Peigneux Urbain Schmitz 2012 SleepandtheBrain

Sleep and the Brain – page 1/1
SLEEP AND THE BRAIN
Philippe PEIGNEUX 1,2,*and Charline URBAIN 1,*, Remy SCHMITZ1
1
Neuropsychology and Functional Neuroimaging Research Unit, Université Libre de
Bruxelles, Brussels, Belgium.
2
Cyclotron Research Centre, University of Liège, Liège, Belgium.
*
These authors share equal first authorship. To whom correspondence should be addressed.
Mailing address:
Neuropsychology and Functional Neuroimaging Research Unit [UR2NF]
Faculty of Psychological and Educational Sciences,
Université Libre de Bruxelles (ULB)
Campus du Solbosch, CP191
Avenue F.D. Roosevelt 50
B-1050 Bruxelles
BELGIUM
Web: http://dev.ulb.ac.be/ur2nf
Email: [email protected] or [email protected]

ABSTRACT
The phenomenological experience of sleep as a cessation of waking activity is misleading.
Indeed, it suggests that sleep constitutes, like a switch, a simple mechanism by which are shut
off all neurophysiological processes associated with an active and costly wake state of
vigilance. In this chapter, we present a summary description of sleep and its defining features,
viewed from behavioural, neurobiological, neurophysiological and functional
neuroanatomical perspectives. Given the universality of sleep and/or sleep-like phenomena
across animal species, we review also the phylogenesis of sleep. As the reader will realize, the
simplistic view that sleep is a mere state of inactivity must be replaced by the conception of a
complex, multidimensional and active state of the brain.
Keywords: NREM, REM, SWS, USWS, Neurobiology, Neurophysiology, Functional
Neuroanatomy, Phylogenesis, EEG, PET, fMRI, MEG
Acknowledgments: CU is supported by a grant from the Fondation Vigneron; RS is
supported by the Fonds National de la Recherche Scientifique (FNRS); Belgium.

At the behavioural level, sleep presents a number of definite features that humans share with
most animal species (Borbely, Hayaishi, Sejnowski, & Altman, 2000). It is a state of physical
quiescence, mostly characterized by no or minimal movements, closure of the eyes and a
stereotypic body posture (e.g. in man, lying down or curling; in bats, hanging upside down).
As compared to quiet wakefulness, there is also reduced responsiveness to external
stimulation during sleep. Additionally, rapid reversibility between states (e.g. the fact that the
sleeper will wake up if the stimulation is reasonably distinctive and/or the need for sleep is
exhausted) distinguishes sleep from other specific states of altered vigilance like coma, brain
death, hypothermia or hibernation.
However, behavioural observations alone are usually not sufficient to ensure that the
individual under scrutiny is genuinely sleeping, rather than being in a relaxed state of
wakefulness or in an intermediate state of drowsiness. Furthermore, mere observation cannot
capture the dramatic changes in cerebral activity from wakefulness to sleep, nor the fact that
sleep is composed of two distinct physiological stages: Non-Rapid Eye Movement (NREM)
and Paradoxical or Rapid Eye Movement (REM) sleep. In humans, NREM sleep is further
subdivided into 3 stages according to sleep depth (Silber et al., 2007), from the intermediate
stage 1 (drowsiness and sleep onset) to light stage 2 sleep then the deepest stage 3 sleep
(previously subdivided into NREM sleep stages 3 and 4; see below), also known as Slow
Wave Sleep (SWS). Under normal nocturnal conditions, NREM always precedes REM sleep
within an ultradian cycle lasting on average 90 minutes and repeating itself (Figure 1), with
the consequence that the sleeper may complete up to five cycles in a typical night (Dement,
1978).
--- INSERT FIGURE 1 HERE ---

Additionally, sleep is a regulated phenomenon, whose timing and duration are contingent
upon two main processes: homeostatic and circadian (Borbely, 1982; Daan, Beersma, &
Borbely, 1984; see Figure 2). During the course of a normal day-night cycle, the pressure for
sleep continuously accumulates with time spent awake, then dissipates during the night of
sleep. Extending the waking period above normal levels (e.g. in a sleep deprivation protocol)
results in a sleep debt with a rebound on the subsequent night where both duration and
intensity are increased, demonstrating the homeostatic regulation of sleep. This gradual
change in sleep pressure is counterbalanced by the circadian process, e.g. a nearly 24-hr
endogenous oscillatory variation in alertness and sleep propensity. The circadian signal for
sleep/alertness is high/low in the early hours and low/high in the evening, with the
consequence that homeostatic and circadian processes work in opposition during the day but
in synchrony during the night to ideally ensure consolidated periods of wakefulness and sleep.
The interaction between these two processes also exerts an influence on variations in
cognitive performance throughout the day, especially in the attentional domain (Schmidt,
Collette, Cajochen, & Peigneux, 2007; Schmidt et al., 2009). Due to the close relationship
between Slow Wave Activity (SWA) in SWS and sleep pressure dissipation (e.g. the
homeostatic process) along the night of sleep, the first half of the night is particularly rich in
slow wave activity (about 80% of time) whereas in each subsequent cycle, the length of REM
periods increases while the length of deep SWS is decreasing (Figure 1), the amount of stage
2 sleep remaining fairly constant.
--- INSERT INFORMATION BOX 1 (Polysomnographic Techniques) ABOUT HERE ---
It is Hans Berger who performed in 1929 the first recording of the electrical activity of the
brain, that he named electroencephalography (EEG). He described different oscillation

patterns in the EEG, the best known being the Berger’s wave or alpha (8-12 Hz) occipital
rhythm, observable during quiet wakefulness but suppressed by the opening of the eyes. He
also showed first that the frequency of EEG oscillations is slowing down with sleep, followed
by Loomis (1937) who divided sleep into five levels (A to E) representing the spectrum of
waking to NREM sleep stages 1-4. REM sleep was only later on discovered as a distinct stage
of sleep, with low-voltage rapid oscillations in brain activity, muscular atonia and rapid ocular
movements (Aserinsky & Kleitman, 1953; Dement & Kleitman, 1957). These findings and
the availability of electrophysiological and physiological techniques (see Information Box 1)
eventually led to the first consensus on how human sleep should be recorded and scored: the
“Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of
Human Subjects” published by Rechtschaffen and Kales (1968). Nowadays, sleep research
has evolved from a fascinating field of human physiology towards a dedicated scientific
discipline and a recognized medical speciality, with accredited clinical units for patients
suffering from a wide spectrum of sleep disorders. Although the classification and
codification of sleep patterns still remains performed more than 40 years later upon visual and
computer-based inspection of 30-second polysomnographic epochs of
electroencephalographic (EEG), electrooculographic (EOG) and electromyographic (EMG)
signals, technological advances have allowed the development of novel methods for the
analysis of sleep (e.g. spectral analysis thought to better reflect specific discharge patterns
observed at the cellular level in NREM sleep stages; Corsi-Cabrera, Guevara, Del Rio-
Portilla, Arce, & Villanueva-Hernandez, 2000; Corsi-Cabrera, Munoz-Torres, Del Rio-
Portilla, & Guevara, 2005). Notwithstanding, limitations of the Rechtschaffen and Kales’s
classification system have been thoroughly discussed (e.g. see Himanen & Hasan, 2000),
leading to revised international consensus guidelines implemented in the “New Sleep Scoring
Manual” (Iber, Ancoli-Israel, Chesson, & Quan, 2007), which we will use below to delineate
the different stages of sleep and wakefulness (see also Summary Table 1 at the end of this
section). One salient modification amongst others in the “New Sleep Scoring Manual” is the
coalescence of NREM sleep stages 3 and 4 from Rechtschaffen and Kales (1968) into a
single, unified NREM sleep stage 3. This change is actually fitting with an established clinical
and research practice where stages 3 and 4 are commonly considered together in the analyses
and interpretations.
Wakefulness
Wakefulness can be defined as a state of full consciousness, allowing interaction with the
environment. In humans the waking EEG is mostly characterized by a so-called
desynchronized pattern of neuronal firing, reflected in the EEG by rapid, high frequency
waves in the beta (β) range (14–40 Hz) with low amplitude (10 to 30 µV) and high muscular
tonus at the EMG. When subjects are awake in a quiet relaxed state or resting, especially with
eyes closed, EEG recorded from the posterior part of the brain (mostly at occipital locations)
displays patterns of alpha (α) or Berger waves of lower frequency (8–12 Hz) and increased
amplitude (20 to 40 µV; Figure 3), reflecting the increased synchrony of underlying neural
activity in non-stimulated brain regions (Borbely et al., 2000).
NREM sleep
NREM sleep stages are characterized in humans by regular respiration, decreased in muscular
tonus and gradual slowing down of the EEG frequency patterns with increasing amplitude
(Figure 3), from stages N1 to N2 or light sleep then N3 or deep slow wave sleep (SWS),
reflecting the progressive synchronisation of activity within and between neuronal
populations. Spectral analyses additionally reveal a background pattern of slow wave activity
(SWA) below 1 Hz (Achermann & Borbely, 1997), not visually apparent in the EEG
recording but having important physiological implications (Steriade, Contreras, Curro Dossi,
& Nunez, 1993). Superimposed on slow rhythmic activities are transient events, mainly K
complexes and sleep spindles in N2 whose recurrence (every 3-10 seconds) is regulated by
the underlying SWA. (Steriade & Amzica, 1998)
NREM sleep stage N1 and sleep onset
NREM sleep stage N1 is a drowsiness transition period between wakefulness and sleep. Stage
N1 is characterized by the occurrence of theta (θ) waves in the EEG, slower in frequency (4-8
Hz) and greater in amplitude (50 to 100 µV) than alpha (α) waves, a decrease in muscular
activity and slow eye movements. A valid electrophysiological marker of sleep onset is the
attenuation of the alpha rhythm, which signs the transition from relaxed wakefulness to stage
N1. It is therefore important to record EEG at occipital derivations where the alpha rhythm is
prominent to accurately determine sleep onset (Silber et al., 2007). At the behavioural level,
subjects start failing to respond at the presentation of auditory tones, although awakening
thresholds remain low, to the point that subjects awoken during this stage may often report
not having been asleep at all.
NREM sleep Stage N2
During stage N2, also known as light NREM sleep, eye movements cease, heart rate slows
down and body temperature decreases, preparing the body to enter in deep sleep. Background
EEG oscillations decrease below 5 Hz in the delta (δ) range (1-4 Hz). Superimposed on slow
oscillations are periodical, transient EEG events named sleep spindles and K complexes
(figure 3). Spindles are short-lasting (0.5-3 sec), waxing and waning oscillations in the sigma
(σ) range (11-16 Hz), whose maximal amplitude is mostly found over central regions
(Borbely et al., 2000; De Gennaro, Ferrara, & Bertini, 2000; McCormick, Nielsen, Nicolas,
Ptito, & Montplaisir, 1997). Behavioural, electrophysiological (De Gennaro and Ferrara,
2003) and neuroimaging (Schabus et al., 2007) data further suggest a functional
differentiation and distinct neuroanatomical bases for slow (11-13 Hz) and fast (13-15 Hz)
spindles. The K complexes are graphoelements characterized by a negative sharp wave of
high amplitude immediately followed by a positive component standing out from the
background EEG, with a total duration at least equal to 0.5 second. Because of their
morphology and duration, K complexes are sufficiently distinctive and no amplitude criterion
is needed (Borbely et al., 2000). K complexes are optimally recorded at frontal electrodes
(e.g. F4 or Fz). Stage N2 should be persistently scored in the absence of K complexes or
spindles until a transition to stage N3 or REM sleep, or the occurrence of a major body
movement followed by slow eye movements or an arousal.
NREM sleep Stage N3 or SWS
N3 is the deepest stage of NREM sleep, also called “Slow Wave Sleep” (SWS), which can be
scored when slower waves in the 0.5-2 Hz frequency range represent at least 20% of the 30-
second EEG epoch. Because the cut-off was previously set at 4 Hz for the superior limit of
slow waves, which may raise confusions with delta activity, revised guidelines strongly
discourage the use of the term “delta waves” (e.g. in the 1-4 Hz range) to mention SWS
(Silber et al., 2007). Usually, slow waves are maximally expressed at frontal sites (Happe et
al., 2002), as well as K complexes. N3 being the deepest stage of sleep, arousal thresholds are
very high, with a longer period of sleep inertia after awakening and possible post-awakening
confusion or disorientation (also known as “sleep drunkenness”).
REM sleep
Contrary to NREM stages, REM sleep is characterized by the presence of desynchronized,
rapid low-amplitude EEG activity visually close to that recorded during wakefulness, hence
its other name of “paradoxical” sleep (Jouvet, Michel, & Courjon, 1959). Five main features
determine REM sleep: low amplitude-mixed frequency (15-30Hz, <50 µV) EEG background,
rapid eye movements, muscular atonia and breath/cardiovascular irregularity. Rapid eye
movements (REMs) are conjugate, irregular and sharply peaked eye movements with an
initial deflection usually lasting less than 500 milliseconds. Presence of saw tooth waves or
transient muscle activity (phasic twitches) is strongly supportive evidence, especially when
one or more of the basic features are equivocal. During the first REM period of the night, one
may observe interspersed K complexes or sleep spindles but in the presence of unequivocal
REMs, theses epochs should be scored as REM sleep until there is a transition to stage W, N2
or N3, manifestations of arousal or major body movements followed by slow eye movements.
--- INSERT SUMMARY TABLE 1 HERE ---
THE PHYLOGENESIS OF SLEEP
Alternation between activity and sleep-like resting states has been found across all studied
animal species up to now, although physiological and neurophysiological characteristics may
largely differ. The universality of sleep-like resting states suggests an important functionality
(or most probably a series of important functionalities) that has/have built up with evolution,
hence the paramount importance to explore the phylogenesis of sleep. Furthermore, even
though sleep appears to be an universal phenomenon, studies conducted in insects,
amphibians, reptiles, avians, mammals, etc, suggest that the differentiation between NREM
and REM sleep states, typical of mammalians and birds, is not present -- or at least cannot be
convincingly disclosed -- in all branches of the evolutionary tree, raising supplementary
questions about the complementary role of our two main states of sleep in evolution. Even if a
logical scheme has not yet been clearly disclosed and adaptations have occurred in some
species, studying sleep in the animal kingdom should eventually allow us to understand the
phylogenetic characteristics of sleep and target its essential components.
As a word of caution, a main caveat when comparing species is that similar levels of
investigations are not always available. On the one hand, sophisticated intra-cerebral
recordings obtained in cats and rodents are only available in exceptional circumstances in
humans (e.g. during pre-surgical recordings) due to their invasive character. On the other
hand, polysomnographic recordings (EEG, EMG, and EOG) in animals have usually to be
carried in laboratory settings, hence preventing their observation in the natural environment,
potentially biasing the results. Although modern telemetric recording techniques make it now
possible to equip the animal of a signal wireless transmitter, allowing recording in more
natural settings, these are not yet generalized and well adapted to all species. Therefore, many
species have been mostly studied at the behavioural level, which limits the scope of possible
comparisons.
Sleep or “close to sleep” states in insects
Insects have a daily rhythm of rest and activity. It is not merely due to the influence of the
dark-light cycle since it continues being observed even when time synchronizers (also named
“zeitgebers”) are removed from the environment. Evidence of a close-to-sleep state in insects
has long been mostly behavioural. For instance, it has been found that the scorpion adopts a
specific position where the body and the head rest flat on the ground, whereas in the bee the
antennae are folded up against the head (Tobler & Neuner-Jehle, 1992). Still, because mere
observation cannot easily delineate boundaries between sleep and quiet wakefulness in
insects, presence of a sleep-analogue condition has been further corroborated using the
homeostatic sleep pressure criteria. In the fruit fly (Drosophila melanogaster), the most
studied kind given its relative simplicity, a homeostatically regulated sleep state has been
observed, that in many respects is similar to sleep in mammals (Hendricks et al., 2000; Huber
et al., 2004; Shaw, Cirelli, Greenspan, & Tononi, 2000). Indeed, insects exhibit an increase in
the duration of the resting state when prior wakefulness is artificially maintained above usual
duration levels of activity, e.g. by moving the insect’s container or introducing a congener in
its environment (Bell-Pedersen et al., 2005; Huber et al., 2004). Furthermore, genetic
mutations affect sleep in Drosophila; conversely, sleep affects gene expression (Cirelli &
Bushey, 2008). Notwithstanding, although changes in brain electrical activity (Nitz, van
Swinderen, Tononi, & Greenspan, 2002) and changes in synaptic markers (Gilestro, Tononi,
& Cirelli, 2009) are reliably correlated with activity state, sleep in invertebrates seems to lack
the large-scale, slow, synchronous neuronal activity similar to that occurring during
mammalian and avian SWS (Cirelli & Bushey, 2008; Hendricks & Sehgal, 2004; van
Swinderen & Andretic, 2003).
Activity/inactivity states in vertebrates without thermal regulation
Fish
Although several studies have reported behavioural sleep in Fishes (specific resting posture,
periods of reduced activity …), only few studies have investigated EEG (for a review see
Hartse, 1994). In tench (Tinca Tinca), simultaneous recording was made of the electric
activity of the brain, muscles and gills activity, respiratory and heartbeat rates, and reactivity
to sensorial stimulations. There was no clear difference between the rapid, low voltage
electrical brain activity during the activity (night) as compared to the rest (day), nor was it
possible to evidence periods of eye movements correlated with vegetative variations
(Peyrethon & Dusan-Peyrethon, 1967; Zhdanova, 2006 for similar results in the zebra fish).
At variance in the catfish (Ictalurus nebulosus), the transition from activity to rest was
characterized by an increase in low frequency activity and spikes (Karmanova, 1978).
Additionally, there is no indication that a periodic state similar to paradoxical sleep exists in
fishes, besides evidence for a global sleep-like state. Also, it remains a matter of debate
whether unihemispherical sleep (see below) exists in constantly swimming fishes, doubts
being raised in part by the absence of unilateral eye closure (Kavanau, 1998).
Amphibians
Available data on sleep in Amphibians are scarce (for a review see Hartse, 1994). Some
species maintain constant vigilance levels during behavioural rest (e.g. the bull-frog), whereas
reactivity to sensorial stimulations decreases in others, e.g. the tree-dwelling frog. Similarly,
EEG changes correlated with behavioural sleep have been observed in some species, but not
in others. Also, there is no evidence for periods of ocular movements during the quiescent
stage in Amphibians. Unilateral eye closure has only been reported in the bull frog (Rana
catesbiana) (Hobson, 1967), however only occurring briefly during respiratory acts and
apparently unrelated with behavioural sleep.
Reptiles
Mammals and reptiles are neighbours in evolution, having led many researchers to investigate
vigilance states in reptiles. Sleep has been studied using continuous polysomnographic
recordings (EEG, EMG, EOG, ECG, respiration) in chelonians (tortoises), crocodilians
(alligators and caimans) and saurians (lizards and snakes). Unequivocal signs of sleep are
present in reptiles at the behavioural level, associated in most studies with intermittent high-
amplitude, spikes and sharp waves in the EEG. At variance, few other studies have reported
an association with high-amplitude, low-frequency activity (Warner, Huggins, 1978) or failed
to detect any sleep-related changes in the EEG (Walker & Berger, 1973).
Although still controversial, there are convincing arguments to support the hypothesis
that high-amplitude, spikes and sharp waves define a reptilian sleep state functionally
homologous to the mammalian and avian SWS (Hartse, 1994). Indeed, EEG spikes are
associated with the presence of a behavioural sleep state in reptilians, and their density
increases after sleep deprivation in chelonian (Flanigan, 1974), iguanid (Flanigan, 1973) and
crocodilian reptiles (Flanigan, Wilcox, & Rechtschaffen, 1973), suggesting homeostatic
regulation. In vitro (Lorenzo, Macadar, & Velluti, 1999; Lorenzo, Velluti, 2004) and in vivo
(Gaztelu, Garcı´a-Austt & Bullock, 1991; Lorenzo et al., 1999) studies in turtles further
suggest that sleep-related spikes in reptilians originate in the medial cortex (the anatomical
and functional homologous of the mammalian hippocampus; Lopez, Vargas, Gomez, & Salas,
2003), then propagate in the adjacent dorsal cortex.
The lack of high amplitude, slow waves in reptiles has long been attributed to the
absence in these species of the thick six-layered neocortex responsible for generating EEG
slow waves in mammals (Hartse, 1994). Alternate hypotheses propose nowadays (a) that the
reptilian dorsal cortex lacks the interconnectivity necessary to generate sleep-related slow
waves in the electroencephalogram (Rattenborg, 2006; 2007), (b) that the
thalamocorticothalamic circuitry is less elaborate in reptiles despite similarities across
mammals, birds and reptiles in the basic neurochemistry, neuroanatomy and neurophysiology
of the thalamic reticular nucleus (Kenigfest et al., 2005; Llinas & Steriade, 2006), involved in
the genesis of sleep-related neuronal oscillations in mammals (Steriade, 2006), and/or (c) that
differences in the type and/or density of glia (Ari & Kalman, 2008) may explain why reptiles
lack SWS (Rattenborg, Martinez-Gonzalez, & Lesku, 2009), given that glia may amplify the
effect of corticocortical connectivity on neuronal synchrony during sleep (Amzica & Steriade,
2000).
Regarding to REM sleep analogues in reptiles, recorded sleep episodes associated with
rapid eye movements and heartbeat variations are very brief (a few seconds) and extremely
rare (a few minutes in several weeks of recording ) in crocodilians and lizards. The analogy of
these episodes with paradoxical sleep is still discussed. Also, the prevalence of unilateral eye
closure during behavioural sleep suggests that reptilian sleep may occur unihemispherical
(Flanigan et al., 1973; Tauber, Roffwarg, & Weitzman, 1966).
REM and NREM sleep in birds and mammals
Since the discovery of REM sleep as a distinct phase in mammalian sleep, researchers have
searched for the origin and causes of the duality between REM and NREM sleep. Because
birds and mammals have evolved independently without common reptilian ancestors, the
presence of REM sleep in both suggests that this state has appeared independently in the two
phylogenetic branches to fulfil a function essential to more complex brains (Jouvet, 1994),
leaving unsolved for now the question of its origins.
Sleep in birds
Like mammals, birds have NREM-REM sleep cycles (Campbell & Tobler, 1984; Lesku,
Roth, Rattenborg, Amlaner, & Lima, 2009; Rattenborg, Amlaner, 2002). They are also the
only other taxonomic group than mammals exhibiting high-amplitude slow waves in the EEG
during NREM sleep (Rattenborg et al., 2009), departing from the high-amplitude spikes and
sharp waves of reptilian sleep. Although some controversies persist, slow wave activity
during SWS appears to be homeostatically regulated in birds. For instance, SWA increases in
pigeons following short-term sleep deprivation (Martinez-Gonzalez, Lesku, & Rattenborg,
2008). It is hypothesised that the confluent evolution of homeostatically regulated SWS in
birds and mammals is directly linked to their common evolution towards large, heavily
interconnected brains capable of performing complex cognitive processes (Rattenborg et al.,
2009).
Adaptative sleep in birds
Like most mammals, birds exhibit bihemispheric NREM and REM sleep in many conditions.
However, they have also developed the ability to sleep with one eye open, the contralateral
hemisphere being awake to overcome the problem of sleeping in specific situations. Spooner
(1964) was first to observe an association between unilateral eye closure and
unihemispherical slow wave sleep (USWS) in young chickens (Gallus gallus domesticus). In
those, the hemisphere contralateral to the open eye showed EEG activity typical of
wakefulness, whereas in the other hemisphere EEG activity was typical of SWS. The fact that
birds are able to control which hemisphere can sleep in response to changes in anticipated
risks suggests that USWS and unilateral eye closure serve a predator detection function.
Indeed, mallard ducks positioned at the edge of the group during rest (a position perceived by
the animals as dangerous; Bednekoff & Ritter, 1994; Elgar, 1989) exhibit a 150% increase in
USWS and a strong preference for directing the open eye toward the potential source of
danger (Rattenborg, Lima, & Amlaner, 1999), as compared to ducks safely sleeping in the
centre of the group, who display bihemispheric sleep. Thus, birds not only have the capacity
to control unihemispherical sleep, but also use this ability in a manner that reduces the
conflict between sleep need and predator detection. Although birds may also use USWS to
continuously monitor their environment for other purposes (e.g. food availability, weather
variations, etc.), predator detection is likely to be the most important given its surviving value.
Additional evidence suggests that some birds use unihemispherical sleep while migrating,
allowing sleep while engaged in long overseas travels.

Sleep in mammals
Even though mammals represent a small fraction of living species, they have been logically
the most thoroughly investigated, humans belonging to this class. Alternating patterns
between NREM and REM sleep were found in almost one hundred species studied using
polysomnographic recordings, suggesting the generality of NREM-REM sleep patterns in
mammalians, but few exceptions discussed later (Fuchs, Maury, Moore, & Bingman, 2009).
REM sleep in mammals
Following the discovery of rapid eye movements (REMs) during sleep by Aserinsky and
Kleitman in 1953, tentatively linked to dreaming activity, William Dement found in 1957 an
association between REMs and distinctive patterns of cortical EEG activity in the sleeping
cat, hence the name of REM sleep for this state. At the same time, the French neurobiologist
Michel Jouvet, who was investigating subcortical activities in sleeping cats, observed periods
of muscle atonia arousing simultaneously with high-voltage spiky waves in the EEG, similar
enough to the waking stage (Jouvet & Michel 1959). The finding was curious and certainly a
paradoxical phenomenon, because at that time fast cortical activity was still regarded as the
unmistakable electrophysiological sign of wakefulness and muscle atonia as an invariable sign
of sleep. This apparent discrepancy led Jouvet (1959) to name this strange state of wake-like
brain activity ‘‘paradoxical sleep’’. It was soon recognized that REM and Paradoxical sleep
were two names for the same phenomenon, which was further studied by Jouvet and others in
more than one hundred species of vertebrates. Their main conclusion was that this essential
phase of sleep exists only among warm-blooded animals.
Outstanding exceptions to standard NREM-REM sleep patterns are archaic
monotremes echidna and platypus who are primitive mammals that lay eggs, as birds or
reptiles do, and cetaceans (whales and dolphins).

Archaic sleep in monotremes
Most studies investigating mammalian sleep have been performed on eutherians or
marsupials, the two main subclasses of mammals. The third subclass is monotremes, found in
Australia and New Guinea, whose two only alive species are echidna and platypus. Fossil and
genetic evidence indicate that monotremes diverged from other mammalian lines about 150
million years ago, and that echidna and platypus are derived from a platypus-like ancestor
(Clemens, 1989; Flannery, 1989; Westerman, 1992). They have more genetic and
physiological similarities with reptiles and birds than other mammals, and are thought to
possess characteristics of the common mammalian ancestor (Grutzner et al., 2004), hence
there are considered “living fossil mammals” which may inform us about the evolution of
sleep.
Initial studies have suggested that echidna lacks REM sleep (Allison & Van Twyver,
1972), because no typical REM sleep low-voltage EEG pattern is observed at the cortical
level like in eutherian and marsupial mammals. However, further investigations have shown
that brainstem activity is different from that seen in other mammals during NREM sleep and
resemble that seen in REM sleep. Indeed, activity of brainstem neurons decreases like during
NREM sleep, but variability increases as during REM sleep (Siegel, Manger, Nienhuis,
Fahringer, & Pettigrew, 1996). Since it is known that brainstem neuronal activity generates
REM sleep, these results suggest that echidna has a REM sleep-like state, but not
accompanied by low-voltage cortical EEG like in other mammals. In the platypus who was
also thought devoid of REM sleep, behavioural observation and telemetric measures have
demonstrated atonia with rapid eye movements, twitching and the electrocardiogram pattern
of rapid eye movement, altogether with moderate of high voltage cortical EEG typical of
NREM sleep and REM-like brainstem neuronal activation during 6-8 hours a day, actually
proposing the platypus as a champion of REM sleep (Siegel et al., 1999). These results in
monotremes suggest that low-voltage electroencephalogram and cortical desynchronization
are more recently evolved features of mammalian REM sleep, which may have had its
precursor state in reptilian species (Siegel et al., 1999).
The evolving sleep of marine mammals
In his book "The Promise of Sleep", William C. Dement (1999) notices that the dolphin,
originally a land mammal that has returned to the sea, maintains a number of terrestrial traits
including bearing live offspring and, unlike fish, breathing air. At variance with terrestrial
mammals however, breathing is under voluntary control in cetaceans -- a process that should
preclude sleep. In order to solve what seems an impossible equation, cetaceans have therefore
opted for unihemispherical sleep (Figure 4), allowing one half of the brain to go to sleep while
the other half remains awake (Lyamin, Manger, Ridgway, Mukhametov, & Siegel, 2008;
Siegel, 2005). Thus, high-voltage slow waves almost never occur in both hemispheres at the
same time, with the eye contra-lateral to the hemisphere with slow waves being closed while
the other eye remains open (Lyamin, Mukhametov, & Siegel, 2004; Mukhametov, Lyamin,
Chetyrbok, Vassilyev, & Diaz, 1992; Mukhametov, Supin, & Polyakova, 1977).
Unihemispherical SWS (USWS) may also serve additional functions like efficient predator
monitoring in the environment and thermogenesis, which has been probably important in the
evolution of USWS in cetaceans but also for their apparent lack of REM sleep (Lyamin et al.,
2008). Indeed, no REM sleep episodes have been detected in any of the four species examined
by Mukhametov and colleagues (Lyamin et al., 2002; Mukhametov, 1984; Mukhametov &
1995; Mukhametov, Oleksenko, & Poliakova, 1988; Mukhametov et al., 1977), despite long
periods of electrophysiological recording, making cetaceans the only studied mammals in
which REM sleep seems to be totally inexistent, at least when accounting for the unusual
form of REM sleep in monotremes. Only one published study has reported EEG features of
REM sleep with marked loss of tonus of trunk muscle in a pilot whale, however for no more
than 6 minutes and one time only out of three non-consecutive nights (Shurley, Serafetinides,
Brooks, Elsner, & Kenney, 1969). USWS has only been observed in three aquatic orders (e.g.
Cetacea, Pinnipedia and Sirenia) among mammals. In cetaceans, virtually all of their sleep is
of USWS type, whereas eared seals and manatees may also display bihemispheric SWS
(BSWS) and REM sleep (Rattenborg, Amlaner, & Lima, 2000)
Unlike the terrestrial environment, there are few warm, safe places to sleep in the
ocean. This may explain why, contrary to all terrestrial mammals, killer whales (Orcinus
orca) and dolphins have minimal amounts of sleep behaviour (e.g., immobility or eye closure)
at birth, slowly increasing to adult levels over months. It may allow the neonate to
thermoregulate in cold ocean water and to be protected during development while swimming
with its mother. As the animal gains mass and blubber and approaches adult size, adult-like
sleep behaviour emerges, including periods of immobility. The mother also presents a near
absence of typical sleep behaviour during the postpartum period (Siegel, 2005), for periods
that greatly exceed those of sleep deprivation reported to kill rats (Rechtschaffen, 1998).
Interestingly, neither mother nor calf seem to exhibit a rebound in the amount of sleep
behaviour after this period, questioning the presence of homeostatic regulation in cetacean
sleep. Still, some evidence has been observed in one study for a rebound after experimental
deprivation of slow waves, but responses were highly variable among animals (Oleksenko,
Mukhametov, Polyakova, Supin, & Kovalzon, 1992). Besides differences in recording
methods, the peculiar properties of cetaceans’ sleep (e.g. USWS combined with lack of
typical motor and sensorial inactivity and apparent lack of homeostatic regulation) are
questioning the very nature of the essential constituents of sleep. Further investigations are
necessary to determine which, if any, neurochemical and neurophysiological aspects of sleep,

besides unilateral neocortical slow waves and eye closure, are preserved in cetaceans and
might constitute the core substance of sleep (Manger, Ridgway, & Siegel, 2003).
NEUROBIOLOGY OF SLEEP
Initiation and control of sleep-wake cycles, and alternation between sleep states are regulated
by activity in specific neuronal populations located in two broad regions, namely the basal
forebrain and hypothalamus. Before describing their mode of action, it is first necessary to
review the neurochemical systems that promote cerebral arousal and prevent the organism
falling asleep (Figure 5), allowing further understanding of the basic mechanisms of sleep
initiation and maintenance (Datta & Maclean, 2007). Over the past decades, a large set of
neurochemical-specific wake-promoting cells have been identified within the Ascending
Activating System (AAS) in the reticular formation, namely acetylcholine, histamine,
norepinephrine, serotonin, hypocretin/orexine, dopamine and glutamate. Dorsal projections
from these pontine and midbrain wake-promoting cells activate thalamocortical systems,
whereas ventral projections activate hypothalamo-cortical and baso-cortical systems (Garcia-
Rill, 2002)
Acetylcholine
(Ach)-synthesizing cholinergic cells are mostly located in the pedunculopontine tegmentum
(PPT) of the brainstem and in the anterior hypothalamus (AH) of the basal forebrain (BF).
Activity in these neuronal groups is high during wakefulness (maximally active in the basal
forebrain) and REM sleep, and strongly diminished during NREM sleep (minimally active for
PPT cholinergic cells). From a functional point of view, PPT and BF cholinergic cells are part
of the main arousal systems in the brainstem and forebrain, respectively. These neuronal
populations are causally involved in the generation of the desynchronized EEG pattern both in
wake and REM sleep stages (Datta & Maclean, 2007; Steriade, Pare, Datta, Oakson, & Curro
Dossi, 1990) by releasing acetylcholine in the diencephalon, hence blocking oscillatory
discharges of thalamic mechanisms responsible for EEG spindles and slow waves
(McCormick, 1989; Steriade, McCormick, & Sejnowski, 1993). Although sharing many
properties, these two clusters of cholinergic cells also present specific features:
a) Cholinergic cells in the pedunculopontine tegmentum
The pedunculopontine tegmentum (PPT) nucleus, being one of the major aggregations
of cholinergic neurons in the mammalian brainstem, promotes wakefulness by
activating thalamo-cortical, hypothalamo-cortical, baso-cortical, suprachiasmatic, and
amygdaloid wake-promoting systems of the forebrain (Datta, 1995; Datta & Siwek,
1997). Bursting discharges of a subgroup of these PPT neurons are also involved in
generation of ponto-geniculo-occipital waves (PGO; see below). Additionally, some
PPT neurons selectively active during REM sleep participate to the suppression of
muscle tone preventing motor activity during this stage of sleep (Datta & Maclean,
2007; Lyamin et al., 2008).
b) Cholinergic cells of the basal forebrain
Cholinergic cells in the basal forebrain (BF) play an important role in hippocampal
and neocortical activation (Detari, Juhasz, & Kukorelli, 1984; Detari & Vanderwolf,
1987; Nunez, 1996; Stewart, MacFabe, & Vanderwolf, 1984). They receive input from
other brainstem and hypothalamic wake-promoting systems and, in turn, have
widespread projections to the cerebral cortex (Detari & Vanderwolf, 1987; Fisher,
Buchwald, Hull, & Levine, 1988; Gritti, Mainville, Mancia, & Jones, 1997;
Zaborszky, Carlsen, Brashear, & Heimer, 1986a; Zaborszky, Cullinan, & Braun, 1991;
Zaborszky, Heimer, Eckenstein, & Leranth, 1986b). BF cholinergic cells are widely
involved in wake-promoting behaviours, including attention, sensory processing, and
learning (Datta & Maclean, 2007).
Histamine
(HA)-synthesizing histaminergic cells are located in the posterior hypothalamus (PH),
especially the tuberomammillary nuclei (TMN). PH-TMN neurons are involved in promoting
and maintaining wakefulness (John, Wu, Boehmer, & Siegel, 2004), sending projections
through wake-promoting structures in brainstem and forebrain (Brown, Stevens, & Haas,
2001; Hass & Panula, 2003; Huang et al., 2001; Inagaki et al., 1988; Lin, Luppi, Salvert,
Sakai, & Jouvet, 1986; Panula, Pirvola, Auvinen, & Airaksinen, 1989; K. Sakai, El-Mansari,
& Jouvet, 1990; Sherin, 1998). Single cell recordings in freely moving cats and rats show that
the majority of TMN histaminergic neurons are active during wakefulness and silent during
sleep (Ko, Estabrooke, McCarthy, & Scammell, 2003; Sakai, Yoshimoto et al., 1990;
Takahashi, 2006; Vanni-Mercier, 1984). Conversely, PH lesions produce a comatose-like
continuous sleepiness (Saper, Chou, & Scammell, 2001). Cessation of histaminergic activity
may be related to the loss of consciousness during sleep (John et al., 2004).
Norepinephrine
Most (NE)-synthesizing noradrenergic cells are located in the locus coeruleus (LC) of the
pons. They project directly to the cerebral cortex, hippocampus, amygdala and other
subcortical areas such as thalamus, hypothalamus and BF (Berridge & Waterhouse, 2003;
Dahlstrom, 1964; Datta & Maclean, 2007; Lewis, 1987). During wakefulness, noradrenergic
neurons have a regular and tonic firing, slowing down during the initial phase of SWS (Aston-
Jones, 1981b; Foote, 1983). Like histaminergic cells, they are inactive during REM sleep
(Datta & Maclean, 2007). Cessation of activity in noradrenergic cells during sleep seems to be
related to loss of muscle tone (John et al., 2004; Lai, 2001). Activation/inactivation of locus
coeruleus neurons results in an increase/decrease of wakefulness, respectively (Berridge &

Foote, 1991; Berridge, Page, Valentino, & Foote, 1993), suggesting that activation of
noradrenergic cells participates in the process of cortical activation and behavioural arousal.
Serotonin
Serotonergic (5-HT)-synthesizing cells are located in cluster nuclei, called raphe nuclei, in the
brainstem. The two main clusters are the rostral cluster (a midbrain/pontine group sending
projections to the telencephalic hemispheres) and the caudal cluster (a medullar group
sending projections to the spinal cord) (Lyamin et al., 2008). Serotonergic cells have a similar
discharge pattern (maximal firing during wakefulness, decreased firing during SWS, no firing
during REM sleep; (Lydic, 1983; McGinty, 1976) and almost project to the same brain
regions than noradrenergic cell projections (Morgane, 2005; Tork, 1990; Vertes, 1988).
Unlike noradrenergic cells however, their role in promoting sleep and/or wakefulness and/or
sleep remains unclear (Datta & Maclean, 2007). It has been proposed that serotonin may play
a role in maintaining arousal, and regulating muscle tone and some phasic events of REM
sleep (John et al., 2004; Wu, Gulyani, Yau, et al., 1999; Wu, John, Boehmer et al., 2004). On
the other hand, a lesion in the raphe nuclei increases wakefulness and suppresses SWS (Sakai
& Crochet, 2001), suggesting that serotoninergic neurons are involved in SWS promotion.
Pharmacological studies also suggest that serotonin may suppress activity of
hypothalamocortical and baso-cortical wake-promoting systems (Cape, 1998; Khateb, 1993).
Another, non exclusive functional hypothesis is that tonic activity of serotonin during waking
tend to suppress phasic events; and during REM sleep allows high voltage bursts of electrical
activity and the generation of the PGO (Siegel, 2000).
Hypocretine/orexine
Hypocretinergic or orexinergic neurons, recently causally linked to sleep, are located in the
lateral hypothalamus, between the sleep-activator neurons of the anterior hypothalamus
(GABAergic cells, see below) and the wake-activator histamine neurons of the posterior
hypothalamus (Gerashchenko, 2004). Hypocretinergic cells promote wakefulness by their
strong projections towards many primary wake-promoting neuronal systems of the brain
(Gerashchenko, 2004; Siegel, 2004). Loss of these hypocretine/orexine cells is linked to
human narcolepsy (Overeem, 2002; Thannickal, 2003).
Dopamine
At variance with other wake-promoting neurotransmitters described above, (DA)-synthesizing
dopaminergic cells located in the substantia nigra compacta (SNc) and the ventral tegmental
area (VTA) present a similar pattern of activation across sleep–wake states (Steinfels, 1983;
Trulson & Preussler, 1984; Trulson, Preussler, & Howell, 1981). Notwithstanding,
extracellular concentrations of dopamine are significantly increased during wakefulness
periods (Feenstra, 2000; Trulson, 1985).
Glutamatergic cells
Glutamatergic cells are located in the mesencephalic reticular formation (MRF). They send
strong projections to thalamic nuclei and the hypothalamus, thereby activating the thalamo-
cortical and hypothalamo-cortical networks, respectively (Datta & Maclean, 2007). Non-
invasive neuroimaging techniques in human subjects have shown that MRF activity is higher
during wakefulness than during SWS (Braun et al., 1997; Kajimura et al., 1999; Maquet et al.,
1990), in line with the proposal that glutamatergic neurons are involved in the maintenance of
behavioural states of wakefulness (Datta & Maclean, 2007). Likewise histaminergic neurons
of the posterior hypothalamus, electrolytic lesions in the mesencephalic reticular formation
region may cause a comatose-like continuous sleepiness (Saper et al., 2001).
Generation and maintenance of NREM sleep

For one part, sleep initiation results from the decreasing power of wake-promoting brain
neurons. NREM sleep generation and maintenance also depend on the implication of four
types of molecules: adenosine, prostaglandin, cytokine, and most importantly inhibitory
amino acid (GABA). Already in 1930, Von Economo demonstrated the existence of a sleep-
promoting area in the brain, by showing a correlation between severe insomnia and damage to
the anterior hypothalamus. A few decades later, GABAergic neurons (also named “NREM-on
cells”, see below) were identified in the ventrolateral preoptic (VLPO) area of the
hypothalamus. GABA cells are unique because, by contrast to most neurons, they are
maximally active during NREM sleep, less active during REM sleep and minimally active
during wakefulness (Siegel, 2004; Szymusiak, 1995; Szymusiak, Steininger, & McGinty,
2001). In this respect, GABAergic neurons may be viewed as the most potent sleep-promoting
component of the brain. Additionally, bursting activity of GABAergic cells in the VLPO
abolishes transmission of incoming signal to the cortex, by inhibiting serotoninergic and
noradrenergic activity of the brainstem, but also in histaminergic and cholinergic systems, two
major arousal systems in the brain. By this way, continuous GABA release suppresses activity
in wake-promoting areas and activates NREM sleep (Datta & Maclean, 2007; Nitz & Siegel,
1997a; Nitz & Siegel, 1997b; Siegel, 2005). Slow Wave Sleep (SWS), which characterizes
deep NREM sleep, emerges by the reduction of neuronal activity in wake-promoting brain
regions due to the activation of GABAergic cells in the preoptic area, which in turn induces
SWS. GABAergic inhibitory function is facilitated by increased synthesis of the growth
hormone-releasing hormone (GHRH), also involved in increasing the depth and duration of
SWS (Krueger, 2003; Obal, 2004).
Adenosine may play a role in the homeostatic regulation of sleep. Indeed, sleep
duration and depth are modulated by adenosine concentration in the basal forebrain
cholinergic region. Adenosine level progressively increases during extended waking periods
and slowly declines during recovery sleep. It is hypothesised that increased adenosine
concentration in the cholinergic basal forebrain would decrease EEG arousal, increase
drowsiness and promote EEG delta wave activity during subsequent NREM sleep (Porkka-
Heiskanen et al., 1997). Additionally, adenosine may play a role in inter-individual variability
in sleep structure, NREM sleep intensity and detrimental effects of sleep loss on
neurobehavioral performance in humans (Landolt, 2008). The exact biochemical mechanisms
underlying the effects of adenosine on NREM sleep homeostasis remain a hotly debated topic
(for further discussion, see Siegel, 2006).
Generation and maintenance of REM sleep
As compared to NREM sleep, mechanisms involved in REM sleep generation and
maintenance are much more complex. In their pioneering study, Jouvet and colleagues
(Jouvet, 1962; Jouvet & Michel 1959, 1960) showed periodic occurrence of REM sleep signs
(REMs, muscle atonia, etc …) in a pontine preparation (i.e. transection just above the
midbrain-pontine junction), demonstrating that REM sleep generation originates from the
brainstem. Further studies have tried to provide a more detailed picture of the REM sleep
controlling network. They have shown that REM signs are controlled by specific neurons,
called “effector neurons” and concentrated for the most part in the reticular formation (RF) of
the pons (McCarley, 2007; Steriade & McCarley, 2005). Generation and maintenance of REM
sleep involve a complex system of neuronal connections between effector neurons, a system
regulated by ratios of aminergic and cholinergic neurotransmitters.
In 1975, McCarley and Hobson published the reciprocal interaction model to explain
the mechanisms of REM sleep. They proposed that REM sleep generation and maintenance
depends on reciprocal interactions between so-called “REM-on” and “REM-off” groups of
cells (Figure 6) (McCarley & Hobson, 1975). REM-on neurons are reticular cholinergic cells
located in the pedunculopontine tegmentum (PPT) and lateral dorsal tegmentum (LDT) of the
brainstem. REM-off cells are monoaminergic (serotoninergic and noradrenergic) neurons
located in the locus coeruleus (LC) (El Mansari, 1989; Thakkar, 1998). During wakefulness
and NREM sleep, high levels of activity in REM-off aminergic neurons actively inhibit the
action of cholinergic REM-on neurons. Throughout NREM sleep however, activity in REM-
off aminergic cells gradually decreases, eventually releasing inhibition on REM-on cells,
whose increased activity will in turn induce REM sleep (Brown & McCarley, 2008)
Additional evidences suggest that REM-on cells have an excitatory effect on REM-off cells
during REM sleep, which will terminate the REM sleep phase when a sufficient level of
activity has been attained as to inhibit again activity in REM-on cells (McCarley & Hobson,
1975). Brainstem PPT/LDT cholinergic neurons are promoters of REM sleep by sending
excitatory cholinergic projections to the effector neurons. For instance, they cause loss of
muscle tone during REM sleep by triggering simultaneous inhibition of and withdrawal of
excitation to motoneurons. When these neurons are artificially activated (e.g. by
microinjection of acetylcholine agonists into specific regions of the pons), prolonged REM
sleep periods are elicited, further showing their crucial role in the regulation of REM sleep
itself (Coleman, 2004)
SLEEP NEUROPHYSIOLOGY
Three regions are know to play a main role in the generation and maintenance of sleep stages
and their distinguishing features (e.g. spindles or ponto-geniculo-occipital waves): (i) the
thalamus, including nuclei such as the thalamic reticular nucleus sending and receiving
projections to and from the cortex; (ii) the hypothalamus located behind the thalamus and (iii)
the reticular formation, located throughout the pons and mesencephalon, sending projections
to the neocortex through thalamic nuclei (Marieb, 1999).

Whereas neurobiological investigations have been mostly conducted at the cellular
level in animals, the neurophysiological study of sleep and the macroscopic delineation of
sleep-related cerebral structures have also been achieved in human using non invasive
neuroimaging and electrophysiological approaches. In this respect, Positron Emission
Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) techniques have
contributed to identify the cortical and subcortical functional neuroanatomical networks
involved in sleep and its components. The spatial accuracy of these techniques (up to a few
millimeters in resolution) is complementary to the high temporal resolution, at the millisecond
scale of neuronal transmission, of electrophysiological techniques that are playing a
fundamental role in the investigation of temporal patterns of neuronal synchronization
oscillatory rhythms using e.g. EEG (Happe et al., 2002), high-density EEG (Massimini,
Huber, Ferrarelli, Hill, & Tononi, 2004; Riedner, 2007) or magnetoencephalography (MEG;
Ioannides et al., 2004) both during REM and NREM sleep. Optimal combinations between
these techniques (e.g. simultaneous EEG-fMRI, see below for instance Dang-Vu et al., 2008;
Schabus et al., 2007) and their intrinsic advantages minimize their respective drawbacks,
providing important information on the physiology of sleep and its regulation.
In this section, we will offer a description of the cerebral networks implicated in a
permissive and/or executive manner in NREM and REM sleep stages. This
neurophysiological macroscopic level of description will be linked with a summary
description of the cortical and subcortical cellular and synaptic interaction processes thought
responsible for these cerebral patterns and their respective implication in the generation of
sleep stages and their specific features. All studies presented in this section refer to “canonical
sleep”, e.g. normal sleep in healthy young humans, without any associated pathology or
interferences due to prior sleep deprivation or pharmacological intervention, that are beyond
the scope of this chapter.

NREM sleep
As discussed above, there is a progressive change from wakefulness to NREM sleep in the
way neuronal populations are firing, from a desynchronized tonic mode towards bursting
synchronous activity. Self-sustained oscillatory activity in thalamic nuclei initiate a cascade of
neurophysiological events, eventually leading to the large-scale synchronization of cortical
neuronal populations responsible for the low frequency, high amplitude EEG typical of
NREM sleep. As illustrated Figure 7, three interconnected neuronal populations are involved
in the generation of NREM sleep oscillations: (i) corticothalamic neurons (neurons A), that
have excitatory synapses on thalamocortical neurons and thalamic reticular neurons; (ii)
thalamocortical relay neurons (neurons B) with their cell bodies in the thalamus and axons
making excitatory synapses on pyramidal neurons in the cerebral cortex and on neurons in the
thalamic reticular nucleus and (iii) thalamic reticular neurons (neurons C) located in the
reticular thalamic nuclei and forming inhibitory synapses on thalamocortical neurons.
Neurons A and B are excitatory glutamaergic neurons, whereas neurons C are GABAergic
inhibitory neurons. The resulting loops into the cortico-thalamo-cortical network are involved
by different ways in the generation of spindles and delta waves, which in turn are organized
by cortically generated slow oscillations (<1 Hz; Steriade, 2001). Altogether, these rhythms
are produced by a “unified oscillatory machine” encompassing thalamic and cortical
structures, under the control of brainstem and forebrain modulatory systems, and are
coalescent within specific time windows corresponding to the depolarizing phase (up state) of
the slow oscillations (Steriade, 2006).
Neural correlates of slow oscillations in NREM sleep

A consequence of large-scale neuronal synchronization is that coincident bursts of activity are
followed by equally synchronous depolarization periods (down state), during which neurons
are virtually silent. When cerebral activity is recorded and averaged over long periods, for
tens of seconds up to minutes as it is the case with PET scanning, it entails that areas in which
activity is most synchronous will be those in which regional cerebral blood flow (CBF) will
be most decreased due to the fact that averaging has included the long depolarization periods
during which energy demands are minimal (Maquet, 2000). Accordingly, PET studies have
consistently reported decreased regional CBF and oxygen consumption during NREM sleep,
as compared to wakefulness or REM sleep, in a set of subcortical and cortical regions
encompassing the dorsal pons and the mesencephalon, the cerebellum, the thalamus, the basal
ganglia, the basal forebrain and the anterior hypothalamus, and neocortical prefrontal and
anterior cingulate cortices, precuneus and mesial part of the temporal lobe (Figure 8)
(Andersson et al., 1998; Braun et al., 1997; Kajimura et al., 1999; Maquet, 2000; Maquet et
al., 1997). The relationship between the depth of NREM sleep and decreased rCBF thought to
reflect increased synchronization is further confirmed by correlations between increased EEG
spectral power for slow oscillations in the delta (1-4 Hz) range and decreased rCBF in most of
the cortical regions reported above, particularly in medial prefrontal regions where response
to homeostatic sleep pressure is prominent (Dang-Vu et al., 2005).
Above rCBF patterns reflecting synchronous activity within specific brain areas, more recent
studies have taken advantage of the better temporal resolution of fMRI (about one second)
combined with simultaneous EEG recordings to highlight transient changes in regional
cerebral activity specifically associated with slow (< 1Hz; >140 µV) and delta waves (0.5-
4Hz; 75–140 µV) during NREM sleep (Dang-Vu et al., 2008). Using an endogenous event-
related approach, these authors searched for brain regions in which changes in activity (i.e.
Blood Oxygen Level-Dependent [BOLD] responses in fMRI) were coincident with the active
depolarized (“up”) state of these oscillations, as indexed by peak negativity in the EEG.
Results show that increased cerebral activity is associated both with slow and delta waves in
several cortical areas including the inferior frontal and medial prefrontal cortices, and the
precuneus and posterior cingulate areas. Besides these commonalities however, slow
oscillations (< 1Hz) are associated with increased activity in the parahippocampical gyrus, the
cerebellum and the brainstem, whereas delta waves are specifically associated with increased
activity in frontal areas (Figure 9).
Additionally, Dang-Vu et al. (2008) found increased activity associated with slow oscillations
in the midbrain and the pontine tegmentum, a region that includes critical structures involved
in the regulation of sleep and wakefulness (especially cholinergic and aminergic nuclei, see
above), the activation encompassing the noradrenergic locus coeruleus (LC). This unexpected
result suggests that these structures are active in phase with slow oscillations, maybe allowing
the brain to periodically restore microwake-like activity patterns in order to facilitate neuronal
interactions. Taken together, these results further confirm that SWS is not, as may have been
thought, a state of brain quiescence, but genuinely is an active state during which phasic
increases in brain activity are synchronized to slow oscillations (Dang-Vu et al., 2008).
Functional neuroanatomy of sleep spindles
As mentioned above, spindles are short-lasting (0.5-3 sec), waxing and waning oscillations in
the sigma range (11-16 Hz) during NREM sleep, especially during Stage N2. Spindles are
affected by a series of factors including circadian modulation (Dijk, 1995a; Knoblauch,
Krauchi, Renz, Wirz-Justice, & Cajochen, 2002; Knoblauch, Martens, Wirz-Justice, Krauchi,
& Cajochen, 2003), age (Landolt, Dijk, Achermann, & Borbély, 1996), menstrual cycle
(Driver, 1996) and drugs (Aeschbach, 1994; Dijk et al., 1995). Behavioural and
electrophysiological data further suggest a functional differentiation between slow (11-13 Hz)
and fast (14-16 Hz) spindles (e.g. for a review De Gennaro & Ferrara, 2003), but their
functional neuroanatomy remained uncertain. PET studies have yielded conflicting results,
with a reported relationship between spindle activity and rCBF in the thalamus (Hofle et al.,
1997) contradicted later on (Dang-Vu et al., 2005). Using a combined EEG-fMRI approach,
Schabus and collaborators (2007) recently found that spindles occurrence is associated with
transient increases in regional brain activity in thalamic and paralimbic areas (anterior
cingulate and insular cortices), and superior temporal gyrus (Figure 10). Besides a common
neuroanatomical pattern, they also found that activity in distinctive thalamo-cortical networks
characterize fast and slow spindles. Whereas slow spindles only elicit additional increased
activity in the frontal gyrus, fast spindles are associated with specific activations in a large set
of cortical regions involved in sensorimotor processing, as well as in orbital and mesial
prefrontal cortex, hippocampus and anterior insula, further supporting the hypothesis that
generation of fast and slow spindles rely upon two functionally separated systems.
REM sleep
At variance with NREM, REM sleep and wakefulness are characterized by sustained,
desynchronized neuronal activity (Steriade & McCarley, 1990) associated with high energy
demands. Therefore, activity as measured using PET or fMRI will be increased in brain
regions actively involved in REM sleep processes as compared to NREM sleep, even above
activity levels observed during wakefulness. Using PET, REM sleep was associated with a
specific neuroanatomical pattern of increased activity in the mesopontine tegmentum (PPT),
thalamic nuclei, basal forebrain, cerebellum, caudate nucleus, limbic and paralimbic
structures (e.g. amygdala, hippocampus, anterior cingulate cortex) and associative posterior
temporo-occipital regions (Braun et al., 1997, 1998; Maquet et al., 1996; Nofzinger, Mintun,
Wiseman, Kupfer, & Moore, 1997; Peigneux et al., 2001). In parallel, decreased regional CBF
was found in frontal and parietal regions (dorsolateral prefrontal cortex, posterior cingulate
gyrus, precuneus and inferior parietal cortex), as well as in primary sensory areas (Braun et
al., 1997; Maquet et al., , 1996, 2000, 2005), indicating that activity in these regions is
strongly diminished during REM sleep (Figure 11).
Increased regional CBF activity in the PTT, thalamus and basal forebrain is in line with the
neurobiological literature, indicating that REM-on neurons and other cellular populations
responsible for REM sleep induction are located in these regions and mediate widespread
cortical activation through innervations in the thalamus and basal forebrain (Capece, 1997;
Datta, 1995, 1997; Steriade, 1990). Also, increased activity in amygdaloid complexes
involved in the generation of REM sleep (Morrison, 1999) reflects their potential role in the
modulation of regional activation/deactivation patterns during REM sleep (Amaral & Price,
1984). Indeed, most activated areas during REM sleep are regions receiving numerous
amygdalar projections, whereas deactivated frontal and parietal cortices are practically devoid
of amygdalar afferents (Aggleton, 1993; Amaral, Price, Pitkänen, & Carmichael, 1992;
Amaral & Price, 1984). Also, animal data have shown that electrical stimulation of the central
nucleus of amygdaloid complexes increases phasic ponto-geniculo-occipital (PGO, see
below) activity (Calvo, Badillo, Morales-Ramirez, & Palacios-Salas, 1987), one of the most
distinguishing features of REM sleep.
Phasic and tonic activities in REM sleep
Widespread thalamocortical synchronized activity characterizes both REM sleep and
wakefulness, in line with PET results (Braun et al., 1997; Braun et al., 1998; Buchsbaum,
Hazlett, Wu, & Bunney, 2001; Maquet et al., 1996; Nofzinger et al., 1997; Peigneux et al.,
2001). Beyond regional patterns of sustained cerebral activity however, fMRI investigations
suggest that transient changes in thalamocortical activity reflect the transition between tonic
and phasic components during REM sleep (Wehrle et al., 2007). Indeed, within human REM
sleep, widespread activity in a thalamocortical network including limbic and parahippocampal
areas seems to occur selectively during phasic REM sleep (e.g. rapid eye movements periods)
as compared with the predominant tonic REM sleep background, suggesting that REM sleep
subdivides into tonic REM sleep with residual alertness and phasic REM sleep with the brain
acting as a functionally isolated and closed intrinsic loop. From an evolutionary point of view
this transition may be beneficial since phasic REM sleep constitutes an extremely vulnerable
state during which sensory inputs are not perceived on top of decreased reactivity capacities
due to general muscle atonia.
Probably the most distinguishing phasic feature of REM sleep are ponto-geniculo-
occipital (PGO) waves which are prominent phasic bioelectrical potentials occurring in
isolation or in bursts during the transition from NREM to REM sleep or during REM sleep
itself (for reviews, see Callaway, Lydic, Baghdoyan, & Hobson, 1987; Datta, 1999). In
animals, REMs are closely related to the occurrence of PGO which propagates throughout the
brain but prominently in the pons, the lateral geniculate bodies and the occipital cortex. PGO
are though a fundamental process of REM sleep, playing a significant role in central nervous
system maturation (Datta & Patterson, 2003). In human, intracerebral recordings in epileptic
patients (Salzarulo, Lairy, Bancaud, & Munari, 1975) as well as non-invasive PET (Peigneux
et al., 2001), fMRI (Wehrle et al., 2005) and magnetoencephalography (MEG; Ioannides et
al., 2004) studies in healthy volunteers indicate that rapid eye movements observed during
REM sleep are generated by mechanisms similar or identical to PGO waves in animals.
CONCLUSIONS
In this chapter, we have tried to guide the reader beyond the appearances of a cessation of
waking activity during sleep. We have seen that despite evolutionary adaptations and
divergences amongst species, sleep is a universal phenomenon whose generation and
maintenance are under control of complex regulatory mechanisms. Most importantly, we
have learnt that above all, sleep is a state of the brain, and even more a series of active
states of the brain. Sleep-related changes in brain activity can be observed at
neurobiological, neurophysiological and neuroanatomical levels, including amongst others
cellular and molecular interactions, re-equilibration of the neurotransmitters balance and
changes in functional neuroanatomical patterns, eventually leading to REM and NREM
sleep stages and their characteristic tonic and phasic patterns in man. Our exponentially
growing knowledge about the way sleep is regulated and organized at the brain level
should ultimately allow answering the fundamental questions of the vital functions played
by sleep in the life span. Indeed, one fascinating but still pending question is the
delineation of the exact function(s) played by sleep. Although we know with certainty that
sleep is an essential process for living species as different as humans and flies, we are still
unable to fully understand why sleep is so tremendously important. Amongst others,
functional hypotheses have proposed that sleep may promote restorative mechanisms for
the brain and body metabolism (e.g. cortical maintenance, energy conservation, body
mass, metabolism and sleep control), whereas others have considered that sleep plays a
prominent role in brain plasticity and memory consolidation processes (see related chapter
“The functions of sleep”). These proposals should not be viewed as mutually exclusive,
but rather reflecting multiple and complementary functions of sleep. An important task to
achieve nowadays is the identification of which of these hypothesized functions may only
be achieved during sleep, and which others may be executed during both waking and
sleep, with sleep merely being a more efficient time for their accomplishment. It also
remains to be determined which, if any, of the proposed functions are universal across
mammalian species and across the lifespan, and which may be limited to particular
species or phases of development. Despite advances that have refined our understanding
of the relationships between sleep and cognitive processes, these underlying mechanisms
still remain to be fully elucidated.
RELATED CHAPTERS
The regulation of human sleep and wakefulness
Sleep homeostasis; circadian physiology; the two-process model; circadian, diurnal and
ultradian factors in sleep & wakefulness; sleep chronotypes; respiratory control;
thermoregulation
The functions of sleep
Evolutionary perspectives; body restitution; cerebral restitution; core and optional sleep;
perspectives on REM sleep; sleep deprivation and its effects
FURTHER READING
Borbely, A. A., Hayaishi, O., Sejnowski, T. J., & Altman, J. S. (Eds.). (2000). The regulation
of sleep. Strasbourg: HFSP.
Datta, S., & 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(5), 775-
824.
Hartse, K. M. (1994). Sleep in insects and nonmammalian vertebrates. In M. H. Kryger, Roth,
T., Dement, W.C. (Eds.) (Ed.), Principles and Practice of Sleep Medicine.1st ed. (pp.
95–104). Philadelphia: Elsevier Saunders.
Iber, C., Ancoli-Israel, S., Chesson, A., & Quan, S. F. (Eds.). (2007). The AASM Manual for
the Scoring of Sleep and Associated Events: Rules, Terminology and Technical
Specifications. Westchester: American Academy of Sleep Medicine.
Maquet, P., Smith, C., & Stickgold, R. (Eds.). (2003). Sleep and Brain Plasticity. Oxford:
Oxford University Press.
Rattenborg, N. C., Martinez-Gonzalez, D., & Lesku, J. A. (2009). Avian sleep homeostasis:
convergent evolution of complex brains, cognition and sleep functions in mammals
and birds. Neurosci Biobehav Rev, 33(3), 253-270.
Siegel, J. M. (2005). Clues to the functions of mammalian sleep. Nature, 437(7063), 1264-
1271.
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INFORMATION BOX 1. POLYSOMNOGRAPHIC TECHNIQUES
Polysomnography is the multi-modality recording of sleep using an array of
electrophysiological and physiological techniques allowing the analysis and scoring of sleep.
The main measures are electroencephalography, electrooculography and electromyography.
1. Electroencephalography (EEG) records electrical activity produced by synchronous

post-synaptic potentials of brain neurons. Recording is made possible using metal current
conductor electrodes placed in contact with the scalp. The resulting signal is amplified and
digitized, filtered and cleaned from artefacts, then examined for rhythmic and transient
activities. Rhythmic activities are continuous oscillations patterns in the EEG that vary in
frequency (cycles per second, expressed in Hertz [Hz]) and amplitude (expressed in
microvolts [µV]). Transient activities are isolated, short-duration events with
characteristic features (e.g. K-complexes, vertex waves and spindles in sleep, see main
text). When the EEG is recorded at multiple scalp locations according to international
conventions (e.g. the 10-20 systems; see Information Box Figure 1 below), it additionally
allows topographic, spatially-based analysis of specific sleep patterns (Finelli, Borbely &
Achermann, 2001).
--- INSERT INFORMATION BOX FIGURE 1 HERE ---
2. Electrooculography (EOG) records changes in voltage induced by the eye rotation, the
moving eyeball acting as a small battery, with the retina negative relative to the cornea.
Two electrodes located lateral to the eyes allow recording of horizontal eye movements,
two other electrodes above and below one eye allow recording vertical movements.
3. Electromyography (EMG) records electrical activity generated by muscles activity. The

EMG is typically recorded from under the chin, where muscular tonus changes with sleep
stages are most obvious.
Besides EEG, EOG and EMG, cardiac rhythms (electrocardiogram, ECG) and respiratory
activity can also be recorded simultaneously. Specific wires for EEG, EOG, EMG, ECG …
electrodes are connected through signal amplifiers to systems allowing recording and pre-
processing, storing and reviewing of the signal.
Thanks to the development of computer techniques, early paper-based analog
recordings have evolved toward digital polygraphs with high-capacity storage allowing
simultaneous recording and on-screen reviewing of multiple channels (up to 256 in high-
density EEG). According to the international consensus guidelines (Iber et al., 2007), EEG
with 16 or more channels would be an optimum to analyse sleep patterns, although a basic
scoring into different stages of sleep can be achieved with a minimum of 3 derivations located
frontally at F4-M1, centrally at C4-M1 and occipitally at O2-M1 (i.e. using right sided active
cortical electrodes F4, C4, O2 and a reference electrode M1 over the left mastoid in the
international 10-20 system; see Information Figure 1). Equally acceptable alternative
derivations are Fz-Cz, Cz-Oz, and C4-M1. In addition, many sleep units have a video camera
located in the bedroom, allowing the observation of the patient’s sleeping behaviour in
relation with variations in polysomnography recording, which is particularly useful in the
investigation of sleep-related disorders.

TABLE 1. Summary of the main features of each sleep stage.
Stages EEG Waveform Characteristics
(Frequency (Amplitude type
-Hz) -µV)
AWAKE 14-40 10 - 30 β State of full consciousness
characterized by a desynchronized
EEG pattern of high beta frequency
waves of low amplitude.
SLEEP 8-12 20 - 40 α Quiet or resting state characterized by
ONSET posterior alpha rhythm (especially over
OR PRE- the occipital cortex) with a lower
SLEEP frequency (8–12 Hz) and increased
synchrony and amplitude (20 to 40
µV).
N1 3-7 50-100 θ Transition period with little or no body
movement characterized by the
diminution of alpha waves and the
appearance of theta waves, slower in
frequency (3 to 7 Hz) and greater in

amplitude (50 to 100 µV) than alpha
waves.
N2 11-16 50-150 Occasional Basal oscillations below 5 Hz called
"sleep “slow waves” on which are

or
spindles" periodically superimposed sleep
Light sleep
spindles (short-lasting, waxing and
(σ)
waning oscillations in the 11- 16 Hz
Occasional
frequency range) and K complexes
"K"
(negative sharp waves immediately
complexes
followed by a positive component
standing out from the background EEG
with a total duration at least equal to
0.5 second).
N3 0.5-2 > 75 Slow The deepest possible state of physical
(previously waves rest. SWS is characterized by high-

Or
0.5-4) amplitude slow oscillations in the 0.5-2
(previously
Slow Wave
Hz frequency range, maximally
δ)
Sleep
expressed at frontal locations.
(SWS)
Slow oscillations (<1Hz) are cortical

<1
oscillations occurring during NREM
>140
sleep. These slow rhythms play a major
role in the synchronization of other
NREM sleep oscillations and events
(e.g. spindles).
REM 15-30 <50 Desynchronized EEG activity close to
that recorded during wakefulness,

Or
characterized by low amplitude-mixed
Paradoxical
frequency (15-30Hz, <50 µV) EEG
sleep
background, rapid eye movements and
muscular atonia.
FIGURE LEGENDS
INFORMATION BOX FIGURE 1. International 10-20 system for topographical disposition
of the electrodes on the scalp (simplified representation). Electrodes are located along
imaginary lines across the head between bony landmarks that intersect at 10% or 20% of their
total length distance intervals, hence the “10-20” name. Letters indicate locations according to
the brain structure below the electrode, Numbers indicate left-right lateral location, and
midline electrodes have the suffix “z” : F (Fp1-Fpz-Fp2-F7-F3-Fz-F4-F8), Frontal; C (C3-Cz-
C4), Central; T (T3-T4-T5-T6), Temporal; P (P3-Pz-P4), Parietal; O, (O1-Oz-O2), Occipital;
M (M1-M2), Mastoid. The use of the 10-20 system ensures symmetrical and reproducible
electrode placement for within- and between-subject comparisons. A basic sleep recording
may be obtained using 3 electrodes (F4-C4-O2) and one reference electrode (M1), represented
here in orange colour.
FIGURE 1. Hypnogram illustrating sleep stages and their cycle in the course of a canonical
night in a healthy young sleeper. Grey bars indicate changes in sleep stages (or wakefulness)
across time. Note the progressive decrease in NREM sleep prevalence from the first half to
the second half of the night, whereas the reverse pattern is observed for REM sleep.
FIGURE 2. Schematic representation of the 3 main processes involved in the regulation of
sleep. The homeostatic process maintains sleep propensity (duration and intensity of sleep)
which builds up during wakefulness and declines during sleep. The circadian process is a
nearly 24-hr endogenous oscillatory variation that determines the timing of the propensity to
sleep. Ultradian mechanisms underlie the NREM–REM sleep cycle. As the sleep episode
progresses, the intensity of NREM sleep declines and the duration of successive REM sleep
intervals increases. W: awake state; S: sleep. From Borbely et al. (2000).
FIGURE 3. EEG patterns of vigilance states.
FIGURE 4. EEG recording in a bottlenose dolphin during waking (A) and unihemispheric
slow wave sleep (USWS) in the right (B) and left (C) hemispheres (1-right cortex, 2-left
cortex, 3-right thalamus, 4-left thalamus). From Mukhametov et al., 1977.
FIGURE 5. Sagittal view of human brain depicting the main neurotransmitter structures and
pathways involved in the generation and the maintenance of sleep and wakefulness.
Acetylcholine (Ach)-synthesizing (cholinergic) cells in the pedunculopontine tegmentum
(PPT) and in the anterior hypothalamus (AH) of the basal forebrain (BF). (HA)-synthesizing
histaminergic cells in the posterior hypothalamic tuberomammillary nucleus (PH-TMN).
Norepinephrine (NE)-synthesizing (noradrenergic) cells in the locus coeruleus (LC).
Serotonin (5-HT)-synthesizing (serotonergic) cells in the raphe nuclei (RN). Hypocretine-
orexine cells in the lateral hypothalamus (LH). Dopamine (DA)-synthesizing dopaminergic
cells in the substantia nigra compacta (SNc) and ventral tegmental area (VTA). (Glut)-
synthesizing glutamatergic cells in the mesencephalic reticular formation (MRF). From Datta
& MacLean (2007).

FIGURE 6. The reciprocal inhibition model for REM sleep (McCarley et Hobson, 1975).
During wakefulness and NREM sleep, noradrenergic (NE) and serotoninergic (5-HT) activity
inhibits cholinergic (Ach) REM-on neurons in the pedunculopontine tegmentum (PPT) and
lateral dorsal tegmentum (LDT). Throughout the course of a NREM sleep episode, inhibitory
feedback gradually decreases NE and 5-HT activity in the locus coeruleus and dorsal raphe
nucleus (5-HT) respectively, releasing inhibition on acetylcholine REM-on cells, whose
increased activity induces REM sleep. Activity in REM-on cells in turn exerts an excitatory
effect on REM-off cells during REM sleep, eventually leading to the termination of REM
sleep when a sufficient level of inhibitory activity has been attained in NE and 5-HT REM-off
cells.
FIGURE 7. Neuronal loops in corticothalamic networks involved in generating the coherent
low-frequency oscillations characteristic of NREM sleep (spindles, delta and slow
oscillations). [A] corticothalamic neurons; [B] thalamocortical relay neurons; [C] thalamic
reticular neurons. From Borbely (2000).
FIGURE 8. Brain areas in which regional CBF (rCBF) decreases during NREM sleep as
compared to wakefulness and REM sleep, measured using PET. Mid- sagittal (left panel) and
transverse (right panel) sections show higher synchronization (as reflected by decreasedrCBF)
in central core structures (brainstem and thalamic nuclei), basal forebrain, basal ganglia,
anterior hypothalamus, orbito-frontal and anterior cingulate cortices, and precuneus. Numbers
in the left panel refer to the corresponding transverse sections on the right. From Maquet et al.
(1997).
FIGURE 9. Combined EEG-fMRI investigation of human NREM sleep. Panels show brain
regions in which increased event-related BOLD responses are commonly associated with the
depolarized (up) state of slow and delta waves. Associated curves show the time course of
fitted response amplitudes (arbitrary units) during slow or delta waves in the corresponding
circled brain area. (A) Pontine tegmentum. (B) Parahippocampal gyrus. (C) Cerebellum. (D)
Medial prefrontal cortex. (E) Inferior frontal gyrus (F) Posterior cingulate cortex. From Dang-
Vu et al. (2008).
FIGURE 10. Functional neuroanatomy of fast and slow spindles. Panels show larger brain
responses for fast (red) than slow (black) spindles in the hippocampus (a), mesial prefrontal
cortex (b), precentral gyrus (c) and postcentral gyrus (d). From Schabus et al. (2007).
FIGURE 11. Schematic representation of the functional neuroanatomy of normal human
REM sleep (Braun et al., 1997; Maquet et al., 2000; Maquet et al., 1996; Nofzinger et al.,
1997). Regions in red colour are those in which there is a relative increase in neural activity
associated with REM sleep; regions in blue correspond to relative decreases in neural activity
associated with REM sleep: (a) lateral view; (b) medial view; (c) ventral view. A: amygdala;
B: basal forebrain; Ca: anterior cingulate gyrus; Cp: posterior cingulate gyrus and precuneus;
F: prefrontal cortex (middle, inferior and orbito-frontal cortices); H: hypothalamus; M: motor
cortex; P: parietal cortex (inferior parietal lobule); PH: parahippocampical gyrus; O: occipital-
lateral cortex; Th: thalamus; T-O: temporo-occipital extrastriate cortex; TP: pontine
tegmentum. From Schwartz and Maquet (2002).

INFORMATION BOX FIGURE 1.

FIGURE 1.
FIGURE 2.
FIGURE 3.
FIGURE 4.
FIGURE 5
FIGURE 6
FIGURE 7
FIGURE 8
FIGURE 9
FIGURE 10
FIGURE 11

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Sleep and the Brain – page 1/1

SLEEP AND THE BRAIN

Philippe PEIGNEUX 1,2,*and Charline URBAIN 1,*, Remy SCHMITZ1

Bruxelles, Brussels, Belgium.

Neuropsychology and Functional Neuroimaging Research Unit [UR2NF]

Faculty of Psychological and Educational Sciences,

Université Libre de Bruxelles (ULB)

Campus du Solbosch, CP191

Avenue F.D. Roosevelt 50

Email: [email protected] or [email protected]

The phenomenological experience of sleep as a cessation of waking activity is misleading.

viewed from behavioural, neurobiological, neurophysiological and functional

neuroanatomical perspectives. Given the universality of sleep and/or sleep-like phenomena

complex, multidimensional and active state of the brain.

Keywords: NREM, REM, SWS, USWS, Neurobiology, Neurophysiology, Functional

Neuroanatomy, Phylogenesis, EEG, PET, fMRI, MEG

Acknowledgments: CU is supported by a grant from the Fondation Vigneron; RS is

supported by the Fonds National de la Recherche Scientifique (FNRS); Belgium.

quiescence, mostly characterized by no or minimal movements, closure of the eyes and a

As compared to quiet wakefulness, there is also reduced responsiveness to external

death, hypothermia or hibernation.

wakefulness or in an intermediate state of drowsiness. Furthermore, mere observation cannot

--- INSERT FIGURE 1 HERE ---

2 sleep remaining fairly constant.

--- INSERT FIGURE 2 HERE ---

--- INSERT INFORMATION BOX 1 (Polysomnographic Techniques) ABOUT HERE ---

brain, that he named electroencephalography (EEG). He described different oscillation

the availability of electrophysiological and physiological techniques (see Information Box 1)

computer-based inspection of 30-second polysomnographic epochs of

electroencephalographic (EEG), electrooculographic (EOG) and electromyographic (EMG)

Portilla, Arce, & Villanueva-Hernandez, 2000; Corsi-Cabrera, Munoz-Torres, Del Rio-

environment. In humans the waking EEG is mostly characterized by a so-called

activity in non-stimulated brain regions (Borbely et al., 2000).

--- INSERT FIGURE 3 HERE ---

reflecting the progressive synchronisation of activity within and between neuronal

the underlying SWA. (Steriade & Amzica, 1998)

NREM sleep stage N1 and sleep onset

not having been asleep at all.

NREM sleep Stage N2

spindles. The K complexes are graphoelements characterized by a negative sharp wave of

(e.g. F4 or Fz). Stage N2 should be persistently scored in the absence of K complexes or

movement followed by slow eye movements or an arousal.

NREM sleep Stage N3 or SWS

confusion or disorientation (also known as “sleep drunkenness”).

Contrary to NREM stages, REM sleep is characterized by the presence of desynchronized,

--- INSERT SUMMARY TABLE 1 HERE ---

THE PHYLOGENESIS OF SLEEP

animal species up to now, although physiological and neurophysiological characteristics may

though sleep appears to be an universal phenomenon, studies conducted in insects,

convincingly disclosed -- in all branches of the evolutionary tree, raising supplementary

phylogenetic characteristics of sleep and target its essential components.

Sleep or “close to sleep” states in insects

Swinderen & Andretic, 2003).

Activity/inactivity states in vertebrates without thermal regulation

possible to evidence periods of eye movements correlated with vegetative variations

characterized by an increase in low frequency activity and spikes (Karmanova, 1978).

apparently unrelated with behavioural sleep.

recordings (EEG, EMG, EOG, ECG, respiration) in chelonians (tortoises), crocodilians

an association with high-amplitude, low-frequency activity (Warner, Huggins, 1978) or failed

Philippe PEIGNEUX 1,2,and Charline URBAIN 1,, Remy SCHMITZ1