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IN NEUROSCIENCE
SLEEP & DREAMS
Insomnia, Narcolepsy
Freud, Memories, Nightmares
Genetics, Medication, REM
Drowsy Society, Sleep Market
Funding Crisis
390
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424 Obstructive sleep apnea
408
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Image Credits Rosalind Cartwright
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488 Ask not what the brain can do for sleep
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p. 486: © Image Source/Corbis Atul Malhotra and Shilpa Rahangdale
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THEME
SLEEP AND DREAMS
Title article
DREAMING
ABOUT SLEEP
By Robert Stickgold
O
ver the last decade, the and feeding behavior, and the application of
field of sleep research new analytical tools, ranging from fMRI to
has undergone remark- large-scale computer models, to the descrip-
able growth. Nowhere tion of sleep.
have I seen this more This is an issue worth reading twice, once
delightfully appar- quickly – reading all the articles will take
ent than in this issue of Frontiers in you two or three hours – just to appreci-
Neuroscience. One third of the articles ate the depth and breadth of research pre-
in this issue discuss possible functions of sented, and then a second time, more slowly,
sleep and, surprisingly, just as many review pausing to think about individual articles,
phenomenological experiences associated both in terms of their specific content
with sleep. While most of these focus on and their larger implications for the field.
dreaming, others discuss sleep in relation Delightfully, many of the authors have cho-
to coma and deep anesthesia. Perhaps not sen to present new models, new concepts,
surprising are the number of articles look- and new approaches that can reframe many
ing at the physiology and pharmacology of of the questions and answers that have
sleep, as well as sleep disorders, but there occupied the field for years. Below, I have
is an excitement and freshness in many of tried to put most of the articles into groups,
these that belies their more staid subject to better allow for their brief description.
matter. Three articles cover the genetics of Many belong in multiple groups, many in
sleep, applying new techniques and organ- groups not defined; apologies to all who feel
isms. Others look at sleep deprivation, sleep mis-categorized.
Raizen’s description of sleep in the worm intact. And at the far end of the spectrum, reticulum stress”, especially in the elderly,
C. elegens, during which molting and a Domhoff argues that dreams serve no where it may contribute to the build-up
doubling of the DNA content of intestinal adaptive function whatsoever, although he of misfolded protein seen, for example, in
cells occurs. With a fully sequenced set of emphasizes that they could still serve as a both Alzheimer’s and Parkinson’s disease. In
six chromosomes, and only 302 neurons source of insight and inspiration. other articles, Monti discusses the roles of
in its entire nervous system, each uniquely Dreaming: Several other articles address serotonin receptor types in sleep, and Aston-
identified, Raizen argues that C. elegens is an possible brain mechanisms responsible for Jones et al. argue for an intact noradrenergic
ideal system for the genetic, neuroanatomi- dreams. Based on human lesion studies, locus coeruleus system being required for
cal, and functional dissection of sleep. Solms argues that Freud’s dream theory robust circadian sleep rhythms.
Other approaches to studying the genet- deserves resurrection, proposing that dreams Miscellanea: In articles focusing on sleep
ics of sleep are presented as well. Franken depend critically on the dopaminergic tract disorders, Mignot proposes narcolepsy as a
gives an overview of the usefulness of com- connecting the ventral tegmental area with model system for brain autoimmune dis-
bined genetic and molecular approaches, the nucleus accumbens, and that “nothing in eases, while others discuss “irregular sleep-
focusing on the potential role of the neu- the brain” comes closer in function to Freud’s wake rhythm disorder”, insomnia, and
ronal activity-induced transcript Homer1a “libidinal instinct”. In contrast, Buzsáki and apnea. Gratifyingly, there are three articles
in sleep regulation in the mouse, while Montgomery cite rat physiological data to that discuss sleep in relationship to ques-
Goel and Dinges discuss the putative role suggest that phasic REM epochs, which tran- tions of consciousness. Hobson compares
of human PER3 in individual differences in siently re-establish wake-like connectivity lucid dreaming as a state of consciousness to
response to sleep deprivation. between the hippocampus and cortex, initi- wake and non-lucid dreaming, while Hutt
A different approach to the function of ate the generation of dream content. Finally, compares slow-wave sleep to anesthesia-
sleep is seen in several articles on dreaming. Maquet points out brain regions with high induced unconsciousness and Noirhomme
Strikingly, most of these discuss the pos- activity during REM sleep as possible neural et al. compare it to coma. Other articles
sible role of dreams in emotional regula- correlates of dreaming. remain unmentioned, not because they are
tion. Articles by Levin et al. and by Kuiken Basic sleep mechanisms: In addition to any less interesting, but because they do not
compare the emotional benefits of healthy those noted above, four additional studies as easily fit into categories.
sleep to the accentuated distress seen with focus on the physiology and chemistry of I have given these descriptions not to help
nightmares, and Germain suggests that the sleep. Both Naidoo and Kimura look at the you pick the articles you want to read, but
nightmares of PTSD may reflect a causal interaction of sleep and stress, although rather to whet your appetite for the entire
contribution of disturbed sleep to the from vastly different perspectives. Kimura series. As your personal doctor, I prescribe
development and maintenance of this dis- describes the impact of corticotropin- one article per day, taken immediately before
order. Walker proposes a more specific role releasing hormone (CRH) on sleep, and sleep, until the entire issue is read. Like Lewis
of REM sleep, and possibly dreaming, in proposes CRH as a possible mediator of the Carroll’s Pillow Problems, they will send
removing the affective “blanket” from emo- reduced REM latency seen in depression. At you off to sleep with your mind abuzz, ripe
tional memories, a process that would leave the cellular level, Naidoo argues that inad- for fruitful dreams and, of course, sleep-
the information contained in the memory equate sleep may exacerbate “endoplasmic dependent memory processing.
We naturally look at sleep from a human phins and related cetaceans can go without
perspective. For many of us, sleep is seen sustained periods of sleep for very long peri-
as being in conflict with productivity and ods of time without ill effects or rebound
recreation and we wish to reduce or elimi- (Lyamin et al., 2005). Cetaceans do not
nate it, as is evidenced by the widespread appear to have REM sleep. Certain animals
use of alarm clocks and caffeine. This has may not sleep at all by the standard behav-
led many in and out of the field of sleep ioral criteria, i.e., they do not show periods
research to wonder why such an apparently of relative unresponsiveness and rebound
maladaptive state is required and to assume inactivity when deprived of this unrespon-
that some vital physiological function must sive state (Siegel, 2008). The tremen-
be subserved by sleep. This approach has dous variation in sleep duration
been greatly reinforced by a study showing across species does not
that rats, sleep deprived by the “disk over appear to correlate
water” technique, die (Rechtschaffen and
Bergmann, 2002). However, other data
suggests that this perspective is incorrect.
No other mammals have been shown to die
in well controlled studies of sleep depriva-
tion. Rats deprived by other techniques do
not show the syndrome exhibited by rats
deprived by the disk over water technique
(Siegel, 2008). The qualities of sleep vary
greatly across animals and within the mam-
malian class. Under certain conditions sleep
“rebound” after deprivation does not
occur. Adult and newborn dol-
AND SLEEP
end of a meal. In contrast, animals deprived
of food present a decrease in total daily
quota of SWS and REM sleep; similarly, a
food restitution results in an increase of both
By Fabio García-García SWS and REM sleep. The existence of such
correlation could suggest a causal relation-
ship or reveal a common determinant which
Sleep is one of the most remarkable behav- the sense that they cannot be accomplished modulates both behaviors. As far as feeding is
ioral signs of satiety, and is thought to inte- simultaneously. concerned, the most commonly recognized
grate the complex energy-saving strategies Furthermore, it has been reported that motivational factor is the availability of
in a number of mammalian species. Sleep there are highly significant correlations nutrients at the cellular level. The same factor
and food intake constitute the most time- between meal size and the total duration of could influence sleep parameters and, there-
consuming and life-supporting activities of sleep. Electroencephalographic studies of fore, be a link for the observed correlation
animals. Both sleep and food intake occur laboratory animals have shown that meal between sleep and feeding. Particularly, evi-
in cyclic patterns and are in competition in size is correlated with the short latency and dences show that there is a highly significant
correlation between the time spent in REM hours results in an increased intake of car- regulation may generate different neuronal
sleep and food intake (Danguir et al., 1987). bohydrate-rich diet. Body weight was also interactions depending on the events that
For that reason it has been suggested that increased and the body temperature remained have the predominant effects during waking
REM sleep participates directly in regulating without change. The increase in intake of (i.e., food intake). As a result of changes in
the expression of motivated behaviors. carbohydrate and body weight could be the the activation of the sleep circuitry, differ-
Additionally, it has been observed that result of an enhanced insulin level and the ent chemical mediators, such as peptides,
REM sleep deprivation for a period of 72 change appears to be mediated by the acti- hormones (CCK, VIP, ghrelin, leptin, etc.)
vation of the hypothalamic feeding center or neurotransmitters, become responsible
(García-García and Drucker-Colín, 2001). for the induction of different sleep pat-
Fabio García-García is a Professor at the Bio- Recently, it has been reported that food terns (Drucker-Colin, 1995; García-García
medicine Department, Health Sciences Insti- intake induces specific sleep patterns. et al., 2009). In conclusion, the relationship
tute, Veracruzana University, where he heads Particularly, food intake increases the dura- between feeding and sleep is quite strong,
the Laboratory of Sleep. His research focuses tion and frequency of SWS and the percent- but much more work is needed before a full
on the biological sleep function, including hor- age of slow wave activity (0.25-4.0 Hz). In understanding of the mechanism which
monal regulation of sleep and how sleep in-
duces neuronal plasticity. Before moving to
addition, REM sleep time and EEG theta relates both is gained. This becomes even
México, he worked at Washington State Uni- frequency (4.0-8.0 Hz) were also increased more apparent in light of recent evidence
versity, Pullman, Washington, US. (García-García et al., 1998). It is conceiv- indicating that sleep loss may be a novel risk
fgarcia@uv.mx able that the circuitry implicated in sleep factor for obesity and type 2 diabetes.
The remarkable success of using model which distinguish it from other quiescent is a core component of the clock that regu-
genetic organisms to understand the circa- behavioral states, such as quiet wakefulness, lates sleep in Drosophila and in mammals.
dian clock was the impetus behind research are reduced responsiveness, reversibility in Further molecular similarity of lethargus to
in the past decade to use fruit flies and round response to strong stimuli, and homeostasis, sleep is demonstrated by the observation
worms to understand other sleep regulatory the phenomenon of increased sleep pres- that epidermal growth factor signaling pro-
mechanisms. Our work centers on sleep in sure with prolonged wakefulness. motes and cAMP signaling inhibits sleep-
the round worm C. elegans. The initial task Based on these criteria, worms have like behavior in C. elegans (Zimmerman
is to determine if these worms sleep. a sleep-like state called lethargus, which et al., 2008), in keeping with the effects on
The small size and the unique neuro- occurs during the development of the nem- sleep of these signaling pathways in flies
anatomy of C. elegans preclude the use of atode C. elegans. In addition to satisfying the and mice.
the electroencephalogram, which is the gold behavioral criteria for sleep (Raizen et al., What questions can we answer in study-
standard for identifying sleep in mammals. 2008), lethargus timing occurs in phase with ing lethargus in C. elegans? The first is to use
Instead, behavioral criteria are used to iden- expression of the C. elegans orthologue of the powerful genetic tools in C. elegans to
tify sleep. The cardinal features of sleep, the gene PERIOD (Jeon et al., 1999), which identify additional regulators of sleep. While
EVEN MODELS
NEED THEIR SLEEP
By Sean Hill
Although the function of sleep remains properties, connectivity, plasticity and neu-
Sean Hill is the Project Manager for Computa-
largely unknown, the present models serve romodulation have been highly simplified
tional Neuroscience with the Blue Brain Project
at the Brain Mind Institute, EPFL. In 2000, he as important tools in the analysis and under- in the present models.
received his Ph.D. in Computational Neurosci- standing of the mechanisms that generate With the integration of additional bio-
ence from the University of Lausanne, Switzer- sleep rhythms and influence information logical details, such as neuromodulation,
land. He developed large-scale computer processing during conscious and uncon- synaptic plasticity and the coupling of neu-
models of wakefulness and sleep in thalamo- scious states. ral, glial and vascular systems, large-scale
cortical circuitry while working as a Post- Presently, there are no large-scale mod- models, such as those being developed in
Doctoral Fellow with Giulio Tononi at the Uni-
versity of Wisconsin, Madison. In 2006, he was
els of REM sleep, and circadian effects and the Blue Brain Project, should provide
hired by IBM Research to work on the Blue transitions between the different stages of deeper insight into the role of wakefulness
Brain Project, and joined the EPFL in 2008. non-REM sleep have yet to be modeled. and sleep in information processing, syn-
sean.hill@epfl.ch In addition, many details of neuron firing aptic plasticity and metabolism.
Deep sleep is characterized by the presence SWA during subsequent sleep (Kattler depends on SWA during sleep. Healthy sub-
of slow waves in the electroencephalogram et al., 1994), whereas under-used circuits jects were trained on a texture discrimina-
(EEG). EEG slow-wave activity (SWA; spec- produced less SWA (Massimini et al., 2009). tion task and were tested 24 hours later
tral power density in the 0.75-4.5 Hz range) Increases in SWA, induced either through after an experimental sleep episode (with or
typically increases in proportion to an indi- practicing a particular learning task, without SWA suppression), and again after
vidual’s prior time awake, and it decreases in through transcranial application of oscil- a night of recovery sleep. In the suppres-
the course of a sleep episode. SWA has been lating potentials during sleep (Diekelmann sion group, SWA during sleep was reduced
the focus of much scientific interest because et al., 2009), or through a pharmacologi- by 30% compared with the control group,
it is thought to be a marker of sleep need, and cal agent (Walsh et al., 2006), have been whereas total sleep time and REM sleep
a manifestation of a sleep regulatory process reported to be paralleled by gains in some remained unaffected. Texture discrimina-
that serves a homeostatic function (Borbély neurobehavioral performance measures tion improved after experimental sleep in
and Achermann, 2000). However, it is cur- during subsequent wakefulness. Much the control group, but not in the suppres-
rently unknown what is ultimately being of the evidence for a causal role of SWA sion group. Overnight improvement cor-
regulated, and whether SWA is simply an in such sleep-dependent gains, however, related positively with EEG power density
EEG epiphenomenon or whether it directly remains correlative. Importantly, if SWA is in the low-frequency range (<7 Hz) and in
serves a fundamental brain function. not simply an EEG epiphenomenon, inter- particular with SWA, but not with power
A growing number of observations has ference with its expression should prevent density in higher-frequency ranges.
linked slow wave sleep (SWS) and SWA to sleep-dependent learning. Our data are consistent with a causal rela-
brain plasticity. Although various aspects Recently, we tested this hypothesis tionship between SWA and sleep-depend-
of sleep have been associated with learning, directly by using an acoustic SWA suppres- ent gains in perceptual performance. The
positive relationships were found specifically sion paradigm (Aeschbach et al., 2008). The results substantiate the proposed functional
between SWS/SWA and overnight gains in goal of this paradigm was to reduce SWA link between processes of sleep homeostasis
declarative memory, perceptual learning, during non-REM sleep by targeted presen- and learning. In this regard, exploration of
and visuomotor learning (for reviews see tation of sounds while avoiding awakenings new strategies – particularly pharmacologi-
Diekelmann et al., 2009; Massimini et al., through careful “titration” of the volume of cal ones – to specifically enhance SWA may
2009). SWA appears to be use-dependent, the sounds. We examined whether overnight take on added relevance in conditions where
such that cortical circuits that were particu- improvement in visual texture discrimina- SWA is reduced, such as in insomnia and
larly active during waking generated more tion, a form of perceptual learning, directly depression.
REM SLEEP
By Subimal Datta and Brian W. Macone
Rapid eye movement (REM) sleep is a a widely distributed network, rather than a ters at multiple sites of its circuit. Turn-on/
highly evolved behavioral state in mam- single REM sleep “center”. For example, mus- turn-off conditions of REM sleep-generating
malian species. Since the discovery of REM cle atonia results from the activation of neu- executive neurons are regulated by the ratio
sleep and its physiological distinction from rons in the locus coeruleus alpha, rapid eye of available aminergic to cholinergic neu-
other sleep states, neuroscientists have been movements from the periabducens reticular rotransmitters within executive cell groups.
allured to study its mechanisms and func- formation, and PGO waves emerge from the During REM sleep, aminergic cell activity
tions. An extensive body of research has caudo-lateral peribrachial area of predator drops markedly or disappears entirely, while
recently emerged providing evidence that mammals and the dorsal part of the nucleus cholinergic cell activity remains compara-
REM sleep is important in the development subcoeruleus of prey; neurons in the pontis tively high (Datta et al., 2009).
and maturation of the brain during early oralis are responsible for hippocampal theta Over the past decade, the brain structures,
mammalian life, and for memory consoli- rhythm, and muscle twitches appear with neurotransmitters, receptors, and neuronal
dation throughout life (Datta, 2006). activation of the nucleus gigantocellularis networks critical to the regulation of REM
During the last fifty years, phenomeno- (especially the caudal part). Cortical EEG sleep have been sufficiently explored (Datta
logical and mechanistic aspects of REM signs of REM sleep are produced jointly by and MacLean, 2007). As such, research on
sleep have been studied more extensively neurons in the mesencephalic reticular for- the mechanisms of REM sleep has begun
than the waking states (Datta and McLean, mation and rostrally-projecting medullary to focus on gene expression and intracellu-
2007). REM sleep is characterized by a con- magnocellular nucleus. The aforementioned lar signaling systems (Bandyopadhya et al.,
stellation of events including: 1) an acti- cell groups simply represent the executive 2006) and must continue to do so. To further
vated pattern of cortical EEG; 2) marked neurons for the individual signs. For final our understanding of the functions of REM
atonia of the postural muscles; 3) rapid expression of each distinct sign, the relevant sleep, a number of researchers have recently
eye movements; 4) a theta rhythm within cell groups employ a specific and unique begun investigating the cellular and molec-
the hippocampus; 5) field potentials in the neuronal circuit. In essence, each REM sleep ular mechanisms of REM sleep-dependent
pons (P-waves), lateral geniculate nucleus sign has a separate, specialized network, and behavioral and structural plasticity. (Datta
and occipital cortex (ponto-geniculo-occip- may be modulated by various neurotransmit- et al., 2008). At this time, we are closer to
ital (PGO) spikes); 6) myoclonic twitches, unraveling the mysteries of REM sleep than
most apparent in the facial and distal limb ever before, but for complete understanding
Subimal Datta is a Professor of Psychiatry and
musculature; and 7) pronounced cardio- the Director of Sleep and Cognitive Neurosci- future research must focus on the cellular
respiratory fluctuations. In addition to ence Laboratories at the Boston University and molecular mechanisms of both REM
these physiological signs, vivid dreaming School of Medicine. His research focuses pri- sleep generation and of REM sleep-specific
is an important mental experience and a marily on studies of the mechanisms of sleep behavioral and cellular plasticity.
trademark of REM sleep. and sleep-dependent memory processing, us-
ing state-of-the-art combined anatomical,
Animal studies over the last three dec-
behavioral, physiological, pharmacological, Brian W. Macone earned his Bachelor’s degree
ades have revealed that each aspect of REM and molecular methodological approaches. His from Boston University. He currently studies
sleep is executed by distinct cell groups in research is funded by the US National Institutes REM sleep mechanisms and functions under
the brainstem (Datta and MacLean, 2007). of Health (NINDS and NIMH). the supervision of Dr. Datta.
These cell groups are discrete components of subimal@bu.edu bmacone@bu.edu
What are the differences between coma and troencephalography (EEG) shows similari- encountered in the vegetative state makes
sleep? Can patients in coma and related ties between coma (or the vegetative state) it utterly difficult to identify possible REM
states have self-awareness or dreamlike – classically showing diffuse slowing of the sleep other than by the presence of muscular
experiences as can be encountered in brain’s basic rhythms – and deep (stage 3-4) atonia and eye movements – note that noc-
sleep? Behaviorally, a coma may resemble sleep. EEG spindle activity (the hallmark turnal penile erections have been convinc-
deep sleep – the major difference being that of stage 2 sleep) can also be observed in ingly shown in vegetative patients (Cologan
comatose patients will never open the eyes, some comatose or vegetative patients and et al., in press).
not even when intense or noxious stimuli seems to be a predictor of good outcome. The brain’s metabolic activity in a coma,
are applied. Patients evolving from a coma Whereas coma patients will never show the as measured by fluorodeoxyglucose posi-
to a vegetative state may, in turn, be com- EEG characteristics of REM sleep, it remains tron emission tomography or FDG-PET,
pared to sleepwalkers – only showing reflex controversial whether vegetative patients decreases to about half of normal waking val-
or automatic behavior, but not command may present periods of REM sleep. The ues, and to ~40-50% of normal values in the
following (Laureys, 2005). In addition, elec- very unstructured and slow waking EEG vegetative state. These massive decreases in
Quentin Noirhomme is a Post-Doctoral Re- Steven Laureys is Clinical Professor of Neu- Mélanie Boly is a Post-Doctoral Research
search Fellow at the Belgian National Funds rology at the University Hospital of Liège and Fellow at the Belgian National Funds for Sci-
for Scientific Research (FNRS). He is a Civil Senior Research Associate at the Belgian entific Research at the Coma Science Group.
Engineer and earned his Ph.D. on the localiza- Funds for Scientific Research. He earned his She earned her M.D. and Ph.D. at the Univer-
tion of brain functions using TMS and EEG at M.D. and M.Sc. in Pharmaceutical Research sity of Liège using fMRI to study conscious-
the University of Louvain. In 2007, he joined from the University of Brussels working on ness in coma and related states. Her research
the Coma Science Group (www.comascience. pain and stroke in the rat. He moved to the focuses on the recovery of neurological dis-
org) of the Cyclotron Research Centre and University of Liège in 1997 where he obtained ability and neuronal plasticity in altered states
Neurology Department of the University and his Ph.D. studying perception in the vegeta- of consciousness, confronting bedside be-
University Hospital of Liège where he works tive state. He is board-certified in neurology havioral evaluation with multimodal func-
on high density EEG and brain-computer in- and in palliative and end-of-life medicine. He tional neuroimaging, combining EEG coupled
terface (BCI) devices in disorders of con- heads the Coma Science Group and has pub- to TMS and fMRI, PET and structural MRI
sciousness. lished The Neurology of Consciousness. morphometry.
quentin.noirhomme@ulg.ac.be steven.laureys@ulg.ac.be mboly@student.ulg.ac.be
The loss of consciousness in sleep and eral anesthetics are able to induce these
anesthesia is a well-known phenomenon, four elements.
but its neural mechanisms are still not Both sleep and general anesthesia show
understood in detail. When we fall asleep, a hypnotic effect, but, even at first glance,
our consciousness fades and we enter so- also have important differences. First of all,
called sleep cycles. These cycles are classi- general anesthetics inhibit parts of the brain
fied as either REM sleep, when remembered which are required for REM sleep cycles.
dreams occur, or non-REM sleep during Hence, anesthetized subjects do not have
which the sleeper may be somnolent, loses REM sleep and, thus, do not remember
consciousness or may be in deep sleep. The dreams. Another notable difference is that
sleeper passes through several of such stages sleep is readily reversed through external
during a typical sleep and several transitions stimuli, e.g., shaking or loud noises, whereas
between REM and non-REM sleep occur. anesthesia is reversed only by discontinu- induced unconsciousness and deep sleep are
Sleep is important for the subjects’ ation of the anesthetic drugs. Studies of remarkably similar.
health, allowing the brain to organize deep sleep using imaging techniques have This view is supported by detailed elec-
knowledge and solidify memories. It also shown that polymodal association areas are troencephalographic (EEG) studies that
plays an important role in the brain devel- affected more profoundly than unimodal demonstrate similar activity patterns dur-
opment of infants. The accompanying brain areas (Franks, 2008). This functional ing non-REM sleep and anesthesia (John
loss of consciousness or awareness (hyp- dissociation implies that during deep sleep and Prichep, 2005). This similarity indi-
nosis) is also advantageous during sur- the brain can respond to external stimuli via cates common neural pathways of sleep
gery, where it is evoked by administered the unimodal areas, but cannot make much and anesthesia that control the arousal of
drugs, so-called general anesthetics. The sense out of the stimuli due to the inhibition the cortex (Lydic and Baghdoyan, 2005).
general anesthesia applied before surgery of the higher level processing in polymo- Recent work suggests several candidates for
needs to guarantee not only the loss of dal areas. Moreover, some of the polymodal the affected arousal pathways. For instance,
consciousness, but also sedation, immo- areas which are affected during deep sleep in both sleep and anesthesia the thalamus
bility, the loss of memory (amnesia), and are also deactivated during sedation. This may serve as a consciousness switch (Alkire
the absence of pain (analgesia). Most gen- indicates that the final state of anesthetic- and Miller, 2005) that disrupts the informa-
SEROTONIN
whereas 5-HT1A and 5-HT2A/2C receptors
have been found in the laterodorsal teg-
mental and pedunculopontine tegmental
IN SLEEP
nuclei and the medial pontine reticular
formation (Hoyer et al., 2002).
Early studies examined the effects of
AND WAKING
predominantly systemic administration
of selective and relatively selective 5-HT
agonists and antagonists on sleep and W
in laboratory animals. More recently, results
from several studies have quantified the
spontaneous sleep/waking cycles in serot-
By Jaime M. Monti onin 5-HT1A, 5-HT1B, 5-HT2A/2C or 5-HT7
Mónica M. González obtained her Ph.D. from Heinrich S. Gompf received his Ph.D. from the
the Université Claude Bernard, France. Her post- Oregon Health and Science University in Port-
doctoral studies at the University of Pennsylva- land, Oregon. He conducted post-doctoral work
nia with Dr. Aston-Jones showed that locus with Dr. Aston-Jones at the University of Penn-
coeruleus neurons provide a circadian regula- sylvania. His primary research interests are the
tion of the sleep-wake cycle, and that an impair- mechanisms by which external stimuli and the
ment of monoaminergic systems after limited internal clock activate arousal systems. His
light exposure promotes depression. Her recent approach has involved in vitro whole-cell
studies at the University of Washington and at patch-clamp and in vivo single unit neuro-
the IFN in Buenos Aires implicate the circadian physiology, neuroanatomy and EEG monitoring
system in the etiology of depression. of sleep and wakefulness in rats and mice.
ratusagon@yahoo.com heinrich.gompf@gmail.com
STRESS,
corticosterone than the control (Dugouvic
et al., 1999). However, our CRH-COE mice
possess undisturbed HPA activity, therefore,
ASTROCYTES
AND SLEEP HOMEOSTASIS
By Pierre J. Magistretti and Jean-Marie Petit
A canonical view for the role of sleep is recov- storage form of glucose selectively localized in in sleep regulation and synaptic plasticity.
ery, in particular as far as energy homeostasis astrocytes. Thus, adenosine, vasoactive intes- Indeed, these mice displayed an attenuated
is concerned. More recently, evidence has been tinal peptide and noradrenaline promote a sleep pressure as reflected by reduced slow-
provided for a function of sleep, in particular rapid (seconds) glycogenolysis and a delayed wave activity; a feature of non-REM sleep
slow wave (non-REM) sleep, in synaptic plas- (hours) and transcriptionally-regulated gly- related to memory consolidation. In addition,
ticity and memory (Tononi and Cirelli, 2006). cogen resynthesis in astrocytes (Magistretti, these mice also displayed an impairment of
Astrocytes play a key role in coupling synaptic 2006). In mice, sleep deprivation is known to short-term memory, which is known to be
activity to energy metabolism and vascular result in accumulation of extracellular adeno- altered by sleep loss. Altogether, these results
responses (Magistretti, 2006; Haydon and sine (Halassa et al., 2009), a mediator of sleep point to an emerging function of astrocytes
Carmignoto, 2006). A particular feature of pressure, which results in a massive induction as potential mediator of the known effects of
neuron-glia metabolic coupling is the abil- of the gene encoding for PTG (protein tar- adenosine on sleep regulation, both, in terms
ity of a selected group of neurotransmitters geting to glycogen) (Petit, 2002). As a result, of their role in neuroenergetics and in synap-
to modulate the metabolism of glycogen, the after sleep deprivation, glucose metabolism tic plasticity.
in the cortex is directed toward glycogen
resynthesis rather than glucose utilization References
Pierre J. Magistretti is Director of the Brain which has an operative effect on astrocytes as Halassa, M. M., Florian, C., Fellin, T.,
Mind Institute at EPFL and of the Center for glycogen is selectively localized in these cells. Munoz, J. R., Lee, S.-Y., Abel, T., Haydon, P. G.,
Psychiatric Neuroscience of the University of Accordingly, glucose utilization is decreased and Frank, M. G. (2009). Astrocytic Modulation of
Lausanne, Switzerland. His laboratory has con- in cortical areas during non-REM sleep. In Sleep Homeostasis and Cognitive Consequences
tributed to the identification of the role of as- of Sleep Loss. Neuron 61, 213-219.
addition to this energetic facet, astrocytes Haydon, P. G., and Carmignoto, G. (2006). Astrocyte
trocytes in coupling synaptic activity to energy
metabolism. He is past president of FENS and are in a position to affect synaptic plasticity, Control of Synaptic Transmission and Neurovascular
has occupied the International Chair at the in particular through the release of so-called Coupling. Physiol. Rev. 863, 1009-1031.
Collège de France in 2007-2008. gliotransmitters, such as glutamate and ATP Magistretti, P. J. (2006). Neuron-glia metabolic
pierre.magistretti@epfl.ch coupling and plasticity. J. Exp. Biol. 209, 2304-2311.
(Haydon and Carmignoto, 2006). The latter
Petit, J.-M., Tobler, I., Allaman, I.,
is rapidly hydrolyzed by ectonucleotidase to Borbély, A. A., and Magistretti, P. J. (2002).
Jean-Marie Petit was trained in Michel Jou- adenosine. Recently, Halassa and colleagues Sleep deprivation modulates brain mRNAs
vet’s laboratory and is now a staff scientist in
(2009) using conditional transgenic mice, in encoding genes of glycogen metabolism.
Pierre Magistretti’s laboratory where he inves- Eur. J. Neurosci. 16, 1163-1167.
tigates the astrocytic metabolism throughout which the vesicular release of gliotransmit-
Tononi, G., and Cirelli, C. (2006). Sleep function
the sleep-wake cycle. ters, notably ATP, was impaired, and dem- and synaptic homeostasis. Sleep Med. Rev. 10, 49.
jean-marie.petit@epfl.ch onstrated an additional role of adenosine
point to inter-individual differences in the SD-induced brain transcriptome changes lar level (Franken and Dijk, 2009). The
homeostatic regulation of sleep. Twin stud- and in silico analysis identified the activity- homeostatic regulation of sleep in humans
ies have shown that genetic factors impor- induced transcript Homer1a as a credible was also found to vary with a polymor-
tantly contribute to these and other sleep candidate for this QTL (Maret et al., 2007). phism for a circadian gene; i.e., Per3. These
traits, in particular EEG activity (Andretic Homer1a is involved in neuronal plasticity examples show that only when these vari-
et al., 2008). Thus, sleep seems amenable consistent with a role of sleep in preserving ous approaches are used in parallel, while
to genetic analyses, which could bring new the integrity of neuronal connectivity and exploiting the available model systems, can
insights into its regulation and, hopefully, signaling (Krueger et al., 2008). Genome- true progress be achieved toward unraveling
function. wide association (GWA) studies have made sleep’s function.
Until recently, little was known about a comparable, forward genetic approach
the specific genes and molecular pathways feasible in humans. Thus far, case-control References
underlying sleep regulation. Therefore, studies, such as for the sleep disorders nar- Andretic, R., Franken, P., and Tafti, M. (2008).
some 14 years ago we began to map genomic colepsy and restless legs syndrome, have Genetics of sleep. Annu. Rev. Genet. 42, 361-388.
loci for sleep and EEG phenotypes in the been the focus of this approach. GWA Franken, P., Chollet, D., and Tafti, M. (2001).
mouse using quantitative-trait loci (QTL) studies should be extended to quantitative Sleep homeostasis is under genetic control.
analysis. With this approach, we identified traits, like sleep duration and the response J. Neurosci. 21, 2610-2621.
variations in the Acads and Rarb1 genes to to SD, to identify genes affecting the regu- Franken, P., and Dijk, D.-J. (2009).
Circadian clock genes and sleep homeostasis.
underlie the EEG differences in theta (6-9 lation of physiological sleep in the general
Eur. J. Neurosci. 29, 1820-1829.
Hz) and delta activity during sleep, respec- population. Krueger, J. M., Rector, D. M., Roy, S.,
tively, implicating fatty-acid β-oxidation Finally, sleep research profited from the Van Dongen, H. P. A., Belenky, G., and
and retinoic acid signaling in shaping the ever increasing number of available trans- Panksepp, J. (2008). Sleep as a fundamental
EEG (Andretic et al., 2008). Mice also greatly genic or mutated lines of mice and fruit property of neuronal assemblies. Nat. Rev.
differed in the SD-induced increase in EEG flies. As an example, we found that mice Neurosci. 9, 910-919.
delta power which mapped to a QTL on with targeted disruptions in circadian clock Maret, S., Dorsaz, S., Gurcel, L., Pradervand,
chromosome 13. Delta power quantifies the genes, besides an altered circadian physiol- S., Petit, B., Pfister, C., Hagenbuchle, O.,
O’Hara, B. F., Franken, P., and Tafti, M. (2007).
delta oscillations (1-4 Hz) characteristic of ogy, also show a pronounced altered sleep
Homer1a is a core brain molecular correlate
the sleep EEG and is widely used as a sleep homeostasis suggesting that these two proc- of sleep loss. PNAS 104, 20090-20095.
need index. Subsequent quantification of esses are not easily separable at a molecu-
90
Immediate A B C D E F
n.s.
B C D E
Percent Correct
80
Wake A B C D E F
B C D E
70
n.s. 1o inference
their integration into a common knowledge both 12 hour groups displayed highly sig-
schema across multiple nights (McClelland nificant relational memory developments.
Matthew P. Walker earned his Ph.D. in Neuro-
et al., 1995; Walker, 2009). Most remarkable, however, if the 12 hour physiology from the Medical Research Council,
For example, a recent study required delay contained a night of sleep, a 25% UK, and subsequently became an Assistant
participants to initially learn five indi- advantage in relational memory was seen Professor of Psychology at Harvard Medical
vidual premises; the object memory pairs for the most distantly connected, non- School. He is currently an Assistant Professor
(A>B, B>C, C>D, D>E, E>F) (Ellenbogen obvious inferential judgment (B>E pair). of Psychology and Neuroscience at University
et al., 2007). Unknown to subjects, the Therefore, sleep preferentially biased the of California Berkeley. His research examines
the impact of sleep on human brain function,
pairs contained an embedded hierarchy development of more distant/weak asso- with a particular focus on the role of sleep in
(A>B>C>D>E>F). Following a delay of ciative links amongst related, yet separate, memory processing, neural plasticity and emo-
20min., 12 hours across the day or 12 hours memory items. tional regulation.
containing a night of sleep, knowledge of Additional quantitative data further mpwalker@berkeley.edu
this associative-hierarchy was tested by confirm such sleep-inspired creativity
examining relational judgments for novel (reviewed in Walker, 2009). For example,
“inference” pairs, either separated by solution performance on tests of cognitive the consolidation of individual items, and
1-degree of associative distance flexibility using anagram puzzles is more instead, intelligently assimilates these details
(B>D, C>E pairs), or by 2-degrees than 30% better following awakenings offline. In doing so, sleep (and perhaps
of associative distance (B>E pair). from REM sleep compared with non-REM dreaming) may offer the ability to test and/
Subjects tested soon after learn- awakenings. Similarly, performance on a or build common informational schemas of
ing in the 20 min. delay group semantic priming task following REM sleep generalized knowledge, affording increas-
showed no evidence of inferential awakenings shows a greater priming effect ingly accurate statistical predictions about
ability, performing at chance by weakly related words than by strong the world, and even creative insights. Is it a
levels (Figure 1). primes. Furthermore, the likelihood of wonder, then, that we are never told to stay
In contrast, gaining insight into hidden task rules can be awake on a problem?
increased three-fold by an intervening night
of sleep. Even the study of mental activ- References
ity (dreams) from REM sleep indicates Ellenbogen, J., Hu, P., Payne, J. D., Titone, D.,
that there is not a concrete episodic and Walker, M. P. (2007). Human relational
replay of daytime experiences, memory requires time and sleep.
but instead, more associa- Proc. Natl. Acad. Sci. USA 104, 7723-7728
McClelland, J. L., McNaughton, B. L.,
tive, semantic-integration
and O’Reilly, R. C. (1995).
processing. Why there are complementary learning systems
In summary, emerg- in the hippocampus and neocortex:
ing evidence suggests insights from the successes and failures
that sleep serves a of connectionist models of learning and memory.
meta-level role in Psychol. Rev. 102, 419-457.
Walker, M. P. (2009). The role of sleep in
memory process-
cognition and emotion. Ann. NY Acad. Sci. 1156,
ing that moves 168-197.
far beyond
Sleep is beneficial to learning, but the under- vated by SWS. The notion that sleep harbors potentiation of glutamatergic synapses (Aton
lying mechanisms remain controversial and differential plasticity in separate circuits is et al., 2009). Evidence of synaptic upscaling
two paradigms currently collide. One of the rooted on data showing that novel experience during sleep was also uncovered in inverte-
competing theories proposes that the cogni- causes an up-regulation of plasticity-related brates (Ganguly-Fitzgerald, 2006).
tive function of sleep is to promote general- factors during subsequent REM (Ribeiro et The divergent theories are based on
ized synaptic downscaling, so as to enable al., 1999; Ulloor and Datta, 2005). The sleep- different assumptions and, consequently,
further waking potentiation. This theory dependent development of the visual cortex different experimental strategies. The
is based on evidence that sleep down-reg- in cats requires the phosphorylation of pro- downscaling theory represents a revival
ulates activity-dependent gene transcripts, teins necessary for the calcium-dependent of the passive sleep paradigm; dominant
calcium-dependent kinases, membrane traf- before the discovery of REM in the 1950’s.
ficking proteins and metabolic enzymes. It It focuses on SWS and disregards experi-
proposes that wakefulness and sleep are ence-dependent changes. In contrast, the
respectively associated with a net increase Sidarta Ribeiro majored in Biology at the Uni- embossing theory considers sleep as a com-
versity of Brasília and received a Master’s
and decrease in cortical synaptic strength. bination of passive and active mechanisms.
degree in Neurobiology from the Federal Uni-
Sleep would play a role in “an overall balance versity of Rio de Janeiro. In 2000, he received It advocates the need to compare sleep with
of synaptic strength” by favoring “global syn- a Ph.D. in Animal Behavior from the Rockefell- and without previous learning. It also dis-
aptic depression” (Vyazovskiy et al., 2008). er University. He performed post-doctoral work tinguishes the contributions of SWS and
The alternative theory proposes that the in neurophysiology at the laboratory of Miguel REM, characterized by very different neu-
cognitive role of sleep stems from the cooper- Nicolelis at Duke University. In 2005, he re- ral dynamics.
turned to Brazil as Scientific Director of the The embossing theory is compatible
ative interaction of its two major states: while
ELS-IINN. Since 2008, he is Professor of Neu-
slow-wave sleep (SWS) reverberates memo- roscience at the Federal University of Rio
with the evidence of synaptic downscaling
ries at the electrophysiological level, rapid eye Grande do Norte, and heads the laboratory at during sleep, as long as the latter occurs in
movement (REM) sleep selectively triggers the ELS-IINN. circuits not engaged by waking experience.
plasticity within specific circuits pre-acti- ribeiro@natalneuro.org.br Downscaling is probably essential for learn-
RHYTHM
the sleep patterns of children. There are
many ways to distract children, keeping
them awake until late at night, such as tel-
DISORDER
evision, radio, cell phones, computers, video
games, the Internet, and others. Several pub-
lications from different countries report an
increase of insomnia and circadian rhythm
sleep disorders during childhood and youth.
By Adrián Poblano and Ulises Jiménez-Correa Contemporary parental upbringing has also
30
20
10
0
18-20 21-23 24-26 27-29 30-32 33-35 36-38 39-41 42-44 45-47 48-50 51-53 54-56 57-59 60-62 63-65 66-68 69-71 72-74 75-77 78-80 81-83 >83
AGE
in OSAS (Lavie, 2003). Apneas during sleep disease, display endothelial dysfunction References
are associated with repeated occurrence of and early signs of atherosclerosis, such Dyugovskaya, L., Lavie, P., and Lavie L. (2002).
hypoxia/reoxygenation events that, similar as increased carotid artery wall thickness, Increased adhesion molecules expression
and production of reactive oxygen species in
to the effect of restoration of blood cir- increased arterial stiffness, and atheromas,
leukocytes of sleep apnea patients.
culation to an ischemic tissue, result in further support this concept (Dyugovskaya Amer. J. Respir. Crit. Care Med. 165, 934-939.
increased production of free radicals. Once et al., 2002; Lavie et al., 2008; Lavie and Lavie, L. (2003). Obstructive sleep apnoea
produced, the toxic free radicals may inflict Lavie, 2009). syndrome--an oxidative stress disorder. Sleep
injury on surrounding tissues and activate These processes start to accrue dur- Med. Rev. 7, 35-51.
specific oxidative stress sensitive transcrip- ing the very first nights that hypoxemic Lavie, P. (2008). Who was the first to use the term
Pickwickian in connection with sleepy patients?
tion factors that encode proinflammatory events appear and from that time on,
History of sleep apnoea syndrome. Sleep Med.
cytokines. This results in activation of night after night, the patient’s blood ves- Rev. 12, 5-17.
endothelial cells, leukocytes and platelets; sels and heart are exposed to the aggres- Lavie, L., Dyugovskaya, L., and Polyakov, A.
increased production of adhesion mole- sion of free radicals. Patients, however, (2008). Biology of peripheral blood cells in
cules that facilitate endothelial cell-leuko- are generally referred for diagnosis only obstructive sleep apnea--the tip of the iceberg.
cyte interactions and adhesion; increased when the characteristic symptoms, such Arch. Physiol. Biochem. 114, 244-254.
toxicity of monocytes and lymphocytes as excessive daytime sleepiness or heavy Lavie, L., and Lavie, P. (2009). Molecular
mechanisms of cardiovascular disease in OSAHS:
against endothelial cells; and increased snoring, start bothering them or their bed
the oxidative stress link. Eur. Resp. J. 33,
neutrophil activation. Findings that OSAS partners, generally around the age of 50, 1467-1484.
patients, free of any overt cardiovascular which may be ten to twenty years after
AS A MODEL
from wakefulness to REM sleep. Recent
findings have shown that the disorder is
caused by the loss of ~70,000 hypothalamic
FOR BRAIN
neurons (Peyron et al., 2000). These neurons
produce an excitatory neuropeptide called
hypocretin/orexin. The lack of this peptide
AUTOIMMUNE
results in narcolepsy, in both humans and
animals. The hypocretin system is now the
object of pharmaceutical efforts in the area
DISEASES
of sleep and sleep disorders.
The cause of the hypocretin cell loss is
the subject of intense research. Narcolepsy
is tightly associated with human leukocyte
antigen (HLA) DQB1*0602 (Mignot et al.,
By Emmanuel J. M. Mignot 2001), suggesting an autoimmune media-
tion. Despite decades of investigations,
however, no definitive evidence has ever
been found. Recently, a genome wide asso-
ciation study (GWAS) was completed which
found a genetic association with Rs1154155
within the T-cell receptor alpha (TCRα) streptococcal infections are known to trig- the TCR Jα region, favors the occurrence
locus across multiple ethnic groups (Asians, ger other autoimmune manifestations, e.g., of a very specific V-J TCRα pathogenic
Caucasians, African American) (Hallmayer Sydenham’s chorea and rheumatic heart dis- T-cell clone recombinants or marks a cod-
et al., 2009). Since the TCR is the receptor for ease, narcolepsy may also be a post-strepto- ing change within a J segment that alters
HLA-peptide presentation, this result sug- coccal autoimmune condition. TCRα-peptide binding.
gests autoimmunity. Interestingly, another Interestingly, narcolepsy onset is not If narcolepsy is a selective autoimmune
study recently found an increased prevalence associated with detectable inflammation. brain disease, it raises the possibility that
of streptococcal infection markers in onset We suggest that in narcolepsy, the immune- other diseases remain to be discovered. The
cases of narcolepsy (Aran et al., 2009). As mediated destruction of hypocretin cells is fact that hypocretin lesions can produce a
selective and self-limited, without signifi- clinically very easily identifiable phenotype
cant epitope-spreading. Limited epitope (narcolepsy-cataplexy) may have made these
Emmanuel J. M. Mignot is the Craig Reynolds spreading may be a feature of neurons as discoveries possible. It is likely that other
Professor of Sleep Medicine, Professor of Psy-
an immune-protected target, and could brain area selective autoimmune diseases
chiatry and Director of the Center for Narco-
lepsy at Stanford University. He is a world-re- explain difficulties in detecting autoim- (with selective neuronal cell loss) do occur
nowned expert in sleep medicine, having mune abnormalities. The fact that HLA but have less specific clinical effects, such as
discovered the cause of narcolepsy, a lack of class II expression in neurons remains psychiatric manifestations. The recent find-
hypocretin in the brain. Dr. Mignot applies ba- constantly repressed (unlike in glial cells), ing that HLA is a susceptibility locus for
sic science techniques, such as genetics, even in the face of local inflammation, may schizophrenia and bipolar disorder in large
pharmacology and molecular biology, to the be important. The specificity of this proc- scale GWAS studies provide some support
study of sleep disorders, most notably sleep
apnea and narcolepsy. He also directs a spe-
ess may also explain the genetic association for this concept (Stefansson et al., 2009).
cialized consultation devoted to the evaluation with TCRs, an association not found in We hope that in time, narcolepsy will not
of patients with narcolepsy and hypersomnia. other autoimmune diseases. In this model, only inform us about sleep, but about other
mignot@stanford.edu Rs1154155 or a tightly linked marker within autoimmune diseases of the brain.
There has been a gradual decline in sleep experiments that evaluated working mem- volunteers were required to briefly retain
duration in most developed societies and ory (Chee and Choo, 2004; Chee et al., 2006), visual stimuli (Chee and Chuah, 2007). Had
this situation has accelerated in recent years we observed that performance decrement, a there been a storage failure, we would have
because of the increasing use of electronic result of sleep deprivation, shows significant expected a state effect to manifest only with
social networks. With a few caveats, the cog- inter-individual differences, which were most higher item load in the memory condition
nitive effects of chronic sleep restriction can reliably captured by variability in response and independent of the number of items in
be characterized with studies that use short- time (Lim et al., 2007). This, and the finding the control condition.
term total sleep deprivation. that superior parietal task-related activation Cholinergic modulation has been shown
Whereas earlier work on cognitive per- yields robustly reproducible state changes, to influence visual processing, attention
formance in sleep-deprived persons was pri- led us to infer that the neural correlates of
marily behavioral, a better understanding of attention failure should be better under-
Michael Chee is Professor and Principal In-
the underpinnings of cognitive decline has stood before seeking to investigate “higher vestigator in the Neuroscience and Behav-
been made possible by various physiological cognitive functions” in detail. ioral Disorders Program and Duke-NUS Grad-
monitoring techniques. Of these, functional While evaluating visual short-term uate Medical School. He received a MBBS
MRI (fMRI) is a particularly attractive meth- memory using a parametric design that from the National University of Singapore and
odology because it affords a non-invasive, varied item load across two conditions, proceeded to complete specialty training in
spatially rich view of online brain function. one in which brief retention was required neurology before making a career switch to
pursue cognitive neuroscience. His research
Our earlier work was dominated by the and another where it was not, we observed focuses on sleep deprivation, as well as healthy
premise that the prefrontal cortex is par- that across these conditions parietal task- cognitive aging, and he uses both structural
ticularly vulnerable to the effects of sleep related activation was reduced from the and functional MRI.
deprivation. However, following several smallest set-size and irrespective of whether michael.chee@duke-nus.edu.sg
2.5 2.5
2 2
activation
activation
1.5 1.5
1 1
0.5 0.5
z = 40 0 0
1 2 3 4 5 6 1 2 3 4 5 6
1.5 1.5
activation
activation
1 1
0.5 0.5
0 0
z = -12 1 2 3 4 5 6 1 2 3 4 5 6
Figure 1. Mean activation (± 1 SEM) in the intraparietal sulcus (IPS) and ventral occipital cortex (VO) associated with the RWP SDP
visual short-term memory (VSTM) and visual perceptual control (VPC) tasks as a function of state (RW: rested wakeful-
ness, SD: sleep deprivation) and set size. There were significant effects of state and set size for the VSTM task, and
significant effects of state for the VPC task in the IPS. In the VO, there were significant effects of state and set size for
both tasks (Chuah and Chee, 2008).
and memory. To evaluate the utility of changes in MR signal and behavior reflect References
fMRI as an adjunct to behavioral testing, the modulation of attention/visual process- Chee, M. W., and Choo, W. C. (2004). Functional
as well as to determine who might benefit ing and suggest that fMRI can be useful as a imaging of working memory after 24 hr of total
from intervention, we conducted a double functionally relevant marker of drug effect. sleep deprivation. J. Neurosci. 24, 4560-4567.
blind, placebo controlled, crossover study In a sister experiment, we found that in Chee, M. W., Chuah, L. Y., Venkatraman, V.,
evaluating the effect of the cholinesterase addition to an effect on improving atten- Chan, W. Y., Philip, P., and Dinges, D. F. (2006).
Functional imaging of working memory following
inhibitor donepezil on visual short-term tion, cholinergic augmentation can facilitate normal sleep and after 24 and 35 h of sleep
memory following 24 hours of sleep dep- episodic memory by modulating prefrontal deprivation: Correlations of fronto-parietal activation
rivation (Chuah and Chee, 2008; Figure 1). cortex activation. with performance. Neuroimage 31, 419-428.
We found that individuals who declined Much work remains if we are to bet- Chee, M. W., and Chuah, Y. M. (2007).
in performance when sleep deprived on ter understand the cause(s) of attention Functional neuroimaging and behavioral
placebo showed the most improvement failure in sleep-deprived persons and how correlates of capacity decline in visual short-term
memory after sleep deprivation.
when given cholinergic augmentation. In these may be ameliorated. Is it our ability Proc. Natl. Acad. Sci. USA 104, 9487-9492.
contrast, individuals whose performance to pre-allocate cognitive resources to the Chuah, L. Y., and Chee, M. W. (2008).
was relatively well maintained during sleep task at hand? Is the representation of sen- Cholinergic augmentation modulates visual task
deprivation did not improve and instead, sory information compromised in sleep- performance in sleep-deprived young adults.
showed a non-significant trend toward deprived persons? Can the provision of J. Neurosci. 28, 11369-11377.
performance decline. Interestingly, drug timely cues alleviate the attention deficits? Lim, J., Choo, W. C., and Chee, M. W. (2007).
Reproducibility of changes in behaviour and fMRI
mediated changes in parietal and extrastri- How would manipulation of noradrenergic
activation associated with sleep deprivation
ate visual cortex fMRI signal correlated with or dopaminergic neurotransmission affect in a working memory task. Sleep 30, 61-70.
the change in performance across state. The attention in this setting?
We have increasingly become a 24/7 soci- and integral membrane proteins are folded
ety with more of us losing sleep each night and post-translationally modified in the ER.
to keep up with the demands of daily life. Perturbations in redox state, pH, calcium
Beyond leaving people drowsy, grouchy homeostasis and energy/glucose depletion
and dependent on their cup of joe, sleep induce ER stress and the UPR. The UPR
loss has major physiological consequences. protects the cell by increasing ER chaper-
Epidemiological studies indicate that sleep one levels, attenuating protein translation
loss leads to insulin resistance, diabetes and increasing the degradation of misfolded
and obesity (Van Cauter et al., 2007). Sleep proteins which prevents the accumulation of
loss has also been shown to lead to deficits misfolded proteins that can form toxic pro-
in cognitive function (Van Dongen and tein aggregates. The UPR is healthy, protective
Dinges, 2003). Molecular studies indicate and adaptive when the ER stress is moder-
that sleep deprivation has marked effects ate. Failure of the adaptive response leads to
on several cellular pathways including mac- the activation of an inflammatory response.
romolecular synthesis (protein, lipid, cho- Prolonged, unresolved ER stress activates
lesterol and heme), synaptic signaling and pro-apoptotic executioner pathways.
chaperoning systems (Cirelli et al., 2004; Our studies indicate that moderately
Mackiewicz et al., 2008). Withholding sleep acute sleep loss leads to the induction of
in mice and rats for as little as six hours leads
to the down-regulation of macromolecule
synthesis and an increase in synaptic signal- Nirinjini Naidoo is an Assistant Professor in
the Division of Sleep Medicine and a member
ing and chaperone activity.
of the Center for Sleep and Respiratory Neuro-
The increase in one particular protein, biology at the University of Pennsylvania. She
the endoplasmic reticulum (ER) chaperone received her Master’s degree in Biochemistry
BiP, was found to be conserved in all species from the University of Durban-Westville, South
(Drosophila, rat, mouse, Djungarian hamster, Africa, and a Ph.D. in Chemistry from the Uni-
white crowned sparrow) studied thus far. This versity of Pennsylvania. Her research interests
chaperone serves as a sentinel for up-regula- include mechanisms of sleep regulation and
mechanisms involved in the aging of sleep and
tion of several signaling pathways collectively wake with particular emphasis on the role of
called the unfolded protein response (UPR) the ER stress response. She is also using pro-
that are activated when protein folding and teomic approaches to study sleep disorders.
ER homeostasis are perturbed. All secretory naidoo@mail.med.upenn.edu
RESISTANCE
restriction. J. Clin. Sleep. Med. 3, 519-528.
Goel, N., Banks, S., Mignot, E., and Dinges, D. F.
(2009). PER3 polymorphism predicts cumulative
TO SLEEP
sleep homeostatic but not neurobehavioral changes
to chronic sleep restriction. PLoS ONE 4(6): e5874.
Groeger, J. A., Viola, A. U., Lo, J. C., von
Schantz, M., Archer, S. N., and Dijk, D. J.
DEPRIVATION
(2008). Early morning executive functioning during
sleep deprivation is compromised by a PERIOD3
polymorphism. Sleep 31, 1159-1167.
Van Dongen, H. P., Baynard, M. D., Maislin, G.,
and Dinges, D. F. (2004). Systematic
By Namni Goel and David F. Dinges interindividual differences in neurobehavioral
impairment from sleep loss: evidence of trait-like
differential vulnerability. Sleep 27, 423-433.
Viola, A. U., Archer, S. N., James, L. M.,
Groeger, J. A., Lo, J. C., Skene, D. J., von
Schantz, M., and Dijk, D. J. (2007). PER3
polymorphism predicts sleep structure and waking
performance. Curr. Biol. 17, 613-618.
References
Lemoine, P., Nir, T., Laudon, M., and Zisapel, N.
(2007). Prolonged-release melatonin improves
sleep quality and morning alertness in insomnia
patients aged 55 years and older and has no
withdrawal effects. J. Sleep Res. 16, 372-380.
Luthringer, R., Muzet, M., Zisapel, N., and
Otmani, S., Demazieres, A., Staner, C.,
Jacob, N., Nir, T., Zisapel, N., and Staner, L.
(2008). Effects of prolonged-release melatonin,
zolpidem, and their combination on psychomotor
functions, memory recall, and driving skills
in healthy middle aged and elderly volunteers.
Hum. Psychopharmacol. 23, 693-705.
Staner, L. (2009). The effect of prolonged-release
melatonin on sleep measures and psychomotor
performance in elderly patients with insomnia.
Int. Clin. Psychopharmacol. [Epub ahead of print].
Wade, A. G., Ford, I., Crawford, G.,
McMahon, A. D., Nir, T., Laudon, M., and
Zisapel, N. (2007). Efficacy of prolonged release
melatonin in insomnia patients aged 55-80 years:
quality of sleep and next-day alertness outcomes.
Curr. Med. Res. Opin. 23, 2597-2605.
Zisapel N. (2007). Sleep and sleep disturbances:
biological basis and clinical implications.
Cell. Mol. Life Sci. 64, 1174-1186.
Major advances in the neuroscience of abnormalities. This general finding has led memory consolidation paradigms recently
the functional relevance of sleep for brain some to suggest that the major problem of demonstrated abnormalities in insom-
function, as evident from this special issue, insomnia is a misperception of their sleep nia. Also, fMRI studies demonstrated that
should inspire us to see to a good night’s state. However, there is a large gap between compensatory brain activation masks per-
sleep. However, for the 10% of us that the routine polysomnographic evaluation formance deficits that were expected with
struggle with chronic insomnia, this is not and the presently available neuroimaging the suboptimal activation of brain circuits
easily accomplished. Insomnia is the most tools. Can we be sure that nothing is wrong dedicated to the cognitive processes probed
frequent complaint in both psychological if we base our conclusion on the somewhat by the task.
practice and the sleep clinic and a major archaic qualitative analysis of staging sleep Thirdly, with a prevalence of about 10%,
risk factor for the development of a psy- on the basis of two EEG-channels? As a it is unlikely that a single diagnostic cate-
chiatric disorder. Yet, our understanding of metaphor: would we send a patient with gory suits the whole heterogeneous group of
its brain mechanisms falls painfully behind cardiovascular complaints home after tak- people wrestling with poor sleep. The situ-
with our accomplishments in understand- ing his pulse only and concluding that noth- ation may be compared to the diagnosis of
ing the neuroscience of normal sleep. ing strange can be observed? We would not, dementia many years ago; by now we know
Therefore, this year, more than 100 since we know that a multichannel cardio- that it is essential to differentiate between
researchers and clinicians from 23 countries gram might be applied to reveal subtle signs Alzheimer’s, vascular, fronto-temporal,
committed themselves to cooperate in the of severe heart failure. etc. Finding homogeneous subgroups of
European Insomnia Network with the aim Likewise, we might learn more about insomnia phenotypes now seems possible.
to accelerate progress in our understand- insomnia by applying state-of-the-art neu- Widespread Internet access now allows for
ing of the neuroscience of this debilitating roimaging tools. For example, researchers large-scale international studies applying
condition. How can we accomplish such on the neural correlates of consciousness questionnaires and computerized tasks to
acceleration? (NCC) that developed and applied sophisti- obtain a multivariate characterization of
A major problem that has obstructed cated analyses of EEG, MEG and MRI, now insomnia in subjective, behavioral, environ-
progress in our understanding of chronic have evidence that the complexity and recur- mental, performance and even molecular
insomnia is that the diagnosis is based exclu- rency of brain activity determine whether genetic dimensions. Subsequent application
sively on subjective complaints. A routine a stimulus induces a conscious experience. of the above mentioned neuroscience tools
polysomnographic evaluation seldom shows Application of these tools to insomnia may to selected homogeneous subgroups will
reveal the neural correlates of the subjec- strongly increase the likelihood of finding
1
Netherlands Institute of Neuroscience, an Institute tive experience of lying awake during a poor robust abnormalities.
of the Royal Netherlands Academy of Arts night’s sleep better than qualitative analysis The European Insomnia Network will
and Sciences, Amsterdam, The Netherlands of a two-channel EEG does. work on the normalization of minimal data
e.van.someren@nin.knaw.nl
2
Klinikum Ingolstadt, and Max Planck Institute
A second major problem has been to sets to allow for exchange and a database;
of Psychiatry, Munich, Germany objectify the subjective complaints of on promoting neuroscientists to learn about
3
Hotel Dieu de Paris, Paris, France daytime functioning. Standard neuropsy- insomnia and sleep scientists to catch up on
4
University of Glasgow, Glasgow, Scotland chological tests have not unequivocally neuroscience; and on promoting the devel-
5
Neurocenter (EOC) of Southern Switzerland, Lugano, demonstrated performance deficits. Here opment of better models and pharmaco-
and Neurology Department, University Hospital,
Zürich, Switzerland
again, application of advanced neuro- logical treatments for insomnia. These are
6
Freiburg University Medical Center, Freiburg, science methods seems necessary. Indeed, essential steps to ameliorate the profound
Germany computerized psychomotor assessment and suffering of one out of ten of us.
Sleep disturbances are a core feature of turbances may be critical in remission and
recovery. Sleep-focused treatments, such as
References
posttraumatic stress disorder (PTSD). Germain, A., Buysse, D. J., and Nofzinger, E.
PTSD is characterized by three symptom imagery rehearsal for nightmares and pra- (2008). Sleep-specific mechanisms underlying
clusters that arise and persist for more than zosin (a noradrenergic alpha-1 antagonist), posttraumatic stress disorder: integrative review
one month after exposure to a traumatic are associated with clinically meaningful and neurobiological hypotheses. Sleep Med.
event, defined as experiencing or witness- improvements in nighttime and daytime Rev. 12, 185-195.
symptoms of PTSD (Maher et al., 2006). Germain, A., Hall, M., Krakow, B.,
ing of a real or perceived threat of death or
Katherine Shear, M., and Buysse, D. J. (2005).
injury to one’s self or others, and associ- However, the study of sleep in PTSD has A brief sleep scale for Posttraumatic Stress
ated with intense feelings of fear, horror, been mostly limited to cross-sectional stud- Disorder: Pittsburgh Sleep Quality Index Addendum
or hopelessness. The symptom clusters are ies using self-report or polysomnographic for PTSD. J. Anxiety Disord. 19, 233-244.
re-experiencing symptoms, avoidance and measures (Kobayashi et al., 2007). Kobayashi, I., Boarts, J. M., and
hyperarousal. Because of the importance of sleep in Delahanty, D. L. (2007). Polysomnographically
Nightmares and insomnia are hallmarks PTSD and the limitations of extant research, measured sleep abnormalities in PTSD:
a meta-analytic review. Psychophysiology 44,
of PTSD (Ross et al., 1989). Nightmares our program at the University of Pittsburgh
660-669.
refer to replays of traumatic events, but encompasses two approaches with a pri- Maher, M. J., Rego, S. A., and Asnis, G. M.
other unpleasant dreams are also com- mary focus on sleep and PTSD. The first (2006). Sleep disturbances in patients with
mon and associated with comparable dis- focuses on investigating the role, nature, post-traumatic stress disorder: epidemiology,
tress. Insomnia refers to difficulty falling and neurobiological underpinnings of sleep impact and approaches to management.
or staying asleep. Other sleep disturbances disturbances that contribute to PTSD. The CNS Drugs 20, 567-590.
endorsed by patients with PTSD include second focuses on evaluating the efficacy Ross, R. J., Ball, W. A., Sullivan, K. A.,
and Caroff, S. N. (1989). Sleep disturbance
bad dreams unrelated to traumatic events, of established and novel sleep-specific as the hallmark of posttraumatic stress disorder.
simple and complex motor behaviors, pharmacological and cognitive-behavioral Am. J. Psychiat. 146, 697-707.
nocturnal panic attacks, and sleep terrors interventions on nighttime and daytime
(Germain et al., 2005). Although consid- symptoms of PTSD, and identifying how
ered symptoms of stress reactions, sleep response to sleep treatments normalizes the sleep and PTSD in combat-exposed military
disturbances can develop into persistent behavioral, psychophysiological, and func- veterans. Our studies include a broad array
and independent comorbid conditions, tional neuroanatomical correlates of PTSD of sleep assessments including validated self-
which are often resistant to pharmaco- during sleep and wakefulness. Our ongoing report measures, objective measures of sleep
logical or cognitive-behavioral PTSD clinical and neuroimaging studies focus on and wakefulness patterns, such as actigra-
treatments. phy (a wristwatch-like device composed of
Findings from animal and human stud- accelerometers to monitor and record activ-
ies support the hypothesis that sleep dis- Anne Germain is Assistant Professor of Psy- ity/movement levels across several 24-hour
chiatry at the University of Pittsburgh School
turbances play an important role in the periods), and in-home or laboratory-based
of Medicine Center. She obtained her doctoral
development and persistence of PTSD and degree in Clinical Psychology from the Univer- sleep studies (polysomnography), quanti-
associated poor health outcomes (Germain sité de Montréal in 2001, and completed her tative electroencephalography (qEEG), and
et al., 2008). For instance, the occurrence post-doctoral training at the University of Pitts- positron emission tomography.
of sleep disturbance after exposure to burgh in 2005. Her research focuses on the Understanding the psychophysiologi-
traumatic events increases the risk for assessment, treatment and neurobiological cal and neurobiological underpinnings of
underpinnings on nightmares and insomnia PTSD across the sleep-wake cycle is essential
developing chronic PTSD, and sleep dis-
comorbid with stress-related disorders, with
turbances independently contribute to emphasis on PTSD. Her research also focuses
in developing and refining prevention and
poor clinical outcomes in patients with on identifying the sleep-specific predictors of intervention strategies to enhance resilience
PTSD. Additionally, clinical observations treatment response. to traumatic stress and to hasten the recov-
suggest that the normalization of sleep dis- germaina@upmc.edu ery of patients with PTSD.
FOR A NEW
G., and Herscovitch, P. (1997). Regional cerebral
blood flow throughout the sleep-wake cycle:
An (H2O)-O-15 PET study. Brain 120, 1173-1197.
NEUROCOGNITIVE
Domhoff, G. W. (1996). Finding meaning in dreams:
A quantitative approach. New York: Plenum.
Domhoff, G. W. (2003). The scientific study of
dreams: Neural networks, cognitive development,
THEORY
and content analysis. Washington, DC: American
Psychological Association.
Domhoff, G. W., and Schneider, A. (2008).
OF DREAMING
Studying Dream Content Using the Archive
and Search Engine on DreamBank.net. Conscious.
Cogn. 17, 1238-1247.
Foulkes, D. (1999). Children’s dreaming and
the development of consciousness. Cambridge,
By G. William Domhoff MA: Harvard University Press.
occurs whenever there is 1) an intact and based on blind analyses that are confirmed
fully mature neural network for dreaming; by the dreamer (Domhoff, 1996; Domhoff
2) an adequate level of cortical activation; and Schneider, 2008).
3) an occlusion of external stimuli; and 4) At the same time, longitudinal and cross-
the loss of conscious self-control, i.e., a shut- sectional studies of children ages 3 to 15
ting down to the cognitive system of “self ” in the sleep laboratory reveal that dream-
(Domhoff, 2003). ing is not simply a brain function; it is a
Studies of neurology patients who have gradual cognitive achievement that emerges
experienced changes in dreaming or loss of between ages 4 and 6 in stages that parallel
dreaming, along with neuroimaging studies waking cognitive development, especially in
of normal adults, suggest a neural network terms of visuospatial skills. Dreaming only
for dreaming that encompasses the lim- becomes adult-like in its cognitive complex-
bic, paralimbic, and association cortices, ity at ages 9-10 and dream content does not
with little or no role for the dorsolateral resemble that of adults in length, content,
prefrontal cortex, sensorimotor cortex, or and emotions, or to have any relationship
primary visual cortex. This truncated neural to personality and waking concerns until
network, cut off from the primary sensory ages 11-13 (Foulkes, 1999).
Research in recent decades has led to a cortices that provide information about Although studies of dream content sug-
neurocognitive theory of dreaming that the external world, and from the prefron- gest that dreams have coherence and con-
transcends old arguments and is test- tal cortices that integrate incoming sensory tinuity with waking concerns, many other
able by those working with neuroimag- information with waking decision-making, studies, including the neuropsychological
ing techniques and/or neurology patients. operates as a closed loop to generate the and developmental studies just summa-
Dreaming draws upon the same conceptual process of dreaming (Braun et al., 1997). rized, suggest that dreaming has no adap-
systems that underlie waking thought and Thus, an unconstrained and freewheeling tive function. Thus, adaptive function and
conceptual system operates during sleep, psychological meaning must be treated
whenever there is sufficient brain activation separately. Dreams are the accidental by-
G. William Domhoff, Ph.D., is a distinguished in either REM or non-REM sleep. Paralleling products of two great evolutionary devel-
Research Professor in Psychology at the
these findings, systematic studies of thou- opments, sleeping and thinking (especially
University of California, Santa Cruz, where
he has taught since 1965. His research find- sands of dream reports show that dream mental imagery). However, because dreams
ings and many articles on dream content, content is often realistic, based in everyday have psychological meaning, people in small
along with details on his neurocognitive concerns, and consistent over years and dec- traditional cultures developed “uses” for
theory of dreams, can be found on his web- ades, which suggests that the neural network them in medicinal and religious practices.
site www.dreamresearch.net; his searchable for dreaming contains enough cognitive They also can be a source of artistic inspira-
archive containing 22,000 dream reports is processing areas, such as the medial frontal tion or personal insight.
available to everyone at www.dreambank.
net. His recent 72-minute lecture on dreams
cortex and anterior cingulate cortex, to pro- The future of dream research lies with
is accessible on YouTube under the title “Your duce coherent dramatizations that reflect those who study neurocognition and/or
Nightly Dreams.” the dreamer’s conceptions and concerns in use quantitative methods to study dream
domhoff@ucsc.edu waking life, as demonstrated by inferences content.
Frequency
100
Power
(Hz) 050
0
18
(0-250Hz)
14
Power
10
120 Time (sec) 150 180 Figure 1. Increased hippocampal synchrony during pha-
2 sic REM sleep. Identification of phasic REM epoch by
bursts of transient increases in wide band power and
1 increased theta frequency oscillation. On the right, intra-
and inter-regional synchrony in hippocampal networks
Amplitude
0
(red) epochs. Bar height reflects within-region synchro-
-1 ny changes, while arrow thickness reflects between-
region coordination changes. Phasic REM is accompa-
-2 nied by the highest synchronization throughout the
156 158 160 trisynaptic circuit.
REM sleep is the brain’s most isolated state significant decreases compared to the wak- References
from the body and environment, but it ing state, suggesting a decreased ability of Cantero J. L., Atienza M., Stickgold R.,
is “paradoxically” associated with physi- the hippocampus to transfer memories Kahana M. J., Madsen J. R., and Kocsis B.
ological forebrain patterns similar to the in tonic REM. In contrast, phasic REM (2003). Sleep-dependent theta oscillations in the
waking, conscious brain (Llinás and Paré, epochs were characterized by higher theta human hippocampus and neocortex. J. Neurosci.
1991; Jouvet, 1999). Since dream content, and gamma synchrony among the dentate, 23, 10897-10903.
Chu N., and Bloom F. E. (1973). Norepinephrine-
assumed to be the product of REM sleep, CA3, and CA1 regions, compared to waking.
containing neurons: changes in spontaneous
reflects the history of the self, it has long Phasic REM epochs could be readily rec- discharge patterns during sleeping and waking.
been postulated that dreams emanate from ognized by the transient (1-2 sec.) increase Science 179, 908 -910.
internal activation of memories; that is from of wide-band power (1-200 Hz), increased Jouvet M. (1999). The paradox of sleep:
the coordinated activity in the hippocam- unit firing in multiple regions and twitching the story of dreaming. Cambridge, MA: MIT.
pal-neocortical system. We suggest that of whiskers and limb muscles. Thus, during Llinás R. R., and Paré D. (1991). Of dreaming
such communication can take place only phasic REM epochs effective hippocampal- and wakefulness. Neuroscience 44, 521-535.
Montgomery S. M., Sirota A., and Buzsáki G.
in the phasic bursts of REM sleep. neocortical communication becomes pos- (2008). Theta and gamma coordination of
During tonic periods of REM sleep (95% sible and the brain transiently re-gains its hippocampal networks during waking and rapid
of total REM in the rat), gamma power and control over the body. In contrast to tonic eye movement sleep. J. Neurosci. 28, 6731-6741.
unit firing in the hippocampal CA1 region REM, characterized by virtual cessation of
and CA3-CA1 gamma coherence showed activity in locus ceruleus, during phasic
epochs neurons in locus ceruleus can dis- we hypothesize that these short but pow-
charge short spike bursts (Chu and Bloom, erful episodes are responsible for generating
György Buzsáki is a Board of Governors Profes- 1973). These bursts may release a sufficient the dream content of sleep. These phasic
sor of Neuroscience at Rutgers University. His amount of the critical neurotransmitter to windows are of particular interest in light
primary interests are brain oscillations, sleep
transiently reinstate synchrony among cor- of recent observations in depth recordings
and memory. With more than 200 papers pub-
lished on these topics, he is among the 250 tical and spinal networks. from the hippocampus in human epileptic
most-cited neuroscientists. Recent book: G. Reinstatement of CA3-CA1 communi- patients. Theta oscillations in these human
Buzsáki (2006). Rhythms of the Brain, OUP. cation during phasic bouts of REM sleep subjects were only observed in short bouts
buzsaki@andromeda.rutgers.edu may provide windows of opportunity for lasting a second or so (Cantero et al., 2003).
information, encoded in the dentate-CA3 The short bouts of highly synchronous
Sean M. Montgomery has graduated from Rut- network during tonic REM, to be replayed hippocampal patterns during phasic REM
gers University in 2008. His main interest is how
cell assemblies serve cognitive functions. For back to the neocortex (Figure 1). Because epochs suggest that multiple event repre-
his non-academic ventures visit http://osiris. phasic REM epochs transiently re-establish sentations are replayed either simultane-
rutgers.edu/frontmid/indexmid.html. waking-like communication between the ously or in rapid succession, which may
produceconsumerobot@gmail.com hippocampal regions and the neocortex, explain the bizarre nature of dreams.
Relative to cognition, surprisingly less emotional stimuli (Yoo et al., 2007), further and other such studies support a role for
research attention has been given to the associated with the loss of top-down medial sleep in recalibrating the appropriate con-
interaction between sleep and affective prefrontal connectivity, yet increased cou- nectivity of limbic circuits, resetting affec-
brain function, despite the prominent co- pling with autonomic activating brainstem tive brain reactivity for next-day emotional
occurrence of abnormal sleep in almost regions. Larger pupillary response (indexing challenges.
all clinical mood disorders. Nevertheless, greater autonomic reactivity) to negative
recent work has begun to describe a clari- picture stimuli following a similar dura- Affective Memory (Re)processing
fying role for sleep in emotion regulation, tion of sleep deprivation have also recently Several reports have described the selective
vignettes of which I review below, followed been reported (Franzen et al., 2009). These memory consolidation of negative (unpleas-
by a proposed REM sleep hypothesis of ant) emotional stimuli across periods con-
emotional brain homeostasis. taining sleep, relative to equivalent daytime
periods awake, as well as late-night versus
Matthew P. Walker earned his Ph.D. in Neuro-
Emotional Reactivity physiology from the Medical Research Council, early-night sleep (rich in REM) (Walker
Numerous studies have described an UK, and subsequently became an Assistant and van der Helm, 2009). Most recently,
increase in subjective affective disturbance Professor of Psychology at Harvard Medical Nishida et al. (2009) reported that REM
following sleep loss, intensifying nega- School. He is currently an Assistant Professor not only facilitates the consolidation of
tive mood reports while reducing posi- of Psychology and Neuroscience at University negative memories, but that specific theta
tive mood ratings associated with daytime of California Berkeley. His research examines brain oscillations during REM correlate
the impact of sleep on human brain function,
activities (Walker and van der Helm, 2009). with a particular focus on the role of sleep in
with these improvements. REM sleep may
Objectively, it has been demonstrated that memory processing, neural plasticity and emo- therefore offer a unique neurophysiologi-
one night of sleep deprivation amplifies tional regulation. cal substrate for the (re)processing of emo-
amygdala reactivity in response to negative mpwalker@berkeley.edu tional experiences.
A REM Sleep Hypothesis such decoupling takes place within the References
While abundant evidence suggests that unique biological theater of REM (and Franzen, P. L., Buysse, D. J., Dahl, R. E.,
emotional experiences persist in our auto- potentially dreaming), such that we sleep Thompson, W., and Siegle, G. J. (2009). Sleep
biographies over time, an equally remark- to forget the emotional tone, yet sleep to deprivation alters pupillary reactivity to emotional
able but less noted change is a reduction remember the tagged memory of that epi- stimuli in healthy young adults. Biol. Psychol. 80,
in the affective “charge/tone” associated sode (SFSR model; Figure 1). Specifically, 300-305.
Nishida, M., Pearsall, J., Buckner, R. L., and
with their recall. The reason emotional increased activity within limbic networks
Walker, M. P. (2009). Prefrontal theta during REM
experiences persist more robustly than during REM sleep dreaming offers the sleep enhances emotional memory. Cereb. Cortex
neutral memories is due to autonomic ability for reactivation of previously 19, 1158-1166.
neurochemical reactions elicited at the acquired affective experiences. Secondly, Walker, M. P., and van der Helm, E. (2009).
time of the experience, creating what we dominant REM-theta oscillations within Overnight therapy? The role of sleep in emotional
term an “emotional-memory” (Figure 1). subcortical and cortical nodes offer large- brain regulation. Psychol. Bull. 135, 731-748.
However, the later recall of these memories scale synchronous network cooperation, Yoo, S. S., Gujar, N., Hu, P., Jolesz, F. A., and
Walker, M. P. (2007). The human emotional brain
tends not to be associated with anywhere allowing the integration and, as a conse- without sleep - a prefrontal amygdala disconnect.
near the same magnitude of autonomic quence, greater understanding of recently Curr. Biol. 17, R877-878.
(re)activation – suggesting that, over- experienced emotional events in the con-
time, the affective “blanket” previously text of pre-existing neocortical memories.
enveloped around the memory during Thirdly, these REM dreaming processes mational core of emotional experiences
learning has been stripped away, whereas critically take place within a brain devoid (the memory), yet depotentiates the auto-
the information contained within that of aminergic stress neurochemistry. As a nomic charge originally acquired during
experience (the memory) remains. This consequence, REM dreaming achieves a learning (the emotion) – a form of over-
proposed REM hypothesis predicts that balanced neural facilitation of the infor- night therapy.
References
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Hobson, J. A., Pace-Schott, E. F., and Stickgold,
R. J. (2000). Dreaming and the brain: toward a
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Functional neuroanatomy of human rapid-eye-
movement sleep and dreaming. Nature 383, 163-166.
Solms, M. (1997). The Neuropsychology
of Dreams. A clinico-Anatomical Study. Mahwah:
Lawrence Erlbaum Associates.
NEURAL STATES
2000). The activation of mesio-temporal
areas would account for the memory con-
tent commonly found in dreams. However,
IN DREAMS
this mesio-temporal activity occurs in the
context of a relatively low activity of ventral
prefrontal cortex, which is deemed partici-
pating in memory retrieval. This pattern of
By Pierre Maquet regional brain activity would explain the
peculiar aspects of episodic memory in
dreams. Usually, “snips” of recent waking
The neural mechanisms underpinning auditory perceptual features of dreams activity are frequently observed in dream
dreaming activity in humans are still might be related to the activation of pos- reports (65 %). In contrast, complete waking
shrouded in mystery. Functional neuroimag- terior (occipital and temporal) cortices. In life episodes, characterized by the associa-
ing studies provide some initial clues about keeping with this hypothesis, visual imagery tion between specific locations, characters,
the organization of brain function during in dreams is absent in some patients with objects and actions, are seldom described as
rapid eye movement (REM) sleep in relation occipito-temporal lesions (Solms, 1997). On such in dream reports (1.7 %) (Fosse et al.,
to dreaming. The distribution of regional the other hand, emotions which are often 2003). The relative quiescence of the anterior
brain activity differs considerably between reported in dreams would be related to the and ventral prefrontal areas would explain
REM sleep and wakefulness in humans and activation of the amygdala, orbito-frontal that, although the dreamer has access to “day
is characterized by three main features. First, cortex and anterior cingulate cortex (Maquet residues” probably spontaneously generated
in agreement with neurophysiological stud- et al., 1996; Hobson et al., 2000; Maquet, by the coordinated activity of the mesio-
ies in animals, functional imaging studies temporal areas and the posterior cortices,
reported a high activity in the brainstem and the successful retrieval of the various details
thalamic nuclei during REM sleep. Secondly, Pierre Maquet is Research Director at the of a specific past episode is hindered. Low
confirming earlier measures of brain energy National Fund for Scientific Research in the frontal activity would also account for the
Cyclotron Research Centre at the University
metabolism in animals, they observed a high deficits in working memory and execu-
of Liège, Belgium. His research work fo-
activity in limbic and paralimbic areas. cuses on the functional neuroimaging of tive functions that manifest themselves in
Thirdly, they further highlighted the con- human sleep using PET, fMRI and EEG. Dr. dream reports from REM sleep awakenings
trast between this limbic activation and the Maquet’s work follows several different as- (Maquet et al., 1996; Hobson et al., 2000;
relative quiescence of the associative frontal pects of sleep, including the characterization Maquet, 2000).
and parietal cortices. This particular pattern of the cerebral correlates of human sleep, None of these hypotheses about the neu-
of cerebral activity is usually assumed to the relation between sleep and the offline ral correlates of dreaming is yet supported
processing of memories, the neural corre-
correlate with, and possibly influence, the lates of sleep/wake regulation, as well as the
by objective experimental evidence. Further
main characteristics of dreaming activity functional neuroanatomy of unconscious studies should provide a detailed account of
(Maquet et al., 1996; Hobson et al., 2000; patients. the neural correlates of specific features of
Maquet, 2000). The prominent visual and pmaquet@ulg.ac.be human dreams.
The role of sleep in offline processing of We are currently characterizing LC unit with cortical network activation, will pro-
information acquired during wakefulness activity in relation to the dominant oscil- mote the synaptic plasticity necessary for
has been an area of interest for neuroscien- lations occurring during non-REM sleep long term memory consolidation.
tists for several decades. Early studies focused that are modulated by learning. The peaks
on REM sleep, while more recent research has of cortical hyperpolarization or down- References
provided substantial evidence that non-REM state and depolarization or up-state, as Eschenko, O., Molle, M., Born, J., and
sleep is beneficial for memory formation. We well as cortical spindles and hippocampal Sara, S. J. (2006). Elevated sleep spindle density
have found that specific high frequency oscil- ripples, are detected and extracted from after learning or after retrieval in rats.
lations – spindles in the cortex and ripples in LFP signals. LC neuronal activity, though J. Neurosci. 26, 12914-12920.
the hippocampus – occurring during non- diminished, is highly synchronized dur- Eschenko, O., Ramadan, W., Molle, M., Born,
J., and Sara, S. J. (2008). Sustained increase in
REM sleep, are increased by an associative ing non-REM sleep. Striking temporal
hippocampal sharp-wave ripple activity during
learning experience prior to the sleep epi- relationships between LC firing, cortical slow-wave sleep after learning. Learn. Mem. 15,
sode, both in humans and in rats (Eschenko up- and down-states and spindle onset 222-228.
et al., 2006; Eschenko et al., 2008). These high are revealed. Firing of LC neurons occurs Eschenko, O., and Sara, S. J. (2008).
frequency oscillations, tuned to the underly- mostly during the transition from down- Learning-Dependent, Transient Increase of
ing slow oscillations characteristic of non- to up-state, in a time window of 50-300 ms Activity in Noradrenergic Neurons of Locus
REM sleep may well be the physiological after the peak of cortical hyperpolariza- Coeruleus during Slow Wave Sleep in the Rat:
Brain Stem-Cortex Interplay for Memory
substrate promoting memory consolidation tion. In addition, LC activity is systemati- Consolidation? Cereb. Cortex 18, 2596-2603.
during sleep (Molle et al., 2006). cally elevated immediately after the spindle Molle, M., Yeshenko, O., Marshall, L.,
The noradrenergic system is engaged in onset. These temporal relations suggest Sara, S. J., and Born, J. (2006). Hippocampal
a late phase of memory consolidation, as functional inter-relationships between the sharp wave-ripples linked to slow oscillations
indicated by pharmacological studies (Sara noradrenergic nucleus and frontal cortex in rat slow-wave sleep. J. Neurophysiol. 96,
et al., 1999). To examine its relation to sleep that may be involved in offline informa- 62-70.
Sara, S. J., Roullet, P., and Przybyslawski, J.
states, we recorded activity of noradrenergic tion processing during non-REM sleep.
(1999). Consolidation of memory for odor-reward
neurons of the locus coeruleus (LC) during Noradenaline released in the forebrain association: beta-adrenergic receptor involvement
the 2-hour period after learning. Rats were during learning-induced surge of LC activ- in the late phase. Learn. Mem. 6, 88-96.
implanted with microdrives into LC, medial ity, in tight temporal relation of LC firing
prefrontal cortex (mPFC) and CA1 region
of hippocampus, for extracellular unit
and local field potential (LFP) recordings. Oxana Eschenko is a Researcher at the Max Susan J. Sara is a Director (Emerita) at the
Recordings were made in freely behaving Planck Institute for Biological Cybernetics, Laboratoire de Physiologie de la Perception et
where she is developing new fMRI methodol- de l’Action, CNRS, Collège de France. Her re-
rats during their rest period before and after ogy for rodents, combining it with intracra- search has contributed to our understanding
learning odor-reward or place-reward asso- nial microinjections, microstimulation and of how arousal, attention and sleep modulate
ciations. During the recording time the rats extracellular recordings. As a Post-Doctoral memory formation and retrieval. Author of
were mostly in non-REM sleep, a behavioral Fellow in the laboratory of Dr. Sara she inves- nearly 100 monographs and peer-reviewed
state that is usually associated with dimin- tigated the role of cortical and hippocampal papers, she is former President of the Euro-
ished neuronal activity in LC. Nevertheless, oscillations for memory consolidation and pean Brain & Behavior Society and former
contribution of the noradrenergic system. A Chair of IBRO/FENS schools. A graduate of
we found a learning-dependent transient
graduate of Moscow State University, she Sarah Lawrence College (NY), she received a
increase in firing rate of LC neurons during obtained post-doctoral training in electro- Ph.D. from Univerity of Louvain (Belgium) and
non-REM sleep, in a narrow time window physiology in the laboratory of Dr. Mizumori, did post-doctoral research at Oxford Univer-
around 2 hours after learning (Eschenko University of Washington, US. sity and NYU Medical School.
and Sara, 2008). oxana.eschenko@tuebingen.mpg.de susan.sara@college-de-france.fr
DISTURBED
DREAMING
By Ross Levin, Gary Fireman and Alice W. Pope
Disturbed dreams (DD) are vivid dreams DD without high levels of waking distress
marked by intense feelings of fear or terror should have minimal impact on waking
and are the most commonly experienced functioning, while even moderate incidence
parasomnia. Disturbed dreams include both rates of DD with affect distress may be an
nightmares and bad dreams, distinguished important pathway for waking psychopa-
largely by whether they awaken the dreamer thology by sensitizing dreamers to the fear-
during sleep or are remembered upon awak- ful components of their imagery.
ening (Zadra and Donderi, 2000). While A number of recent investigations pro-
occasional DDs are nearly ubiquitous, vide support for this model. In a 21-day
high incidence rates of DD is associated prospective investigation of the sleep and
with poorer psychological well-being and dreaming patterns of over 300 partici-
are a defining symptom of posttraumatic pants, Levin et al. (unpublished material)
stress disorder (Levin and Nielsen, 2007). found that affect load was associated with
However, little is known about the patho- increased DD frequency, but was independ-
genesis of DD or their relation to waking. ent of DD distress. In contrast, affect distress
One promising line of recent work (Levin was uniquely associated with DD distress
and Fireman, 2002) suggests that the waking levels and self-reported psychopathology.
distress engendered by these dreams (DD These results are consistent with earlier
distress), rather than DD frequency, medi- findings by Levin and Fireman (2002) and
ates the relationship between DD and wak- others. Thus, affect load accounted for all
ing psychological impairment. In this way, the unique variance in predicting DD fre-
these data parallel findings in the insomnia quency, and affect distress accounted for
literature. Based on this, Levin and Nielsen all the unique variance in predicting DD
(2007) recently proposed a model that distress and psychopathology.
posits that DDs reflect transitory break-
downs in the naturally occurring emotion
regulation capacities of REM sleep and/or Ross Levin is a Behavioral Sleep Specialist in a Gary Fireman is Professor and Chair of the
private practice in New York City and has pub- Department of Psychology at Suffolk Uni-
dreaming. A key tenet of this model is that versity, Boston, MA. His research interest
lished over 75 peer-reviewed empirical papers
both DD frequency and distress are related on sleep and dreaming over the past 20 years. is in the role of emotional complexity, inten-
but distinct components of the dream- His primary work has been in nightmares and sity, and experience in relation to social
ing process and are largely determined by understanding the connection between waking competence, personal narrative and sleep
different mechanisms. Levin and Nielsen stress, and coping and sleep processes. Dr. quality. He has published over 40 peer-re-
propose that DD frequency is affected by Levin’s work on the pathogenesis of disturbed viewed papers, edited a book, and received
dreaming has been featured in numerous media federal, state and foundation grant funding
transitory shifts in daily stress levels (affect
including the New York Times, ABC Nightline to support his research. Dr. Fireman is a li-
load) while DD distress is determined by a and The New Yorker magazine and he is cur- censed psychologist who has a clinical and
longer standing personality disposition to rently writing a book on emotion regulatory consulting practice in the Boston Metro-
experience heightened distress in response processes during sleep and dreaming. politan area.
to emotional stimuli (affect distress). Thus, rss_levin@yahoo.com gfireman@suffolk.edu
NIGHTMARES
scenarios that metaphorically represent dis-
tressing life events and enable covert rehearsal
of self-protective or self-restorative responses.
VS EXISTENTIAL
These theories are consistent with evidence
that dreams disproportionately involve mis-
fortunes and negative emotions, but they also
DREAMS
have led some investigators to consider the
threat, fear, and defense that is characteristic
of posttraumatic nightmares as prototypic of
dreaming in general. Without denying the
importance of posttraumatic nightmares,
By Don Kuiken theories that one-sidedly emphasize threat,
harm-avoidance, vivid olfactory and audi- dence linking existential dreams to the sepa-
tory phenomena, and physical metamor- ration distress that accompanies bereavement
phoses are prevalent. In existential dreams, (Kuiken, 1993). Also, empirical assessment
intense sadness, separation and loss, strong of the immediate after-effects of nightmares
and clear bodily feelings, and spontaneous indicates that they are consistently followed
changes in feeling are common. Nightmares by lingering anxiety (e.g., environmental vigi-
and existential dreams both include visual lance, apprehension about recurrence; Levin
discontinuities (e.g., sudden scene shifts, and Nielsen, 2007), while the after-effects of
looking closely at dream objects), suggest- existential dreams include lingering sadness
ing the activation of alerting systems that and reported self-perceptual depth (e.g.,
respond to unexpected stimuli (i.e., startle, changes in self-perception, affirmation of
orienting); both involve intense feelings, neglected values; Kuiken et al., 2006).
especially at the moment of awakening; These studies have important implica-
and the imagery of both dream types seems tions for clinical and research definitions of
“real” even after awakening. nightmares. Nightmares often are defined
Despite such evidence of their shared as abrupt awakenings from late night sleep
intensity, nightmares and existential dreams with clear recall of a frightening dream
are precipitated by different life events and narrative (cf. Diagnostic and Statistical
have different effects on the thoughts and Manual of Mental Disorders-IV-TR).
feelings that follow awakening. There is ample However, according to some clinical defi-
evidence linking nightmares to the distress nitions (cf. International Classification of
precipitated by traumatic life events (Levin Sleep Disorders, 2nd edition), the associated
and Nielsen, 2007), and there is some evi- narrative may involve any kind of dysphoric
emotion. Broadening the definition of
fear, and defense may underestimate the nightmares in this way may have unfortu-
influence of other emotion coordinating sys- Don Kuiken is a Professor of Psychology at nate consequences, both clinically and in
tems on dreaming and on dream function. the University of Alberta. He received his B.A. research, because nightmares and existential
in Psychology from the University of Iowa
Beyond the psychobiological system for dreams appear to have different origins and
(1965) and his Ph.D. in Social Psychology
traumatic distress (threat/fear), there is evi- from the University of Texas at Austin (1970). different after-effects. Restricting the defi-
dence of a separate system for coordinat- He has published widely in the areas of nition of nightmares to awakenings from
ing separation distress (sadness/pain). The dreaming and psychological esthetics, with late night sleep with clear recall of a (spe-
importance of distinguishing between these particular attention to the influence of ex- cifically) frightening dream narrative would
two systems is indicated by systematic clas- ceptional dreams and exceptional moments enable more precise location of that source
sificatory studies that have identified two of literary reading on subsequent thoughts of largely unmitigated dream distress. It
and feelings. He has studied these phenom-
types of dreams involving intense negative ena using procedures that range from elec-
would also ensure separate consideration
affect: nightmares and existential dreams trophysiological measurement to phenom- of the sources of dream distress that alter
(Busink and Kuiken, 1996; Kuiken and enological methods. self-understanding and constructively affect
Sikora, 1993). In nightmares, intense fear, dkuiken@ualberta.ca the course of bereavement.
DREAMING
dreaming, subjects are on the edge of both
states. That may be why lucid dreaming so
often gives way to waking or is lost to non-
lucid dreaming. Lucid dreaming is on the
By J. Allan Hobson cusp of two states which are programmed
to be all-or-none, winner take all, with ties
improbable. That’s why lucid dreaming is
so rare and why it is so evanescent.
Brain Imaging
Michael Czisch and his group in Munich
(personal communication), have used MRI
techniques to study brain regional activa-
tion in lucid dreaming subjects. Compared
to non-lucid dreaming, the brain regional
activation pattern was markedly different.
Lucid dreamers showed increased activation
Neurobiologists and cognitive scientists are ing elements of both waking and dreaming patterns of especially those brain regions that
engaged in new efforts to establish the brain consciousness (LaBerge, 1990). distinguish humans from macaque monkeys.
basis of consciousness. Progress in brain For the experimentalist, this means that These areas are not only frontal, as might
imaging and in quantitative EEG recording it may be possible to measure the physio- have been predicted (Voss et al., 2009), but
in humans and in unit recording in animals logical correlates of three conscious states, are temporal and even occipital as well.
have all contributed to this advancement. waking, non-lucid dreaming and lucid Lucid dreaming is an unusual state char-
But progress has been limited by the rela- dreaming in the laboratory. Since the three acterized by elements of both waking and
tive poverty of the paradigms used in these states are psychologically distinct, they dreaming. It is a rare but robust condition,
studies, many of which do not take subjec- should be physiologically distinct. If detect- which has attracted the attention of scien-
tive experience into account. One prom- able, those physiological distinctions might tists with an interest in further specifying
ising, but problematical paradigm, lucid be enlightening. the brain basis of consciousness (Hobson,
dreaming, has recently been employed in press). Quantitative EEG studies indi-
with encouraging and complimentary, if Quantitative EEG Studies cate that both 40 Hz power and fronto-
preliminary, results. Here we consider the Taking advantage of recent improvements occipital coherence are correlates of waking
pros and cons of this approach and interpret in the resolving power and data analysis of consciousness. Brain imaging research has
the results of the new findings. the human electroencephalogram, Ursula shown that the regional activation pattern in
Voss et al. (2009) have been able to show lucid dreaming correlates with those cortical
What is Lucid Dreaming? that lucid dreaming is associated with an areas known to be more highly developed in
It is the rare but robust awareness that we are EEG power and coherence profile that humans than in monkeys. To become aware
dreaming and that we are not really awake is significantly different from non-lucid that one is dreaming, it would appear to be
as we usually assume when dreaming. Thus, dreaming and waking, but intermediate important to ratchet up frontal 40 Hz power
lucid dreaming is paradoxical in contain- between those two states. Lucid dreaming and coherence in a human brain.
is characterized by more 40 Hz power than
William C.
Dement
F
rontiers is delighted to present to REM and established the well known all
Dr. Dement who, more than night sleep patterns. He is one of the first
anyone else, has dedicated his researchers who studied sleeping subjects
whole life to sleep research. using EEG (electroencephalography) and
Even now, at the age of 91, discovered the five stages of sleep. He also
he is still teaching. William initiated a special narcolepsy clinic and
Charles Dement, known as “the father of found that disordered REM sleep proc-
sleep” or “Mr. Sandman”, closes his talks by esses are in fact part of the syndrome of
explaining that he will continue to learn and narcolepsy.
teach until he cannot anymore. Such pas- In 1970, Dement started the first sleep
sion and determination is truly admirable. disorder clinic in the world. Patients with
Dr. Dement started his journey sleep-related complaints were studied with
by earning his M.D.
at the University of
Chicago in 1955 and, “You’re not healthy,
two years later, his Ph.D.
in Neurophysiology. unless your sleep is healthy”
Afterwards, he joined
the lab of Dr. Nathaniel Kleitman, where the first all-night polysomnographic exami-
he helped discover rapid eye movement nation with full management and medical
(REM) sleep, the sleep stage when dreams responsibility. To make an objective assess-
occur. In 1957, he moved to New York City ment of the relationship between daytime
to work at Mount Sinai Hospital. Even function and nighttime sleep, Dement
back then, his private life was involved as developed, with Mary Carskadon, the
he installed a sleep lab at home where he Multiple Sleep Latency Test, which remains
deprived volunteers, including his wife, of the standard diagnostic measure of day-
REM sleep. time sleepiness, i.e., to see how fast people
In 1961, Dr. Dement co-founded the fall asleep. His team were the pioneers in
Sleep Research Society. He joined his understanding the clinical implications and
present department in 1963 and spent the high prevalence of sleep apnea syndromes,
last 46 years studying the neurochemistry of narcolepsy, periodic leg movement, delayed
sleep and the functional significance of the sleep phase syndrome, drug dependency
different sleep stages. Dement showed that insomnia, psychophysiological insomnia,
the visual experience of a dream is related and a host for other disorders.
Nightmares
and existential dreams PTSD
Don Kuiken Anne Germain
Edmonton, AB, Pittsburgh, PA, USA
Canada
Norepinephrine
Gary Aston-Jones
Charleston, SC, USA
Sleep labs
Dalia Shechter-Amir
Freudian theory Ramat Gan, Israel
of dreams
Mark Solms Pharmacology of sleep Sleep deprivation
Cape Town, Nava Zisapel Michael Chee
South Africa Tel Aviv, Israel Singapore, Singapore
SOCIETY
“Sleep needs
to be recognized
as one of the pillars
of good health,
along with diet and
exercise, and people
have to be encouraged
to get adequate sleep”
460 | December 2009 | Volume 3 | Issue 3
THE HIGH PRICE
OF INSUFFICIENT SLEEP
An interview with Dr. Lawrence Epstein
L
awrence Epstein, M.D., is decline in reaction times, vigilance, thinking is predisposed to a more severe problem,
the Chief Medical Officer of and decision-making capabilities and pro- like manic depression, shift work can trigger
Sleep HealthCenters, a Sleep duces deficits in information processing. the disorder.
Medicine specialty group. People who have been without sleep for 24
Dr. Epstein is an instruc- hours perform as badly on driving and other What number of shift workers are we talk-
tor in medicine at Harvard performance tests as people with a blood ing about?
Medical School and the program director alcohol level of 0.10‰, which is above the More than 20% of workers in the indus-
for the Sleep Medicine fellowship training legal limit in every state in the US. trialized world regularly work at night. It
program at Brigham and Women’s Hospital. includes large numbers of people in 24-hour
He was the president of the American How does sleep deprivation affect our industries, like power, mining, transporta-
Academy of sleep medicine from 2005 until society? tion, manufacturing, health care, emer-
2006 and is the co-author of the Harvard As a society, we pay a high price for insuf- gency services (police, firefighters, doctors,
Medical School Guide to a Good Night’s ficient sleep. According to the 2005 National nurses), etc.
Sleep. Sleep Foundation survey, almost three in ten
working adults admit they have missed work What role does lack of sleep play in motor
We sleep 1/3 of our life. Therefore, time or made errors at work because of sleep- vehicle accidents?
spent sleeping is not wasted time. Why do related issues in the past three months. Sleep In the US, the National Highway Traffic
we need to sleep? deprivation together with sleep disorders Safety Administration estimates that 100,000
Sleep is far from wasted time. Befitting are estimated to cost the United States over crashes are caused by drowsy driving each
something we spend so much time doing, US$100 billion per year in lost productiv- year, causing 76,000 injuries and 15,000
sleep serves multiple functions in addition ity, medical expenses, sick leave, and prop- deaths. A 2005 Canadian survey found that
to a conservation function that of reducing erty and environmental damage. Also sleep one in five drivers admitted they had nod-
cardiac, muscle and brain function to curb deprivation played a role in several national ded off at the wheel at least once in the pre-
caloric consumption. Sleep is not a static and international catastrophes, such as the vious year. A 2006 review by the Institute of
time, but rather a dynamic one in which Exxon Valdez oil spill off the coast of Alaska, Medicine of the National Academies found
we grow, repair the body, consolidate our the Space Shuttle Challenger disaster, and that almost 20% of all serious car accidents
memories and sort through the experiences the nuclear accident at Three Mile Island, and 57% of fatal accidents are associated
and lessons of the day. Pennsylvania. with driver’s sleepiness.
What happens if we do not get an adequate Why is sleep deprivation caused by shift How have sleep patterns changed in the
amount of sleep? work so dangerous for an individual, as last century?
Multiple studies have shown that lack of sleep well as for a society? Over the last 50 years, it is estimated that
is directly linked to poor health. Several stud- Shift work results in chronic sleep depriva- Americans have reduced their sleep time by
ies, including the >71,000 subject Nurse’s tion, which often leads to difficulty staying a little over an hour a day on average. In a
Health study from Brigham and Women’s awake on the job and at the wheel caus- 2002 study of over a million Americans, 20%
Hospital in Boston, MA, have shown that get- ing industrial and motor vehicle accidents. reported sleeping 6.5 hours or less each night.
ting too little sleep is associated with a shorter Researchers have linked long-term shift
lifespan. According to another study, only work with an increased risk of heart dis- Does it mean that we live in a sleep sick
four hours a night for several nights results ease of up to 30-40%. It is believed that society?
in changes in metabolism that are similar shift work can cause or contribute to mental Sleep deprivation is a by-product of many
to those in patients developing diabetes health problems, e.g., mood swings, irrita- of the advances of modern society. Artificial
and obesity. Sleep deprivation also causes a bility or mild depression, and if the person light can shift the circadian rhythm that reg-
ulates sleep and wake times, as well as make What efforts are being made to increase
it possible to continue wake behaviors in the the public awareness about the importance
sleep period. Communication, information of sleep?
and entertainment technologies provide us In 2006, the Institute of Medicine of the
the opportunity to engage in around-the- National Academies published a report
clock activities. Transportation advances titled Sleep Disorders and Sleep Deprivation,
allow us to move farther and faster than our an Unmet Public Health Problem. They
body’s sleep/wake system can keep up with. documented the deleterious health con-
As a result, a large part of our population is sequences of sleep loss and sleep disorders
getting less sleep than they need. However, including an increased risk of hypertension,
the individual is a poor judge of the impact diabetes, obesity, depression, heart attack
of sleep deprivation. A recent study from and stroke.
the University of Pennsylvania showed that However, they concluded that awareness
subjects who chronically restricted their among the general public and health care
sleep time became more and more impaired professionals is low, given the magnitude
the longer they maintained that schedule. In of the burden, and called for efforts to
spite of this, their perception of their own increase general awareness and professional
sleepiness plateaued after a few days. They education on the need for adequate sleep.
didn’t think they were getting sleepier even Professional societies, such as the American
while their performance and their reaction Academy of Sleep Medicine and the National
times worsened. Sleep Foundation, have mounted efforts to
educate the public on the dangers of sleep
How, with the pace of modern life, as we deprivation and sleep disorders. Training
fight our biological clock by drinking sev- programs in sleep medicine have been
eral cups of coffee a day, can we still main- established to train physicians to take care
tain the proper sleep hygiene? of patients with sleep disorders.
The key is to recognize the importance of The National Center for Sleep Disorders
sleep and to make “getting adequate sleep” Research has been established to direct
a priority. Sleep is a basic biological drive, research in sleep science. These efforts
like eating or drinking. Not getting an have had some impact: truck drivers
adequate amount of either is detrimental and pilots are now evaluated for sleep
to our health; the same is true of sleep. We disorders on a regular basis, work hour
currently have no substitute for getting the restrictions are in place for medical train-
required amount of sleep. Just as we won’t ing programs and school start times have
go without food or drink, we need to make been changed in some locations to accom-
sure we don’t go without sleep. Setting a modate children’s sleep needs. However,
regular routine with the same bed- and much more needs to be done. Sleep needs
wake-time, setting aside time before bed- to be recognized as one of the pillars of
time to wind down and prepare for sleep, good health, along with diet and exercise,
and understanding the negative effects of and people have to be encouraged to get
caffeine and alcohol on sleep are the first adequate sleep.
steps to developing good sleep habits. By Anna Muller
The International Classification of Sleep common cause is restless legs syndrome, societal impact when the abnormal behav-
Disorders, published by the American which has also been posited as a cause of ior is a criminal act. Murder, sexual assault
Academy of Sleep Medicine in 1990 and hypertension. and other violent crimes have all been
revised in 2005, currently describes more Another frequent sleep-related complaint committed during reported parasomnia
than seventy distinct disorders. While is excessive daytime sleepiness (EDS), the episodes; many of the accused have been
these volumes have clearly improved the most common cause of which is restricted acquitted based upon medical evidence of
recognition of sleep pathology, a marked sleep time. This problem has become more a tendency towards such sleep-related phe-
underdiagnosis and undertreatment of frequent, in part due to the development nomena. Given the increasing awareness of
sleep disorders persists (Young et al., 1997; of a 24-hour society that accompanied such disorders, legal systems throughout the
Owens, 2001). Because of the impressive worldwide advances in technology and world will likely be hearing other sleep-
prevalence of these disorders and their communication. Societal repercussions of related defenses.
repercussions, the societal cost of fail- this problem include absenteeism, reduced Sleep medicine is a fairly novel medical
ure of diagnosis and therapy is massive. productivity and an increased frequency of specialty, and it is likely that our under-
Though most available data come from the industrial and motor vehicle accidents. A standing of sleep disorders will continue
United States, there is reason to believe that second common cause of EDS is obstruc- to grow. While educating scientists and
international statistics are similarly high tive sleep apnea syndrome (OSAS), found clinicians about such diseases will improve
(Soldatos et al., 2005). in approximately 4% and 2% of middle- health worldwide, it is only through further
Insomnia affects more than one third aged men and women, respectively (Young education of the public that optimal care
of Americans annually, and this figure is et al., 1993). OSAS has been associated can be achieved. Until then, sleep pathology
expected to increase. Data from France with hypertension, stroke, diabetes, heart will continue to have a profound impact on
show a direct cost of US$2 billion for 1995 attacks and mortality; affected individu- international society.
for insomnia treatment (Leger et al., 1999), als have also been shown to have a four- to
though the effects of work inefficiency as seven-fold increase in motor-vehicle acci-
a result of fatigue and the treatment of dent (MVA) frequency, presumably due to David A. Schulman received his B.A. degree
from Yale University and his degree in Medicine
other disorders, such as depression, that inattention and fatigue (Teran-Santos et
from Johns Hopkins. He completed a residen-
can be worsened by chronic insomnia al., 1999). The US National Commission cy in internal medicine at the University of
likely drive the total societal cost much on Sleep Disorders Research has estimated Rochester and then trained in pulmonary,
higher. The majority of affected individ- that 36.1% of fatal MVAs may be related critical care and sleep medicine at Boston
uals do not seek advice from healthcare to sleepiness. University. Since 2001, he has served as the
providers about this problem, leading to Parasomnias are sleep-related events that Director of the Sleep Laboratory at Emory Uni-
involve abnormal movements or behaviors; versity in Atlanta, where he also serves as Chief
a prolonged duration of symptoms and
of Pulmonary and Critical Care Services at
increased use of non-prescription treat- night terrors, sleepwalking and bruxism Emory University Hospital and the Director of
ments, including alcohol, to help promote (teeth grinding) are among the most com- the Pulmonary and Critical Care Fellowship
sleep. While insomnia is often related to mon. While such events can be distressing to training program.
an underlying mood disorder, another affected patients, they can have significant daschul@emory.edu
Sleep: A Groundbreaking
Guide to the Mysteries,
the Problems,
and the Solutions
by Carlos H. Schenck
Avery - a member of Penguin Group, US, (2008)
Drowsy society
By Rosalind Cartwright
CAUSES OF SLEEPINESS 2. Insomnia (involuntary) rates are much Studies of truck drivers tested for sleepiness
higher: adult women 61% and men 55%. found 13.5% were sleepy due to short sleep
How much daytime sleepiness is due to Those under 30 and over 65 years have hours and 4.7% due to severe sleep apnea
voluntary short sleep, insomnia, or sleep most trouble falling asleep, staying asleep (Pack et al., 2006).
apnea? or awaking early.
3. Sleep apnea. All studies show men have Pack, A., Maislin, G., Staley, B., Pack, F.,
1. Voluntary short sleep. Both polls and higher rates than women. Polls show Rogers, W., George, F., and Dinges, D. (2006).
research studies agree that 13.5% of 12% of males report apnea a few nights Impaired performance in commercial drivers:
adults average 6 hours or less per night; a week and 8% of women. Older people the role of sleep apnea and short sleep dura-
fewer than the recommended 8. are less subject to this sleep disorder. tion. Am. J. Resp. Crit. Care 174, 446-454.
l l l l l l l l l l l l
CONSEQUENCES In the National Sleep Foundation’s poll (Johnson, 2000) of 1,154 US adults, 62% answered
OF SLEEPINESS they had sleep problems:
In the US, 57% of accidents leading to the Wake “unrefreshed” or daytime sleepy? An average 43% agreed.
driver’s death have been blamed on “fatigue”.
In 2000, 800,000 drivers involved in acci- Working hours Shift work Regular hours
dents were said to have sleep apnea. Truck
drivers, engineers of high speed trains, air- 60 or more 41-60 31-40
plane pilots, medical residents and crews 58% 40% 39% 42% 31%
of supertankers all work long or irregular
shifts contributing to accidents that impact Those who work more hours, or shift work, report higher rates of sleepiness.
public safety and the environment. Those
with chronic short sleep of five hours or less Shift workers also report more work errors – 28% vs 20% by regular hours workers.
suffer the most from daytime sleepiness and
impaired waking functioning. Drowsy while driving? An average 51% agreed.
540
520
500
480
minutes
460
440
420
400
Korea
Japan
Norway
Sweden
Germany
Italy
Mexico
United Kingdom
Belgium
Finland
Poland
Canada
Austria
Tuykey
New Zeland
Spain
United States
France
The French spend more time sleeping than anyone else
in OECD countries – 530 minutes a night, 10 minutes short
of 9 hours. The average French person sleeps for over
an hour a day longer than the Koreans, who sleep the least
in the OECD – 469 minutes, 11 minutes short of 8 hours.
On average in OECD countries one sleeps 502 minutes
per night, or 8 hours 22 minutes.
Source: Organisation for Economic Co-operation and Development (OECD), 2009, Society at a Glance 2009 - OECD
Social Indicators (www.oecd.org/els/social/indicators/SAG). Data based on surveys on nationally representative
samples of between 4,000 and 200,000 people.
IN DIFFERENT
cross-cultural study of sleep. As Head of the
Laboratory for Comparative Human Biology,
she leads in development of field-friendly bio-
CULTURES
markers and cross-culturally robust psychobe-
havioral and ethnographic methods to examine
interactions of culture and biology that contrib-
ute to differences in mental and physical health.
This work spans 12 countries and includes
large ongoing longitudinal studies in the US.
By Carol M. Worthman worthman@emory.edu
ADOLESCENCE
conspire to push sleep later and later into
the night. For most, the school-bell sched-
ule ends sleep prematurely, requiring teens
AND LEARNING
to wake after too short a time and at the
absolute abyss of their circadian alertness
cycle. Many survey studies have shown that
around the time of middle school, young-
By Mary A. Carskadon sters start to go to bed later and sleep in later
Conventional wisdom holds that not only lescent development. As Roenneberg and
is sleep important to prepare the brain for colleagues (2004) demonstrated with their Mary A. Carskadon, Ph.D., trained under the
mentorship of William C. Dement at Stanford
learning, but sleeping on nights following measure of chronotype, the timing of the
University. She is Director of the E.P. Bradley
learning carries added benefit. middle of sleep periods on “free” nights (i.e., Hospital Chronobiology and Sleep Laboratory
Adolescent brain maturation affects the vacations or weekends) progresses later and and Professor in Psychiatry and Human Be-
two sleep regulatory processes: 1) sleep later across the second decade: at age 10, the havior at the Alpert Medical School of Brown
homeostasis by a slowing of the accumula- average chronotype is about 2-3 a.m.; by age University. Carskadon’s research focuses on
tion of sleep pressure during wakefulness 20, it is on average about 4:30 a.m. in women the associations of biological processes and
(Jenni et al., 2005); 2) circadian tim- and later than 5 a.m. in men. The authors sleep/wake patterns of children, adolescents
and young adults. Her research findings have
ing system by a delay in circadian phase infer that the natural timing of midsleep is raised public health issues regarding the con-
(Carskadon et al., 2004). These changes at these delayed times. sequences of insufficient sleep and concerns
collude with 21st century lifestyles to place These developmental changes have an about early starting times of schools.
sleep at increasingly later hours across ado- impact on the sleep of many adolescents in mary_carskadon@brown.edu
Enhancing performance in the workplace is Decreased performance is especially troubling formance on a range of cognitive tasks to the
a constant challenge. Employee fitness and when lives are on the line: aircraft operation, same extent as a night’s sleep. A recent study
wellness programs, telecommuting, free medical care and military campaigns. of napping examined creative problem solv-
coffee and snacks have all been tried in an Sleep is a reliable countermeasure to ing, a valuable asset in most work environ-
effort to have employees give 110%. While decreased performance. It seems counterin- ments (Cai et al., 2009). The authors showed
intended to improve performance, it is diffi- tuitive and somewhat embarrassing to sleep that naps containing rapid eye movement
cult to objectively measure the value of these at work. However, naps appear capable of (REM) sleep produced 40% enhancement
interventions and quantify improvements. reversing daytime fatigue and increasing in creativity, compared with non-REM naps
If the workplace is a combination of cognition. Studies have shown that naps can or quiet rest. These performance improve-
isolated behaviors that can be studied in a enhance alertness, productivity and mood, ments make a case for napping at work. But,
laboratory, research suggests that we cannot and maintain performance at optimal levels. is napping superior to the strategy utilized
give 100% for a sustained period. Laboratory Furthermore, naps produce enhanced per- most often: caffeine?
studies show that repeated testing across a
day results in decreased performance. For
Sara C. Mednick is Assistant Professor in the William A. Alaynick earned his doctorate in
example, training four times in one day on a Department of Psychiatry at the University of Biomedical Sciences from UC, San Diego,
simple visual discrimination task produces a California, San Diego. Her research focuses on studying molecular endocrinology at The Salk
15% decrease in perceptual abilities with each the role of sleep (naps) in memory consolidation. Institute for Biological Studies. With a long-
test session (Mednick et al., 2002). Similarly, In 2003, she received her Ph.D. in Psychology from standing interest in neuroscience, his post-
motor fatigue has been shown to build within Harvard University. She moved to the Salk Insti- doctoral fellowship at The Salk is focusing on
a single session on a typing task (Rickard et al., tute for Biological Studies in La Jolla, Calif., with statistical methods to quantify the molecular
a National Institute of Health, National Research and electrophysiological development of spinal
2008), and verbal memory is vulnerable to for- Service Award fellowship. In 2007, she was cord circuitries. He is a Founder of ScholarN-
getting (Squire, 1986). For shift workers, this awarded a National Institute of Mental Health, exus, L.L.C., a non-traditional consultancy serv-
is compounded by unintentional sleepiness, K01 Mentored Research Scientist Award. ing academics with entrepreneurial interests.
and decreased performance in most skills. smednick@ucsd.edu will@scholarnexus.com
lll
Homicidal somnambulists: Sleepwalking appears to be the most
frequent sleep disorder claimed as defense against murder. As a
References legal defense it has been used, both successfully and not, depend-
Graebner, W. (1965). My Dear Mister Churchill. ing on many variables. In the case of Kenneth Parks, who killed his
London, M. Joseph. mother-in-law, the jury ruled that he had no motive for the murder,
Naska, A., Oikonomou, E., Trichopoulou, A., was unaware of the action and, thus, he was found not guilty. On
Psaltopoulou, T., and Trichopoulos, D. (2007). the other hand, in the case of Scott Falater, the jury ruled that the
Siesta in Healthy Adults and Coronary Mortality actions he took to kill his wife included too much calculation and
in the General Population. Arch. Intern. Med. 167,
were too complex for the mind of a sleeping individual. He was
296-301.
Stang, A., Dragano, N., Poole, C., Moebus, S., sentenced to life in prison without parole.
Möhlenkamp, S., Schmermund, A.,
Siegrist, J., Erbel, R., and Jöckel, K.-H. (2007). lll
Daily siesta, cardiovascular risk factors,
and measures of subclinical atherosclerosis: Rogue proteins cause fatal insomnia in genetically cursed fami-
results of the Heinz Nixdorf Recall Study. lies: A prominent Venetian family had been suffering for untold
Sleep 30, 1111-1119.
Vgontzas, A. N., Pejovic, S., Zoumakis, E.,
generations from a strange affliction; members would suddenly
Lin, H. M., Bixler, E. O., Basta, M., Fang, J., fall into a state of constant insomnia and die of exhaustion within
Sarrigiannidis, A., and Chrousos, G. P. (2007). a year. The reason was unknown until a doctor, who married into
Daytime napping after a night of sleep loss the family, started to investigate the problem in 1979. It was later
decreases sleepiness, improves performance, elucidated that the hereditary disease is due to a protein that
and causes beneficial changes in cortisol and mutates in the brain, similar to the effects of mad cow disease.
interleukin-6 secretion. Am. J. Physiol. Endocrinol.
Twenty-seven other families have now been identified as having
Metab. 292, 253-261.
the disease, five of which in the US. There is currently no cure,
but an association has been formed to help find a cure and raise
the money for research. Scientists hope that the studies may open
Another reason why some people do the door to cures for other rogue protein diseases, and similar
not like to nap is the feeling of groggi- maladies like Alzheimer’s and Parkinson’s.
ness and drowsiness upon awakening.
Determining ones sleep cycle, which lasts lll
between 90 and 110 minutes, can circum-
vent this. During the first 45 minutes or Killer shift: Back in the early 1980s, Philadelphia Police Department
so, a person can be woken easily because received numerous complaints from officers about fatigue, high
they have not yet entered the deep sleep rates of hypertension and cardiovascular disease, and many cases of
phase. Alternatively, one should sleep job-related accidents, injuries and death before reaching retirement
until entering the last and probably best age. All that due to the problematic shift schedule which for many
“remembered” phase, the REM period, in years required officers to rotate among three different shifts: one
which brain waves increase to a level simi- week from 7 a.m. to 3 p.m., the next week from 11 p.m. to 7 a.m.,
lar to being awake. Keeping this in mind, and the third week from 3 p.m. to 11 p.m. Such a “backward” rapid
maybe there is no reason to disdain the rotation was constantly disorientating the internal body clocks of
siesta after all. These days, sleep depriva- the policemen, never allowing them to fully adjust to the new shift.
tion gnaws at us all, with most adolescents After the yearlong study, Dr. Charles Czeisler, an expert in circadian
and adults considering it a luxury to sleep rhythms at Harvard Medical School, suggested to change the work
for eight continuous hours. How can we schedule to a clockwise rotation and to stay on one shift for longer
maintain human ingenuity, creativity and than a week. The alertness of officers improved immediately result-
productiveness with tired minds? ing in much better performance, which in the end contributed to
By Nicole Detzer increased safety on the streets of Philadelphia.
news.bbc.co.uk/2/hi/uk_news/scotland/glasgow_
1
I
nvestigating the level of funding of normally commission research to address
global sleep research is a challeng- specific questions. The applications are gen-
ing task and results were obtained erally submitted by the scientific community
only after a lengthy study. Even in ‘response mode’ and the MRC always
then, the available statistical welcomes high quality applications for sup-
results were extremely limited in port into any aspect of human health. The
their content and only organizations from primary considerations in funding decisions
three countries - the US, United Kingdom are research excellence and importance to
and Australia were found to publish their health. However, high quality proposals in
data regarding sleep research funding. areas of particular strategic importance may
In light of the lack of information pub- be given priority in competition for funds. As
lished on sleep research funding, one can such, they do not have a particular budget
only estimate the ranking of the funding for research funding in sleep, but they were
agencies. According to the data discovered, able to provide an estimate of £1.4 million
the US National Institutes of Health (NIH) directed into sleep disorders research in the
comes first with an increasing amount of year 2007/08.”
funding in this area since 2005. Even the European Union, which is
Table 1 displays the annual support level supposedly the biggest European fund-
for sleep research based on grants, contracts ing agency for general scientific research,
and other funding mechanisms used across does not regularly issue any specific data
the NIH1. on the funding allocated to sleep research.
On second place in the ranking of pub- Only one specific program within the 7th
lished sleep research funding is the Australian Framework Programme (FP7)2 called
National Health and Medical Research “Opportunities for funding and networking
Council (NHMRC). Unlike other agencies, in sleep research3” was published in 2007.
the NHMRC provides very detailed informa- Such a gap in the published data of a high
tion on their research funding (Figure 1). status EU organization should not be dis-
Within Europe, the only detailed infor- regarded. Even more alarming, the statistics
mation on the funding of sleep research was released by the World Health Organization
provided by the British Medical Research are similarly patchy. The WHO publishes its
Council (MRC). When contacted, a repre- statistics in an online database that contains
sentative explained that the council “pro- a vast range of indicators related to devel-
vides funding for research through a range oping countries. However, data on sleep
of grants and personal awards to scientists
at universities, medical schools and other
research institutes. However, it does not 2
This is the main instrument for the European Union to
fund and promote European research and
technological development for the period of 2007 –
Table published January 15, 2009, table revised May
1
2013. Over these 7 years, the program has an
7, 2009: columns for FY 2009 and FY 2010 estimates assigned budget of e 53.2 billion.
updated. Source: report.nih.gov/rcdc/categories/ 3
www.esrs.eu/cms/front_content.php?idcat=88
4
www.nationmaster.com/graph/mor_sle_dis_percap-
mortality-sleep-disorders-per-capita 1.000.000
5
Report: www.reportlinker.com/p0135904/
Reportlinker-Adds-World-Sleep-Disorders-Market-
Analysis-2009-2024.html 0
6
www.mindbranch.com/Sleep-Disorders-R155-372/
7
Source: www.nhmrc.gov.au/grants/dataset/issues/ 2000 2001 2002 2003 2004 2005 2006 2007 2008
sleep.php Note that many grants address more than
one disorder/condition type and may be reported in
more than one type. Some grants may only be Sleep Disorders NEC Snoring Related Issues Sudden Infant Death Syndrome
included in the All Sleep Disorders category because Sleep Apnea Narcolepsy Insomnia
they cannot be clearly defined against a particular
type. Therefore, the total of each type is a discrete
total and adding up all funding for the specific types Figure 1. The sleep research funding in Australia is divided into different categories related to specific sleep disorders,
will not equal the All Sleep Disorders funding row. with sleep apnea receiving the most and narcolepsy the least funding from 2000 to 20087 (in AU$).
about work initially supported by the RLS arts community. Board members live through- ity, it is possible we will fund less than that
Foundation that helped establish a multi- out the United States, including California, in a given year. We are looking for proposals
institutional program project award from Oklahoma and Illinois, as well as in Australia. which will result in furthering the under-
the NIH. Of course, being able to attract Edward Blair, a partner with William Blair standing and treatment of sleep disordered
additional funding is not our only mile- and Company, serves as chairman of the breathing. Semi-annual reports to the foun-
stone, particularly during these difficult foundation; Fiona Tudor is executive director. dations are required, with evidence the study
economic times. Our primary benchmark is The Australian ResMed Foundation has four is moving forward in a timely and effective
the number of publications in peer-reviewed board members and is chaired by Rob Sauer, a manner. Results of many of the studies have
journals that were supported by the RLS partner in the law firm Dibbs Barker Gosling. been published and presented at a variety of
Foundation.” In 2007, to streamline and coordinate assess- symposia.”
INDUSTRY
Wally Cox wears face mask while reading, 1953
SLEEP IS MONEY
T
oday, sleep along with Funding for research and development
other bodily activities is of new continuous positive airway pres-
increasingly the subject sure (CPAP) masks is a priority, as com-
of attention in science. pliance and comfort are important issues
According to experts, for patients. Other trends include smaller
approximately 30% of devices and less complicated equipment.
the world’s population may be suffering The market also looks set to expand the
from sleep disorders. Amongst the well reach of the sleep lab. Since March 2008,
known disorders are insomnia, narcolepsy, portable devices are authorized for home
obstructive sleep apnea (OSA), restless legs testing by the Center for Medicare Services
syndrome (RLS), bruxism, sleep-walking in the US, causing a negative market effect
and chronic insufficient sleep which alto- for sleep labs, but an upsurge in sales for
gether form a multi-billion dollar treat- CPAP devices. The segment is foreseen to
ment market. grow by up to 18% per year, based on an
Capturing only a part of this market independent market analysis.
offers enormous potential and everyone The primary factors driving the market
seems to want a bite of it. Companies all penetration and contributing to the growth
over the world are trying to sell us “a per- of the segment include the large undiagnosed
fect night’s sleep” through pills, mattresses, patient population and growing awareness,
pillows, aromatherapy, as well as more sci- which is supported by projections from
entifically advanced technologies. The sleep manufacturers and independent studies.
market is surely not sleeping; it is growing The OSA devices are very likely to remain
and offering us highly diverse products the most widely used devices in sleep.
ranging from books and eye-masks, to full- Products and Technologies: facial interfaces,
face oxygen masks, implants and high-tech full-face masks, nasal pillows, chin straps,
equipment. ComfortFit, Sleep Weaver, Breeze, Opus 360,
V2 maska, Twilight, ComfortGel, CPAP’s,
Sleep Apnea Device Market bi-levels, Auto PAP’s, humidifiers, ARES™,
The market segment for diagnostic and MediByte, SleepScout, Embletta, Alice PDx,
treatment devices for sleep apnea is grow- Stardust II, Ambulatory PSG, and portable
ing with increasingly informed patients sleep testing (PST)
and manufacturers focused on developing Companies: Respironics, ResMed, Fisher &
new and innovative technologies. In the Paykel, Evo, Circadiance, Covidien, Hans
US, an estimated 38 million people suffer Rudolph, Vital Signs, Inc., DeVilbiss, Drive
from some form of sleep apnea. 15 million Medical, Advanced Brain Monitoring, Inc.,
people have some form of OSA and are in Braebon Medical, CleveMed, Embla, and
need of treatment, which alone presents an SleepQuest
enormous market for treatment and moni-
toring devices1. As a result, a great number Top Device Companies, 4 February 2009. http://www.
1
Over-the-Counter
and Herbal Supplements
According to the 2009 Sleep in America™
Poll, more than 15%, or one in ten, use
relaxation techniques to aid in falling asleep,
about 7% use over-the-counter (OTC) sleep
aids a few nights a week, and over 3% take
some kind of herbal supplement or use
alternative therapy to treat symptoms of
insomnia. A major increase in use of sleep
medications has been noted for both pre-
scribed and OTC sleep aids. Packaged Facts
has estimated that the OTC market in the
US will total over US$759 million by 2013.
This encompasses OTC sleep medications,
both analgesic and non-analgesic, and
herbal supplements intended to aid sleep. In
the US, OTC medications are more widely
used than prescription medications.
The most common and widely avail-
able antihistamines used to treat sleep
problems are diphenhydramine and
doxylamine. These antihistamines are the
most widely available OTC medications
marketed as sleep aids. Other common
alternatives include valerian, chamomile
and melatonin.
Packaged Facts has estimated that the
total market of OTC sleep remedies will
reach the US$759 million mark by 2013.
Trends within this segment are to focus
marketing on a particular group or for a par- alternative sleep products. The retail sleep where you can actually pay for taking a
ticular purpose, such as children, women, device market segment consists of prod- YeloNap; a 20 to 40 minute power nap. A
jetlag, driving, or the aging population. ucts and accessories designed to enhance growing number of consumers are seeking
Products and Technologies: antihistamines, and aid sleep without any prescription. relief and alternative products that aid in
valerian (valeriana officinalis), chamomile The devices and products are easily acces- sleep and relaxation and the market is offer-
(matricaria recutita), melatonin, passion sible and usable by the consumers. Getting ing a virtually endless sea of products.
flower, ashwagandha, catnip, kava (piper enough sleep represents a boost of produc- Products and Technologies: dreamate,
methysticum), Sleep-Eez, Sominex, Nytol, tivity and marketers in the retail sleep sector nasal dialators, nasal strips, snore stop-
Unisom, Tylenon PM, and Sleepinal focus also on health improvements to lure per, SleepMate, Antisnor Therapeutic Ring,
Companies: Avon Products, Inc., Glaxo consumers. The emphasis on performance SLEEPTRACKER®, sound machines, white
SmithKline, Green Pharmaceuticals, Inc., today makes consumers the perfect target noise machines, light boxes, eye shades, sleep
HoMedics, Inc., Johnson & Johnson, NBTY, for the array of devices that claim to make masks, earplugs, sleep pods, sleep and insom-
Inc. , Dreamerz Foods, and Nature’s Way us more productive. nia books, sleep lounges, fluorescent bulb-
The retail sleep market is as vast as it has based equipment, The Wake Up Light-dawn
Retail Sleep Market growth potential and the market for sleep Stimulator, sleep courses, and music
The retail sleep market is mainly focused therapy products continues to grow. Even Companies: Apollo Health, Brookstone,
on consumers, market space and product hotels market sleep solutions, such as pro- Hammacher Schlemmer, Dream Essentials,
trends. More and more people become grams especially designed by sleep special- Yelo, Metro Naps, The Litebook Company,
conscious about sleep being as important ists, e.g., the Crowne Plaza Sleep Advantage® Ltd., The Sunbox, Co., Verilux, and SoothSoft
as exercise and food. This enables great program offered at the Crowne Plaza Hotels Comfort Technology
marketing opportunities for traditional and and at Yelo, a sleep pod in New York City, By Johanna Reichen
In recent years, we have learned that sleep The development of modern sleep med- Although insomnia affects everyone
deprivation and undiagnosed sleep disor- icine is closely linked to the discovery of occasionally, about one out of every three
ders are arguably one of our largest health the electrical activity of the brain. Richard adults indicates it is a significant problem,
problems. During the last two decades, a Caton was the first to record brain electrical and 50% of these persons consider it to be
strong diagnostic industry has been thriv- activity of animals in England in 1875. The severe. Snoring is another highly prevalent
ing to develop the sleep field including, development of the electroencephalogram condition that has been reported to disrupt
but not limited to, Neurovirtual, Philips (EEG) in 1929, by German Psychiatrist, the sleep of bed partners. Obstructive sleep
Respironics, Embla, and Cardinal Health. Hans Berger, allowed the examination of apnea (OSA) is the most common category
brain activity during sleep. In 1937, A. L. of sleep-disordered breathing and restless
A Look Back Loomis in the United States first docu- legs syndrome (RLS) is also highly prevalent
Sleep medicine is a specialty in the field mented the characteristic patterns of what conditions.
of medicine; sleep disorders have become is now called non-REM sleep: vertex waves, The treatment for sleep apnea is also
a public health concern and sleep sci- sleep spindles, K complexes, and delta slow- non-surgical. It ranges between behavioral
ence has earned its spot as an important ing. He divided sleep into five stages of changes, dental appliances, and continuous
area of research. The American Medical increasing depth from A through E, which positive airway pressure (CPAP). Behavioral
Association recognized sleep medicine as formed the basis for the current classifica- changes refer to dealing with obesity and
a specialty in 1996. However, take a look tion of non-REM sleep. changing positions while sleeping, whereas
back, and you will find the history of sleep Today, the advances in medicine over dental appliances require equipments in
medicine is relatively short and most of the time have contributed significantly to the order to help the person breathe properly.
individuals involved with its development understanding of sleep and sleep research. There are a number of over-the-counter
are still living. There are few, if any, medical specialties that drugs available for the treatment of insom-
The critical importance of sleep to good do not intersect with the past, present, and nia and other sleep related disorders. These
health and life was illuminated by the exper- future understanding and study of sleep. contain sedatives or suppressants that slow
iments conducted in rats by Rechtschaffen. Neurology, pulmonology, psychology, psy- down the activity of the central nervous
In these experiments, total sleep deprivation chiatry, physiology, cardiology, otolaryn- system.
resulted in the death of all rats within two to gology, etc., are all integral areas of sleep
three weeks. Selective deprivation of non- study. The Sleep Industry
rapid eye movement (non-REM) and rapid During the last two decades, a strong diag-
eye movement (REM) sleep also resulted Waking up to the Problem nostic industry has been thriving to develop
in the death of the animals over a slightly In addition to the major problem of sleep the sleep field including Neurovirtual/
longer period of time. deprivation related to social or occupational Sleepvirtual, Philips Respironics, Embla, and
In human beings, there is also informa- activities, the International Classification of Cardinal Health. A number of foundations
tion on the long-term effects of insufficient Sleep Disorders (ICSD) lists 88 sleep-related have been organized to improve the quality
sleep. An early study, conducted by Kripke, disorders. In recent years, we have learned
used information collected by the American that sleep deprivation and undiagnosed
Cancer Society on more than one million sleep disorders are arguably some of the Lenneice A. Drew is a Communications/Public
human beings. Mortality rates after six years biggest health problems. Relations professional for global leader Neuro-
of follow-up were significantly increased virtual. She works diligently to share the com-
for people who had less than four hours pany’s commitment to excellence in sleep
Ed Faria is Founder and Chief Executive Officer medicine. Lenneice has years of experience in
or more than ten hours of sleep per night. at Neurovirtual/Sleepvirtual. He received his the field of print and broadcast journalism. She
These results were reconfirmed in a second Master in Business Administration from the has a B.Sc. degree in Journalism/Mass Commu-
survey of 1.1 million human beings con- University of California, Irvine. nication from Florida International University.
ducted between 1982 and 1988. efaria@neurovirtual.com ldrew@neurovirtual.com
NeuroVigil
NeuroVigil was founded in California in
2007. The technology of the company, a NeuroVirtual/
highly sophisticated algorithm, can inter- SleepVirtual
pret sleep EEG data in less than a minute Sleep Virtual is a sleep technology com-
which generally takes a highly trained neu- pany based in Florida. They have recently
rologist between 30-60 minutes to analyze. launched a new sleep data acquisition device
The technology may increase efficiency, called BWII PSG. It is currently the most
cost-effectiveness and availability of diag- advanced acquisition device on the market,
nostics for sleep disorders. NeuroVigil is the as it is compact, easy to use and keeps you
only company in the world to provide non- up-to-date with live sleep statistics. The
invasive, rapid and high-resolution brain device comes with a report generator and
activity monitoring. The main markets that report templates to facilitate the process of
NeuroVigil aims to target are evaluation of creating sleep reports. This state-of-the-art
sleep apnea, pharmaceutical effect on sleep gadget weighs only eight pounds and can
and a transportation safety device. therefore be easily transported and con-
www.neurovigil.com nected to any laptop or desktop computer.
www.sleepvirtual.com
Transcept
Pharmaceuticals, Inc. ResMed
Transcept Pharmaceuticals, Inc., is a phar- ResMed, a producer of medical equipment
maceutical company focused on the devel- based in San Diego, California, that spe-
opment of products that are aimed at cializes in the production of non-invasive
treating illnesses within the neuroscience ventilation technology for patients suffer-
field. They currently have a product in ing from sleep-disordered breathing. They
development called Intermezzo ® which have a large range of products available
contains a low dose of zolpidem and is a including ventilation and sleeping devices,
treatment for insomnia. This drug should masks, humidifiers, screening equipment,
alleviate middle of the night awakenings data management and various accessories.
and allow individuals to enjoy a long night’s ResMed’s products are now available in over
sleep. Transcept merged with Novacea, Inc., 70 countries worldwide through a large net-
in January 2009. work of distributors.
www.transcept.com www.resmed.com
mum health and productivity. They special- includes a headstrap recorder that registers helping its clients improve brain function
ize in workplace fatigue management and nocturnal data and measures blood pres- through brainwave assessment, biofeedback
provide online training sessions, as well as sure, pulse rate, oxygen airflow and satu- and entrainment. They work in correlation
workshops and events to help patients boost ration, as well as snoring levels and any with coaches and organizations to ensure
their low energy levels at work. Currently head movements. Along with this comes the best care and guidance for their clients
available on four continents, MetroNaps a screener that evaluates your risk of suf- to achieve their goals. Neurotech also offers
will help train employees and increase their fering from OSA and a data management non-invasive treatment for disorders, such
productivity by improving their sleep, fit- system that helps you evaluate and study as sleep, ADD, OCD, ODD, behavioral,
ness and eating habits. the processed data. anger, anxiety and depression problems.
www.metronaps.com www.b-alert.com www.neurotechcoaching.com
US SLEEP
AIDS MARKET
The sleep market in the United States was to, or inconvenience using, regular sleep
worth around US$23.7 million in 2007; laboratories.
compared to 2000 this is a growth of 77%. Considering that over 70 million US citi-
For 2012, a further growth of 36% has been zens are said to suffer from sleep disorders,
forecasted so the total of the market would the market for sleep medication seems very
then sum up to US$ 32.3 billion. calm. The average age of the eleven most
Six groups of products comprise this prescribed drugs is 29.2 years and 75% of
market and over time their participation these drugs have been on the market for
in the total sales has changed considerably. more than twenty years. When the patent
Mattresses were responsible for almost 70% for the only blockbuster sleep medication,
in 2000, but until 2012 a decrease to 53% Ambien by Sanofi-Aventis, expired in 2007,
of the market revenue is predicted, while the earning in this sector fell from US$3.3
the yearly sales augment from US$9.2 bil- billion in 2006 to US$2.0 billion in 2008.
lion in 2009 to US$17.2 billion in 2012. However, with several products in the
This drive in sales is due to costumer pref- pharmaceutical pipeline, recuperation to
erence to buy more expensive products. In US$3.7 billion in 2012 is expected. Among
2003, 44.3% of all mattresses were priced the new developments is Almorexant, which
below US$500, whereas in 2007, 46.9% of will be distributed by GlaxoSmithKline and
the mattresses sold cost between US$1,000 Actelion. Representing a new approach in
and 1,500. The participation of mattresses treatment, this drug is being observed with
in the price categories US$1,500-2,000 and curiosity. Except for melatonin based prod-
2,000 augmented as well, and in 2007 only ucts, like Rozerem by Takeda, traditional
26.7% of all mattresses sold were priced sleep medications are GABAergic drugs
below US$500. which enhance the activity of the inhibi-
The next important product is sleep tory neurotransmitter GABA. Among the
laboratories and annexed services with side effects of these drugs are hangover-like
revenues of US$2.2 billion in 2000 and sensations on the day following the intake,
a predicted growth of almost 160% to and little to no recollection of actions, such
US$5.8 billion until 2012. An important as eating, walking or driving. They also bear
factor for this development was the deci- a dangerous addiction potential. The FDA
sion of the Center for Medicare Services issued a safety warning for the entire class
in March 2008 to reimburse devices that of sleep GABA agonists in 2007. Almorexant
can be applied at home, thus increasing pursues a different approach by temporar-
the demand by people with little access ily reducing the level of the excitatory neu-
others: 0,1
pillows: 0,9
CPAP* sleep apnea devices: 2
Vapotherm
Precision Flow™ -
High flow oxygen
therapy
www.vtherm.com
Stevensville, MD,
USA
Aspire Medical
Minimally invasive surgical
solutions for treating OSA
www.aspiremedical.com
Sunnyvale, CA, USA
SleepQuest
Sleep diagnostic therapy
and compliance services
www.sleepquest.com
San Carlos, CA, USA
Neurocrine Biosciences
Sleep drug development
www.neurocrine.com
San Diego, CA, USA
The map presents Ethics International Business Medtronic
key companies and Trade The Pillar® Procedure
involved in the Non-invasive treatments non-invasive treatment
sleep industry for sleep disordered breathing for snoring and OSA
across the world. www.aveosleep.ca www.restoremedical.com
Discover the San Diego, CA, USA North Jacksonville, FL, USA
companies and visit NeuroVigil Neuro Virtual / Sleep Virtual
their websites to Analysis of sleep EEG data Sleep medicine technologies
learn more about www.neurovigil.com www.sleepvirtual.com
sleep products. La Jolla, CA, USA Doral, FL, USA
Pacific Medico
Respiratory care products
www.pacific-medico.com
Tokyo, Japan
Hsiner
Respiratory care products
www.hsiner.com
Shengang, Taiwan (R.O.C.)
HypnoCore
Web-based software
for evaluation and diagnosis
of sleep disorders
www.hypnocore.com
Compumedics Limited
Yehud, Israel
Sleep disorder diagnostic
Itamar Medical technologies
Sleep apnea home www.compumedics.com
diagnostic device Abbotsford, Australia
www.itamar-medical.com
Starlab Neurotech Coaching Fisher & Paykel Healthcare
Caesarea, Israel
Enobio® - home CPAP, humidification CPAP, humidification
EEG/ECG/EOG Sanofi-Aventis Neurim Pharmaceuticals and interface technologies and interface technologies
data analysis Sleep drug development Sleep drug development for the treatment of OSA for the treatment of OSA
www.starlab.es www.sanofi-aventis.com www.neurim.com www.neurotechcoaching.com.au www.fphcare.com
Barcelona, Spain Paris, France Tel-Aviv, Israel Woonoona, Australia Auckland, New Zealand
AROUSAL THRESHOLD
IN OBSTRUCTIVE
SLEEP APNEA:
SLEEP APNEA, RISKS
AND PREVENTION
By Atul Malhotra and Shilpa Rahangdale
Obstructive sleep apnea (OSA) is a common Recent evidence has demonstrated that
disease with major neurocognitive and car- even patients with severe OSA have some
diovascular sequelae. OSA affects roughly periods of breathing stability (Younes et
5% of the population and is characterized al., 2007a). Emerging data suggest that
by repetitive pharyngeal collapse during high levels of genioglossal activity are nec-
sleep. Despite OSA’s high prevalence and essary and sufficient to stabilize breathing
well recognized consequences, treatment (Jordan et al., 2009). Thus, upper airway
of OSA remains unacceptable due to poor muscles can preserve pharyngeal patency
adherence to and variable efficacy of exist- when adequately recruited, if respiratory
ing therapies, leading to interest in underly-
ing mechanisms to identify new therapeutic
targets. Atul Malhotra, M.D., is Medical Director of the
The prevailing theories regarding OSA Sleep Disorders Research Program at Brigham
mechanisms involve interplay between and Women’s Hospital and is an Associate
Professor at Harvard Medical School. He has
pharyngeal anatomical compromise and
authored almost 100 original manuscripts in the
protective reflex driven activity in the pha- area of obstructive sleep apnea pathogenesis.
ryngeal dilator muscles, the best studied amalhotra1@partners.org
of which is the genioglossus (the major
protruder of the tongue). With the onset Shilpa Rahangdale, M.D., is a Pulmonary and
of sleep, however, these protective reflexes Critical Care and Sleep Medicine specialist at
are lost, leading to a fall in genioglossal Brigham and Women’s Hospital and an Instruc-
tor in Medicine at Harvard Medical School. Her
activity, and pharyngeal collapse in those primary research focus is related to mecha-
anatomically predisposed. Thus, the regu- nisms underlying the cardiovascular complica-
lation of these muscles is critical in OSA tions of sleep apnea.
pathogenesis. srahangdale@partners.org
UA negative
pressure EMGGG
Upper Airway Ideal arousal
adequate for UA opening
threshold
(UA) Collapse without arousal
CO2 /
O2
Prolonged UA
High arousal
threshold
closure, severe
CO2 /
O2
Figure 1. Variability in the arousal threshold can yield different breathing during sleep. A very low arousal threshold
can promote breathing instability whereas a very high arousal threshold may yield profound disturbances in blood
gases prior to arousal. Thus, strategies to manipulate arousal threshold could potentially improve the quality of sleep,
improve cognitive function, and reduce cardiovascular risk. EMGgg = genioglossus electomyogram.