregnant women who snore 

have a twofold greater incidence of hypertension, pre-eclampsia, and fetal growth

restriction compared to nonsnorers.

• Self-reported sleep quality, derived from

sleep diaries, shows considerable sleep 

disturbances in the early postpartum 

period. Sleep efficiency improves during 

the first year postpartum, but it is unclear

whether sleep quantity and quality return 

to pre-pregnancy levels. 

• There is a relationship between sleep 

and mood during pregnancy, and through

the first 3 to 4 months postpartum.

Increased disturbances in self-reported 

sleep and decreased reported total sleep

time are associated with depressed 

mood postpartum. 

Sleep and Menopausal Transition

• Longitudinal studies of midlife women

showed increased self-reported insomnia,

night sweats, and hot flushes across 

the menopausal transition from late 

perimenopause to postmenopause. 

Self-reported sleep disturbance in 

middle-aged women also has been 

associated with worse mood, higher 

blood pressure, higher waist/hip ratios, 

and chronic dissatisfaction with sleep. 

• The prevalence of self-reported insomnia

is 17 percent in a community-based cohort

of racially mixed perimenopausal menstruating women. Reduced estradiol, increased

hot flashes, and psychosocial factors are all

associated with poor sleep quality after controlling for current sleep medication use.

• Sleep quality, as measured by polysomnography (PSG), does not appear to be 

different in peri- or postmenopausal 

women compared to premenopausal

women. Also, there do not appear to 

be any differences in PSG sleep quality

in women who use HRT versus those 
56 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

who do not. These observations imply 

that sleep disturbances in midlife women

are not a “normal” part of the menopausal transition.

• HRT (estrogen preparations) is effective 

in reducing menopausal symptoms and 

self-reported sleep disturbances (insomnia

and daytime sleepiness), and in increasing

REM sleep and the amount of slow-wave

sleep in the first third of the night. In one

randomized trial, comparing two different

forms of progesterone in combination 

with estrogen therapy, PSG sleep efficiency improved, with reduced wake 

after sleep onset in the group receiving

micronized progesterone.

• The prevalence of SDB in postmenopausal

women on HRT is significantly lower than 

in postmenopausal women not on HRT,

indicating that menopause may be a significant risk factor for SDB in women, and

HRT may reduce that risk. The hypothesis

that healthy postmenopausal women not

on HRT have more SDB compared to

women on HRT has also been confirmed 

in a large population-based study. 

RESEARCH RECOMMENDATIONS

• Establish how sex-related differences in

sleep and its regulation influence the 

mechanisms and risks of developing 

disease and sleep disorders. Studies of 

sex differences in sleep and homeostatic

regulation across species are needed to

more fully understand the role that sleep

plays in normal development, maturation,

adaptation, aging, and disease propensity.

Animal models of sleep disorders need 

to be developed that incorporate careful

delineation of sex-related differences in 

susceptibility to development of these 

disorders and their consequences. Studies 

of the specific cellular and molecular 

mechanisms underlying sex differences

in sleep disorders throughout the lifespan

should be pursued.

• Conduct longitudinal studies of sleep 

during pregnancy and through the postpartum period that include both subjective

and objective sleep indicators and include

baseline measurements. Fuller description 

of the extent of sleep disorders developing during pregnancy and postpartum is

needed so that novel and existing therapies

can be instituted to reduce health risks to

the mother and the fetus. The relationship

between extent of disturbed sleep during

the late stages of pregnancy and delivery

and the development of postpartum 

depression warrants study as a basis for

designing novel interventions. Effects 

of sleep disturbance postpartum on 

maternal-infant interactions also require 

further study.

• Determine the extent to which the 

prevalence of insomnia and sleep disorders increases during the menopausal

transition, identify factors that predict 

which premenopausal women are at high

risk for developing insomnia, and evaluate

alternative and traditional therapies for

improving sleep in menopausal women.

• Obtain normative sleep data on girls 

before, during, and after puberty, as well 

as on women of childbearing age, to 

assess changes associated with different

phases of the menstrual cycle, changes 

in endogenous sex hormones, and in

response to exogenous hormones.

• Determine the extent to which adolescent

girls and young women with significant 

dysmenorrhea are at risk for insomnia

and depression.

• Study how sleep disturbance in pregnancy

affects fetal development and health as 

well as the maturation of fetal physiology

related to sleep, and the extent to which

fetal effects may be associated with longterm pediatric consequences. 
SECTION IV—SLEEP AND HEALTH 57

BACKGROUND

Racial and ethnic minorities have significant

health disparities compared to the rest of the

population. To achieve the objectives of the

“Healthy People 2010” initiative, there is a

need for more consistent and reliable racial

and ethnic data. Such data are needed to

develop and implement effective prevention,

intervention, treatment programs, policies, 

and services. For sleep disorders and for 

health status in general, efforts to eliminate disparities in health outcomes need 

to address not only social and environmental

factors, such as education and access to 

health care, but also possible biological 

or genetic differences, including geneenvironment interactions.

Many clinical conditions appear to contribute to racial and ethnic disparities in health

outcomes. A few account for most of these

disparities, including smoking-related diseases,

hypertension, HIV, diabetes and trauma. The

leading cause of death in African Americans

and Hispanic Americans is heart disease. 

Sleep disorders, particularly Sleep-Disordered

Breathing (SDB), may contribute to the increased prevalence and severity of heart 

disease, and may also contribute to these 

disparities through other mechanisms not 

yet clarified.

PROGRESS IN THE LAST 5 YEARS

• Since release of the original Sleep Disorders

Research Plan in 1996, studies across ethnically diverse populations have identified 

significant differences in the prevalence 

of SDB in African Americans and have 

suggested distinct pathophysiological 

mechanisms. Among young African

Americans, the likelihood of having 

SDB is twice that in young Caucasians.

Frequent snoring is more common 

among African American and Hispanic

women and Hispanic men compared to

non-Hispanic Caucasians, independent 

of other factors including obesity. 

• SDB appears to be in part genetic, with

increased prevalence not only in African

Americans but also Asians and Hispanics

compared to Caucasians. African 

Americans appear to have a different 

maxillo-mandibular structure than

Caucasians, which may contribute to

increased risk for SDB. African Americans

with SDB develop symptoms at a younger

age than Caucasians but appear less likely

to be diagnosed and treated in a timely

manner. This delay may at least in part be

due to reduced access to care. Additional

studies are also needed to explore the

extent to which ethnic disparities in other

diseases, such as stroke and diabetes, are

related to a sleep problem such as SDB. 

• The adverse impact of low socioeconomic

status (SES) on health status may in part 

be mediated by decrements in sleep duration and quality. Low SES is frequently 

associated with diminished opportunity for

sufficient sleep or environmental conditions

compromising sleep quality. Hispanic children have less Stage 3 and 4 sleep and

more Stage 2 sleep than their Caucasian

RACIAL AND ETHNIC DISPARITIES
58 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

counterparts, suggesting that there 

may also be racial/ethnic differences in 

sleep quality.

• Sleep loss has been shown to be associated with decreased glucose tolerance,

elevated evening cortisol levels, and

increased sympathetic activity. Sleep loss

may thus contribute to increased risk 

for chronic conditions such as obesity, 

diabetes, and hypertension, all of which

have increased prevalence in underserved,

underrepresented minorities. Racial and 

ethnic disparities related to obesity may 

also contribute to disparities in health 

outcomes related to SDB. Obesity is 

more common in African Americans and

Mexican Americans than in Caucasians. 

• African Americans are at increased risk 

for cardiovascular disease, diabetes, infections, certain cancers and alcoholism.

Recent studies suggest that alcoholics 

of African American descent may have

more profound sleep abnormalities and

abnormal immune function than Caucasian alcoholics and healthy individuals.

Disordered sleep and sleep loss may 

disrupt the maintenance of internal 

physiological mechanisms. Therefore, 

investigating the interrelationships 

between alcoholism, sleep loss and 

ethnicity and irregularities in hormonal,

autonomic nervous, and immune systems

may yield new insights regarding mechanisms for the increased mortality rate

among African American alcoholics.

• Blood pressure normally drops (dips) 

by about 10 percent during the night.

African Americans, however, tend to be

“nondippers” compared to Caucasians,

independent of weight, gender and SDB.

Studies in elderly African Americans and

Caucasians suggest that for many older

African Americans with hypertension, 

blood pressure does not fall the expected

amount at night, and that this nondipping

is associated with more severe SDB. Non

dippers with high systolic blood pressure

(SBP) during the day or high SBP or diastolic blood pressure (DBP) during the night

were more likely to have more severe SDB.

African Americans who are non dippers

may therefore benefit from screening 

for SDB. 

• Studies have also identified an increased

prevalence of SDB in African American

children compared to Caucasian children.

African American children are also 50 

percent less likely to have had their tonsils

and adenoids removed (T&A) and more 

likely to have residual disease if a T&A 

has been performed. In children with 

sickle cell disease, there is not only a 

higher risk of SDB, but also higher 

prevalence and associated morbidity 

due to vaso-occlusive crises. 

• Racial and ethnic disparities also appear 

to exist in the prevalence of other sleep 

disorders. Non-Caucasian adults report an

insomnia rate of 12.9 percent compared 

to only 6.6 percent for Caucasians. 

Genetic studies have shown a higher 

degree of genetic polymorphisms and 

lower linkage disequilibrium in some 

populations, especially African Americans.

Narcolepsy studies conducted in African

Americans have resulted in identification 

of specific HLA alleles that are involved 

in mediating HLA class II susceptibility to

narcolepsy (e.g., HLA-DQB1*0602). 

• The relationship between health-related

quality of life (HRQOL) and SDB has been

examined in elderly African Americans

screened for snoring and daytime sleepiness who completed a sleep recording, 

a comprehensive sleep questionnaire

(Quality of Well-Being Scale, QWB), 

and the Medical Outcomes Study Core

Measures of HRQOL. Those with moderate to severe SDB had significantly lower

Physical Component outcomes summary

scores than those with no SDB. Mild but 

not more severe SDB is independently 
SECTION IV—SLEEP AND HEALTH 59

related to both general physical functioning and general mental health functioning.

The QWB scores of this SDB sample were

similar to those found in patients with

depression and chronic obstructive 

pulmonary disease, suggesting that 

sleep disturbances may impact daily 

living and health as much as other 

medical conditions.

• African Americans appear to have fewer

chronic sleep complaints than Caucasians.

The largest differences are in waking during

the night, with African Americans having a

prevalence of wakefulness during sleep of

only about 60 percent that in Caucasians.

The prevalence of insomnia for African

Americans is also lower (19.8 percent versus 23.6 percent). African American women

have a higher incidence of insomnia than

African American men, perhaps related in

part to higher risk for chronic persisting

symptoms. Caucasian males and females 

do not differ in incidence. Depressed mood

is associated with insomnia in both racial

groups. Continued presence of fair or poor

health and physical mobility difficulties 

are associated with incident insomnia

in Caucasians, but not among African

Americans. The latter, however, show an

association between incident insomnia

and incident development of perceived 

fair or poor health. African Americans 

aged 75 years or more are less likely 

than Caucasian or Hispanic Americans 

to attribute sleep problems, as well as 

heart disease and arthritis, to being part 

of the normal aging process (about 32 

percent versus 46 percent and 43 percent, respectively).

• Interviews and polysomnography (PSG) 

have been conducted on Hmong people 

to collect data on sleep disorders and 

especially SDB in this ethnic group at 

high risk for Sudden Unexpected 

Nocturnal Death Syndrome. Hmong 

subjects appear to have a high 

prevalence of SDB. 

RESEARCH RECOMMENDATIONS

• Conduct studies to identify the neurophysiological, neuroanatomical, genetic, 

and gene-environmental interactions 

contributing to racial and ethnic disparities in prevalence and severity of 

individual sleep disorders.

• Develop strategies to reach underrepresented minorities in public health

education programs designed to maintain

health and prevent development and 

progression of sleep-related conditions.

• Determine the extent to which higher

prevalence of SDB, and lower rates of 

diagnosis and treatment, contributes 

to the higher prevalence of learning 

problems and academic underachievement in African American children.

• Determine the best public health

approaches among underserved, underrepresented populations for increasing

access to and knowledge of sleep 

medicine resources.

• Determine the bidirectional link between

parameters of sleep, sympathetic nervous

system activity, and cellular immunity in

African Americans with alcohol dependence.

• Determine the extent to which racial 

and ethnic disparities in health outcomes

related to sleep disorders may contribute 

to differential responses to treatment or 

to differences in adherence to treatment

recommendations.

• Determine whether ethnic differences in

alcohol-induced sleep disturbances contribute to the sympathetic nervous system

and immunological effects of alcohol.

• Develop effective strategies to include 

racial and ethnic minorities in overall 

efforts to recruit increased numbers of 

biomedical investigators to sleep-related

research, and in sleep-related curriculum

development for health care professionals.
60 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Aging is associated with changes in sleep

amount, sleep quality, and specific sleep

pathologies and disorders. For instance,

increased age is associated with increased

prevalence of insomnia complaints, daytime

sleepiness, Sleep-Disordered Breathing (SDB),

Restless Legs Syndrome (RLS), and Periodic

Limb Movement Disorder (PLMD) (see Section

V). Insomnia alone affects about one third of

the older population in the United States.

Nocturnal sleep difficulties can result in 

excessive daytime sleepiness, attention and

memory problems, depressed mood, and 

lowered quality of life. Evidence also suggests

that SDB has been associated with dementia

and cognitive deficits in the elderly. 

Other factors associated with aging, including medical and psychiatric disorders, changes

in environment, and psychosocial stressors,

such as bereavement, can also be independent contributors to sleep problems. Sleep 

disturbances can also lead to changes in 

physiological systems, especially production 

of appropriate hormone levels and proper

metabolic functioning. In addition, the circadian regulation of sleep-wake rhythms is

altered with age, such that older adults sleep

at an earlier phase of their circadian cycle 

(see Section I). These changes are seen in 

the sleep of the healthy elderly, unrelated 

to complaints about disturbed sleep, but are

magnified in those with medical and neuropsychiatric disorders (see Section V). Disrupted

sleep-wake patterns are also a major source 

of stress among caregivers of patients with

dementia, whether in the home or in 

institutions. Treatments for sleep problems 

in the elderly can also be associated with 

morbidity including, for example, the association between hypnotic use and falls or 

hip fractures.

Recent neuroscience findings regarding 

sleep regulation have largely focused on

young, healthy organisms, and have not

explored how age modifies these regulatory

mechanisms, or whether such age-related

changes can be modified. In humans, there 

is little consensus regarding which sleep

changes are normative developmental

changes, and which changes are pathological. This has direct implications for identifying when an intervention is advisable. Given 

the potential for greater risk of adverse 

effects in the elderly, there is also a need to

develop a broader range of efficacious, safe

treatments for all sleep disorders. This issue is

particularly salient for individuals with significant medical or neuropsychiatric comorbidity.

PROGRESS IN THE LAST 5 YEARS

• Epidemiologic studies have identified consistent risk factors for late-life insomnia, 

and have examined the course of this 

disorder (see Section V). In addition, 

the epidemiology of SDB in older adults 

has been well described (see Section V).

SDB has also been identified as a risk 

factor for adverse cardiovascular outcomes

in the elderly, including hypertension and

coronary heart disease.

SLEEP AND AGING
SECTION IV—SLEEP AND HEALTH 61

• Excessive daytime sleepiness, a possible

marker for SDB, has been found to be 

associated with diagnosis of incident

dementia and incident cognitive decline 

3 years later, after adjusting for age and

other factors. In contrast, insomnia is not

associated with either incident cognitive

decline or dementia.

• The period of endogenous circadian

rhythms in healthy older persons does 

not differ from that of healthy young 

adults. However, older individuals have

greater difficulty sleeping at specific 

circadian phases, which may account for

some of the increased sleep complaints 

seen in aging.

• Behavioral and psychological interventions

have been found to be efficacious and

durable treatments for older adults with

insomnia. On the other hand, behavioral

and environmental interventions have

shown limited efficacy among institutionalized individuals with dementia.

• Evidence supporting the efficacy of 

melatonin for treating Insomnia in the 

elderly is equivocal. Low doses of melatonin that raise blood levels to the normal

young adult nighttime range significantly

improve sleep quality in individuals suffering from age-related insomnia in some 

studies, but not in others.

• Studies have shown the important sleep

regulatory functions of a hypothalamic 

circuit involving the ventrolateral preoptic

nucleus (VLPO). No differences in numbers

of VLPO neurons are noted with increasing

age, nor are there any differences in levels

of adenosine A1 receptor mRNA. Age, 

however, may affect adenosine receptor

function rather than number. While the

suprachiasmatic nucleus (SCN) appears to

function normally with aging, aging may

impair the function of both entrainment

(afferent) systems and target (efferent) 

systems downstream from the SCN.

RESEARCH RECOMMENDATIONS

• Investigate the neurobiological mechanisms of age effects on sleep, particularly

those related to homeostatic and circadian

mechanisms. Circadian studies should 

investigate the neurobiological causes 

and consequences of age-related changes 

in circadian rhythm parameters other than

period (e.g., amplitude, waveform), which

may be directly related to changes in SCN

output or efferent pathways and downstream effector systems. Both basic science

and human studies are needed. Genetic,

neuroanatomic, neurophysiologic, and 

neurochemical approaches may be useful 

in such studies. Conversely, studies investigating the potential effects of sleep, 

circadian regulation, and sleep disorders 

on the aging process and the diseases 

associated with late age are also a 

high priority.

• Test the efficacy and effectiveness of sleep

disorder treatments among individuals 

with a broader range of medical comorbidities, e.g., individuals with “usual” 

aging. These studies should include 

conditions such as insomnia and SDB, 

and populations such as nursing 

home residents.

• Develop a range of novel, safe, and 

efficacious treatments for sleep disorders in the elderly. These may include 

the development of new behavioral, 

pharmacologic, hormonal, behavioral, 

and physical/environmental (e.g., light)

treatments for conditions such as 

Insomnia, sleep-wake disruptions 

in dementia, and SDB. Long-term 

trials investigating the efficacy and 

adverse effects of pharmacologic 

and behavioral/ psychological treatments for insomnia are needed in 

older patients with both primary and 

secondary forms of insomnia. The use of 

techniques such as pharmacogenomics
62 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

should be employed to identify which 

treatments are likely to be most efficacious in specific patients or populations 

(see Section I).

• Better define the boundaries of normal 

and abnormal age-related sleep changes, 

as well as guidelines for intervention.

Examples include defining normative 

age-related changes in sleep, and 

thresholds for when SDB or periodic 

limb movements during sleep require 

intervention.

• Better define the prevalence of specific

sleep disorders in aging. Such studies 

should employ clinical diagnostic criteria 

for sleep disorders as well as polysomnographic monitoring. The relationships

between sleep disorders and cognitive

decline in aging also need investigation.

• Investigate the relationship between 

daytime and nighttime care procedures 

and sleep quality and circadian function in

the institutionalized elderly. These studies

should also investigate modifications of 

care procedures designed to minimize

adverse effects on sleep.
SECTION IV—SLEEP AND HEALTH 63

BACKGROUND

Demands on human wakefulness and 

alertness through increased requirements 

for shift work, oncall and prolonged work

hours, and increased use of time for waking

activities, have resulted in more people being

awake more of the time. Paralleling these

increased demands has been a growing 

appreciation of the risks posed by fatigue. 

In this context, fatigue is defined as a reduced capacity for cognitive performance 

due to time-on-task, inadequate sleep, 

adverse circadian timing, or the interaction 

of these factors. Fatigue can adversely affect

public health and safety, due, for example, 

to oil spills, truck, bus and automobile 

crashes, railroad and commuter train 

disasters, aviation accidents, power 

plant mishaps, and medical errors. 

The National Highway Traffic Safety

Administration (NHTSA) estimates that

100,000 to 150,000 motor vehicle crashes

each year and 4 percent of all fatal crashes 

are caused by drowsy driving. Drowsy driving

crashes have a fatality rate and injury severity

level similar to alcohol-related crashes. Risk

factors for drowsy driving crashes include: 

late night/early morning driving, people with

untreated excessive sleepiness, people who

sleep 6 or fewer hours per day, young adult

males (ages 16 to 24), commercial truck 

drivers, and night shift workers.

Recent reports from the National Academy 

of Sciences, Institute of Medicine, concluded

that as many as 100,000 patient deaths per

year may be due to medical errors. Based 

on surveys of medical residents and other

information, it is widely believed that 

substantial numbers of these adverse 

events result from fatigue due to prolonged

work hours and inadequate sleep among 

doctors and nurses. 

These problems of sleepiness and fatigue, 

and the contributions of inadequate sleep 

and night work, to human error and accidents have high costs in both lives lost and

economic impact. Options, therefore, for 

mitigating sleepiness and fatigue need to be

explored. The Department of Transportation

(DOT) is investing significant resources to 

better understand and manage fatigue in

transportation systems. For example, recent

research supported by the Federal Motor

Carrier Safety Administration suggests that

both work schedules and sleep disorders are

primary contributors to fatigue and sleepiness among truck drivers. Long and irregular

work schedules that require operators to 

juggle work demands with family and social

demands lead to reduced or disrupted sleep

and, therefore, to fatigue.

Excessive fatigue and its risks are largely 

preventable when the causes are identified

and mitigated. For example, establishing 

cost-effective techniques for identifying 

and treating transportation workers (such 

as commercial truck drivers) who have SleepDisordered Breathing (SDB) could lessen 

the likelihood of fatigue-related accidents.

Preventing cumulative sleep debt by providing adequate recovery sleep opportunities 

SLEEP AND SAFETY
64 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

for workers could reduce the risks of fatiguerelated performance failures and catastrophic

outcomes in many industries. Moving school

start times to a later hour for adolescents

could reduce the likelihood of drowsy-driving

automobile crashes and injuries in school 

activities in this at-risk group. Finding ways 

to prevent fatigue-related medical errors by

physicians and nurses could save thousands 

of patient lives each year, and improve 

the learning and safety of the doctors 

and nurses. 

Although ensuring public and personal 

safety through adequate sleep is a broad 

issue of interest to many Federal, State, 

and private entities, the National Institutes 

of Health have a unique role in ensuring 

that scientifically sound evidence is acquired

on the basic biomedical and health-related 

factors mediating sleep need, behavioral 

alertness, and risk. 

PROGRESS IN THE LAST 5 YEARS

• Scientific evidence increasingly demonstrates that fatigue is a significant causal

and contributing factor to adverse events

including motor vehicle and other fatiguerelated accidents. However, there is no 

general consensus that these data are 

definitive and compelling.

• Field and simulator studies in safetysensitive occupations (e.g., medical and 

surgical residents, truck drivers, airline 

pilots) have demonstrated that performance in real-world tasks degrades under

conditions of partial sleep loss and night

work. Such studies highlight that the 

biology of neurobehavioral deficits from

sleep loss and fatigue is not dependent 

on one’s profession, motivation, or 

compensation. 

• Experiments have demonstrated that 

chronic reductions in sleep duration by

healthy adults result in cumulative deficits 

in basic neurobehavioral functions, including vigilance performance, cognitive speed

and accuracy, short-term memory, and 

executive functions. Such data are vital 

to establishing reliable, evidence-based 

recommendations for sleep need. 

• Research has identified some technologies that can detect fatigue and drows

ness before they result in a serious 

performance error. Some of these 

technologies include biobehavioral and

physiological assessments, but few 

have undergone rigorous double-blind 

validation in controlled experiments.

• Mathematical models of the regulation 

of sleep have been extended to predict

waking performance capability based on

sleep history, circadian phase estimates, 

and additional behavioral and biological

variables. There is considerable belief that

such models can be used to precisely 

identify schedules that minimize fatigue. 

• Recognition that fatigue-related errors 

and accidents are inherent in 24/7 operations has led to fatigue management 

using countermeasures that are preventive

(e.g., education about the biological basis 

of fatigue) and operational (e.g., naps in 

the workplace). These fatigue management interventions have only recently 

been developed, however, and have not 

yet been widely studied to determine the

extent to which they will be effective.

• Work-related sleep loss and fatigue in 

medical professionals, particularly during

training, has until recently received little

attention. There have been relatively few

controlled studies that have examined 

the impact of sleep loss and fatigue in 

the medical setting, and many published 

studies are methodologically flawed. The

consequences related to sleep loss and 

shift work among physicians and nurses

include effects on performance of professional duties, learning and memory, 
SECTION IV—SLEEP AND HEALTH 65

personal health and family consequences,

and safety and liability. While the issue of

work hours for physicians and nurses is 

currently being debated nationally, there

remains a need for research to elucidate 

the effects of education and training

of physicians and nurses in sleep and

fatigue management. 

RESEARCH RECOMMENDATIONS

• Identify the effects of varying amounts 

of time for sleep, rest, and recovery 

(e.g., days off) on biological and behavioral

resilience to fatigue-inducing work schedules. One of the most contentious but 

least well-understood features of fatigue

and its consequences for safety concerns

the role of recovery days off work. There 

are very limited data on the chronic (over

weeks and months) effects of inadequate

recovery opportunities outside the circadian

cycle. There is a need to establish timeconstants for fatigue buildup as a function

of different recovery opportunities. Another

need is to identify ways to scientifically

design and evaluate work schedules that

prevent the accumulation of excessive

fatigue by allowing restorative sleep 

at reasonable intervals.

• Establish the validity and reliability of 

innovative biobehavioral technologies 

and monitoring techniques that can detect

drowsiness, fatigue and sleep propensity in

medical and other workplaces. As devices

predicated on detecting changes in the 

biology of wakefulness, these technologies

have great potential. To be used effectively

as either diagnostic devices or safety

devices, however, they should meet rigorous standards for determining whether

what is being measured is related to the

neurobehavioral deficits induced by 

sleepiness and fatigue.

• Establish the biological benefits for brain

function, performance, and safety of nap

sleep interventions (number of naps, their

durations and circadian timing) as a sleep

loss countermeasure and fatigue management strategy. Increasingly, 24/7 industries

permit opportunities for naps in the workplace (e.g., sleeper berths on trucks, bunks

on airplanes, sleeping areas on trains, oncall rooms for residents). There is a need 

for laboratory, simulator and field experiments on nap sleep physiology and waking

neurobehavioral functions to establish the

effectiveness of naps used repeatedly as

countermeasures. There are many experiments on naps in response to acute sleep

loss, but few that determine whether 

chronic use of naps or split sleep opportunities can effectively maintain waking

neurobehavioral functions. If optimal 

napping strategies can be found to 

manage sleepiness and its neurobehavioral

effects, this can form a basis for evaluating

evidenced-based model fatigue management to determine the extent to which

fatigue-related neurobehavioral deficits 

and risks can be reduced.

• Assess the impact of sleep loss and fatigue

in the context of medical training, including quality of patient care and patient 

safety/medical errors, learning and memory

in medical education, and the health and

well-being of resident physicians (motor

vehicle crashes, mental health, etc.).

Evaluate the effectiveness of fatigue

management educational programs in

improving the health and well being of

medical trainees, including evaluation of 

the effectiveness of controlled countermeasures (napping, caffeine, etc.) and 

evaluation of the impact of “systemic”

interventions (work hour restrictions, 

“night float” etc.) on sleep loss, performance, and medical errors.
66 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Develop cost-effective methods to screen

populations working in safety-sensitive

occupations to identify those who are 

most likely to have sleep disorders that 

produce excessive sleepiness and 

performance-impairing risks. A major

impediment to removing the risks posed 

by sleepiness due to unrecognized sleep 

disorders in the workplace is the lack 

of valid, simple, cost-effective tools for 

identifying who is most likely to benefit

from a full evaluation. Such tools are 

needed, however, to enable physicians 

to certify that people in specific safetysensitive occupations are fit to perform 

their jobs safely. 

• Develop novel techniques to facilitate 

worker acclimation to therapeutic interventions and effective use of therapies 

for sleep disorders (e.g., CPAP adherence). 

It is not sufficient to diagnose and to treat

workers without a treatment compliance

program in place. 

• Perform studies on the effects of chronic

pharmacological enhancement of wakefulness in healthy persons on biology,

behavior, and safety. This should extend

from unregulated stimulants (e.g., 

caffeine), to regulated stimulants (e.g.,

amphetamines), and novel wake-promoting substances. These studies should 

include identification of long-term effectiveness, side effects, and complications 

of use and abuse. 

• Assess the extent to which educational 

programs on the biological basis of fatigue,

and mitigation of the performance deficits

produced by it, are: (1) effective in facilitating improved sleep, alertness, and the use

of fatigue countermeasures, and (2) result 

in reduced risks of adverse events due to

sleep loss and circadian biology. 

• Determine the extent to which mathematical models of waking performance

capability (relative to dynamic interactions 

of sleep and circadian biology) can be used

to precisely identify and develop work-rest

schedules that minimize fatigue. Although

efforts have been underway to identify 

the strengths and weaknesses of such 

computational models, more research 

is needed to ensure they accurately 

reflect the underlying biology of circadian

rhythms and homeostatic sleep need as

they pertain to work-rest schedules.
SECTION IV—SLEEP AND HEALTH 67

BACKGROUND

Individuals with a variety of common medical

illnesses—including adult and juvenile arthritis,

asthma, cancer, cardiopulmonary diseases,

chronic fatigue syndrome (CFS), diabetes, 

end-stage renal disease (ESRD), fibromyalgia

(FM), human immunodeficiency virus (HIV), 

irritable bowel syndrome (IBS), obesity, and

temporomandibular joint disorders (TMJD)—

frequently experience sleep disturbances. 

It is recognized that medical illnesses can

adversely affect sleep quality, and that pain,

infection, and inflammation can induce 

symptoms of excessive daytime sleepiness

and fatigue. It is less clear, however, how 

sleep quality affects disease progression and

morbidity. In addition, patients with these

medical illnesses may also have a primary 

sleep disorder (see Section V) that further 

contributes to significant morbidity. The role 

of sleep disturbances and sleep disorders in

the morbidity of most chronic conditions is

understudied in children and adults and, as 

a result, is poorly understood. Similarly, how

sleep disturbances affect responses and 

adherence to medical therapy for the primary illness and the best ways to manage 

disturbed sleep in most chronic conditions is

understudied. The relationship between sleep

processes and the development, progression,

and management of chronic diseases, therefore, requires further study.

Insomnia associated with abnormal sleep

architecture is most evident in disorders 

characterized by known structural pathology,

e.g., arthritis, cancer, heart failure, and ESRD.

In chronic pain-related conditions without

known structural pathology (e.g., FM, CFS,

IBS), the most striking observation in these

“unexplained disorders,” is a self-report of

poor and nonrestorative sleep that is often 

out of proportion to modest changes in 

objective measures of sleep. This discrepancy

between subjective and objective sleep indicators has been studied extensively in FM 

and is most evident when patients are 

selected on the basis of appropriate case 

definition, compared to women of similar 

age, and screened for psychiatric disorders,

particularly depression. Insomnia in these

chronic conditions is known to exacerbate

symptoms of pain, fatigue, and daytime 

sleepiness, negatively impact work performance, social and family relationships, 

quality of life, and increase use of health 

care services. Controversy still exists, however, regarding the clinical significance 

and diagnostic value of abnormal sleep 

physiology in these unexplained disorders. 

Sleep is considered restorative and important

for illness recovery. It remains unknown, 

however, whether sleep actually facilitates

recovery processes. Clinicians advise patients

to “get plenty of sleep” during an acute

febrile illness or following surgery or trauma,

but sleep is often fragmented and disrupted.

These sleep disturbances are considered 

“incident” or “transient” forms of insomnia

that are treated readily with hypnotic medications and often resolve with recovery.

However, mutually exacerbating effects of 

SLEEP IN MEDICAL CONDITIONS
68 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

disturbed sleep and primary illness may be 

a significant barrier to full recovery. The role 

of acute illness-related insomnia in the 

development and pathogenesis of chronic 

conditions both in children and adults is

understudied and perhaps underestimated. 

In addition, the impact of acute care environments in exacerbating sleep disruption 

and further limiting successful implementation of medical or behavioral regimens 

is understudied.

PROGRESS IN THE LAST 5 YEARS

• Asthma and other pulmonary diseases 

commonly exacerbate during sleep, 

but the mechanisms involved are 

poorly understood. 

• There is an association between 

daytime sleepiness and cardiovascular 

disease-related morbidity and mortality

(e.g., hypertension, myocardial infarction,

and congestive heart failure).

• Severity of diabetes is directly associated

with severity of disturbed sleep, and 

partial sleep deprivation of healthy 

adults increases insulin resistance. 

• Patients with ESRD have disrupted 

nocturnal sleep with excessive daytime

sleepiness and the timing of dialysis 

treatment affects mortality. ESRD patients

on dialysis have among the highest incidence of both SDB and periodic leg 

movements (PLMs) in sleep, and PLMs 

are a significant predictor of survival and

mortality in this population.

• Sleep disturbance and fatigue are highly

prevalent and disabling symptoms in a

majority of individuals infected with HIV.

Recent findings suggest that symptoms 

of sleep disturbance and fatigue are independently associated with survival among

people with HIV infection. However, sleep

disturbances in children and adults with 

HIV remains understudied, underdiagnosed, and, therefore, undertreated. 

• “Unexplained disorders” are more 

prevalent in females than in males, but 

the biologic basis of this sex difference 

is poorly understood. Failure to identify 

a structural basis for these disorders has 

led some researchers and clinicians to

embrace sociocultural explanations that 

can bias research and care. 

• Altered timing and reduced nocturnal 

concentrations of sleep-dependent hormones (e.g., growth hormone, prolactin,

melatonin) have been described in a 

number of chronic conditions and are 

possibly linked with altered sleep physiology and reduced sleep continuity.

• Lack of altered circadian rhythms 

observed in FM patients coupled with 

lower concentrations of sleep-dependent

hormones (growth hormone and prolactin)

in other studies, underscores the possibility

of dysfunctional homeostatic sleep regulation as a basis for symptoms of poor 

sleep and fatigue.

• Pain is a major factor associated with 

disrupted sleep in many chronic conditions.

Experimental studies in healthy young men

and in animals show reduced responsiveness to noxious stimuli during sleep, but 

the mechanisms involved in sleep-related

pain modulation are unknown. 

• Neuroimaging studies have identified 

areas of the thalamus and basal ganglia

that may be hypofunctional in women 

with FM and hence may contribute to

abnormal sleep physiology. 
SECTION IV—SLEEP AND HEALTH 69

RESEARCH RECOMMENDATIONS

• As the United States’ population ages, 

the number of people living with chronic

medical illnesses will increase dramatically 

in the next two decades. It will be important to identify chronically ill populations 

at highest risk for sleep disturbances, 

determine the factors most associated 

with disturbed sleep, and the best 

ways to improve such sleep disturbances.

There is also a need to understand how

sleep disturbances affect adherence to 

treatments for chronic disease and ways

that improving sleep may improve treatment outcomes.

• Study the bidirectional relationship 

between sleep processes and disease 

development, progression, and morbidity.

Determine identifiable, measurable characteristics of sleep quality that could serve 

as potential indicators of primary disease

diagnosis, progression, and severity. Such

markers might indicate how sleep regulation and timing are reciprocally coupled 

to disease pathophysiology. 

• Epidemiological and clinical research is

needed in children and adults to elucidate

the benefits of sleep, the risks associated

with insufficient sleep during an acute 

illness, and the extent of unresolved acute

illness-related insomnia. The beneficial 

outcomes associated with improved sleep

during illness using behavioral, pharmacological, and environmental approaches

need to be explored.

• Conduct interdisciplinary basic science 

studies of the effects of pain and 

inflammation on sleep physiology 

both in animals and in humans.

• Conduct experimental challenge studies

using sleep delay or partial sleep deprivation to assess the extent of homeostatic sleep regulation dysfunction in 

chronic illnesses. 

• Study sleep, neuroendocrine and autonomic functioning in newly diagnosed

patients with FM compared to patients 

with CFS and with primary insomnia.

Studies of children, adolescents, and 

young women should be particularly 

informative. 

• In patients with chronic illness, determine

the effectiveness of self-management 

strategies (e.g., cognitive-behavioral 

and sleep hygiene) designed for treating 

primary insomnia, in relieving symptoms

and improving clinical outcomes. 

SECTION V

SLEEP DISORDERS

• Immunomodulation, Neuroendocrinology, 

and Sleep

• Sleep-Disordered Breathing

• Insomnia

• Narcolepsy and Other Hypersomnias

• Restless Legs Syndrome/Periodic Limb 

Movement Disorder

• Sleep in Other Neurological Disorders

• Parasomnias

• Sleep in Psychiatric, Alcohol, and 

Substance Use Disorders

SECTION V—SLEEP DISORDERS 73

IMMUNOMODULATION, NEUROENDOCRINOLOGY, 

AND SLEEP

the host is exposed. Many cytokines affect

sleep, each in different ways (e.g., IL-1, 

-2, -15, -18, tumor necrosis factor (TNF), 

inter-feron). Different combinations of

cytokines expressed during infection may 

have different overall effects on sleep.

Genetic factors that determine sleep patterns interact with environmental factors 

to contribute to final effects on disease outcome. Genetic host factors, in interaction 

with environmental factors, influence the 

set point of neuroendocrine stress response

and cytokine production patterns that interact with cytokine patterns produced in

response to different pathogens/antigens. 

Control of complex phenotypes such as 

sleep is likely to have the same characteristics as other complex phenotypes, including behavior or complex illnesses such as

inflammation/arthritis. Thus, it is likely that

many genes, each with small effect (polygenic/multigenic), regulate different aspects 

of sleep. Inheritance of sleep phenotypes 

could therefore be additive, as in other 

complex phenotypes, and hence depend 

not on single genes but on inherited regions

of DNA. Finally, such complex phenotypes

often exhibit large environmental variance.

Therefore, an important area of study will 

be to address and dissect gene-environment

interactions and to systematically assess the

effect of environmental factors on genetic

factors in sleep phenotypes and disease outcome. Potential environmental variables that

could be examined in the context of defined

BACKGROUND

Both the neuroendocrine output arm and 

the immune stimulus arm of brain-immune

communications affect sleep. Relevant 

immune factors include the broad family 

of immune molecules termed cytokines that

include interleukins (IL), chemokines, and 

other immune products that allow immune

cells to communicate. Cytokines are pleiotropic, both affecting and originating from

many other cells and organs than simply 

those of the immune system, and are key

communicator molecules that affect many

aspects of nervous system and neuroendocrine system function. Resultant sleep alterations induced by cytokines probably affect

the course of and susceptibility to a variety 

of diseases including infectious, inflammatory/autoimmune, and endocrine.

Reciprocal interactions between neuroendocrine and immune factors and sleep 

include the following:

• Immune molecules alter sleep architecture.

• Sleep deprivation alters neuroendocrine

and immune responses.

• Immune system activation and neuroendocrine responses alter sleep.

• Sleep quality probably affects the course 

of and susceptibility to infectious disease.

During infection, patterns of cytokines

produced depend on a combination of host

responses and specific pathogens to which 
74 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

genetic backgrounds impacting on sleep

include: (1) relative effects of different 

neuroendocrine and neural stress response

pathways; (2) effects, pathways and mechanisms of different pathogen and cytokine 

exposures; and (3) early developmental 

factors (maternal-infant interactions). 

PROGRESS IN THE LAST 5 YEARS

• Progress has been made in identifying 

individual and interfacing effects of 

different cytokines on sleep architecture

and identifying interactions between the

individual components of the hormonal

stress response system (including CRH 

and cortisol) and the neuronal stress

response system (including sympathetic 

nervous system responses). 

• Progress has included genetic linkage 

and segregation analysis of linkage 

regions to identify molecules that affect

infectious, cytokine, and sleep interactions.

In addition, knock-out animal models and

inbred strains have been used to elucidate

the role of individual immune and endocrine molecules in sleep.

• Short-term sleep deprivation is associated

with complex altered immune responses,

but the influence on disease outcome is

unclear. There is some evidence that sleep

loss and chronic sleep restriction may 

be associated, in addition to cytokines, 

with other inflammatory markers (e.g., 

C-reactive protein) that could impact the

development and severity of cardiovascular

disease as well as daytime sleepiness and

fatigue in sleep disorders. 

RESEARCH RECOMMENDATIONS

• Identify the effects of interactions between

the neuroendocrine and immune systems

on sleep phenotype and disease outcome 

in defined genetic models. These studies

should identify the molecular and cellular

mechanisms and neuroanatomical pathways of these interactions and their effects

on sleep architecture, sleep responses to

cytokines, and infectious disease outcome. 

• Further define the role of sleep, sleep 

deprivation, and chronic sleep restriction

on host defense. Human studies are 

needed to determine the extent to which

sleep disturbance and sleep deprivation

are related to markers of nonspecific inflammatory responses (e.g., leukocytes,

cytokines, C-reactive protein). Studies are

needed in transgenic or knock-out animals,

including linkage and segregation studies,

to identify the functional significance to

infection resistance and susceptibility of 

candidate genes in linkage regions or of

newly discovered cytokines, candidate 

neurohormones, or other molecules. 

• Study the biology of the relationships

among cytokines, neuroendocrine function, and sleep, including studies of the 

relationships of the neuroendocrine stress

response and cytokine induction of sleep 

in animal models and human studies.

Analysis of gene-environment interactions

and of sleep responses to infectious agents

in genetically manipulated animal models 

is relevant to the question of how sleep

alters disease susceptibility and outcome.

Specific pharmacological agents (e.g., 

specific cytokine or neuroendocrine

antagonists/agonists) will be useful to 

assess the effects of specific neurotransmitters/neurohormones/interleukins/

cytokines on sleep phenotypes. 
SECTION V—SLEEP DISORDERS 75

• Conduct genetic studies to identify 

neuroendocrine and immune genes 

relevant to sleep phenotypes. Approaches 

to identify potential candidate genes of

interest could include animal studies 

utilizing candidate gene knock-out and

transgenic animals, expression microarrays,

and linkage and segregation studies including congenics studies. Studies in humans

and animals could include sequencing of

candidate genes and phenotype characterization of subjects with candidate 

gene mutations or of transgenic or 

knock-out animal models.

• Conduct animal and human studies to 

integrate circadian biology and homeostatic sleep regulation with cytokine 

biology. This approach could include 

both in vitro and in vivo studies.
76 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Adult 

BACKGROUND

Sleep-Disordered Breathing (SDB) describes 

a group of disorders characterized by abnormalities of respiratory pattern (pauses in

breathing) or the quantity of ventilation 

during sleep. Obstructive sleep apnea

(OSA), the most common such disorder, 

is characterized by the repetitive collapse 

or partial collapse of the pharyngeal airway

during sleep and the need to arouse to 

resume ventilation. Sleep is thus disrupted,

yielding waking somnolence and diminished

neurocognitive performance. The recurrent

sleep arousal in association with intermittent hypoxia and hypercapnia has been 

implicated in the occurrence of adverse 

cardiovascular outcomes. In addition, there 

is evolving evidence that SDB may contribute

to insulin resistance and other components 

of the metabolic syndrome. Despite considerable progress, most patients remain 

undiagnosed, and the principal therapeutic

approach—continuous positive airway pressure (CPAP)—remains somewhat cumbersome and therefore is not associated with

optimal compliance rates. 

SDB is exacerbated by alcohol intake. 

In addition, current understanding of the 

neurobiologic mechanisms responsible for 

the sleep-induced changes in upper airway motor control that lead to pharyngeal 

collapse is incomplete. The reversibility, with

therapy, of apnea-induced hypertension and

other presumed adverse cardiovascular 

outcomes is largely untested. The explanations for reduced prevalence of SDB in 

women compared to men, and why women

present for therapy even less often than the

prevalence numbers would suggest, remain

unclear. It is unclear to what extent SDB in 

the elderly represents the same disorder 

as is encountered in younger populations 

and thus deserves similar therapy.

Cheyne-Stokes respiration, another type 

of SDB, is characterized by a crescendo—

decrescendo pattern of respiration and is 

commonly seen during sleep in patients with

congestive heart failure. The presence of this

respiratory pattern appears to be an important risk factor for the progression of heart

failure. More data are needed, however, to

clarify the mechanisms leading to CheyneStokes respiration, the impact of this abnormal ventilatory pattern on cardiac function,

and the effect of treatment on survival.

PROGRESS IN THE LAST 5 YEARS

• Reversibility with CPAP therapy of many 

of the neurocognitive and quality of life

detriments associated with SDB is suggested by relatively small, short-term trials.

• The strength of the association between

SDB and systemic hypertension in animal

SLEEP-DISORDERED BREATHING
SECTION V—SLEEP DISORDERS 77

models and large, prospective epidemiologic studies is becoming more evident.

Cross-sectional data also suggest an 

important association between SDB 

and stroke, myocardial infarction, and 

congestive heart failure.

• Studies addressing control of the pharyngeal musculature, both awake and asleep,

have demonstrated the ability of these 

muscles to respond to local stimuli awake,

thereby compensating for deficient anatomy/collapsibility and maintaining airway

patency. The loss of these reflex mechanisms during sleep is an important factor 

in the pathogenesis of SDB.

• Increasing evidence suggests a familial/

genetic influence on predisposition to 

SDB, independent of obesity. This genetic

influence may be mediated differently 

in different racial and ethnic groups 

(see Section IV).

• The efficacy of oral appliances (primarily

mandibular advancing devices) in patients

with mild to moderate SDB and of upper

airway surgical procedures over a range 

of apnea severity has been evaluated.

However, more information is needed

before the respective roles of these

approaches can be clearly delineated.

• Data suggest that positive airway pressure therapy can, over several weeks, 

eliminate Cheyne-Stokes respiration

in heart failure patients and lead to

improved transplant-free survival.

RESEARCH RECOMMENDATIONS

• Investigate and advance understanding 

of the genetic, neurobiologic, and physiologic mechanisms that are pathophysiologically important in the development,

potentiation, and maintenance of SDB.

Studies are also needed to access the 

interaction between cardiac dysfunction 

and the ventilatory control system in the

pathogenesis of Cheyne-Stokes respiration.

• Conduct adequately powered clinical 

trials, particularly in high-risk populations, 

to assess the impact of therapy of SDB 

on functional status, psychiatric disorders, 

neurocognitive function, and other disease

processes (hypertension, cardiovascular 

disease, metabolic syndromes, etc.). 

Studies assessing the impact of successful therapy of Cheyne-Stokes respiration

on cardiac dysfunction, quality of life

and survival are also needed.

• Design new and improved modalities for

the treatment of SDB, including pharmacologic, surgical, oral appliance, behavioral,

muscle stimulation, positive airway pressure

(including CPAP compliance), and other

novel approaches. Methods to individualize these therapies to the different SDB 

phenotypes are also needed, for example,

improved upper airway imaging approaches

to define site of collapse.

• Develop novel noninvasive screening/

diagnostic methodologies that are less

expensive and more widely applicable 

than standard full polysomnography. This

might include biomarkers as indicators 

of the presence of SDB, its severity, or 

its consequences.
78 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Pediatric

BACKGROUND

Snoring, a symptom of increased upper 

airway resistance during sleep, is extremely 

frequent in children, and affects 18 to 20 percent of infants, 7 to 13 percent of children

ages 2 to 8, and 3 to 5 percent of older children. The pathophysiology of SDB in children

is still poorly understood. Indeed, while adenotonsillar hypertrophy is certainly a major contributor to SDB, other factors, such as obesity,

craniofacial genetics, and neural control mechanisms of upper airway patency, also appear 

to be important. It is clear that the spectrum

of disease and morbidity associated with SDB

in children is expanding. As such, degrees of

severity that might have once been considered clinically irrelevant are now recognized 

as having substantial neurobehavioral and 

cardiovascular consequences.

PROGRESS IN THE LAST 5 YEARS

• In recent years, it has become apparent 

that SDB and snoring are not as innocuous

as previously thought. Indeed, epidemiological and pre-post treatment analyses 

have identified substantial morbidities 

that primarily affect cardiovascular and 

neurobehavioral systems. These morbidities include pulmonary hypertension, 

arterial hypertension, nocturnal enuresis,

reduced somatic growth, learning and 

cognitive deficits, and behavioral problems that resemble attention deficithyperactivity disorder.

• Failure to diagnose and treat in a timely

manner may prevent some of these morbid complications from being completely

reversible, leading to long-lasting residual

consequences. However, the point of transition between what constitutes pathology

and what is normal remains to be defined. 

• Improved phenotypic characterization of

SDB and its manifestations are facilitating

extrapolation of basic science concepts to

the pediatric population. Extended population studies are needed that incorporate

gene databases and also include multiorgan multifunctional categorization of

SDB-related morbidity and response to 

therapy. Such studies would allow for 

development of databases permitting 

correlation analyses of large datasets 

and exploration of multiple hypotheses 

generated from basic research findings. 

• As part of such phenotype delineation,

development of more sensitive and accurate tools for definition of disease and 

morbidity is needed. Currently available

tools are insensitive to morbidity and do 

not provide accurate determinations of the

degree of homeostatic disturbance that

occurs during sleep and during daytime.

RESEARCH RECOMMENDATIONS

• Develop longitudinal normative data on

sleep and cardiorespiratory patterning 

in children.

• Identify genes and gene products that 

may contribute to the pathophysiology 

of SDB. Conducting these studies in 

pediatric populations may have distinct

advantages, because they are less likely 

to be “contaminated” by age-associated

comorbidities present in adult populations.

Some of the “at-risk genes” may be operative only during infancy and childhood, 

e.g., genes responsible for immune modulation and lymphatic tissue growth, while

other genes, such as those underlying 

obesity or craniofacial phenotype, appear

applicable to both children and adults. In

addition, environmental factors or genegene interactions during childhood may

modify the phenotypic expression of the 

disease during adulthood.
SECTION V—SLEEP DISORDERS 79

• There is considerable variation in the 

magnitude of SDB associated morbidities in both children and adults, and this

heterogeneity in end-organ injury could 

be due to differences in gene and protein

responses to the various components of

SDB. Identification of such genes/proteins,

their functions and interactions, and their

posttranslational modifications, using currently available genomic and proteomic

approaches, may provide opportunities 

for development of promising targets for

intervention and for reducing morbidity. 

• Longitudinal studies are needed to assess

the long-term impact of SDB during childhood and into adulthood. Attention to 

outcomes among obese children is particularly important considering the increasing

prevalence of obesity in children. 

• One of the major limitations in diagnosing SDB is the need for relatively complex, 

burdensome, and costly procedures, such 

as overnight polysomnography. Research

efforts need to focus on development of

reliable screening methods that are applicable to children and to provide accurate

indicators of either the presence/absence 

of the disease or the occurrence of endorgan morbidity. Such developments

include, for example, application of new

biomedical sensor technologies, multimodality imaging strategies, development

of disease-related artificial intelligence networks, and systematic exploration of gene

and protein markers in biological fluids.

• First-line treatment of pediatric SDB routinely relies on surgical removal of the 

tonsils and adenoids. However, since this

treatment does have measurable morbidity,

mortality, and financial cost, novel interventional approaches need to be developed. 
80 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Adult

BACKGROUND

Insomnia is defined as difficulty falling asleep,

difficulty staying asleep, or short sleep duration, despite having an adequate opportunity

for sleep. It is the most common sleep complaint, affecting approximately 30 to 40 percent of the adult population. Even when more

stringent criteria are required, such as daytime impairment or marked distress, insomnia

disorders have a prevalence of approximately

10 percent. Evidence suggests that insomnia

has significant consequences on quality of 

life, health care utilization, and subsequent

psychiatric disorders. Efficacious short-term

behavioral and pharmacologic treatments 

for insomnia are available, and progress has

been made in epidemiology and risk-factor

identification, identification of adverse outcomes, and in identifying effective treatments.

However, much remains unknown regarding

the causes, characterization, consequences,

and optimal management of insomnia disorders. For instance, we do not have a consistent phenotype(s) for insomnia disorders

that could be applied to human and animal

studies. Despite major research advances in

the neurobiology of sleep and circadian

rhythms (see Section I), the implications of

these findings for insomnia have not been

carefully investigated. Instead, the pathophysiology of insomnia has been examined from 

a number of clinically derived theoretical

frameworks, with little replication of the 

findings reported in individual studies. 

Effective treatments for insomnia have been

developed, but important issues still remain.

For instance, the exportability of behavioral

treatments to usual care settings and the

effectiveness (as opposed to efficacy) of 

insomnia treatments have yet to be determined. Finally, there is a need to develop 

novel pharmacologic treatments based on 

new findings in sleep neurobiology.

PROGRESS IN THE LAST 5 YEARS

• The efficacy and durability of standardized

behavioral treatments for insomnia have

been demonstrated in a number of wellcontrolled clinical trials.

• The epidemiology of insomnia in adults 

has been well described. Consistent risk 

factors, such as psychological symptoms,

medical illness, and female sex, have 

been identified.

• Independent studies have demonstrated

that insomnia is a risk factor for subsequent development of psychiatric disorders

and for worse outcomes among individuals

with concurrent psychiatric disorders.

• A small but growing body of evidence 

has demonstrated “hyperarousal” among

patients with insomnia, including increased

central nervous system activation (indexed

by increased high-frequency EEG activity),

sympathetic nervous system activation, 

and hypothalamic-pituitary-adrenal (HPA)

axis activation.

INSOMNIA
SECTION V—SLEEP DISORDERS 81

RESEARCH RECOMMENDATIONS

• Basic and preclinical studies are needed 

that focus on the neurobiology of insomnia. These should include: (1) the development of animal models of insomnia with

specific insomnia phenotypes; (2) the 

application of neurophysiological, neurochemical, neuroanatomic, and functional

neuroimaging approaches to human 

studies; and (3) genetic, genomic, and 

proteomic studies.

• Pharmacological treatment studies are 

needed to define the efficacy, safety, 

abuse liability and role of long-term 

hypnotic treatment. Priority should be 

given to studies defining the optimal 

duration and pattern of administration of

traditional hypnotic medications, including

investigations of their use in populations

with high rates of utilization, such as with

psychiatric disorders. Studies are also needed on widely used but poorly documented

treatments, such as sedating antidepressants, and on the development and testing

of novel pharmacologic agents based on

neuroscience findings (e.g., drugs affecting corticotropin release, adenosine, or

hypocretin systems).

• Insomnia phenotypes need to be characterized and include: (1) development and

validation of clinical phenotypes (e.g., 

define diagnostic criteria), (2) physiological

characterization and biomarkers (which 

may include measures of EEG, HPA axis,

sympathetic nervous system, and functional neuroanatomy using neuroimaging

techniques), and (3) indices of discriminant

validity versus mood and anxiety disorders.

Definition of insomnia phenotypes should

also address subjective-objective discrepancies in sleep measures, as well as 

the relationship between insomnia and 

co-existing sleep, psychiatric, and 

physical disorders.

• Further studies of behavioral/psychological treatments are needed. These studies

should include: (1) the use of behavioral/

psychological treatments in routine care 

settings (e.g., primary care offices), 

(2) the development of alternative delivery methods (e.g., simplified treatment 

regimens, computer or Internet administration), (3) studies in patients with 

medical or psychiatric comorbidity, and 

(4) large-scale effectiveness studies. Priority should also be placed on investigating

the specific efficacious components of 

these behavioral treatments.

• More precisely define the potential physical health risks, morbidity, and functional

consequences of insomnia, distinct from 

the morbidity and consequences of associated medical and psychiatric conditions.

• Examine the extent of use, efficacy, and

adverse effects associated with alternative

treatment approaches, including nutritional

supplements, herbal remedies, and nonpharmacological treatments.

Pediatric

BACKGROUND

Difficulties in initiating and maintaining sleep

are extremely common in children. The overall prevalence of sleep onset delay/bedtime

resistance has been reported to be in the

range of 15 to 25 percent in healthy schoolaged children and even higher in adolescents.

However, because behaviorally-based sleep

problems in children are often defined by 

caregivers, the range of sleep behaviors that

may be considered “normal” or “pathologic”

is wide and the definitions highly variable. In

addition, population-based normative data 

on sleep patterns across childhood are lacking, creating further challenges in defining

“abnormal” sleep in infants, children, and
82 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

adolescents. Therefore, a common nosology

for defining sleep disorders in children needs

to be developed and evaluated.

Insomnia in Special Populations

Sleep disturbances in pediatric special needs

populations are extremely common, and 

often a source of considerable stress for 

families. Prevalence of sleep problems in 

children with severe mental retardation has

been estimated to be as high as 80 percent,

and to be 50 percent in children with less

severe cognitive impairment. The prevalence 

of sleep problems in children with autism is

estimated to be 50 to 70 percent.

Significant problems with initiation and 

maintenance of sleep, shortened sleep 

duration, irregular sleeping patterns, and 

early morning waking have been reported 

in many neurodevelopmental disorders, including autism and pervasive developmental

disorder, Asperger’s syndrome, Smith-Magenis

syndrome, Angelman’s syndrome, tuberous

sclerosis, San Filippo syndrome, Rett syndrome, and William syndrome. Other studies

have suggested that similar rates of sleep

problems also occur in both younger and 

older blind children, with the most common

concerns being difficulty falling asleep, night

wakings, and restless sleep. 

The types of sleep disorders in these children

are not unique to this population, but are

more frequent and more severe than in the

general population and often reflect the 

child’s developmental level rather than 

chronological age. Multiple sleep disorders 

are also likely to occur simultaneously. The

incremental impact of disrupted and/or inadequate sleep on cognitive, emotional, 

social development, and behavior in these

already at risk children is potentially profound.

Little is understood, on either a pathophysiologic or behavioral level, about the interaction between sleep disorders and acute 

and chronic health conditions such as asthma,

diabetes, and juvenile rheumatoid arthritis. In

chronic pain conditions, these interactions 

are likely to significantly impact morbidity 

and quality of life.

PROGRESS IN THE LAST 5 YEARS

• In addition to risk factors such as social 

and communication developmental 

abnormalities and cognitive impairment, 

a primary arousal dysfunction in children

with neurodevelopmental disorders may

contribute to sleep problems.

• There may also be a primary disturbance 

of melatonin production and synchronization in autistic children, and some autistic

children seem to respond to treatment 

with exogenous melatonin. Studies have

documented improvements in sleep onset

delay, night wakings, early morning waking

and total hours of sleep using a small dose

(0.3 to 0.5 to 2.5 to 5 mg) of melatonin

approximately 1 hour before desired bedtime in up to 80 percent of children with

disorders such as cortical blindness, Rett

syndrome, autism, tuberous sclerosis, and

Asperger’s syndrome. However, melatonin is

not effective in all developmentally delayed

children with sleep problems, and little is

known overall about long-term side effects. 

• Some, studies have examined the role of

sleep disturbances in chronic medical conditions of childhood, such as sickle cell 

disease and asthma, disorders particularly

common in high-risk and minority populations. The interaction between sleep 

and physical and emotional dysfunction in

acute and chronic pain conditions such as

burns and juvenile rheumatoid arthritis, 
SECTION V—SLEEP DISORDERS 83

has also begun to be explored. Additional

factors, such as the impact of hospitalization, family dynamics, underlying disease

processes, and concurrent medications are

also important in assessing the bidirectional

relationship of insomnia and chronic illness

in children.

• Clinical psychology and pediatric studies

have examined the efficacy of empirical

behavioral treatment for sleep problems 

in small samples. Most of these studies 

have relied on parental assessment of 

treatment success. Additional outcomes

research to systematically assess efficacy 

of various treatment modalities for sleep

disorders, including behavioral management protocols, is needed to generate 

recommendations for “best practices.” 

• Pharmacologic intervention in conjunction with behavioral techniques has been

shown to be effective in some cases.

However, little is known overall about 

the safety and efficacy of pharmacologic

interventions for sleep disturbances in 

children, alone or in combination with

behavioral therapy. Medications used to

treat insomnia in children include diphenhydramine, chloral hydrate, trazadone,

clonidine, and benzodiazepines. Hypnotic

medications, however, can result in unpredictable side effects, development of 

tolerance necessitating increasingly higher

doses, paradoxical effects (agitation instead

of sedation), and withdrawal effects.

Rebound sleep onset delay on discontinuation and morning “hangover” can 

be significant problems as well. Little is 

known about the scope and patterns 

of use of pharmacologic interventions in

pediatric sleep disorders, about possible

indications, and about potential target 

populations for short-term use of hypnotics

in conjunction with behavioral interventions.

RESEARCH RECOMMENDATIONS

• Develop a common definition and document the prevalence and functional impact

of pediatric insomnia across the age spectrum in the general population and in 

high-risk populations, such as special 

needs children (e.g., neurodevelopmental

disorders, sensory deficits) and children 

with chronic medical conditions (e.g., 

diabetes, asthma). Normative data should

be collected regarding sleep practices and

patterns in order to define “abnormal”

sleep. Studies should also examine the

developmental aspects of insomnia in 

children—including the role of early 

sleep patterns and behaviors, parenting

practices, temperament, and genetics—

as well as risks and protective factors for 

the persistence of insomnia into adolescence and adulthood.

• Develop and evaluate optimal evidencebased treatment strategies and management protocols for pediatric insomnia:

– In otherwise healthy children, using 

standardized measures for such outcome variables as sleep quality and 

quantity, sleepiness/alertness, mood,

behavior, academic functioning and

parental stress.

– In children with special needs, including evidence-based behavioral and 

pharmacologic treatments for insomnia

and circadian rhythm disturbances, and

including outcome measure, such as 

neurocognitive performance measures

and assessment of impact on quality 

of life for children and caregivers.

• Examine the interrelationships between

insomnia and chronic medical conditions 

in children, including effects on disease

processes, pain management, quality of 

life, and caregiver well-being.
84 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Narcolepsy is a disabling neurological disorder

characterized by sleepiness and symptoms of

abnormal rapid eye movement (REM) sleep

such as sleep paralysis, hypnagogic hallucination, cataplexy and, frequently, disturbed

nocturnal sleep. Narcolepsy is most commonly

diagnosed using nocturnal polysomnography

and the Multiple Sleep Latency Test (MSLT). 

In this test, sleep latencies and the occurrence of REM sleep are evaluated during 4 

to 5 naps, scheduled every 2 hours during 

the daytime. Narcoleptic patients typically 

display short mean sleep latency, indicative 

of daytime sleepiness and more than two 

REM episodes in the MSLT. 

Narcolepsy-cataplexy affects 1 in 2,000 

people and is the fourth most common 

condition treated in sleep disorder clinics. 

The exact prevalence of essential hypersomnia

and narcolepsy without cataplexy, two related

disorders characterized by sleepiness and

abnormal MSLT results, is unknown. These 

two disabling disorders are at least of similar

frequency as narcolepsy with cataplexy, but

few research data are available.

In humans, narcolepsy-cataplexy is genetically

complex, human leukocyte antigen (HLA) 

associated, and environmentally influenced.

Fine mapping studies in the HLA class II 

region indicate a primary role for HLA-DQ.

Multiplex families are rare, but relative risk 

in first-degree relatives is 20 to 40-fold 

higher than in the general population for 

narcolepsy-cataplexy. HLA susceptibility 

genes play a minor role in overall genetic

susceptibility. Human narcolepsy is currently

treated symptomatically with dopaminergic

amphetamine-like stimulants, gammahydroxybutyrate, and monoaminergic antidepressant

therapy. Behavioral and social interventions 

are also helpful.

The study of narcolepsy is facilitated by 

the existence of two animal models: canine

and murine narcolepsy. A 10-year positional

cloning study identified canarc-1 as the

hypocretin (orexin) receptor-2 gene (Hcrtr2).

This was followed by the discovery that 

preprohypocretin knockout mice also have 

narcolepsy and by the discovery that human

narcolepsy is associated with decreased

hypocretin transmission. Hypocretin-1 and 

2 (orexin-1 and 2) are excitatory neuropeptides encoded by a single gene selectively

expressed in a small subset of lateral hypothalamic neurons. Hypocretin neurons project widely in the central nervous system and

have especially dense monoaminergic cell

group projections. Two hypocretin receptors

(Hcrtr1 and Hcrtr2) with differential neuroanatomical distribution are currently known. 

In humans, narcolepsy cases are not associated with hypocretin ligand or receptor

mutations but, rather, with undetectable 

cerebral spinal fluid (CSF) hypocretin-1 levels.

NARCOLEPSY AND OTHER HYPERSOMNIAS
SECTION V—SLEEP DISORDERS 85

Only a single hypocretin gene mutation in 

an unusual patient with a very early onset 

(age 6 months) disorder and severe symptomatology has been reported to date. In 

sporadic cases, neuropathological studies 

indicate a dramatic loss of both hypocretin-1

and hypocretin-2 in the brain and a disappearance of hypocretin-containing cells in 

the hypothalamus. Together with the observation that hypocretin-1 is potently wakepromoting in vivo, these results demonstrate

that narcolepsy-cataplexy is due to a hypocretin deficiency. HLA association in humans

suggests the possibility of an autoimmune 

disorder directed against hypocretin-containing cells in the lateral hypothalamus. 

The cause(s) of narcolepsy without cataplexy and of other hypersomnias of central 

origin (e.g., idiopathic hypersomnia) are 

currently unknown. 

PROGRESS IN THE LAST 5 YEARS

• Our understanding of narcolepsycataplexy has been revolutionized in 

the last 5 years. The discovery in 1999 

that hypocretin gene alterations produce

narcolepsy in canines and mice rapidly 

led to the finding that human narcolepsy is associated with decreased 

hypocretin transmission. 

• Novel pharmaceutical treatments have 

been developed including modafinil, 

a wake-promoting compound, and

gammahydroxybutyric acid (GHB), a 

sedative used for treating disturbed nocturnal sleep and cataplexy. These are 

useful therapeutic treatments but only

symptomatically treat the condition.

RESEARCH RECOMMENDATIONS

• Conduct basic research on hypocretins in

animal models. Even though recent findings have stimulated some basic research

studies on hypocretins, the exact role of 

this system in the regulation of normal 

sleep and other behaviors is still unknown. 

• Study the epidemiology and pathophysiology of narcolepsy without cataplexy,

essential hypersomnia, and periodic 

hypersomnia. Our understanding of 

narcolepsy has been largely limited to 

cases with cataplexy, and little information 

is available on these other conditions. With

the increased availability of wake-promoting

medications, such as modafinil, there is an

urgent need to evaluate the prevalence,

treatment strategies, and etiologies of 

these related conditions.

• The field is ready for direct clinical applications. Measuring CSF hypocretin-1 has 

been shown to be a reliable diagnostic 

procedure for narcolepsy-cataplexy in 

limited case series, and efforts should be

made to further validate and distribute 

this new diagnostic procedure. Furthermore, efforts should be made to design

alternate diagnostic procedures based on

the knowledge that narcolepsy is caused 

by hypocretin abnormalities. These may

involve (but should not be limited to) 

measuring hypocretin levels in blood or

imaging studies of the hypothalamus. 

• Study the effectiveness of replacing

hypocretins or hypocretin-producing 

cells. Since animal models are available 

to test this hypothesis and design new 

treatments, studies should be conducted 

in both animals and humans. Hypocretin

peptide supplementation, the development of hypocretin receptor agonists, 

cell transplantation, and gene therapy 

are all possible treatments. 
86 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Studies designed to identify the causes of

destruction of hypocretin-containing cells 

in human narcolepsy are needed. Studies

are also needed to define the immune 

connection in narcolepsy and/or to discover why narcolepsy is HLA-associated. 

In this regard, the study of cases of recent

onset (most likely still at the stage of active

destruction) may be critical.

• Studies to find other narcolepsy genes, 

and identify rare cases of narcolepsy without known hypocretin abnormalities, 

are needed to better understand these

pathologies.

• Studies of new medications such as

modafinil and gammahydroxybutyric

acid (GHB) are needed to determine 

their mode of action. Efforts to study 

the mode of action of current narcolepsy

treatments could lead to improving current

treatments. Additionally, there is a need 

for studies on the effect of drugs used in

other areas of neurology and psychiatry 

as novel indications in narcolepsy (e.g., 

stimulants for daytime sleepiness, antidepressants for cataplexy, sedative 

agents for disturbed nocturnal sleep). 

• Since narcolepsy typically starts in childhood or early adolescence, management 

of these patients is particularly challenging

and clinical protocols need to be developed.

Studying narcolepsy as closely as possible 

to its onset, generally during childhood,

may also provide unique clues to the 

cause of the disorder.

• Commonly used therapies in narcolepsy

include napping and other behavioral 

treatments, but data establishing efficacy

are sparse. More research in this area 

is needed.

• Studies in twins indicate that not only

genetic background but also environmental factors are involved in the pathophysiology of narcolepsy. Studies are 

needed to characterize these factors and

determine the potential effectiveness of 

prevention strategies. 
SECTION V—SLEEP DISORDERS 87

BACKGROUND

Restless Legs Syndrome (RLS) is a sensorimotor disorder characterized by periodic 

irresistible urges to move the legs, usually

associated with unpleasant and uncomfortable sensations in the legs. These symptoms

occur during wakefulness, but are exacerbated

or engendered by rest/inactivity and partially

relieved by movement. The diurnal pattern 

of symptoms likely reflects modulation by 

the circadian system. RLS is reported to 

profoundly disturb sleep, yet the extent of

nocturnal sleep disturbance and of daytime

sleepiness has not been established. Estimates

of RLS in various populations range from 2 

to 15 percent, but incidence and prevalence

have not been precisely defined, particularly 

as a function of gender and ethnicity. Several

reports indicate a higher prevalence of RLS in

women than in men, and also in individuals 

of Northern European ancestry. The etiology

and pathogenesis of RLS are thought to

involve alterations in efficiency of central

dopamine neurotransmission, based largely 

on the clinical observation that dopaminergic

drugs relieve symptoms. The inheritance 

pattern of RLS suggests an autosomal dominant mode of transmittance, but the genes

accounting for this observation are not 

known. RLS is also associated with iron deficiency, and it is quite common in end-stage

renal disease (ESRD) and during pregnancy. 

About 85 to 90 percent of patients with RLS 

also exhibit periodic limb movements (PLMs)

during sleep. Unlike RLS, which is diagnosed

on the basis of history and symptoms, periodic

limb movement disorder (PLMD) relies upon

quantification of repetitive stereotypic leg

movements associated with a brief arousal

during sleep monitoring. Patients manifesting PLMD have complaints of daytime fatigue

and sleepiness or insomnia. As in RLS, PLMD

may involve altered central dopamine mechanisms since dopaminergic agents or other

drugs that interact with dopamine mechanisms, (e.g., opiates) are equally effective 

treatments for most patients. The incidence 

of PLMD, as with RLS, is higher in the elderly.

Without better understanding of the etiology,

pathogenesis, and neurophysiology of these

disorders, treatment strategies are limited and

can therefore be unsatisfactory. Both disorders

can have profound negative impacts on the

quality of life including daytime functioning,

work performance, and social and family life. 

Controversy exists about the clinical significance of PLMs during sleep in the absence 

of sensory complaints consistent with RLS.

PLMs can occur without associated electroencephalographic (EEG) micro-arousals and in 

the absence of sleep complaints or of daytime

symptoms. If associated with micro-arousals,

the frequency of PLMs does not correlate 

with objective measures of daytime sleepiness

or with indices of disrupted sleep. This lack 

of a correlation may reflect insensitivity in the

methods used for scoring EEG micro-arousals

and sleep fragmentation. Abnormal limb

movements during sleep have been associated with physiological correlates of arousal in

autonomic or cortical functioning, suggesting

RESTLESS LEGS SYNDROME/PERIODIC LIMB

MOVEMENT DISORDER
88 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

that PLMs are part of an underlying arousal

disorder. It is possible that abnormal limb

movements during sleep may be associated

with an unidentified neurophysiological 

alteration in microstructure of the EEG 

sleep pattern. 

PROGRESS IN THE LAST 5 YEARS

• Several potential animal models of RLS 

and PLMD have been developed based

upon interruption of normal dopaminergic responsivity.

• Imaging studies suggest reduced central

dopamine receptor binding with age, 

but only small and inconsistent decreases 

in dopaminergic transmission have been

reported in traditional nigrostriatal dopaminergic pathways in patients with RLS. 

This finding suggests that alterations 

might exist in extrastriatal dopaminergic pathways. 

• RLS and PLMD are more common in 

children with attention deficit hyperactivity

disorder (ADHD) providing an opportunity

to address developmental aspects of these

disorders and responsivity to dopaminergic interventions.

• Neurophysiological studies in humans 

suggest that RLS is associated with inefficiencies of spinal cord inhibition 

that may be brainstem mediated and 

state dependent.

• RLS shows high familial aggregation. 

A recent study of genes involved in 

central dopaminergic transmission and

metabolism showed no evidence of involvement in RLS. However, other recent

studies have identified a susceptibility 

locus for RLS on chromosome 12q in 

a large French-Canadian family, and a 

polymorphism in a gene involved in 

catecholamine (monoamine oxidase A)

metabolism in women with RLS.

• Central nervous system (CNS) imaging 

studies have shown reduced iron concentrations in some brain regions. These

reductions correlate with RLS severity 

and low cerebral spinal fluid (CSF) ferritin

combined with high serum and CSF 

transferrin levels. 

• The RLS case definition was updated 

and revised in 2002, thereby providing 

a basis for the development of specific

questionnaires to advance clinical recognition, and to clarify RLS prevalence. 

• EEG patterns of cortical activation precede

PLMs and indices of autonomic arousal,

suggesting that PLMs are associated with 

an underlying arousal disorder.

RESEARCH RECOMMENDATIONS

• Determine the role of altered central

dopaminergic mechanisms, iron metabolism, and other possible mediators in the

pathogenesis of RLS and PLMD through 

animal and human studies. The development, refinement, and validation of 

animal models for RLS and PLMD are 

needed. Modern techniques of neropathology in the evaluation of brains and 

spinal cords from patients with RLS and

PLMD should be used to identify potential

abnormalities underlying these disorders.

• Identify and further characterize genes

involved in RLS and PLMD.

• Determine the extent of nocturnal sleep 

disturbance and daytime sleepiness in 

children and adults with RLS and PLMs. 

• Develop and validate questionnaires 

based on the new RLS case definition, 

and determine the population-based 

incidence, prevalence, and morbidity, 

particularly in children and as a function 

of gender, race, and ethnic distribution.
SECTION V—SLEEP DISORDERS 89

• Establish the developmental changes in

adults explaining the higher incidence 

of RLS and PLMD in the elderly. 

• Pregnancy and uremia provide reversible

models to study the development and

remission of RLS and the role of altered 

iron metabolism. Conduct clinical trials 

of iron supplementation in RLS patients 

with low ferritin levels.

• Improve available treatment strategies 

for RLS and PLMD. Dopamine agonists, 

opioids, and anticonvulsants are used 

most frequently, and are effective in 

reducing RLS symptoms and PLMs, but 

the necessary large multicenter trials 

and long term studies have not been 

conducted. These studies should include

assessment of quality of life and assess 

the sensitivity of existing questionnaires 

to treatment changes. 
90 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Sleep disturbances and sleep disorders are

commonly associated with neurological 

diseases, and neurological impairments of

sleep reveal much about the brain circuitry

involved in sleep regulation. Many neurological disorders are now recognized to 

cause disruptions of sleep. For example, 

pathological sleepiness is associated with 

neurological and neurodegenerative disorders such as Parkinson’s disease (PD),

Alzheimer’s disease (AD), and progressive

supranuclear palsy. Pathological sleepiness 

is also associated with neuromuscular 

disorders such as myotonic dystrophy, inflammatory conditions such as encephalitis

or multiple sclerosis, and with traumatic or

ischemic injury to the brain. In addition, 

conditions such as REM Sleep Behavior

Disorder (RBD) are recognized as precursors 

of PD. Conversely, Fatal Familial Insomnia (FFI),

a prion disorder related to Creutzfeldt-Jakob

disease, causes prolonged wakefulness. 

Sleep is a powerful modulator of epilepsy, 

with some epilepsy syndromes occurring 

exclusively or predominantly during sleep.

These include benign childhood epilepsy

with centrotemporal spikes, autosomal 

dominant nocturnal frontal lobe epilepsy, 

and continuous spike-wave activity during

sleep. Sleep deprivation has also been

described as a risk factor for epileptic 

seizures, although alcohol use and workrelated stress are confounding factors.

Treatment of sleep disorders that fragment

sleep, such as Sleep-Disordered Breathing

(SDB), has improved seizure control in 

case series.

Sleep disorders can also occur as a consequence of treating neurological disorders. 

For example, pathological sleepiness may

occur during treatment of PD and other 

movement disorders with dopamine-related

drugs. In addition, many drugs used to treat

neurological disorders can cause excessive

sleepiness or wakefulness. 

Sleep disorders also interact in complex 

ways with neurological disorders and are 

frequent after head trauma, stroke, encephalitis, or in association with neuromuscular 

disorders. For example, stroke has been 

shown to be associated with SDB, and SDB

likely decreases potential for recovery in 

stroke patients. Stroke may also produce 

SDB by interacting with the central regulation of breathing. Similarly, the intermittent

hypoxia that accompanies SDB may hasten 

the neurodegenerative cascade in disorders

such as PD and AD. 

Neurological disorders provide models 

for understanding sleep circuitry in the 

brain. In addition, understanding sleep 

mechanisms and disorders will be integral 

to treating these neurological diseases.

SLEEP IN OTHER NEUROLOGICAL DISORDERS
SECTION V—SLEEP DISORDERS 91

PROGRESS IN THE LAST 5 YEARS

• Studies of patients with Parkinson’s disease

reveal a range of sleep disorders, including

PLMS, RBD, and daytime sleepiness. These

disorders are part of the disease spectrum,

occur commonly, and suggest an important

role for dopaminergic pathways in sleep/

wake regulation. Dopamine-like drugs are

useful in treating these disorders, and it is

recognized that when these drugs stimulate

dopamine D2/D3 receptors they can cause

“attacks” of excessive sleepiness, potentially

resulting in automobile and other accidents. 

• An important advance has been the 

empirical application of wake-promoting

drugs to treat sleep disorders in various 

neurological conditions. The use of wakepromoting compounds in treating fatigue

and sleepiness in various neurological 

disorders such as PD, head trauma, and

multiple sclerosis is increasing, but these

treatments deserve controlled study. 

• Vagus nerve stimulation (VNS), an approved

treatment for medically refractory epilepsy,

has been shown to cause apneas and shallow breaths (hypopneas) during sleep, but

these effects are ameliorated by reducing

VNS stimulus frequency. In addition, VNS

has been shown to reduce daytime sleepiness in epilepsy patients. These findings

emphasize the interconnections of the

vagus nerve with brainstem networks 

that regulate respiration and alertness.

• Advances in all of these disorders depend

upon understanding the brain circuitry

involved in sleep regulation. Elucidation 

of important components of the wake 

and sleep promoting circuitry in the 

hypothalamus and the brainstem has

occurred over the last 5 years. Drug 

development is currently under way to 

take advantage of this new information 

in order to treat pathological wakefulness 

or sleepiness and to cause sedation, when

necessary, with fewer side effects.

RESEARCH RECOMMENDATIONS

• Evaluate the prevalence and impact of 

sleep disorders and disturbances in neurological conditions, such as neurodegenerative disorders (e.g., Alzheimer’s disease,

Parkinson’s disease), movement disorders,

post head trauma, encephalitis, stroke, 

and epilepsy. These studies should evaluate whether sleep disorders predispose to

specific neurological conditions, whether

neurological conditions can produce sleep

disorders, and whether sleep disorders

impair recovery from selected neurological disorders. Studies of sleep in animal

models of neurological disorders should 

also be conducted.

• Study natural models of locally disrupting sleep circuits (tumors, trauma, multiple

sclerosis plaques, infarcts, neurodegenerative conditions, paraneoplastic syndrome,

etc.). Studies should be performed that

combine imaging techniques or neuropathology with sleep/sleep disorders

analyses.

• Study the impact of pharmacological 

and nonpharmacological neurological 

treatments on sleepiness and sleep (for

example, in epilepsy, multiple sclerosis, PD).

• Study sleep and sleepiness in inflammatory

states (encephalitis, infarcts, multiple sclerosis, autoimmune disorders, etc.).

• Determine if sleep disruption due to sleep

disorders or sleep deprivation lowers the

threshold for epileptic seizures, and explore

the mechanisms responsible for this effect.

• Perform controlled studies to determine 

if treatment of sleep disorders improves

seizure control. 
92 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

PARASOMNIAS

Numerous secondary parasomnias, such 

as sleep-related expiratory groaning or

esophageal spasm, have been reported.

Typically, descriptions have been provided 

for single cases or very small case series, 

making scientific evaluation difficult. These

phenomena are likely to be quite common,

but they are often unrecognized, misdiagnosed, or ignored in clinical practice. The

pathophysiology, morbidity, and functional

consequences of secondary parasomnias 

are unknown.

PROGRESS IN THE LAST 5 YEARS

• Epidemiological studies have shown that

disorders of arousal occur in about 10 

percent of adults, and are usually not 

associated with significant underlying 

psychiatric or psychological disorders. 

These disorders are very common in 

children but may begin during adulthood or persist into adulthood. There 

is growing evidence for genetic determinants of these disorders of arousal.

• Exogenous triggers, including sleep deprivation, alcohol ingestion, and medications

have been identified for disorders of 

arousal in predisposed individuals.

• The basic sleep architecture and sleep

macrostructure is normal in patients with

disorders of arousal. “Hypersynchronous

delta” activity has not been substantiated 

as an EEG marker for disorders of arousal.

Adult

BACKGROUND

Parasomnias are undesirable behavioral, 

autonomic nervous system, or experiential

phenomena during sleep, usually characterized by increased motor and/or autonomic

activity, sleep-wake state dissociation, altered

responsiveness to the environment, and 

retrograde amnesia. Specific parasomnias 

arise during sleep-wake transitions, non 

rapid eye movement (NREM) sleep, or rapid

eye movement (REM) sleep, and are often 

classified as either primary parasomnias—

disorders of sleep states per se—or secondary parasomnias—disorders of other organ 

systems that arise during sleep. Virtually all 

primary parasomnias represent an admixture

or simultaneous occurrence of elements of

both wakefulness and sleep

The most common primary parasomnias are

disorders of arousal and REM sleep disorders.

Disorders of arousal include confusional

arousals, sleepwalking, and sleep terrors, all

characterized by partial arousals from NREM

sleep. REM sleep parasomnias include nightmares, characterized by frightening dreams

and autonomic arousal, and REM behavior 

disorder (RBD), characterized by absence of

the muscle atonia normally present during

REM sleep. The behaviors associated with 

primary parasomnias may lead to injury of 

the patient or bed partner and may have

forensic implications.
SECTION V—SLEEP DISORDERS 93

However, quantitative EEG analyses in

patients with disorders of arousal indicate

instability of slow-wave sleep, particularly

during the first slow-wave sleep period of

the night. This instability may be related 

to cyclic alternating patterns.

• RBD, which may have a prevalence rate 

as high as 0.5 percent, has two striking

demographic features: 90 percent of 

affected individuals are male, and most

cases begin after 50 years of age.

Clonazepam is efficacious in 90 

percent of cases.

• At least 50 percent of RBD cases are 

related to recognized neurologic conditions, particularly narcolepsy and the 

synucleinopathies (Parkinson’s disease, 

multiple system atrophy, and dementia

with Lewy bodies). RBD may precede the

appearance of other features of the underlying disease by as many as 10 years. RBD

may also be iatrogenic, due primarily to

medications such as selective serotonin

reuptake inhibitors (SSRIs).

• Functional neuroimaging studies have 

documented reduced dopamine transporters and decreased dopaminergic 

innervation of the basal ganglia in 

patients with RBD.

• Other conditions characterized by 

sleep-wake state dissociations have 

been identified, and may be related 

to RBD. These include parasomnia overlap syndrome, agrypnia excitata, and 

status dissociatus.

RESEARCH RECOMMENDATIONS

• Better define the pathophysiology and 

neuroanatomic substrates of primary 

parasomnias in human and animal studies.

In humans, specific methods could include

functional neuroimaging and quantitative

EEG studies (e.g., investigations of cyclic

alternating pattern in disorders of arousal).

Psychophysiological and neurophysiological studies could help to identify factors 

that trigger and maintain chronic parasomnias. A brain bank for RBD and other

parasomnias would be particularly useful 

to study their structural and genetic origins.

The identification of genetic and environmental factors involved in the etiology and

pathogenesis of primary parasomnias may

be facilitated by the presence of distinctive

phenotypes for these disorders. Animal

models for parasomnias could involve 

techniques such as genetic manipulations,

brain lesions and brain stimulation, sleep

deprivation, and other behavioral provocation techniques, and pharmacologic

manipulations. In particular, animal studies investigating motor control and sleep

could help to further elucidate the pathophysiology of parasomnias. 

• Investigate pharmacologic and behavioral

treatments for primary and secondary 

parasomnias in clinical trials. Intervention

studies could help to identify both common

and distinctive mechanisms of action for 

different treatments in different disorders.

• Further define the relationships between 

the different parasomnias, and between

parasomnias and other neurological disorders. For instance, the relationship

between disorders of arousal and nocturnal seizures, particularly nocturnal 

frontal lobe epilepsy, should be further

investigated. Relationships between RBD,

neuropsychiatric disorders, and specific

medications need to be better defined.

• Obtain clinical and physiological information regarding secondary parasomnias 

as a first step toward identifying the prevalence, etiology, and efficacious treatment 

of these disorders.
94 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Pediatric

BACKGROUND

Although parasomnias are among the 

most common clinical sleep disturbances 

experienced in childhood, little is known 

about the underlying neurophysiologic 

mechanisms and neurotransmitter systems

responsible for their development and 

relative importance. 

Although a genetic predisposition exists 

for many parasomnias, the specific genes

involved have yet to be identified, and little 

is known about the interaction between

genetic phenotype, other aspects of sleep

physiology, such as arousal threshold, and

sleep inertia and environmental factors.

Treatment strategies involving pharmacologic and behavioral interventions have 

been developed, but most outcome studies

have included very small sample sizes and

short-term follow up.

PROGRESS IN THE LAST 5 YEARS

• Several studies have reported an 

association between partial arousal

parasomnias and both migraine headaches and Tourette’s syndrome in children,

thus raising the possibility that serotonergic

pathways may be involved. Case reports 

of novel treatment strategies for partial

arousal parasomnias have suggested 

that behavioral interventions, such as 

scheduled awakenings and hypnotherapy,

may be effective nonpharmacologic treatment options, but little is known about 

he underlying mechanism responsible 

for the clinical response.

RESEARCH RECOMMENDATIONS

• Examine interactions between the 

developing central nervous system, 

genetics, other aspects of sleep 

physiology, and environmental 

factors in determining phenotypic 

expression of partial arousal

parasomnias in childhood.

• Examine the role of various 

neurotransmitter systems in 

the neurophysiology of partial 

arousal parasomnias.

• Evaluate the efficacy of, and 

underlying mechanisms for, 

pharmacologic and nonpharmacologic treatment strategies 

for partial arousal parasomnias 

and rhythmic movement disorders

in childhood.
SECTION V—SLEEP DISORDERS 95

BACKGROUND

Virtually all psychiatric and substance 

use disorders are associated with sleep 

disruption. Epidemiological and clinical 

studies indicate that psychiatric disorders are

the most common cause of chronic insomnia.

Alcohol dependence leads to complaints of

insomnia and sleep disruption that can persist for months into abstinence and recovery.

Psychiatric disorders can also be associated

with daytime sleepiness, fatigue, abnormal 

circadian sleep patterns, disturbing dreams,

and nightmares. Conversely, evidence increasingly suggests that primary insomnia

(without concurrent psychiatric disorder) is 

a risk factor for later developing psychiatric

disorders, particularly depression, anxiety, 

and substance use disorders

Preliminary studies suggest that sleep disorders such as Sleep-Disordered Breathing

(SDB), Restless Legs Syndrome (RLS), and

sleep-related movement disorders may 

be unrecognized or under recognized in 

children and adults presenting with psychiatric symptoms and psychiatric disorders,

and occur with increased prevalence in

alcohol-dependent persons. The relationship

between sleep and psychiatric disorders is 

further supported by the observation that

sleep deprivation can ameliorate depressive

symptoms and exacerbate manic symptoms,

and that alcohol-dependent persons show

impairment in the homeostatic recovery of

sleep following sleep deprivation. Moreover,

insomnia and certain types of electroencephalographic (EEG) sleep patterns, such 

as reduced rapid eye movement (REM) 

latency or increased REM sleep, have been

associated with poor treatment outcomes 

in psychiatric disorders, including relapse or

recurrence of depression and alcoholism. 

Increasing attention has been paid to sleep

abnormalities in post traumatic stress disorder (PTSD) and nightmares, both in terms 

of descriptive studies (e.g., findings regarding

REM and NREM dream disturbances, movement disorders), and therapeutic studies 

(e.g., dream rehearsal therapies). Polysomnographic markers for adult depression, 

such as decreased latency to REM sleep

onset, have not been consistently found 

in depressed children and adolescents, 

but other EEG measures (such as interand intrahemispheric coherence) have been

identified as potential correlates of mood 

disorders in children. African Americans 

are particularly vulnerable to the effects of

alcohol dependence, and polysomnographic

and spectral analytic studies show a striking

loss of delta sleep and delta power in this 

population. Furthermore, studies using 

structural and functional neuroimaging

paradigms have begun to elucidate possible

mechanisms linking sleep disturbance and 

psychiatric illness. 

Psychoactive substances have acute and 

chronic effects on sleep architecture. Several

aspects of sleep are compromised in individuals taking these drugs, depending on 

the drug. Difficulty in initiating and maintaining sleep as well as poor sleep quality are 

common in patients who take opiates. 

SLEEP IN PSYCHIATRIC, ALCOHOL, AND

SUBSTANCE USE DISORDERS
96 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

In fact, heroin addicts seeking treatment 

often report sleep disturbances, notably insomnia, as precipitating causes of relapse. 

A similar dysregulation in the normal cycles 

of sleep may contribute to severe dependence

observed with gammahydroxybutyrate (GHB)

where regular users report constant waking

and must take more to reinstate sleep. Even

patients stabilized on methadone may have

SDB, daytime sleepiness, and poorer sleep 

efficiency. Infants born to substance-abusing

mothers have a several times greater risk 

of Sudden Infant Death Syndrome (SIDS).

Chronic cocaine users also have lower sleep

efficiency and significant sleep onset delay. 

By contrast, abstinence from cocaine as well 

as amphetamines produces hypersomnia.

Since some investigators have observed sleep

disruption despite long abstinence in chronic

cocaine users, the mechanisms underlying

sleep architecture and homeostasis and the

mechanisms underlying effects of psychoactive drugs may have much in common.

Further understanding of these relationships

will advance both fields.

Most of the recent research progress has 

been related to improved understandings 

of the associations between psychiatric

disorders and various sleep symptoms 

(e.g., insomnia and nightmares), sleep 

EEG patterns (e.g., delta EEG activity), and 

sleep disorders (e.g., SDB and movement 

disorders). Less progress has been made in

identifying fundamental pathophysiological

mechanisms linking psychiatric disorders and

sleep. Despite some promising early leads, 

for example, sensitive and specific sleep 

biomarkers of psychiatric disorders have 

not been validated. Similarly, endogenous 

circadian rhythm disturbances have not 

been identified in most patients with 

depression or other psychiatric disorders. 

Based on basic observations that cytokines

regulate sleep in animals, increasing attention has focused on the role of cytokines

in the regulation of sleep in humans and 

the contribution of abnormal regulation 

of the complex cytokine network to sleep 

disturbance in alcohol-dependent persons.

Despite initial progress in the study of sleep

disturbances among children with depression,

little is known about the characteristics or 

consequences of sleep disturbances in most

childhood psychiatric disorders. After focusing almost exclusively on the relationships

between sleep and depression, psychiatric

sleep research has only recently begun to

focus attention on other disorders, such 

as PTSD. The application of sleep and 

circadian rhythm therapies to psychiatric

disorders has also been limited, and their 

efficacy not consistently demonstrated. 

Clinical neuroscience studies are only beginning to move beyond the examination of 

EEG sleep correlates of psychiatric disorders 

to the investigation of common mechanisms

and the consequences of disordered sleep 

in psychiatric and substance dependent 

populations. Abnormalities of immune 

system functioning are coupled, for example,

with disordered sleep in alcohol-dependent

populations. Finally, insomnia and sleep disturbances are known to be risk factors for 

psychiatric disorders including alcohol dependence, but long-term followup studies have

not yet been done to determine whether 

intervention can reduce these risks and 

the progression of these disorders.

PROGRESS IN THE LAST 5 YEARS

• Insomnia has been identified as a risk 

factor for the subsequent development 

of psychiatric disorders, including mood,

anxiety, and substance use disorders.

• Insomnia has also been correlated with 

poor outcomes in depression, schizophrenia, and alcohol dependence.

• Structural and functional neuroimaging studies have begun to identify 

neuroanatomic correlates of sleep 

disturbance in depression and schizophrenia, and of therapeutic sleep 

deprivation in depression. For instance,
SECTION V—SLEEP DISORDERS 97

slow-wave sleep deficits in schizophrenia

are associated with negative symptoms 

and frontal cortical volume loss. Patients

with depression have higher absolute 

cerebral glucose metabolic rate than 

healthy subjects, and blunted activation 

of limbic structures (amygdala, anterior 

cingulate) during REM sleep compared to

wakefulness. Improvement of depression

following 1 night of sleep deprivation is

associated with decreased relative metabolism in the anterior cingulate cortex. 

• Reduced latency to REM sleep has been

identified as a familial sleep biomarker for

increased risk of developing depression.

• Differences in sleep responses to cholinergic and serotonergic drugs have been

identified in patients with depression

compared to healthy controls.

• Individuals with PTSD have a high incidence of SDB, motor dyscontrol, and 

dream disturbances during both NREM

and REM sleep.

• The efficacy of dream imagery rehearsal 

for traumatic nightmares has been demonstrated in early clinical trials.

• Abnormalities of sleep quantity and sleep

depth persist for months into recovery 

from alcohol dependence, and are more

profound in African American alcoholics

compared to Euro-American alcoholics. 

The decay of delta sleep in alcoholics is 

coupled with impairment in the regulation

or plasticity of slow-wave sleep.

• Dysregulation of cytokine expression is a

biomarker of abnormal sleep in recovering

alcohol-dependent persons. 

• Sleep disturbances are apparent in individuals taking psychoactive drugs and 

have been found to persist long after 

withdrawing from these drugs. For some,

sleep disturbance can be so severe as to

reverse treatment success and precipitate 

a relapse to addiction or dependence.

• Drugs can damage brain areas and neural

systems involved in sleep maintenance. 

For example, studies primarily in animals

have shown that MDMA (“ecstasy”) 

causes reduction in serotonin in axons 

and axon terminals. Cocaine causes severe

depletion of dopaminergic neural systems.

RESEARCH RECOMMENDATIONS

• Evaluate whether insomnia and hypersomnia are modifiable risk factors for 

poor outcomes in mood, anxiety, and 

psychotic disorders, alcoholism, and 

substance abuse disorders. Three types of

studies are needed: (1) Studies to investigate whether insomnia and hypersomnia

are modifiable risk factors for the development of new-onset psychiatric disorders; 

(2) Studies to investigate whether insomnia

or specific EEG sleep characteristics are

modifiable risk factors for poor outcomes

among individuals with existing psychiatric

disorders; and (3) Prospective, long-term

longitudinal studies to follow the concurrent course of sleep and psychiatric disorders from childhood into adulthood and 

to elucidate possible mechanisms for the 

relationship between sleep disturbance 

and psychiatric disorders. These studies 

will be aided by the identification of 

sensitive, specific, and objective markers 

of insomnia and hypersomnia.

• Further evaluate the relationships between

stress and sleep in clinical disorders such 

as PTSD and other forms of acute and

chronic stress. Studies are specifically 

needed to: (1) further characterize the 

nature of stress-related sleep disturbances

(e.g., insomnia, nightmares and other

dream disturbances, movement disorders during sleep); (2) examine causal 

relationships between stress and sleep 

disturbances; and (3) investigate the 

efficacy of behavioral and pharmacological

interventions for treating stress-related 

sleep disturbances.
98 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Evaluate the neurobiological characteristics

and mechanisms of sleep disturbances in

primary insomnia, depressive disorders, 

and anxiety disorders to better define 

the inter-relationships. Such studies should

include approaches such as functional 

neuroimaging studies and neurochemical

studies in living human subjects and in 

brain tissue.

• Identify relationships between neurobiological mechanisms involved in the 

development of regulatory aspects of

arousal, affect, and sleep in childhood 

and adolescence, including the role of 

various neurotransmitter systems. Examine

the relationship between critical periods 

of brain development and sleep-wake

cycle regulation, and the impact of sleep

disturbances and insufficient sleep in early

childhood in modifying the normal evolution of these various regulatory systems.

These studies should also assess: (1) potential links between entrainment of circadian

rhythms in the first year of life and circadian irregularity during childhood and

subsequent vulnerability to psychiatric

illness, (2) potential effects of stressful 

or traumatic events on hyper and hypo

arousal mechanisms in children, and 

(3) development of sleep patterns and 

maladaptive coping mechanisms.

• Determine the role of cytokines in the

homeostatic regulation of sleep in humans

and whether abnormalities in the cytokine

network lead to disturbances of sleep in

psychiatric populations also at risk for 

infectious or inflammatory disorders. 

Studies are also needed to determine

whether proinflammatory cytokine 

antagonists can ameliorate sleep disturbance in alcohol populations who show 

evidence of immune activation. 

• Evaluate the efficacy and safety of behavioral and pharmacologic treatments for

sleep disturbances in both adults and 

children with psychiatric disorders. The 

influence of such treatments on outcome 

of the coexisting psychiatric disorder 

should also be examined. Examples include

the concurrent treatment of insomnia in

individuals with major depression, and 

the use of dream-imagery rehearsal in 

individuals with PTSD.

• Assess the efficacy of behavioral and 

pharmacological interventions targeting

sleep in improving the clinical course of

alcoholism and risk of relapse. 

• Further investigate the neurobiological 

basis for the beneficial effects of sleep

deprivation in mood disorders. Such 

studies should also be useful generally to

address fundamental questions regarding

the mechanism of antidepressant treatments. Functional imaging methodologies,

including receptor ligand studies, may be

particularly relevant.

• Investigate the prevalence and impact of

primary sleep disorders (e.g., SDB and 

sleep-related movement disorders) on 

psychiatric disorders.

• Investigate sleep effects of medications

commonly used to treat psychiatric disturbances in adults, children, and adolescents.

Studies should include short and long-term

investigations examining beneficial and

adverse effects of these medications on 

subjective measures, sleep architecture, 

respiration during sleep, and motor 

control during sleep.

• Investigate the brain mechanisms underlying sleep architecture that are also affected

by psychoactive drugs, including temporary

acute effects and long-term effects related

to chronic drug taking. Knowledge of the

neural changes brought on by drug effects

should help to better understand which of

these neural mechanisms are associated

with sleep cycles. Conversely, an improved

knowledge base of neural systems involved

in sleep can aid in the understanding of 

the process of drug reward, addiction, 

and dependence.
SECTION VI

PEDIATRICS

• Sleep and Early Brain Development 

and Plasticity

• Adolescent Sleep

• Sleep in Medical Disorders

• Neuropsychiatric Disorders in Childhood 

and Sleep 

SECTION VI—PEDIATRICS 101

SLEEP AND EARLY BRAIN DEVELOPMENT

AND PLASTICITY

mediates brain maturation. The resulting

hypothesis is that one function of REM 

sleep is to generate specific patterns of 

intrinsic activity in neuronal populations 

whose development is dependent upon 

activity. The classic example of activitydependent maturation is the visual system, 

in which spontaneous neural activity in each

retina in the fetus (before visual experience) 

is necessary for the anatomic segregation 

of eye-specific synaptic connections in the 

lateral geniculate nucleus. Research studies 

in experimental models support the idea 

that activity-dependent maturation occurs 

during sleep.

Understanding the roles of sleep in brain 

maturation and plasticity is of critical importance since perturbations during fetal life or

early postnatal life can have major impact 

on developmental processes and thus on 

adult phenotype. Suppression of neonatal

REM sleep in rats, for example, alters ventilatory pattern, metabolism, and regional 

brain concentrations of neurotransmitters 

and their receptors at maturity, suggesting

adverse adult consequences on brain rewiring due to disruptions in sleep in early life.

Furthermore, early hyperoxic exposures as 

may occur in mechanically ventilated premature infants, or sleep-associated episodic

hypoxemia such as occurring in apnea of 

prematurity, may result in permanent impairments in cardiovascular and respiratory 

control. Thus, despite the existence of redundant protective mechanisms and increased 

BACKGROUND

Sleep may have important roles in adult 

brain plasticity related to learning and memory

consolidation. Unlike adults, the human fetus

and neonate spend a remarkable proportion 

of their time sleeping, with approximately 80

percent of their day in rapid eye movement

(REM) sleep and the remainder in non rapid

eye movement (NREM) sleep and wakefulness.

By 5 to 6 months of age, human infants spend

only 20 to 30 percent of their time in REM

sleep, with the remainder of time equally

spent in NREM sleep and wakefulness. Reasons

for such increased requirements for sleep, particularly REM sleep, in early life are not well

understood, but improved understanding 

of these developmental requirements may 

provide insight into the functions of sleep

throughout life. 

The high percentage of time spent in REM

sleep during the critical period in human 

brain growth and maturation in late fetal 

and early postnatal life may indicate that 

the neural activity controlled by REM state

mechanisms may be developmentally functional and contribute directly to physiological

and structural brain maturation. REM sleep

may be important in providing early stimulation and activity requirements of the 

growing brain. Subsequent recognition of

activity-dependent development of neural 

connections in utero provides a specific 

mechanism by which endogenously controlled, correlated, spontaneous neural activity
102 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

system plasticity at these early stages of 

development, the fetus and newborn are 

likely to be extremely susceptible to disruption of the normal homeostatic processes 

for normal tissue and organ growth and 

function. Furthermore, although the interactions between sleep processes and early 

life perturbations are unknown, it is reasonable to assume that these early disruptive

events may alter the hierarchical organization

of functional gene clusters and lead to both

early and late increases in vulnerability to 

specific disease states.

Those at greatest risk for early disruptions in

sleep and sleep-related brain maturation are

premature infants in intensive care nurseries.

Sleep deprivation in this setting is a major

problem, due largely to the absence of a 

diurnal rhythm of light/dark cycles, and 

sleep interruption by constant medical and

nursing procedures. The functional shortterm and long-term implications associated

with disruption of the normal sleep cycles 

at such early stages of development are just

beginning to be understood. Premature 

infants exposed to bright/dim light cycles in 

the nursery are more likely to sleep longer,

begin to feed earlier, and grow better than

those under constant bright lights. There 

has been extensive progress in understanding the functional properties and cellular 

and molecular mechanisms regulating sleepwake periodicities and the circadian clock, 

but little is known about the maturation 

of such systems, especially considering the

huge alterations in sleep-wake schedules 

that accompany fetal and early postnatal

development.

PROGRESS IN THE LAST 5 YEARS

• Sleep has been shown to enhance the

effects of a preceding period of monocular deprivation on visual cortical responses

during the peak critical period of the maturation of the visual cortex. These findings

demonstrate that sleep and sleep loss 

modify experience-driven cortical plasticity

in vivo, and support a crucial role for sleep

in early life upon brain development.

• Sleep and sleep loss have been shown 

to modify the expression of several 

genes and gene products that appear 

to be important for synaptic plasticity.

• Studies in neonatal animals indicate that

suppression of REM sleep can lead to

behavioral, anatomic, and biochemical 

deficiencies, including respiratory problems, that extend into adulthood. 

Neonatal active sleep may be a critical 

factor in the normal development and

expression of respiration.

• The functional properties of the suprachiasmatic nucleus are developing and

become functional from mid-to-late 

gestation in experimental animals, allowing for sleep-wake rhythm entrainment

before and at birth.

• National guidelines for the regulation 

of light intensity in neonatal intensive 

care units have been established. 
SECTION VI—PEDIATRICS 103

RESEARCH RECOMMENDATIONS

• Establish the ontogeny of fundamental 

biological mechanisms mediating the 

regulation of sleep and waking needs 

to better understand the normal and 

abnormal consequences of the development of such systems. 

• Conduct studies to elucidate the underlying mechanisms of changes in circadian

rhythmicity during early postnatal life in 

full-term and premature animal models 

and in humans. 

• Conduct studies to assess the effects 

of prematurity per se and of treatment 

conditions (e.g., light-darkness cycles) 

in intensive care nurseries on cognitive 

function and brain development, and 

on the physiological maturation of 

circadian regulation. 

• Increase basic understanding of the 

specific effects of sleep state on neural 

plasticity and synaptic connectivity in 

developing mammals.

• Investigate the neurochemical, cellular, 

and molecular aspects of human sleep

ontogeny, including the use of mapping

techniques in post mortem human fetal 

and infant brains.

• Study the short- and long-term consequences of medical conditions associated

with disruption of normal pregnancy and/

or early postnatal life, (e.g., maternal cigarette smoking, cocaine or opiate addiction,

materno-fetal insufficiency, prematurity).

These results may yield a better understanding of altered sleep and cardiorespiratory control in early life and may provide

insight into regulatory mechanisms ultimately responsible for the occurrence 

of disorders such as apnea of prematurity,

sudden infant death syndrome (SIDS), 

congenital central hypoventilation 

syndrome, and developmental 

neurobehavioral deficits.
104 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Sleep and the unique features of physical, 

cognitive, and social-emotional development

that take place in adolescence must be considered separately and in relationship to 

sleep in children and in adults. Not only 

do the biological changes associated with

puberty profoundly affect sleep and wakefulness, but many environmental and social

factors are also implicated. Several sleep 

disorders are particularly prevalent (delayed

sleep phase syndrome) or emergent (narcolepsy) in adolescence. Furthermore, the 

public health consequences of inadequate

sleep (academic failure, drowsy driving) and

the potential for primary and secondary prevention in this age group are important.

PROGRESS IN THE LAST 5 YEARS

• Studies of normal sleep and sleep 

patterns in adolescents have identified

important issues regarding the basic 

developmental physiology of sleep and 

circadian rhythms in adolescence. The 

role of pubertal/hormonal influences on 

circadian sleep-wake cycles and melatonin

secretion has been recognized, and the

effects include development of a relative

phase delay (later sleep onset and wake

times) in early puberty and the development of a physiologically based decrease 

in daytime alertness levels in mid-to-late

puberty. The genotypic expression in 

adolescence of delayed circadian phase

preference has also been explored as an

important factor determining the timing 

of sleep/wake cycles.

• Studies of homeostatic regulation of 

sleep and wakefulness have demonstrated that sleep needs in adolescence

do not decline significantly, and optimal

sleep amounts remain about 9 hours 

into late adolescence. However, epidemiological research on “normal” 

sleep patterns and amounts suggests 

that adolescents only average 7 to 7.5

hours of sleep per night, resulting in 

the accumulation of a considerable 

sleep debt over time. These data suggest

that chronic partial sleep deprivation is 

a serious problem in this age group and

that particular subgroups may be at 

relatively higher risk. 

• Environmental and social factors also 

impact significantly upon delayed sleep

onset in adolescents, including. For 

example, many adolescents have highly

irregular sleep/wake patterns from weekday to weekend. Another important factor

potentially contributing to insufficient sleep

is the early start time of many middle and

high schools in the United States. 

• Chronic sleep restriction in adolescents 

leads to significant neurobehavioral consequences related to decline in alertness 

levels, including negative impact on mood,

vigilance, reaction time, attention, memory,

behavioral control, and motivation. These

ADOLESCENT SLEEP
SECTION VI—PEDIATRICS 105

impairments may, in turn, be associated

with significant declines in school and

work/occupational performance, increased

risk-taking behaviors (use of alcohol, illicit

drugs, nicotine, caffeine, stimulants), and

injuries. Adolescent males, for example, 

are one of the highest risk groups for 

motor vehicle crashes associated with 

falling asleep. 

RESEARCH RECOMMENDATIONS

• Ascertain the impact of chronic partial 

sleep deprivation on health outcomes,

including susceptibility to infection, 

metabolic consequences, immune function,

and use of potentially harmful alertnesspromoting agents, such as caffeine and

stimulant medications. Delineate the 

effects of chronic partial sleep deprivation

and sleepiness in adolescents on higher 

level cognitive or “executive” functions, 

such as verbal creativity and working 

memory, on motivation, and on affect 

regulation. The assessment of health outcomes should also include occupational 

and sports injuries, and motor vehicle 

crashes, and should determine scope of 

the problem, high-risk groups, and interactions with other high-risk behaviors and

substances (alcohol, marijuana, etc.). 

• Define the specific neurophysiologic 

mechanisms involved in the relationship

between sleep and circadian timing 

and puberty.

• Determine the extent, patterns, and 

psychosocial factors responsible for 

chronic sleep restriction in adolescence.

These studies should include cross-cultural

analyses and should also include special 

and high-risk populations such as adolescents with comorbid psychiatric

conditions, mood disorders, attention 

deficit hyperactivity disorder (ADHD), 

and chronic illness.

• Determine the impact of interventions 

to address chronic sleep restriction in 

adolescents, including later school 

start times and high school education 

programs about sleep.

• Determine the biopsychosocial and 

genetic factors that result in delayed 

sleep phase syndrome in adolescents, 

and assess the safety and efficacy of 

various treatment modalities, including

administration of exogenous melatonin,

chronotherapy, and bright light therapy.
106 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Genetic Diseases and Syndromes 

Affecting Sleep and Breathing 

BACKGROUND

A large number of unique genetic disorders

have primary or secondary sleep abnormalities. Understanding the pathophysiology 

of the autonomic nervous system (ANS) 

dysregulation that occurs in many of these

pediatric disorders could improve our understanding of the maturation of the ANS and

the abnormalities that occur in common 

sleep disorders such as Sleep-Disordered

Breathing (SDB). Investigating anatomical

mechanisms for the upper airway obstruction found in children with craniofacial malformation could shed light on mechanisms 

for upper airway obstruction in SDB. Understanding how other disorders produce primary insomnia or daytime hypersomnolence

may also shed light on novel sleep-regulatory

mechanisms.

Studies have demonstrated SDB and symptoms compatible with ANS dysregulation in

children with Idiopathic Congenital Central

Hypoventilation Syndrome (CCHS), Rett

Syndrome (Xq28, MECP2), and Familial

Dysautonomia (9q31, IKBKAP). Few sleep 

studies have been performed, however, in 

children with craniofacial malformations, 

chromosomal/genetic abnormalities, or in 

children with neuromuscular diseases. 

Genetic and familial craniofacial syndromes 

are often subdivided into those with micrognathia, midfacial hypoplasia, and protuberant

tongue disorders. The micrognathia syndromes include Treacher Collins Syndrome, 

an autosomal dominant syndrome (5q32-33.1,

TCOF1), and Pierre Robin Sequence. Infants

with these syndromes can experience profound SDB that requires aggressive intervention to prevent physiologic compromise.

The midfacial hypoplasia syndromes include

Apert Syndrome (10q26, FGFR2), Crouzon

Syndrome (10q26, FGFR2), and Pfeiffer

Syndrome (8p11.2-p11.1 or 10q26, FGFR1 

or 2). These are all autosomal dominant and

typically represent a fresh mutation. Children

with midfacial hypoplasia often have increasingly severe SDB with advancing age due to

maldevelopment and surgical intervention.

Another example of midfacial hypoplasia 

is achondroplasia, an autosomal dominant

skeletal dysplasia (4p16.3, FGFR3) in which

respiratory compromise is caused by an 

abnormal rib cage, small foramen magnum,

and SDB. Disorders with a protuberant 

tongue include the mucopolysaccharidoses,

(e.g., Hunter Syndrome and Hurler Syndrome)

and Down Syndrome (Trisomy 21), all with

identified genetic mutations and often with

severe SDB requiring early intervention. 

Disorders of the neuromuscular system 

impose a substantial burden at the multisystem level. Many of these children exhibit

dysfunction of the respiratory and upper 

airway musculature that contributes to the

development of SDB. For example, 15 to 20 

percent of children with Duchenne Muscular

Dystrophy will develop sleep disturbances, 

and this prevalence is even greater among

patients with spinal muscular atrophy and

SLEEP IN MEDICAL DISORDERS
SECTION VI—PEDIATRICS 107

myelomeningocele. Since no well-defined 

clinical or biological criteria currently exist 

that enable prediction of which affected 

children will have a sleep disturbance, there 

is significant under recognition of these problems. The morbidity and impact on quality 

of life due to sleep disturbances in this population are, therefore, currently unknown.

SDB is frequently observed in the abovedescribed syndromes as a result of anatomic

malformation, neuromuscular weakness, or

morbid obesity. In addition, however, central

factors also appear to be involved in addition

to or independently of symptoms related to

SDB. This may be the case for Prader Willi

Syndrome (15q12, SNRPN) and Angelman

Syndrome (15q11-q13, UBE3A), in which daytime sleepiness and low hypocretin levels have

been reported independently of SDB, suggesting hypothalamic dysregulation of sleep regulation. These disorders also frequently produce

complex behavioral and medical problems with

secondary effects on sleep, particularly disturbed nocturnal sleep and sleep apnea. It is

often difficult, therefore, to identify diseasespecific sleep phenotypes. 

Other unique genetic syndromes without overt

SDB may also have associated primary central

nervous system (CNS) sleep disorders. Fragile X

Syndrome (Xq28, FRAXF; Xq28, L1CAM) children experience sleep disturbances and low

melatonin levels, while subjects with Norrie

disease (genetic alterations in a region encompassing the monoamine oxidase genes at

Xp11.4, NDP; Xp11.2, BMP15) or Niemann

Pick Type C (18q-q12, NCPC1; 18q12.1-q12.2,

DSG2) may experience cataplexy and sleep disturbances. Subjects with myotonic dystrophy

(DM1, 19q13) often have abnormal breathing

during sleep and possibly centrally mediated

hypersomnolence. Smith-Magenis syndrome

(SMS), including multiple congenital anomalies and mental retardation (17p11.2, SMCR;

17q, PSORS2), is also associated with severe

sleep disturbances.

PROGRESS IN THE LAST 5 YEARS

• The phenomenon of generalized ANS 

dysfunction has become clearer among 

children with CCHS and Rett syndrome.

Patients with Rett syndrome exhibit 

unique respiratory disturbances that 

are state-dependent. 

• Patients with Prader Willi syndrome

present with universal reductions in 

their hypoxic ventilatory responses and 

with frequent alterations in their breathing patterns during sleep. Animal models

for some of these genetic conditions 

have become available, thereby opening 

important opportunities for the study of 

respiratory control and sleep interactions.

• The study of control of breathing patterns 

in wakefulness and sleep in inbred mice

strains has allowed for identification of

putative chromosomal locations for several

of the respiratory control components.

• Despite extensive progress in understanding the molecular and genetic mechanisms

underlying many of the neuromuscular 

diseases, the progress achieved in understanding and defining when patients with

these disorders will manifest sleep disturbances has been extremely limited.

RESEARCH RECOMMENDATIONS

• Conduct extended population studies in

children, incorporating gene databases 

and including multi organ and multifunctional categorization of disease-related 

morbidity and response to therapy, to

improve phenotypic and genotypic 

characterization of SDB with ANS dysfunction and craniofacial maldevelopment.

• Increase our understanding of primary 

sleep disturbances in genetic disorders 

of children, with the goal of discovering

new sleep-regulating mechanisms.
108 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Conduct studies in naturally occurring 

diseases of ANS dysfunction to better

understand the ontogeny of the ANS 

from infancy through adulthood.

• Conduct studies in naturally occurring 

diseases with anatomical malformations 

of the face and upper airway, to better

understand SDB, and its pathophysiology

and consequences with advancing age. 

• Determine how and if SDB in these 

unique diseases during childhood is 

linked to other diseases in adulthood.

• Develop novel interventional approaches 

to treat SDB in these special children, 

in collaboration with craniofacial and 

dental colleagues.

• Develop animal models to test hypotheses

generated from delineation of phenotypegenotype correlations.

• Establish the clinical correlates of sleep 

disruption and SDB in children with 

neuromuscular disease. 

• Determine the implications of sleep 

disturbances on end-organ morbidity and

mortality as well as on health related cost

and quality of life in children with neuromuscular disease. 

Sudden Infant Death Syndrome (SIDS)

SIDS is the sudden and unexpected death 

of an infant under 1 year of age that remains

unexplained after an autopsy, examination of

the death scene, and thorough review of the

medical and family history. With the introduction of the Back to Sleep programs over the

past decade, a remarkable decline in the 

incidence of SIDS has occurred worldwide. 

In the United States alone, the aggressive 

educational campaign targeting infant sleep

position and other modifiable factors known

to be related to SIDS has resulted in a decrease from 7,000 babies dying annually to

fewer than 3,000. The National Institute 

of Child Health and Human Development

(NICHD) has completed a 5-year SIDS 

plan divided into four sections: Etiology 

and Pathogenesis, Prognostics and Diagnostics, Prevention, and Health Disparities. 

The NICHD plan, in each of these sections, 

discusses: background, and makes specific 

recommendations to address gaps in knowledge, intervention activities, and infrastructure needs. For a comprehensive review 

of SIDS and concomitant research recommendations, readers are directed to the 

NICHD document, available online at

http://www.nichd.nih.gov/strategicplan/

cells/SIDS_Syndrome.pdf).
SECTION VI—PEDIATRICS 109

BACKGROUND

Attention Deficit Hyperactivity Disorder (ADHD)

is one of the most common psychiatric disorders in childhood, affecting approximately 

5 to 10 percent of children. The etiology of 

sleep disturbances observed in association 

with ADHD is likely to be multifactorial and 

to vary among patients. In addition to medication-related sleep effects, and the influence

on sleep behavior of such common comorbid

conditions as oppositional defiant disorder,

depression, and anxiety disorders, primary

sleep disorders, such as Sleep-Disordered

Breathing (SDB) and Restless Legs Syndrome/

Periodic Limb Movement Disorder (RLS/PLMD)

may present with “ADHD-like” symptoms 

or exacerbate underlying ADHD. Primary

abnormalities in central nervous system (CNS)

regulation of arousal, behavioral inhibition 

and self-regulation, and/or vigilance associated with ADHD have also been postulated 

to result in sleep disturbances, suggesting 

a more primary or fundamental sleep-wake

dysregulation in at least some children. Considerable evidence suggests brain systems 

regulating sleep and attention/arousal are

linked and that abnormalities in similar 

neurotransmitters, such as the noradrenergic and dopaminergic systems, may be found

in ADHD and in sleep disturbances. These relationships are at present still poorly understood.

PROGRESS IN THE LAST 5 YEARS

• Studies of children with ADHD have 

examined the relationship between sleep

architecture, sleep patterns and behaviors,

and sleep disturbances and ADHD. When

using primarily parental (or self-report) 

surveys or polysomnography (PSG), results

have been mixed and, at times, contradictory. While most “objective” studies have

not found consistent significant differences

in sleep architecture and patterns between

children with ADHD and controls, most

parental report studies have reported sleep

problems including difficulty falling asleep,

night wakings and restless sleep in children

with ADHD. These consistent discrepancies

between parental and more objective sleep

measures remain an important research 

and clinical question. In addition, methodological concerns with many of these 

studies include small sample sizes and 

selection bias, variability in diagnostic 

criteria for ADHD, variability in defining 

the control groups, and failure to consider

the effects of potential confounders, such

as diagnostic subgroup of ADHD, medication status, the presence of comorbid 

psychiatric conditions, and age. Virtually 

no studies have examined sleep disturbance in adolescents and young adults 

with ADHD. 

NEUROPSYCHIATRIC DISORDERS IN CHILDHOOD AND SLEEP
110 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

• Studies have examined the complex 

relationship between primary sleep disorders, such as SDB and PLMD, and the

constellation of neurobehavioral symptoms

that comprise the syndrome of ADHD 

(inattention, hyperactivity, impulsivity, 

executive function impairment).

• Some small studies have explored the use 

of medications, such as clonidine for sleep

disturbances associated with ADHD, but 

no systematic studies of behavioral and/or

clinical trials of pharmacologic treatment

have been conducted.

RESEARCH RECOMMENDATIONS

• Examine the neuroanatomical and 

neurophysiologic relationships between 

regulation of sleep and of attention and

arousal, including the roles of the noradrenergic, dopaminergic, and other 

neurotransmitter systems. Develop 

animal models that present phenotypes

associated with ADHD. 

• Describe the scope and magnitude 

of sleep disturbances in children and 

adolescents with ADHD, compared to 

the general population, including the 

natural history of sleep disturbances as

ADHD progresses into adolescence and

adulthood. Describe the impact of ADHD 

on morbidity, including adverse behavioral

outcomes such as injuries and motor 

vehicle crashes, substance abuse, and 

academic failure. Describe the risks and 

protective factors for sleep disturbances 

in children and adolescents with ADHD, 

and the impact of potential confounders,

such as comorbid psychiatric disorders 

and ADHD medication use. 

• Examine the relationships and clarify 

directionality between primary sleep disorders, such as SDB and RLS/PLMD, and

symptoms of hyperactivity and inattention

in children and adolescents. Prevalence

studies of primary sleep disorders in 

children diagnosed with ADHD are 

also needed. 

• Evaluate the efficacy of various treatment

modalities for sleep problems in ADHD,

including behavioral interventions and 

pharmacotherapy, and the impact of 

treatment on the natural history of the 

disorder into adulthood. 

• Examine the long-term effects of 

psychopharmacologic treatment for 

ADHD, especially with psychostimulants, 

on sleep and sleep patterns of children 

and adults with ADHD. 
SECTION VII

EDUCATION AND TRAINING

• Scientific Training

• Clinical Education and Training

• Public and Patient Education

SECTION VII—EDUCATION AND TRAINING 113

SCIENTIFIC TRAINING

PROGRESS IN THE LAST 5 YEARS

• Despite growth in the number of trainees 

in sleep science at all levels in the past 

5 years, this growth has been modest 

and has not kept pace with the number of

basic and clinical science research questions. 

• Efforts to determine the barriers to attracting more students to scientific work on

sleep have focused on: (1) lack of departmental or graduate program support for 

the study of sleep, (2) lack of sleep science

training opportunities in established laboratories, (3) insufficient numbers of physicians

engaged in sleep research, and (4) uncertainty about career opportunities in sleep

research. Recent multidisciplinary conferences involving sleep researchers have

sought to attract trainees from other 

scientific areas to the study of sleep.

SCIENTIFIC TRAINING

RECOMMENDATIONS

• Enhance and sustain entry of new investigators in the basic sciences and patientoriented research, as well as researchers

with multidisciplinary backgrounds into 

the sleep research field. Expand programs 

in sleep research training, including the

training of investigators in new, basic, 

and behavioral research areas targeted 

at sleep research questions (genetics, proteomics, molecular biology, neuroimaging,

BACKGROUND

A critical mass of appropriately trained scientists across multiple disciplines is necessary 

to address fundamental scientific questions

regarding mechanisms and functions of 

sleep, its circadian regulation, and its role 

in human health, safety, and quality of life.

Sleep research is highly multidisciplinary. The

Sleep Research Society’s current membership,

for example, includes more than two dozen

academic disciplines. 

This diversity notwithstanding, the number 

of scientists being trained in sleep research

remains inadequate for the many basic and

patient-oriented research questions needing

investigation. Implementation of recommendations in this Plan, for example, will require

scientific training opportunities in all relevant

areas and at all career levels. Encouragement

and mentoring of trainees (Ph.D. and M.D.) 

at the graduate, postgraduate, fellowship, 

and early career levels is a particularly urgent

need. Scientific trainees learn cutting-edge

techniques in stable academic laboratories,

which, in turn, requires a critical mass of

established investigators in sleep research.

Expanded opportunities to become engaged 

in sleep research would enhance the entry 

of young investigators into the field, thereby

seeding the future with the needed numbers

of sleep researchers in many scientific areas. 
114 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

bioinformatics, etc.) and patientoriented sleep research areas (clinical 

trials, epidemiology, preventive medicine). 

Expand dedicated sleep training programs

and provide incentives to existing non 

sleep training programs to include sleep

research tracks where there is a critical 

mass of investigators. This would build 

upon existing training infrastructures 

and also would be cost effective.

• Increase the number of investigators in

sleep neuroscience. Systems neuroscience,

particularly neurophysiological, is a strong

component of current sleep research.

However, the number of investigators 

in this field is small in comparison to 

the number of scientific questions.

• Encourage training of basic scientists 

and clinical investigators with interest in

sleep research in development, as well as

endocrine, metabolic, cardiovascular, and

immune functions, given evidence that

sleep may have important roles in these

areas. Currently there are few opportunities to combine training in these areas 

with sleep research. Training awards 

that specifically provide incentives to 

both trainees and established investigators should help close this gap. 

• Encourage innovative collaborative 

training mechanisms, with interactive 

training provided by investigators from 

different disciplines with complementary

skills. Training investigators in patientoriented sleep research will be critical 

in addressing the clinical and applied

research recommendations in this 

Research Plan. Residency research 

tracks that include sleep research electives are needed. Medical school research

tracks that focus on sleep should also 

be encouraged.

• Develop research training programs that

encourage and support the initiation of

small sleep research projects by medical 

students, nursing and other allied health

professionals, and postgraduate trainees 

in related disciplines.
SECTION VII—EDUCATION AND TRAINING 115

BACKGROUND

Education and training are integral to meeting the goals of sleep medicine in improving

clinical practice and patient-oriented outcomes. Successful educational interventions

require the development, implementation, 

and dissemination of materials covering a 

wide range of topics, including the basic 

neurobiology of sleep and circadian rhythms,

clinical sleep disorders and evidenced-based

treatment, the consequences of sleep deprivation, and the role of sleep in health and 

disease. Education and training must be 

targeted toward all relevant professional 

and public audiences, and must include 

evaluation of the impact of such programs 

on public health. 

Physician Education and Training

The practice of sleep medicine is inherently

multidisciplinary, drawing physicians from

many areas such as geriatrics, neurology, 

internal medicine and pediatrics (including 

pulmonology, neonatology, critical care), 

psychiatry, and surgery. Because of this 

diversity, the field of sleep medicine continues to evolve standards, practices, and 

training opportunities. In April 2002, for 

example, the American Academy of Sleep

Medicine submitted an application to the

Accreditation Council on Graduate Medical

Education requesting the establishment of 

a Residency Review Committee approval of 

fellowship training programs in sleep medicine.

Despite advances in defining sleep medicine 

as a specialty and in formalizing training

infrastructure to sustain sufficient growth 

in the field, empirical data from survey and

clinical outcome studies indicate that, in 

general, physician education regarding the

recognition, diagnosis, management, and 

prevention of clinical sleep disorders in both

adults and children is inadequate. Substantial

knowledge deficits exist at the medical school

level, as well as at the post-graduate training

and continuing education levels. 

Important public health implications result

from the large gaps between scientific 

knowledge, clinical teaching and practice. 

For example, it is known that physicians 

outside sleep medicine significantly underdiagnose or misdiagnose sleep disorders, 

leading to increased morbidity and decreased

quality of life. Furthermore, early intervention

efforts to detect and prevent sleep disorders

are likely to be significantly compromised by

this lack of education and training.

To address these concerns, the need exists 

to further define a knowledge base in sleep

medicine and circadian biology, develop a

basic sleep curriculum for medical schools, 

and create appropriate educational tools 

as a foundation for enhanced learning 

at all levels. Current medical education 

activities are involved with curriculum

development, and will require application 

of rigorous methodological criteria for 

outcome measures and demonstration of 

efficacy of teaching methods and tools.

CLINICAL EDUCATION AND TRAINING
116 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Knowledge, competence, and behavioral

change objectives involve different methods 

of assessment. Specific knowledge acquisition, for example, is usually measured with

standard written tests, skills acquisition with

performance-based assessment, and behavioral changes with self-report or structured

observational methods. 

Assessment of impact on clinical practice 

may depend upon a variety of health outcome measures, including quality of life

and disease prevalence data, tracking of 

health care utilization, and cost-benefit

analyses. However, little research in sleep 

education has yet been directed toward 

evaluation of these types of outcomes 

elated to professional knowledge, attitudes, 

and changes in clinical practice behavior. 

Some evaluation tools do exist, such as 

knowledge surveys and standardized clinical

examinations, but most are not validated, 

and few are widely available. Although 

clinical care is likely to be improved by continuing medical education efforts targeted 

at improving knowledge and skills, and 

fostering behavioral change in practicing 

physicians, sleep medicine has not been

included in research on effective strategies 

to change physician behavior. Prospective,

multicenter, structured trials are needed 

to accomplish these goals. 

Education and Training of 

Other Health Professionals

Dentists, nurses, pharmacists, and psychologists are increasingly involved in identification

and treatment of sleep disorders. These disciplines should also be targeted for educational

interventions. The educational needs of these

various disciplines overlap with those of physicians, but additional educational resources

and strategies are needed to address their

unique concerns. For example, nurses potentially have a key role in the identification of

sleep disorders in patients being treated by

other medical specialties. Psychologists have

become increasingly important in the evaluation and behavioral treatment of insomnia.

Dentists have become actively involved in 

the treatment of sleep apnea with mandibular devices. These health care initiatives 

would benefit from coordination of evaluation research to determine the impact on

behavioral change, clinical practice, and 

ultimately on the quality of patient care 

in sleep medicine across these disciplines.

PROGRESS IN THE LAST 5 YEARS

• In a 1978 survey of sleep education 

in medical schools in the United States, 

the American Sleep Disorders Association 

found that less than 10 percent of schools

offered adequate training and 46 percent

included no sleep medicine at all in the 

curriculum. In 1990, a medical education

survey reported relatively little progress, 

with 37 percent of medical schools offering no sleep education. In those schools

that did, the average time devoted to 

sleep in the 4-year curriculum was less 

than 2 hours. Subsequent surveys of postgraduate training programs in adult and

pediatric medicine have found similar

results, with lack of time in the curriculum

and of qualified instructors cited as major

barriers. Surveys of practicing physicians

conducted in the last 5 years reveal similar

gaps in knowledge and clinical practice

despite increasing recognition of the 

importance of sleep in the health and 

well-being of their patients.

• In 1996, the National Center on Sleep

Disorders Research (NCSDR) developed 

the Sleep Academic Award (SAA) Program to help address these educational

gaps. Twenty medical schools in the 

United States were awarded 5-year 
SECTION VII—EDUCATION AND TRAINING 117

grants to develop model medical school 

curricula in sleep medicine, to promote

interdisciplinary learning environments, 

and to improve the quality of sleep 

education and education research at 

all levels, including the public arena. 

The SAA Program has raised awareness 

of sleep education in both the sleep and

general medical communities, and has 

laid the foundation for continued sleep 

education development by facilitating 

the creation of screening and evaluation

tools such as the ASK-ME Survey of sleep

knowledge, regional and national faculty

development workshops, and public education programs on sleep. Development 

of MedSleep, a Web-based repository 

of over 50 sleep education tools and 

products developed by the awardees 

and available to all health professional 

and educators, was the result of a collaborative effort between the SAA Program 

and the American Academy of Sleep

Medicine (AASM).

• The SAA Program, in collaboration with 

the AASM and the American Medical

Association (AMA), has initiated a 

collaborative education and research 

effort to address the issue of sleep 

and fatigue in medical training. Several

research projects, including a multiple site

collaborative study, have evolved from this

initiative. In 2001, a national conference

was held to define specific research goals

and objectives regarding consequences of

sleep loss in physicians and to develop

effective interventions.

CLINICAL EDUCATION AND

TRAINING RECOMMENDATIONS

• Develop sleep education programs at 

the medical school, postgraduate, and 

continuing medical education levels, and

develop a coordinated, structured, and 

scientifically rigorous approach to evaluate

the impact of sleep education programs 

and tools across multiple institutions and

clinical settings. Outcome measures should

include assessment of changes in:

– Physician knowledge, attitudes, skills, 

and behavior

– Clinical practice

– Patient health and quality of life

• Evaluate the effectiveness of strategies 

to address these training gaps. This 

should be based on a needs assessment 

of educational gaps in sleep training

among other health professions including but not restricted to nursing, dentistry,

pharmacy, clinical psychology and other

mental health disciplines. Outcome 

measures should include assessment 

of changes in: 

– Professional knowledge, attitudes, 

skills, and behavior 

– Clinical practice 

– Patient health and quality of life
118 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

BACKGROUND

Support and promotion of health education

are necessary steps to establish links between

basic science and clinical outcomes and to

facilitate the translation of research findings 

to address public health concerns, such as

those outlined in the U.S. Department of

Health and Human Services “Healthy People

2010” initiative. Health education initiatives

support primary prevention and increase

recognition of sleep disorders in the general

community, as well as broaden the scope of

secondary and tertiary prevention efforts in

patients with diagnosed sleep disorders. Public

education campaigns provide information to

increase knowledge, to enable modification 

of health risks, and also to help foster a supportive social environment for facilitating positive behavioral change. To accomplish these

goals, effective teaching tools and strategies

need to be developed and mechanisms need

to be implemented for evaluation of sleep

educational materials for the general public. 

It is important to delineate the educational

needs of the target audience, to define and

prioritize the educational messages, and to

identify potential opportunities and barriers

related to health-related behavioral change.

Specific topics that have been identified as 

key components in public and patient sleep

education programs include those related to

basic regulation of sleep and circadian rhythms,

sleep deprivation (extent, signs, causes, and

consequences), and sleep hygiene. Prevalent,

serious, and/or frequently under recognized

sleep disorders, including SDB, insomnia, narcolepsy, and Restless Legs Syndrome/Periodic

Limb Movement Disorder (RLS/PLMD) are

another key component. Target audiences 

may be defined as high risk for sleep disorders

and/or sleep deprivation by virtue of age

(elderly, adolescents), demographics (minority,

medically underserved), gender (pregnant or

menopausal women, young adult males),

other health risks (obesity), and work schedules (shift workers, commercial drivers).

Educational campaigns directed toward highrisk populations (e.g., adolescents) and toward

receptive audiences (e.g., elementary school

children) may be efficient and cost-effective

ways to enhance prevention and early detection

of sleep problems. These campaigns also should

include groups that can facilitate behavioral

change but may be hard to reach, including

teachers, coaches, school nurses/health educators, parents, and pediatricians). Specific

educational strategies should include culturally

sensitive materials appropriate for a range of

literacy levels and novel methods of translation

and dissemination of information (e.g., Webbased products). Finally, outcome measures 

to assess the effectiveness of educational 

interventions include changes in knowledge,

attitudes, health-related behaviors, and ultimately in the health of the target audience.

Process measures describing the extent to which

information is disseminated, programs are utilized, and target audiences are reached may

be surrogate measures for evaluating results.

PROGRESS IN THE LAST 5 YEARS

The National Center on Sleep Disorders

Research (NCSDR), part of the National 

Heart, Lung, and Blood Institute (NHLBI), 

PUBLIC AND PATIENT EDUCATION
SECTION VII—EDUCATION AND TRAINING 119

coordinates public and patient sleep disorders education in collaboration with the

Office of Prevention, Education, and Control

(OPEC). These efforts facilitate the translation

and dissemination of research and scientific

consensus to the general public, patients, 

and health professionals. Recent sleep 

education programs include: 

• Initiation of a 5-year media-based public

awareness campaign on Sleep-Disordered

Breathing (SDB). 

• Development of fact sheets for the public

and patients on sleep disorders including

SDB, insomnia, narcolepsy, RLS, and problem sleepiness. Companion booklets for 

primary care physicians have been developed and published in the journal American

Family Physician. Partnerships with professional organizations, such as the American

Academy of Family Practice, the American

Academy of Pediatrics, the American Sleep

Apnea Association, the American Academy 

of Sleep Medicine, and other national 

organizations involved in sleep research 

and education, have enabled wider 

dissemination of these materials than 

would otherwise have been possible.

• Development of the NCSDR Web site,

www.nhlbi.nih.gov/sleep, where educational materials are available and can 

be viewed and downloaded. 

• Development of a “Sleep IQ” quiz to 

raise public awareness of the signs of 

sleep deprivation and the symptoms of

sleep disorders.

• Development of a drowsy-driving educational campaign targeted at high school

students in partnership with the National

Highway Traffic and Safety Administration.

• Initiation of Latino education efforts about

sleep disorders, including translation of

selected materials into Spanish and development of lay health educator programs.

School-based interventions were 

implemented to encourage awareness of

sleep as a health issue and to foster healthy

sleep habits in children and adolescents.

These interventions include the “Sleep 

well. Do well. Star Sleeper” campaign 

for children ages 7 to 11, and a high 

school supplemental curriculum on the 

biology of sleep, “Sleep, Sleep Disorders,

and Biological Rhythms”. The school-aged

intervention highlights Garfield as the

“spokescat” for healthy sleep and includes

classroom activities, national and local

media components, and a Web site with

content targeted specifically for children,

teachers, and pediatricians.

RESEARCH RECOMMENDATIONS

• Develop effective and innovative educational

approaches based on needs assessments 

of high risk and target groups that include

both quantitative and qualitative research

methodologies. These approaches should

identify specific educational opportunities

and barriers, target sleep health educational

interventions, and improve strategies for

dissemination of educational materials to

patients and the general public.

• Evaluate the effectiveness of: 

– Public sleep education initiatives on public health outcomes in high risk, minority,

and medically underserved populations.

– School-based sleep education programs

on knowledge, attitudes, and sleep 

practices of children and adolescents,

parents, and teachers.

– Educational efforts directed to relevant

State regulatory agencies (e.g., Departments of Motor Vehicles) and related 

to adverse consequences of sleep 

deprivation and sleep disorders on 

safety including drowsy driving, and 

to identifying education efforts that 

have positive impact on public 

education and safety.
120 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

ABBREVIATIONS

AD Alzheimer’s disease

ADHD Attention Deficit Hyperactivity Disorder

ANS Autonomic Nervous System

ASPS Advanced Sleep Phase Syndrome

CCHS Congenital Central Hypoventilation Syndrome

CFS Chronic Fatigue Syndrome

CNS Central Nervous System

CPAP Continuous Positive Airway Pressure

DHHS Department of Health and Human Services

EMG Electromyogram

EOG Electrooculogram

ESRD End Stage Renal Disease

FM Fibromyalgia

fMRI Functional Magnetic Resonance Imaging

IL Interleukin

MEG Magnetoelectroencephalography

MRS Magnetic Resonance Spectroscopy

NCSDR National Center on Sleep Disorders Research

NHLBI National Heart, Lung, and Blood Institute

NIH National Institutes of Health

NIR Near-Infrared Optical Imaging

NREM Non-Rapid Eye Movement Sleep

OSA Obstructive Sleep Apnea

PD Parkinson’s disease

PET Positron Emission Tomography

PLMD Periodic Limb Movement Disorder

PSG Polysomnography

RBD REM Sleep Behavior Disorder

REM Rapid Eye Movement Sleep

RLS Restless Legs Syndrome

SCN Suprachiasmatic Nucleus

SDB Sleep-Disordered Breathing

SIDS Sudden Infant Death Syndrome

SPECT Single Photon Emission Computed Tomography

TMJD Temporomandibular Joint Disorder
INDEX 121

INDEX

Accreditation Council on Graduate 

Medical Education 115

achondroplasia 106

adenosine 61, 81

adenotonsillar hypertrophy 78

adolescence 3, 9, 47, 50-53, 83, 86, 98, 

104-105, 110

advanced sleep phase syndrome 2, 36

African American 57-59, 95, 97

aging 10, 14-15, 20, 43, 52, 56, 59, 60-62

airway patency 5, 77-78

alcohol vii, 7, 20-21, 54, 59, 63, 76, 90, 92,

95-98, 105

Alzheimer’s disease 7, 20, 41, 90-91

amygdala 97

anemia 55

Angelman’s syndrome 82

anticonvulsants 89

antidepressant 21, 39, 81, 84, 98

Apert Syndrome 106

apnea 2-3, 5, 33, 36, 76-77, 91, 101, 103,

107, 116, 119

arousal 7, 18-19, 42, 76, 82, 87-88, 92-94,

98, 109-10

arthritis 59, 67, 73, 82

Asperger’s syndrome 82

asthma 67-68, 82-83

attention deficit hyperactivity disorder 

3, 88, 109

autism 82

autonomic nervous system 7, 92, 106

basal ganglia 38, 68, 93

bed-sharing 48

benzodiazepine 19, 21, 26, 83

blindness 82

body temperature 52, 54-55

brain bank 8, 93

brainstem 2, 17, 21, 38, 41, 43, 88, 91

caffeine 19-21, 26-27, 65-66, 105

cancer 50, 54, 58, 67

cardiopulmonary 51, 67

cataplexy 17-18, 36, 84-86, 107

catecholamine 88

Cheyne-Stokes respiration 76-77

chloral hydrate 83

cholinergic 21, 97

chronic fatigue syndrome 67

chronic partial sleep loss 14, 25-26

circadian iii, 2-5, 9, 13-16, 19-22, 26, 34-37,

48, 51-52, 54-55, 60-66, 68, 75, 80, 83,

87, 95-96, 98, 102-05, 113, 115, 118

clock genes 2, 13, 36

clonidine 83, 110

Congenital Central Hypoventilation 

syndrome 3, 106

congestive heart failure 3, 7, 68, 76-77

continuous positive airway pressure 6, 76

corticotropin 81

cost-benefit 116

craniofacial 7, 78, 106-08

Creutzfeldt-Jakob disease 90

curriculum 3-4, 59, 115-16, 119

cytokines 73-74, 96, 98

d-amphetamine 21, 26

daytime sleepiness iii, vii, 29, 48-50, 53, 

56, 60-61, 67-68, 74, 84, 86-88, 91, 

95-96, 107

delayed sleep phase syndrome 14, 104-105

delta sleep 95, 97

dementia 42, 60-61, 93

depression 3, 7, 39, 49, 51, 53, 56, 59, 67,

95-98, 109

dextroamphetamine 21

diabetes 14, 49, 51, 57-58, 67-68, 82-83

diphenhydramine 83

disparities vii, 1, 9, 48, 57-59, 108

dopamine 17, 20, 87-91, 93

Down syndrome 106

drosophila 16

drowsiness 65
122 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

drowsy driving 4, 63, 104, 119

dysmenorrhea 53, 55-56

electromyographic 33

electrooculographic 33

encephalitis 7, 90-91

encephalographic 21-22

end-stage renal disease 67, 87

epilepsy 7, 90-91, 93

esophageal spasm 92

ethanol 19, 21

extrastriatal 88

fatal familial insomnia 20, 42, 90

fatigue 3, 54-55, 63-68, 74, 87, 91, 95, 117

fibromyalgia 67

functional magnetic resonance imaging 38

gammahydroxybutyric 85-86

gene-environment 9, 59, 73-74

genetic 2, 4-7, 9-10, 14, 16-21, 27, 35-37, 

41, 43, 50-51, 57-59, 61, 73-75, 77-78, 

81, 83-84, 86, 92-94, 105-07, 113, 

134-135

glucose tolerance 58

gonadatropin 52

hallucination 84

health care utilization 80, 116

health education vii, 3, 9, 118-19

health-related quality of life 58

Healthy People 2010 4, 47, 57, 118

heart disease 19, 49-50, 57, 59-60

Hispanic 57, 59

HIV 57, 67-68

homeostatic sleep regulation 68

hormone replacement therapy 20, 54

host defense 74

human leukocyte antigen 84

hyperarousal 80

hypercapnia 76

hyperoxic 101

hypersomnia 37, 84-85, 96-97

hypertension 3, 54-55, 57-58, 60, 68, 76-78

hypnotherapy 94

hypocretin 2, 6, 14, 16-18, 36, 41-42, 81, 

84-86, 107

hypopneas 33, 91

hypothalamus 2, 14, 17, 42-43, 85, 91

injuries 64, 105, 110

insomnia 1, 3, 5-7, 14, 19-20, 34, 42, 50, 

53-56, 58-61, 67-69, 80-83, 87, 95-98,

106, 116, 118-119

insulin resistance 3, 49, 68, 76

interleukins 73-74

intermittent hypoxia 7, 52, 90, 136-37

knock-out 74-75

lateral geniculate nucleus 101

leptin 20

Lewy bodies 42, 93

light exposure 48, 51

limbic system 42

low birth weight 54

magnetic resonance spectroscopy 38

magnetoelectroencephalography 38

MDMA 19, 97

medical and surgical residents 64

melatonin 26, 61, 68, 82, 104-05, 107

memory 16, 25-26, 29, 60, 64-65, 101, 

104-05

menopause 9, 52, 54, 56

menstrual 53-56

mental retardation 82, 107

metabolic syndrome 76-77

methylphenidate 21, 26

minority 82, 118, 119

modafinil 20-21, 26, 85-86

mood disorders 53, 95, 98, 105

Morphine 21

motor vehicle crashes 49, 63, 65, 105, 110

multiple sclerosis 90-91

Multiple Sleep Latency Test 84

murine 13, 16-17, 36, 84

muscular atrophy 106
INDEX 123

myotonic dystrophy 90, 107

naps 50, 64-65, 84

narcolepsy 2, 5-6, 16, 18-20, 27, 36-37, 

41-42, 58, 84-86, 93, 118-119

National Center on Sleep Disorders Research

iii, vii, viii, 116, 118

National Heart, Lung, and Blood Institute 

iii, v, vii, 118

near-infrared optical imaging 38

neonatal 101-02

neurobehavioral 3, 25-29, 50, 52, 64-65, 

78, 103-04, 110

neurobiology 2, 4, 6, 10, 16, 25, 80-81, 

115, 134, 136-37

neurodevelopmental 7, 28, 82-83

neuroendocrine 28, 52-53, 69, 73-75

neuroimaging 5, 8, 28-29, 38-39, 68, 81, 

93, 95, 98, 113

neurology 10, 86, 115

neuropathology 9, 10, 41, 43, 91

night sweats 54-55

nightmares 92, 95-97

nigrostriatal 88

non-REM sleep 4, 16-18, 26-27, 33, 38-39,

92, 96-97, 101

nonrestorative 67

noradrenergic 109

nutrition 47, 50

obesity 6, 14, 49, 51, 57-58, 67, 77-79, 

107, 118

ontogeny 103, 108

opiates 19, 87, 95, 103

oral appliances 6, 77

oral contraceptives 55

oximetry 33

pain vii, 7, 21, 39, 67-69, 82-83

parasomnia 17, 18, 92-94

Parkinson’s disease 7, 90-91, 93

partial sleep deprivation 3, 25, 27, 29, 68,

104-05, 137

pediatric 1, 3, 6-7, 10, 28, 56, 78-79, 81-83,

94, 106, 115-16, 119

performance deficits 25, 27, 29, 66

periodic limb movement disorder 5-6, 53, 

60, 87, 109, 118

Pfeiffer syndrome 106

pharmacogenomics 61

Pharmacology 19-21

phase delay 104

phenotype 5-6, 8-9, 17, 19, 27, 35-37, 47,

51, 73-75, 77-78, 80-81, 93-94, 101, 

107-08, 110

Pierre Robin sequence 106

plasticity 26-28, 97, 101-03

polysomnography 33, 59, 77, 79, 84, 109

positron emission tomography 38

post traumatic stress disorder 7, 95

Prader Willi syndrome 107

pre-eclampsia 54-55

pregnancy 9, 18, 52-56, 87, 89, 103

prematurity 50, 101, 103

preprohypocretin 36, 84

prion disorder 42, 90

progesterone 53, 55-56

progressive supranuclear palsy 90

prolactin 68

psychiatric vii, 3, 7, 60, 67, 77, 80-81, 92, 

95-98, 105, 109-10, 135

psychoactive 95, 97-98

psychostimulants 19, 21, 110

puberty 52-53, 56, 104-05

public health iii, vii, 3-4, 6, 9-10, 47, 49, 59,

63, 104, 115, 118, 119

quality of life vii, 6-8, 54, 58, 60, 67, 76-77,

82, 87, 89, 108, 113, 115-17

racial and ethnic minorities vii, 9, 57, 59

Rechtschaffen and Kales 33

REM behavior disorder 39, 42

REM latency 55, 95
124 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

REM sleep 2, 4, 16-18, 21, 39, 42, 55-56, 

84, 90, 92, 95, 97, 101-02

respiration 5, 9, 33, 34, 76, 91, 98, 102

restless legs syndrome 5-6, 14, 19, 36, 39,

42, 53, 60, 87, 95, 109, 118, 135

reticular activating system 39

Rett syndrome 3, 41, 82, 106-07

rhythmic movement disorders 94

San Filippo syndrome 82

schizophrenia 41, 97

school start times 64, 105

sedative/hypnotics 19

selective serotonin reuptake inhibitors 93

serotonergic 41-42, 94, 97

sex differences 1, 52-53, 56

sexual dimorphism 52

shift work 2, 14-15, 25-26, 63-64

sickle cell disease 58, 82

single photon emission computed 

tomography 38

Sleep Academic Award 3, 116

sleep architecture 21, 33, 54, 67, 73-74, 92,

95-96, 98, 109

sleep debt 16-18, 28, 49-51, 63, 104

sleep deprivation 3, 7-8, 14, 16, 21, 25-28,

37, 39, 51-53, 73-74, 90-91, 93, 95, 

97-98, 102, 105, 118-19

sleep efficiency 54-55, 96

sleep inertia 20, 26-27, 39, 94

sleep paralysis 84

sleep position 48, 51, 108

sleep quality vii, 4-5, 7, 19, 48-55, 57-58, 

60-62, 67, 69, 73, 83, 95

sleep restriction vii, 3, 16, 25-29, 47, 50, 

74, 104-05

sleep surface 48, 50-51

sleep terrors 92

Sleep-Disordered Breathing 2, 5-6, 17, 20, 

27, 33, 36, 42, 48, 52, 57, 60, 63, 76, 

90, 95, 106, 109, 119

sleep-wake 10, 13, 18, 33, 47, 60-61, 92-93,

98, 102, 104, 109

sleepwalking 92

Smith-Magenis syndrome 82, 107

smoking 50, 57, 103

snoring 54-55, 57-58, 78

socioeconomic status 51, 57

special needs populations 82

stroke 3, 7, 57, 77, 90-91

substance use disorders 3, 7, 95-96

Sudden Infant Death syndrome 3, 20, 41, 

48, 96, 103, 108

Sudden Unexpected Nocturnal Death 

syndrome 59

suprachiasmatic nucleus 2, 13, 61

sympathetic nervous system 59, 74, 80-81

temporomandibular joint disorders 67

thalamus 38, 42-43, 68

training iii, viii, 3, 9, 10, 41, 64, 65, 113-17

transgenic 74-75

trauma 7, 57, 67, 90-91

trazadone 83

Treacher Collins syndrome 106

truck drivers 63-64

tuberous sclerosis 82

uremia 89

vagus nerve stimulation 91

ventilatory control 5, 77

ventrolateral preoptic nucleus 61

visual cortical responses 102

William syndrome 82
APPENDICES

• Appendix A: National Sleep Disorders 

Research Plan Revision Task Force

• Appendix B: National Sleep Disorders 

Research Advisory Board

• Appendix C: NIH Sleep-Related Initiatives, 

1996 to 2002

APPENDICES 127

APPENDIX A: NATIONAL SLEEP DISORDERS RESEARCH PLAN

REVISION TASK FORCE

Chair: David P. White, M.D.

Associate Professor of Medicine

Harvard Medical School

Division of Sleep Medicine

Brigham and Women’s Hospital

Boston, MA

dpwhite@rics.bwh.harvard.edu 

Steven J. Henriksen Ph.D.

The Scripps Research Institute

Department of Neuropharmacology

La Jolla, CA

steven@scripps.edu 

Hannah C. Kinney, M.D.

Associate Professor of Neuropathology

Department of Pathology

Harvard Medical School

Children’s Hospital 

Boston, MA

hannah.kinney@TCH.Harvard.edu 

Carol A. Landis, D.N.Sc., R.N.

Professor, Biobehavioral Nursing and 

Health Systems

Scientific Director, Biobehavioral Laboratories

Center for Women’s Health Research

University of Washington

Seattle, WA

calandis@u.washington.edu 

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

Director, Center for Narcolepsy

Stanford University School of Medicine

Stanford, CA

mignot@leland.stanford.edu 

Judith A. Owens, M.D., M.P.H.

Associate Professor of Pediatrics

Brown Medical School

Director, Pediatric Sleep Disorders Clinic

Hasbro Children’s Hospital 

Providence, RI 

Owensleep@aol.com 

Thomas J. Balkin, Ph.D. 

Chief, Department of Behavioral Biology 

Walter Reed Army Institute of Research 

Silver Spring, MD

thomas.balkin@na.amedd.army.mil 

Gene D. Block, Ph.D. 

Vice President and Provost

University of Virginia 

Charlottesville, VA

gdb@virginia.edu

Daniel Buysse, M.D.

Associate Professor of Psychiatry

University of Pittsburgh

Western Psychiatric Institute and Clinic

Pittsburgh, PA 

BuysseDJ@MSX.UPMC.EDU

David F. Dinges, Ph.D.

Professor of Psychology in Psychiatry

Chief, Division of Sleep and Chronobiology

Department of Psychiatry

University of Pennsylvania School of Medicine

Philadelphia, PA

dinges@mail.med.upenn.edu 

David Gozal, M.D.

Professor and Vice-Chair for Research

Department of Pediatrics

University of Louisville

Louisville, KY

d0goza01@gwise.louisville.edu 
128 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Jerome Siegel, Ph.D.

Professor of Psychiatry and 

Biobehavioral Sciences

Center for Sleep Research

VA GLAHS-Sepulveda

North Hills, CA

JSiegel@UCLA.edu 

Esther Sternberg, M.D.

Director, Integrative Neural-Immune Program 

Chief, Section on Neuroendocrine 

Immunology and Behavior

National Institute of Mental Health/NIH

Bethesda, MD 

es93d@nih.gov 

Debra E. Weese-Mayer, M.D.

Professor of Pediatrics 

Rush University

Chicago, IL

Debra_E_Weese-Mayer@rush.edu 

Consultants

Clifford B. Saper, M.D., Ph.D. 

Harvard Medical School

Boston, MA 

Mark W. Mahowald, M.D.

University of Minnesota

Minneapolis, MN
APPENDICES 129

APPENDIX B: NATIONAL SLEEP DISORDERS RESEARCH

ADVISORY BOARD

Chair: Stuart F. Quan, M.D. (2005)

Professor of Medicine, Respiratory Sciences Center

The University of Arizona College of Medicine

1501 North Campbell Avenue

Tucson, AZ 85724

squan@resp-sci.arizona.edu

Susan Redline, M.D., M.P.H. (2006)

Chief, Division of Clinical Epidemiology

Department of Pediatrics

Case Western Reserve University 

Rainbow Babies and Childrens’ Hospital 

11400 Euclid Avenue

Cleveland, OH 44106

sxr15@po.cwru.edu 

Clifford B. Saper, M.D., Ph.D. (2005)

Professor and Chair

Department of Neurology and Program 

in Neuroscience

Harvard Medical School

Beth Israel Deaconess Medical Center

330 Brookline Avenue 

Boston, MA 02215

csaper@caregroup.harvard.edu 

Michael J. Sateia, M.D. (2006)

Professor of Psychiatry

Director, Section of Sleep Medicine

Dartmouth-Hitchcock Medical Center

Lebanon, NH 03756

Michael.J.Sateia@dartmouth.edu 

Dara D. Spearman (2003)

2816 Pittsfield Boulevard

Ann Arbor, MI 48104

dspearma@med.umich.edu 

Phillip L. Williams (2004)

4472 Golf Club Lane

Brooksville, FL 34609 

pwilli16@tampabay.rr.com 

Gene D. Block Ph.D. (2004)

Vice President and Provost

University of Virginia

Charlottesville, VA 22904-2477

gdb@virginia.edu 

Sarah J. Caddick, Ph.D. (2004)

Executive Director

Wadsworth Foundation

3601 Fremont Ave N. Ste. 303

Seattle, WA 98103

sarahc@wadsworthfoundation.org

Mary Carskadon, Ph.D. (2003)

Professor

Department of Psychiatry and Human Behavior

Brown University School of Medicine

E. P. Bradley Hospital Sleep Research Laboratory

1011 Veterans Memorial Parkway

East Providence, RI 02915

mary_carskadon@brown.edu

Kathryn A. Lee, Ph.D. (2006)

Professor, Family Health Care Nursing

School of Nursing

University of California, San Francisco

2 Koret Way, Box 0606

San Francisco, CA 94143

kathy.lee@nursing.ucsf.edu 

Sandra McGinnis (2003)

176 Governors Road

Ponte Vedra Beach, FL 32082

james.mcginnis@mx3.com 

Rafael Pelayo, M.D. (2006)

Assistant Professor

Department of Psychiatry and Behavioral Sciences

Stanford University

401 Quarry Road, PBS 3350

Stanford, CA 94305

pelayo@stanford.edu
130 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Colonel Gregory Belenky, M.D.

Director, Division of Neuropsychiatry

Walter Reed Army Institute of Research

Washington, DC 20307-5100

gregory.belenky@na.amedd.army.mil 

Robert Wolfe Greene, M.D., Ph.D.

University of Texas

Southwestern Medical Center

4500 South Lancaster Road

Dallas, TX 75214

robertw.greene@utsouthwestern.edu 

Carl E. Hunt, M.D., SDRAB Executive Secretary

Director

National Center on Sleep Disorders Research

National Heart, Lung, and Blood Institute/NIH

Two Rockledge Center, Suite 10038

6701 Rockledge Drive MSC 7920

Bethesda, MD 20892-7920

huntc@nhlbi.nih.gov 

Israel Lederhendler, Ph.D.*

Coordinator for Sleep Research

National Institute of Mental Health/NIH

Neuroscience Center, MSC 9637

6001 Executive Boulevard, Room 7169

Bethesda, MD 20892-9637

ilu@helix.nih.gov 

Claude Lenfant, M.D.

Director

National Heart, Lung, and Blood Institute/NIH

9000 Rockville Pike

Building 31, Room 5A52

Bethesda, MD 20892

lenfantc@nhlbi.nih.gov

Merrill M. Mitler, Ph.D.*

Program Director, Systems and 

Cognitive Neuroscience

National Institute of Neurological Disorders 

and Stroke/NIH

6001 Executive Boulevard, Room 2108, MSC 9521

Bethesda, MD 20892-9521

mitlerm@ninds.nih.gov

Andrew Monjan, Ph.D., M.P.H.*

Chief of Neurobiology and Neuropsychology

Neuroscience and Neuropsychology of 

Aging Program

National Institute on Aging/NIH

Gateway Building, Suite 3C307

Bethesda, MD 20892

am39m@nih.gov

Marian Willinger, Ph.D.* 

Health Scientist Administrator

Pregnancy and Perinatology Branch

National Institute of Child Health and 

Human Development/NIH

6100 Executive Boulevard, Room 4B03D

Bethesda, MD 20892

mw75q@nih.gov 

Eve E. Slater, M.D.

Assistant Secretary for Health 

Department of Health and Human Services 

Washington, DC 20201

Elias Zerhouni, M.D.

Director, National Institutes of Health 

One Center Drive

Building 1, Room 126, MSC 0148

Bethesda, MD 20892

execsec1@od.nih.gov

SLEEP DISORDERS RESEARCH ADVISORY BOARD

EX OFFICIO MEMBERS

* Member of the Trans-NIH Sleep Research Coordinating Committee
APPENDICES 131

Deborah Ader, Ph.D.*

National Institute of Arthritis and

Musculoskeltal and Skin Diseases

45 Center Drive, Room# 5AS19H

Bethesda, MD 20892

aderd@mail.nih.gov

Daniel P. Chapman, Ph.D., M.S.

Centers for Disease Control and Prevention

4770 Buford Highway, N.E., Mailstop K-45

Atlanta, GA 30341

dpc2@cdc.gov 

Harold Gordon, Ph.D.*

Program Official, Clinical Neurobiology Branch

Division of Treatment Research and Development

National Institute on Drug Abuse/NIH

6001 Executive Boulevard, Room 4233, 

MSC 9551

Bethesda, MD 20892-9551

hg23r@nih.gov 

Mary Leveck, Ph.D., R.N.*

Deputy Director, National Institute of 

Nursing Research

Building 31, Room 5B05

Bethesda, MD 20892-2178

mary.leveck@nih.gov 

Adrienne Oneto

Chief, Health Surveys Branch

Bureau of the Census, Demographic 

Surveys Division

Building 3, Room 3442

Washington, DC 20233

Adrienne.C.Oneto@census.gov 

Nancy Pearson, Ph.D.*

National Center for Complementary 

and Alternative Medicine/NIH

6707 Democracy Boulevard, Room 401

Bethesda, MD 20892

pearsonn@mail.nih.gov 

Christopher Platt, Ph.D.

Program Director, Neuroscience

Division of Integrative Biology and Neuroscience

National Science Foundation 

4201 Wilson Boulevard, Room 685

Arlington, VA 22230

cplatt@nsf.gov 

Thomas G. Raslear, Ph.D.

Senior Human Factors Program Manager

Office of Research and Development

Federal Railroad Administration

United States Department of Transportation

Washington, DC 20590

thomas.raslear@fra.dot.gov 

Roger R. Rosa, Ph.D.

National Institute for Occupational Safety 

and Health 

200 Independence Avenue, N.W., Room 715H

Washington, DC 20201

rrosa@cdc.gov 

George Ruby, M.D.

United States Department of 

Occupational Safety and Health Administration

Division of Science Technology and Medicine

Department of Labor

200 Constitution Ave., N.W., Room N3653

Washington, DC 20210

george.ruby@osha.gov

SLEEP DISORDERS RESEARCH ADVISORY BOARD

LIAISON MEMBERS

* Member of the Trans-NIH Sleep Research Coordinating Committee
132 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Bette Siegel, Ph.D.

BioAstronautics Division, Code UB, Room 8Q13

NASA Headquarters, 300 E Street, S.W.

Washington, DC 20546

bette.siegel@nasa.gov 

Ellen Witt, Ph.D.*

National Institute on Alcohol Abuse 

and Alcoholism/NIH

Willco Building, Suite 402 

6000 Executive Boulevard, MSC 7003

Bethesda, MD 20982-7003

ewitt@willco.niaaa.nih.gov 

* Member of the Trans-NIH Sleep Research Coordinating Committee
APPENDICES 133

APPENDIX C: 1996 NATIONAL SLEEP DISORDERS

RESEARCH PLAN RECOMMENDATIONS AND

RESULTING NIH SLEEP-RELATED RESEARCH INITIATIVES

(1996 TO 2002)

The title of each RFA/PA and total funding awarded for each initiative (cumulative through 

Fiscal Year 2002) are listed in descending chronological order by year of initiative release under 

the relevant research recommendations from the 1996 National Sleep Disorders Research Plan. 

In some instances, an individual initiative applies to more than one recommendation and is 

therefore listed under each relevant recommendation. 
134 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

1996 National Sleep Disorders Research Plan Research Recommendations

BASIC SCIENCE RESEARCH RECOMMENDATIONS

 Increase efforts to understand the basic mechanisms responsible for sleep by applying molecular 

biological approaches in concert with techniques of cellular and systems neurobiology.

 Conduct basic studies to understand the brain mechanisms responsible for sleepiness.

 Study basic mechanisms underlying the interaction between the circadian and neurophysiological

systems that regulate sleep and wakefulness.. 

 Characterize the genetic factors controlling the basic mechanisms of sleep. 

 Increase research efforts to elucidate the fundamental functions of sleep.

Total Costs 

Participating Awarded 

Initiative Title Institutes/Centers (through FY 2002)

Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253

and Blood Diseases: HL01-009*†

Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605

Oxygen Sensing During Intermittent Hypoxia: HL00-004* NHLBI 10,673,975

Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381

Phenotypic Characterization of Sleep in Mice: HL99-001 NHLBI, NIMH, 13,512,185

NIA, NINDS

Bioengineering Research Grants: PAR 99-009 NCI, NCRR, NEI, NHGRI, 546,594

NHLBI, NIA, NIAAA, 

NIAID, NIAMS, NICHD, 

NIDA, NIDCD, NIMH, 

NINDS, NINR, NLM

Research on Musculoskeletal Fitness and NIAMS, NICHD, NINR 999,146

Sports Medicine: PA97-025* 

SCOR in Neurobiology of Sleep and Sleep NHLBI 18,553,207

Apnea: HL96-014*† 

Molecular Biology and Genetics of Sleep NHLBI, NIMH, NICHD 7,335,059

and Sleep Disorders: HL96-015*

Basic and Clinical Research on Sleep and NIA, NIAAA, NICHD, 28,384,156

Wakefulness: PA95-014* NIDA, NHLBI, NIMH, 

NINDS, NINR

* Also listed under Patient-Oriented Research Recommendations

† Also listed under Applied Research Recommendations
APPENDICES 135

PATIENT-ORIENTED RESEARCH RECOMMENDATIONS

 Identify the genetic basis of sleep disorders that have a genetic component.

 Conduct epidemiological research to assess prevalence, risk factors, and long-term consequences 

of common sleep disorders and determine the role of ethnicity, age, and gender in their causation.

 Conduct outcomes research and clinical trials on the management of common sleep disorders.

 Develop new technological approaches for diagnosis of sleep disorders, screening for sleep 

disorders among high-risk populations in whom sleepiness presents a particular danger (e.g., 

transportation workers), monitoring the effectiveness of therapy, and detecting abnormalities 

of sleep as early biological markers of psychiatric illnesses.

 Elucidate the pathogenesis/pathophysiology of sleep disorders and their consequences.

 Provide the research infrastructure needed to carry out patient-oriented research.

Total Costs 

Participating Awarded 

Initiative Title Institutes/Centers (through FY 2002)

Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253

and Blood Diseases: HL01-009*†

Sleep and Sleep Disorders in Children: HL01-006 NHLBI, NIMH, 1,499,621

NINR, NICHD

Restless Legs Syndrome and Periodic Limb NINDS, NHLBI, 334,178

Movement Disorder: PA01-086 NIA, NIMH

Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605

Ancillary Studies in Conjunction with SHOW Trial: DK-00-017 NIDDK, NHLBI, NINR, 1,143,165

NIAMS, NIDCR

Oxygen Sensing During Intermittent Hypoxia: HL00-004 NHLBI 10,673,975

Biobehavioral Research for Effective Sleep: PA00-046*† NINR, NHLBI, NIA, 1,717,977

NIAAA, NICHD, 

NIDA, NIMH, NCI

Data Coordinating Center for Sleep Heart NHLBI 2,913,228

Health Study: HL99-014

Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381

Occupational Safety and Health Research: PA99-143† NIOSH, NCI, NHLBI, 381,250

NIA, NIAAA, NIAID, 

NIAMS, NIDCD, NIEHS

Obstructive Sleep Apnea in Children: HL98-004† NHLBI, NIDR, NICHD 10,826,226

(CONTINUED ON PAGE 138)
136 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

Total Costs 

Participating Awarded 

Initiative Title Institutes/Centers (through FY 2002)

Sleep Academic Award: HL97-015, HL96-021, HL96-006‡ NHLBI $ 4,995,123

Institutional National Research Service Award in NHLBI, NIA, NIAAA, 737,625

Sleep Research: PA97-064† NICHD, NIDA, NIMH, 

NINDS, NINR

Research on Musculoskeletal Fitness and Sports NIAMS, NICHD, NINR 999,146

Medicine: PA97-025*

Molecular Biology and Genetics of Sleep and Sleep NHLBI, NIMH, NICHD 7,335,059

Disorders: HL96-015*

SCOR in Neurobiology of Sleep and Sleep NHLBI 18,553,207

Apnea: HL96-014*†

Basic and Clinical Research on Sleep and NHLBI, NIA, NIAAA, 28,384,156

Wakefulness: PA95-014*† NICHD, NIDA, NIMH, 

NINDS, NINR

* Also listed under Basic Science Research Recommendations

† Also listed under Applied Research Recommendations

‡ Also listed under Research Training Recommendations

PATIENT-ORIENTED RESEARCH RECOMMENDATIONS (CONTINUED)
APPENDICES 137

APPLIED RESEARCH RECOMMENDATIONS

 Conduct epidemiological research to define the prevalence, etiology, risk factors, morbidity, and

costs of sleepiness in the general population.

 Define the decrement and recovery processes associated with chronic partial sleep deprivation.

 Develop efficient, objective measures of daytime sleepiness.

 Evaluate the utility of interventions to prevent and manage sleepiness, with the goal of improving

productivity and safety.

Total Costs 

Participating Awarded 

Initiative Title Institutes/Centers (through FY 2002)

Interrelationships Between Sleep and Heart, Lung, NHLBI, NIDA $ 1,357,253

and Blood Diseases: HL01-009*†

Research on Alcohol and Sleep: AA00-005*† NIAAA 4,512,605

Biobehavioral Research for Effective Sleep: PA00-046† NINR, NHLBI, NIA, 1,717,977

NIAAA, NICHD, NIDA, 

NIMH, NCI

Nocturnal Asthma, Chronobiology and Sleep: HL99-011*† NHLBI 3,530,381

Implementation of the National Occupational NIOSH, NCI, NHLBI, 423,750

Research Agenda: OH99-02 NIA, NIDCD, NIEHS

Occupational Safety and Health Research: PA99-143† NIOSH, NCI, NHLBI, 381,250

NIA, NIAAA, NIAID, 

NIAMS, NIDCD, NIEHS

Human Brain Project (Neuroinformatics): PAR 99-138 NIMH, NIDA, NSF, 370,125

NIA, NICHD, NIDCD, 

NLM, NASA, FIC, DOE, 

NIAAA, NHLBI, NIDCR, 

NCI, NINDS

Obstructive Sleep Apnea in Children: HL98-004† NHLBI, NIDR, NICHD 10,826,226

Institutional National Research Service Award in NHLBI, NIA, NIAAA, 737,625

Sleep Research: PA97-064† NICHD, NIDA, NIMH, 

NINDS, NINR

Innovative Approaches to Developing New NCRR 222,740

Technologies: PAR-97-014

SCOR in Neurobiology of Sleep and NHLBI 18,553,207

Sleep Apnea: HL96-014*† 

Basic and Clinical Research on Sleep and NHLBI, NIA, NIAAA 28,384,156

Wakefulness: PA95-014*† NICHD, NIDA, NIMH, 

NINDS, NINR

* Also listed under Basic Science Research Recommendations

† Also listed under Patient-Oriented Research Recommendations
138 2003 NATIONAL SLEEP DISORDERS RESEARCH PLAN

RESEARCH TRAINING RECOMMENDATIONS

 Enhance the number of trained investigators and trainees in biological and behavioral research 

related to basic sleep mechanisms and patient-oriented research.

Total Costs 

Participating Awarded 

Initiative Title Institutes/Centers (through FY 2002)

Sleep Academic Award: HL97-015, HL96-021, HL96-006* NHLBI $4,995,123

* Also listed under Patient-Oriented Research Recommendations

GRAND TOTAL $ 114,969,569 

NIH TOTAL SLEEP DISORDERS RESEARCH FUNDING, 1996 TO 2002 

Institute/

Center 1996 1997 1998 1999 2000 2001 2002

Dollars in thousands

NHLBI 16,450 19,219 22,932 31,845 35,128 37,579 45,155

NINDS 9,453 11,598 13,639 15,231 12,495 17,603 22,918

NICHD 7,368 7,217 9,131 7,116 6,797 7,084 7,344

NIA 7,800 9,179 11,818 13,296 13,034 14,533 14,600

NIMH 27,231 28,601 34,027 39,219 40,667 50,742 56,647

NIDA 1,201 1,042 1,586 2,163 2,553 2,517 3,235

NIAAA 551 728 766 736 1,132 1,681 4,342

NINR 2,842 3,565 3,394 3,503 4,635 5,375 8,091

NCRR 3,247 3,570 5,542 6,637 7,117 7,193 11,490

NCCAM † N/A N/A N/A N/A N/A 177 900

NIAMS † N/A N/A N/A N/A N/A N/A 300

NHGRI N/A N/A N/A N/A N/A 599 0

Total 76,143 84,719 102,835 119,746 123,558 145,083 175,022

* Detailed listings of NIH Sleep Related Grants for Fiscal Years 1999 through 2002 can be found online at: 

http://www.nhlbisupport.com/sleep/research/research3.htm

† Became Trans-NIH Sleep Research Coordinating Committee Member Institute in FY 2002
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provides information to health professionals, patients, and the public about 

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For more information, contact:

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Heart, Lung, and Blood Institute

NIH Publication No. 03-5209

July 2003