DEPARTMENT OF HEALTH AND HUMAN SERVICES

                          Public Health Service
                      National Institutes of Health
                      
                  National Sleep Disorders Research Plan

                             January 1996
                                    

                                                      


Foreword

The National Center on Sleep Disorders Research (NCSDR) was
established within the National Heart, Lung, and Blood
Institute (NHLBI) as a result of the National Institutes of
Health (NIH) Revitalization Act of 1993.  Its mandate is the
following:

   The conduct and support of research, training, health
   information dissemination, and other activities with
   respect to sleep disorders, including biological and
   circadian rhythm research, basic understanding of sleep,
   chronobiological and other sleep related research

   and

   To coordinate the activities of the Center with similar
   activities of other Federal agencies, including the other
   agencies of the National Institutes of Health, and
   similar activities of other public entities and nonprofit
   entities.

The legislation further provided for establishment of a
Sleep Disorders Research Advisory Board composed of
nonfederal experts and ex officio federal members and it
mandated development of this National Sleep Disorders
Research Plan.

The Plan is broad in scope and multidisciplinary in nature. 
Its vision is "to improve the health, safety, and
productivity of Americans by promoting basic, clinical, and
applied research on sleep and sleep disorders."  To achieve
this vision, the Plan's recommendations call for
strengthening existing sleep research programs and creating
new programs that address important research gaps and
opportunities.

Two themes cut across all the Plan's recommendations.  The
first is the need to apply today's most advanced techniques
and technologies to the study of sleep.  In basic science,
the tools of cellular and molecular biology and molecular
genetics are particularly relevant, as are neuroimaging,
neurophysiology, neuropharmacology, and computational
neuroscience.  For public health and patient-oriented
research, modern techniques from epidemiology, clinical
outcomes research, experimental therapeutics, and behavioral
sciences should be utilized.

The second theme is the need to understand daytime
sleepiness and reduce its negative impact on society. 
Investigation of this significant public health problem
requires a multidisciplinary approach that includes all
types of research (e.g., basic, clinical, applied) and all
research methods.

Needs and opportunities receiving special emphasis in the
Plan include the following:

      Understanding the cellular, molecular, and genetic
       basis of sleep and its disorders.

      Determining the epidemiology of sleep and sleepiness
       in health and disease. 

      Identifying the effects of sleep loss on the waking
       function of the brain, other systems, and behavior.

      Elucidating the pathophysiology and optimal management
       of common sleep disorders and developing new
       technologies to accomplish this task.  

      Learning to manage sleep-wake function to optimize
       health and performance in the 24-hour society,
       including developing new technologies to address
       evaluation, diagnosis, and prevention of the causes of
       sleepiness.

      Discovering the functions of sleep.

      Training investigators to expand the pool of sleep
       researchers. 

The 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 its recommendations will provide a
solid foundation to assist the NIH in achieving its mandate
of improving the health of the nation.  

                                                                        
          
                                                Harold Varmus, M.D.
                                                Director, NIHNational Sleep Disorders Research Plan

Contents



Executive Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Basic Science Research Recommendations . . . . . . . . . . . . . . . . 6

Patient-Oriented Research Recommendations. . . . . . . . . . . . . . .13

Applied Research Recommendations . . . . . . . . . . . . . . . . . . .18

Research Training Recommendations. . . . . . . . . . . . . . . . . . .23

Selected References. . . . . . . . . . . . . . . . . . . . . . . . . .24
                            Executive Summary


Sleep-related problems affect millions of Americans, occur
in all age groups, and have a major impact on society. 
Three broad categories of problems have been identified:

      Sleep disorders.  More than 70 types of sleep
       disorders chronically affect millions of Americans. 
       Many people are unaware of their illness and are not
       receiving adequate treatment for it.

      The sleep-disease connection.  This problem has two
       facets.  First, some psychiatric, substance abuse, and
       medical disorders disturb sleep; and the resulting
       sleep abnormalities further exacerbate the original
       problem, creating a vicious circle.  Second, sleep
       affects the expression of many diseases (e.g., asthma,
       in which episodes occur more commonly during sleep).

      Sleep deficits resulting from lifestyles and work
       schedules.  Many people (e.g., student night owls,
       jet-lagged business travelers, shift workers)
       regularly fail to get the sleep they need to function
       effectively during waking hours.

Recognizing the serious, pervasive public health threat
posed by sleep problems, the Congress established the
National Center on Sleep Disorders Research (NCSDR) within
the National Heart, Lung, and Blood Institute (NHLBI),
National Institutes of Health (NIH), in 1993.  The NCSDR
authorizing legislation also mandated development of a
National Sleep Disorders Research Plan:

   After consultation with the Director of the Center and
   the advisory board . . . the Director of the National
   Institutes of Health shall develop a comprehensive plan
   for the conduct and support of sleep disorders research.

   The plan . . . shall identify priorities with respect to
   such research and shall provide for the coordination of
   such research conducted or supported by the agencies of
   the National Institutes of Health.
                                    
   The Director of the National Institutes of Health (after
   consultation with the Director of the Center and the
   advisory board . . . shall revise the plan . . . as
   appropriate.

The Plan described herein was developed by the Research
Subcommittee of the Sleep Disorders Research Advisory Board,
which comprised Drs. J. Christian Gillian, chair, Allan I.
Pack, and Thomas Roth.  Their report was reviewed and
approved by the full Advisory Board, the Trans-NIH Sleep
Research Coordinating Committee, and the NHLBI.
                                                     
The Plan is broad in scope and multidisciplinary in nature. 
Its vision is "to improve the health, safety, and
productivity of Americans by promoting basic, clinical, and
applied research on sleep and sleep disorders."  To achieve
this vision, the Plan's recommendations call for
strengthening existing sleep research programs, training new
investigators, and creating new programs that address
important research gaps and opportunities.  

The following are key recommendations:

   Basic Science Research: 

   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 the basic mechanisms
   underlying the interaction between circadian and
   neurophysiological systems that regulate sleep and
   wakefulness.

   Increase attention to genetic factors controlling the
   basic mechanisms of sleep.

   Increase research efforts to elucidate the fundamental
   functions of sleep.

   Patient-Oriented Research:

   Identify the genetic basis of sleep disorders that have a
   genetic or familial 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.

   Applied Research:

   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.

   Research Training:

   Enhance the number of trained investigators and trainees
   in biological and behavioral research related to basic
   sleep mechanisms and patient-oriented research. 

                                Overview


Congressional interest in sleep led to establishment in 1988
of the National Commission on Sleep Disorders Research.  The
Commission studied the scope of the problem and the current
state of research and found that sleep disorders are a
significant public health and economic problem that warrants
major national attention.  Establishment of the NCSDR within
NIH was a major recommendation of the Commission.

With the establishment of the NCSDR in 1993, the Congress
recognized the opportunity to multiply the impact of the
nation's dynamic sleep research and training programs. 
Developing a National Sleep Disorders Research Plan, as
called for in the NCSDR legislation, was an important step
in this process.

How the Plan Was Developed

To develop a coordinated plan that many agencies could
implement, the NCSDR used a collaborative planning model.  A
Research Subcommittee of the Sleep Disorders Research
Advisory Board was appointed and given primary
responsibility for preparing the Plan.

The first step in their process was soliciting suggestions
from interested organizations and scientists around the
country.  The Subcommittee then consolidated these ideas and
set priorities, producing recommendations for filling
identified research gaps and taking advantage of suggested
opportunities.  Each member of the group focused on one
category of need, including basic, clinical, and applied
sleep research and research training.  Subcommittee members
and several members of the Trans-NIH Sleep Research
Coordinating Committee reviewed the individual
recommendations.

The final Plan presented here also reflects additional
review, revision, and approval from the full Sleep Disorders
Research Advisory Board, the complete Trans-NIH Sleep
Research Coordinating Committee, and the NHLBI.  By working
together to develop the Plan, agencies with an interest in
sleep and sleep disorders research set the stage for
collaborative implementation of the Plan's recommendations.

Vision of the Research Plan

   To improve the health, safety, and productivity of
Americans by promoting basic, clinical, and applied research
on sleep and sleep disorders.

To achieve this vision, the Plan's recommendations call for
maintaining and strengthening existing research programs on
sleep and wakefulness.  These include the study of sleep
mechanisms, using systems neuroscience approaches.  Other
research programs focus on such important issues as age-
related sleep disorders, sleep-related cardiopulmonary
disorders, the effects of mental illness and substance abuse
disorders on sleep, neurological disease and sleep, and
sudden infant death syndrome, and the effects of lifestyle
and work schedules on sleep and wakefulness.

Strengthening current programs is necessary to accomplish
the vision, but it is not sufficient.  The Plan's
recommendations also reflect the need to support three
specific types of research:
   
      Basic research, using state-of-the-art approaches, to
       elucidate the functions of sleep and the fundamental
       molecular and cellular processes underlying sleep.

      Patient-oriented research to understand the cause,
       evaluate the scope, and improve the diagnosis and
       treatment of sleep disorders.

      Applied research to evaluate the scope and
       consequences of sleepiness and to develop new
       approaches to prevent impaired performance during
       waking hours.

Training scientists and health-care workers who have the
capacity to study and treat sleep disorders and their
related health problems is another important focus of the
plan.

The following sections describe important directions that
should be undertaken in these key areas.  General
recommendations are numbered, and specific needs and
opportunities are highlighted in bulleted form.

Basic Science Research Recommendations

Sleep state remains one of the major mysteries of the brain: 
Why do people sleep and how are sleep and wakefulness
controlled?  The answers to these questions may be expected
to have a positive impact on medical care, including
improved diagnosis and management of sleep disorders, and on
policy decisions about sleep, work, and rest schedules.  The
ability to improve sleep and reduce sleepiness also has
potential to improve the productivity and well-being of
millions of Americans.  

Progress made during the past decade provides a strong
foundation for rapidly advancing knowledge.  New research
technologies, particularly cellular and molecular biology
and genetics, can build on and complement what has been
learned from traditional systems techniques about brain
areas and specific neuronal groups involved in sleep.  In
addition, the study of basic sleep mechanisms can provide a
new paradigm for applying an integrated systems/cellular/
molecular/ genetic approach to understanding a complex
behavior. 

Another advance that has positioned the field for progress
is the recognition of rapid eye movement (REM) and nonREM
sleep states and their regulation.  It is now clear that
many features of REM sleep are mediated in the brain by
specific cholinergic neurons in the dorsal tegmentum.  The
activity of these neurons is influenced by noradrenergic and
serotonergic neurons originating in the locus coeruleus and
dorsal raphe, respectively.  

Much also has been learned about specific neural pathways,
various neurochemical receptors, and patterns of electrical
activity within the specific REM-promoting and
REM-inhibiting neurons.  These findings have important
implications for understanding the pathophysiology of sleep
disorders in which REM sleep is disturbed.

Electrophysiological and anatomical studies have provided a
new understanding of the neurophysiological mechanisms
underlying changes in the electroencephalogram (EEG) during
sleep and wakefulness.  For example, delta waves (high-
amplitude, low-frequency EEG waves) define stages 3 and 4
sleep in humans and slow-wave sleep in many mammalian
species.  Delta sleep is relatively abundant in children and
adolescents, but begins to decline as adults age.  It is
increased following sleep deprivation and is reduced in such
clinical disorders as insomnia, Alzheimer's disease,
alcoholism, and psychiatric dysfunction.  Sleep spindles and
delta waves also occur out of phase with each other in
nonREM sleep, reflecting different levels of
hyperpolarization of the thalamocortical membrane.
       
It is also known that the neuronal mechanisms responsible
for cortical EEG patterns reside in diverse brain areas,
including the basal forebrain, the brainstem, the thalamus,
and the hypothalamus.  The role of specific
neurotransmitters, receptors, and ion channels has been
clarified.

As these examples suggest, the groundwork has been
established to achieve rapid advances in understanding the
basic brain mechanisms and functions of sleep.  The field is
ready to move ahead by using multidisciplinary approaches
and integrating the classical methods of systems physiology
and cellular neurobiology with exciting new methods
available in genetics and molecular biology.  The
recommendations that follow are intended to catalyze this
important advance.

Recommendations

1.     Increase efforts to understand the basic mechanisms
       responsible for sleep by applying molecular biological
       approaches in concert with techniques of cellular and
       systems neurobiology.

      Investigate the mechanisms of sleep regulation and
       homeostasis at molecular, cellular, and systems
       levels.

      Develop methods to study cellular and molecular
       mechanisms of sleep regulation in mammalian and
       nonmammalian species and simpler biological systems.

      Take advantage of the naturally occurring changes in
       sleep processes, both early in fetal and postnatal
       life and late in life, to advance understanding of the
       molecular/cellular and neurophysiological mechanisms
       regulating sleep.

Over the last several years the major focus for sleep
research has been to understand the neurophysiological basis
of many of the phenomena that occur during sleep (e.g., slow
waves, muscle atonia).  The fundamental control of sleep has
received much less attention.  Sleep is a homeostatic
process in which increased amounts of sleep occur after
prolonged periods of wakefulness, but how the homeostatic
process is regulated remains a major question.

The prevailing concept is that homeostasis is the result of
an accumulation of sleep-promoting compounds during
wakefulness.  A large number of such compounds have been
identified.  Some seem to affect nonREM sleep; others, REM
sleep.  Knowledge of these compounds is largely confined to
demonstration that their administration increases sleep, but
there is also evidence that administration of antagonists
reduces sleep or the amount of recovery sleep following
sleep deprivation.

Such studies, combined with the results from early sleep
research, provide the impetus for application of molecular
biological approaches to the major unsolved puzzle,
regulation of sleep.  It is important to address how levels
of sleep-promoting compounds are controlled in the sleep-
wake cycle.  Is transcriptional regulation of genes the
control mechanism?  If so, what are the signals that
regulate the genes in relation to the sleep-wake cycle?  As
genes related to the sleep-wake cycle are found, it will be
important to address whether altering their transcription
alters the sleep process.  For example, does sleep
deprivation increase transcription of such genes as IL-
1beta, TNF, or specific prostaglandins?  Where are these
genes regulated (e.g., cell type, location), and what are
the signals that account for transcriptional regulation? 
Understanding this will provide a more fundamental knowledge
of sleep.

Studies complementing this approach are needed to determine
whether experimental alteration of specific genes alters
sleep behavior.  For example, use of  tissue-specific or
gene knockout techniques should be explored to determine if
changes in gene transcription (e.g., IL-1beta knockout or
transgenic animals) affect the sleep-wake state or response
to sleep deprivation.  Studies in behavioral biology have
shown the power of this approach.  For example, deletion of
single genes affects memory and learning and produces highly
aggressive behavior. 
   
This work, of necessity, demands research in species (e.g.,
mice) that facilitate genetic studies, and will involve
recording sleep behavior in large numbers of such animals. 
Current EEG-based techniques to monitor sleep are limiting
in this regard.  New technologies will be needed to simplify
the analysis of sleep-wake cycles in mice and other
mammalian species.

If, as is believed, sleep is a fundamental and essential
biological process, then it should be present in
nonmammalian species also.  Nonmammalian species present
exciting model systems to learn more about the basic control
mechanism of a neurobiological process.  This has been true
for memory (Aplysia), neuronal development (C. elegans), and
circadian rhythm (Drosophila).  

Study of sleep in nonmammalian species is hampered, however,
by difficulty in recognizing and characterizing the state. 
Current definitions of sleep based on the EEG are not
applicable.  A redefinition of the sleep state will
facilitate its identification and investigation in simpler
model systems.  For example, does the rest period in
Drosophila that is coupled to the circadian clock have
features similar to sleep in mammals?  Is there evidence of
altered brain metabolism during the rest period?   New
definitions may be based on rest/activity and recovery rest
following a period of deprivation of the rest period, or on
metabolic changes in the brain.  Development of new
approaches to enable study in nonmammalian species should be
strongly encouraged. 

Developmental and age-related changes in sleep mechanisms
present other significant opportunities for integrating
molecular, cellular, and systems neurobiology approaches. 
In fetal and postneonatal life, large amounts of REM sleep
occur that may be critical for neuronal development.  Late
in life, however, sleep is shallow and fragmented, and older
people have less recovery sleep after sleep deprivation than
younger adults.  Although it is clear that some fundamental
changes take place in the processes regulating sleep across
the life span, the neurobiological basis of these changes is
not known.  Are they age-related changes associated with
neural circuits controlling sleep, or do they occur at a
more fundamental level, such as in the transcription of
critical genes?  Study of naturally occurring age-related
changes in sleep processes may uncover fundamental
discoveries about sleep mechanisms.

Improved understanding of sleep-regulating processes at the
cellular and molecular levels promises to open a new world
of scientific endeavor.  For example, current knowledge of
most compounds used to promote both sleep and wakefulness is
empirical.  Although much is already known of how sleeping
pills and stimulants work at a cellular and molecular level,
further clarification of the basic mechanisms of sleep and
wakefulness may lead to new therapies, not only for
ameliorating sleep disorders, but also for optimizing
function during wakefulness.

2.     Conduct basic studies to understand the brain
       mechanisms responsible for sleepiness.

      Understand at the molecular/cellular level the changes
       that take place in the brain when it is deprived of
       sleep.

      Address the effects of sleepiness on different brain
       regions and on the tasks they perform.

      Conduct basic studies to determine whether different
       causes of sleepiness (e.g., sleep deprivation,
       circadian factors, central nervous system pathology,
       drugs) impair performance by similar or different
       mechanisms.

Although daytime sleepiness has been identified as a major
public health problem and an important symptom of many sleep
disorders, its basic neural mechanisms are still unknown. 
One fundamental question is whether the brain mechanisms in
acute or chronic sleep deprivation in normal individuals are
similar to those in patients with sleep disorders (e.g.,
sleep apnea).

Most recent research on sleepiness and its behavioral
consequences has been performed in humans.  To address
current questions, it is necessary to move from descriptive
studies in humans to mechanistic studies in the brain.  Why
do many people feel sleepy in mid-afternoon?  What happens
in the brain to make people fall asleep while driving,
despite the obvious importance of staying awake behind the
wheel?  Answering these questions requires an understanding
of the neurobiology of wakefulness, including the
possibility that some molecules are likely to accumulate or
decrease in the brain during wakefulness.  It is important
to determine how these molecules are temporally regulated
and what neuronal populations have a degraded performance as
a result.  Again, a combined systems/cellular/molecular
approach, using the whole range of modern neurobiological
techniques, offers important potential.

Sleepiness, even in the absence of falling asleep, degrades
performance in some brain areas and functions, but not in
others.  For example, the ability to perform complicated
movements is less likely to be impaired than is the ability
to learn or pay attention.  Sleepiness particularly affects
higher level processing and, hence, cognition, foresight,
and situational awareness.  The mechanism for this
differential behavioral effect is unknown.

Because sleep deprivation affects some functions more than
others, understanding this differential effect may provide
an important clue to the basic mechanisms of sleep. 
Achieving this understanding will require a combination of
approaches, such as functional brain imaging, cognitive
neuroscience, behavioral biology, multi-unit recording,
neurochemical assays, and molecular biological techniques. 
Because of the apparent impact of sleepiness on higher
functions, basic studies of sleepiness should include humans
as well as animals.

The common assumption that all situations leading to
sleepiness (e.g., acute total sleep deprivation, chronic
partial sleep loss, sleep fragmentation, drugs, and such
sleep disorders as sleep apnea and narcolepsy) do so by
common mechanisms is unproven and may be unwarranted.  For
example, an adaptive process may limit the impact of
sleepiness in individuals who are chronically sleep-
deprived.  Addressing such issues at a basic level will
complement the applied studies recommended in another
section of this report.

3.     Study basic mechanisms underlying the interaction
       between the circadian and neurophysiological systems
       that regulate sleep and wakefulness.

      Investigate interactions between the sleep and
       circadian systems at every level (e.g.,
       neuroanatomical, neurophysiological, neuropharmaco-
       logical, behavioral, and gene regulation).

      Take advantage of animal species that have different
       interactions between the sleep and circadian systems
       (e.g., nocturnal and diurnal animals) to elucidate the
       nature of this interaction.
   
Both homeostatic and circadian factors are known to
contribute to regulation of sleep and wakefulness throughout
the 24-hour day.  Although the propensity to sleep increases
with duration of wakefulness, the timing, duration, and
characteristics of sleep are strongly affected by the
circadian pacemaker.  The pacemaker also probably modulates
levels of alertness and performance throughout wakefulness
(e.g., the normal increase in sleepiness experienced by
humans in mid-afternoon).  Exciting opportunities now exist
to understand the interaction between biological clocks and
sleep-wake behaviors.
  
The circadian pacemaker lies in the suprachiasmatic nucleus
in the anterior hypothalamus.  Lesions of the
suprachiasmatic nucleus abolish the circadian sleep-wake
cycle in animals.  Nevertheless, the basic mechanisms by
which the suprachiasmatic nucleus interacts with and is
regulated by the sleep-wake system and affects states of
consciousness are unclear. 

Conversely, sleep and wakefulness also can affect the
circadian pacemaker.  For example, exercise can reset the
phase position of the biological clock.  The mechanisms by
which sleep, wakefulness, and behavior affect the circadian
pacemaker are unknown, although it is clear that these
systems interact in a complex fashion.  Theories (e.g., dual
process or opponent process model) to describe the nature of
the interaction have been proposed, based on behavioral
studies conducted in humans and animals, but little, if any,
research has been done on the  neurobiological basis of the
interaction.  Neurobiological mechanisms that may mediate
the interaction include direct projections from the
suprachiasmatic nucleus, neuroendocrine profiles or humoral
mechanisms under the influence of the circadian pacemaker,
and circadian regulation of expression of genes involved in
sleep control.  

Differences in the nature of the interaction between sleep
mechanisms and circadian systems in different species may
also provide important information.  For example, lesions of
the suprachiasmatic nucleus increase total sleep time in
monkeys, but not in rats.  Some species have highly
consolidated sleep bouts while others have multiple shorter
bouts.  In addition, some animals sleep by day, some sleep
by night, and others are awake at dawn and dusk.
Understanding the basis of this interaction may lead to new
approaches to change the timing and quality of sleep and,
thus, provide solutions to such problems as jet lag, shift
work, and circadian derangements in the timing of sleep.

4.     Characterize the genetic factors controlling the basic
       mechanisms of sleep.

      Encourage studies using genetic approaches (e.g.,
       family and twin studies, inbred strains) to identify
       genes involved in the control of sleep.

      Encourage studies to identify and study animals with
       specific mutations that cause abnormalities in sleep.

      Encourage molecular epidemiological approaches to
       study differences in sleep patterns.

Although genetic factors are believed to play a role in
sleep, relatively little is known about their contribution. 
Early attempts to characterize the inheritance of sleep
patterns in inbred mice revealed qualitative and
quantitative differences in amount of sleep and its daily
distribution.  Moreover, crossbreeding demonstrated that
some traits, such as the amount of REM sleep and the diurnal
ratio of sleep to wakefulness, are heritable. 

Twin studies in humans have suggested that sleep duration
and nonREM sleep measures (stages 2-4) are under genetic
influence.  One study in normal volunteers found that REM
latency (the time from the onset of sleep until the first
REM period) was shorter in normal controls who were positive
for the HLA-DR2 antigen than in those who were negative,
suggesting a genetic contribution to the onset of REM sleep.
Other encouraging data suggest that certain features of
sleep are highly correlated in monozygous twins.

Genetic factors also have been implicated in several sleep
disorders, including narcolepsy, restless legs syndrome
(RLS), some forms of insomnia and parasomnias, and sleep
apnea.  A point mutation at codon 178 and a polymorphism on
codon 129 on the prion gene on chromosome 20 appears to
account for fatal familial insomnia, a rare disorder in
which patients suffer from a progressive reduction in total
sleep time, abnormalities in autonomic function, and loss of
neurons and astrogliosis in specific nuclei of the thalamus.
These observations suggest that sleep as a behavior can now
be characterized in intricate detail; it is less affected by
confounding factors than are some other behaviors.   Such
studies could use linkage analysis in families to identify
genes involved in control of specific aspects of sleep. 
Molecular epidemiology techniques provide another powerful
approach.  Developing new technologies to measure sleep
characteristics in large numbers of individuals in different
families may considerably speed the process.  Studies in
humans could be complemented by studies in inbred strains of
rodents, in which confounding factors may be minimized by
controlled breeding.
 
Animals with specific mutations also present an opportunity
to try new approaches.  Mutations affecting the period of
circadian systems were initially found in Drosophila,
leading to major new discoveries regarding the molecular
mechanisms of the biological clock.  Mutations have been
associated with altered clock periods (Tau mutant) in
hamsters and with short circadian periods (clock mutant) in
mice.  The latter offers particular opportunities to
understand the molecular basis of the circadian clock in
mammals.

Identifying mutants with sleep abnormalities is more
difficult than identifying circadian mutants.  New methods
are needed to screen for genetic mutants that affect sleep
and wakefulness.
 
One specific sleep disorder, narcolepsy, is found in dogs
and is inherited as an autosomal recessive trait.  Limited
knowledge of the dog genome has impeded analysis to identify
the gene involved.  Because the mouse genome is well
characterized, a mouse model with narcolepsy may facilitate
rapid identification of the gene.

A better understanding of sleep, at both the behavioral and
genetic levels, and the of pathogenesis of common sleep
disorders is expected to facilitate development of new
therapeutic and preventive approaches.
 
5.     Increase research efforts to elucidate the fundamental
       functions of sleep.

One of the major barriers to understanding and investigating
sleep is that the functions of this state are unknown.  Why
people sleep remains one of the major unanswered questions
of modern biology.  Various hypotheses that relate sleep to
metabolic, immune, endocrine and brain functions (e.g.,
restoration of neuronal energy stores, memory enhancement
during sleep) have been proposed to answer this question. 
Each of these theories has some evidence to support it, but
none has, to date, been a major focus of investigation.  For
example, is adenosine regulated in relation to the sleep-
wake state or increased by prior sleep deprivation? What
metabolic pathways cause changes in adenosine levels? 
Attempts to develop and investigate comprehensive hypotheses
about the function of sleep should be encouraged.


Patient-Oriented Research Recommendations

The societal impact, scientific knowledge, and current
levels of research vary widely among the more than 70
identified sleep disorders.  Recommendations detailed in
this section, recognizing that understanding of specific
sleep disorders is currently at different stages of
development, address the greatest needs and best
opportunities for progress in patient-oriented research.

Although some disorders are well defined, with objective
criteria available and prevalence established, others are in
the early descriptive stages and have no rigorous research
definition.  To facilitate rapid progress, the
recommendations focus principally on disorders that are
better defined at this time.    

Recommendations

1.     Identify the genetic basis of sleep disorders that
       have a genetic component.

      Determine the genetic basis of narcolepsy in humans. 
       Studies are needed on families in which multiple
       members have narcolepsy and on pairs of twins among
       whom one member is narcoleptic.

      Determine the genetic basis of RLS and other disorders
       that have a genetic component.  As with narcolepsy,
       studies on families and twins are needed.

With knowledge about the human genome growing every day,
rapid identification of genetic components in a number of
sleep disorders is now feasible.  Scientists now have
particularly exciting opportunities to identify the basis of
genetic influence for narcolepsy and, possibly, RLS.  In
addition, understanding the genetic basis of these disorders
may provide important new knowledge about sleep itself.

Considerable evidence suggests that narcolepsy has a genetic
component.  For example, a canine narcolepsy model with an
autosomal recessive inheritance pattern has been described. 
In addition, human narcolepsy shows a very strong linkage
with HLA antigen DR-2.  Families in whom multiple members
have narcolepsy are well described.  A first-degree relative
of a narcoleptic is known to have about one percent risk of
developing the disease: this represents a relative risk 20
to 40 times that of the general population.  However, only
10 to 20 percent of monozygotic twins are concordant for
narcolepsy, which indicates that other factors are necessary
for the disease to be expressed.

Based on family studies, RLS also seems to have a genetic
component.  Inspection of a number of identified pedigrees
suggests that RLS is inherited as an autosomal dominant
trait, but that full expression of the disease may not occur
until later in life.

In narcolepsy, sleep control may be relatively well
understood, because control of REM sleep is so abnormal in
this disease.  In RLS, which is characterized by periodic
leg movements, studies may reveal more information about
involuntary motor control. 

Advances in the genetics of sleep disorders offer many
potential benefits, including reliable diagnostic tests;
ability, if deemed appropriate, to screen for carriers; and
opportunities for gene therapy.
  
2.     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.

      Using subjective and objective criteria and careful
       differential diagnosis, identify the prevalence of the
       chronic insomnias; identify risk factors for and
       determine consequences of different subtypes.

      Identify the prevalence of risk factors (including the
       role of ethnicity) for obstructive sleep apnea in
       children and its consequences.

Insomnia is more clearly a set of complaints than a specific
disease.  Careful differential diagnosis, identification of
comorbid diagnoses, and establishment of primary and
secondary diagnoses are needed.  Many underlying causes,
which are usually age-dependent, appear to exist, but
depression seems to be an important cause at any age.                   

Current prevalence estimates are based on self-report. 
Epidemiological studies using objective measures are needed
to determine the overall scope of the problem and the
underlying patterns of sleep difficulty (e.g., difficulty
initiating sleep, early morning awakening).  These data will
provide an important foundation for assessing the
consequences of insomnia and treatment outcomes.

The prevalence of obstructive sleep apnea in middle-aged and
elderly populations has been relatively well characterized. 
The scope of the problem in children is unknown, however. 
It is clear that the nature of sleep disturbances resulting
from sleep-disordered respiration is different in children
than in adults, as are risk factors for the disease.  Among
children, the major risk factor is likely to be
tonsillar/adenoidal enlargement.  Sleep apnea appears to be
more common among black young adults, and probably also
among black children, although this has not been proven.  

Obstructive sleep apnea may have unique consequences in
children.  For example, it is likely that the sleepiness
caused by sleep apnea impairs school performance and
learning.  Current treatment strategies also are different
for children than for adults, but efficacy has not been
established.



3.     Conduct outcomes research and clinical trials on the
       management of common sleep disorders.

      Conduct defined clinical trials to assess the relative
       efficacy and effectiveness of different treatment
       modalities for insomnia. 

      Conduct clinical trials to assess the efficacy and
       effectiveness of different treatment modalities for
       sleep apnea.  

Little is known about the long-term outcomes of behavioral
treatments and pharmacotherapy for various subtypes of
insomnia.  Optimal treatment is likely to be different for
patients with varying severities of sleep apnea.  Clinical
trials focusing on this variable are needed.

4.     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.

      Develop more cost-effective approaches (including in-
       home techniques) for diagnosis of obstructive sleep
       apnea.

      Develop ambulatory approaches (including those that
       can be delivered in non-laboratory settings) to assess
       the extent/level of sleepiness caused by sleep             
       disorders.

      Develop approaches for in-home assessment of sleep
       disturbances and therapeutic effectiveness.  Systems
       that communicate information to the physician about
       the use of treatments such as CPAP and intra-oral
       devices, sleep patterns of those with insomnia, and
       degree of movements during sleep would have important
       clinical value.

Currently, diagnosis of many sleep disorders and assessment
of the magnitude of sleepiness is usually done using in-
laboratory techniques, which can be expensive and
inconvenient.  New approaches using in-home studies are
beginning to be used for some disorders.  Other technologies
that are accurate and cost-effective should be developed and
used.  In addition, clinical decisionmaking concepts should
to be applied to facilitate their optimal use. 

The availability of inexpensive, reliable, ambulatory
monitoring devices to study sleep-wake patterns may
contribute to identification and treatment of millions of
Americans with undiagnosed sleep disorders.  By enabling
employers to identify and treat employees with undiagnosed
sleep disorders cost-effectively, they may reduce the danger
and cost of catastrophic accidents.  Improvements in
treatment are also likely, because physicians will have
objective tools to assess treatment effectiveness and make
clinical decisions.  Finally, new technological approaches
will facilitate extension of earlier epidemiological studies
that suggested that insomnia and hypersomnia are risk
factors for mortality and morbidity in several conditions,
including mood disorders.

5.     Elucidate the pathogenesis/pathophysiology of sleep
       disorders and their consequences.
   
      Investigate why obesity leads to sleep apnea and
       whether the presence of apnea exaggerates obesity.

      Elucidate the association between psychiatric
       disorders and insomnia (i.e., determine why patients
       with insomnia are more likely to develop a major
       depressive illness). 

      Understand how sleep affects movement control and
       neurological function, thus rendering movement
       disorders of various types more common during sleep.

The major risk factor for obstructive sleep apnea in middle
age is obesity; although the problem has been less
extensively studied in women, in the general population of
men the best predictor of sleep apnea is increased collar
size.  The mechanism by which obesity produces apnea is,
however, unknown.  It has been suggested that the
peripharyngeal fat pads compress the upper airway in obese
individuals, but certain data are incompatible with this
hypothesis.  

Some evidence in genetic models of rats suggests that
appetite control, control of weight, and ventilatory control
are interrelated.  Other studies have indicated that sleep
apnea disturbs endocrine function and leads to insulin
resistance.  Thus, obesity may be exaggerated by the
presence of apnea, creating a vicious circle.  This area
offers new possibilities for studying the relationship
between obesity and sleep disorders. 

Depression is one of the most common factors associated with
insomnia.  Over the last 2 decades, sleep patterns in
depressed individuals have been examined with varying
results.  More information is needed to determine the brain
mechanisms that link depression and sleep disturbance and to
identify the biological basis for the effect of sleep
deprivation on mood.  In addition, understanding the sleep
mechanisms associated with mania may be informative, because
affected patients go for long periods with little sleep and
little sleepiness.  Elucidating the basis for these
associations may increase understanding of insomnia and
provide fundamental knowledge about brain behavior.

Pathophysiological studies of movement disorders of sleep
constitute another potentially fruitful area of inquiry. 
Periodic leg movements are more common in sleep than in
wakefulness and increase as a function of age.  What is
unique about the sleep state that permits these movements to
occur?  Is the age-related change indicative of progressive
neurodegeneration in critical pathways and, if so, where
does it occur?  Are there other explanations?  Other
movement disorders (e.g., REM behavior disorder) exist that
occur only in sleep, but the pathogenetic mechanisms are
completely unknown.  Studies of these phenomena during sleep
may provide fundamental knowledge about sleep disorders
themselves and about movement control.

6.     Provide the research infrastructure needed to carry
       out patient-oriented research. 

      Establish a Sleep Clinical Research Network to
       facilitate patient-oriented research in sleep
       disorders. 

      Establish registries with emphasis on families/twins
       for disorders to facilitate genetic research. 

      Create cell-line banks for disorders to facilitate
       genetic and other studies.

      Develop a more rigorous set of definitions for sleep
       disorders, with criteria that facilitate research. 
   
Cost-effective infrastructures, such as the General Clinical
Research Centers, should be developed to facilitate research
on sleep and sleep disorders.  Moreover, a research nosology
of sleep disorders should be developed, including
definitions of the criteria to be used for clinical research
studies.
Applied Research Recommendations

Sleepiness is a problem for otherwise healthy persons, as
well as for those suffering from a wide spectrum of sleep
disorders and conditions affecting sleep-wake functions.  It
is known that sleepiness affects millions of Americans and
has major negative consequences for safety, productivity,
and well-being.  Applied research in this context is defined
as research on sleepiness and its consequences apart from
any sleep pathology.  In general, it involves research on
people who are sleep-deprived because of their lifestyles.

In addition to promoting a better understanding of the
nature and extent of this public health problem in society,
the recommendations in this section focus on the human
performance issues that sleepiness raises.  To achieve the
critical goal of improving safety and productivity, research
must determine how and why sleep loss creates impairment,
how to measure sleepiness and alertness objectively, and how
to prevent and manage the condition most effectively. 
Current knowledge about the nature of performance deficits
provides an important point of departure for further
progress.  The challenge now is to evaluate sleepiness and
its countermeasures systematically, while developing new
technologies with practical application at home and on the
job.

Recommendations

1.     Conduct epidemiological research to define the
       prevalence, etiology, risk factors, morbidity, and
       costs of sleepiness in the general population.

      Identify the distribution of sleepiness in the general
       population, using multiple criteria for sleepiness,
       including standardized questionnaires and objective
       measures. 

      Identify the relative prevalence among sleepy
       individuals of different etiologies of sleepiness.

      Identify the consequences of sleepiness in various at-
       risk populations.

Currently available prevalence rates of daytime sleepiness
are quite variable and use nonstandardized assessment tools. 
The distribution of sleepiness in the general population
should be definitively determined using standardized
measures of sleepiness.  At least two validated sleepiness
questionnaires are available for use in such studies, as
well as mood scales that include a sleepiness/alertness
dimension.
  
Studies identifying specific populations at increased risk
of daytime sleepiness also are needed.  Among the
populations that warrant investigation are young adults,
high school students, shift workers, working parents,
transportation workers, medical students, residents, nurses,
and individuals who snore.

In addition, the morbidity associated with daytime
sleepiness should be evaluated using a variety of
methodologies.  Needed are large-scale, cross-sectional
studies evaluating the relationship between sleepiness and
motor vehicle accidents and longitudinal studies of specific
subpopulations using selected outcome measures.  For
example, it is important to examine the relationships
between levels of sleepiness and school grades in students
or productivity in shift workers.  Where data are available
(e.g., the transportation industry and industries that have
shift work and extended work schedules), the dollar costs of
sleepiness should be assessed.  Factors affecting costs
include decreased productivity, increased error rates, and
increased accident rates. 

Finally, laboratory studies are needed to define the
etiology of daytime sleepiness.  Each of the various at-risk
groups should be studied, because the cause of sleepiness
(e.g., sleep loss, sleep fragmentation, circadian
disturbances) is likely to be different for different
groups.  New methodologies must be developed that can
identify subjects who have a chronic sleep debt.
   
This information is critical to the development of programs
to combat sleepiness.  An understanding of the scope of the
problem will enable decision makers to estimate accurately
the resources required to address it.  With detailed
information on the populations at risk, planners will be
able to identify educational and other interventions to
solve specific problems.

2.     Define the decrement and recovery processes associated
       with chronic partial sleep deprivation.

      Determine how the severity of sleepiness relates to
       varying rates of accumulated sleep loss.

      Identify the biological and behavioral adaptive
       processes modulating the consequences of chronic
       partial sleep loss.

      Determine the aspects of human performance that are
       influenced by chronic partial sleep loss and the level
       of sleepiness that is associated with impairment of
       various functions.

      Elucidate the nature of recovery of alertness
       associated with different sleep schedules.
   
Decrements in alertness and performance are the primary and
most profound effects of sleep loss.  Studies have shown
that a reduction of only 2 hours of sleep in a single night
produces measurable impairments in alertness.  However, the
level of risk associated with sleep loss for different
lengths of time is still undefined.

The nature of impairment due to chronic sleep loss also must
be evaluated systematically.  Recent data suggest that
cognitive performance, including functions such as foresight
and situational awareness, is most affected by sleep loss. 
Long, monotonous performance tasks are associated with
micro-sleeps, but these micro-sleeps do not account for all
the performance decrements. 

Brain imaging studies have shown that region-specific
reductions in metabolic activities occur during sleep
deprivation.  However, the physiological basis of
alertness/performance decrements during sleep loss are
unknown.  More information is needed on the effects of
chronic partial sleep loss on a broad range of behavioral
measures, as well as on different assays of brain functions.

Recent studies have begun to evaluate the rate of
performance recovery following acute total sleep
deprivation.  Results suggest that the recovery process does
not require an hour of recovery for each hour of lost sleep. 
Many investigators have hypothesized that the recovery value
of sleep is related to the depth of sleep.  However,
recovery studies have not generally supported this view. 
Studies parametrically defining the recovery of performance
following different schedules of recovery sleep are needed
to resolve this issue.

Identifying the degree and the nature of sleepiness
associated with different amounts and rates of sleep loss
may lead to countermeasures that increase productivity and
safety in a variety of work settings.  With this
information, for example, employers may be able to design
work schedules to minimize dangerous levels of sleepiness. 
The new data also will permit identification of sleepiness
levels at which countermeasures should be applied. 

3.     Develop efficient, objective measures of daytime
       sleepiness.

      Develop physiological, biochemical, and behavioral
       assays of sleepiness.

      Evaluate assays of sleepiness in an occupational
       setting to determine their predictive value for
       alertness testing.

      Develop methods to monitor levels of alertness
       continuously over extended periods of time.
   
Assessments of sleepiness have been performed using measures
that vary in reliability, sensitivity, and difficulty of
administration.  Of the various self-report, performance,
and physiological parameters, the multiple sleep latency
test (MSLT) has proven to be the most reliable and the most
sensitive to various causes of sleepiness, including sleep
loss, sleep fragmentation, sleep disorders, circadian
variations, and drugs.  The Maintenance of Wakefulness Test
(MWT), which assesses the ability to remain awake while
sedentary, is a measure of the capacity to override
sleepiness.  However, both the MSLT and the MWT require a
specialized facility and many hours to administer.  Research
to develop behavioral, physiological, and biochemical assays
of sleepiness is needed.  Such assays should be able to
measure sleepiness at a single point in time and be
sensitive to the various causes of sleepiness.

To date, assays of sleepiness have been evaluated primarily
for sensitivity.  However, another potentially important
characteristic of a sleepiness measure is its predictive
value.  For example, the productivity and safety of workers
in a variety of occupational settings may depend on the
ability to predict their potential to maintain alertness. 
Studies are needed to evaluate various measures of
sleepiness for their predictive value in fitness-for-duty
testing and to translate and validate laboratory measures of
sleepiness for use in practical workplace tests.

The ability to maintain optimal performance depends on the
duration of the work shift as well as the context in which
the work is being carried out.  Thus, development of
monitors that can continuously evaluate level of alertness
is important for enhancing workplace productivity and
safety.

Sleepiness is commonplace in our society, and its chronicity
may compromise an individual's ability to perceive levels of
sleepiness accurately.  When people do not recognize how
sleepy they are, they may put themselves and others at risk. 
Development of technologies to detect and monitor sleepiness
objectively has the potential to overcome this problem and
provide solutions.

4.     Evaluate the utility of interventions to prevent and
       manage sleepiness, with the goal of improving
       productivity and safety.

      Evaluate the effectiveness of caffeine and
       prescription drugs in counteracting the effects of
       sleep loss.  Evaluate the effectiveness of
       nonpharmacological approaches (e.g., good sleep
       hygiene) to prevent and manage sleepiness.  Develop
       different sleep-wake schedules, including the
       distribution of short-sleep periods and shifting core
       body temperature cycles, and evaluate their utility
       for inhibiting the onset of sleepiness and providing
       temporary relief from sleepiness.

      Develop new pharmacological agents to increase
       alertness, using developing knowledge of the
       neuropharmacology of the sleep-wake system.  

      Develop countermeasures for specific causes of
       sleepiness, including methods to alter the output of
       the circadian clock to optimize sleep and wakefulness.

Effective management of sleepiness in normal individuals
ultimately will depend on understanding the basic mechanisms
of sleep and drowsiness and the mechanisms by which these
states affect the ability to function effectively.  This
understanding will come from studies conducted as part of
the basic sciences component of the Plan.  In the interim,
studies should be conducted to evaluate the effectiveness of
interventions used to prevent and alleviate sleepiness. 
Currently, the two most commonly used interventions to
offset sleepiness are naps and pharmacological agents.

Although napping is often used as a countermeasure for
sleepiness, its effectiveness has not been evaluated
systematically.  In particular, the timing and duration of
naps in relation to the degree of sleepiness experienced
require study.  Systematic investigation of various work
schedules and their impact on the quality and quantity of
sleep and working performance may have important practical
relevance for the workplace.

Caffeine is commonly used to combat sleepiness, but studies
of its utility in both normal and chronically sleepy persons
are needed.  Data on normal volunteers undergoing sleep
deprivation may provide information about use of caffeine as
a prophylactic measure, and data on chronically sleepy
individuals may enlighten scientists about its effectiveness
as a countermeasure for sleepiness.  In conducting such
studies, it is important to define efficiency (e.g., dose-
response curve), duration of effectiveness, and populations
in which caffeine is effective.  

In certain situations (e.g., the military), use of
prescription agents to counteract sleepiness is necessary. 
However, the safety and efficiency of various stimulants
remain to be established in clinical trials.  Trials are
also needed to evaluate the safety and efficacy of new
agents (e.g., melatonin and adenosine antagonists). 

Research on shift work has focused on developing schedules
to minimize the negative effects of shift changes on sleep
and waking functions.  More recently, melatonin and bright
lights have been shown to adjust the timing of sleep and
wake function systematically.  Clinical trials of light and
melatonin, alone and in combination, are warranted in shift
workers.

The ability to prevent and manage sleepiness for defined
periods of time is critical to safety, and many employers
recognize the importance of this issue.  Although some
research is being done in a variety of occupational settings
to monitor levels of sleepiness, there is a need to develop
new ideas and techniques and to evaluate their potential in
field trials.    

 Research Training Recommendations

Accomplishing the vision of the Plan requires adequate
numbers of sleep researchers and investigators with
multidisciplinary skills.  One approach is to attract
established researchers with expertise in allied disciplines
into the sleep field.  At the same time, it is important to
develop a new cadre of sleep investigators, not only to
nurture existing strengths, but also to pursue new and
critical research directions identified in the Plan.  At
present, the number of sleep researchers is small, and only
a few investigators are studying the molecular biology of
sleep and the genetic basis and epidemiology of sleep
disorders.  Thus, multidisciplinary research training is
necessary in both basic and patient-oriented research. 
Trainees require breadth, as well as depth, to develop the
perspective that is essential to a successful research
career.

1.     Enhance the number of trained investigators and
       trainees in biological and behavioral research related
       to basic sleep mechanisms and patient-oriented
       research. 

      Nurture ongoing training efforts in sleep research,
       which are small in number, and primarily focus on
       training in systems neuroscience and behavioral
       approaches.

      Train new investigators to employ cellular, molecular
       biological, and genetic approaches and modern methods
       of patient-oriented research. 
       
Systems neuroscience, particularly the neurophysiological
aspect, is a strong component of current sleep research. 
However, the number of investigators in this field is small
in comparison to the size of the task.  Thus, continuing to
train investigators in this approach to the study of sleep
is an important need.

Existing programs are inadequate to train the cadre of
individuals needed to implement the recommendations in the
research plan.  Innovative collaborative training
mechanisms, with interactive training provided by
investigators from different disciplines with complementary
skills, are needed.  Training investigators in patient-
oriented research is critical because many of the clinical
and applied research recommendations in the Plan cannot be
carried out without them.

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