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.
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.
the Plan Was Developed
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.
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.
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
Vision of the Research Plan
improve the health, safety, and productivity of Americans by promoting basic,
clinical, and applied research on sleep and sleep disorders.
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
- 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.
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.
Back to Contents
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
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.
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.
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.
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
- 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.
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.
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
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
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
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.
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).
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
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.
- 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
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
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
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.
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.
- 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, neuropharmacological, 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.
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.
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.
- 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
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.
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.
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.
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.
better understanding of sleep, at both the behavioral and genetic levels, and
of the pathogenesis of common sleep disorders is expected to facilitate
development of new therapeutic and preventive approaches.
- Increase research efforts to elucidate the
fundamental functions of sleep.
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.
Back to Contents
|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
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.
- 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.
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
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
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.
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
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.
- 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
- Identify the prevalence of risk factors
(including the role of ethnicity) for obstructive sleep apnea in children and
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.
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.
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.
- 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
- Conduct clinical trials to assess the
efficacy and effectiveness of different treatment modalities for sleep
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.
- 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 be applied to facilitate their optimal
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.
- 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.
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.
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
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
- 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
Back to Contents
|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
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.
- 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.
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.
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.
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.
- 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.
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
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
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
- Develop efficient, objective measures of
- 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.
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.
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.
- Evaluate the utility of interventions to
prevent and manage sleepiness, with the goal of improving productivity and
- 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
- 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.
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
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.
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.
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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.
- 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
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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Ackermann, P. and Borbely, A.A. Simulation of
daytime vigilance by the additive interaction of a homeostatic and circadian
process. Biological Cybernetics 71:115-121, 1994.
R.M., Obermeyer, W.H., Thisted, R.A., and Gillin, J.C. Sleep and psychiatric
disorders: A meta-analysis. Arch. Gen. Psychiatry 49:651-668, 1992.
Benington, J.H. and Heller, H.C. Restoration of brain
energy metabolism as the function of sleep. Prog. Neurobiol. 45:347-360, 1995.
Buchsbaum, M.S., Gillin, J.C., Wu, J., Haslett, E.,
Sicotte, N., Dupont, R., and Bunney, W.E., Jr. Regional cerebral glucose
metabolic rate in human sleep assessed by positron emission tomography. Life
Sci. 45:1349-1356, 1989.
Cravatt, B.F., Prospero-Garcia, O., Siuzdak, G.,
Gilula, N.B., Henriksen, S.J., Boger, D.L., and Lerner, R.A. Chemical
characterization of a family of brain lipids that induce sleep. Science
D.-J. and Czeisler, C.A. Contribution of the circadian pacemaker and the sleep
homeostat to sleep propensity, sleep structure, electroencephalographic slow
waves, and sleep spindle activity in humans. J. Neurosci. 15:3526-3538, 1995.
D.M., Dement, W.C., and Fuller, C.A. Effect of SCN lesions on sleep in the
squirrel monkey: Evidence for opponent processes in sleep-wake regulation. J.
Neurosci. 13:1065-1079, 1993.
R. Sleep disorders in childhood. In: Sleep Disorders Medicine. (Ed) S.
Chokroverty. Butterworth- Heinemann, pp 417-428, 1994.
D.J., Monjan, A., Brown, S., Simonsick, E., Wallace, R., and Blazer, D., Sleep
complaints among elderly persons: An epidemiologic study of three communities.
Sleep 18:425-432, 1995.
D.E. and Kamerow, D.B. Epidemiologic study of sleep disturbance and psychiatric
disorders: An opportunity for prevention? JAMA 262:1479-1484, 1989.
Guilleminault, C., Lugaresi, E., Montagna, P.,
Gambetti, P. Fatal familial insomnia. Raven Press, 1994.
Krueger, J.M. and Karnowsky, M.L. Sleep as a
neuroimmune phenomenon: A brief historical perspective. Advances in
Neuroimmunology 5:5-12, 1995.
M.H., Roth, T., and Dement, W.C. (Eds). Principles and Practice of Sleep
Medicine. Philadelphia: W.B. Saunders Company, 1994.
Matsumura, H., Nakajima, T., Osaka, T., Satoh, S., et
al. Prostaglandin D-2 sensitive, sleep promoting zone defined in the ventral
surface of the rostral forebrain. Proc. Nat. Acad. Sci. 91:1998-2002, 1994.
E., Wang, C., Rattazzi, C., Gaiser, C., Lovett, M., Guilleminault, C., Dement,
W.C., and Grumet, F.C. Genetic linkage of autosomal recessive canine narcolepsy
with a µ immunoglobulin heavy-chain switch-like segment. Proc. Nat. Acad.
Sci. USA 88:3475-3478, 1991.
M., Wagner-Smith, K., Wesley, C., Youngm M., and Sehgal, A. Positional cloning
and sequence analysis of the Drosophila clock gene, timeless. Science
Rechtschaffen, A., Bergmann, B.M., and Everson, C.A.
Sleep deprivation in the rat, X: Integration and discussion of the findings.
Sleep 12:68-87, 1989.
T., Beare, D., Zorick, F. and Roth, T. Sleepiness and ethanol effects on
simulated driving. Alcohol Clin Exp Res 18(1):154-158, 1994.
T., Roehrs, T.A., Vogel, G.W., and Dement, W.C. Evaluation of hypnotic
medications. In: Sleep Disorder in Anxiety and Depression. Vol. 28 (eds) R.
Maou, C. Shapiro. Elsevier Sci Ltd. pp 1-3, 1994.
A., Rothenfluh-Hilfiker, A., Hunter-Ensor, M., Chen, Y., Myers, M., and Young,
M. Rhythmic expression of timeless: A basis for promoting circadian cycles in
period gene autoregulation. Science 270:808-810, 1995.
Shiromani, P.J., Malik, M., Winston, S., and McCarley,
R.W. Time course of fos-like immunoreactivity associated with cholinergically
induced REM sleep. J. Neurosci. 15:3500- 3508, 1995.
Saunders, N.A., and Sullivan, C.E. Sleep and breathing.
In: Lung Biology in Health and Disease. Vol 71., (exec ed) Claude Lenfant.
Marcel Dekker, Inc. 1994.
Steriade, M., Contreras, D., and Amzica, F.
Synchronized sleep oscillations and their paroxysmal developments. Trends
Neurosci. 17:199-208, 1994.
Walters, A.S., Picchietti, D.L., Ehrenberg, B.L., and
Wagner, M.L. Restless legs syndrome in childhood and adolescence. Pediatr
Neurol. 11:241-245, 1994.
M.A. and McNaughton, B.L. Reactivation of hippocampal ensemble memories during
sleep. Science 265(5172):676-679, 1994.
J.C., Gillin, J.C., Buchsbaum, M.S., Hershey, T., Johnson, J.C. and Bunney,
W.E., Jr. Effect of sleep deprivation on brain metabolism of depressed
patients. Am. J. Psych. 149:538-543, 1992.
J., Sampogna, S., Lopez-Rodriguez, F., Luppi, P.H., Morales, F.R., and Chase,
M.H. Fos and serotonin immunoreactivity in the raphe nuclei of the cat during
carbachol-induced active sleep: A double-labeling study. Neuroscience
T., Palta, M., Dempsey, J., Skatrud, J., Weber, S., and Badr, S. The occurrence
of sleep disordered breathing among middle-aged adults. N. Engl. J. Med.
Vitaterna, M., King, D., Chang, A. , Kornhauser, J.,
Lowrey, P., McDonald, J., Dove, W., Pinto, L., Turek, F., and Takahashi, J.
Mutagenesis and mapping of a mouse gene, clock, essential for circadian
behavior. Science 264:719-725, 1994.
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