December 2009 | Volume 3 | Issue 3 www.frontiersin.

org

IN NEUROSCIENCE
SLEEP & DREAMS
Insomnia, Narcolepsy
Freud, Memories, Nightmares
Genetics, Medication, REM
Drowsy Society, Sleep Market
Funding Crisis

Astrocytic Excitability, Transsynaptic Viruses,

Agranular Cortex, Population-Code in Man and Monkey,
Reward Networks, Neuroscience Simulations
About Frontiers in
Neuroscience THEME: SLEEP AND DREAMS
Organization: Frontiers journals are operated by the Research
Frontiers Research Foundation, a non-profit organi-
zation that addresses the social needs of scholarly 390 Dreaming about sleep
publishing, namely equal opportunity publishing and Robert Stickgold
free dissemination of research results by supporting

390
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researchers for researchers”. Frontiers Media SA is a Jerome M. Siegel
publishing company specifically aligned with the Fron-
tiers vision that addresses the commercial needs of 396 Satiety and sleep
high quality article processing, an advanced Internet
Fabio García-García

398
platform, hardcopy production and distribution, adver-
tising and providing services. 398 Worms also sleep
Peer-Review: Peer-review is carried out by expert David M. Raizen
researchers in the capacities of Chief, Associate and
Review Editors. 400 Even models need their sleep
Open Access: All peer-reviewed articles and re-
Sean Hill
lated content are freely available on the Internet at 402 Searching for function in deep sleep
www.frontiersin.org/neuroscience. For online access to
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Jaime M. Monti
Frontiers in Neuroscience: Frontiers in Neuroscience,
ISSN 1662-4548, is an open-access, peer-reviewed, 412 Norepinephrine
Field Journal published online and in hardcopy to ad- in sleep-wake circadian rhythms
dress the general neuroscience community.
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402
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Pierre J. Magistretti and Jean-Marie Petit
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Matthew P. Walker
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Sidarta Ribeiro, Catia M. Pereira, Jean Faber,
Wilfredo Blanco and Miguel A. L. Nicolelis
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Adrián Poblano and Ulises Jiménez-Correa
424 Obstructive sleep apnea

408
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 THEME
SLEEP AND DREAMS
 Title article

REM Dreams by Wendy J. St. Christopher, www.art166.info

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  389

 RESEARCH
SLEEP AND DREAMS
DREAMING
ABOUT SLEEP
By Robert Stickgold
O
ver the last decade, the
field of sleep research
has undergone remark-
able growth. Nowhere
have I seen this more
delightfully appar-
ent than in this issue of Frontiers in
Neuroscience. One third of the articles
in this issue discuss possible functions of
sleep and, surprisingly, just as many review
phenomenological experiences associated
with sleep. While most of these focus on
dreaming, others discuss sleep in relation
to coma and deep anesthesia. Perhaps not
surprising are the number of articles look-
ing at the physiology and pharmacology of
sleep, as well as sleep disorders, but there
is an excitement and freshness in many of
these that belies their more staid subject
matter. Three articles cover the genetics of
sleep, applying new techniques and organ-
isms. Others look at sleep deprivation, sleep
390  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
and feeding behavior, and the application of
new analytical tools, ranging from fMRI to
large-scale computer models, to the descrip-
tion of sleep.
This is an issue worth reading twice, once
quickly – reading all the articles will take
you two or three hours – just to appreci-
ate the depth and breadth of research pre-
sented, and then a second time, more slowly,
pausing to think about individual articles,
both in terms of their specific content
and their larger implications for the field.
Delightfully, many of the authors have cho-
sen to present new models, new concepts,
and new approaches that can reframe many
of the questions and answers that have
occupied the field for years. Below, I have
tried to put most of the articles into groups,
to better allow for their brief description.
Many belong in multiple groups, many in
groups not defined; apologies to all who feel
mis-categorized.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  391
 An illustration by Arthur Rackham from a 1907 edition
of Alice’s Adventures in Wonderland by Lewis Carroll

The functions of sleep and dreams: The

functions proposed for sleep in this issue are
remarkably diverse, and none appear to be
mutually exclusive. Several look at sleep’s puta-
tive role in memory processing. Aeschbach
describes how experimental manipulation
of slow-wave activity levels leads to paral-
lel changes in overnight improvement on a
procedural task. Eschenko and Sara review
studies demonstrating locus coeruleus neu-
ronal activity synchronized with sleep spin-
dles and with slow-wave associated ripple
onset during non-REM sleep. Two articles
by Walker propose more detailed models on
the specific memory functions that sleep may
carry out, and one by Ribeiro et al. points out
how a combination of non-uniform synap-
tic downscaling and memory replay could
work together to “emboss” recently formed
memories. Datta and Macone, in discuss-
ing the discrete physiological components
of REM sleep, touch on the mechanisms of
REM-dependent plasticity, and Magistretti
and Petit, while reviewing the role of astro-
cytes in adenosine regulation, comment on
their role not only in neuroenergetics, but in
synaptic plasticity as well.
Articles by Raizen and by Siegel propose
more diverse roles for sleep. Siegel, look-
ing across a wide range of species, sug-
gests that sleep should be thought of as an
adaptive state that protects animals from
predators and accident, saves energy, and
accomplishes “recuperative functions”, a
proposal that can be neatly juxtaposed to

392  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 Robert Stickgold is an Associate Professor of
Psychiatry at Beth Israel Deaconess Medical
Center and Harvard Medical School. He re-
ceived his B.A. from Harvard University and his
Ph.D. from the University of Wisconsin, Madi-
son, both in biochemistry. He has published
over 100 scientific publications, including pa-
pers in such prestigious journals as Science,
Nature, JAMA, and Nature Neuroscience. His
current work looks at the nature and function
of sleep and dreams from a cognitive neurosci-
ence perspective, with an emphasis on the role
of sleep and dreams in memory consolidation
and integration. His work is funded by NIMH.
rstickgold@hms.harvard.edu
Raizen’s description of sleep in the worm
C. elegens, during which molting and a
doubling of the DNA content of intestinal
cells occurs. With a fully sequenced set of
six chromosomes, and only 302 neurons
in its entire nervous system, each uniquely
identified, Raizen argues that C. elegens is an
ideal system for the genetic, neuroanatomi-
cal, and functional dissection of sleep.
Other approaches to studying the genet-
ics of sleep are presented as well. Franken
gives an overview of the usefulness of com-
bined genetic and molecular approaches,
focusing on the potential role of the neu-
ronal activity-induced transcript Homer1a
in sleep regulation in the mouse, while
Goel and Dinges discuss the putative role
of human PER3 in individual differences in
response to sleep deprivation.
A different approach to the function of
sleep is seen in several articles on dreaming.
Strikingly, most of these discuss the pos-
sible role of dreams in emotional regula-
tion. Articles by Levin et al. and by Kuiken
compare the emotional benefits of healthy
sleep to the accentuated distress seen with
nightmares, and Germain suggests that the
nightmares of PTSD may reflect a causal
contribution of disturbed sleep to the
development and maintenance of this dis-
order. Walker proposes a more specific role
of REM sleep, and possibly dreaming, in
removing the affective “blanket” from emo-
tional memories, a process that would leave
the information contained in the memory
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  393
intact. And at the far end of the spectrum,
Domhoff argues that dreams serve no
adaptive function whatsoever, although he
emphasizes that they could still serve as a
source of insight and inspiration.
Dreaming: Several other articles address
possible brain mechanisms responsible for
dreams. Based on human lesion studies,
Solms argues that Freud’s dream theory
deserves resurrection, proposing that dreams
depend critically on the dopaminergic tract
connecting the ventral tegmental area with
the nucleus accumbens, and that “nothing in
the brain” comes closer in function to Freud’s
“libidinal instinct”. In contrast, Buzsáki and
Montgomery cite rat physiological data to
suggest that phasic REM epochs, which tran-
siently re-establish wake-like connectivity
between the hippocampus and cortex, initi-
ate the generation of dream content. Finally,
Maquet points out brain regions with high
activity during REM sleep as possible neural
correlates of dreaming.
Basic sleep mechanisms: In addition to
those noted above, four additional studies
focus on the physiology and chemistry of
sleep. Both Naidoo and Kimura look at the
interaction of sleep and stress, although
from vastly different perspectives. Kimura
describes the impact of corticotropin-
releasing hormone (CRH) on sleep, and
proposes CRH as a possible mediator of the
reduced REM latency seen in depression. At
the cellular level, Naidoo argues that inad-
equate sleep may exacerbate “endoplasmic
reticulum stress”, especially in the elderly,
where it may contribute to the build-up
of misfolded protein seen, for example, in
both Alzheimer’s and Parkinson’s disease. In
other articles, Monti discusses the roles of
serotonin receptor types in sleep, and Aston-
Jones et al. argue for an intact noradrenergic
locus coeruleus system being required for
robust circadian sleep rhythms.
Miscellanea: In articles focusing on sleep
disorders, Mignot proposes narcolepsy as a
model system for brain autoimmune dis-
eases, while others discuss “irregular sleep-
wake rhythm disorder”, insomnia, and
apnea. Gratifyingly, there are three articles
that discuss sleep in relationship to ques-
tions of consciousness. Hobson compares
lucid dreaming as a state of consciousness to
wake and non-lucid dreaming, while Hutt
compares slow-wave sleep to anesthesia-
induced unconsciousness and Noirhomme
et al. compare it to coma. Other articles
remain unmentioned, not because they are
any less interesting, but because they do not
as easily fit into categories.
I have given these descriptions not to help
you pick the articles you want to read, but
rather to whet your appetite for the entire
series. As your personal doctor, I prescribe
one article per day, taken immediately before
sleep, until the entire issue is read. Like Lewis
Carroll’s Pillow Problems, they will send
you off to sleep with your mind abuzz, ripe
for fruitful dreams and, of course, sleep-
dependent memory processing.
SLEEP
IN THE ANIMAL KINGDOM
By Jerome M. Siegel

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-

394  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 Jerome M. Siegel is Chief of Neurobiology
Research at VA GLAHS Sepulveda and Profes-
sor of Psychiatry at UCLA, US. He studies the
evolution and function of sleep and the mecha-
nisms controlling the generation and expression
of sleep. His recent publications can be viewed
at www.semel.ucla.edu/sleepresearch.
jsiegel@ucla.edu
strongly, monotonically or consistently with
brain or body weight, or with measures of
health or intellectual function in humans
(Siegel, 2005; Siegel, 2009). Viewing sleep
from a wider perspective may help us to bet-
ter understand its adaptive role. Dormant
states are widespread through the ani-
mal and plant kingdoms. From a
genetic survival perspective,
inactivity is often far
more adaptive than
activity for passing
on an animal’s
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  395
References
Lyamin, O., Pryaslova, J., Lance, V., and Siegel,
J. M. (2005). Animal behaviour: continuous activity
in cetaceans after birth. Nature 435, 1177.
Rechtschaffen, A., and Bergmann, B. M.
(2002). Sleep deprivation in the rat: an update
of the 1989 paper. Sleep 25, 18-24.
Siegel, J. M. (2005). Clues to the functions
of mammalian sleep. Nature 437, 1264-1271.
Siegel, J. M. (2008). Do all animals sleep? Trends
Neurosci. 31, 208-213.
Siegel, J. M. (2009). Sleep viewed as a state
of adaptive inactivity. Nat. Rev. Neurosci.
[Epub ahead of print].
genes, once vital needs have been met. Sleep
can be best viewed not as a maladaptive state
which persists because of some mysterious
adaptive physiological or cognitive func-
tion, but as a behaviorally adaptive state,
protecting animals with safe sleep sites
from predators and accident, saving energy
and accomplishing recuperative functions
whose quality and intensity is determined
by the environment. When safe sleep sites
are not available, sleep duration and depth
are minimized. In contrast to hibernation
and torpor, sleep allows animals to rap-
idly respond to significant environmental
changes while minimizing brain energy
consumption. Although recuperative proc-
esses undoubtedly occur in both sleep and
waking, the main determinant of sleep
duration appears to be ecological factors
(Siegel, 2009).
SATIETY
AND SLEEP
By Fabio García-García
Sleep is one of the most remarkable behav-
ioral signs of satiety, and is thought to inte-
grate the complex energy-saving strategies
in a number of mammalian species. Sleep
and food intake constitute the most time-
consuming and life-supporting activities of
animals. Both sleep and food intake occur
in cyclic patterns and are in competition in
396  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
the sense that they cannot be accomplished
simultaneously.
Furthermore, it has been reported that
there are highly significant correlations
between meal size and the total duration of
sleep. Electroencephalographic studies of
laboratory animals have shown that meal
size is correlated with the short latency and
higher duration of slow wave sleep (SWS)
and rapid eye movement (REM) sleep epi-
sodes that occur immediately following the
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
SWS and REM sleep. The existence of such
correlation could suggest a causal relation-
ship or reveal a common determinant which
modulates both behaviors. As far as feeding is
concerned, the most commonly recognized
motivational factor is the availability of
nutrients at the cellular level. The same factor
could influence sleep parameters and, there-
fore, be a link for the observed correlation
between sleep and feeding. Particularly, evi-
dences show that there is a highly significant

correlation between the time spent in REM
sleep and food intake (Danguir et al., 1987).
For that reason it has been suggested that
REM sleep participates directly in regulating
the expression of motivated behaviors.
Additionally, it has been observed that
REM sleep deprivation for a period of 72
Fabio García-García is a Professor at the Bio-
medicine Department, Health Sciences Insti-
tute, Veracruzana University, where he heads
the Laboratory of Sleep. His research focuses
on the biological sleep function, including hor-
monal regulation of sleep and how sleep in-
duces neuronal plasticity. Before moving to
México, he worked at Washington State Uni-
versity, Pullman, Washington, US.
fgarcia@uv.mx
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  397
Benefits Supervisor Sleeping by Lucian Freud
hours results in an increased intake of car-
bohydrate-rich diet. Body weight was also
increased and the body temperature remained
without change. The increase in intake of
carbohydrate and body weight could be the
result of an enhanced insulin level and the
change appears to be mediated by the acti-
vation of the hypothalamic feeding center
(García-García and Drucker-Colín, 2001).
Recently, it has been reported that food
intake induces specific sleep patterns.
Particularly, food intake increases the dura-
tion and frequency of SWS and the percent-
age of slow wave activity (0.25-4.0 Hz). In
addition, REM sleep time and EEG theta
frequency (4.0-8.0 Hz) were also increased
(García-García et al., 1998). It is conceiv-
able that the circuitry implicated in sleep
References
Danguir, J. (1987). Cafeteria diet promotes
sleep in rats. Appetite 8, 49-53.
Drucker-Colín, R. (1995). The function of sleep
is to regulate brain excitability in order
to satisfy the requirements imposed by waking.
Behav. Brain Res. 69, 117-124.
García-García, F., Acosta-Peña, E.,
Venebra-Muñoz, A., and Murillo-Rodríguez, E.
(2009). Sleep-inducing factors. CNS Neurol.
Disord. Drug Targets 8, 235-244.
García-García, F., Beltrán-Parrazal, L.,
Jiménez-Anguiano, A., Vega-González, A.,
and Drucker-Colín, R. (1998).
Manipulations during forced wakefulness have
differential impact on sleep architecture,
EEG power spectrum, and Fos induction.
Brain Res. Bull. 47, 317-324.
García-García, F., and Drucker-Colín, R.
Nutritional impact on sleep-wake cycle.
In Nutrition and Brain. J.D. Fernstrom;
R. Uauy; P. Arroyo (eds). Nestlé Nutrition
Workshop Series Clinical & Performance Program,
Vol. 5, pp. 189-199, Nestec Ltd., Vevey/S.
Karger AG, Basel, 2001.
regulation may generate different neuronal
interactions depending on the events that
have the predominant effects during waking
(i.e., food intake). As a result of changes in
the activation of the sleep circuitry, differ-
ent chemical mediators, such as peptides,
hormones (CCK, VIP, ghrelin, leptin, etc.)
or neurotransmitters, become responsible
for the induction of different sleep pat-
terns (Drucker-Colin, 1995; García-García
et al., 2009). In conclusion, the relationship
between feeding and sleep is quite strong,
but much more work is needed before a full
understanding of the mechanism which
relates both is gained. This becomes even
more apparent in light of recent evidence
indicating that sleep loss may be a novel risk
factor for obesity and type 2 diabetes.
WORMS ALSO SLEEP
By David M. Raizen
The remarkable success of using model
genetic organisms to understand the circa-
dian clock was the impetus behind research
in the past decade to use fruit flies and round
worms to understand other sleep regulatory
mechanisms. Our work centers on sleep in
the round worm C. elegans. The initial task
is to determine if these worms sleep.
The small size and the unique neuro-
anatomy of C. elegans preclude the use of
the electroencephalogram, which is the gold
standard for identifying sleep in mammals.
Instead, behavioral criteria are used to iden-
tify sleep. The cardinal features of sleep,
398  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
which distinguish it from other quiescent
behavioral states, such as quiet wakefulness,
are reduced responsiveness, reversibility in
response to strong stimuli, and homeostasis,
the phenomenon of increased sleep pres-
sure with prolonged wakefulness.
Based on these criteria, worms have
a sleep-like state called lethargus, which
occurs during the development of the nem-
atode C. elegans. In addition to satisfying the
behavioral criteria for sleep (Raizen et al.,
2008), lethargus timing occurs in phase with
expression of the C. elegans orthologue of
the gene PERIOD (Jeon et al., 1999), which
is a core component of the clock that regu-
lates sleep in Drosophila and in mammals.
Further molecular similarity of lethargus to
sleep is demonstrated by the observation
that epidermal growth factor signaling pro-
motes and cAMP signaling inhibits sleep-
like behavior in C. elegans (Zimmerman
et al., 2008), in keeping with the effects on
sleep of these signaling pathways in flies
and mice.
What questions can we answer in study-
ing lethargus in C. elegans? The first is to use
the powerful genetic tools in C. elegans to
identify additional regulators of sleep. While
Figure 1. Fourth larval stage C. elegans worm in lethargus.
some of these regulators will be unique to
worms, others might be shared with other
animals including mammals, thereby gaining
information of potential clinical relevance.
Therefore, a gene discovery approach will
prove fruitful in C. elegans, as it already has
in Drosophila (Cirelli et al., 2005). The sec-
ond question lethargus can help us answer is
the mother of all questions in sleep research:
what is the function of sleep? Or, to be more
accurate, why did sleep and sleep-like states
evolve?
In approaching this question, one begins
by asking what happens during lethargus.
Here, the most striking feature of lethargus
is the association with the molts (Figure 1).
The need to secrete a complete new cuticle
is among the most biosynthetically taxing
tasks for a worm. Another biosynthetic
event that occurs during lethargus is the
David M. Raizen is an Assistant Professor of
Neurology and Medicine at the University of
Pennsylvania School of Medicine, Philadelphia.
He received a combined M.D./Ph.D. degree
from the University of Texas Southwestern
Medical School in Dallas. After a clinical resi-
dency in neurology followed by a fellowship in
sleep medicine at the Hospital of the Univer-
sity of Pennsylvania he stayed on faculty, first
as an instructor, and then, in 2007, as an As-
sistant Professor. His current research focus-
es on the use of C. elegans to understand the
regulation and function of sleep-like states.
raizen@mail.med.upenn.edu
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  399
References
Cirelli, C., Bushey, D., Hill, S., Huber, R.,
Kreber, R., Ganetzky, B., and Tononi, G. (2005).
Reduced sleep in Drosophila Shaker mutants.
Nature 434, 1087-1092.
Hedgecock, E. M., and White, J. G. (1985).
Polyploid tissues in the nematode Caenorhabditis
elegans. Dev. Biol. 107, 128-133.
Jeon, M., Gardner, H., Miller, E., Deshler, J.,
and Rougvie, A.E. (1999). Similarity of the
C. elegans developmental timing protein LIN-42
to circadian rhythm proteins. Science 286,
1141-1146.
Raizen, D. M., Zimmerman, J. E., Maycock, M.
H., Ta, U.D., You, Y.-J., Sundaram, M. V., and
Pack, A. I. (2008). Lethargus is a Caenorhabditis
elegans sleep like state. Nature 451, 569-572.
Zimmerman, J. E., Naidoo, N., Raizen, D. M.,
and Pack, A. I. (2008). Conservation of sleep:
insights from non-mammalian model systems.
Trends Neurosci. 31, 371-376.
endoreduplication of intestinal nuclei, a
process of doubling of DNA content with-
out subsequent mitosis and cytokinesis
(Hedgehock and White, 1985). Therefore,
lethargus is a major biosynthetic event in
the worm’s life cycle. This observation is
intriguing in light of studies suggesting
that mammalian sleep, too, is a time of
enhanced biosynthesis. Future research
should address whether sleep-like behavior
is a direct consequence of these biosyn-
thetic events or whether each is controlled
by upstream regulators.

EVEN MODELS
NEED THEIR SLEEP
By Sean Hill
As wakefulness fades and unconsciousness
sets in, the sleeping brain remains remark-
ably active and exhibits a broad variety of
activities and oscillations (Steriade et al.,
2001). During the early stages of slow wave
sleep (non-REM), the reticular nucleus of
the thalamus sets the pace of spindle oscil-
lations (7-14 Hz), which activate the cor-
tex through thalamocortical projections.
The isolated cortical network is capable of
generating low-frequency rhythms, which,
in the intact brain, become slow oscilla-
tions (<1 Hz) and group other thalamic
and cortical sleep rhythms into periods
of depolarization (up-states) and hyper-
polarization (down-states). Sleep is a net-
work phenomenon that involves the same
circuitry that produces wakefulness. Large-
scale computer models provide a way to
learn more about the cellular and synaptic
mechanisms that produce these two differ-
ent emergent behaviors.
One of the first large-scale models
integrating thousands of model neurons
to explain sleep rhythms was developed
400  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Thalamus nerve cells. Confocal light micrograph
of neurons (nerve cells, red) and glial cells
(support cells, green) from the thalamus of the brain.
to model the interactions of cells in the
reticular nucleus of the thalamus and tha-
lamocortical relay cells (Wang et al., 1995).
This model provides insight into how the
combination of intrinsic bursting proper-
ties in the thalamus and convergent inhibi-
tory projections from the reticular nucleus
could give rise to the spindle rhythm.
Following experimental observations
that the isolated cortex spontaneously gen-
erates up- and down-states, a large-scale
model was constructed, which illustrated
how synaptic quantal release, ionic currents,
and network connectivity can generate acti- firing, orientation selectivity and gamma
vated up-states (Bazhenov et al., 2002). This frequency oscillations of wakefulness, but
model was the first to demonstrate potential when a set of ionic conductances are altered
cellular and network mechanisms for gener- to model the neuromodulatory changes that
ating the slow oscillation in a thalamocorti- transition the brain to sleep, the system
cal network. dynamics change and the model thalamo-
A model, integrating aspects of both cortical system begins to generate the slow
wakefulness and sleep, was built by includ- oscillation. This model continues to be used
ing the basic cellular and network features for studies of sleep, plasticity, and the cel-
of the thalamus, reticular nucleus and two lular and synaptic properties that underlie
areas of cortex (Hill and Tononi, 2005). The the changes in information processing that
model recreates the irregular spontaneous occur during sleep (Esser et al., 2009).

Sean Hill is the Project Manager for Computa-
tional Neuroscience with the Blue Brain Project
at the Brain Mind Institute, EPFL. In 2000, he
received his Ph.D. in Computational Neurosci-
ence from the University of Lausanne, Switzer-
land. He developed large-scale computer
models of wakefulness and sleep in thalamo-
cortical circuitry while working as a Post-
Doctoral Fellow with Giulio Tononi at the Uni-
versity of Wisconsin, Madison. In 2006, he was
hired by IBM Research to work on the Blue
Brain Project, and joined the EPFL in 2008.
sean.hill@epfl.ch
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  401
Although the function of sleep remains
largely unknown, the present models serve
as important tools in the analysis and under-
standing of the mechanisms that generate
sleep rhythms and influence information
processing during conscious and uncon-
scious states.
Presently, there are no large-scale mod-
els of REM sleep, and circadian effects and
transitions between the different stages of
non-REM sleep have yet to be modeled.
In addition, many details of neuron firing
References
Bazhenov, M., Timofeev, I., Steriade, M.,
and Sejnowski, T. J. (2002). Model of
thalamocortical slow-wave sleep oscillations
and transitions to activated States.
J. Neurosci. 22, 8691-8704.
Esser, S. K., Hill, S. L., and Tononi, G. (2009).
Breakdown of effective connectivity during
slow wave sleep: investigating the mechanism
underlying a cortical gate using large-scale
modeling. J. Neurophysiol. Published online
August 5, 2009.
Hill, S., and Tononi, G. (2005). Modeling sleep
and wakefulness in the thalamocortical system.
J. Neurophysiol. 93, 1671-1698.
Steriade, M., Timofeev, I., and Grenier, F.
(2001). Natural waking and sleep states:
a view from inside neocortical neurons.
J. Neurophysiol. 85, 1969-1985.
Wang, X. J., Golomb, D., and Rinzel, J.
(1995). Emergent spindle oscillations
and intermittent burst firing in a thalamic model:
specific neuronal mechanisms. Proc. Natl.
Acad. Sci. USA 92, 5577-5581.
properties, connectivity, plasticity and neu-
romodulation have been highly simplified
in the present models.
With the integration of additional bio-
logical details, such as neuromodulation,
synaptic plasticity and the coupling of neu-
ral, glial and vascular systems, large-scale
models, such as those being developed in
the Blue Brain Project, should provide
deeper insight into the role of wakefulness
and sleep in information processing, syn-
aptic plasticity and metabolism.
SEARCHING
FOR FUNCTION
IN DEEP SLEEP
By Daniel Aeschbach

Dr. Steven LeBerge, Professor at Stanford University

in Palo Alto, California, and author of Exploring
the World of Lucid Dreaming, uses goggles that alert
he is dreaming during REM sleep.

402  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 Daniel Aeschbach is an Assistant Professor of
Medicine at Brigham and Women’s Hospital
and Harvard Medical School. He received his
M.Sc. and his Ph.D. in Biology from the Swiss
Federal Institute of Technology in Zürich, and
completed post-doctoral training at the Na-
tional Institute of Mental Health in Bethesda.
His work focuses on human sleep regulation,
its inter-individual variation, and its effect on
waking functions. His work has been sup-
ported by NIH, the National Alliance for Re-
search on Schizophrenia and Depression, and
the Swiss National Science Foundation.
daeschbach@hms.harvard.edu
Deep sleep is characterized by the presence
of slow waves in the electroencephalogram
(EEG). EEG slow-wave activity (SWA; spec-
tral power density in the 0.75-4.5 Hz range)
typically increases in proportion to an indi-
vidual’s prior time awake, and it decreases in
the course of a sleep episode. SWA has been
the focus of much scientific interest because
it is thought to be a marker of sleep need, and
a manifestation of a sleep regulatory process
that serves a homeostatic function (Borbély
and Achermann, 2000). However, it is cur-
rently unknown what is ultimately being
regulated, and whether SWA is simply an
EEG epiphenomenon or whether it directly
serves a fundamental brain function.
A growing number of observations has
linked slow wave sleep (SWS) and SWA to
brain plasticity. Although various aspects
of sleep have been associated with learning,
positive relationships were found specifically
between SWS/SWA and overnight gains in
declarative memory, perceptual learning,
and visuomotor learning (for reviews see
Diekelmann et al., 2009; Massimini et al.,
2009). SWA appears to be use-dependent,
such that cortical circuits that were particu-
larly active during waking generated more
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  403
SWA during subsequent sleep (Kattler
et al., 1994), whereas under-used circuits
produced less SWA (Massimini et al., 2009).
Increases in SWA, induced either through
practicing a particular learning task,
through transcranial application of oscil-
lating potentials during sleep (Diekelmann
et al., 2009), or through a pharmacologi-
cal agent (Walsh et al., 2006), have been
reported to be paralleled by gains in some
neurobehavioral performance measures
during subsequent wakefulness. Much
of the evidence for a causal role of SWA
in such sleep-dependent gains, however,
remains correlative. Importantly, if SWA is
not simply an EEG epiphenomenon, inter-
ference with its expression should prevent
sleep-dependent learning.
Recently, we tested this hypothesis
directly by using an acoustic SWA suppres-
sion paradigm (Aeschbach et al., 2008). The
goal of this paradigm was to reduce SWA
during non-REM sleep by targeted presen-
tation of sounds while avoiding awakenings
through careful “titration” of the volume of
the sounds. We examined whether overnight
improvement in visual texture discrimina-
tion, a form of perceptual learning, directly
References
Aeschbach, D., Cutler, A. J., and Ronda, J. M.
(2008). A role for non-rapid-eye-movement
sleep homeostasis in perceptual learning.
J. Neurosci. 28, 2766-2772.
Borbély, A. A., and Achermann, P. (2000).
Sleep homeostasis and models of sleep
regulation. In: Principles and Practice of Sleep
Medicine (Kryger, M. H., Roth, T., and
Dement, W. C., eds), pp 377-390. Philadelphia:
W.B.Saunders Company.
Diekelmann, S., Wilhelm, I., and Born, J.
(2009). The whats and whens of sleep-dependent
memory consolidation. Sleep Med. Rev. 13,
309-321.
Kattler, H., Dijk, D. J., and Borbély, A. A. (1994).
Effect of unilateral somatosensory stimulation
prior to sleep on the sleep EEG in humans.
J. Sleep Res. 3, 159-164.
Massimini, M., Tononi, G., and Huber, R.
(2009). Slow waves, synaptic plasticity and
information processing: insights from transcranial
magnetic stimulation and high-density EEG
experiments. Eur. J. Neurosci. 29, 1761-1770.
Walsh, J. K., Randazzo, A. C., Stone, K.,
Eisenstein, R., Feren, S. D., Kajy, S., Dickey, P.,
Roehrs, T., Roth, T., and Schweitzer, P. K.
(2006). Tiagabine is associated with sustained
attention during sleep restriction: evidence for the
value of slow-wave sleep enhancement?
Sleep 29, 433-443.
depends on SWA during sleep. Healthy sub-
jects were trained on a texture discrimina-
tion task and were tested 24 hours later
after an experimental sleep episode (with or
without SWA suppression), and again after
a night of recovery sleep. In the suppres-
sion group, SWA during sleep was reduced
by 30% compared with the control group,
whereas total sleep time and REM sleep
remained unaffected. Texture discrimina-
tion improved after experimental sleep in
the control group, but not in the suppres-
sion group. Overnight improvement cor-
related positively with EEG power density
in the low-frequency range (<7 Hz) and in
particular with SWA, but not with power
density in higher-frequency ranges.
Our data are consistent with a causal rela-
tionship between SWA and sleep-depend-
ent gains in perceptual performance. The
results substantiate the proposed functional
link between processes of sleep homeostasis
and learning. In this regard, exploration of
new strategies – particularly pharmacologi-
cal ones – to specifically enhance SWA may
take on added relevance in conditions where
SWA is reduced, such as in insomnia and
depression.

REM SLEEP
By Subimal Datta and Brian W. Macone
Rapid eye movement (REM) sleep is a
highly evolved behavioral state in mam-
malian species. Since the discovery of REM
sleep and its physiological distinction from
other sleep states, neuroscientists have been
allured to study its mechanisms and func-
tions. An extensive body of research has
recently emerged providing evidence that
REM sleep is important in the development
and maturation of the brain during early
mammalian life, and for memory consoli-
dation throughout life (Datta, 2006).
During the last fifty years, phenomeno-
logical and mechanistic aspects of REM
sleep have been studied more extensively
than the waking states (Datta and McLean,
2007). REM sleep is characterized by a con-
stellation of events including: 1) an acti-
vated pattern of cortical EEG; 2) marked
atonia of the postural muscles; 3) rapid
eye movements; 4) a theta rhythm within
the hippocampus; 5) field potentials in the
pons (P-waves), lateral geniculate nucleus
and occipital cortex (ponto-geniculo-occip-
ital (PGO) spikes); 6) myoclonic twitches,
most apparent in the facial and distal limb
musculature; and 7) pronounced cardio-
respiratory fluctuations. In addition to
these physiological signs, vivid dreaming
is an important mental experience and a
trademark of REM sleep.
Animal studies over the last three dec-
ades have revealed that each aspect of REM
sleep is executed by distinct cell groups in
the brainstem (Datta and MacLean, 2007).
These cell groups are discrete components of
404  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
a widely distributed network, rather than a
single REM sleep “center”. For example, mus-
cle atonia results from the activation of neu-
rons in the locus coeruleus alpha, rapid eye
movements from the periabducens reticular
formation, and PGO waves emerge from the
caudo-lateral peribrachial area of predator
mammals and the dorsal part of the nucleus
subcoeruleus of prey; neurons in the pontis
oralis are responsible for hippocampal theta
rhythm, and muscle twitches appear with
activation of the nucleus gigantocellularis
(especially the caudal part). Cortical EEG
signs of REM sleep are produced jointly by
neurons in the mesencephalic reticular for-
mation and rostrally-projecting medullary
magnocellular nucleus. The aforementioned
cell groups simply represent the executive
neurons for the individual signs. For final
expression of each distinct sign, the relevant
cell groups employ a specific and unique
neuronal circuit. In essence, each REM sleep
sign has a separate, specialized network, and
may be modulated by various neurotransmit-
Subimal Datta is a Professor of Psychiatry and
the Director of Sleep and Cognitive Neurosci-
ence Laboratories at the Boston University
School of Medicine. His research focuses pri-
marily on studies of the mechanisms of sleep
and sleep-dependent memory processing, us-
ing state-of-the-art combined anatomical,
behavioral, physiological, pharmacological,
and molecular methodological approaches. His
research is funded by the US National Institutes
of Health (NINDS and NIMH).
subimal@bu.edu
Eye movement during REM sleep
ters at multiple sites of its circuit. Turn-on/
turn-off conditions of REM sleep-generating
executive neurons are regulated by the ratio
of available aminergic to cholinergic neu-
rotransmitters within executive cell groups.
During REM sleep, aminergic cell activity
drops markedly or disappears entirely, while
cholinergic cell activity remains compara-
tively high (Datta et al., 2009).
Over the past decade, the brain structures,
neurotransmitters, receptors, and neuronal
networks critical to the regulation of REM
sleep have been sufficiently explored (Datta
and MacLean, 2007). As such, research on
the mechanisms of REM sleep has begun
to focus on gene expression and intracellu-
lar signaling systems (Bandyopadhya et al.,
2006) and must continue to do so. To further
our understanding of the functions of REM
sleep, a number of researchers have recently
begun investigating the cellular and molec-
ular mechanisms of REM sleep-dependent
behavioral and structural plasticity. (Datta
et al., 2008). At this time, we are closer to
unraveling the mysteries of REM sleep than
ever before, but for complete understanding
future research must focus on the cellular
and molecular mechanisms of both REM
sleep generation and of REM sleep-specific
behavioral and cellular plasticity.
Brian W. Macone earned his Bachelor’s degree
from Boston University. He currently studies
REM sleep mechanisms and functions under
the supervision of Dr. Datta.
bmacone@bu.edu
 References
Bandyopadhya, R. S., Datta, S., and Saha, S.
(2006). Activation of pedunculopontine tegmental
protein kinase A: a mechanism for rapid eye
movement sleep generation in the freely moving rat.
J. Neurosci. 26, 8931-8942.
Datta, S. (2006). Activation of phasic pontine-wave
generator: a mechanism for sleep-dependent memory
processing. Sleep and Biological Rhythms 4, 16-26.
Datta, S., Li, G., and Auerbach, S. (2008).
Activation of phasic pontine-wave generator in the
rat: a mechanism for expression of plasticity-related
genes and proteins in the dorsal hippocampus and
amygdala. Eur. J. Neurosci. 27, 1876-1892.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  405
Datta, S., and MacLean, R. R. (2007).
Neurobiological mechanisms for the regulation
of mammalian sleep-wake behavior:
reinterpretation of historical evidence and inclusion
of contemporary cellular and molecular evidence.
Neurosci. Biobehav. Rev. 31, 775-824.
Datta, S., Siwek, D. F., and Stack, E. C. (2009).
Identification of cholinergic and
non-cholinergic neurons in the pons expressing
phosphorylated cyclic AMP response
element-binding protein as a function of rapid
eye movement sleep.
Neurosci. 163, 397-414.
SLEEP VS COMA
By Quentin Noirhomme, Steven Laureys and Mélanie Boly

What are the differences between coma and
sleep? Can patients in coma and related
states have self-awareness or dreamlike
experiences as can be encountered in
sleep? Behaviorally, a coma may resemble
deep sleep – the major difference being that
comatose patients will never open the eyes,
not even when intense or noxious stimuli
are applied. Patients evolving from a coma
to a vegetative state may, in turn, be com-
pared to sleepwalkers – only showing reflex
or automatic behavior, but not command
following (Laureys, 2005). In addition, elec-
troencephalography (EEG) shows similari-
ties between coma (or the vegetative state)
– classically showing diffuse slowing of the
brain’s basic rhythms – and deep (stage 3-4)
sleep. EEG spindle activity (the hallmark
of stage 2 sleep) can also be observed in
some comatose or vegetative patients and
seems to be a predictor of good outcome.
Whereas coma patients will never show the
EEG characteristics of REM sleep, it remains
controversial whether vegetative patients
may present periods of REM sleep. The
very unstructured and slow waking EEG
encountered in the vegetative state makes
it utterly difficult to identify possible REM
sleep other than by the presence of muscular
atonia and eye movements – note that noc-
turnal penile erections have been convinc-
ingly shown in vegetative patients (Cologan
et al., in press).
The brain’s metabolic activity in a coma,
as measured by fluorodeoxyglucose posi-
tron emission tomography or FDG-PET,
decreases to about half of normal waking val-
ues, and to ~40-50% of normal values in the
vegetative state. These massive decreases in

406  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 PET scanning. Side view of a patient undergoing
a Positron Emission Tomography (PET) brain scan.
cortical metabolism are comparable to what
is observed in deep sleep (~60% of waking
values) but much lower than what is seen in
REM sleep (where overall cerebral metabo-
lism is comparable to normal wakefulness).
The areas that are the most dysfunctional
in coma and vegetative states are the fron-
toparietal associative cortices, also known to
show the lowest metabolism in sleep (and in
sleepwalking) (Laureys, 2005).
In response to external stimulation,
functional magnetic resonance imaging
(fMRI) and event related potential (ERP)
studies have shown residual activation of
“lower order” primary sensory cortices (but
not of “higher order” frontoparietal asso-
ciative networks) in coma and vegetative
states, similar to what has been observed
in sleep (Owen et al., 2009). In clinical
practice, the absence of primary cortex
activation, as measured by somatosensory
ERPs, is a strong indicator of bad outcome
in coma. Recent research is employing
fMRI to study the brain’s so called “rest-
ing state” or “default” activity (where in the
normal waking state mind wandering, inner
speech and mental imagery are occurring
in the absence of any external stimulation).
Preliminary results show some partially pre-
served cerebral default network connectiv-
ity in both coma and vegetative states and
in non-REM sleep – but it remains to be
shown whether this truly reflects conscious
cognitive activity or some residual struc-
tural (thought-independent) connectivity
(Boly et al., 2009).
References
Boly, M., Tshibanda, L., Vanhaudenhuyse, A,.,
Noirhomme, Q., Schnakers, C., Ledoux, D.,
Boveroux, P., Garweg, C., Lambermont, B.,
Phillips, C., et al. (2009). Functional connectivity
in the default network during resting state is
preserved in a vegetative but not in a brain dead
patient. Hum. Brain Mapp. 30, 2393-2400.
Cologan, V., Schabus, M., Ledoux, D.,
Moonen, G., Maquet, P., and Laureys, S.
(in press). Sleep in disorders of consciousness.
Sleep Med. Rev.
Laureys, S. (2005). The neural correlate of
(un)awareness: lessons from the vegetative state.
Trends Cogn. Sci. 9, 556-559.
Schnakers, C., Perrin, F., Schabus, M.,
Majerus, S., Ledoux, D., Damas, P., Boly, M.,
Vanhaudenhuyse A., Bruno M. A., Moonen G.,
and Laureys S. (2008). Voluntary brain processing
in disorders of consciousness. Neurology 71,
1614-1620.
Sorger, B., Dahmen, B., Reithler, J.,
Gosseries, O., Maudoux, A., Laureys, S.,
and Goebel R. (2009). Another kind of ‘‘BOLD
Response’’: answering multiple-choice questions
via online decoded single-trial brain signals.
Prog. Brain Res. 177, 275-293.
Owen, A. M., Schiff, N. D., and Laureys, S.
(2009). A new era of coma and consciousness
science. Prog. Brain Res. 177, 399-411.
Functional neuroimaging techniques
have only recently begun to probe for
residual consciousness in coma and sleep.
fMRI and ERP studies are now uncover-
ing undeniable signs of awareness in some
clinically vegetative or minimally con-
scious coma survivors (Schnakers et al.,
2008). The logical next step is to employ
these novel real-time fMRI or EEG-based
brain-computer interfaces to permit these
exceptional, but very challenging patients,
to communicate their possible inner
thoughts (Sorger et al., 2009), inaccessi-
ble even to the most detailed behavioral
assessments.

Quentin Noirhomme is a Post-Doctoral Re-
search Fellow at the Belgian National Funds
for Scientific Research (FNRS). He is a Civil
Engineer and earned his Ph.D. on the localiza-
tion of brain functions using TMS and EEG at
the University of Louvain. In 2007, he joined
the Coma Science Group (www.comascience.
org) of the Cyclotron Research Centre and
Neurology Department of the University and
University Hospital of Liège where he works
on high density EEG and brain-computer in-
terface (BCI) devices in disorders of con-
sciousness.
quentin.noirhomme@ulg.ac.be
Steven Laureys is Clinical Professor of Neu-
rology at the University Hospital of Liège and
Senior Research Associate at the Belgian
Funds for Scientific Research. He earned his
M.D. and M.Sc. in Pharmaceutical Research
from the University of Brussels working on
pain and stroke in the rat. He moved to the
University of Liège in 1997 where he obtained
his Ph.D. studying perception in the vegeta-
tive state. He is board-certified in neurology
and in palliative and end-of-life medicine. He
heads the Coma Science Group and has pub-
lished The Neurology of Consciousness.
steven.laureys@ulg.ac.be
Mélanie Boly is a Post-Doctoral Research
Fellow at the Belgian National Funds for Sci-
entific Research at the Coma Science Group.
She earned her M.D. and Ph.D. at the Univer-
sity of Liège using fMRI to study conscious-
ness in coma and related states. Her research
focuses on the recovery of neurological dis-
ability and neuronal plasticity in altered states
of consciousness, confronting bedside be-
havioral evaluation with multimodal func-
tional neuroimaging, combining EEG coupled
to TMS and fMRI, PET and structural MRI
morphometry.
mboly@student.ulg.ac.be

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  407

SLEEP
AND
ANESTHESIA
By Axel Hutt
The loss of consciousness in sleep and
anesthesia is a well-known phenomenon,
but its neural mechanisms are still not
understood in detail. When we fall asleep,
our consciousness fades and we enter so-
called sleep cycles. These cycles are classi-
fied as either REM sleep, when remembered
dreams occur, or non-REM sleep during
which the sleeper may be somnolent, loses
consciousness or may be in deep sleep. The
sleeper passes through several of such stages
during a typical sleep and several transitions
between REM and non-REM sleep occur.
Sleep is important for the subjects’
health, allowing the brain to organize
knowledge and solidify memories. It also
plays an important role in the brain devel-
opment of infants. The accompanying
loss of consciousness or awareness (hyp-
nosis) is also advantageous during sur-
gery, where it is evoked by administered
drugs, so-called general anesthetics. The
general anesthesia applied before surgery
needs to guarantee not only the loss of
consciousness, but also sedation, immo-
bility, the loss of memory (amnesia), and
the absence of pain (analgesia). Most gen-
408  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
eral anesthetics are able to induce these
four elements.
Both sleep and general anesthesia show
a hypnotic effect, but, even at first glance,
also have important differences. First of all,
general anesthetics inhibit parts of the brain
which are required for REM sleep cycles.
Hence, anesthetized subjects do not have
REM sleep and, thus, do not remember
dreams. Another notable difference is that
sleep is readily reversed through external
stimuli, e.g., shaking or loud noises, whereas
anesthesia is reversed only by discontinu- induced unconsciousness and deep sleep are
ation of the anesthetic drugs. Studies of remarkably similar.
deep sleep using imaging techniques have This view is supported by detailed elec-
shown that polymodal association areas are troencephalographic (EEG) studies that
affected more profoundly than unimodal demonstrate similar activity patterns dur-
brain areas (Franks, 2008). This functional ing non-REM sleep and anesthesia (John
dissociation implies that during deep sleep and Prichep, 2005). This similarity indi-
the brain can respond to external stimuli via cates common neural pathways of sleep
the unimodal areas, but cannot make much and anesthesia that control the arousal of
sense out of the stimuli due to the inhibition the cortex (Lydic and Baghdoyan, 2005).
of the higher level processing in polymo- Recent work suggests several candidates for
dal areas. Moreover, some of the polymodal the affected arousal pathways. For instance,
areas which are affected during deep sleep in both sleep and anesthesia the thalamus
are also deactivated during sedation. This may serve as a consciousness switch (Alkire
indicates that the final state of anesthetic- and Miller, 2005) that disrupts the informa-
tion flow through the thalamic gateway and
triggers the transition between sleep stages.
Moreover, sleep and anesthesia are not only
supposed to affect the same pathways dur-
ing unconsciousness but, more generally, act
similarly on these pathways. For instance,
the spread of cortical activity is reduced
during deep sleep and sedation reflecting
a breakdown of cortical connectivity and
information flow (Alkire et al., 2008).
These experimental and theoretical
results show that sleep and anesthesia are
different phenomena, but the common loss
of consciousness shares underlying neuro-
nal mechanisms. axel.hutt@loria.fr
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  409
Axel Hutt received his Ph.D. from the Univer-
sity of Stuttgart where he worked in the
group of H. Haken. In 2000, while at the Max
Planck Institute for Cognitive Neuroscience
in Leipzig, he was awarded the Schloess-
mann Fellowship of the Max Planck Society.
After several post-doctoral positions he be-
came a Research Associate at the Univer-
sity of Ottawa in the group of Andre Longtin.
Presently, he is Charge de Recherche at
INRIA Nancy, France, in the group CORTEX.
His current research focuses on mathemat-
ical population models of anesthetic actions
and multivariate data analysis of EEG during
anesthesia.
References
Alkire, M. T., Hudetz, A. G., and Tononi, G.
(2008). Consciousness and anesthesia. Science
322, 876-880.
Alkire, M. T., and Miller, J. (2005). General
anesthesia and the neural correlates of
consciousness. Prog. Brain Res. 150, 229-244.
Franks, N. P. (2008). General anesthesia: from
molecular targets to neuronal pathways of sleep
and arousal. Nature Rev. Neurosci. 9, 370-386.
John, E. R., and Prichep, L. S. (2005). The anesthetic
cascade: A theory of how anesthesia suppresses
consciousness. Anesthesiology 102, 447-471.
Lydic, R., and Baghdoyan, H. A. (2005). Sleep,
anesthesiology, and the neurobiology of arousal
state control. Anesthesiology 103, 1268-1295.
 Serotonin (5-HT) shares with other neuro-
transmitters the ability to promote waking
(W) and to suppress slow-wave sleep (SWS)
and rapid eye movement (REM) sleep.
Serotonergic neurons of raphe regions of
the brain stem form rostral and caudal cell
groups. The two major rostral cell groups
contributing ascending serotonergic inner-
vation are the dorsal raphe nucleus (DRN)
and the median raphe nucleus (MRN). The
activity of serotonergic DRN neurons is at
its highest during W, it diminishes during
SWS and is virtually suppressed when the
animal starts REM sleep.
Attempts to characterize the role of
5-HT receptors on sleep variables have
been limited to studies of the 5-HT1A,
5-HT1B, 5-HT2A/2B/2C, 5-HT3 and 5-HT7
receptors. All these receptors are expressed
in structures that are relevant to the
modulation of sleep and W, including the
cerebral cortex, hippocampus, thalamus,
locus coeruleus and DRN. In addition,
5-HT1B, 5-HT2A/2C and 5-HT7 receptors
have been characterized in the preoptic
area, anterior and lateral hypothalamic
areas and tuberomammillary nucleus,

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

410  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

receptor knockout mice. Much less is known
about the effects of local microinjection of
5-HT receptor ligands into central nervous
system structures relevant to the regulation
of sleep and W. Systemic injection of the
selective 5-HT1A receptor agonists flesinoxan
or 8-OHDPAT, the selective 5-HT1B receptor
agonists CGS 12066B or CP-94,253 and the
5-HT2A/2C receptor agonists DOI or DOM
increases W and reduces SWS and REM
sleep. Similar effects have been observed fol-
lowing the i.c.v. administration of the 5-HT3
receptor agonist m-chlorophenylbiguanide.
On the other hand, the effect of the 5-HT7
receptor agonist LP-211 on sleep variables is
limited to a reduction of REM sleep (Monti
et al., 2008a).
Mutant mice that do not express 5-HT1A
or 5-HT1B receptor exhibit greater amounts
of REM sleep than their wild counterparts.
The increase of REM sleep in 5-HT1A or
5-HT1B receptor knockout mice could be
related to the absence of an inhibitory effect
on cholinergic cells involved in the induc-
tion of REM sleep. Unexpectedly, 5-HT2A
or 5-HT2C receptor knockout mice show a
Jaime M. Monti is Professor of Pharmacology
and Therapeutics, School of Medicine Clinics
Hospital, Montevideo, Uruguay. His research
focuses on the preclinical (basic) and clinical
pharmacology of sleep. His most recent publi-
cations deal with the role of serotonin and
dopamine in the regulation of the behavioral
states. He has published over 150 scientific
publications in peer-reviewed journals (Brain
Research, Behavioral Brain Research, Sleep,
Sleep Medicine Reviews, and Progress in
Neuro-Psychopharmacology & Biological Psy-
chiatry) and books.
jmonti@mednet.org.uy
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  411
significant increase of W and a reduction of
SWS, whereas values corresponding to REM
sleep remain unchanged. The available evi-
dence tends to indicate that the increase of
W and reduction of SWS in these animals
is related, at least in part, to the increased
release of norepinephrine and dopamine.
Overall, a normal circadian sleep pattern is
observed in 5-HT7 receptor knockout mice.
However, the mutants spend less time in
REM sleep than their wild-type counter-
parts (Adrien, 2008).
Intra-DRN administration of a full ago-
nist of the 5-HT1A receptor reduces 5-HT
levels and significantly increases REM sleep;
the effect depends on the activation of the
somatodendritic 5-HT1A receptor. On the
other hand, microinjection of selective
5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT7 receptor
agonists consistently suppresses REM sleep.
Indirect mechanisms involving GABAergic
and glutamatergic interneurons would be
responsible for the reduction of REM sleep
(Monti and Jantos, 2008).
Thus, based on electrophysiological,
neurochemical, genetic and neurophar-
macological approaches, it is currently
accepted that 5-HT functions to promote
W and to inhibit SWS and REM sleep.
Accordingly, the selective serotonin re-
uptake inhibitors (SSRIs) increase the syn-
aptic availability of 5-HT and behave as
activating antidepressants. Acute or chronic
administration of SSRIs (fluoxetine, cita-
lopram) in patients with major depression
prolongs sleep onset latency, increases the
number of awakenings and reduces total
sleep time and sleep efficiency.
On the other hand, administration of
5-HT2A/2C receptor antagonists (ritanserin,
seganserin) increases SWS in subjects
with normal sleep, poor sleepers, patients
with chronic insomnia and psychiatric
patients with generalized anxiety disorder.
Their administration together with ben-
zodiazepine or nonbenzodiazepine hyp-
notic drugs would be expected to further
improve sleep and to increase SWS values
in patients with insomnia (Monti et al.,
2008b).
References
Adrien, J. (2008). Sleep and waking in mutant
mice that do not express various proteins involved
in serotonergic neurotransmission such as the
serotonergic transporter, monoamine oxidase A,
and 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C and 5-HT7
receptors. In: Monti, J. M., Pandi-Perumal, S. R.,
Jacobs, B. L., and Nutt, D. J. (eds.): Serotonin and
Sleep: Molecular, Functional and Clinical Aspects.
Birkhäuser Verlag, Basel, 457-475.
Hoyer, D., Hannon, J. P., and Martin, G. R.
(2002). Molecular, pharmacological and functional
diversity of 5-HT receptors. Pharmacol. Biochem.
Behav. 71, 533-554.
Monti, J. M. and Jantos, H. (2008). Mechanisms
involved in the inhibition of REM sleep by
serotonin. In: Monti, J. M., Pandi-Perumal, S. R.,
Jacobs, B. L., and Nutt, D. J. (eds.): Serotonin and
Sleep: Molecular, Functional and Clinical Aspects.
Birkhäuser Verlag, Basel, 371-385.
Monti, J. M., Jantos, H., and Monti, D. (2008a).
Serotonin and sleep-wake regulation. In:
Monti, J. M., Pandi-Perumal, S. R., and
Sinton, C. M. (eds.): Neurochemistry of Sleep and
Wakefulness. Cambridge University Press,
Cambridge, 244-279.
Monti, J. M., Pandi-Perumal, S. R., and Langer,
S. Z. (2008b). Zolpidem: its use in the treatment
of sleep disorders. In: Pandi-Perumal, S. R.,
Verster, J. C., Monti, J. M., Lader, M., and Langer, S. Z.
(eds.): Sleep Disorders: Diagnosis and Therapeutics.
Informa, London, 295-323.
NOREPINEPHRINE
IN SLEEP-wake
circadian rhythms
By Gary Aston-Jones, Mónica M. González and Heinrich S. Gompf

The noradrenergic (NA)-locus coeruleus

(LC) system regulates arousal and the
sleep-waking cycle; a decrease in LC activ-
ity facilitates sleep, whereas activation of LC
drives wakefulness and modulates associ-
ated behaviors like attention, performance,
stress, and anxiety (Aston-Jones and Cohen,
2005). NA-LC neurons fire in a circadian
rhythm; faster during the active than the
rest period. Lesion of the major relay
between suprachiasmatic nucleus (SCN)
and NA-LC, the dorsomedial hypothalamic
nucleus (DMH), abolishes this circadian
fluctuation in LC (Aston-Jones et al., 2001).
SCN outputs regulate the amplitude of the
sleep-wake rhythm through DMH, and
DMH projections to LC use the neuropep-
tide orexin (hypocretin; Gompf and Aston-
Jones, 2008). Also, we found that circadian
regulation of LC neurons requires orexin
inputs to LC (Gompf and Aston-Jones,
2008). In addition, anesthetics that inhibit
orexin neurons also abolish circadian vari-
ation in LC impulse activity. We provided
the first behavioral confirmation that the
NA-LC provides circadian regulation of
the sleep-waking cycle, finding that lesion
of NA-LC projections decreases sleep-
wake rhythm amplitude (Gonzalez and
Aston-Jones, 2006). Interestingly, lesions
of LC elicited only minor changes in total
wakefulness over the 24-hour cycle. Thus,

Gary Aston-Jones received his Ph.D. in Neu-

robiology from the California Institute of Tech-
nology, and conducted Ph.D. and post-doctor-
al work at the Salk Institute with Drs. Floyd
Bloom and Stephen Foote. He is currently a
Professor and the Murray Chair of Excellence
in Neuroscience at the Medical University of
South Carolina. His research interests focus
on the neurobiology of motivated behavior. His
lab conducts research programs in addiction
neuroscience and cognitive neuroscience.
astong@musc.edu

412  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org


Hormone receptor nerve cells. Confocal light
micrograph of orexin receptors (red) in the brain.
our results lead to a new concept about the
participation of the LC in sleep-wake regu-
lation. They suggest that the NA-LC con-
tributes primarily to circadian properties
of sleep-wake, and that inputs from DMH
orexin neurons are involved via circadian
regulation of LC activity.
We also found that constant darkness
(DD) alone decreased the amplitude of
the circadian sleep-wake rhythm simi-
lar to that of LC-lesioned animals. This
effect was associated with fewer NA fib-
ers/boutons in the cerebral cortex of unle-
sioned DD rats than in unlesioned animals
housed in normal light-dark (LD) condi-
tions (Gonzalez and Aston-Jones, 2006).
Rats kept in DD also showed significant
apoptosis in aminergic systems that regu-
late mood (NA-LC, serotoninergic-raphe
and dopaminergic-ventral tegmental neu-
rons). The most apoptosis was observed
in NA-LC neurons, and this was associ-
ated with decreased NA boutons in the
prefrontal cortex. Given the role of NA in
mood, we extended our study to examine
the depressive profile of light-deprived ani-
mals. DD induced a depression-like condi-
tion as measured by increased immobility
in a forced swim test. Chronic treatment
with the NA uptake blocker and antide-
pressant desipramine ameliorated all the
above symptoms seen in light-deprived
Mónica M. González obtained her Ph.D. from
the Université Claude Bernard, France. Her post-
doctoral studies at the University of Pennsylva-
nia with Dr. Aston-Jones showed that locus
coeruleus neurons provide a circadian regula-
tion of the sleep-wake cycle, and that an impair-
ment of monoaminergic systems after limited
light exposure promotes depression. Her recent
studies at the University of Washington and at
the IFN in Buenos Aires implicate the circadian
system in the etiology of depression.
ratusagon@yahoo.com
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  413
References
Aston-Jones, G., Chen, S., Zhu, Y., and
Oshinsky, M. (2001). A neural circuit for circadian
regulation of arousal. Nature Neurosci. 4,
732-738.
Aston-Jones, G., and Cohen, J. D. (2005).
An integrative theory of locus coeruleus-
norepinephrine function: adaptive gain and optimal
performance. Annu. Rev. Neurosci. 28, 403-450.
Gompf, H. S., and Aston-Jones, G. (2008). Role
of orexin input in the diurnal rhythm of locus
coeruleus impulse activity. Brain Res. 1224, 43-52.
Gonzalez, M. M., and Aston-Jones, G. (2006).
Circadian regulation of arousal: role of the
noradrenergic locus coeruleus system and light
exposure. Sleep 29, 1327-1336.
Gonzalez, M. M., and Aston-Jones, G. (2008).
Light deprivation damages monoamine neurons
and produces a depressive behavioral phenotype
in rats. Proc. Natl. Acad. Sci. USA 105, 4898-4903.
subjects, suggesting that DD is a novel
means to model depression in intact and
drug-free animals, and has high face valid-
ity as a model of seasonal affective disorder
(Gonzalez and Aston-Jones, 2008). Given
that nocturnal animals, such as rats, are
less sensitive to light manipulations than
diurnal animals (humans), we hypothesize
that these effects of light deprivation might
be greater in diurnal subjects. Together,
our results indicate that an intact NA-LC
is needed for robust circadian sleep-wake
rhythms, that orexin inputs to LC from
DMH are important for circadian prop-
erties of NA-LC neurons, and that light is
required for the maintenance of proper
functioning of LC and its related behav-
ioral and mental processes (i.e., sleep-wake
rhythm, performance, and mood).
Acknowledgments
This work was supported by PHS grants
R01 NS24698 and R37 DA06214, and by
the National Association for Research on
Schizophrenia and Depression.
Heinrich S. Gompf received his Ph.D. from the
Oregon Health and Science University in Port-
land, Oregon. He conducted post-doctoral work
with Dr. Aston-Jones at the University of Penn-
sylvania. His primary research interests are the
mechanisms by which external stimuli and the
internal clock activate arousal systems. His
approach has involved in vitro whole-cell
patch-clamp and in vivo single unit neuro-
physiology, neuroanatomy and EEG monitoring
of sleep and wakefulness in rats and mice.
heinrich.gompf@gmail.com

STRESS,
SLEEP AND CRH
By Mayumi Kimura
Mayumi Kimura graduated from Kanazawa
University and completed her Ph.D. in Physiol-
ogy at Tokyo Medical and Dental University.
She was formally appointed at Tokyo Medical
and Dental University, the University of Ten-
nessee, Memphis, the University of Texas
Southwestern Medical Center at Dallas, and
Louisiana State University Penninton Biomed-
ical Research Center. Since 2003, Dr. Kimura
is the Head of the Neurogenetics of Sleep
research group at the Max Planck Institute of
Psychiatry and studies neuro-humoral mech-
anisms of sleep-wake regulation in various
animal models.
kimura@mpipsykl.mpg.de
Sleep is a very complex phenotype.
Although genetic susceptibility contributes
significantly to sleeping habits in individu-
als (Kimura and Winkelmann, 2007), tem-
poral or even chronic alterations in sleep
occur under the influence of various envi-
ronmental factors; stress is one of them.
When we are exposed to stress, no matter
how pleasant or unpleasant it is, most of us
experience difficulties in falling asleep or
maintaining deep sleep. During the process
of stress recognition, autonomic reflexes are
activated; therefore, we can keep bodily and
mental tension to deal with stress-induced
414  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
problems. That leads to the increased level
of arousal on the one hand, and on the
other hand a stress-coping mechanism in
our body system works, which is operated
principally by the hypothalamic-pituitary-
adrenal (HPA) axis and presumably affects
sleep-wake regulation in response to stress
and in the case of mood disorders (Steiger,
2007).
A key chemical modulator, which we pre-
dict to cause sleep disturbances in such dis-
orders, is corticotropin-releasing hormone
(CRH). CRH is a hypothalamic polypep-
tide that initially activates the HPA axis. In
fact, when tested centrally in rodents, CRH
is capable of promoting wakefulness and
suppressing sleep (Chang and Opp, 2001).
However, we should carefully interpret the
outcome. The effects induced after a bolus
injection of CRH might include the actions
of other descending stress hormones, such
as adrenocorticotropic hormone (ACTH)
or glucocorticoids. Therefore, it is techni-
cally very difficult to demonstrate whether
brain CRH really impairs sleep separately
from the altered HPA system.
To investigate a sole effect of central CRH
on sleep-wake regulation, we generated two
types of conditional CRH overexpressing
(COE) mice. Both CNS-specific (Nes) and
forebrain-specific (Cam) CRH-COE mice
show elevated levels of REM sleep, but non-
REM sleep is slightly attenuated only in CRH-
COE-Nes mice. Such enhanced REM sleep
increases further when the mice are subjected
to sleep deprivation, which could be normal-
ized by treatment with a CRH-R1 antagonist
(DMP696 orally given with 30 mg/kg). The
results we obtained from CRH-COE mice
suggest that central CRH, especially limbic
CRH, is responsible for promoting REM sleep
as similarly seen in depressed patients, e.g.,
REM sleep disinhibition. The sleep patterns
we observed also correspond with those of
other rodent models of depression, in which
more REM sleep is evident in the affected
group that shows higher plasma levels of
corticosterone than the control (Dugouvic
et al., 1999). However, our CRH-COE mice
possess undisturbed HPA activity, therefore,
REM sleep enhancement seen in this model
could result from the effects of central CRH.
More details are reported in our recent pub-
lication (Kimura et al., 2009).
So far, we had the wrong impression
that stress always caused insomnia. In a
way, such a statement is still correct, but
we need to modify it as stress also triggers
a drive toward REM sleep. Significance of
REM sleep in general is not well described.
Nevertheless, accumulated evidence pro-
poses an idea that imbalance of REM sleep
serves as a biomarker to detect a sign of
depression. Protecting our sleep is definitely
important to avoid a risk of being sick, both
physically and mentally.
References
Chang, F. C., and Opp, M. R. (2001).
Corticotropin-releasing hormone (CRH) as
a regulator of waking.
Neurosci. Biobehav. Rev. 25, 445-453.
Dugouvic, C., Maccari, S., Weibel, L.,
Turek, F. W., and Van Reeth, O. (1999). High
corticosterone levels in prenatally stressed rats
predict persistent paradoxical sleep alterations.
J. Neurosci. 19, 8656-8664.
Kimura, M., Müller-Preuss, P., Lu, A.,
Wiesner, E., Flachskamm, F., Wurst, W.,
Holsboer, F., and Deussing, J. M. (2009).
Conditional corticotropin-releasing hormone
overexpression in the mouse forebrain enhances
rapid eye movement sleep. Mol. Psychiatry,
doi:10.1038/mp.2009.46.
Kimura, M., and Winkelmann, J. (2007).
Genetics of sleep and sleep disorders.
Cell. Mol. Life Sci. 64, 1216-1226.
Steiger, A. (2007). Neurochemical regulation
of sleep. J. Psychiat. Res. 41, 537-552.
 Brain cells. Immunofluorescent light micrograph
of astrocytes, with other neuroglial
precursor cells, cultured in the laboratory.
ASTROCYTES
AND SLEEP HOMEOSTASIS
By Pierre J. Magistretti and Jean-Marie Petit
A canonical view for the role of sleep is recov-
ery, in particular as far as energy homeostasis
is concerned. More recently, evidence has been
provided for a function of sleep, in particular
slow wave (non-REM) sleep, in synaptic plas-
ticity and memory (Tononi and Cirelli, 2006).
Astrocytes play a key role in coupling synaptic
activity to energy metabolism and vascular
responses (Magistretti, 2006; Haydon and
Carmignoto, 2006). A particular feature of
neuron-glia metabolic coupling is the abil-
ity of a selected group of neurotransmitters
to modulate the metabolism of glycogen, the
Pierre J. Magistretti is Director of the Brain
Mind Institute at EPFL and of the Center for
Psychiatric Neuroscience of the University of
Lausanne, Switzerland. His laboratory has con-
tributed to the identification of the role of as-
trocytes in coupling synaptic activity to energy
metabolism. He is past president of FENS and
has occupied the International Chair at the
Collège de France in 2007-2008.
pierre.magistretti@epfl.ch
Jean-Marie Petit was trained in Michel Jou-
vet’s laboratory and is now a staff scientist in
Pierre Magistretti’s laboratory where he inves-
tigates the astrocytic metabolism throughout
the sleep-wake cycle.
jean-marie.petit@epfl.ch
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  415
storage form of glucose selectively localized in
astrocytes. Thus, adenosine, vasoactive intes-
tinal peptide and noradrenaline promote a
rapid (seconds) glycogenolysis and a delayed
(hours) and transcriptionally-regulated gly-
cogen resynthesis in astrocytes (Magistretti,
2006). In mice, sleep deprivation is known to
result in accumulation of extracellular adeno-
sine (Halassa et al., 2009), a mediator of sleep
pressure, which results in a massive induction
of the gene encoding for PTG (protein tar-
geting to glycogen) (Petit, 2002). As a result,
after sleep deprivation, glucose metabolism
in the cortex is directed toward glycogen
resynthesis rather than glucose utilization
which has an operative effect on astrocytes as
glycogen is selectively localized in these cells.
Accordingly, glucose utilization is decreased
in cortical areas during non-REM sleep. In
addition to this energetic facet, astrocytes
are in a position to affect synaptic plasticity,
in particular through the release of so-called
gliotransmitters, such as glutamate and ATP
(Haydon and Carmignoto, 2006). The latter
is rapidly hydrolyzed by ectonucleotidase to
adenosine. Recently, Halassa and colleagues
(2009) using conditional transgenic mice, in
which the vesicular release of gliotransmit-
ters, notably ATP, was impaired, and dem-
onstrated an additional role of adenosine
in sleep regulation and synaptic plasticity.
Indeed, these mice displayed an attenuated
sleep pressure as reflected by reduced slow-
wave activity; a feature of non-REM sleep
related to memory consolidation. In addition,
these mice also displayed an impairment of
short-term memory, which is known to be
altered by sleep loss. Altogether, these results
point to an emerging function of astrocytes
as potential mediator of the known effects of
adenosine on sleep regulation, both, in terms
of their role in neuroenergetics and in synap-
tic plasticity.
References
Halassa, M. M., Florian, C., Fellin, T.,
Munoz, J. R., Lee, S.-Y., Abel, T., Haydon, P. G.,
and Frank, M. G. (2009). Astrocytic Modulation of
Sleep Homeostasis and Cognitive Consequences
of Sleep Loss. Neuron 61, 213-219.
Haydon, P. G., and Carmignoto, G. (2006). Astrocyte
Control of Synaptic Transmission and Neurovascular
Coupling. Physiol. Rev. 863, 1009-1031.
Magistretti, P. J. (2006). Neuron-glia metabolic
coupling and plasticity. J. Exp. Biol. 209, 2304-2311.
Petit, J.-M., Tobler, I., Allaman, I.,
Borbély, A. A., and Magistretti, P. J. (2002).
Sleep deprivation modulates brain mRNAs
encoding genes of glycogen metabolism.
Eur. J. Neurosci. 16, 1163-1167.
Tononi, G., and Cirelli, C. (2006). Sleep function
and synaptic homeostasis. Sleep Med. Rev. 10, 49.
UNDERSTANDING
SLEEP THROUGH
GENETIC
ANALYSIS
By Paul Franken

Hypotheses on sleep’s neurobiological func-

tion primarily concern the brain because,
among other reasons, its activity during
sleep, measured with the EEG, greatly differs
from that during wakefulness, and because
sleep loss negatively impacts cognitive per-
formance. It is further assumed that a need
for sleep can only be efficiently alleviated
during sleep. Thus, sleep is thought to fulfill
a homeostatic function assuring that sleep
need remains low. Trait-like inter-individ-
ual differences have been reported for the
degree sleep deprivation (SD) compromises
performance. Also, the large differences
found in habitual sleep duration might

Paul Franken works at the Center for Integra-

tive Genomics (CIG), University of Lausanne,
Switzerland, where he heads a laboratory
which aims at understanding sleep need at a
cellular level focusing on the inter-relationship
between energy metabolism, circadian clock
genes and sleep loss (www.unil.ch/cig/
page35061_en.html). He received his Ph.D. from
the University of Groningen, Netherlands, and,
before joining the CIG, worked at the Universi-
ties of Geneva and Zürich, Switzerland, and at
Stanford University, US.
paul.franken@unil.ch

416  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org


point to inter-individual differences in the
homeostatic regulation of sleep. Twin stud-
ies have shown that genetic factors impor-
tantly contribute to these and other sleep
traits, in particular EEG activity (Andretic
et al., 2008). Thus, sleep seems amenable
to genetic analyses, which could bring new
insights into its regulation and, hopefully,
function.
Until recently, little was known about
the specific genes and molecular pathways
underlying sleep regulation. Therefore,
some 14 years ago we began to map genomic
loci for sleep and EEG phenotypes in the
mouse using quantitative-trait loci (QTL)
analysis. With this approach, we identified
variations in the Acads and Rarb1 genes to
underlie the EEG differences in theta (6-9
Hz) and delta activity during sleep, respec-
tively, implicating fatty-acid β-oxidation
and retinoic acid signaling in shaping the
EEG (Andretic et al., 2008). Mice also greatly
differed in the SD-induced increase in EEG
delta power which mapped to a QTL on
chromosome 13. Delta power quantifies the
delta oscillations (1-4 Hz) characteristic of
the sleep EEG and is widely used as a sleep
need index. Subsequent quantification of
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  417
SD-induced brain transcriptome changes
and in silico analysis identified the activity-
induced transcript Homer1a as a credible
candidate for this QTL (Maret et al., 2007).
Homer1a is involved in neuronal plasticity
consistent with a role of sleep in preserving
the integrity of neuronal connectivity and
signaling (Krueger et al., 2008). Genome-
wide association (GWA) studies have made
a comparable, forward genetic approach
feasible in humans. Thus far, case-control
studies, such as for the sleep disorders nar-
colepsy and restless legs syndrome, have
been the focus of this approach. GWA
studies should be extended to quantitative
traits, like sleep duration and the response
to SD, to identify genes affecting the regu-
lation of physiological sleep in the general
population.
Finally, sleep research profited from the
ever increasing number of available trans-
genic or mutated lines of mice and fruit
flies. As an example, we found that mice
with targeted disruptions in circadian clock
genes, besides an altered circadian physiol-
ogy, also show a pronounced altered sleep
homeostasis suggesting that these two proc-
esses are not easily separable at a molecu-
QTL analyses of the EEG in mice have uncovered sev-
eral gene pathways involved in shaping oscillatory neu-
ronal activity characteristic of sleep.
lar level (Franken and Dijk, 2009). The
homeostatic regulation of sleep in humans
was also found to vary with a polymor-
phism for a circadian gene; i.e., Per3. These
examples show that only when these vari-
ous approaches are used in parallel, while
exploiting the available model systems, can
true progress be achieved toward unraveling
sleep’s function.
References
Andretic, R., Franken, P., and Tafti, M. (2008).
Genetics of sleep. Annu. Rev. Genet. 42, 361-388.
Franken, P., Chollet, D., and Tafti, M. (2001).
Sleep homeostasis is under genetic control.
J. Neurosci. 21, 2610-2621.
Franken, P., and Dijk, D.-J. (2009).
Circadian clock genes and sleep homeostasis.
Eur. J. Neurosci. 29, 1820-1829.
Krueger, J. M., Rector, D. M., Roy, S.,
Van Dongen, H. P. A., Belenky, G., and
Panksepp, J. (2008). Sleep as a fundamental
property of neuronal assemblies. Nat. Rev.
Neurosci. 9, 910-919.
Maret, S., Dorsaz, S., Gurcel, L., Pradervand,
S., Petit, B., Pfister, C., Hagenbuchle, O.,
O’Hara, B. F., Franken, P., and Tafti, M. (2007).
Homer1a is a core brain molecular correlate
of sleep loss. PNAS 104, 20090-20095.
 SLEEP-
DEPENDENT
MEMORY
INTEGRATION
By Matthew P. Walker

Substantive evidence supports a role for

sleep in the consolidation (solidification)
of newly acquired memories. However, as
critical as consolidation may be – an oper-
ation concerned with individual memory
items – the integration of new experiences
into pre-existing networks of knowledge
is equally, if not more, important. Here, I
champion the thesis that the end goal of
sleep, and especially REM-dreaming, is
not simply the strengthening of individual
memories across a single night, but instead,

418  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org


A *
100
90
Percent Correct
80
70
n.s.
60
(chance) 50
o o
1 2
Inference pairs
20 min 12hr wake
their integration into a common knowledge
schema across multiple nights (McClelland
et al., 1995; Walker, 2009).
For example, a recent study required
participants to initially learn five indi-
vidual premises; the object memory pairs
(A>B, B>C, C>D, D>E, E>F) (Ellenbogen
et al., 2007). Unknown to subjects, the
pairs contained an embedded hierarchy
(A>B>C>D>E>F). Following a delay of
20min., 12 hours across the day or 12 hours
containing a night of sleep, knowledge of
this associative-hierarchy was tested by
examining relational judgments for novel
“inference” pairs, either separated by
1-degree of associative distance
(B>D, C>E pairs), or by 2-degrees
of associative distance (B>E pair).
Subjects tested soon after learn-
ing in the 20 min. delay group
showed no evidence of inferential
ability, performing at chance
levels (Figure 1).
In contrast,
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  419
*
B
*
Immediate A B C D E F
n.s.
B C D E
Wake A B C D E F
B C D E
1o inference
Sleep A B C D E F Figure 1. Sleep-dependent integration of human rela-
1o & 2 o inference
tional memory. A) Delayed inference (associative) mem-
o o o o
ory performance (% correct) in a relational memory task
1 2 1 2
following different offline delays; B) A conceptual model
of the effects of sleep on memory integration. *p < 0.05;
12hr sleep error bars indicate s.e.m.
both 12 hour groups displayed highly sig-
nificant relational memory developments.
Matthew P. Walker earned his Ph.D. in Neuro-
Most remarkable, however, if the 12 hour physiology from the Medical Research Council,
delay contained a night of sleep, a 25% UK, and subsequently became an Assistant
advantage in relational memory was seen Professor of Psychology at Harvard Medical
for the most distantly connected, non- School. He is currently an Assistant Professor
obvious inferential judgment (B>E pair). of Psychology and Neuroscience at University
Therefore, sleep preferentially biased the of California Berkeley. His research examines
the impact of sleep on human brain function,
development of more distant/weak asso- with a particular focus on the role of sleep in
ciative links amongst related, yet separate, memory processing, neural plasticity and emo-
memory items. tional regulation.
Additional quantitative data further mpwalker@berkeley.edu
confirm such sleep-inspired creativity
(reviewed in Walker, 2009). For example,
solution performance on tests of cognitive the consolidation of individual items, and
flexibility using anagram puzzles is more instead, intelligently assimilates these details
than 30% better following awakenings offline. In doing so, sleep (and perhaps
from REM sleep compared with non-REM dreaming) may offer the ability to test and/
awakenings. Similarly, performance on a or build common informational schemas of
semantic priming task following REM sleep generalized knowledge, affording increas-
awakenings shows a greater priming effect ingly accurate statistical predictions about
by weakly related words than by strong the world, and even creative insights. Is it a
primes. Furthermore, the likelihood of wonder, then, that we are never told to stay
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
DOWNSCALE
OR EMBOSS
SYNAPSES
DURING SLEEP?
By Sidarta Ribeiro, Catia M. Pereira1, Jean Faber2,
Wilfredo Blanco3 and Miguel A. L. Nicolelis4
Sleep is beneficial to learning, but the under-
lying mechanisms remain controversial and
two paradigms currently collide. One of the
competing theories proposes that the cogni-
tive function of sleep is to promote general-
ized synaptic downscaling, so as to enable
further waking potentiation. This theory
is based on evidence that sleep down-reg-
ulates activity-dependent gene transcripts,
calcium-dependent kinases, membrane traf-
ficking proteins and metabolic enzymes. It
proposes that wakefulness and sleep are
respectively associated with a net increase
and decrease in cortical synaptic strength.
Sleep would play a role in “an overall balance
of synaptic strength” by favoring “global syn-
aptic depression” (Vyazovskiy et al., 2008).
The alternative theory proposes that the
cognitive role of sleep stems from the cooper-
ative interaction of its two major states: while
slow-wave sleep (SWS) reverberates memo-
ries at the electrophysiological level, rapid eye
movement (REM) sleep selectively triggers
plasticity within specific circuits pre-acti-
420  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
vated by SWS. The notion that sleep harbors
differential plasticity in separate circuits is
rooted on data showing that novel experience
causes an up-regulation of plasticity-related
factors during subsequent REM (Ribeiro et
al., 1999; Ulloor and Datta, 2005). The sleep-
dependent development of the visual cortex
in cats requires the phosphorylation of pro-
teins necessary for the calcium-dependent
Sidarta Ribeiro majored in Biology at the Uni-
versity of Brasília and received a Master’s
degree in Neurobiology from the Federal Uni-
versity of Rio de Janeiro. In 2000, he received
a Ph.D. in Animal Behavior from the Rockefell-
er University. He performed post-doctoral work
in neurophysiology at the laboratory of Miguel
Nicolelis at Duke University. In 2005, he re-
turned to Brazil as Scientific Director of the
ELS-IINN. Since 2008, he is Professor of Neu-
roscience at the Federal University of Rio
Grande do Norte, and heads the laboratory at
the ELS-IINN.
ribeiro@natalneuro.org.br
potentiation of glutamatergic synapses (Aton
et al., 2009). Evidence of synaptic upscaling
during sleep was also uncovered in inverte-
brates (Ganguly-Fitzgerald, 2006).
The divergent theories are based on
different assumptions and, consequently,
different experimental strategies. The
downscaling theory represents a revival
of the passive sleep paradigm; dominant
before the discovery of REM in the 1950’s.
It focuses on SWS and disregards experi-
ence-dependent changes. In contrast, the
embossing theory considers sleep as a com-
bination of passive and active mechanisms.
It advocates the need to compare sleep with
and without previous learning. It also dis-
tinguishes the contributions of SWS and
REM, characterized by very different neu-
ral dynamics.
The embossing theory is compatible
with the evidence of synaptic downscaling
during sleep, as long as the latter occurs in
circuits not engaged by waking experience.
Downscaling is probably essential for learn-
ing, but if it occurred in both activated and
non-activated circuits, it should promote
generalized forgetting, not learning. On the
other hand, the combination of upscaling
in activated circuits and downscaling in
non-activated circuits should increase the
signal-to-noise ratio of memory consoli-
dation during sleep. One corollary of the
embossing theory is that the net change in
1
Edmond and Lily Safra International Institute of
Neuroscience of Natal (ELS-IINN), Natal/RN – Brazil
pereiracm@natalneuro.org.br
2
Edmond and Lily Safra International Institute of
Neuroscience of Natal (ELS-IINN), Natal/RN – Brazil
jeanfaber@gmail.com
3
Edmond and Lily Safra International Institute of
Neuroscience of Natal (ELS-IINN), Natal/RN – Brazil;
Federal University of Rio Grande do Norte (UFRN),
Natal/RN – Brazil
wblancof@gmail.com
4
Edmond and Lily Safra International Institute of
Neuroscience of Natal (ELS-IINN), Natal/RN – Brazil;
Department of Neurobiology, Duke University,
Durham/NC – USA
nicoleli@neuro.duke.edu
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  421
synaptic strength during sleep is determined
by the strength of the preceding experience,
i.e., by how much synaptic change resulted
from waking.
More experimentation is required to
convincingly refute either theory. At the
2009 SfN meeting, our team presented
fresh biochemical, electrophysiological
and computational data in support of
the embossing hypothesis. We reported
an experience-dependent increase in the
phosphorylation of calcium-dependent
kinases during REM. We also showed that
only neurons activated by waking experi-
ence are reactivated during ensuing sleep.
Finally, computer simulations showed
that higher firing rates during REM may
cause synaptic weights to increase, carv-
ing strong pathways in a lattice of weak
connections. These results corroborate
the notion that sleep promotes synaptic
upscaling within circuits selected by wak-
ing experience. Nat. Neurosci. 2, 200-208.
References
Aton S. J., Seibt J., Dumoulin M., Jha S.K.,
Steinmetz N., Coleman T., Naidoo N., and
Frank M. G. (2009). Mechanisms of sleep-
dependent consolidation of cortical plasticity.
Neuron 61, 454-466.
Ganguly-Fitzgerald I., Donlea J., and Shaw P.
J. (2006). Waking experience affects sleep need in
Drosophila. Science 313, 1775-1781.
Ribeiro, S., Goyal, V., Mello, C. V., and
Pavlides, C. (1999). Brain gene expression during
REM sleep depends on prior waking experience.
Learn. Mem. 6, 500-508.
Ulloor, J., and Datta, S. (2005). Spatio-temporal
activation of cyclic AMP response element-
binding protein, activity-regulated cytoskeletal-
associated protein and brain-derived
nerve growth factor: a mechanism for pontine-
wave generator activation-dependent two-way
active-avoidance memory processing in the rat.
J. Neurochem. 95, 418-428.
Vyazovskiy V. V., Cirelli C., Pfister-Genskow M.,
Faraguna U., and Tononi G. (2008). Molecular
and electrophysiological evidence for net synaptic
potentiation in wake and depression in sleep.
SLEEP-WAKE
The modern lifestyle and technologies in
communication have modified the human
wake-sleep rhythms including changes in

RHYTHM
the sleep patterns of children. There are
many ways to distract children, keeping
them awake until late at night, such as tel-

DISORDER
By Adrián Poblano and Ulises Jiménez-Correa
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.
Contemporary parental upbringing has also

422  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

EOGi
EOGd
EMGm
FP1-F3
F3-C3
C3-P3
P3-01
F7-T3
T3-T5
T5-01
EKG
FP2-F4
F4-C4
C4-P4
P4-02
F8-T4
T4-T6
T6-02
EMGp
Flujo
Torax
Abdomen
Ronquido
SaO2
HR-A
Pos-B
changed allowing children more freedom,
which has resulted in an increase in behav-
ioral problems and, secondary, in the lack
or weakness of limits. This scenario must
be modified so that physicians, parents,
and guardians are able to prevent a possible
increase of behavioral sleep disorders in the
younger population.
Irregular sleep-wake rhythm (ISWR)
disorder is characterized by a relative
absence of a circadian pattern in the sleep-
wake cycle. Total sleep time is essentially
normal, but there are multiple irregular
sleep periods during a 24-hour cycle. ISWR
is more common in blind subjects, because
they lost the sun light as a biofeedback to
help control their biological pacemaker.
On the other hand, ISWR can be associ-
ated with neurologic impairment, such as
dementia and mild head injury (Avalon et
al., 2007; Okawa et al., 1991). Furthermore,
in teenagers, as they progress through the
transition from childhood to adolescence,
many shifts occur in sleep/wake patterns,
Adrián Poblano is a Senior Researcher at the
Clinic of Sleep Disorders, School of Medicine,
National University of Mexico, since 2004. He
received his M.D., M.Sc. and D.Sc. degrees
from Metropolitan University, Mexico City. He
also works as a Clinical Neurophysiologist at
the National Institute of Communication Disor-
ders, Mexico City, and is a National Investiga-
tor at the National Council of Science and
Technology, Mexico. His research explores the
development of sleep and its disorders in in-
fants, children and adolescents.
drdyslexia@latinmail.com
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  423
which are related to intrinsic and extrinsic
developmental changes. These shifts have
shown to result in corresponding shifts
in sleep phases and sleep deprivation in
Western societies (Yan et al., 2005) and may
predispose to ISWR.
ISWR is a rare condition in persons who
are not unsighted. The sleep-wake pattern is
temporarily disorganized, thus, sleep peri-
ods are variable throughout the 24-hour
period. Individuals experience symptoms
of insomnia and excessive drowsiness.
However, there is a lack of research on the
neurological basis of the ISWR disorder.
Recently, we had the opportunity to observe
a young patient with ISWR and electro-
encephalographic (EEG) alterations. The
patient was not unsighted, and reported
great difficulty in maintaining a regular
sleep schedule, with insomnia alternating
with involuntary diurnal sleepiness. We
performed a full nocturnal polysomono-
graphic (PSG) study with complete EEG
recording. The PSG result was reported
Ulises Jiménez-Correa is a Senior Research-
er at the Clinic of Sleep Disorders, School of
Medicine, National University of Mexico,
since 1999. He received his B.Sc. and M.Sc.
degree in Psychology from the National Uni-
versity of Mexico, and his Ph.D. from Metro-
politan University at Iztapalapa, Mexico. His
research explores pathophysiological mech-
anisms, development of diagnostic tools and
treatment of insomnia.
ulisesjc@clinicadeldormirunam.com
Figure 1. Typical 10 sec. PSG-EEG epoch of patient with
ISWR during N2 sleep state. Note asynchrony of sleep-
spindles onset between left and right hemispheres, at 2-3
sec. of recording. This comprises one of the EEG abnor-
malities found in this ISWR patient.
References
Ayalon, L., Borodkin, K., Dishon, L., Kanety, H.,
and Dagan, Y. (2007). Circadian rhythm sleep
disorders following mild traumatic brain injury.
Neurology 68, 1136-1140.
Okawa, M., Mishima, K., Hishikawa, Y.,
Hosumi, S., Hori, H., and Takahashi, K. (1991).
Circadian sleep disorders in sleep-waking and
body temperature in elderly patients and
dementia and their treatment. Sleep 14, 478-485.
Yan, C. K., Kin, J. K., Patel, S. R., and Lee J. H.
(2005). Age-related changes in sleep/wake
patterns among Korean teenagers. Pediatrics 115
(suppl. 1), 250-256.
without changes; while the EEG record-
ing in the awake, eyes-closed state showed
mild asymmetry of alpha rhythm, the EEG
during sleep demonstrated sleep-spindle
asynchrony and slow wave sleep exhibited
irregular delta activity.
We found no previous reports of EEG
alterations in patients with ISWR. Therefore,
we propose herein that the ISWR disorder
is probably associated with EEG disorgani-
zation and sleep-spindle asynchrony. The
question, whether ISWR and neurophysi-
ologic asynchrony have a common ori-
gin, cannot be answered by this patient’s
results alone, but deserves major investiga-
tion in future studies. We will investigate
in subsequent patients with ISWR, clinical
EEG-PSG, and magnetic resonance imag-
ing (MRI) examinations in search of the
neurologic basis of ISWR. Moreover, we
suggest that patients with ISWR must be
evaluated through neurophysiological and
neuroimaging examinations.
 OBSTRUCTIVE
SLEEP APNEA
By Lena Lavie and Peretz Lavie

Since the late 19th century, obese patients

complaining of intense sleepiness were
termed “Pickwickian” because of their
resemblance to Joe, the sleepy fat boy from
Dickens’s book The Pickwick Papers. The
true nature of this disorder was unveiled
more than half a century later when
Pickwickian patients were first monitored
during sleep by electrophysiological meth-
ods. These revealed that their daytime symp-
tom of excessive sleepiness and the peculiar
nature of their restless nights were caused
by intermittent obstructions of the upper
airways during sleep that resulted in epi-
sodic hypoxemia and repeated awakenings.
Then, the term Pickwickian was replaced by
obstructive sleep apnea syndrome (OSAS).
The formal diagnosis of OSAS is based on
a combination of sleep laboratory findings
and typical complaints, such as excessive
daytime sleepiness. The syndrome is very
prevalent affecting at least 2% and 4% of the
middle aged women and men, respectively,
and is strongly associated with cardiovas-
cular morbidity. Figure 1 depicts the rela-
tionship of co-morbidities with age in these
patients. Worldwide, OSAS patients com-
prise the vast majority of patients examined
in sleep clinics (Lavie, 2008).
Results from our laboratory and others
demonstrate that two fundamental compo-
nents of atherosclerosis – oxidative stress
and inflammation – are activated nightly

424  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 70 Diabetes Hypertension
60
50
Percentage / AHI
40
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
in OSAS (Lavie, 2003). Apneas during sleep
are associated with repeated occurrence of
hypoxia/reoxygenation events that, similar
to the effect of restoration of blood cir-
culation to an ischemic tissue, result in
increased production of free radicals. Once
produced, the toxic free radicals may inflict
injury on surrounding tissues and activate
specific oxidative stress sensitive transcrip-
tion factors that encode proinflammatory
cytokines. This results in activation of
endothelial cells, leukocytes and platelets;
increased production of adhesion mole-
cules that facilitate endothelial cell-leuko-
cyte interactions and adhesion; increased
toxicity of monocytes and lymphocytes
against endothelial cells; and increased
neutrophil activation. Findings that OSAS
patients, free of any overt cardiovascular
Lena Lavie obtained her Ph.D. from the Depart-
ment of Biology, the Technion, Israel, and her
post-doctoral training at the Department of
Biological Chemistry in Harvard. She is a Senior
Research Fellow (Associate Professor) and
Head of the Lloyd Rigler Sleep Apnea Research
Laboratory in the Faculty of Medicine, Tech-
nion. She specialized in biochemistry and cel-
lular biology with an emphasis on oxidative
stress and inflammation. Her research is aimed
at understanding the pathophysiological mech-
anisms leading to cardiovascular morbidity in
sleep apnea syndrome.
lenal@tx.technion.ac.il
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  425
Heart Disease AHI
AGE
disease, display endothelial dysfunction
and early signs of atherosclerosis, such
as increased carotid artery wall thickness,
increased arterial stiffness, and atheromas,
further support this concept (Dyugovskaya
et al., 2002; Lavie et al., 2008; Lavie and
Lavie, 2009).
These processes start to accrue dur-
ing the very first nights that hypoxemic
events appear and from that time on,
night after night, the patient’s blood ves-
sels and heart are exposed to the aggres-
sion of free radicals. Patients, however,
are generally referred for diagnosis only
when the characteristic symptoms, such
as excessive daytime sleepiness or heavy
snoring, start bothering them or their bed
partners, generally around the age of 50,
which may be ten to twenty years after
Peretz Lavie obtained his Ph.D. from the De-
partment of Psychology at the University of
Florida and his post-doctoral training at the
University of California San Diego. He holds
the Andre Ballard Chair of Biological Psy-
chiatry in the Faculty of Medicine in the
Technion where he established a sleep re-
search laboratory and a Sleep Medicine
Center. He was the Dean of the Faculty of
Medicine (1993-1999), Vice President for De-
velopment (2001-2008) and on October 1st
2009 he assumed the position of the Presi-
dent of the Technion.
plavie@tx.technion.ac.il
Figure 1. The percentage of sleep apnea patients (N=8,700
men) in different ages with a history of diabetes mellitus,
hypertension and heart disease at the time of sleep apnea
diagnosis. AHI (apnea/hypopnea index) calculated as the
total number of apneas plus hypopneas divided by the
hours of sleep, represents the severity of the syndrome
(AHI: 10-20: mild, 21-40: moderate, and >40: severe). Note
that the severity of sleep apnea stabilizes at around the
age of 40, while the percentages of patients with co-
morbidities gradually increase with age.
References
Dyugovskaya, L., Lavie, P., and Lavie L. (2002).
Increased adhesion molecules expression
and production of reactive oxygen species in
leukocytes of sleep apnea patients.
Amer. J. Respir. Crit. Care Med. 165, 934-939.
Lavie, L. (2003). Obstructive sleep apnoea
syndrome--an oxidative stress disorder. Sleep
Med. Rev. 7, 35-51.
Lavie, P. (2008). Who was the first to use the term
Pickwickian in connection with sleepy patients?
History of sleep apnoea syndrome. Sleep Med.
Rev. 12, 5-17.
Lavie, L., Dyugovskaya, L., and Polyakov, A.
(2008). Biology of peripheral blood cells in
obstructive sleep apnea--the tip of the iceberg.
Arch. Physiol. Biochem. 114, 244-254.
Lavie, L., and Lavie, P. (2009). Molecular
mechanisms of cardiovascular disease in OSAHS:
the oxidative stress link. Eur. Resp. J. 33,
1467-1484.
they first display apneas in sleep. During
that time there is an accumulated damage
to the cardiovascular system which could
be irreversible. To prevent cardiovascular
morbidities, the diagnosis and treatment
of OSAS should be done at the earliest age
possible. Treatment with nasal continuous
positive airway pressure that ameliorates
the apneas during sleep which was shown
to abort the atherosclerotic process and
reverse its course, should be initiated at
the earliest age possible to prevent cardio-
vascular damage in OSAS patients.
NARCOLEPSY
Narcolepsy affects 1 in 2,000 people. It is
characterized by excessive daytime sleepi-
ness, cataplexy and abnormal transitions

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

426  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org


within the T-cell receptor alpha (TCRα)
locus across multiple ethnic groups (Asians,
Caucasians, African American) (Hallmayer
et al., 2009). Since the TCR is the receptor for
HLA-peptide presentation, this result sug-
gests autoimmunity. Interestingly, another
study recently found an increased prevalence
of streptococcal infection markers in onset
cases of narcolepsy (Aran et al., 2009). As
Emmanuel J. M. Mignot is the Craig Reynolds
Professor of Sleep Medicine, Professor of Psy-
chiatry and Director of the Center for Narco-
lepsy at Stanford University. He is a world-re-
nowned expert in sleep medicine, having
discovered the cause of narcolepsy, a lack of
hypocretin in the brain. Dr. Mignot applies ba-
sic science techniques, such as genetics,
pharmacology and molecular biology, to the
study of sleep disorders, most notably sleep
apnea and narcolepsy. He also directs a spe-
cialized consultation devoted to the evaluation
of patients with narcolepsy and hypersomnia.
mignot@stanford.edu
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  427
streptococcal infections are known to trig-
ger other autoimmune manifestations, e.g.,
Sydenham’s chorea and rheumatic heart dis-
ease, narcolepsy may also be a post-strepto-
coccal autoimmune condition.
Interestingly, narcolepsy onset is not
associated with detectable inflammation.
We suggest that in narcolepsy, the immune-
mediated destruction of hypocretin cells is
selective and self-limited, without signifi-
cant epitope-spreading. Limited epitope
spreading may be a feature of neurons as
an immune-protected target, and could
explain difficulties in detecting autoim-
mune abnormalities. The fact that HLA
class II expression in neurons remains
constantly repressed (unlike in glial cells),
even in the face of local inflammation, may
be important. The specificity of this proc-
ess may also explain the genetic association
with TCRs, an association not found in
other autoimmune diseases. In this model,
Rs1154155 or a tightly linked marker within
References
Aran, A., Lin, L., Nevsimalova, S., Plazzi, G.,
Hong, S. C., Weiner, K., Zeitser, J., and
Mignot, E. (2009). Elevated anti-streptococcal
antibodies in patients with recent narcolepsy
onset. Sleep 32, 979-983.
Hallmayer, J., Faraco, J., Lin, L., Hesselson, S.,
Winkelmann, J., Kawashima, M., Mayer, G.,
Plazzi, G., Nevsimalova, S., Bourgin, P., et al.
(2009). Narcolepsy is strongly associated with
the T-cell receptor alpha locus. Nat. Genet. 41,
708-711.
Mignot, E., Lin, L., Rogers, W., Honda, Y.,
Qiu, X., Lin, X., Okun, M., Hohjoh, H., Miki, T.,
Hsu, S. H, et al. (2001). Complex HLA-DR
and -DQ interactions confer risk of narcolepsy-
cataplexy in three ethnic groups. Am. J. Hum.
Genet. 68, 686-699.
Peyron, C., Faraco, J., Rogers, W., Ripley, B.,
Overeem, S., Charnay, Y., Nevsimalova, S.,
Aldrich, M., Reynolds, D., Albin, R., et al.
(2000). A mutation in a case of early onset
narcolepsy and a generalized absence of
hypocretin peptides in human narcoleptic brains.
Nat. Med. 6, 991-997.
Stefansson, H., Ophoff, R. A., Steinberg, S.,
Andreassen, O. A., Cichon, S., Rujescu, D.,
Werge, T., Pietilainen, O. P., Mors, O.,
Mortensen, P. B., et al. (2009). Common
variants conferring risk of schizophrenia.
Nature 460, 744-747.
the TCR Jα region, favors the occurrence
of a very specific V-J TCRα pathogenic
T-cell clone recombinants or marks a cod-
ing change within a J segment that alters
TCRα-peptide binding.
If narcolepsy is a selective autoimmune
brain disease, it raises the possibility that
other diseases remain to be discovered. The
fact that hypocretin lesions can produce a
clinically very easily identifiable phenotype
(narcolepsy-cataplexy) may have made these
discoveries possible. It is likely that other
brain area selective autoimmune diseases
(with selective neuronal cell loss) do occur
but have less specific clinical effects, such as
psychiatric manifestations. The recent find-
ing that HLA is a susceptibility locus for
schizophrenia and bipolar disorder in large
scale GWAS studies provide some support
for this concept (Stefansson et al., 2009).
We hope that in time, narcolepsy will not
only inform us about sleep, but about other
autoimmune diseases of the brain.
MISSING THE POINT
WHEN SLEEP DEPRIVED
By Michael Chee
There has been a gradual decline in sleep
duration in most developed societies and
this situation has accelerated in recent years
because of the increasing use of electronic
social networks. With a few caveats, the cog-
nitive effects of chronic sleep restriction can
be characterized with studies that use short-
term total sleep deprivation.
Whereas earlier work on cognitive per-
formance in sleep-deprived persons was pri-
marily behavioral, a better understanding of
the underpinnings of cognitive decline has
been made possible by various physiological
monitoring techniques. Of these, functional
MRI (fMRI) is a particularly attractive meth-
odology because it affords a non-invasive,
spatially rich view of online brain function.
Our earlier work was dominated by the
premise that the prefrontal cortex is par-
ticularly vulnerable to the effects of sleep
deprivation. However, following several
428  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
experiments that evaluated working mem-
ory (Chee and Choo, 2004; Chee et al., 2006),
we observed that performance decrement, a
result of sleep deprivation, shows significant
inter-individual differences, which were most
reliably captured by variability in response
time (Lim et al., 2007). This, and the finding
that superior parietal task-related activation
yields robustly reproducible state changes,
led us to infer that the neural correlates of
attention failure should be better under-
stood before seeking to investigate “higher
cognitive functions” in detail.
While evaluating visual short-term
memory using a parametric design that
varied item load across two conditions,
one in which brief retention was required
and another where it was not, we observed
that across these conditions parietal task-
related activation was reduced from the
smallest set-size and irrespective of whether
volunteers were required to briefly retain
visual stimuli (Chee and Chuah, 2007). Had
there been a storage failure, we would have
expected a state effect to manifest only with
higher item load in the memory condition
and independent of the number of items in
the control condition.
Cholinergic modulation has been shown
to influence visual processing, attention
Michael Chee is Professor and Principal In-
vestigator in the Neuroscience and Behav-
ioral Disorders Program and Duke-NUS Grad-
uate Medical School. He received a MBBS
from the National University of Singapore and
proceeded to complete specialty training in
neurology before making a career switch to
pursue cognitive neuroscience. His research
focuses on sleep deprivation, as well as healthy
cognitive aging, and he uses both structural
and functional MRI.
michael.chee@duke-nus.edu.sg
 A. R Intraparietal Sulcus
R 3 VSTM VPC 3

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

B. R Ventral Occipital Cortex

2 VSTM 2
R VPC

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

SET SIZE SET SIZE

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
fMRI as an adjunct to behavioral testing,
as well as to determine who might benefit
from intervention, we conducted a double
blind, placebo controlled, crossover study
evaluating the effect of the cholinesterase
inhibitor donepezil on visual short-term
memory following 24 hours of sleep dep-
rivation (Chuah and Chee, 2008; Figure 1).
We found that individuals who declined
in performance when sleep deprived on
placebo showed the most improvement
when given cholinergic augmentation. In
contrast, individuals whose performance
was relatively well maintained during sleep
deprivation did not improve and instead,
showed a non-significant trend toward
performance decline. Interestingly, drug
mediated changes in parietal and extrastri-
ate visual cortex fMRI signal correlated with
the change in performance across state. The
changes in MR signal and behavior reflect
the modulation of attention/visual process-
ing and suggest that fMRI can be useful as a
functionally relevant marker of drug effect.
In a sister experiment, we found that in
addition to an effect on improving atten-
tion, cholinergic augmentation can facilitate
episodic memory by modulating prefrontal
cortex activation.
Much work remains if we are to bet-
ter understand the cause(s) of attention
failure in sleep-deprived persons and how
these may be ameliorated. Is it our ability
to pre-allocate cognitive resources to the
task at hand? Is the representation of sen-
sory information compromised in sleep-
deprived persons? Can the provision of
timely cues alleviate the attention deficits?
How would manipulation of noradrenergic
or dopaminergic neurotransmission affect
attention in this setting?
References
Chee, M. W., and Choo, W. C. (2004). Functional
imaging of working memory after 24 hr of total
sleep deprivation. J. Neurosci. 24, 4560-4567.
Chee, M. W., Chuah, L. Y., Venkatraman, V.,
Chan, W. Y., Philip, P., and Dinges, D. F. (2006).
Functional imaging of working memory following
normal sleep and after 24 and 35 h of sleep
deprivation: Correlations of fronto-parietal activation
with performance. Neuroimage 31, 419-428.
Chee, M. W., and Chuah, Y. M. (2007).
Functional neuroimaging and behavioral
correlates of capacity decline in visual short-term
memory after sleep deprivation.
Proc. Natl. Acad. Sci. USA 104, 9487-9492.
Chuah, L. Y., and Chee, M. W. (2008).
Cholinergic augmentation modulates visual task
performance in sleep-deprived young adults.
J. Neurosci. 28, 11369-11377.
Lim, J., Choo, W. C., and Chee, M. W. (2007).
Reproducibility of changes in behaviour and fMRI
activation associated with sleep deprivation
in a working memory task. Sleep 30, 61-70.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  429

SLEEP
DEPRIVATION,
AGING AND
CELLULAR STRESS
By Nirinjini Naidoo
We have increasingly become a 24/7 soci-
ety with more of us losing sleep each night
to keep up with the demands of daily life.
Beyond leaving people drowsy, grouchy
and dependent on their cup of joe, sleep
loss has major physiological consequences.
Epidemiological studies indicate that sleep
loss leads to insulin resistance, diabetes
and obesity (Van Cauter et al., 2007). Sleep
loss has also been shown to lead to deficits
in cognitive function (Van Dongen and
Dinges, 2003). Molecular studies indicate
that sleep deprivation has marked effects
on several cellular pathways including mac-
romolecular synthesis (protein, lipid, cho-
lesterol and heme), synaptic signaling and
chaperoning systems (Cirelli et al., 2004;
Mackiewicz et al., 2008). Withholding sleep
in mice and rats for as little as six hours leads
to the down-regulation of macromolecule
synthesis and an increase in synaptic signal-
ing and chaperone activity.
The increase in one particular protein,
the endoplasmic reticulum (ER) chaperone
BiP, was found to be conserved in all species
(Drosophila, rat, mouse, Djungarian hamster,
white crowned sparrow) studied thus far. This
chaperone serves as a sentinel for up-regula-
tion of several signaling pathways collectively
called the unfolded protein response (UPR)
that are activated when protein folding and
ER homeostasis are perturbed. All secretory
430  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
and integral membrane proteins are folded
and post-translationally modified in the ER.
Perturbations in redox state, pH, calcium
homeostasis and energy/glucose depletion
induce ER stress and the UPR. The UPR
protects the cell by increasing ER chaper-
one levels, attenuating protein translation
and increasing the degradation of misfolded
proteins which prevents the accumulation of
misfolded proteins that can form toxic pro-
tein aggregates. The UPR is healthy, protective
and adaptive when the ER stress is moder-
ate. Failure of the adaptive response leads to
the activation of an inflammatory response.
Prolonged, unresolved ER stress activates
pro-apoptotic executioner pathways.
Our studies indicate that moderately
acute sleep loss leads to the induction of
Nirinjini Naidoo is an Assistant Professor in
the Division of Sleep Medicine and a member
of the Center for Sleep and Respiratory Neuro-
biology at the University of Pennsylvania. She
received her Master’s degree in Biochemistry
from the University of Durban-Westville, South
Africa, and a Ph.D. in Chemistry from the Uni-
versity of Pennsylvania. Her research interests
include mechanisms of sleep regulation and
mechanisms involved in the aging of sleep and
wake with particular emphasis on the role of
the ER stress response. She is also using pro-
teomic approaches to study sleep disorders.
naidoo@mail.med.upenn.edu
 References
Cirelli, C., Gutierrez, C., and Tononi, G. (2004).
Extensive and Divergent Effects of Sleep
and Wakefulness on Brain Gene Expression.
Neuron 41, 35-43.
Mackiewicz, M., Shockley, K. R., Romer, M. A.,
Galante, R. J., Zimmerman, J. E., Naidoo, N.,
Baldwin, D. A., Jensen, S. T., Churchill, G. A.,
and Pack, A. I. (2008). Macromolecule biosynthesis
- a key function of sleep. Physiol. Genomics.
doi:10.1152/physiolgenomics.00275.2006
Naidoo, N., Ferber, M., Master, M., Zhu, Y.,
and Pack, A. I. (2008). Aging impairs the unfolded
protein response to sleep deprivation and leads
to proapoptotic signaling. J. Neurosci. 28,
6539-6548.
Van Cauter, E., Spiegel, K., Tasali, E., and
Leproult, R. (2007). Impact of Sleep and Sleep
Loss on Neuroendocrine and Metabolic Function.
Horm. Res. 67 (suppl. 1), 2-9.
Van Dongen, H. P., and Dinges, D. F. (2003).
Investigating the interaction between
the homeostatic and circadian processes
of sleep-wake regulation for the prediction o
f waking neurobehavioural performance.
J. Sleep Res. 12, 181-187.

the adaptive, protective UPR in the cer-

ebral cortex of young (2-3 month old) mice
(Naidoo et al., 2008). There is up-regulation
of BiP, an attenuation of protein translation
as evidenced by phosphorylation of PERK
and eIF2a and an increase in the number of
proteins tagged for degradation by the ubiq-
uitin-proteasomal pathway. In contrast, aged
(22-24 month old) mice fail to display the
adaptive response when subjected to sleep
deprivation. Instead, there is a large increase
in pro-apoptotic signaling markers, such as
CHOP, suggesting sustained ER stress and an
impairment of the adaptive response.
These observations suggest that inade-
quate sleep or sleep loss in the elderly, who
normally experience sleep disturbances,
could exacerbate an already-impaired
protective response to protein misfolding
that happens in aging cells. Many of the
aging related diseases, like Alzheimer’s and
Parkinson’s, are characterized by protein
misfolding. Studies underway indicate that
some of the daytime sleepiness/impaired
wakefulness experienced in the aged may
be due, in part, to ER stress and dyshomeos-
tasis in select groups of wake active neurons.
The mechanisms underlying the deficits in
cognitive function and insulin resistance
observed following sleep loss remain to be
elucidated. It is not unlikely that the ER
stress response may play a role.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  431

GENETIC
RESISTANCE
TO SLEEP
DEPRIVATION
By Namni Goel and David F. Dinges
Namni Goel, Ph.D., is Assistant Professor of Psy-
chology in Psychiatry at the University of Penn-
sylvania School of Medicine. She received her
Ph.D. from the University of Michigan, Ann Arbor.
She is the current President of the Society for
Light Treatment and Biological Rhythms and
member of several editorial boards. She investi-
gates the physiological and behavioral factors
affecting sleep, circadian rhythms, mood and
cognition. She recently has begun to identify
genes involved in differential vulnerability to the
effects of sleep deprivation.
goel@mail.med.upenn.edu
David F. Dinges, Ph.D., is Professor of Psychol-
ogy in Psychiatry at the University of Pennsylva-
nia School of Medicine and Chief of the Division
of Sleep and Chronobiology. His research fo-
cuses on the cognitive, neurobehavioral and
physiological effects of sleep loss in humans,
and includes development of biological, behav-
ioral, and technological means to detect and
prevent these effects.
dinges@mail.med.upenn.edu
Chronic partial sleep deprivation (PSD) is
a condition associated with a wide range
of serious health consequences and experi-
enced by millions of people on a consecu-
tive and daily basis due to a wide range
of factors, including medical conditions,
sleep disorders, work demands, and social
and domestic responsibilities. Sleep dep-
rivation is also associated with substantial
social, financial and health-related costs,
in large part because it produces impaired
432  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
cognitive performance due to increasing
sleep propensity and instability of wak-
ing neurobehavioral functions (Banks and
Dinges, 2007).
Subjects undergoing total sleep depriva-
tion (TSD), in which no sleep is obtained,
show differential vulnerability to sleep loss
demonstrating robust inter-individual (trait-
like, phenotypic) differences in response to
the same laboratory conditions, as measured
by various physiological and subjective sleep
measures and neurobehavioral tasks sensi-
tive to sleep loss (Van Dongen et al., 2004).
While some subjects are buffered from the
effects of sleep loss (resistant), some are
markedly affected (vulnerable), and others
show intermediate responses. Such differen-
tial vulnerability has also been documented
in chronic PSD conditions, in which sleep is
restricted to 3-7 hours time in bed per night
(Goel et al., 2009).
Until recently, the genetic basis of such
differential vulnerability to sleep loss on
functioning in healthy subjects undergo-
ing either TSD or PSD has received little
investigation (Goel et al., 2009). The role
of the variable number tandem repeat
(VNTR) polymorphism of the circadian
gene PERIOD3 (PER3) in response to TSD
was recently investigated in two related stud-
ies: the PER35/5 polymorphism was associ-
ated with higher sleep propensity both at
baseline and after TSD, and worse cognitive
performance on certain executive function
tests during 6-8 a.m. following TSD. Sleep
References
Banks, S., and Dinges, D. F. (2007). Behavioral
and physiological consequences of sleep
restriction. J. Clin. Sleep. Med. 3, 519-528.
Goel, N., Banks, S., Mignot, E., and Dinges, D. F.
(2009). PER3 polymorphism predicts cumulative
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.
(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
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.
homeostasis was hypothesized to mediate
such performance differences (Viola et al.,
2007; Groeger et al., 2008).
Subsequently, in the first study to employ
a candidate gene approach in subjects under-
going chronic PSD, we found that the PER3
VNTR polymorphism was not associated
with individual differences in neurobe-
havioral responses to PSD, although it was
slightly, but significantly, related to one puta-
tive marker of sleep homeostatic response
(Goel et al., 2009). Our results suggest that
sleep homeostatic and cognitive measures
in response to sleep deprivation may be
orthogonal and influenced by distinct genetic
mechanisms. Furthermore, equivalent base-
line physiological, cognitive and subjective
measures and comparable inter-individual
vulnerability to PSD indicated that variations
in genes other than PER3 contribute to the
cumulative behavioral effects of chronic PSD
(Goel et al., 2009).
Our group is actively searching for other
potential genetic biomarkers of differential
vulnerability to sleep deprivation. Among
other advantages, identification of such
markers will provide a viable means to
determine those individuals in the general
population who may need effective counter-
measures early and repeatedly. Biomarkers
may also identify those individuals who can
tolerate longer periods with little or no sleep
without developing the unstable cognitive
performance found in more vulnerable
individuals (Van Dongen et al., 2004).

THE SLEEP LAB
By Dalia Shechter-Amir
The advances in medicine and technology
over the years have contributed significantly
to the exploration of the sleep process and
to the development of sleep medicine. Due
to the improvement of electrophysiologi-
cal techniques, it was demonstrated that
the brain is active during sleep rather than
inhibited as suggested before.
Berger demonstrated differences in wake
brain activity versus sleep brain activity
by recording electrical impulses from the
skull, as described in his publication “On
the Electroencephalogram of Man” in 1929.
His discovery led to the development and
use of the EEG as a clinical and diagnos-
tic tool for the evaluation of brain activity
and sleep staging. REM sleep, characterized
by rapid eye movements and dream recol-
lection, was discovered by Aserinky and
Kleitman (1953). Staging sleep was stand-
Dalia Shechter-Amir is the Head of the Institute
for Sleep Medicine and Fatigue at the Sheba
Medical Center, Tel Hashomer, Israel. She
graduated from the Tel Aviv University, Sackler
School of Medicine, in 1988 and completed
residency in Neurology at the Sapir Medical
Center in Kfar Saba, Israel, in 1996. She com-
pleted a one-year fellowship training program
in Sleep Medicine at the University of Toronto,
Centre for Sleep and Chronobiology, in 1998.
Since then, she has been integrating clinical
work at the sleep clinic and neurology practice
in the Epilepsy Clinic at the Sheba Medical
Center, Tel Hashomer.
dalia.shechter-amir@sheba.health.gov.il
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  433
ardized by Rechtschaffen and Kales (1968).
The term “PSG” was proposed by Holland
et al. (1974) to describe the recording of
several parameters during sleep. PSG is an
essential tool in studying normal sleep and
in diagnosing sleep disorders.
The parameters measured in the PSG are
as follows:
• The EEG measures the brain wave activity.
• The EOG (electro-oculogram) records
eye movements which help to determine
the dreaming period.
• The EMG (electromyogram) records
muscle activity. Sharp decrease in EMG
(“atonia”) characterizes REM sleep.
Integrating the EEG, EOG and EMG data
defines the various sleep stages.
A nasal airflow sensor and the chest/
abdomen belts display sleep-related breath-
ing events, either obstructive or central.
Oximetry recording helps in determin-
ing the breathing disorder and its severity.
Snoring is recorded through a microphone.
Additional information is derived from the
ECG (electrocardiogram) and video moni-
toring. The gathered raw data is manually
scored and the polysomnography report
provides the sleep specialist with the
sleep architecture (hypnogram), type and
number of respiratory events, abnormal
motor activity in sleep, ECG findings and
any unusual observed behavior.
Though PSG is the gold standard for
the evaluation of sleep disorders, in-lab
PSG is expensive and inaccessible at times.
Portable sleep study systems offer an alter-
native to in-lab PSG recordings (Collop et
al., 2007). The ambulatory systems are a
viable option for patients with clinically sus-
pected obstructive sleep apnea (OSA).These
sleep systems require a minimum of four
channels, including respiratory movements,
airflow, oxygen saturation and ECG.
Wireless PSG is another promising
option for increasing the availability of sleep
studies in different environments. The setup
is fast and the patient is more comfortable,
but its reliability has not yet been fully
assessed for each environment.
Recently, other types of home sleep sys-
tems have been developed which are based
on autonomic nervous system activity in
wake and in sleep. The data analysis is based
on heart rate variability measures and a
hypnogram, and respiratory measurements
are obtained (Bianchi et al., 2006).
Combining data obtained by in-lab PSG
or ambulatory systems with clinical evalua-
tions, allows the sleep specialist to make the
proper diagnosis and suggest the optimal
treatment. One of the main future chal-
lenges for sleep medicine researchers is to
reduce the number of recording channels
and to further maximize and optimize the
sleep data acquired.
References
Aserinsky, E., and Kleitman, N. (1953).
Regularly occurring periods of eye motility,
and concomitant phenomena, during sleep.
Science 118, 273-274.
Bianchi, A. M., Villantieri, O. P., Mendez, M. O.,
and Cerutti, S. (2006). Signal processing and
feature extraction for sleep evaluation in wearable
devices. Conf. Proc. IEEE Eng. Med. Biol. Soc. 1,
3517-3520.
Collop, N. A., Anderson, W. M., Boehlecke, B.,
Claman, D., Goldberg, R., Gottlieb, D. J.,
Hudgel, D., Sateia, M., and Schwab, R. (2007).
Clinical guidelines for the use of unattended
portable monitors in the diagnosis of obstructive
sleep apnea in adult patients. Portable Monitoring
Task Force of the American Academy of Sleep
Medicine. J. Clin. Sleep Med. 3, 737-747.
Holland, J. V., Dement, W. C., and Raynal, D. M.
(1974). Polysomnography: a response to a need
for improved communication. Presented
at the 14th Annual Meeting of the Association
for the Phychophysiological Study of Sleep.
Jackson Hole, Wyo.
Rechtschaffen, A., and Kales, A. (1968).
A Manual of Standardized Terminology,
Techniques and Scoring System for Sleep Stages
of Human Subjects. Washington: Public Health
Service, US Government Printing Office.
MEDICATIONS
FOR SLEEP
By Nava Zisapel
Insomnia is a common disorder character-
ized by a difficulty in initiating or main-
taining sleep or inadequate sleep quality.
Insomnia prevalence rises with age, affect-
ing over 30% of the over-65 year olds.
Hypnotic drugs (benzodiazepines and non-
benzodiazepines) used to treat insomnia
work by enhancing the inhibitory activity
of the brain’s GABA-A receptors. However,
these drugs can cause side effects, such as
amnesia, cognitive impairments, risk of
falling and car accidents, and their use can
lead to physical dependency and withdrawal
symptoms (Zisapel, 2007).
A promising new treatment for sleep
disorders has recently emerged: melatonin
substitution therapy. Melatonin (N-acetyl-
5-methoxytryptamine) is a hormone that
is produced naturally by the pineal gland
at night. It signals darkness and serves to
facilitate synchronization of the circadian
clock with the ambient day-night cycle. In
addition, melatonin is an endogenous sleep
regulator that induces sleep-like brain acti-
vation patterns (Zisapel, 2007). Melatonin
production declines with age, thus, depriv-
ing the brain of an important time and sleep
regulator. We hypothesized that melatonin
substitution therapy might improve sleep
in older insomnia patients. Melatonin is
too short-lived in blood for substitution
therapy; following ingestion of regular mela-
tonin formulations, peak plasma levels are
reached after 20-60 minutes, depending on
dose, and decline rapidly. We thus developed
a prolonged-release formulation (Circadin)
that mimics the physiological release of the
hormone peak plasma levels occurring 2.6
hours and persisting over 3.5 hours after
ingestion and declining toward the morn-
ing. Ingestion of 2 mg Circadin yields mela-
tonin levels comparable to those normally
present in the brain at night. In clinical tri-
434  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
als conducted in collaboration with leading
sleep medicine experts, patients aged 55
years and older and suffering from primary
insomnia received Circadin every evening
for three weeks. Benefits were shown in
treated patients (compared to patients who
received placebo) in sleep onset latency, sub-
jective quality of sleep, daytime functioning
and quality of life, and even some improve-
ments in performance in the morning were
observed (Wade et al., 2007; Luthringer et
al., 2009; Lemoine et al., 2007).
Results of a six-month double blind pla-
cebo controlled study, announced at the 2009
meeting of the Associated Professional Sleep
Societies, indicated that Circadin efficacy is
sustained over long-term periods and there
are no main safety concerns. In particular,
Circadin treatment is not associated with
memory or cognitive impairments, risks
of falls or accidents, or residual daytime
or “hangover” effects. Treatment does not
cause discernible withdrawal symptoms or
rebound insomnia (more severe than before
treatment) (Luthringer et al., 2009; Lemoine
et al., 2007; Otmani et al., 2008).
The efficacy of Circadin treatment is
derived from the reinstatement of a physi-
ological melatonin pattern. Improvement
Nava Zisapel holds a B.Sc. in Chemistry, and
M.Sc. and Ph.D. degrees in Biochemistry from
Tel-Aviv University, Israel. She is a full Professor
at Tel-Aviv University, where she works as a
specialist in neurobiology and biological clocks,
and the incumbent of the Michael Gluck Chair
in Neuropharmacology and ALS Research. In
1991, she founded Neurim Pharmaceuticals, a
drug discovery and development company in
Tel Aviv and currently serves as its Chief Sci-
entific Officer. Together with her students and
collaborators, Zisapel has authored over 180
publications in peer-reviewed journals.
navazis@post.tau.ac.il
 Serotonin crystals. Polarised light micrograph
of the neurotransmitter serotonin.
The hormone melatonin is made from serotonin
in the brain’s pineal gland.

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.

in morning alertness has not been hitherto

documented with any other hypnotic drug,
including the MT1/MT2 melatonin recep-
tor subtype specific agonist Ramelteon,
implying that Circadin’s effects may be
mediated in part by non-MT1/MT2 path-
ways. Further studies on its mechanism of
action are thus warranted. Circadin was
approved in Europe following a positive
risk-benefit evaluation by the European
Medicines Agency (EMEA) and awaits
further approval outside of Europe for the
treatment of primary insomnia character-
ized by poor quality of sleep in patients aged
55 and over. Thus, Circadin represents a new
therapeutic treatment for sleep disorders,
particularly for the elderly.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  435

THE EUROPEAN
INSOMNIA NETWORK
By Eus J. W. Van Someren1, Thomas Pollmächer2, Damien Leger3,
Colin Espie4, Claudio Bassetti5 and Dieter Riemann6
Major advances in the neuroscience of
the functional relevance of sleep for brain
function, as evident from this special issue,
should inspire us to see to a good night’s
sleep. However, for the 10% of us that
struggle with chronic insomnia, this is not
easily accomplished. Insomnia is the most
frequent complaint in both psychological
practice and the sleep clinic and a major
risk factor for the development of a psy-
chiatric disorder. Yet, our understanding of
its brain mechanisms falls painfully behind
with our accomplishments in understand-
ing the neuroscience of normal sleep.
Therefore, this year, more than 100
researchers and clinicians from 23 countries
committed themselves to cooperate in the
European Insomnia Network with the aim
to accelerate progress in our understand-
ing of the neuroscience of this debilitating
condition. How can we accomplish such
acceleration?
A major problem that has obstructed
progress in our understanding of chronic
insomnia is that the diagnosis is based exclu-
sively on subjective complaints. A routine
polysomnographic evaluation seldom shows
1
Netherlands Institute of Neuroscience, an Institute
of the Royal Netherlands Academy of Arts
and Sciences, Amsterdam, The Netherlands
e.van.someren@nin.knaw.nl
2
Klinikum Ingolstadt, and Max Planck Institute
of Psychiatry, Munich, Germany
3
Hotel Dieu de Paris, Paris, France
4
University of Glasgow, Glasgow, Scotland
5
Neurocenter (EOC) of Southern Switzerland, Lugano,
and Neurology Department, University Hospital,
Zürich, Switzerland
6
Freiburg University Medical Center, Freiburg,
Germany
436  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
abnormalities. This general finding has led
some to suggest that the major problem of
insomnia is a misperception of their sleep
state. However, there is a large gap between
the routine polysomnographic evaluation
and the presently available neuroimaging
tools. Can we be sure that nothing is wrong
if we base our conclusion on the somewhat
archaic qualitative analysis of staging sleep
on the basis of two EEG-channels? As a
metaphor: would we send a patient with
cardiovascular complaints home after tak-
ing his pulse only and concluding that noth-
ing strange can be observed? We would not,
since we know that a multichannel cardio-
gram might be applied to reveal subtle signs
of severe heart failure.
Likewise, we might learn more about
insomnia by applying state-of-the-art neu-
roimaging tools. For example, researchers
on the neural correlates of consciousness
(NCC) that developed and applied sophisti-
cated analyses of EEG, MEG and MRI, now
have evidence that the complexity and recur-
rency of brain activity determine whether
a stimulus induces a conscious experience.
Application of these tools to insomnia may
reveal the neural correlates of the subjec-
tive experience of lying awake during a poor
night’s sleep better than qualitative analysis
of a two-channel EEG does.
A second major problem has been to
objectify the subjective complaints of
daytime functioning. Standard neuropsy-
chological tests have not unequivocally
demonstrated performance deficits. Here
again, application of advanced neuro-
science methods seems necessary. Indeed,
computerized psychomotor assessment and
memory consolidation paradigms recently
demonstrated abnormalities in insom-
nia. Also, fMRI studies demonstrated that
compensatory brain activation masks per-
formance deficits that were expected with
the suboptimal activation of brain circuits
dedicated to the cognitive processes probed
by the task.
Thirdly, with a prevalence of about 10%,
it is unlikely that a single diagnostic cate-
gory suits the whole heterogeneous group of
people wrestling with poor sleep. The situ-
ation may be compared to the diagnosis of
dementia many years ago; by now we know
that it is essential to differentiate between
Alzheimer’s, vascular, fronto-temporal,
etc. Finding homogeneous subgroups of
insomnia phenotypes now seems possible.
Widespread Internet access now allows for
large-scale international studies applying
questionnaires and computerized tasks to
obtain a multivariate characterization of
insomnia in subjective, behavioral, environ-
mental, performance and even molecular
genetic dimensions. Subsequent application
of the above mentioned neuroscience tools
to selected homogeneous subgroups will
strongly increase the likelihood of finding
robust abnormalities.
The European Insomnia Network will
work on the normalization of minimal data
sets to allow for exchange and a database;
on promoting neuroscientists to learn about
insomnia and sleep scientists to catch up on
neuroscience; and on promoting the devel-
opment of better models and pharmaco-
logical treatments for insomnia. These are
essential steps to ameliorate the profound
suffering of one out of ten of us.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  437
SLEEP AND DREAMS
IN POSTTRAUMATIC
STRESS DISORDER
By Anne Germain
Sleep disturbances are a core feature of
posttraumatic stress disorder (PTSD).
PTSD is characterized by three symptom
clusters that arise and persist for more than
one month after exposure to a traumatic
event, defined as experiencing or witness-
ing of a real or perceived threat of death or
injury to one’s self or others, and associ-
ated with intense feelings of fear, horror,
or hopelessness. The symptom clusters are
re-experiencing symptoms, avoidance and
hyperarousal.
Nightmares and insomnia are hallmarks
of PTSD (Ross et al., 1989). Nightmares
refer to replays of traumatic events, but
other unpleasant dreams are also com-
mon and associated with comparable dis-
tress. Insomnia refers to difficulty falling
or staying asleep. Other sleep disturbances
endorsed by patients with PTSD include
bad dreams unrelated to traumatic events,
simple and complex motor behaviors,
nocturnal panic attacks, and sleep terrors
(Germain et al., 2005). Although consid-
ered symptoms of stress reactions, sleep
disturbances can develop into persistent
and independent comorbid conditions,
which are often resistant to pharmaco-
logical or cognitive-behavioral PTSD
treatments.
Findings from animal and human stud-
ies support the hypothesis that sleep dis-
turbances play an important role in the
development and persistence of PTSD and
associated poor health outcomes (Germain
et al., 2008). For instance, the occurrence
of sleep disturbance after exposure to
traumatic events increases the risk for
developing chronic PTSD, and sleep dis-
turbances independently contribute to
poor clinical outcomes in patients with
PTSD. Additionally, clinical observations
suggest that the normalization of sleep dis-
438  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
turbances may be critical in remission and
recovery. Sleep-focused treatments, such as
imagery rehearsal for nightmares and pra-
zosin (a noradrenergic alpha-1 antagonist),
are associated with clinically meaningful
improvements in nighttime and daytime
symptoms of PTSD (Maher et al., 2006).
However, the study of sleep in PTSD has
been mostly limited to cross-sectional stud-
ies using self-report or polysomnographic
measures (Kobayashi et al., 2007).
Because of the importance of sleep in
PTSD and the limitations of extant research,
our program at the University of Pittsburgh
encompasses two approaches with a pri-
mary focus on sleep and PTSD. The first
focuses on investigating the role, nature,
and neurobiological underpinnings of sleep
disturbances that contribute to PTSD. The
second focuses on evaluating the efficacy
of established and novel sleep-specific
pharmacological and cognitive-behavioral
interventions on nighttime and daytime
symptoms of PTSD, and identifying how
response to sleep treatments normalizes the
behavioral, psychophysiological, and func-
tional neuroanatomical correlates of PTSD
during sleep and wakefulness. Our ongoing
clinical and neuroimaging studies focus on
Anne Germain is Assistant Professor of Psy-
chiatry at the University of Pittsburgh School
of Medicine Center. She obtained her doctoral
degree in Clinical Psychology from the Univer-
sité de Montréal in 2001, and completed her
post-doctoral training at the University of Pitts-
burgh in 2005. Her research focuses on the
assessment, treatment and neurobiological
underpinnings on nightmares and insomnia
comorbid with stress-related disorders, with
emphasis on PTSD. Her research also focuses
on identifying the sleep-specific predictors of
treatment response.
germaina@upmc.edu
References
Germain, A., Buysse, D. J., and Nofzinger, E.
(2008). Sleep-specific mechanisms underlying
posttraumatic stress disorder: integrative review
and neurobiological hypotheses. Sleep Med.
Rev. 12, 185-195.
Germain, A., Hall, M., Krakow, B.,
Katherine Shear, M., and Buysse, D. J. (2005).
A brief sleep scale for Posttraumatic Stress
Disorder: Pittsburgh Sleep Quality Index Addendum
for PTSD. J. Anxiety Disord. 19, 233-244.
Kobayashi, I., Boarts, J. M., and
Delahanty, D. L. (2007). Polysomnographically
measured sleep abnormalities in PTSD:
a meta-analytic review. Psychophysiology 44,
660-669.
Maher, M. J., Rego, S. A., and Asnis, G. M.
(2006). Sleep disturbances in patients with
post-traumatic stress disorder: epidemiology,
impact and approaches to management.
CNS Drugs 20, 567-590.
Ross, R. J., Ball, W. A., Sullivan, K. A.,
and Caroff, S. N. (1989). Sleep disturbance
as the hallmark of posttraumatic stress disorder.
Am. J. Psychiat. 146, 697-707.
sleep and PTSD in combat-exposed military
veterans. Our studies include a broad array
of sleep assessments including validated self-
report measures, objective measures of sleep
and wakefulness patterns, such as actigra-
phy (a wristwatch-like device composed of
accelerometers to monitor and record activ-
ity/movement levels across several 24-hour
periods), and in-home or laboratory-based
sleep studies (polysomnography), quanti-
tative electroencephalography (qEEG), and
positron emission tomography.
Understanding the psychophysiologi-
cal and neurobiological underpinnings of
PTSD across the sleep-wake cycle is essential
in developing and refining prevention and
intervention strategies to enhance resilience
to traumatic stress and to hasten the recov-
ery of patients with PTSD.
FOUNDATIONS
FOR A NEW
NEUROCOGNITIVE
THEORY
OF DREAMING
By G. William Domhoff
Research in recent decades has led to a
neurocognitive theory of dreaming that
transcends old arguments and is test-
able by those working with neuroimag-
ing techniques and/or neurology patients.
Dreaming draws upon the same conceptual
systems that underlie waking thought and
G. William Domhoff, Ph.D., is a distinguished
Research Professor in Psychology at the
University of California, Santa Cruz, where
he has taught since 1965. His research find-
ings and many articles on dream content,
along with details on his neurocognitive
theory of dreams, can be found on his web-
site www.dreamresearch.net; his searchable
archive containing 22,000 dream reports is
available to everyone at www.dreambank.
net. His recent 72-minute lecture on dreams
is accessible on YouTube under the title “Your
Nightly Dreams.”
domhoff@ucsc.edu
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  439
occurs whenever there is 1) an intact and
fully mature neural network for dreaming;
2) an adequate level of cortical activation;
3) an occlusion of external stimuli; and 4)
the loss of conscious self-control, i.e., a shut-
ting down to the cognitive system of “self ”
(Domhoff, 2003).
Studies of neurology patients who have
experienced changes in dreaming or loss of
dreaming, along with neuroimaging studies
of normal adults, suggest a neural network
for dreaming that encompasses the lim-
bic, paralimbic, and association cortices,
with little or no role for the dorsolateral
prefrontal cortex, sensorimotor cortex, or
primary visual cortex. This truncated neural
network, cut off from the primary sensory
cortices that provide information about
the external world, and from the prefron-
tal cortices that integrate incoming sensory
information with waking decision-making,
operates as a closed loop to generate the
process of dreaming (Braun et al., 1997).
Thus, an unconstrained and freewheeling
conceptual system operates during sleep,
whenever there is sufficient brain activation
in either REM or non-REM sleep. Paralleling
these findings, systematic studies of thou-
sands of dream reports show that dream
content is often realistic, based in everyday
concerns, and consistent over years and dec-
ades, which suggests that the neural network
for dreaming contains enough cognitive
processing areas, such as the medial frontal
cortex and anterior cingulate cortex, to pro-
duce coherent dramatizations that reflect
the dreamer’s conceptions and concerns in
waking life, as demonstrated by inferences
References
Braun, A., Balkin, T., Wesensten, N., Carson,
R., Varga, M., Baldwin, P., Selbie, S., Belenky,
G., and Herscovitch, P. (1997). Regional cerebral
blood flow throughout the sleep-wake cycle:
An (H2O)-O-15 PET study. Brain 120, 1173-1197.
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,
and content analysis. Washington, DC: American
Psychological Association.
Domhoff, G. W., and Schneider, A. (2008).
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,
MA: Harvard University Press.
based on blind analyses that are confirmed
by the dreamer (Domhoff, 1996; Domhoff
and Schneider, 2008).
At the same time, longitudinal and cross-
sectional studies of children ages 3 to 15
in the sleep laboratory reveal that dream-
ing is not simply a brain function; it is a
gradual cognitive achievement that emerges
between ages 4 and 6 in stages that parallel
waking cognitive development, especially in
terms of visuospatial skills. Dreaming only
becomes adult-like in its cognitive complex-
ity at ages 9-10 and dream content does not
resemble that of adults in length, content,
and emotions, or to have any relationship
to personality and waking concerns until
ages 11-13 (Foulkes, 1999).
Although studies of dream content sug-
gest that dreams have coherence and con-
tinuity with waking concerns, many other
studies, including the neuropsychological
and developmental studies just summa-
rized, suggest that dreaming has no adap-
tive function. Thus, adaptive function and
psychological meaning must be treated
separately. Dreams are the accidental by-
products of two great evolutionary devel-
opments, sleeping and thinking (especially
mental imagery). However, because dreams
have psychological meaning, people in small
traditional cultures developed “uses” for
them in medicinal and religious practices.
They also can be a source of artistic inspira-
tion or personal insight.
The future of dream research lies with
those who study neurocognition and/or
use quantitative methods to study dream
content.
REM DREAMS
By György Buzsáki and Sean M. Montgomery
The Dream by Pablo Picasso, 1932

440  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 150
Frequency
100
(Hz) 050
18
(0-250Hz)
14
Power
10
120 Time (sec)
2 sic REM sleep. Identification of phasic REM epoch by
1 increased theta frequency oscillation. On the right, intra-
Amplitude
(mV)
0
-1
-2
156
REM sleep is the brain’s most isolated state
from the body and environment, but it
is “paradoxically” associated with physi-
ological forebrain patterns similar to the
waking, conscious brain (Llinás and Paré,
1991; Jouvet, 1999). Since dream content,
assumed to be the product of REM sleep,
reflects the history of the self, it has long
been postulated that dreams emanate from
internal activation of memories; that is from
the coordinated activity in the hippocam-
pal-neocortical system. We suggest that
such communication can take place only
in the phasic bursts of REM sleep.
During tonic periods of REM sleep (95%
of total REM in the rat), gamma power and
unit firing in the hippocampal CA1 region
and CA3-CA1 gamma coherence showed
György Buzsáki is a Board of Governors Profes-
sor of Neuroscience at Rutgers University. His
primary interests are brain oscillations, sleep
and memory. With more than 200 papers pub-
lished on these topics, he is among the 250
most-cited neuroscientists. Recent book: G.
Buzsáki (2006). Rhythms of the Brain, OUP.
buzsaki@andromeda.rutgers.edu
Sean M. Montgomery has graduated from Rut-
gers University in 2008. His main interest is how
cell assemblies serve cognitive functions. For
his non-academic ventures visit http://osiris.
rutgers.edu/frontmid/indexmid.html.
produceconsumerobot@gmail.com
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  441
4
Power
0
150 180
158 160
significant decreases compared to the wak-
ing state, suggesting a decreased ability of
the hippocampus to transfer memories
in tonic REM. In contrast, phasic REM
epochs were characterized by higher theta
and gamma synchrony among the dentate,
CA3, and CA1 regions, compared to waking.
Phasic REM epochs could be readily rec-
ognized by the transient (1-2 sec.) increase
of wide-band power (1-200 Hz), increased
unit firing in multiple regions and twitching
of whiskers and limb muscles. Thus, during
phasic REM epochs effective hippocampal-
neocortical communication becomes pos-
sible and the brain transiently re-gains its
control over the body. In contrast to tonic
REM, characterized by virtual cessation of
activity in locus ceruleus, during phasic
epochs neurons in locus ceruleus can dis-
charge short spike bursts (Chu and Bloom,
1973). These bursts may release a sufficient
amount of the critical neurotransmitter to
transiently reinstate synchrony among cor-
tical and spinal networks.
Reinstatement of CA3-CA1 communi-
cation during phasic bouts of REM sleep
may provide windows of opportunity for
information, encoded in the dentate-CA3
network during tonic REM, to be replayed
back to the neocortex (Figure 1). Because
phasic REM epochs transiently re-establish
waking-like communication between the
hippocampal regions and the neocortex,
Figure 1. Increased hippocampal synchrony during pha-
bursts of transient increases in wide band power and
and inter-regional synchrony in hippocampal networks
during waking (black), tonic REM (blue) and phasic REM
(red) epochs. Bar height reflects within-region synchro-
ny changes, while arrow thickness reflects between-
region coordination changes. Phasic REM is accompa-
nied by the highest synchronization throughout the
trisynaptic circuit.
References
Cantero J. L., Atienza M., Stickgold R.,
Kahana M. J., Madsen J. R., and Kocsis B.
(2003). Sleep-dependent theta oscillations in the
human hippocampus and neocortex. J. Neurosci.
23, 10897-10903.
Chu N., and Bloom F. E. (1973). Norepinephrine-
containing neurons: changes in spontaneous
discharge patterns during sleeping and waking.
Science 179, 908 -910.
Jouvet M. (1999). The paradox of sleep:
the story of dreaming. Cambridge, MA: MIT.
Llinás R. R., and Paré D. (1991). Of dreaming
and wakefulness. Neuroscience 44, 521-535.
Montgomery S. M., Sirota A., and Buzsáki G.
(2008). Theta and gamma coordination of
hippocampal networks during waking and rapid
eye movement sleep. J. Neurosci. 28, 6731-6741.
we hypothesize that these short but pow-
erful episodes are responsible for generating
the dream content of sleep. These phasic
windows are of particular interest in light
of recent observations in depth recordings
from the hippocampus in human epileptic
patients. Theta oscillations in these human
subjects were only observed in short bouts
lasting a second or so (Cantero et al., 2003).
The short bouts of highly synchronous
hippocampal patterns during phasic REM
epochs suggest that multiple event repre-
sentations are replayed either simultane-
ously or in rapid succession, which may
explain the bizarre nature of dreams.
REM, DREAMS
AND EMOTIONAL
BRAIN
HOMEOSTASIS
By Matthew P. Walker
Relative to cognition, surprisingly less
research attention has been given to the
interaction between sleep and affective
brain function, despite the prominent co-
occurrence of abnormal sleep in almost
all clinical mood disorders. Nevertheless,
recent work has begun to describe a clari-
fying role for sleep in emotion regulation,
vignettes of which I review below, followed
by a proposed REM sleep hypothesis of
emotional brain homeostasis.
Emotional Reactivity
Numerous studies have described an
increase in subjective affective disturbance
following sleep loss, intensifying nega-
tive mood reports while reducing posi-
tive mood ratings associated with daytime
activities (Walker and van der Helm, 2009).
Objectively, it has been demonstrated that
one night of sleep deprivation amplifies
amygdala reactivity in response to negative
442  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
emotional stimuli (Yoo et al., 2007), further
associated with the loss of top-down medial
prefrontal connectivity, yet increased cou-
pling with autonomic activating brainstem
regions. Larger pupillary response (indexing
greater autonomic reactivity) to negative
picture stimuli following a similar dura-
tion of sleep deprivation have also recently
been reported (Franzen et al., 2009). These
Matthew P. Walker earned his Ph.D. in Neuro-
physiology from the Medical Research Council,
UK, and subsequently became an Assistant
Professor of Psychology at Harvard Medical
School. He is currently an Assistant Professor
of Psychology and Neuroscience at University
of California Berkeley. His research examines
the impact of sleep on human brain function,
with a particular focus on the role of sleep in
memory processing, neural plasticity and emo-
tional regulation.
mpwalker@berkeley.edu
and other such studies support a role for
sleep in recalibrating the appropriate con-
nectivity of limbic circuits, resetting affec-
tive brain reactivity for next-day emotional
challenges.
Affective Memory (Re)processing
Several reports have described the selective
memory consolidation of negative (unpleas-
ant) emotional stimuli across periods con-
taining sleep, relative to equivalent daytime
periods awake, as well as late-night versus
early-night sleep (rich in REM) (Walker
and van der Helm, 2009). Most recently,
Nishida et al. (2009) reported that REM
not only facilitates the consolidation of
negative memories, but that specific theta
brain oscillations during REM correlate
with these improvements. REM sleep may
therefore offer a unique neurophysiologi-
cal substrate for the (re)processing of emo-
tional experiences.

A REM Sleep Hypothesis
While abundant evidence suggests that
emotional experiences persist in our auto-
biographies over time, an equally remark-
able but less noted change is a reduction
in the affective “charge/tone” associated
with their recall. The reason emotional
experiences persist more robustly than
neutral memories is due to autonomic
neurochemical reactions elicited at the
time of the experience, creating what we
term an “emotional-memory” (Figure 1).
However, the later recall of these memories
tends not to be associated with anywhere
near the same magnitude of autonomic
(re)activation – suggesting that, over-
time, the affective “blanket” previously
enveloped around the memory during
learning has been stripped away, whereas
the information contained within that
experience (the memory) remains. This
proposed REM hypothesis predicts that
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  443
such decoupling takes place within the
unique biological theater of REM (and
potentially dreaming), such that we sleep
to forget the emotional tone, yet sleep to
remember the tagged memory of that epi-
sode (SFSR model; Figure 1). Specifically,
increased activity within limbic networks
during REM sleep dreaming offers the
ability for reactivation of previously
acquired affective experiences. Secondly,
dominant REM-theta oscillations within
subcortical and cortical nodes offer large-
scale synchronous network cooperation,
allowing the integration and, as a conse-
quence, greater understanding of recently
experienced emotional events in the con-
text of pre-existing neocortical memories.
Thirdly, these REM dreaming processes
critically take place within a brain devoid
of aminergic stress neurochemistry. As a
consequence, REM dreaming achieves a
balanced neural facilitation of the infor-
Figure 1. The sleep to forget and sleep to remember
(SFSR) model of emotional memory processing: a) Neural
dynamics of waking formation of an episodic emotional
memory, followed by the subsequent REM sleep repro-
cessing, resulting in, on the one hand, a depotentiation
of the affective tone initially associated with the event(s)
at encoding, while on the other, a progressive neocortical
consolidation of the experience in the context of prior
semantic knowledge (the conscious expression of which
may contribute to dreaming). Cross-connectivity between
structures is represented by number and thickness of
lines. Circles within cortical and hippocampal structures
represent information nodes; depth of shade reflects
extent of connectivity. Shading and arrows from amygda-
la represent magnitude of co-activation and influence on
the hippocampus. b) Conceptual outcome. Through mul-
tiple iterations of this mechanism across the night, and/
or across multiple nights, the long-term consequence of
such REM sleep reprocessing allows for the strengthen-
ing and retention of salient information previously tagged
as emotional at the time of learning, yet the divorcing of
the autonomic charge acquired during learning.
References
Franzen, P. L., Buysse, D. J., Dahl, R. E.,
Thompson, W., and Siegle, G. J. (2009). Sleep
deprivation alters pupillary reactivity to emotional
stimuli in healthy young adults. Biol. Psychol. 80,
300-305.
Nishida, M., Pearsall, J., Buckner, R. L., and
Walker, M. P. (2009). Prefrontal theta during REM
sleep enhances emotional memory. Cereb. Cortex
19, 1158-1166.
Walker, M. P., and van der Helm, E. (2009).
Overnight therapy? The role of sleep in emotional
brain regulation. Psychol. Bull. 135, 731-748.
Yoo, S. S., Gujar, N., Hu, P., Jolesz, F. A., and
Walker, M. P. (2007). The human emotional brain
without sleep - a prefrontal amygdala disconnect.
Curr. Biol. 17, R877-878.
mational core of emotional experiences
(the memory), yet depotentiates the auto-
nomic charge originally acquired during
learning (the emotion) – a form of over-
night therapy.
ACTING OUT
DREAMS
By Tore Nielsen, Connie Svob and Don Kuiken
Dreaming is typically viewed as a sleep-
related cognitive activity characterized by
imagined scenarios, in which one appears
to, but does not actually, move, speak or
express emotions. However, our recent
demonstration (Nielsen and Paquette,
2007) shows that 63% of new mothers,
56% of pregnant women and 40% of null
gravida controls report episodes of act-
ing out some form of real motor, speech
or emotional behavior that is ongoing in
their dream, suggesting that this view may
be limited. Our findings also raise ques-
tions about whether such dream-enacting
(DE) behaviors are gender specific; what
forms of questioning may be best suited for
assessing them; how diverse such behaviors
are; whether behaviors are related to other
parasomnias (abnormal sleep behaviors or
cognitions), such as somnambulism (sleep-
walking) and nightmares, or to personality
traits and habitual frequency of dream recall;
and whether reporting of DE behaviors is
influenced by socially desirable responding.
A series of follow-up studies was designed
to investigate these questions in a normal
population (Nielsen et al., in press).
We studied three groups of undergradu-
ate students who completed questionnaires
Tore Nielsen, Ph.D., is full Professor in the
Department of Psychiatry at the Université de
Montréal and Director of the Dream and Night-
mare Laboratory, which is part of the Sleep and
Biological Rhythms Research Center in Mon-
treal’s Sacré-Coeur Hospital. His research
deals with the phenomenology, demographics,
physiology and function of normal and dis-
turbed dreaming and is funded by the Cana-
dian Institutes for Health Research, the Natural
Sciences and Engineering Research Council
of Canada and the Social Sciences and Hu-
manities Research Council of Canada.
tore.nielsen@umontreal.ca
444  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
about DE behaviors, social desirability and
personality traits (alexithymia, absorption).
Study 1 employed a single nonspecific ques-
tion about DE behaviors; study 2 used the
same question with accompanying exam-
ples; study 3 used seven questions describ-
ing specific behavior subtypes: speaking,
crying, smiling/laughing, fear, anger, gen-
eral movement, and sexual arousal. Study
3 instructions also clearly differentiated
DE behaviors from somnambulism and
somniloquy (sleep-talking) and assessed
frequencies of somnambulism, somnilo-
quy, nightmares and habitual dream recall.
Factor analyses were conducted to deter-
mine the independence of DE behaviors
from other parasomnias and the clustering
of DE behavior subtypes.
DE prevalence increased with increas-
ing question specificity (35.9%, 76.7%,
and 98.2% for studies 1, 2 and 3, respec-
tively). Gender differences were observed
only for the specific questions (studies 2
and 3); females reported more speaking,
crying, fear and smiling/laughing than
did males; males reported more sexual
arousal. Gender differences persisted when
somnambulism, somniloquy, nightmares
and dream recall were controlled. Factor
solutions revealed that DE behaviors were
intercorrelated (except for sexual arousal)
and independent of other parasomnias
and dream recall frequency. A moderate
association was noted between dream- Don Kuiken is a Professor of Psychology at the
talking and somniloquy. Sexual arousal University of Alberta. He received his B.A. in
was related only to age. DE behaviors Psychology from the University of Iowa (1965)
and his Ph.D. in Social Psychology from the
University of Texas at Austin (1970). He has
Connie Svob, B.A., is a Master’s student at the published widely in the areas of dreaming and
University of Alberta. She is funded by the So- psychological esthetics, with particular atten-
cial Sciences and Humanities Research Coun- tion to the influence of exceptional dreams and
cil of Canada for her research on varying forms exceptional moments of literary reading on
of dream remembering. subsequent thoughts and feelings.
svob@ualberta.ca dkuiken@ualberta.ca
were independent of social desirability
and alexithymia, but moderately related
to absorption.
DE behaviors are very prevalent in
healthy subjects and are sensitive to ques-
tion wording. Their prevalence differs with
gender and is independent of other paras-
omnias. DE behaviors resemble in type and
variety those seen routinely in evaluations of
REM sleep behavior disorder (RBD), but are
much less frequent and severe. Nonetheless,
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  445
the findings show that state dissociations,
i.e., combinations of, or rapid oscillations
between sleep/wake states, occur more com-
monly in non-clinical populations than is
generally appreciated. Moreover, these
results suggest that absorption, understood
as the disposition to experience focused
attention, fantasy, and altered states of con-
sciousness, influences the occurrence of DE
behaviors. Future studies should identify
sleep physiological markers that accompany
DE behaviors and determine the conditions
of stress, fatigue and sleep deprivation that
may induce them.
References
Nielsen, T., and Paquette, T. (2008).
Dream-associated behaviors affecting pregnant
and postpartum women. Sleep 30, 1162-1169.
Nielsen, T., Svob, C., and Kuiken, D.
(in press). Dream-enacting behaviors in a normal
population. Sleep.

NEURAL STATES
IN DREAMS
By Pierre Maquet
The neural mechanisms underpinning
dreaming activity in humans are still
shrouded in mystery. Functional neuroimag-
ing studies provide some initial clues about
the organization of brain function during
rapid eye movement (REM) sleep in relation
to dreaming. The distribution of regional
brain activity differs considerably between
REM sleep and wakefulness in humans and
is characterized by three main features. First,
in agreement with neurophysiological stud-
ies in animals, functional imaging studies
reported a high activity in the brainstem and
thalamic nuclei during REM sleep. Secondly,
confirming earlier measures of brain energy
metabolism in animals, they observed a high
activity in limbic and paralimbic areas.
Thirdly, they further highlighted the con-
trast between this limbic activation and the
relative quiescence of the associative frontal
and parietal cortices. This particular pattern
of cerebral activity is usually assumed to
correlate with, and possibly influence, the
main characteristics of dreaming activity
(Maquet et al., 1996; Hobson et al., 2000;
Maquet, 2000). The prominent visual and
446  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
auditory perceptual features of dreams
might be related to the activation of pos-
terior (occipital and temporal) cortices. In
keeping with this hypothesis, visual imagery
in dreams is absent in some patients with
occipito-temporal lesions (Solms, 1997). On
the other hand, emotions which are often
reported in dreams would be related to the
activation of the amygdala, orbito-frontal
cortex and anterior cingulate cortex (Maquet
et al., 1996; Hobson et al., 2000; Maquet,
Pierre Maquet is Research Director at the
National Fund for Scientific Research in the
Cyclotron Research Centre at the University
of Liège, Belgium. His research work fo-
cuses on the functional neuroimaging of
human sleep using PET, fMRI and EEG. Dr.
Maquet’s work follows several different as-
pects of sleep, including the characterization
of the cerebral correlates of human sleep,
the relation between sleep and the offline
processing of memories, the neural corre-
lates of sleep/wake regulation, as well as the
functional neuroanatomy of unconscious
patients.
pmaquet@ulg.ac.be
Polarised light micrograph of the crystalline structure
of somatotrophin releasing hormone
References
Fosse, M. J., Fosse, R., Hobson, J. A.,
and Stickgold, R. J. (2003). Dreaming
and episodic memory: a functional dissociation?
J. Cogn. Neurosci. 15, 1-9.
Hobson, J. A., Pace-Schott, E. F., and Stickgold,
R. J. (2000). Dreaming and the brain: toward a
cognitive neuroscience of conscious states. Behav.
Brain Sci. 23, 793-842; discussion 904-1121.
Maquet, P. (2000). Functional neuroimaging
of normal human sleep by positron emission
tomography. J. Sleep Res. 9, 207-231.
Maquet, P., Peters, J., Aerts, J., Delfiore, G.,
Degueldre, C., Luxen, A., and Franck, G. (1996).
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.
2000). The activation of mesio-temporal
areas would account for the memory con-
tent commonly found in dreams. However,
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
regional brain activity would explain the
peculiar aspects of episodic memory in
dreams. Usually, “snips” of recent waking
activity are frequently observed in dream
reports (65 %). In contrast, complete waking
life episodes, characterized by the associa-
tion between specific locations, characters,
objects and actions, are seldom described as
such in dream reports (1.7 %) (Fosse et al.,
2003). The relative quiescence of the anterior
and ventral prefrontal areas would explain
that, although the dreamer has access to “day
residues” probably spontaneously generated
by the coordinated activity of the mesio-
temporal areas and the posterior cortices,
the successful retrieval of the various details
of a specific past episode is hindered. Low
frontal activity would also account for the
deficits in working memory and execu-
tive functions that manifest themselves in
dream reports from REM sleep awakenings
(Maquet et al., 1996; Hobson et al., 2000;
Maquet, 2000).
None of these hypotheses about the neu-
ral correlates of dreaming is yet supported
by objective experimental evidence. Further
studies should provide a detailed account of
the neural correlates of specific features of
human dreams.
BRAIN STEM-CORTICAL
SYNCHRONIZATION
IN SLEEP
By Oxana Eschenko and Susan J. Sara
The role of sleep in offline processing of
information acquired during wakefulness
has been an area of interest for neuroscien-
tists for several decades. Early studies focused
on REM sleep, while more recent research has
provided substantial evidence that non-REM
sleep is beneficial for memory formation. We
have found that specific high frequency oscil-
lations – spindles in the cortex and ripples in
the hippocampus – occurring during non-
REM sleep, are increased by an associative
learning experience prior to the sleep epi-
sode, both in humans and in rats (Eschenko
et al., 2006; Eschenko et al., 2008). These high
frequency oscillations, tuned to the underly-
ing slow oscillations characteristic of non-
REM sleep may well be the physiological
substrate promoting memory consolidation
during sleep (Molle et al., 2006).
The noradrenergic system is engaged in
a late phase of memory consolidation, as
indicated by pharmacological studies (Sara
et al., 1999). To examine its relation to sleep
states, we recorded activity of noradrenergic
neurons of the locus coeruleus (LC) during
the 2-hour period after learning. Rats were
implanted with microdrives into LC, medial
prefrontal cortex (mPFC) and CA1 region
of hippocampus, for extracellular unit
and local field potential (LFP) recordings.
Recordings were made in freely behaving
rats during their rest period before and after
learning odor-reward or place-reward asso-
ciations. During the recording time the rats
were mostly in non-REM sleep, a behavioral
state that is usually associated with dimin-
ished neuronal activity in LC. Nevertheless,
we found a learning-dependent transient
increase in firing rate of LC neurons during
non-REM sleep, in a narrow time window
around 2 hours after learning (Eschenko
and Sara, 2008).
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  447
We are currently characterizing LC unit
activity in relation to the dominant oscil-
lations occurring during non-REM sleep
that are modulated by learning. The peaks
of cortical hyperpolarization or down-
state and depolarization or up-state, as
well as cortical spindles and hippocampal
ripples, are detected and extracted from
LFP signals. LC neuronal activity, though
diminished, is highly synchronized dur-
ing non-REM sleep. Striking temporal
relationships between LC firing, cortical
up- and down-states and spindle onset
are revealed. Firing of LC neurons occurs
mostly during the transition from down-
to up-state, in a time window of 50-300 ms
after the peak of cortical hyperpolariza-
tion. In addition, LC activity is systemati-
cally elevated immediately after the spindle
onset. These temporal relations suggest
functional inter-relationships between the
noradrenergic nucleus and frontal cortex
that may be involved in offline informa-
tion processing during non-REM sleep.
Noradenaline released in the forebrain
during learning-induced surge of LC activ-
ity, in tight temporal relation of LC firing
Oxana Eschenko is a Researcher at the Max
Planck Institute for Biological Cybernetics,
where she is developing new fMRI methodol-
ogy for rodents, combining it with intracra-
nial microinjections, microstimulation and
extracellular recordings. As a Post-Doctoral
Fellow in the laboratory of Dr. Sara she inves-
tigated the role of cortical and hippocampal
oscillations for memory consolidation and
contribution of the noradrenergic system. A
graduate of Moscow State University, she
obtained post-doctoral training in electro-
physiology in the laboratory of Dr. Mizumori,
University of Washington, US.
oxana.eschenko@tuebingen.mpg.de
with cortical network activation, will pro-
mote the synaptic plasticity necessary for
long term memory consolidation.
References
Eschenko, O., Molle, M., Born, J., and
Sara, S. J. (2006). Elevated sleep spindle density
after learning or after retrieval in rats.
J. Neurosci. 26, 12914-12920.
Eschenko, O., Ramadan, W., Molle, M., Born,
J., and Sara, S. J. (2008). Sustained increase in
hippocampal sharp-wave ripple activity during
slow-wave sleep after learning. Learn. Mem. 15,
222-228.
Eschenko, O., and Sara, S. J. (2008).
Learning-Dependent, Transient Increase of
Activity in Noradrenergic Neurons of Locus
Coeruleus during Slow Wave Sleep in the Rat:
Brain Stem-Cortex Interplay for Memory
Consolidation? Cereb. Cortex 18, 2596-2603.
Molle, M., Yeshenko, O., Marshall, L.,
Sara, S. J., and Born, J. (2006). Hippocampal
sharp wave-ripples linked to slow oscillations
in rat slow-wave sleep. J. Neurophysiol. 96,
62-70.
Sara, S. J., Roullet, P., and Przybyslawski, J.
(1999). Consolidation of memory for odor-reward
association: beta-adrenergic receptor involvement
in the late phase. Learn. Mem. 6, 88-96.
Susan J. Sara is a Director (Emerita) at the
Laboratoire de Physiologie de la Perception et
de l’Action, CNRS, Collège de France. Her re-
search has contributed to our understanding
of how arousal, attention and sleep modulate
memory formation and retrieval. Author of
nearly 100 monographs and peer-reviewed
papers, she is former President of the Euro-
pean Brain & Behavior Society and former
Chair of IBRO/FENS schools. A graduate of
Sarah Lawrence College (NY), she received a
Ph.D. from Univerity of Louvain (Belgium) and
did post-doctoral research at Oxford Univer-
sity and NYU Medical School.
susan.sara@college-de-france.fr

DISTURBED
DREAMING
By Ross Levin, Gary Fireman and Alice W. Pope
Disturbed dreams (DD) are vivid dreams
marked by intense feelings of fear or terror
and are the most commonly experienced
parasomnia. Disturbed dreams include both
nightmares and bad dreams, distinguished
largely by whether they awaken the dreamer
during sleep or are remembered upon awak-
ening (Zadra and Donderi, 2000). While
occasional DDs are nearly ubiquitous,
high incidence rates of DD is associated
with poorer psychological well-being and
are a defining symptom of posttraumatic
stress disorder (Levin and Nielsen, 2007).
However, little is known about the patho-
genesis of DD or their relation to waking.
One promising line of recent work (Levin
and Fireman, 2002) suggests that the waking
distress engendered by these dreams (DD
distress), rather than DD frequency, medi-
ates the relationship between DD and wak-
ing psychological impairment. In this way,
these data parallel findings in the insomnia
literature. Based on this, Levin and Nielsen
(2007) recently proposed a model that
posits that DDs reflect transitory break-
downs in the naturally occurring emotion
regulation capacities of REM sleep and/or
dreaming. A key tenet of this model is that
both DD frequency and distress are related
but distinct components of the dream-
ing process and are largely determined by
different mechanisms. Levin and Nielsen
propose that DD frequency is affected by
transitory shifts in daily stress levels (affect
load) while DD distress is determined by a
longer standing personality disposition to
experience heightened distress in response
to emotional stimuli (affect distress). Thus,
448  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Wheel of Dreams: fractal image
of part of the Mandelbrot Set
DD without high levels of waking distress
should have minimal impact on waking
functioning, while even moderate incidence
rates of DD with affect distress may be an
important pathway for waking psychopa-
thology by sensitizing dreamers to the fear-
ful components of their imagery.
A number of recent investigations pro-
vide support for this model. In a 21-day
prospective investigation of the sleep and
dreaming patterns of over 300 partici-
pants, Levin et al. (unpublished material)
found that affect load was associated with
increased DD frequency, but was independ-
ent of DD distress. In contrast, affect distress
was uniquely associated with DD distress
levels and self-reported psychopathology.
These results are consistent with earlier
findings by Levin and Fireman (2002) and
others. Thus, affect load accounted for all
the unique variance in predicting DD fre-
quency, and affect distress accounted for
all the unique variance in predicting DD
distress and psychopathology.
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-
versity, Boston, MA. His research interest
lished over 75 peer-reviewed empirical papers
on sleep and dreaming over the past 20 years. is in the role of emotional complexity, inten-
His primary work has been in nightmares and sity, and experience in relation to social
understanding the connection between waking competence, personal narrative and sleep
stress, and coping and sleep processes. Dr. quality. He has published over 40 peer-re-
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
including the New York Times, ABC Nightline to support his research. Dr. Fireman is a li-
and The New Yorker magazine and he is cur- censed psychologist who has a clinical and
rently writing a book on emotion regulatory consulting practice in the Boston Metro-
processes during sleep and dreaming. politan area.
rss_levin@yahoo.com gfireman@suffolk.edu
 In a second prospective study, Levin,
Bagestose and Fireman (unpublished mate-
rial) found that DD was uniquely activated
under conditions of heightened affect
distress and that problem focused coping
Alice W. Pope is Associate Professor of Psy-
chology at St. John’s University. She received
her Ph.D. in Clinical Psychology from the Penn-
sylvania State University and previously held
faculty positions at Texas Tech University and
New York University School of Medicine.
alicewildpope@gmail.com
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  449
(problem-solving) was significantly associ-
ated with a decrease of DD and improved
sleep quality compared to emotion-focused
coping. This coping style is marked by rumi-
native focus on how bad it feels to feel bad
and is often seen in anxiety and depression.
Taken together, these studies suggest that
high levels of waking distress are a signifi-
cant preceptor in the pathogenesis of DD
and that clinical efforts to reduce these lev-
els of distress would bolster the individuals’
emotion regulatory processes during sleep
as well as waking.
References
Levin, R., and Fireman, G. (2002). Nightmare
prevalence, nightmare distress, and self-reported
psychological disturbance. Sleep 25, 205-212.
Levin, R., and Nielsen, T. A. (2007). Disturbed
dreaming, posttraumatic stress disorder, and
affect distress: A review and neurocognitive
model. Psychol. Bull. 133, 482-528.
Nielsen, T. A., and Levin, R. (2007). Nightmares:
A new neurocognitive model. Sleep Med. Rev. 11,
295-310.
Zadra, A., and Donderi, D. C. (2000). Nightmares
and bad dreams: Their prevalence and relationship
to well-being. J. Abnorm. Psychol. 109, 273-281.
 According to several prominent theories of
dream function, dreams present disturbing

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,

450  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 Taken from The Triumph of Death
by Pieter Brueghel the Elder
harm-avoidance, vivid olfactory and audi-
tory phenomena, and physical metamor-
phoses are prevalent. In existential dreams,
intense sadness, separation and loss, strong
and clear bodily feelings, and spontaneous
changes in feeling are common. Nightmares
and existential dreams both include visual
discontinuities (e.g., sudden scene shifts,
looking closely at dream objects), suggest-
ing the activation of alerting systems that
respond to unexpected stimuli (i.e., startle,
orienting); both involve intense feelings,
especially at the moment of awakening;
and the imagery of both dream types seems
“real” even after awakening.
Despite such evidence of their shared
intensity, nightmares and existential dreams
are precipitated by different life events and
have different effects on the thoughts and
feelings that follow awakening. There is ample
evidence linking nightmares to the distress
precipitated by traumatic life events (Levin
and Nielsen, 2007), and there is some evi-
fear, and defense may underestimate the
influence of other emotion coordinating sys- Don Kuiken is a Professor of Psychology at
tems on dreaming and on dream function. the University of Alberta. He received his B.A.
in Psychology from the University of Iowa
Beyond the psychobiological system for
(1965) and his Ph.D. in Social Psychology
traumatic distress (threat/fear), there is evi- from the University of Texas at Austin (1970).
dence of a separate system for coordinat- He has published widely in the areas of
ing separation distress (sadness/pain). The dreaming and psychological esthetics, with
importance of distinguishing between these particular attention to the influence of ex-
two systems is indicated by systematic clas- ceptional dreams and exceptional moments
sificatory studies that have identified two of literary reading on subsequent thoughts
and feelings. He has studied these phenom-
types of dreams involving intense negative ena using procedures that range from elec-
affect: nightmares and existential dreams trophysiological measurement to phenom-
(Busink and Kuiken, 1996; Kuiken and enological methods.
Sikora, 1993). In nightmares, intense fear, dkuiken@ualberta.ca
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  451
References
Busink, R., and Kuiken, D. (1996). Identifying
types of impactful dreams: A replication.
Dreaming 6, 97-119.
Kuiken, D. (1993, June). Dreams and stress:
Loss and dream impact. Paper presented
at the Conference of the Association for the Study
of Dreams, Santa Fe, New Mexico.
Kuiken, D., Lee, M. N., Eng, T. C., and Singh, T.
(2006). The influence of impactful dreams on
self-perceptual depth and spiritual transformation.
Dreaming 16, 258-279.
Kuiken, D., and Sikora, S. (1993). The impact of
dreams on waking thoughts and feelings. In Moffit,
A., Kramer, M., and Hoffman, R. (Eds.), Functions
of dreaming (pp. 419-476). Albany: SUNY Press.
Levin, R., and Nielsen, T. A. (2007). Disturbed
dreaming, posttraumatic stress disorder,
and affect distress: A review and neurocognitive
model. Psychol. Bull. 133, 482-528.
dence linking existential dreams to the sepa-
ration distress that accompanies bereavement
(Kuiken, 1993). Also, empirical assessment
of the immediate after-effects of nightmares
indicates that they are consistently followed
by lingering anxiety (e.g., environmental vigi-
lance, apprehension about recurrence; Levin
and Nielsen, 2007), while the after-effects of
existential dreams include lingering sadness
and reported self-perceptual depth (e.g.,
changes in self-perception, affirmation of
neglected values; Kuiken et al., 2006).
These studies have important implica-
tions for clinical and research definitions of
nightmares. Nightmares often are defined
as abrupt awakenings from late night sleep
with clear recall of a frightening dream
narrative (cf. Diagnostic and Statistical
Manual of Mental Disorders-IV-TR).
However, according to some clinical defi-
nitions (cf. International Classification of
Sleep Disorders, 2nd edition), the associated
narrative may involve any kind of dysphoric
emotion. Broadening the definition of
nightmares in this way may have unfortu-
nate consequences, both clinically and in
research, because nightmares and existential
dreams appear to have different origins and
different after-effects. Restricting the defi-
nition of nightmares to awakenings from
late night sleep with clear recall of a (spe-
cifically) frightening dream narrative would
enable more precise location of that source
of largely unmitigated dream distress. It
would also ensure separate consideration
of the sources of dream distress that alter
self-understanding and constructively affect
the course of bereavement.
LUCID
DREAMING
By J. Allan Hobson
Neurobiologists and cognitive scientists are
engaged in new efforts to establish the brain
basis of consciousness. Progress in brain
imaging and in quantitative EEG recording
in humans and in unit recording in animals
have all contributed to this advancement.
But progress has been limited by the rela-
tive poverty of the paradigms used in these
studies, many of which do not take subjec-
tive experience into account. One prom-
ising, but problematical paradigm, lucid
dreaming, has recently been employed
with encouraging and complimentary, if
preliminary, results. Here we consider the
pros and cons of this approach and interpret
the results of the new findings.
What is Lucid Dreaming?
It is the rare but robust awareness that we are
dreaming and that we are not really awake
as we usually assume when dreaming. Thus,
lucid dreaming is paradoxical in contain-
J. Allan Hobson is Professor of Psychiatry Emer-
itus at Harvard Medical School where he found-
ed and directed the Laboratory of Neurophysiol-
ogy at the Massachusetts Mental Health Center.
Since the closure of the hospital in 2003, he
shares his time between Boston and Sicily where
he lives with his family and from which he lec-
tures, teaches and consults worldwide. His most
recent books are: DREAMING, An Introduction
to Sleep Science (Oxford) and Thirteen Dreams
Freud Never Had (Pierson). He is the winner of
the Farrell Prize of the Division of Sleep Medicine
at Harvard and the Distinguished Scientist Award
of the Society for Sleep Research.
allan_hobson@hms.harvard.edu
452  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
ing elements of both waking and dreaming
consciousness (LaBerge, 1990).
For the experimentalist, this means that
it may be possible to measure the physio-
logical correlates of three conscious states,
waking, non-lucid dreaming and lucid
dreaming in the laboratory. Since the three
states are psychologically distinct, they
should be physiologically distinct. If detect-
able, those physiological distinctions might
be enlightening.
Quantitative EEG Studies
Taking advantage of recent improvements
in the resolving power and data analysis of
the human electroencephalogram, Ursula
Voss et al. (2009) have been able to show
that lucid dreaming is associated with an
EEG power and coherence profile that
is significantly different from non-lucid
dreaming and waking, but intermediate
between those two states. Lucid dreaming
is characterized by more 40 Hz power than
non-lucid dreaming, especially in frontal
regions. Since 40 Hz power has been cor-
related with waking consciousness, it can
be suggested that enough 40 Hz power has
been added to the non-lucid dreaming brain
to support the increase in subjective aware-
ness that permits lucidity, but not enough
to cause full awakening.
By measuring the temporal correlation
between frontal and occipital EEG pat-
terns it could be demonstrated that sub-
jects enjoyed more EEG coherence when
lucid than when not and, again, less than
in full waking. A reasonable interpretation
of this finding is that dreaming is the result
of posterior brain activation while waking
requires frontal activation as well. In lucid
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
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
patterns of especially those brain regions that
distinguish humans from macaque monkeys.
These areas are not only frontal, as might
have been predicted (Voss et al., 2009), but
are temporal and even occipital as well.
Lucid dreaming is an unusual state char-
acterized by elements of both waking and
dreaming. It is a rare but robust condition,
which has attracted the attention of scien-
tists with an interest in further specifying
the brain basis of consciousness (Hobson,
in press). Quantitative EEG studies indi-
cate that both 40 Hz power and fronto-
occipital coherence are correlates of waking
consciousness. Brain imaging research has
shown that the regional activation pattern in
lucid dreaming correlates with those cortical
areas known to be more highly developed in
humans than in monkeys. To become aware
that one is dreaming, it would appear to be
important to ratchet up frontal 40 Hz power
and coherence in a human brain.
References
Hobson, J. A. (in press). REM Sleep and
Dreaming: Toward a Theory of
Protoconsciousness. Nature Neurosci.
LaBerge, S. (1990). Lucid dreaming:
Psychophysiological studies of consciousness
during REM sleep. In: Sleep and cognition, ed.
Bootzin, R. R., Kihlstrom, J. F., and Schacter, D. L.
American Psychological Association.
Voss, U., Holzmann, R., Tuin, I.,
and Hobson, J. A. (2009). Lucid dreaming:
A state of consciousness with features
of both waking and non-lucid dreaming. Sleep 32,
1191-1200.
FREUDIAN
DREAMS TODAY
By Mark Solms
In the 1950’s, psychiatry was dominated by
psychoanalysis. The psychoanalytical theory
of the mind was based fundamentally on the
wish-fulfillment theory of dreams outlined
in Freud’s The Interpretation of Dreams
which claimed that dreaming was driven
by “libidinal” instincts that were released
from inhibition during sleep. Against this
background, the discovery of the very high
correlation between dreaming and REM
sleep (Dement and Kleitman, 1957) opened
the possibility of finally establishing dream
theory – and thereby psychiatry – on an
objective neurobiological footing.
The brain basis of REM sleep soon proved
to be totally incompatible with Freud’s theory.
REM was automatically generated by “mind-
less” cholinergic cells located in the pontine
brainstem. REM, and therefore dreaming,
was said to be “motivationally neutral”, and
Freud’s detractors wasted no time in pointing
out the dire implications for psychoanalysis
(Hobson and McCarley, 1977).
Remarkably, however, the claim that
dreaming was generated by the cholinergic
pontine cells that activated REM was never
proven by the standard method of behavioral
neuroscience: no one had empirically dem-
onstrated that obliteration of the pontine
tegmentum caused cessation of REM sleep
and dreaming. This only became apparent
when Solms (1997) observed that dreaming
Mark Solms is Professor in Neuropsychology
at the University of Cape Town and President
of the South African Psychoanalysis Associa-
tion. He is also Co-Chair of the International
Neuropsychoanalysis Society, London, and
Research Co-Director of the Hope for Depres-
sion Research Foundation, New York. He has
authored five books including The Neuropsy-
chology of Dreams and The Brain and the
Inner World, and has won several awards
including the George Sarton medal of the
Reiksuniversiteit Ghent and the International
Psychiatrist Award of the American Psychi-
atric Association.
mark.solms@uct.ac.za
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  453
was preserved in cases with extensive pontine
lesions. Even more striking was the finding
that dreaming was indeed obliterated by dam-
age to a specific brain region, but this was a
completely different region from the one
which generates REM sleep, namely the ven-
tromesial frontal white matter. This revealed
that dreaming and REM sleep are doubly dis-
sociable states; although they are highly cor-
related, they are not the same thing.
The focus of dream science now shifted
to the ventromesial frontal white matter.
Solms hypothesized that the critical com-
ponent of this densely packed region was
the dopaminergic pathway which connects
the ventral tegmental area (VTA) with the
nucleus accumbens. This view was based on
the observation that prefrontal leucotomy,
which targets the same region, resulted in
reduction in hallucinations and delusions,
as well as dreaming, and developments
in psychopharmacology revealed that the
dopaminergic pathway was the critical medi-
ator of this effect. This view is now supported
References
Dahan, L., Astier, B., Vautrelle, N., Urbain, N.,
Kocsis, B., and Chouvet, G. (2007). Prominent
burst firing of dopaminergic neurons in the ventral
tegmental area during paradoxical sleep.
Neuropsychopharmacol. 32, 1232-1241.
Dement, W., and Kleitman, N. (1957). The
relation of eye movements during sleep to dream
activity: An objective method for the study of
dreaming. J. Exp. Psychol. 53, 89-97.
Hartmann, E., Russ, D., Oldfield, M., Falke, R.,
and Skoff, B. (1980). Dream content: Effects of
L-DOPA. Sleep Res. 9, 153.
Hobson, J. A., and McCarley, R. (1977). The
brain as a dream-state generator: An activation-
synthesis hypothesis of the dream process.
Am. J. Psychiat. 134, 1335-1368.
Lena, I., Muffat, S., Deschaux, O., Parrot, S.,
Sauvinet, V., Suaud-Chagny, M. F., Renaud, B.,
and Gottesmann, C. (2004). Dreaming and
schizophrenia have the same neurochemical
background. J. Sleep Res. 13, suppl. 1, 141.
Solms, M. (1997). The Neuropsychology of Dreams.
A clinico-anatomical study. New Jersey: Erlbaum.
by several lines of evidence. First, Hartmann
et al. (1980) showed that dopamine agonists
greatly increase dreaming. Secondly, Lena et
al. (2004) showed that dopamine release in
the nucleus accumbens is maximal during
REM sleep. And thirdly, Dahan et al. (2007)
showed that VTA cells fire in clear bursts dur-
ing REM sleep, thereby explaining the mas-
sive dopamine release during dreams.
What is the function of this dopamine
pathway? Neurobiologists have variously
described it as the reward, seeking and
wanting system. The common denomina-
tor behind these terms reveals a consen-
sus, namely that this is the mammalian
brain’s basic motivational system. In fact,
nothing in the brain comes closer in func-
tion to what Freud called the libidinal
instinct. Accordingly, at the 2006 Tucson
Consciousness Conference, when Hobson
and Solms debated the scientific status of
Freud’s dream theory today, two thirds of the
delegates acknowledged its continued viabil-
ity. Dream science has come full circle.
 RESEARCH HIGHLIGHTS
SLEEP AND DREAMS
SLEEP SHRINKS SYNAPSES
By Junjie U. Guo
One hypothetical purpose of sleep is to
scale down overall synaptic transmission
efficacy to counteract potentiation from
daytime activity. Led by two of the earli-
est supporters of this hypothesis, a recent
study provides evidence of this mechanism
at work in flies (Gilestro et al., 2009). They
measured the overall levels of synaptic pro-
teins, and found that these protein levels
gradually decreased during sleep. In addi-
tion, synaptic protein levels were higher
in flies that were subjected to several types
of sleep deprivation. Interestingly, such
protein homeostatic regulation by sleep
was observed in all major regions in the
fly brain.
Comment on: Gilestro, G. F., Tononi, G.,
and Cirelli, C. (2009). Widespread changes
in synaptic markers as a function of sleep
and wakefulness in Drosophila. Science 324,
109-112.
guojj@jhmi.edu
SLEEP DEPRIVATION AND
INFORMATION-INTEGRATION
CATEGORIZATION
By W. Todd Maddox
and David M. Schnyer
24 hours of sleep deprivation led to a defi-
cit in a form of categorization optimally
mediated by a procedural-based (PB) cat-
egorization system (information-integra-
tion) (Maddox et al., in press). However,
model-based analyses indicated that PB
strategies are not strongly affected by sleep
deprivation, but rather that the applica-
tion of PB strategies may require active
inhibition of less optimal, verbally medi-
ated hypothesis-testing strategies. This
inhibitory process is likely vulnerable to
the effects of sleep deprivation – an inter-
pretation in line with recent results from
our lab (Schnyer et al., in press) in which
frontal patients were found to exhibit a PB
category learning deficit.
Comment on: Maddox, W. T., Glass, B. D.,
Wolosin, S. M., Savarie, Z. R., Bowen, C.,
Matthews, M. D., and Schnyer, D. M. (in
press). The effects of sleep deprivation on
information-integration categorization per-
formance. Sleep.
454  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Schnyer, D. M., Maddox, W. T., Davis, S., Ell,
S. W., Pacheco, J., and Verfaellie, M. (in press)
Rule-based and information-integration cat-
egory learning are both impaired with ventral
medial PFC lesions. Neuropsychologia.
maddox@psy.utexas.edu
schnyer@psy.utexas.edu
BRAIN STRUCTURE
DIFFERENCES PREDICT SLEEP
DEPRIVATION VULNERABILITY
By Matthew Rocklage
and David M. Schnyer
Recently, we demonstrated that individual
differences in brain structure, likely as a
result of development, are predictive of a
person’s cognitive vulnerability to sleep dep-
rivation (SD) (Rocklage et al., 2009). Using
a simple visual-motor task, a percent change
score was calculated from performance
pre- and post-24 hours of SD. Significant
correlations between SD vulnerability and
a MRI measure of white matter microar-
chitecture, fractional anisotropy (FA), were
revealed. Participants showing greater per-
formance decline between sessions also
displayed lower FA values across multiple
brain regions. We speculate that as a result
of greater brain connectivity, SD resistant
individuals can recruit additional resources
that buttress their efforts to remain vigilant
in the face of SD pressures.
Comment on: Rocklage, M., Williams, V.,
Pacheco, J., Schnyer, D. M. (2009). White
matter differences predict cognitive vulner-
ability to sleep deprivation. Sleep 32, 1100-
1103.
rocklage.1@osu.edu
schnyer@psy.utexas.edu
NEURAL BASES OF DREAM
HALLUCINOSIS DURING REM
By Edward F. Pace-Schott
Contemporaneously with other PET find-
ings, Braun et al. (1998) contrasted REM
with slow wave sleep (SWS) and waking,
and proposed a unified view of REM visual
system events relevant to dreaming. REM,
vs wake and SWS, showed increased acti-
vation in ventral stream visual association
and limbic cortices, but decreased activity in
striate and lateral prefrontal cortices. Braun
et al. suggest REM provides an opportunity
for visual and limbic cortices to process
information in a manner dissociated from
visual input from, and intentional output
to, the external world.
Comment on: Braun, A. R., Balkin, T. J.,
Wesensten, N. J., Gwadry. F., Carson, R. E.,
Varga, M., Baldwin, P., Belenky, G., and
Herscovitch, P. (1998). Dissociated pattern
of activity in visual cortices and their pro-
jections during human rapid eye movement
sleep. Science 279, 91-95.
epacesch@bidmc.harvard.edu
EFFECTS OF SLEEP
DEPRIVATION ON ATTENTION
By Logan Trujillo
and David M. Schnyer
Using a standard cued-target task, we exam-
ined the effects of 24 hours of sleep depriva-
tion (SD) on endogenous (internally-driven)
and exogenous (externally-driven) shifts
of selective visuospatial attention to task-
relevant targets. For both types of attention
shifts, SD slowed response times, decreased
accuracy rates, and modulated intermediate
and late target-locked event-related poten-
tial (ERP) brain responses. In contrast, an
early ERP response was modulated with
SD for endogenously cued targets only.
These findings suggest that mild SD affects
all stages of attention selection, but affects
endogenous selective attention to a greater
degree than exogenous selective attention.
Comment on: Trujillo, L., Kornguth, S., and
Schnyer, D. M. (2009). An ERP Examination
of the Different Effects of Sleep Deprivation on
Exogenously Cued and Endogenously Cued
Attention. Sleep 32, 1285-1297.
trujillo@psy.utexas.edu
schnyer@psy.utexas.edu
IT REALLY IS BEST TO
SLEEP ON IT
By Adrien Peyrache
and Francesco P. Battaglia
Sleep is important for memory consolida-
tion: the process that stabilizes memories
after they are acquired. For this, information
likely flows between hippocampus and neo-
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  455
cortex as, respectively, the initial and final
memory store. During sleep, hippocampus
and neocortex replay experience-related
neural patterns, possibly supporting this
exchange. Peyrache et al. (2009) found that
during slow-wave sleep, replay in the rat
prefrontal cortex took place in transient rare
events correlated with hippocampal activity
bursts names sharp waves, themselves linked
to replay. Replay dynamics was orchestrated
by cortical slow oscillations. Further, pat-
terns relative to rewarded task rules were
preferentially replayed, hinting information
triaging during consolidation.
Comment on: Peyrache A., Khamassi M.,
Benchenane K., Wiener S. I., and Battaglia
F. P. (2009). Replay of rule-learning related
neural patterns in the prefrontal cortex dur-
ing sleep. Nat. Neurosci. 12, 919-926.
adrien.peyrache@gmail.com
fpbattaglia@gmail.com
NOVEL MODEL TAKES
A BROAD VIEW
By Knud Thomsen
The recently proposed Ouroboros Model,
claimed to underlie efficient data process-
ing in living brains, as well as for artificial
agents, features at its core an iterative proc-
ess where continual expectations derived
from available knowledge are compared to
actually encountered data. Sleep and dream
are conceptualized as house keeping func-
tions for maintaining appropriate signal/
noise levels by actively disposing of inevi-
table “data garbage”, i.e., activations which
could not fully be assigned or resolved by
the comparison stage.
Comment on: Thomsen, K. (2008). The
Ouroboros Model, BICA 08, Technical Report
FS-08-04, Menlo Park, California: AAAI Press,
Cogprints 6081, http://cogprints.org/6081/.
knud.thomsen@psi.ch
HOW TO LEARN SLEEP
BY HEART
By Anda Baharav and Yair Fuxman
Power spectral analysis of instantaneous
heart rate fluctuations reveal components
which are correlates of autonomic nerv-
ous system functions. These components
display differential profiles in the different
sleep stages, permitting classification of
sleep stages from the electrocardiogram
(Baharav et al., 1995). Based on these facts,
we developed a sophisticated algorithm, the
HC1000P, which permits conducting a sleep
study based on a single ECG channel that
can be automatically scored to obtain infor-
mation on sleep architecture and efficiency,
arousals, autonomic nervous function and
respiratory function during sleep. Thus, the
HC1000P provides a powerful new tool for
the diagnosis of sleep disorders in general
and sleep apnea in particular.
Comment on: Baharav, A., Kotagal, S.,
Gibbons, V., Rubin, B. K., Pratt, G., Karin,
J., and Akselrod, S. (1995). Fluctuations in
autonomic nervous activity during sleep dis-
played by power spectrum analysis of heart
rate variability. Neurology 45, 1183-1187.
abaharav@hypnocore.com
yfuxman@hypnocore.com
STRENGTHENING MEMORIES
DURING SLEEP
By John D. Rudoy,
Joel L. Voss, Carmen E. Westerberg
and Ken A. Paller
Memory consolidation processes are active
during sleep. Periods of sleep after encod-
ing can benefit later recall, and reinstating
the learning context during sleep can result
in even greater benefits. Our study asked
whether sounds could be used to reacti-
vate specific memories during sleep, later
enhancing retrieval of those memories dur-
ing waking. While asleep, people heard a set
of sounds, each linked with a visual object the
location of which had been learned earlier.
Upon waking, individuals recalled correct
object locations more accurately for the cued
objects than for control objects for which
cues were not played during sleep. Thus,
consolidation operates during sleep with
Sealy’s Window 1 by Wendy J. St. Christopher, www.art166.info
high specificity and may be systematically
influenced through auditory stimulation.
Comment on: Rudoy, J. D., Voss, J. L.,
Westerberg, C. E., and Paller, K. A. (in press).
Strengthening Individual Memories By
Reactivating Them During Sleep. Science.
j-rudoy@northwestern.edu
joelvoss@illinois.edu
c-westerberg@northwestern.edu
kap@northwestern.edu
 FEATURED SCIENTIST
SLEEP AND DREAMS
William C.
Dement
F
rontiers is delighted to present
Dr. Dement who, more than
anyone else, has dedicated his
whole life to sleep research.
Even now, at the age of 91,
he is still teaching. William
Charles Dement, known as “the father of
sleep” or “Mr. Sandman”, closes his talks by
explaining that he will continue to learn and
teach until he cannot anymore. Such pas-
sion and determination is truly admirable.
Dr. Dement started his journey
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
he helped discover rapid eye movement
(REM) sleep, the sleep stage when dreams
occur. In 1957, he moved to New York City
to work at Mount Sinai Hospital. Even
back then, his private life was involved as
he installed a sleep lab at home where he
deprived volunteers, including his wife, of
REM sleep.
In 1961, Dr. Dement co-founded the
Sleep Research Society. He joined his
present department in 1963 and spent the
last 46 years studying the neurochemistry of
sleep and the functional significance of the
different sleep stages. Dement showed that
the visual experience of a dream is related
456  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
to REM and established the well known all
night sleep patterns. He is one of the first
researchers who studied sleeping subjects
using EEG (electroencephalography) and
discovered the five stages of sleep. He also
initiated a special narcolepsy clinic and
found that disordered REM sleep proc-
esses are in fact part of the syndrome of
narcolepsy.
In 1970, Dement started the first sleep
disorder clinic in the world. Patients with
sleep-related complaints were studied with
the first all-night polysomnographic exami-
nation with full management and medical
responsibility. To make an objective assess-
ment of the relationship between daytime
function and nighttime sleep, Dement
developed, with Mary Carskadon, the
Multiple Sleep Latency Test, which remains
the standard diagnostic measure of day-
time sleepiness, i.e., to see how fast people
fall asleep. His team were the pioneers in
understanding the clinical implications and
high prevalence of sleep apnea syndromes,
narcolepsy, periodic leg movement, delayed
sleep phase syndrome, drug dependency
insomnia, psychophysiological insomnia,
and a host for other disorders.
 Dement’s top initiatives:
(courtesy of SleepQuest, http://www.sleep-
quest.com/sq_dement.shtml)
• Create measurable progress toward public
awareness concerning sleep. Create age
appropriate curriculum and ensure manda-
tory inclusion in schools.
• Require mandatory, in-depth training for
the most common sleep disorders and their
relationship to other co-morbidities and
symptoms. Create measurable progress
concerning how primary care physicians
conduct medical appointments for their
knowledge, as well as behavior toward
sleep disorders; to cause higher identifica-
tion of afflicted patients.
• Identify all very severe obstructive sleep
apnea patients and assure that they are
treated successfully.
• Improve timely access to the diagnosis of
sleep disorders by allowing the 80% of people
who do not live near a sleep specialist, to be
able to choose ambulatory out-patient sleep
testing as a viable diagnostic tool.
whose suffering could be greatly reduced by
using the knowledge we have now. For many
years, he helped lobby the US Congress to
invest in this problem, resulting in the crea-
tion of the National Commission on Sleep
Disorders Research in 1990. This commission
was decisive in the creation of the National
Center on Sleep Disorders Research in the
National Institutes of Health. As a chairman
of this commission, Dr. Dement realized that
the results of his medical research did not
reach the public ear and he decided to go on
a mission to educate the public; starting with
his home town. He just could not ignore it
and go back to academia.
In 2001, the largest National Institutes
of Health research grant in sleep medicine’s
history was offered to him for establishing
the effectiveness and benefits of continuous
positive air pressure (CPAP) treatment for
large populations of patients with obstruc-
tive sleep apnea.
William Dement is currently the Lowell
W. and Josephine Q. Berry Professor of
Psychiatry and Behavioral Sciences at the
Stanford University School of Medicine. He
is the Chief Scientific Advisor of SleepQuest
and is convinced that early detection and
adequate treatment of sleep apnea can be
used as a means of diminishing the health-
care cost. In his later years, Dement has
turned his focus from primarily research to
educating the public. His discoveries and his
role in the study of sleep have created the
standards for which Dement received several
awards and honors. His passion for the field
resulted in more than 500 articles, includ-
ing an overview of sleep called Some Must
Watch While Some Must Sleep and numerous
academic books, as well as books written for
the general public. He co-edited the defini-
tive sleep medicine textbook Principles and
Practice of Sleep Medicine.
By Nathalie Tzaud

1971 marked the start of his renown “Sleep

and Dreams” talks; the consequence of a
strong desire to educate students on sleep and
the danger of sleep deprivation. And, due to
its incredible success, this course is still taught
today.
Numerous studies on insomnia, circa-
dian rhythm, sudden infant death syndrome
(SIDS), jet lag, sleep loss, and sleep hygiene
were done under his supervision. All this
helped to build a deep understanding of
daytime sleepiness, including findings, such
as sleep loss is cumulative, the circadian
curve of sleepiness is biphasic, and sleep
can be defined with daytime alertness char-
acteristics. With Christian Guilleminault,
he established a new measure, the Apnea/
Hyponea Index (AHI), used to define sleep
apnea and to rate its severity.
Photo courtesy of Stanford Office of Communication & Public Affairs

He then founded the American Sleep

Disorders Association (ASDA) in 1975. During
his twelve years of presidency, the ASDA grew
from five sleep disorders centers with around
twenty members to about 140 accredited cent-
ers with more than 2,000 members. Dement
founded, as co-editor, the premier scientific
journal Sleep in 1978. He also founded the
Sleep Research Center, the world’s first sleep
laboratory, at Stanford University.
For most of his career, Dement, as scien-
tist, teacher, sleep doctor, and clinic and labo-
ratory administrator, worked to change the
way society deals with sleep. He feels deeply
concerned about the millions of people

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  457

 GLOBAL RESEARCH
SLEEP AND DREAMS
Sleep deprivation Pathogenesis Dream-enacting Sleep and dreams
Namni Goel of disturbed dreaming behaviors Robert Stickgold
Philadelphia, PA, USA Ross Levin Tore Nielsen Boston, MA, USA
New York, NY, USA Montréal, QC,
Sleep deprivation Deep sleep
Canada
Nirinjini Naidoo REM dreams Daniel Aeschbach
Philadelphia, PA, USA György Buzsáki Boston, MA, USA
Newark, NJ, USA
C. elegans REM sleep
David M. Raizen Subimal Datta
Philadelphia, PA, USA Boston, MA, USA
Lucid dreaming
J. Allan Hobson
Brookline, MA, USA

Nightmares
and existential dreams PTSD
Don Kuiken Anne Germain
Edmonton, AB, Pittsburgh, PA, USA
Canada
Norepinephrine
Gary Aston-Jones
Charleston, SC, USA

The world map

shows the global Sleep in animals
presence of the Jerome M. Siegel
authors that North Hills, CA, USA
contributed Neurocognitive
articles describing theory of dreaming
their research G. William Domhoff
perspectives Santa Cruz, CA, USA
on sleep and dreams. Narcolepsy Sleep-wake rhythm
The representation Emmanuel J. M. Mignot disorder
is a small subset Palo Alto, CA, USA Adrián Poblano
of the global Mexico City, Mexico
Sleep-dependent Neurobiology of sleep Synaptic changes
research effort memory Satiety and waking during sleep
in this domain Matthew P. Walker Fabio García-García Jaime M. Monti Sidarta Ribeiro
of neuroscience. Berkeley, CA, USA Veracruz, Mexico Montevideo, Uruguay Natal, Brazil

458  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

Insomnia Anesthesia Modeling sleep Stress and CRH
Eus J.W. Van Someren Axel Hutt Sean Hill Mayumi Kimura
Amsterdam, Villers-les-Nancy, Lausanne, Switzerland Munich, Germany
The Netherlands France
Astrocytes Cortical oscillations
Pierre J. Magistretti Oxana Eschenko
Coma Lausanne, Switzerland Tübingen, Germany
Quentin Noirhomme
Liège, Belgium Genetic analysis
Paul Franken
Neural correlates Lausanne, Switzerland
of dreaming
Pierre Maquet
Liège, Belgium

Obstructive sleep apnea

Lena Lavie
Haifa, Israel

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

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  459

 SLEEP AND DREAMS

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
the Chief Medical Officer of
Sleep HealthCenters, a Sleep
Medicine specialty group.
Dr. Epstein is an instruc-
tor in medicine at Harvard
Medical School and the program director
for the Sleep Medicine fellowship training
program at Brigham and Women’s Hospital.
He was the president of the American
Academy of sleep medicine from 2005 until
2006 and is the co-author of the Harvard
Medical School Guide to a Good Night’s
Sleep.
We sleep 1/3 of our life. Therefore, time
spent sleeping is not wasted time. Why do
we need to sleep?
Sleep is far from wasted time. Befitting
something we spend so much time doing,
sleep serves multiple functions in addition
to a conservation function that of reducing
cardiac, muscle and brain function to curb
caloric consumption. Sleep is not a static
time, but rather a dynamic one in which
we grow, repair the body, consolidate our
memories and sort through the experiences
and lessons of the day.
What happens if we do not get an adequate
amount of sleep?
Multiple studies have shown that lack of sleep
is directly linked to poor health. Several stud-
ies, including the >71,000 subject Nurse’s
Health study from Brigham and Women’s
Hospital in Boston, MA, have shown that get-
ting too little sleep is associated with a shorter
lifespan. According to another study, only
four hours a night for several nights results
in changes in metabolism that are similar
to those in patients developing diabetes
and obesity. Sleep deprivation also causes a
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  461
decline in reaction times, vigilance, thinking
and decision-making capabilities and pro-
duces deficits in information processing.
People who have been without sleep for 24
hours perform as badly on driving and other
performance tests as people with a blood
alcohol level of 0.10‰, which is above the
legal limit in every state in the US.
How does sleep deprivation affect our
society?
As a society, we pay a high price for insuf-
ficient sleep. According to the 2005 National
Sleep Foundation survey, almost three in ten
working adults admit they have missed work
or made errors at work because of sleep-
related issues in the past three months. Sleep
deprivation together with sleep disorders
are estimated to cost the United States over
US$100 billion per year in lost productiv-
ity, medical expenses, sick leave, and prop-
erty and environmental damage. Also sleep
deprivation played a role in several national
and international catastrophes, such as the
Exxon Valdez oil spill off the coast of Alaska,
the Space Shuttle Challenger disaster, and
the nuclear accident at Three Mile Island,
Pennsylvania.
Why is sleep deprivation caused by shift
work so dangerous for an individual, as
well as for a society?
Shift work results in chronic sleep depriva-
tion, which often leads to difficulty staying
awake on the job and at the wheel caus-
ing industrial and motor vehicle accidents.
Researchers have linked long-term shift
work with an increased risk of heart dis-
ease of up to 30-40%. It is believed that
shift work can cause or contribute to mental
health problems, e.g., mood swings, irrita-
bility or mild depression, and if the person
is predisposed to a more severe problem,
like manic depression, shift work can trigger
the disorder.
What number of shift workers are we talk-
ing about?
More than 20% of workers in the indus-
trialized world regularly work at night. It
includes large numbers of people in 24-hour
industries, like power, mining, transporta-
tion, manufacturing, health care, emer-
gency services (police, firefighters, doctors,
nurses), etc.
What role does lack of sleep play in motor
vehicle accidents?
In the US, the National Highway Traffic
Safety Administration estimates that 100,000
crashes are caused by drowsy driving each
year, causing 76,000 injuries and 15,000
deaths. A 2005 Canadian survey found that
one in five drivers admitted they had nod-
ded off at the wheel at least once in the pre-
vious year. A 2006 review by the Institute of
Medicine of the National Academies found
that almost 20% of all serious car accidents
and 57% of fatal accidents are associated
with driver’s sleepiness.
How have sleep patterns changed in the
last century?
Over the last 50 years, it is estimated that
Americans have reduced their sleep time by
a little over an hour a day on average. In a
2002 study of over a million Americans, 20%
reported sleeping 6.5 hours or less each night.
Does it mean that we live in a sleep sick
society?
Sleep deprivation is a by-product of many
of the advances of modern society. Artificial
light can shift the circadian rhythm that reg-

ulates sleep and wake times, as well as make
it possible to continue wake behaviors in the
sleep period. Communication, information
and entertainment technologies provide us
the opportunity to engage in around-the-
clock activities. Transportation advances
allow us to move farther and faster than our
body’s sleep/wake system can keep up with.
As a result, a large part of our population is
getting less sleep than they need. However,
the individual is a poor judge of the impact
of sleep deprivation. A recent study from
the University of Pennsylvania showed that
subjects who chronically restricted their
sleep time became more and more impaired
the longer they maintained that schedule. In
spite of this, their perception of their own
sleepiness plateaued after a few days. They
didn’t think they were getting sleepier even
while their performance and their reaction
times worsened.
How, with the pace of modern life, as we
fight our biological clock by drinking sev-
eral cups of coffee a day, can we still main-
tain the proper sleep hygiene?
The key is to recognize the importance of
sleep and to make “getting adequate sleep”
a priority. Sleep is a basic biological drive,
like eating or drinking. Not getting an
adequate amount of either is detrimental
to our health; the same is true of sleep. We
currently have no substitute for getting the
required amount of sleep. Just as we won’t
go without food or drink, we need to make
sure we don’t go without sleep. Setting a
regular routine with the same bed- and
wake-time, setting aside time before bed-
time to wind down and prepare for sleep,
and understanding the negative effects of
caffeine and alcohol on sleep are the first
steps to developing good sleep habits.
462  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
The mission control room for NASA’s Deep Space
Network at the Jet Propulsion Labs in California
What efforts are being made to increase
the public awareness about the importance
of sleep?
In 2006, the Institute of Medicine of the
National Academies published a report
titled Sleep Disorders and Sleep Deprivation,
an Unmet Public Health Problem. They
documented the deleterious health con-
sequences of sleep loss and sleep disorders
including an increased risk of hypertension,
diabetes, obesity, depression, heart attack
and stroke.
However, they concluded that awareness
among the general public and health care
professionals is low, given the magnitude
of the burden, and called for efforts to
increase general awareness and professional
education on the need for adequate sleep.
Professional societies, such as the American
Academy of Sleep Medicine and the National
Sleep Foundation, have mounted efforts to
educate the public on the dangers of sleep
deprivation and sleep disorders. Training
programs in sleep medicine have been
established to train physicians to take care
of patients with sleep disorders.
The National Center for Sleep Disorders
Research has been established to direct
research in sleep science. These efforts
have had some impact: truck drivers
and pilots are now evaluated for sleep
disorders on a regular basis, work hour
restrictions are in place for medical train-
ing programs and school start times have
been changed in some locations to accom-
modate children’s sleep needs. However,
much more needs to be done. 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.
By Anna Muller
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  463
THE SOCIETAL
IMPLICATIONS
OF SLEEP DISORDERS
By David A. Schulman
The International Classification of Sleep
Disorders, published by the American
Academy of Sleep Medicine in 1990 and
revised in 2005, currently describes more
than seventy distinct disorders. While
these volumes have clearly improved the
recognition of sleep pathology, a marked
underdiagnosis and undertreatment of
sleep disorders persists (Young et al., 1997;
Owens, 2001). Because of the impressive
prevalence of these disorders and their
repercussions, the societal cost of fail-
ure of diagnosis and therapy is massive.
Though most available data come from the
United States, there is reason to believe that
international statistics are similarly high
(Soldatos et al., 2005).
Insomnia affects more than one third
of Americans annually, and this figure is
expected to increase. Data from France
show a direct cost of US$2 billion for 1995
for insomnia treatment (Leger et al., 1999),
though the effects of work inefficiency as
a result of fatigue and the treatment of
other disorders, such as depression, that
can be worsened by chronic insomnia
likely drive the total societal cost much
higher. The majority of affected individ-
uals do not seek advice from healthcare
providers about this problem, leading to
a prolonged duration of symptoms and
increased use of non-prescription treat-
ments, including alcohol, to help promote
sleep. While insomnia is often related to
an underlying mood disorder, another
464  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
common cause is restless legs syndrome,
which has also been posited as a cause of
hypertension.
Another frequent sleep-related complaint
is excessive daytime sleepiness (EDS), the
most common cause of which is restricted
sleep time. This problem has become more
frequent, in part due to the development
of a 24-hour society that accompanied
worldwide advances in technology and
communication. Societal repercussions of
this problem include absenteeism, reduced
productivity and an increased frequency of
industrial and motor vehicle accidents. A
second common cause of EDS is obstruc-
tive sleep apnea syndrome (OSAS), found
in approximately 4% and 2% of middle-
aged men and women, respectively (Young
et al., 1993). OSAS has been associated
with hypertension, stroke, diabetes, heart
attacks and mortality; affected individu-
als have also been shown to have a four- to
seven-fold increase in motor-vehicle acci-
dent (MVA) frequency, presumably due to
inattention and fatigue (Teran-Santos et
al., 1999). The US National Commission
on Sleep Disorders Research has estimated
that 36.1% of fatal MVAs may be related
to sleepiness.
Parasomnias are sleep-related events that
involve abnormal movements or behaviors;
night terrors, sleepwalking and bruxism
(teeth grinding) are among the most com-
mon. While such events can be distressing to
affected patients, they can have significant
societal impact when the abnormal behav-
ior is a criminal act. Murder, sexual assault
and other violent crimes have all been
committed during reported parasomnia
episodes; many of the accused have been
acquitted based upon medical evidence of
a tendency towards such sleep-related phe-
nomena. Given the increasing awareness of
such disorders, legal systems throughout the
world will likely be hearing other sleep-
related defenses.
Sleep medicine is a fairly novel medical
specialty, and it is likely that our under-
standing of sleep disorders will continue
to grow. While educating scientists and
clinicians about such diseases will improve
health worldwide, it is only through further
education of the public that optimal care
can be achieved. Until then, sleep pathology
will continue to have a profound impact on
international society.
David A. Schulman received his B.A. degree
from Yale University and his degree in Medicine
from Johns Hopkins. He completed a residen-
cy in internal medicine at the University of
Rochester and then trained in pulmonary,
critical care and sleep medicine at Boston
University. Since 2001, he has served as the
Director of the Sleep Laboratory at Emory Uni-
versity in Atlanta, where he also serves as Chief
of Pulmonary and Critical Care Services at
Emory University Hospital and the Director of
the Pulmonary and Critical Care Fellowship
training program.
daschul@emory.edu
 BookS
References
Leger, D., Lévy, E., and Paillard, M. (1999).
The direct costs of insomnia in France. Sleep 22
(suppl. 2), 394-401.
Owens, J. A. (2001). The Practice of Pediatric
Sleep medicine: Results of a Community Survey.
Pediatrics 108, e51.
Soldatos, C. R., Allaert, F. A., Ohta, T.,and
Dikeos, D. G. (2005). How do individuals sleep
around the world? Results from a single-day
survey in ten countries. Sleep Med. 6, 5-13.
Teran-Santos, J., Jimenez-Gomez, A., and
Cordero-Guevara, J. (1999). The association
between sleep apnoea and the risk of traffic
accidents. N. Engl. J. Med. 340, 847-51.
Young, T., Evans, L., Finn, L., and Palta, M.
(1997). Estimation of the clinically diagnosed
proportion of sleep apnea syndrome in
middle-aged men and women. Sleep 20, 705-706.
Young, T., Palta, M., Dempsey, J., Skatrud, J.,
Weber, S., and Badr, S. (1993). The occurrence
of sleep disordered breathing among middle age
adults. N. Engl. J. Med. 328, 1230-1235.

Sleep: A Groundbreaking
Guide to the Mysteries,
the Problems,
and the Solutions
by Carlos H. Schenck
Avery - a member of Penguin Group, US, (2008)

Dr. Schenck discusses the causes and treat-

ments for common problems like insomnia,
restless legs syndrome, sleep apnea, and more.
But what sets this book apart is the rare glimpse
it offers into the cutting-edge science that he
and others have pioneered in identifying, un-
derstanding and explaining the realm of “para-
somnias”- the mysterious, more extreme sleep
disorders, such as dream enactment, sleep-
related eating disorder, sexsomnia, sleepwalk-
ing, sleep terrors, sleep paralysis, and even
sleep violence, which affect at least 20 million
Americans.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  465

 “Education to increase public
awareness of the hazards of sleepiness
must emphasize the need to devote
time to sleep and healthy lifestyle”

Drowsy society
By Rosalind Cartwright

CAUSES OF SLEEPINESS
How much daytime sleepiness is due to
voluntary short sleep, insomnia, or sleep
apnea?
1. Voluntary short sleep. Both polls and
research studies agree that 13.5% of
adults average 6 hours or less per night;
fewer than the recommended 8.
2. Insomnia (involuntary) rates are much
higher: adult women 61% and men 55%.
Those under 30 and over 65 years have
most trouble falling asleep, staying asleep
or awaking early.
3. Sleep apnea. All studies show men have
higher rates than women. Polls show
12% of males report apnea a few nights
a week and 8% of women. Older people
are less subject to this sleep disorder.
Studies of truck drivers tested for sleepiness
found 13.5% were sleepy due to short sleep
hours and 4.7% due to severe sleep apnea
(Pack et al., 2006).
Pack, A., Maislin, G., Staley, B., Pack, F.,
Rogers, W., George, F., and Dinges, D. (2006).
Impaired performance in commercial drivers:
the role of sleep apnea and short sleep dura-
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.

Gender Age Shift Work Regular

Hours
Rosalind Cartwright received the Distinguished
Scientist Award from the Sleep Research So- Men Women 18-29 30-64 65 plus
ciety in 2004. Her studies cover sleepwalking 63% 43% 60% 54% 21% 66% 57%
violence, dreams that aid depression remission,
and innovative treatments for sleep apnea,
which have been reported in over 200 journal More males, younger drivers and shift workers experience drowsiness while driving.
articles and book chapters.
info@rosalindcartwright.com Johnson, E. (2000). Sleep in America, the National Sleep Foundation.

466  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

STATISTICS Sleep time on average in the OECD countries

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.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  467

 Research in diverse cultures offers unex-
pected insights into how humans sleep that
challenge scientific, clinical, and popular
western views and suggest how interac-
tions of culture and biology shape sleep
physiology (Jenni and O’Connor, 2005). As
a behavior, sleep has emerged as both more
flexible and more social than was thought;
indeed, there may be no one “right way” to
sleep. Human sleep evolved in risky settings
that fostered complex sleep architecture and
regulation of vigilance in sleep to suit local
circumstances (Lima et al., 2005). A study
sampling ten groups including foragers,
herders, and cultivators from South America,
Africa, central and southeast Asia, and the
Pacific yielded an arrestingly diverse view of
when, where, how, and with whom people
sleep (Worthman and Melby, 2002).
In all these groups, sleeping together
brings safe sleep by providing warmth, com-
fort, and security that someone is awake or
wake-able at any time in case of danger of
distress. Such shared sleeping spaces are enli-
vened by other sleepers, domestic animals,
hearth fires for warmth and protection,
and nighttime activities of others nearby.
Mattresses, profuse bedding, and pillows are
rare or non-existent because they harbor
pests and parasites. Night is an important
social time for gossip and stories, ritual and
other performances, handiwork, or politics
and parties, and sleep is woven into daily
activities as needed. Fixed bedtimes are vir-
tually absent, opportunistic napping and a
not-awake-not-asleep state of somnolence

SLEEP Carol M. Worthman is the Samuel Candler

Dobbs Professor of Anthropology at Emory
University and a pioneer in the comparative

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

468  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org


References
Jenni, O. G., and O’Connor, B. B. (2005).
Children’s sleep: an interplay between culture
and biology. Pediatrics 115, 204-215.
Lima, S. L., Rattenborg, N. C., Lesku, J. A.,
and Amlaner, C. J. (2005). Sleeping under
the risk of predation. Anim. Behav. 70, 723-736.
McKenna, J. J., and McDade, T. W. (2005).
Why babies should never sleep alone: a review
of the co-sleeping controversy in relation to SIDS,
bedsharing and breast feeding. Paediatr. Respir.
Rev. 6, 134-152.
Siegel, J. M. (2005). Clues to the functions
of mammalian sleep. Nature 437, 1264-1271.
Worthman, C. M. (2008). After dark:
the evolutionary ecology of human sleep.
In W. R. Trevathan, E. O. Smith and J. J. McKenna
(Eds.), Perspectives in Evolutionary Medicine
(pp. 291-313): Oxford University Press.
Worthman, C. M., and Brown, R. A. (2007).
Companionable sleep: Social regulation of sleep
and cosleeping in Egyptian families. J. Fam.
Psychol. 21, 124-135.
Worthman, C. M., and Melby, M. (2002).
Toward a comparative developmental ecology
of human sleep. In M. A. Carskadon (Ed.),
Adolescent Sleep. Patterns: Biological, Social,
and Psychological Influences (pp. 69-117).
New York: Cambridge University Press.
are common, and the boundary between
sleep and wake is fluid. Nighttime rituals,
such as initiations in Papua New Guinea or
reburials, shadow plays, and temple ceremo-
nies in Bali apparently exploit sleep depriva-
tion effects. Indeed, the Balinese capacity
for fear sleep (tadoet poeles, abrupt sleep
response to trauma) illustrates how far the
enculturation of state regulation may be
pushed.
In sum, among non-western cultures,
sleep settings are social and solitary sleep
rare; bedtimes fluid and napping common;
bedding minimal; hearth fires present; and
conditions dim-to-dark and relatively noisy
with people, animals, and little or no acous-
tic and physical barrier to ambient condi-
tions. Such sleep settings offer rich, dynamic
sensory properties including comfort and
security via social setting; fuzzy spatial and
temporal boundaries; and effortful climate
control. Indeed, habitual co-sleepers experi-
ence better sleep quality when they co-sleep
(Worthman and Brown, 2007).
Contemporary western sleep condi-
tions and practices appear unusual by
comparison. Western postindustrial socie-
ties cultivate more sensorily impoverished,
unperturbed sleeping conditions featuring
solitary or low-contact sleeping arrange-
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  469
BookS
ments; scheduled bed- and wake-times for a
single sleep period; padded bed and profuse
bedding; absence of hearth fires; darkness;
silence; and robust acoustic, as well as physi-
cal, barriers around sleep spaces. Such static
sleep conditions typically provide security
and comfort through physical setting; rigid
boundaries in time and space; and climate
control. These settings generally offer rela-
tive freedom from parasites and vectors of
disease, fear of predators and ambush, dis-
comfort from harsh temperatures or rough
bedding, or disruptions from crowding,
noise or activities of others. Features that
might make sleep regulation more difficult
include habitual solitary sleep or limited co-
sleep from infancy onwards (McKenna and
McDade, 2005); a “lie down and die” model
of sleep in restricted intervals with few, brief
sleep-wake transitions; and sensory depri-
vation of physical and social cues in sleep
settings. An untested question is whether
these unusual habits and settings place high
and sustained burdens on sleep-wake regu-
lation systems that contribute to contempo-
rary sleep problems and disorders.
Across cultures, humans exhibit a range
of arousal states that blur binary sleep-wake
distinctions, including capacities for sus-
tained somnolence or resting wakefulness,
for adjusting level of vigilance in sleep, and Sleep and Dreaming.
for non-consolidated sleep patterns includ- Scientific Advances
ing napping and night waking. When and as and Reconsiderations
necessary, humans can and will restrict sleep by Edward F. Pace-Schott, Mark Solms,
for extended periods to pursue reward- Mark Blagrove and Stevan Harnad (Eds.)
ing activities or meet perceived survival Cambridge University Press (2003)
demands: people do not just lose sleep, they
stay awake because they want to or must From the study of brainstem-based models of
sleep cycle control, current research is moving
(Worthman, 2008).
toward combined brainstem/forebrain models
Culture shapes sleep habits and thereby of sleep cognition. The book presents five papers
shapes sleep architecture: for example, the by contemporary leading scientists, and more
proportion of REM sleep increases with than 75 commentaries on those papers by
sleep duration (Siegel, 2005). But we do not nearly all of the other distinguished authorities
know how culture-based lifetime differences in the field. Topics include mechanisms of
in sleep patterns and settings influence sleep dreaming and REM sleep, memory consolidation
in REM sleep, and an evolutionary hypothesis of
architecture, amounts and quality of sleep, the function of dreaming. The papers and com-
sleep problems, or even memory, the capacity mentaries, together with the authors’ rejoinders,
for state regulation, and mental health. These represent significant advances in the under-
compelling questions await future study. standing of the sleeping and dreaming brain.
SLEEP,
whom maturation of sleep regulatory proc-
esses and the compulsion of modern life-
styles (social networking, electronic media)

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
is sleep important to prepare the brain for
learning, but sleeping on nights following
learning carries added benefit.
Adolescent brain maturation affects the
two sleep regulatory processes: 1) sleep
homeostasis by a slowing of the accumula-
tion of sleep pressure during wakefulness
(Jenni et al., 2005); 2) circadian tim-
ing system by a delay in circadian phase
(Carskadon et al., 2004). These changes
collude with 21st century lifestyles to place
sleep at increasingly later hours across ado-
lescent development. As Roenneberg and
colleagues (2004) demonstrated with their
measure of chronotype, the timing of the
middle of sleep periods on “free” nights (i.e.,
vacations or weekends) progresses later and
later across the second decade: at age 10, the
average chronotype is about 2-3 a.m.; by age
20, it is on average about 4:30 a.m. in women
and later than 5 a.m. in men. The authors
infer that the natural timing of midsleep is
at these delayed times.
These developmental changes have an
impact on the sleep of many adolescents in
Mary A. Carskadon, Ph.D., trained under the
mentorship of William C. Dement at Stanford
University. She is Director of the E.P. Bradley
Hospital Chronobiology and Sleep Laboratory
and Professor in Psychiatry and Human Be-
havior at the Alpert Medical School of Brown
University. Carskadon’s research focuses on
the associations of biological processes and
sleep/wake patterns of children, adolescents
and young adults. Her research findings have
raised public health issues regarding the con-
sequences of insufficient sleep and concerns
about early starting times of schools.
mary_carskadon@brown.edu

470  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

on weekends. A 2006 poll by the National
Sleep Foundation1 found that school-night
bedtime changed on average from about
9:25 p.m. in 6th grade to about 11 p.m. in
12th grade. On weekends, the comparable
bedtimes were 10:30 p.m. and 12:45 a.m.
The amount of sleep school teens need is
about 8.5 to 9.5 hours; however, this poll
showed decreased amounts of school-night
sleep from about 8.4 hours in 6th grade to 7
hours or less in the 11th and 12th grade. At
least once a week, more than one quarter of
high school students report falling asleep
(not good for learning) in school, 22% fall
asleep doing homework and 14% arrive
late or miss school because they oversleep.
Those students with less than 8 hours of
sleep were also more likely to report feeling
cranky and irritable, drinking coffee every
day, and having a more depressed mood.
Under these circumstances, informa-
tion acquisition is impaired from lack of
www.sleepfoundation.org/article/sleep-america-
1 and to be in school when their brains are
polls/2006-teens-and-sleep
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  471
References
Carskadon, M. A., Acebo, C., and Jenni, O. G.
(2004). Regulation of adolescent sleep: implications
for behavior. Ann. N.Y. Acad. Sci. 1021, 276-291.
Jenni, O. J., Achermann, P., and
Carskadon, M. A. (2005). Homeostatic sleep
regulation in adolescents. Sleep 28, 1446-1454.
Roenneberg, T., Kuehnle, T., Pramstaller, P. P.,
Ricken, J., Havel, M., Guth, A., and
Merrow, M. (2004). A marker for the end of
adolescence. Current Biol. 14, R1038-1039.
sleep, and the added benefits of sleep for
learning are lost due to short nights of
sleep. The teens who may be in the class-
room, but whose brains are left behind on
the pillow, are not ready to learn. In fact,
learning may be better served by letting
the sleeping teens lie. Indeed, the National
Sleep Foundation and a number of school
districts have advocated changing the start-
ing time for school to allow adolescents a
better opportunity to get adequate sleep
more attuned to learning. miracle of all.
BookS
The Promise of Sleep:
A Pioneer in Sleep
Medicine Explores
the Vital Connection
Between Health,
Happiness, and a Good
Night’s Sleep
by William C. Dement and Chistopher Vaughan
Dell, a division of Random House, Inc. (2000)
Healthful sleep has been empirically proven to
be the single most important factor in predicting
longevity, more influential than diet, exercise, or
heredity. And yet we are a sleep-sick society,
ignorant of the facts of sleep – and the price of
sleep deprivation. In this groundbreaking book,
based on decades of study on the frontiers of
sleep science, Dr. William Dement, founder and
director of the Stanford University Sleep Re-
search Center, explains what happens when we
sleep, when we don’t, and how we can reclaim
the most powerful – and underrated – health
ENHANCED PERFORMANCE:
A CASE FOR
NAPPING AT WORK
By Sara C. Mednick and William A. Alaynick
Enhancing performance in the workplace is
a constant challenge. Employee fitness and
wellness programs, telecommuting, free
coffee and snacks have all been tried in an
effort to have employees give 110%. While
intended to improve performance, it is diffi-
cult to objectively measure the value of these
interventions and quantify improvements.
If the workplace is a combination of
isolated behaviors that can be studied in a
laboratory, research suggests that we cannot
give 100% for a sustained period. Laboratory
studies show that repeated testing across a
day results in decreased performance. For
example, training four times in one day on a
simple visual discrimination task produces a
15% decrease in perceptual abilities with each
test session (Mednick et al., 2002). Similarly,
motor fatigue has been shown to build within
a single session on a typing task (Rickard et al.,
2008), and verbal memory is vulnerable to for-
getting (Squire, 1986). For shift workers, this
is compounded by unintentional sleepiness,
and decreased performance in most skills.
472  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Decreased performance is especially troubling
when lives are on the line: aircraft operation,
medical care and military campaigns.
Sleep is a reliable countermeasure to
decreased performance. It seems counterin-
tuitive and somewhat embarrassing to sleep
at work. However, naps appear capable of
reversing daytime fatigue and increasing
cognition. Studies have shown that naps can
enhance alertness, productivity and mood,
and maintain performance at optimal levels.
Furthermore, naps produce enhanced per-
Sara C. Mednick is Assistant Professor in the
Department of Psychiatry at the University of
California, San Diego. Her research focuses on
the role of sleep (naps) in memory consolidation.
In 2003, she received her Ph.D. in Psychology from
Harvard University. She moved to the Salk Insti-
tute for Biological Studies in La Jolla, Calif., with
a National Institute of Health, National Research
Service Award fellowship. In 2007, she was
awarded a National Institute of Mental Health,
K01 Mentored Research Scientist Award.
smednick@ucsd.edu
formance on a range of cognitive tasks to the
same extent as a night’s sleep. A recent study
of napping examined creative problem solv-
ing, a valuable asset in most work environ-
ments (Cai et al., 2009). The authors showed
that naps containing rapid eye movement
(REM) sleep produced 40% enhancement
in creativity, compared with non-REM naps
or quiet rest. These performance improve-
ments make a case for napping at work. But,
is napping superior to the strategy utilized
most often: caffeine?
William A. Alaynick earned his doctorate in
Biomedical Sciences from UC, San Diego,
studying molecular endocrinology at The Salk
Institute for Biological Studies. With a long-
standing interest in neuroscience, his post-
doctoral fellowship at The Salk is focusing on
statistical methods to quantify the molecular
and electrophysiological development of spinal
cord circuitries. He is a Founder of ScholarN-
exus, L.L.C., a non-traditional consultancy serv-
ing academics with entrepreneurial interests.
will@scholarnexus.com
 out of the ordinary
References
Cai, D. J., Mednick, S. A., Harrison, E. M.,
Kanady, J. C., and Mednick, S. C. (2009).
REM, not incubation, improves creativity by
priming associative networks. Proc. Natl. Acad.
Sci. USA 106, 10130-10134.
Mednick, S.C., Cai, D. J., Kanady, J., and
Drummond, S. P. A. (2008). Comparing the benefits
of caffeine, naps and placebo on verbal, motor and
perceptual memory. Behav. Brain Res. 193, 79-86.
Mednick, S. C., Nakayama, K., Cantero, J. L.,
Atienza, M., Levin, A. A., Pathak, N., and
Stickgold, R. (2002). The restorative effect of naps
on perceptual deterioration. Nat. Neurosci. 5, 677-681.
Rickard, T. C., Cai, D. J., Rieth, C. A., Jones, J.,
and Ard, M. C. (2008). Sleep does not enhance
motor sequence learning. J. Exp. Psychol. Learn.
Mem. Cogn. 34, 834-842.
Sigmon, S.C., Herning, R. I., Better, W.,
Cadet, J. L., and Griffiths, R. R. (2009). Caffeine
withdrawal, acute effects, tolerance, and absence
of net beneficial effects of chronic administration:
cerebral blood flow velocity, quantitative EEG, and
subjective effects. Psychopharmacol. 204, 573-585.
Squire, L.R. (1986). Mechanisms of memory.
Science 232, 1612-1619.
Caffeine is the most popular stimulant in the
world, used daily by 90% of North Americans.
The National Sleep Foundation annually
reports that our increased caffeine consump-
tion mirrors and contributes to our society’s
reduction in sleep. While it appears caffeine
can enhance wakefulness and performance
on attention and concentration tasks, more
complex cognitive processes do not fare as well.
A study compared caffeine with napping and
placebo conditions on three memory domains:
perceptual, motor and verbal (Mednick et
al., 2008). Caffeine worsened performance
on verbal and motor skills, whereas napping
enhanced performance across all three tasks.
Furthermore, a recent study examining the
withdrawal syndrome of caffeine showed
that objective and subjective enhancements
that appear with acute caffeine administra-
tion completely disappear with chronic use
(Sigmon et al., 2009). Thus, the perceived ben-
efits of caffeine may be more related to release
from withdrawal symptoms rather than actual
performance enhancement.
Waking up to the benefits of napping in
the workplace requires more than just data.
Employers need to support employee napping
practices, throw away the espresso machines,
and trust that as with most workplace revolu-
tions, such as the telecommuting trend of the
90’s, what may seem counterintuitive at first
will make perfect sense both economically and
medically in the long term. observation.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  473
Polyphasic sleep and genius: 15th century inventor, painter and
thinker Leonardo da Vinci only slept for 15 minute periods every
two hours. In modern times, this kind of polyphasic sleep pattern
is called “da Vinci sleep” after him.
lll
Dreams, a writer’s block remedy: Author Robert Louis Stevenson
once said that “dreams are witnessed in that small theater of the
brain that we keep brightly lighted all night long.” His famous
novel The Strange Case of Dr. Jekyll and Mr. Hyde was inspired by a
nightmare. In his writing process, Stevenson claimed he was able to
manipulate his dreams, often returning to a dream he had dreamt
previously to give it a different ending and to conceive of plots for
his stories.
lll
Sleepless infant: Though it may seem to parents that their infants
barely sleep, in the case of 3-year old Rhett Lamb, it was a reality.
Due to a rare brain disorder called chiari malformation, his brain
stem was crowded by the cerebellum, causing him to sleep only
one or two hours a night. The condition severely impacted his
mood and ability to socialize with others, as well as his develop-
ment. After a risky surgery, he is now able to sleep through the
night and has nearly caught up in development to children his
own age.
lll
Dangerous precedents of not sleeping: The Guinness Book of
World Records discontinued its record of sleep deprivation in 1989
because of the fear that it was encouraging unhealthy behavior.
Accounts of the actual record for going without sleep vary, but the
record for scientifically documented sleep deprivation first belonged
to 17-year old Randy Gardner who went without sleep for 264 hours,
or 11 days, in 1964. Later that same year, his record was broken
by a Finnish man who stayed awake for 276 hours, but it was not
scientifically monitored. Not aware of this second record, in 2008,
a researcher named Tony Wright went without sleep for 266 hours,
thinking that he had broken the world record.
Maureen Weston, a rocking chair marathon rocker, claimed in 1977
that she had gone without sleep for 449 hours (18 days, 7 hours).
Though she tended to hallucinate, had problems with vision, speech,
memory and concentration toward the end of this surely ill-advised
test, she surprisingly suffered no lasting ill effects.
Although Gardner’s record had been surpassed by others, it is still
the most frequently cited, because the study was rigorously moni-
tored by the pioneering sleep researcher, Dr. William C. Dement
of Stanford University. The main problem with determining if the
record is the longest one or not is that people take “microsleeps”
without noticing it and so the only way to find out if a person
has been constantly awake is to keep them under close scientific
Viva la Siesta
Historically, the siesta is seen as part of
the Mediterranean life style; in the heat
of the midday sun the locals retire to their
cooler homes for a daily afternoon slum-
ber. Walking through Barcelona, Spain, on
a midsummer afternoon, only tourists can
be found glancing at shop windows and
walking away in disappointment because
opening hours reflect the local way of liv-
ing. But it is not only the heat that makes
people feel drowsy. The human biological
clock, the circadian rhythm, has an approxi-
mately 24-hour cycle, but with a dip every
12 hours. Winston Churchill once said: “You
must sleep sometime between lunch and
dinner, and no halfway measures. Take off
your clothes and get into bed. That’s what
I always do. Don’t think you will be doing
less work because you sleep during the day.
474  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
That’s a foolish notion held by people who
have no imaginations. You will be able to
accomplish more. You get two days in one
– well, at least one and a half, I’m sure.”
(Graebner, 1965). Alternatively – have a cof-
fee. Many, mainly western, cultures believe
these days that afternoon rests are only for
children and the elderly. Napping is asso-
ciated with unproductiveness and laziness
which, within the framework of globaliza-
tion and the 24/7 society, is unacceptable.
However, this change only happened over
the last 200 years with the industrial revolu-
tion, when it became too expensive to shut
down big machines just for the afternoon.
But the real question is: are siestas good
or bad or, more precisely, how long and
how frequently should we indulge our-
selves without putting our health at risk?
It was found that a 30 minute siesta at least
three times a week lowers the risk of heart-
related death by 37% (Naska et al., 2007).
However, daily napping for more than one
hour leads to a higher prevalence of coro-
nary artery disease risk factors and men also
increase their risk for developing subclinical
atherosclerosis. Additionally, long siestas are
associated with depressed mood, nocturnal
sleep disturbances and a poor self-perceived
health status (Stang et al., 2007).
Then again, there are also situations
in which the body benefits from a longer
siesta. A night of sleep deprivation causes an
increase in somnogenic proinflammatory
cytokines. Napping for two hours the fol-
lowing afternoon lowers the level again and
causes beneficial changes in cortisol concen-
tration increasing our alertness (Vgontzas
et al., 2007). Unfortunately, napping also
activates hormones and mechanisms in the
body that stop insulin from working effec-
tively and people who nap regularly are 26%
more likely to develop type 2 diabetes1.
 out of the ordinary
References
Graebner, W. (1965). My Dear Mister Churchill.
London, M. Joseph.
Naska, A., Oikonomou, E., Trichopoulou, A.,
Psaltopoulou, T., and Trichopoulos, D. (2007).
Siesta in Healthy Adults and Coronary Mortality
in the General Population. Arch. Intern. Med. 167,
296-301.
Stang, A., Dragano, N., Poole, C., Moebus, S.,
Möhlenkamp, S., Schmermund, A.,
Siegrist, J., Erbel, R., and Jöckel, K.-H. (2007).
Daily siesta, cardiovascular risk factors,
and measures of subclinical atherosclerosis:
results of the Heinz Nixdorf Recall Study.
Sleep 30, 1111-1119.
Vgontzas, A. N., Pejovic, S., Zoumakis, E.,
Lin, H. M., Bixler, E. O., Basta, M., Fang, J.,
Sarrigiannidis, A., and Chrousos, G. P. (2007).
Daytime napping after a night of sleep loss
decreases sleepiness, improves performance,
and causes beneficial changes in cortisol and
interleukin-6 secretion. Am. J. Physiol. Endocrinol.
Metab. 292, 253-261.
Another reason why some people do
not like to nap is the feeling of groggi-
ness and drowsiness upon awakening.
Determining ones sleep cycle, which lasts
between 90 and 110 minutes, can circum-
vent this. During the first 45 minutes or
so, a person can be woken easily because
they have not yet entered the deep sleep
phase. Alternatively, one should sleep
until entering the last and probably best
“remembered” phase, the REM period, in
which brain waves increase to a level simi-
lar to being awake. Keeping this in mind,
maybe there is no reason to disdain the
siesta after all. These days, sleep depriva-
tion gnaws at us all, with most adolescents
and adults considering it a luxury to sleep
for eight continuous hours. How can we
maintain human ingenuity, creativity and
productiveness with tired minds? ing in much better performance, which in the end contributed to
By Nicole Detzer
news.bbc.co.uk/2/hi/uk_news/scotland/glasgow_
1
and_west/7931508.stm. Retrieved August 7, 2009.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  475
Loudest snorer: The wife of the The Guinness Book of World
Records Loudest Snorer became deaf in one ear. Melvin Switzer
had a 92 decibel snore - louder than a pneumatic drill, or the US
noise limit in the workplace.
lll
Homicidal somnambulists: Sleepwalking appears to be the most
frequent sleep disorder claimed as defense against murder. As a
legal defense it has been used, both successfully and not, depend-
ing on many variables. In the case of Kenneth Parks, who killed his
mother-in-law, the jury ruled that he had no motive for the murder,
was unaware of the action and, thus, he was found not guilty. On
the other hand, in the case of Scott Falater, the jury ruled that the
actions he took to kill his wife included too much calculation and
were too complex for the mind of a sleeping individual. He was
sentenced to life in prison without parole.
lll
Rogue proteins cause fatal insomnia in genetically cursed fami-
lies: A prominent Venetian family had been suffering for untold
generations from a strange affliction; members would suddenly
fall into a state of constant insomnia and die of exhaustion within
a year. The reason was unknown until a doctor, who married into
the family, started to investigate the problem in 1979. It was later
elucidated that the hereditary disease is due to a protein that
mutates in the brain, similar to the effects of mad cow disease.
Twenty-seven other families have now been identified as having
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
the door to cures for other rogue protein diseases, and similar
maladies like Alzheimer’s and Parkinson’s.
lll
Killer shift: Back in the early 1980s, Philadelphia Police Department
received numerous complaints from officers about fatigue, high
rates of hypertension and cardiovascular disease, and many cases of
job-related accidents, injuries and death before reaching retirement
age. All that due to the problematic shift schedule which for many
years required officers to rotate among three different shifts: one
week from 7 a.m. to 3 p.m., the next week from 11 p.m. to 7 a.m.,
and the third week from 3 p.m. to 11 p.m. Such a “backward” rapid
rotation was constantly disorientating the internal body clocks of
the policemen, never allowing them to fully adjust to the new shift.
After the yearlong study, Dr. Charles Czeisler, an expert in circadian
rhythms at Harvard Medical School, suggested to change the work
schedule to a clockwise rotation and to stay on one shift for longer
than a week. The alertness of officers improved immediately result-
increased safety on the streets of Philadelphia.
For resources please visit www.frontiersin.org/neuroscience
 SLEEP AND DREAMS
FOUNDATION Sleep research
funding crisis
I
nvestigating the level of funding of
global sleep research is a challeng-
ing task and results were obtained
only after a lengthy study. Even
then, the available statistical
results were extremely limited in
their content and only organizations from
three countries - the US, United Kingdom
and Australia were found to publish their
data regarding sleep research funding.
In light of the lack of information pub-
lished on sleep research funding, one can
only estimate the ranking of the funding
agencies. According to the data discovered,
the US National Institutes of Health (NIH)
comes first with an increasing amount of
funding in this area since 2005.
Table 1 displays the annual support level
for sleep research based on grants, contracts
and other funding mechanisms used across
the NIH1.
On second place in the ranking of pub-
lished sleep research funding is the Australian
National Health and Medical Research
Council (NHMRC). Unlike other agencies,
the NHMRC provides very detailed informa-
tion on their research funding (Figure 1).
Within Europe, the only detailed infor-
mation on the funding of sleep research was
provided by the British Medical Research
Council (MRC). When contacted, a repre-
sentative explained that the council “pro-
vides funding for research through a range
of grants and personal awards to scientists
at universities, medical schools and other
research institutes. However, it does not
Table published January 15, 2009, table revised May
1
7, 2009: columns for FY 2009 and FY 2010 estimates
updated. Source: report.nih.gov/rcdc/categories/
476  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
normally commission research to address
specific questions. The applications are gen-
erally submitted by the scientific community
in ‘response mode’ and the MRC always
welcomes high quality applications for sup-
port into any aspect of human health. The
primary considerations in funding decisions
are research excellence and importance to
health. However, high quality proposals in
areas of particular strategic importance may
be given priority in competition for funds. As
such, they do not have a particular budget
for research funding in sleep, but they were
able to provide an estimate of £1.4 million
directed into sleep disorders research in the
year 2007/08.”
Even the European Union, which is
supposedly the biggest European fund-
ing agency for general scientific research,
does not regularly issue any specific data
on the funding allocated to sleep research.
Only one specific program within the 7th
Framework Programme (FP7)2 called
“Opportunities for funding and networking
in sleep research3” was published in 2007.
Such a gap in the published data of a high
status EU organization should not be dis-
regarded. Even more alarming, the statistics
released by the World Health Organization
are similarly patchy. The WHO publishes its
statistics in an online database that contains
a vast range of indicators related to devel-
oping countries. However, data on sleep
2
This is the main instrument for the European Union to
fund and promote European research and
technological development for the period of 2007 –
2013. Over these 7 years, the program has an
assigned budget of e 53.2 billion.
3
www.esrs.eu/cms/front_content.php?idcat=88
research funding are nowhere to be found. FY2004 FY2005 FY2006 FY2007 FY2008 FY2009 FY2010
Even when contacted directly, the WHO’s Actual Actual Actual Actual Actual Estimated Estimated
statistics department offers no information
about sleep research. This could be inter- Sleep $189 $199 $190 $219 $225 $232 $235
preted as lack of awareness and appropriate Research
attention to sleep research. Even though the
weighted average death rate is 0.4 per mil- Table 1. Estimated sleep research funding (in million US$, rounded).
lion people4, the burden of sleep problems
should not be underestimated. They are
contributing factors to a number of seri-
ous conditions, such as diabetes, obesity,
depression, heart attack and stroke, and 7.000.000
an estimated 30% of the world’s popula-
tion suffers from sleep disorders5. Sleep is
currently listed among the prevalent public 6.000.000
health concerns in the global agenda6.
A lack of sufficient in-depth data on sleep
research often leads to an inefficient alloca- 5.000.000

tion of resources and causes certain impor-

tant areas in the sleep field left uninvestigated.
4.000.000
As a result, there is an imperative need for a
more detailed, centralized and transparent
structure of research funding, which would
3.000.000
allow an increased coordination within the
global research community.
By Shamsa Abdulrasak and Marta Pyrzyk 2.000.000

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$).

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  477

 FOUNDATION HIGHLIGHTS
SLEEP AND DREAMS
BRITISH SLEEP SOCIETY
Location: Huntingdon, UK
www.sleeping.org.uk
Dr. Andrew Hall, honorary Secretary
of the British Sleep Society, Consultant
in Anaesthesia Intensive Care & Sleep
Disorders Medicine at the University
Hospitals of Leicester NHS Trust, Leicester
General Hospital, describes the society as
a multidisciplinary professional body, rep-
resenting those working in sleep-related
science, medicine and healthcare, with the
aim to promote sleep-related health issues
(e.g., good sleep hygiene, driver safety, and
patient welfare issues).
“Two conferences are organized every
year: one mainly aimed at technical aspects
of monitoring and diagnosis along with prac-
tical aspects of treatment, while the other one
is more a scientific meeting in which research
and academic matters are addressed. Most
attending doctors have a medical background,
specialized in sleep medicine, respiratory
medicine, neurology, ears, nose and throat
medicine, pediatrics and psychiatry, but we
also have members, such as psychologists and
physiologists, who are interested in sleep and
This section its disorders, and healthcare technologists who
highlights some of
work in sleep medicine” describes Dr. Hall.
the organizations
He underlines the fact that the activities
which support
of the British Sleep Society focus mainly on
sleep and sleep
sleep disorders and that the project involves
disorder related
research. many specialists who help to improve the
Representatives knowledge on sleep disorders in the profes-
of these sional community.
organizations To conclude, for Dr. Hall, the only way
kindly accepted to measure the effectiveness of the society’s
to describe their activities is in terms of growth of member-
sleep research ship. Growth in the number of clinical sleep
funding activities services and research groups across the
in an interview country in the past year is a clear way to
with Frontiers. determine the success of the project.
478  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
RESTLESS LEG SYDROME
FOUNDATION
Location: Rochester, Minn., US
www.rls.org
Mrs. Georgianna Bell, Executive Director of
the Restless Legs Syndrome Foundation, por-
trays the foundation’s activities and its mis-
sion to improve the lives of millions of men,
women and children who live with this often
debilitating disease. Restless Legs Syndrome
(RLS) is a neurological condition that affects
sleep, and the foundation’s research grant
program focuses exclusively on RLS. The
organization’s goals are to increase aware-
ness, to improve treatments, and through
research, to find a cure for RLS.
“Grants to our research program are
accepted from RLS researchers around the
world. They typically range from US$25,000
- 35,000 for a one year grant, which can be
renewed for a second year of funding. Our first
grant was a US$10,000 post-doctoral award in
1997 to an RLS researcher within NIH” says
Mrs. Bell. “We have funded over US$1.2 mil-
lion in grants in the past twelve years in areas
of both basic research and clinical outcomes.
Several of our researchers have used the data
generated from their RLS grant in a success-
ful NIH grant application. We generally have
more than twenty applications each year from
around the world. Members of our scientific
advisory board comment that the quality of

the applications has vastly improved over the
years as our collective understanding of RLS
improves.”
Mrs. Bell’s reply to Frontiers’ question,
if she feels that the foundation projects are
successful, is that “there is no direct meas-
urement regarding treatment improvement
but that’s the foundation’s hope. The RLS
Foundation promotes its research on its
website to improve effectiveness and through
meetings, such as the RLS Scientific Meeting
held last year in Baltimore, Md.”
The progress of the foundation’s activi-
ties is measured through interim and final
reports from the research institutions.
“All of our funded research grantees were
invited to attend the 2008 RLS Scientific
Meeting and present their research results
at a poster session. Some of our funded inves-
tigators have been awarded research grants
from other agencies having used our funds
as seed money. We are particularly excited
about work initially supported by the RLS
Foundation that helped establish a multi-
institutional program project award from
the NIH. Of course, being able to attract
additional funding is not our only mile-
stone, particularly during these difficult
economic times. Our primary benchmark is
the number of publications in peer-reviewed
journals that were supported by the RLS
Foundation.”
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  479
THE RESMED FOUNDATION
Location: La Jolla, Calif., US;
Bella Vista, Australia
www.resmed.com
When Dr. Klaus Schindhelm, Senior Vice
President of Global Applied Research and
Board of Trustees Member of the ResMed
Foundation, US, granted us an interview,
Frontiers asked him to depict the founda-
tion’s special feature venture. He replied:
“In 2002, ResMed created two charitable
foundations to promote sleep and breath-
ing research, and to increase both physician
and community awareness of sleep disorders
and their consequences. One foundation is
based in the United States, the other one in
Australia. Each has a similar charter in pur-
suing these goals.”
“An additional goal of each foundation
is to contribute a percentage of its annual
funding allocation to promote causes in the
areas of education, health, culture and the
arts. The philanthropy is geared to fund com-
munity projects in the areas where the corpo-
rate headquarters and the operational centers
are located. The US foundation focuses these
activities in the San Diego area while the
Australian foundation focuses on the wider
Australian environment.”
“The ResMed Foundations are entities
that are not part of ResMed’s corporate infra-
structure”, adds Dr. Schindhelm. “As such,
they fulfill the need to provide independent
research funding and awareness building in
the field of sleep disordered breathing (SDB).
This also allows for philanthropic outreach to
further the arts and facilitate the understand-
ing of the importance of science and technol-
ogy to society.”
Dr. Schindhelm continues by provid-
ing more details about the structure of the
foundations: “the US ResMed Foundation
Board currently has nine board members,
who are leaders in the medical, business and
arts community. Board members live through-
out the United States, including California,
Oklahoma and Illinois, as well as in Australia.
Edward Blair, a partner with William Blair
and Company, serves as chairman of the
foundation; Fiona Tudor is executive director.
The Australian ResMed Foundation has four
board members and is chaired by Rob Sauer, a
partner in the law firm Dibbs Barker Gosling.
In 2007, to streamline and coordinate assess-
ment and funding of scientific grants, a cen-
tral scientific review committee was formed,
which consists of members of both the US and
Australian foundations.”
Regarding the foundations’ funding pro-
gram, he says that “each year the ResMed
Foundations provide grants for scientific
research internationally, funding for scien-
tific meetings and/or physician awareness,
and support for increasing public awareness
of the hazards of SDB. The scientific research
areas of particular focus include: cardiovas-
cular disease, hypertension, coronary artery
disease, heart failure, and atrial fibrillation,
diabetes, occupational health and safety,
chronic obstructive pulmonary disease and
anesthesia.”
Two recently funded projects were the
“development of an interventional plan to
increase detection, diagnosis and appropri-
ate management of sleep disorders in the
Australian primary care setting”, conducted
at Monash University, Sydney, Australia,
and “SDB and blood glucose control in
type 2 diabetes”, which was carried out at the
University of Chicago, Chicago, Ill., US.
“Additionally, in the foundations con-
tinuing quest to promote awareness of SDB
in both the clinical and the public arenas, the
following are recently funded projects and
meetings” explains Dr. Schindhelm. “The
Royal Australian College of Physicians – a
fellowship in sleep medicine research, and The
Science Network – sponsorship of a program
entitled “Waking Up to Sleep,” that was held
at the Salk Institute and webcasted on the
Science Network; the program received over
100,000 hits.”
“The foundations’ budgets fund US$
1 million in research studies on SDB each
year”, says the vice president. “However, if
the proposals we receive do not fit within our
guidelines, or if the methodology or hypothesis
is neither outstanding nor deemed a prior-
Sealy’s Window 2 by Wendy J. St. Christopher, www.art166.info
ity, it is possible we will fund less than that
in a given year. We are looking for proposals
which will result in furthering the under-
standing and treatment of sleep disordered
breathing. Semi-annual reports to the foun-
dations are required, with evidence the study
is moving forward in a timely and effective
manner. Results of many of the studies have
been published and presented at a variety of
symposia.”
THE KLEINE-LEVIN SYNDROME
FOUNDATION
Location: San Jose, Calif., US
www.klsfoundation.org
The Co-President of the Kleine-Levin
Syndrome (KLS) Foundation, Neal M. Farber,
Ph.D., introduced us to the foundation’s
main activities and described it in the fol-
lowing terms: “The KLS Foundation provides
information and support to those diagnosed
with KLS and their families. The foundation
exchanges information with patients and the
medical community to help in the diagnosis
and care of those affected by KLS, and sup-
ports research programs. Our goals are to raise
awareness, support scientific research, to find
the cause, effective treatment and ultimately a
cure for Kleine-Levin Syndrome.”
Dr. Farber explains that the KLS
Foundation was formed ten years ago by two
families who, despite a separation of 3,000
miles, were brought together by searching
for information and support to deal with a
rare disease affecting their children. “Cindy
and Dick Maier, who live in California, set up
the non-profit foundation and developed the
480  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
first website, while Varda and I, who live in
Boston, undertook to raise funds and promote
biomedical research” says Dr. Farber. “At the
time we believed there might be perhaps a
handful of KLS cases in the United States. The
foundation board has expanded and evolved
to help support hundreds of families and indi-
viduals that have since been identified with
KLS through the foundation’s activities.”
Fundraising began soon after the foun-
dation was established. “Raising funds for a
rare disease, such as KLS, begins with friends
and family, and numerous events have been
held throughout the United States with essen-
tially all funds raised going to KLS research
and education. We sincerely thank and appre-
ciate all contributions”.
Dr. Farber explains that “the KLS
Foundation set out to establish research
efforts to investigate the cause, treatment and
ultimately cure for KLS by providing initial
seed funding. This has blossomed into larger
research programs at leading academic and
hospital centers around the world, including
Stanford University in California, the Tel
Aviv Medical Center in Israel, the University
of California, San Francisco, and the Hôpital
Pitié-Salpêtrière in Paris. These efforts have
led to Prof. Emmanuel Mignot of Stanford
University receiving the first NIH grant for
KLS research, a very competitive five year
research award.”
The representative concludes the inter-
view by telling us that the year before, the
KLS Board approved soliciting additional
proposals to fund innovative ideas on basic
scientific and medical research directed at
finding the cause and better treatments for
KLS. “Grants are primarily designed to pro-
vide seed funding to Ph.D. and M.D. research-
ers for pilot projects or to supplement existing
funding” says Dr. Farber, “and the original
plan was to award one grant for up to two
years. However, given the quality of the pro-
posals and the foundation’s mission, two pro-
posals were accepted. Grants were awarded at
a maximum of US$40,000 per year for up to
two years, subject to a project report after year
one. Applications were welcomed worldwide
and from collaborative efforts. Funds cannot
be used for indirect costs”.
By Shamsa Abdulrasak
 Dreamstorm by Wendy J. St. Christopher, www.art166.info

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  481

 GLOBAL FOUNDATION
SLEEP AND DREAMS
Restless Leg Syndrome Dream Science Foundation Foundation for Research
Foundation dreamscience.org in Sleep Disorders
www.rls.org Chicago, IL, USA http://www.med.nyu.edu/
Rochester, MN, USA sleep/clinical/foundation.html
American Sleep
New York, NY, USA
Medicine Foundation
www.discoversleep.org
Weschester, IL, USA

The map provides

a non-exhaustive
global view
of some of the
major foundations Kleine-Levin Syndrome
supporting sleep Foundation
and sleep disorders www.klsfoundation.org National Sleep Foundation
research. Those San Jose, CA, USA www.sleepfoundation.org
foundations Washington, DC, USA
The Sleep Education
represent the and Research Foundation American Sleep Apnea
funding initiative www.sleepeducation Association
into sleep research andresearch.com www.sleepapnea.org
across the world. Palo Alto, CA, USA Washington, DC, USA

482  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

Irish Sleep Apnoea Trust Narcolepsy Association UK The Belgian Association Austrian Sleep Research
www.isat.ie www.narcolepsy.org.uk for the Study of Sleep Association (ASRA)
Dublin, Irland Penicuik, UK www.belsleep.org www.schlafmedizin.at
Edegem, Belgium Innsbruck, Austria
British Sleep Society
www.sleeping.org.uk
Leicester, UK

Saans Foundation ResMed Foundation

www.saansfoundationindia.com www.resmed.com/au
New Delhi, India Bella Vista, Australia

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  483

 SLEEP AND DREAMS
INDUSTRY
SLEEP IS MONEY
T
oday, sleep along with
other bodily activities is
increasingly the subject
of attention in science.
According to experts,
approximately 30% of
the world’s population may be suffering
from sleep disorders. Amongst the well
known disorders are insomnia, narcolepsy,
obstructive sleep apnea (OSA), restless legs
syndrome (RLS), bruxism, sleep-walking
and chronic insufficient sleep which alto-
gether form a multi-billion dollar treat-
ment market.
Capturing only a part of this market
offers enormous potential and everyone
seems to want a bite of it. Companies all
over the world are trying to sell us “a per-
fect night’s sleep” through pills, mattresses,
pillows, aromatherapy, as well as more sci-
entifically advanced technologies. The sleep
market is surely not sleeping; it is growing
and offering us highly diverse products
ranging from books and eye-masks, to full-
face oxygen masks, implants and high-tech
equipment.
Sleep Apnea Device Market
The market segment for diagnostic and
treatment devices for sleep apnea is grow-
ing with increasingly informed patients
and manufacturers focused on developing
new and innovative technologies. In the
US, an estimated 38 million people suffer
from some form of sleep apnea. 15 million
people have some form of OSA and are in
need of treatment, which alone presents an
enormous market for treatment and moni-
toring devices1. As a result, a great number
of companies are entering the sleep apnea
device market.
484  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Wally Cox wears face mask while reading, 1953
Funding for research and development
of new continuous positive airway pres-
sure (CPAP) masks is a priority, as com-
pliance and comfort are important issues
for patients. Other trends include smaller
devices and less complicated equipment.
The market also looks set to expand the
reach of the sleep lab. Since March 2008,
portable devices are authorized for home
testing by the Center for Medicare Services
in the US, causing a negative market effect
for sleep labs, but an upsurge in sales for
CPAP devices. The segment is foreseen to
grow by up to 18% per year, based on an
independent market analysis.
The primary factors driving the market
penetration and contributing to the growth
of the segment include the large undiagnosed
patient population and growing awareness,
which is supported by projections from
manufacturers and independent studies.
The OSA devices are very likely to remain
the most widely used devices in sleep.
Products and Technologies: facial interfaces,
full-face masks, nasal pillows, chin straps,
ComfortFit, Sleep Weaver, Breeze, Opus 360,
V2 maska, Twilight, ComfortGel, CPAP’s,
bi-levels, Auto PAP’s, humidifiers, ARES™,
MediByte, SleepScout, Embletta, Alice PDx,
Stardust II, Ambulatory PSG, and portable
sleep testing (PST)
Companies: Respironics, ResMed, Fisher &
Paykel, Evo, Circadiance, Covidien, Hans
Rudolph, Vital Signs, Inc., DeVilbiss, Drive
Medical, Advanced Brain Monitoring, Inc.,
Braebon Medical, CleveMed, Embla, and
SleepQuest
Top Device Companies, 4 February 2009. http://www.
1
topdevicecompanies.com/2009/02/respironics-once-
sluggish-sleep-apnea-gets-active-.html
Implants
Palatal or dental implants are the most
common implants used to treat OSA.
Neurostimulation is a relatively new
treatment which applies regular bursts
of electricity to keep the airways open.
This technology still needs further testing
and there are other techniques available
that are cheaper and more effective. One
device, developed by Apnex stimulates the
hypoglossal nerve. The company raised
US$16 million to develop the technology,
in response to the Inspire II developed by
Inspire Medical Systems, Inc., a subsidi-
ary of Medtronic. This type of device costs
about US$30,000 including the implanta-
tion, in contrast to a CPAP mask, its main
competitor, which costs only around
US$1,000.
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  485
Products and Technologies: Inspire II, Apnex
Hypoglossal Nerve Stimulation (HGNS™)
System, and Pillar Procedure
Companies: Apnex Medical, Inc., Inspire
Medical Systems, Inc., and Restore Medical
Sleep Labs
Sleep labs perform sleep studies and design
treatment programs for sleep apnea, insom-
nia and other sleep disorders. There are three
main types of labs, which include hospital
based, practice based and independently
based. Currently, the market for sleep labs
is shaken by the uprise in home testing. A
multitude of new testing and diagnostic
options are appearing on the market, allow-
ing for patient analysis outside of the lab.
New technologies aid the sleep labs by
offering more comfortable polysomnogra-
phy systems through wireless systems. This
is a great advance to the cables that previ-
ously caused a nuisance to patients. Thus,
patients adjust more readily to the sleep lab
environment and this in turn helps produce
more accurate results. Other advances are
in data transmission and networking. The
wireless systems also allow sleep labs to com-
pete with home diagnostic devices. Sleep
labs now reach the home testing market by
providing remotely attended sleep studies
in home settings. In order for sleep labs to
succeed in the competitive market of today,
they need to truly highlight the benefits of
sleep disorders being diagnosed and treated
by professionals.
According to Marketdata Enterprises,
Inc., the typical sleep lab has revenues of
around US$1.33 million and conducts
approximately 1,250 sleep studies per year.
The estimated number of labs in the US is
above 3,300 and the segment alone is worth
about US$5 billion.
Products and Technologies: polysom-
nograms, Split Night Study, Multiple Sleep
Latency Test, CPAP titration study, MSLTs,
RPSGTs, EEG, EOG, EMG, ECG, and ambu-
latory PSG system
Companies: SleepMed, Sleep Services of
America, Sleep Works, Pacific Sleep, Total
Sleep, Avastra Sleep Centres, Columbus Sleep
Consultants, and Sleep Solutions
Mattress and Pillow Market
Manufacturers of mattresses and pillows
rely on the relationship between sleep and
health when marketing products. Today,
beds are advertised as individual health
centers rather than just a place to sleep.
486  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Product claims of manufacturers include
medical facts and promises of increased
blood circulation, decreased snoring, etc.
Current estimates on the specialty
sleep market vary greatly, as it is difficult
to differentiate and define the products.
Approximations value the specialty sleep
market to cover from 5-20% of all retail
sleep products in the mattress and pillows
sector. According to an independent market
research company, the mattress market is
worth US$13.7 billion and the pillow mar-
ket adds a further US$900 million. The
market has increased by nearly 40% since
2000, according to the International Sleep
Products Association. The rebranding of the
specialty sleep mattress and pillow market
from medical products to lifestyle products
has dramatically increased sales and lowered
the age of the average customer. Emphasis
on lifestyle and health makes this market
sector boom.
Products and Technologies: StarryNight,
Sona Pillow, Distinct Rest air bed, visco-
elastic products, latex mattresses, and latex
toppers
Companies: Tempur Pedic International,
Inc., Sealy, Serta, Select Comfort, Simmons,
Leggett & Platt, Hastens, Restonic Mattress,
Corp., United Sleep Products, Therapedic,
Eclipse International, Natura World, and
Boyd Specialty Sleep
Sleep Medications
The market for insomnia drugs has not
reached its saturation point by far. Up to
now, the market focus has been driven
by the development of medications with
reduced side effects and dangers of over-
dose. Compared to the well established
business with antidepressants, the sleep
prescription drug market is still virgin
territory.
The potential treatment population is
still one of the largest in medicine. Many
of the blockbuster drugs that dominated
the market are coming off patent protec-
tion. New technologies and innovative
approaches, along with generics, are set to
stir some motion in the segment. Currently,
gamma aminobutyric acid (GABA) agents
dominate the market, but more than a
dozen insomnia drugs are in phase II and III
clinical trials in the US. So far, efficacy and
safety have been the main restraints of the
sleep disorder market. In 2007, the major
producers of sleep medications spent over
US$619 million on marketing and advertis-
ing insomnia drugs. Advertising has proven
effective in informing the public about
potential medications, thereby increasing
awareness and acceptance. Another factor
to affect this product group is the online
market, as no prescription is needed. This
way of purchasing will continue to evolve
and will have some effect on the market.
Underdiagnosed and undertreated, the
sleep disorder market presents a major
opportunity for pharmaceutical companies.
Only 10% of the total patient population is
estimated to use prescribed insomnia treat-
ments and the sleep market looks set for
dramatic growth.
Products and Technologies: Prosom,
Dalmane, Restoril, Halcione, Imovan,
Lunesta, Sonata, Ambien, Rozerem, Provigil,
Indiplon, Silenor, and Volinanserin
Companies: Pfizer, Sanofi Aventis, Takeda
Pharmaceuticals, Cephalon, Inc., Neurocrine
Biosciences, Inc., Lundbeck, Eli Lilly, and
Merck

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

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  487

ASK NOT WHAT THE BRAIN
CAN DO FOR SLEEP –
ASK WHAT SLEEP CAN DO
FOR THE BRAIN
By Philip Low

488  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

 Philip Low is Chairman, Chief Scientific and
Chief Executive Officer of NeuroVigil, Inc., Ad-
junct Professor at Stanford School of Medicine,
Research Affiliate at the M.I.T. Media Lab and
the Salk Institute and the President of the 1st In-
ternational Conference on Alzheimer’s Disease
and Advanced Neurotechnologies, to be held
in Monaco in February 2010. Dr. Low is well-
known for his many groundbreaking contribu-
tions to the neuroscience of sleep, which in-
clude a new sleep state and a 1 page Ph.D.
dissertation. To bring his innovations to the
market, Dr. Low founded NeuroVigil, an award-
winning Computational Neurodiagnostics com-
pany headquartered in La Jolla, California.
philip@neurovigil.com
Advanced Sleep Analysis for the sole pur-
pose of identifying sleep disorders, such
as apnea, or merely counting sleep stages
would be akin to doing a blood test for
nothing more than diagnosing sepsis or
tabulating red and white blood cells: sleep is
an untapped opportunity to study the brain,
an opportunity which neuroscientists, the
medical community, the pharmaceutical
industry and most of you – and us – have
yet to wake up to.
Several neuropathologies are already
known to have an effect on certain sleep
metrics: schizophrenic patients have fewer
sleep spindles, clinical depression is posi-
tively correlated with increases in REM
sleep, and Alzheimer patients can suffer
from a fragmentation of REM sleep; to
name just a few. Interestingly, while REM
sleep appears important to form new mem-
ories, REM deprivation has been shown to
abate symptoms of depression. It has even
been proposed that more sleep is positively
correlated with shorter lifespan. None of
these observations (Ferrarelli et al., 2007;
Feinberg et al., 1982; Kripke et al., 2002)
make much sense if one is led to arbitrarily
believe that particular sleep stages are always
good for you, that we all need the same eight
hours of sleep and that “light sleep” (where
spindles take place) is insignificant.
While sleep may provide a mirror of a
vast array of conditions, conversely, treat-
ing sleep with the assumption that side
effects may be self-contained within the
realm of sleep is again akin to suggesting
that injecting a compound into the blood-
stream may only affect the blood. Several
drug companies have realized the cost of
such dangerous assumptions when some
sleep inducing drugs were found to gen-
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  489
erate profound mood disorders and even
amnesia. More recently, the FDA asked a
dozen drug manufacturers of sleep inducing
drugs to write on their drug bottles that the
compounds may cause “sleep driving”, i.e.,
that the drug may still have an effect in the
form of impairment on waking behavior.
This raises the following questions:
1) Can we leverage the dynamic oscillations
produced during sleep in order to system-
atically detect severe neuropathologies?
2) Can we use sleep to make safer drugs?
Yes, we can.
Currently, the sleep diagnostics market is
driven by the sleep disorders market. While
there are over 70 million individuals in the
United States estimated to suffer from sleep
disorders, of those, only 4 million are fol-
lowed clinically, leading to 7 million tests per
year, mostly for apnea. These tests require
protracted hospital stays wherein a patient
has to sleep tethered to a wall with elec-
trodes glued on the scalp, chin, abdomen and
around the eyes. The data are then analyzed
by hand by human scorers who agree with
one another 75% of the time. The discom-
fort, inaccuracy, time and cost requirements
of this setup have been a major bottleneck in
the clinical evaluation and treatment of the
vast majority of sleep patients.
This entire clinical setup can be reduced
to a single channel of EEG (Low, 2007). This
channel can be used to create a frequency
coded map of brain activity and has revealed
the presence of a new sleep state, which
offers far more information than the hyp-
nogram, a stair step plot of sleep stages and
its associated statistics. In this map, the hip-
pocampus, thalamus, basal ganglia, septum,
cortex, cerebellum, etc., produce different
signatures throughout the sleep/wake cycle
depending on whether they are diseased or
not, or whether they are being adversely
affected by medication. Contributions of
these structures can be teased out by con-
trasting these results with analysis from ani-
mals with a differing genetic make-up or
neuroarchitecture, as well as human stroke
patients. Many of the animal recordings can
now be performed using a single channel as
in the human recordings, and some even
non-invasively. Work with zebra finches has
shown that certain brain patterns, which are
associated with the neocortex in mammals,
do not, in fact, necessarily require a neocor-
tex (Low et al., 2008).
Toy, gadget, sensor, lifestyle, consumer,
FDA and non-FDA regulated companies
and others appear to have done a responsible
and promising effort in order to develop dry
non-contact sensors which do not require
electrogel, collodion glue, etc.
The combination of algorithms, wireless
sensors, databases and regulatory approval
will prove necessary to create a simple
portable wireless neurodiagnostics system
for neuropathologies of interest. We have
embarked upon this path, with the develop-
ment of an iPod for the brain – the iBrain
– as well as with the construction of a data-
base of sleep derived biomarkers, in part-
nership with leading research institutions
and pharmaceutical companies who test
their drugs for efficacy and side effects on
the brain, which at low doses may not pro-
duce noticeable symptoms over the course
of a short clinical trial.
Brain activity during sleep is a mosaic
of highly variable patterns, which will serve
as a magnifying glass for the non-invasive
detection of neuropathologies and drug
side effects, well before the onset of symp-
toms, while providing important bound-
ary conditions for comparative, clinical,
cognitive neuroscience and pharmaceutical
research.
References
Ferrarelli, F., Huber, R., Peterson, M. J.,
Massimini, M., Murphy, M., Riedner, B. A.,
Watson, A., Bria, P., and Tononi, G. (2007).
Reduced sleep spindle activity in schizophrenia
patients. Am. J. Psychiat. 164, 483-492.
Feinberg, M., Gillin, J. C., Carroll, B. J.,
Greden, J. F., and Zis, A. P. (1982). EEG studies
of sleep in the diagnosis of depression.
Biol. Psychiat. 17, 305-316.
Kripke, D. F., Garfinkel, L., Wingard, D. L.,
Klauber, M. R., and Marler, M. R. (2002).
Mortality associated with sleep duration
and insomnia. Arch. Gen. Psychiat. 59, 131-136.
Low, P. S. (2007). A New Way to Look at Sleep.
Ph.D. thesis, UC San Diego, 1.
Low, P. S., Shank, S. S., Sejnowski, T. J.,
and Margoliash, D. (2008). Mammalian-like
features of sleep structure in zebra finches.
Proc. Natl. Acad. Sci. USA 105, 9081-9086.
SLEEP MEDICINE –
THEN AND NOW
By Ed Faria and Lenneice A. Drew
In recent years, we have learned that sleep
deprivation and undiagnosed sleep disor-
ders are arguably one of our largest health
problems. During the last two decades, a
strong diagnostic industry has been thriv-
ing to develop the sleep field including,
but not limited to, Neurovirtual, Philips
Respironics, Embla, and Cardinal Health.
A Look Back
Sleep medicine is a specialty in the field
of medicine; sleep disorders have become
a public health concern and sleep sci-
ence has earned its spot as an important
area of research. The American Medical
Association recognized sleep medicine as
a specialty in 1996. However, take a look
back, and you will find the history of sleep
medicine is relatively short and most of the
individuals involved with its development
are still living.
The critical importance of sleep to good
health and life was illuminated by the exper-
iments conducted in rats by Rechtschaffen.
In these experiments, total sleep deprivation
resulted in the death of all rats within two to
three weeks. Selective deprivation of non-
rapid eye movement (non-REM) and rapid
eye movement (REM) sleep also resulted
in the death of the animals over a slightly
longer period of time.
In human beings, there is also informa-
tion on the long-term effects of insufficient
sleep. An early study, conducted by Kripke,
used information collected by the American
Cancer Society on more than one million
human beings. Mortality rates after six years
of follow-up were significantly increased
for people who had less than four hours
or more than ten hours of sleep per night.
These results were reconfirmed in a second
survey of 1.1 million human beings con-
ducted between 1982 and 1988.
490  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
The development of modern sleep med-
icine is closely linked to the discovery of
the electrical activity of the brain. Richard
Caton was the first to record brain electrical
activity of animals in England in 1875. The
development of the electroencephalogram
(EEG) in 1929, by German Psychiatrist,
Hans Berger, allowed the examination of
brain activity during sleep. In 1937, A. L.
Loomis in the United States first docu-
mented the characteristic patterns of what
is now called non-REM sleep: vertex waves,
sleep spindles, K complexes, and delta slow-
ing. He divided sleep into five stages of
increasing depth from A through E, which
formed the basis for the current classifica-
tion of non-REM sleep.
Today, the advances in medicine over
time have contributed significantly to the
understanding of sleep and sleep research.
There are few, if any, medical specialties that
do not intersect with the past, present, and
future understanding and study of sleep.
Neurology, pulmonology, psychology, psy-
chiatry, physiology, cardiology, otolaryn-
gology, etc., are all integral areas of sleep
study.
Waking up to the Problem
In addition to the major problem of sleep
deprivation related to social or occupational
activities, the International Classification of
Sleep Disorders (ICSD) lists 88 sleep-related
disorders. In recent years, we have learned
that sleep deprivation and undiagnosed
sleep disorders are arguably some of the
biggest health problems.
Ed Faria is Founder and Chief Executive Officer
at Neurovirtual/Sleepvirtual. He received his
Master in Business Administration from the
University of California, Irvine.
efaria@neurovirtual.com
Although insomnia affects everyone
occasionally, about one out of every three
adults indicates it is a significant problem,
and 50% of these persons consider it to be
severe. Snoring is another highly prevalent
condition that has been reported to disrupt
the sleep of bed partners. Obstructive sleep
apnea (OSA) is the most common category
of sleep-disordered breathing and restless
legs syndrome (RLS) is also highly prevalent
conditions.
The treatment for sleep apnea is also
non-surgical. It ranges between behavioral
changes, dental appliances, and continuous
positive airway pressure (CPAP). Behavioral
changes refer to dealing with obesity and
changing positions while sleeping, whereas
dental appliances require equipments in
order to help the person breathe properly.
There are a number of over-the-counter
drugs available for the treatment of insom-
nia and other sleep related disorders. These
contain sedatives or suppressants that slow
down the activity of the central nervous
system.
The Sleep Industry
During the last two decades, a strong diag-
nostic industry has been thriving to develop
the sleep field including Neurovirtual/
Sleepvirtual, Philips Respironics, Embla, and
Cardinal Health. A number of foundations
have been organized to improve the quality
Lenneice A. Drew is a Communications/Public
Relations professional for global leader Neuro-
virtual. She works diligently to share the com-
pany’s commitment to excellence in sleep
medicine. Lenneice has years of experience in
the field of print and broadcast journalism. She
has a B.Sc. degree in Journalism/Mass Commu-
nication from Florida International University.
ldrew@neurovirtual.com
 Dr. Allan Hobson, Harvard University
neurophysiologist and psychiatrist, supervised and
watched over the setup of Dreamstage
at the Museum of Science in Boston in 1979.

of life for people who suffer from sleeping

problems and disorders. The National Sleep
Foundation partners with many govern-
ment agencies and organizations like the
Centers for Disease Control and Prevention,
the National Institutes of Health and the
Department of Transportation to raise
awareness of the importance of sleep and
alertness.
The prevalence of sleep disorders within
the population, combined with scientific
progress in our ability to diagnose and
treat these disorders, has created a tremen-
dous demand for knowledgeable physi-
cians trained in the area of sleep medicine.
The American Academy of Sleep Medicine
(AASM) is constantly working to raise the
standard in the field of sleep medicine and
fostering the development of scientific
knowledge. In 2008, the AASM published
a new scoring manual that seems to better
reflect the weight of scientific evidence and
expertise in the field of sleep.
In just a short time, a number of soci-
eties have developed across the US in
the field of sleep medicine. For example,
the Florida Sleep Consortium, Illinois
Society of END Technologists, and the
New Jersey Sleep Society are hosting sleep
medicine events this year, and there are
many others. Global leader Neurovirtual/
Sleepvirtual based in Doral, Florida, is
also advancing the field of sleep medicine
with state-of-the-art technology. The com-
pany is offering routine sleep acquisition
systems specifically enhanced for artifact
reduction, facilitated file transferability,
and endless reading/scoring station con-
nections. Neurovirtual is one of the key
players in developing, manufacturing, and
servicing high-technology medical devices
used in the fields of neurology and sleep
medicine in America.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  491

 INDUSTRY HIGHLIGHTS
SLEEP AND DREAMS
NeuroScience, Inc.
NeuroScience, Inc., was established in 2003.
The company is a research-based medical
solutions company and an industry leader in
assessing and addressing neurotransmitter-
related disorders. The testing menu includes
16 different neurotransmitters, neuro-
modulators, metabolites and amino acids,
for which more than 25 formulas exist to
address specific imbalances. NeuroScience,
Inc., launched NeuroSLP in 2009, which is
a medical protocol for imbalances in sleep
regulating neurotransmitters. The aim is
for health care practitioners to be able to
pinpoint specific imbalances and offer tai-
lored therapy.
www.neurorelief.com

NeuroVigil
NeuroVigil was founded in California in
2007. The technology of the company, a
highly sophisticated algorithm, can inter-
pret sleep EEG data in less than a minute
which generally takes a highly trained neu-
rologist between 30-60 minutes to analyze.
The technology may increase efficiency,
cost-effectiveness and availability of diag-
nostics for sleep disorders. NeuroVigil is the
only company in the world to provide non-
invasive, rapid and high-resolution brain
activity monitoring. The main markets that
NeuroVigil aims to target are evaluation of
sleep apnea, pharmaceutical effect on sleep
and a transportation safety device.
www.neurovigil.com
NeuroVirtual/
SleepVirtual
Sleep Virtual is a sleep technology com-
pany based in Florida. They have recently
launched a new sleep data acquisition device
called BWII PSG. It is currently the most
advanced acquisition device on the market,
as it is compact, easy to use and keeps you
up-to-date with live sleep statistics. The
device comes with a report generator and
report templates to facilitate the process of
creating sleep reports. This state-of-the-art
gadget weighs only eight pounds and can
therefore be easily transported and con-
nected to any laptop or desktop computer.
www.sleepvirtual.com

Transcept
Pharmaceuticals, Inc.
Transcept Pharmaceuticals, Inc., is a phar-
maceutical company focused on the devel-
opment of products that are aimed at
treating illnesses within the neuroscience
field. They currently have a product in
development called Intermezzo ® which
contains a low dose of zolpidem and is a
treatment for insomnia. This drug should
alleviate middle of the night awakenings
and allow individuals to enjoy a long night’s
sleep. Transcept merged with Novacea, Inc.,
in January 2009.
www.transcept.com
ResMed
ResMed, a producer of medical equipment
based in San Diego, California, that spe-
cializes in the production of non-invasive
ventilation technology for patients suffer-
ing from sleep-disordered breathing. They
have a large range of products available
including ventilation and sleeping devices,
masks, humidifiers, screening equipment,
data management and various accessories.
ResMed’s products are now available in over
70 countries worldwide through a large net-
work of distributors.
www.resmed.com

492  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

Philips Respironics
Philips Respironics is one of the largest res-
piratory sleep therapy manufacturers. The
company specializes in providing effective
monitoring, diagnosis and treatment solu-
tions for OSA. The company consists of
three sub-groups: the sleep and home res-
piratory group, the hospital group and the
international group. They offer an endless
range of sleep-related products including,
but not limited to CPAP and BIPAP, therapy
devices, masks, titration services, pulse oxi-
meters, oxygen concentrators and portable
home ventilators, among many others.
www.respironics.com
XSENSOR Technology
Corporation
XSENSOR Technology Corporation is
the largest company specializing in pres-
sure imaging of sleepers, patient safety
and automotive industry. Having recently
won the 2009 Alberta Export Awards in
the Advancing Technologies category,
XSENSOR provides its customers with full
body pressure imaging services and solu-
tions for comfortable sleep and relief. Their
pressure imaging systems are used by large
organizations such as NASA, Sealy, Mayo
Clinic and Select comfort, the US Airforce
and several major automotive companies.
www.xsensor.com
MetroNaps
Based in Australia, MetroNaps is a fatigue
management solution company that pro-
vides its services to both public and pri-
vate organizations. Since 2003, they have
worked at improving the cardiovascular
fitness, nutrition and sleep conditions of
their patients to help them reach their opti-
mum health and productivity. They special-
ize in workplace fatigue management and
provide online training sessions, as well as
workshops and events to help patients boost
their low energy levels at work. Currently
available on four continents, MetroNaps
will help train employees and increase their
productivity by improving their sleep, fit-
ness and eating habits.
www.metronaps.com
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  493
Human Bionics
Based in North Virginia, Human Bionics is a
Comprehensive Behavioral Health Services
company that specializes in neurotherapy
(brain music therapy) and training, as well
as nutrition. Their brain music therapy pro-
gram aims at alleviating insomnia, stress
and anxiety through recording your brain
waves with EEG technology and transform-
ing them into unique musical sounds. The
therapy emits two types of sounds – relaxing
and stimulating – to help your body relax
and achieve a sound state of mind. This type
of therapy is very effective for individuals
that need help to relax and enjoy a good
night’s sleep. Human Bionics also offers
cognitive assessment and neurotherapy.
www.humanbionics.com
Advanced Brain
Monitoring, Inc.
Since 1997, Advanced Brain Monitoring,
Inc., is a company that specializes in the pro-
duction of memory dysfunction measure-
ment, sleep apnea diagnosis and alertness
monitoring technology. Based in California,
this company has received over US$14 mil-
lion in grants to promote its developments
within the market. Its main product, Apnea
Risk Evaluation Systems ® (ARES ®) helps
patients assess the existence and severity
of obstructive sleep apnea. The product
includes a headstrap recorder that registers
nocturnal data and measures blood pres-
sure, pulse rate, oxygen airflow and satu-
ration, as well as snoring levels and any
head movements. Along with this comes
a screener that evaluates your risk of suf-
fering from OSA and a data management
system that helps you evaluate and study
the processed data.
www.b-alert.com
SleepQuest
Based in California, SleepQuest is a com-
pany with expertise in advising patients and
professionals in the area of sleep apnea, and
CPAP treatment and testing. Their team of
medical professionals is trained to analyze
sleep studies and provide advice to ensure
that patients can benefit from home-based
CPAP and sleep treatment. SleepQuest has
been in the industry for over ten years and
now also offers web-based services and
solutions for patients; with specialists that
monitor patient progress, offer sleep advice
in forums and post educational videos to aid
them in combating their sleep disorders.
www.sleepquest.com
Alertness Solutions
Alertness Solutions provides solutions that
enhance performance, health and safety in
a number of settings. The company aims at
providing strategies that are tailored for indi-
viduals and organizations and the product
array covers a number of different solutions to
manage your sleep and alertness. The product
range includes solutions for managing jetlag,
staying awake at the wheel, a management
program for pilots to stay alert and a healthy
sleep program. Based in California, Alertness
Solutions have been providing their services
for over ten years. The founder and president
of the company, Mark Rosekind, is the former
director of the Fatigue Countermeasures
Program at NASA.
www.alertness-solutions.com
Neurotech Coaching
Neurotech Coaching, based in Australia,
is a consultancy company that focuses on
Sealy’s Window 3 by Wendy J. St. Christopher, www.art166.info
helping its clients improve brain function
through brainwave assessment, biofeedback
and entrainment. They work in correlation
with coaches and organizations to ensure
the best care and guidance for their clients
to achieve their goals. Neurotech also offers
non-invasive treatment for disorders, such
as sleep, ADD, OCD, ODD, behavioral,
anger, anxiety and depression problems.
www.neurotechcoaching.com
 ON THE HORIZON
SLEEP AND DREAMS
Starry Night - US$50,000 Bed
No need to leave bed ever again with
StarryNightTM. The modern sleep archetype
may have it all: anti-snore technology, tem-
perature control, sleep diagnostic center,
Internet, wireless media center, iPod dock-
ing station and possible wireless control for
lamps, thermostats, security system, etc.
lll
Home Gadget
to Monitor Your Sleep
You can now monitor your night sleep and
breathing patterns with the SleepMinder by
BiancaMed in Ireland. No more need to lie
on a plastic pad or wear electrodes in bed to
analyze your sleep efficiency. All you need to
do is log onto a personal website to discover
your sleep pattern.
lll
An Alternative to CPAP
Ventus Medical of California has developed
a disposable device the size of a US quar-
ter coin to treat OSA. The device uses the
breathing of the user to create pressure that
acts as a splint to keep the airways open.
lll
Sleep Prescriptions
on the Rise
Did you know that in 2008 over 56 million
prescriptions were dispensed in the US. This
is a 7% increase since 2007.
lll
Snore Stopper
With a highly sensitive microphone, the
True Sleep snore stopper, worn like a watch,
will stimulate your wrist by sending electric
pulses. This in turn will make you change
position and stop snoring.
494  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Solve All Problems
with CPAP
RemZzzsTM may be the solution to all dis-
comforts of wearing a CPAP mask. The
RemZzzsTM mask liners absorb facial oil
and perspiration, which results in a better
seal, reduction of skin irritation and more
comfort and compliance. This may reduce
the number of CPAP mask wearers that dis-
continue treatment due to the discomfort
of masks.
lll
Acupressure Sleep Gadget
If you suffer from strange sleep patterns you
may be able to solve it by using the Dreamate
Sleep Inducer. This device uses acupressure
techniques to massage precise pressure points
on your left wrist. The device claims to offer
sleep relief within a week with maximum
effect after eight weeks of use.
lll
Cutting-Edge Brainwave
Entrainment Technology
By using binaural beats you can achieve a
deep and sound sleep as your brain syn-
chronises to the optimum state for rest. The
recordings will set a new pattern for the fre-
quencies that the brain follows.
lll
Relaxation CD
Why not try the pzizz softwareTM for PC
and MAC if you are having trouble falling
asleep. The software creates unique sound-
tracks that will help you fall asleep to a mix
of voices, music, sound effects and binaural
beats. Every soundtrack is different and you
can adapt the length to suit you.
Track Your Sleep
By using the Fitbit you can track your
physical activity during the night. The
small gadget clips onto your pyjamas and
the data acquired will be wirelessly trans-
mitted to your computer. Another similar
option is the aBbo, which can track two
sleeping individuals simultaneously. This
option requires you to wear a wristband
that gathers sleep data over a number of
days and then displays them in individual
sleep graphs. In addition you can also set it
to wake you up at the best and most optimal
time for your body.
lll
Sleeptracker Wristwatch
Wear the Sleeptracker® watch and wake up
at the optimal time. The watch will monitor
your body as you sleep and alert you at the
most ideal time to get up.
lll
Advertising Sleep Drugs
Did you know that major anti-insomnia
drug producers spend over US$500,000 per
year on advertising and earn around US$3
billion on product sales.
lll
Are You Suffering
from Sleep Apnea?
The website www.aviisha.com offers
online testing to determine whether you
are suffering from apnea. The site is an
attempt to teach more about the condi-
tion, the possible health effects and treat-
ment options.
F or resources and references visit www . frontiersin . org / neuroscience
Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  495
FDA Requests Label
Change for All Sleep
Disorder Drug Products
The FDA has requested that all manufacturers
of sedative-hypnotic drug products, a class of
drugs used to induce and/or maintain sleep,
toughen their product labeling by including
stronger language concerning potential risks.
These risks include severe allergic reactions
and complex sleep-related behaviors, which
may include sleep-driving.
lll
Internet CBT
may Help Insomniacs
A small study has proven that cognitive
behavioral therapy over the Internet can be
as effective as face-to-face therapy. Although
this type of therapy may not be right for all
patients the potential as a first intervention
is very promising.
lll
New Non-Invasive
Snore Solution
Dr. SleepGood, Inc., has released the
SnoreSling™, a new non-invasive option
for apnea patients and persons suffering
from snoring. The device is actually a piece
of fabric with an adjustable strap, which
keeps the jaw closed, thereby preventing
the tongue from falling back and blocking
the airways.
lll
Registered Polysomniac
Technologists (RPSGT)
Did you know that in 1979 only eight sleep
techs took the first RPSGT exam at the State
University of New York, US. Today there are
over 14,000 RPSGT’s in the world.
Sleep Debt Takes
an Economic Toll
According to a study conducted in 2007,
insomnia costs employers roughly nine days
of salary per year for each untreated indi-
vidual, from direct costs alone. It appears
that it could be cost-effective for companies
to motivate employees to seek treatment at
an early stage.
lll
New OSA Diagnostic
Recording Device
from Philips
Philips has released Alice PDx Portable
Sleep System, a new portable home solution
for screening and diagnostic evaluation of
OSA. The data recorded by the device can be
sent to a clinician from a personal computer.
This new system is aimed at patients with
limited access to lab facilities.
lll
A Need for More Sleep
Technologists
Did you know that there are more than
40 million Americans suffering from sleep
disorders but only 3,000 registered sleep
technologists in the US.
lll
Keep a YawnLog
Track your sleep and share it with everyone
on Twitter. With the YawnLog you can accu-
rately document the hours of your sleep and
track sleep patterns over a period of time.
You can label dreams with tags and visualize
your data in a number of ways.
 STATISTICS
SLEEP AND DREAMS
US SLEEP
AIDS MARKET
The sleep market in the United States was
worth around US$23.7 million in 2007;
compared to 2000 this is a growth of 77%.
For 2012, a further growth of 36% has been
forecasted so the total of the market would
then sum up to US$ 32.3 billion.
Six groups of products comprise this
market and over time their participation
in the total sales has changed considerably.
Mattresses were responsible for almost 70%
in 2000, but until 2012 a decrease to 53%
of the market revenue is predicted, while
the yearly sales augment from US$9.2 bil-
lion in 2009 to US$17.2 billion in 2012.
This drive in sales is due to costumer pref-
erence to buy more expensive products. In
2003, 44.3% of all mattresses were priced
below US$500, whereas in 2007, 46.9% of
the mattresses sold cost between US$1,000
and 1,500. The participation of mattresses
in the price categories US$1,500-2,000 and
2,000 augmented as well, and in 2007 only
26.7% of all mattresses sold were priced
below US$500.
The next important product is sleep
laboratories and annexed services with
revenues of US$2.2 billion in 2000 and
a predicted growth of almost 160% to
US$5.8 billion until 2012. An important
factor for this development was the deci-
sion of the Center for Medicare Services
in March 2008 to reimburse devices that
can be applied at home, thus increasing
the demand by people with little access
496  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
to, or inconvenience using, regular sleep
laboratories.
Considering that over 70 million US citi-
zens are said to suffer from sleep disorders,
the market for sleep medication seems very
calm. The average age of the eleven most
prescribed drugs is 29.2 years and 75% of
these drugs have been on the market for
more than twenty years. When the patent
for the only blockbuster sleep medication,
Ambien by Sanofi-Aventis, expired in 2007,
the earning in this sector fell from US$3.3
billion in 2006 to US$2.0 billion in 2008.
However, with several products in the
pharmaceutical pipeline, recuperation to
US$3.7 billion in 2012 is expected. Among
the new developments is Almorexant, which
will be distributed by GlaxoSmithKline and
Actelion. Representing a new approach in
treatment, this drug is being observed with
curiosity. Except for melatonin based prod-
ucts, like Rozerem by Takeda, traditional
sleep medications are GABAergic drugs
which enhance the activity of the inhibi-
tory neurotransmitter GABA. Among the
side effects of these drugs are hangover-like
sensations on the day following the intake,
and little to no recollection of actions, such
as eating, walking or driving. They also bear
a dangerous addiction potential. The FDA
issued a safety warning for the entire class
of sleep GABA agonists in 2007. Almorexant
pursues a different approach by temporar-
ily reducing the level of the excitatory neu-
 The US sleep market 2007 (in million US$)

others: 0,1
pillows: 0,9
CPAP* sleep apnea devices: 2

sleep medication: 2,7

sleep labs: 4,2

ropeptide hormone orexin, which promotes

wakefulness. Instead of inducing sedation
to the brain as the GABAergic drugs do,
Almorexant would lower wakefulness
and therefore represents a lower level of
intervention. mattresses: 13,7
The products that most increased sales
in the considered period of time are CPAP
devices for sleep apnea. Until 2012, a
growth of 650% from US$600,000 in 2000 The US sleep market 2000-2012 (in million US$)
to US$4.1 billion is predicted. By then, the
participation of CPAP devices in the sleep
35000
market will have grown from 4% to 12.7%.
Currently, medication to treat obstructive
30000
sleep apnea is under development, for
example by the UK-based pharma company
25000
BTG, whose product combines two widely
used serotonin active drugs. These medica-
20000
tions, originally developed for the treatment
of depression, have two effects that are posi-
15000
tive for obstructive sleep apnea treatment:
they increase the respiration in the upper
airways and decrease REM sleep. Observers 10000
of this new development are skeptic since
it represents a high level of intervention 5000
in comparison to the external sleep apnea
devices. 0
Pillows maintain a stable participation 2000 2001 2002 2003 2004 2005 2006 2007 2008 F 2012 F
of around 4% of the market; in 2007, US
citizens spent US$900 million. Other retail others pillows CPAP* sleep apnea devices
devices and services include aromatherapy, sleep medication sleep labs mattresses
music and other innovations, and represent
less than 1% of the market. Source: Marketdata Enterprises, Inc. http://tiny.cc/nMzvE
By Julia Alexander * CPAP: continuous positive airway pressure

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  497

 GLOBAL INDUSTRY
SLEEP AND DREAMS
Silencer Products
International
Sleep apnea and snoring
treatment
www.the-silencer.com
Surrey, BC, Canada
SleepTech Hypnion
Sleep diagnostics SCORE-2004™ - predictive
www.sleeptech.com sleep-wake bioassay system
Wayne, NJ, USA www.hypnion.com
Lexington, MA, USA
Neurogen Corporation
Sleep drug development
www.neurogen.com
Branford, CT, USA

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

498  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org

Covidien Proximagen Neuroscience Lundbeck Actelion Pharmaceuticals
Respiratory care products, Sleep drug development Sleep drug development Sleep drug development
sleep therapy and diagnostics www.proximagen.com www.lundbeck.com www.actelion.com
www.covidien.com London, UK Copenhagen, Denmark Allschwil, Switzerland
Dublin, Ireland
BiancaMed
Overnight sleep monitoring
www.biancamed.com
Dublin, Ireland

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

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  499

Supplement to the research section
AROUSAL THRESHOLD
IN OBSTRUCTIVE
SLEEP APNEA:
SLEEP APNEA, RISKS
AND PREVENTION
By Atul Malhotra and Shilpa Rahangdale
Obstructive sleep apnea (OSA) is a common
disease with major neurocognitive and car-
diovascular sequelae. OSA affects roughly
5% of the population and is characterized
by repetitive pharyngeal collapse during
sleep. Despite OSA’s high prevalence and
well recognized consequences, treatment
of OSA remains unacceptable due to poor
adherence to and variable efficacy of exist-
ing therapies, leading to interest in underly-
ing mechanisms to identify new therapeutic
targets.
The prevailing theories regarding OSA
mechanisms involve interplay between
pharyngeal anatomical compromise and
protective reflex driven activity in the pha-
ryngeal dilator muscles, the best studied
of which is the genioglossus (the major
protruder of the tongue). With the onset
of sleep, however, these protective reflexes
are lost, leading to a fall in genioglossal
activity, and pharyngeal collapse in those
anatomically predisposed. Thus, the regu-
lation of these muscles is critical in OSA
pathogenesis.
500  |  December 2009  |  Volume 3  |  Issue 3 www.frontiersin.org
Recent evidence has demonstrated that
even patients with severe OSA have some
periods of breathing stability (Younes et
al., 2007a). Emerging data suggest that
high levels of genioglossal activity are nec-
essary and sufficient to stabilize breathing
(Jordan et al., 2009). Thus, upper airway
muscles can preserve pharyngeal patency
when adequately recruited, if respiratory
Atul Malhotra, M.D., is Medical Director of the
Sleep Disorders Research Program at Brigham
and Women’s Hospital and is an Associate
Professor at Harvard Medical School. He has
authored almost 100 original manuscripts in the
area of obstructive sleep apnea pathogenesis.
amalhotra1@partners.org
Shilpa Rahangdale, M.D., is a Pulmonary and
Critical Care and Sleep Medicine specialist at
Brigham and Women’s Hospital and an Instruc-
tor in Medicine at Harvard Medical School. Her
primary research focus is related to mecha-
nisms underlying the cardiovascular complica-
tions of sleep apnea.
srahangdale@partners.org
 Sleep
Low arousal
threshold
fragmentation,
UA opening

 
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.

stimuli are of sufficient magnitude and hypoxemia/hypercapnia occur prior to References

for an adequate duration. Both nega-
tive intrapharygneal pressure and CO2
activate the genioglossus during wake-
fulness, but less so during sleep, unless
the two stimuli are given in combination
(Stanchina et al., 2002). Of note, accumu-
lation of respiratory stimuli (elevation of
CO2 and effort-induced negative airway
pressure) does not occur abruptly. As a
result, sleep must be sustained for some
time for adequate muscle recruitment.
Therefore, a low arousal threshold can
be deleterious if arousal prevents accu-
mulation of respiratory stimuli. Thus, if
an individual wakes up prematurely fol-
lowing pharyngeal collapse, there may be
insufficient stimulus to recruit the pha-
ryngeal muscles and restore airway pat-
ency (Figure 1). The result of insufficient
dilator muscle activation would be repeti-
tive awakening, fragmented sleep, and
ongoing respiratory events. On the other
hand, an excessively high arousal thresh-
old in OSA may be deleterious if profound
arousal, yielding end organ damage.
OSA patients with a low arousal
threshold who wake up too early during
respiratory events lose the opportunity
to recover airway patency by means of
brainstem respiratory reflexes without
cortical EEG activation. Thus, strategies
to manipulate the EEG arousal threshold
to respiratory stimuli could potentially
improve the quality of EEG-defined
sleep, improve cognitive function, and
reduce cardiovascular risk (Younes et
al., 2007b). Therefore, agents that raise
arousal threshold (e.g., non-myorelaxant
hypnotics such as trazodone) are likely
to benefit some unselected OSA patients
although they could theoretically worsen
outcome in others (who already have
high arousal thresholds and may expe-
rience prolonged apneas) (Heinzer et
al., 2008). We would encourage further
research into a therapeutic role of cer-
tain hypnotics in carefully selected OSA
patients.
Heinzer, R. C., White, D. P., Jordan, A. S., Lo,
Y.-L., Dover, L., Stevenson, K. and Malhotra,
A. (2008). Trazodone increases arousal threshold
in obstructive sleep apnoea. Eur. Respir. J. 31,
1308-1312.
Jordan, A. S., White, D. P., Lo, Y.-L., Wellman,
A., Eckert, D. J., Yim-Yeh, S., Eikermann, M.,
Smith, S. A., Stevenson, K. E., and Malhotra,
A. (2009). Airway dilator muscle activity and lung
volume during stable breathing in obstructive
sleep apnea. Sleep 32, 361-368.
Stanchina, M. L., Malhotra, A., Fogel, R. B.,
Ayas, N., Edwards, J. K., Schory, K., and
White, D. P. (2002). Genioglossus muscle
responsiveness to chemical and mechanical
stimuli during non-rapid eye movement sleep. Am.
J. Respir. Crit. Care Med. 165, 945-949.
Younes, M., Ostrowski, M., Atkar, R.,
Laprairie, J., Siemens, A., and Hanly, P.
(2007a). Mechanisms of breathing instability in
patients with obstructive sleep apnea. J. Appl.
Physiol. 103, 1929-1941.
Younes, M., Park, E., and Horner, R. L. (2007b).
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478-488.

Frontiers in Neuroscience December 2009  |  Volume 3  |  Issue 3  |  501