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The Study of
Brain Activity in Sleep
The hours of our life
other activities (19%)
work and work-related (16%)
sport (1%)
television (11%)
phone/e-mail (1%)
household activities (8%)
eat/drink (5%)
socializing (3%)
By the age of 80, a person will have spent more than 25 years sleeping.
American Time Use Survey, Bureau of Labor Statistics.
Sleep: A Definition
Behavioral Definition: Behavioral state with
characteristic immobile posture and diminished
but readily reversible sensitivity to external
Electrophisiological Definition:
Electrophyiological Characteristics
of Human Sleep
The study of sleep
Electrooculogram (EOG)
Electromiogram (EMG)
Electroencephalography (EEG)
In clinical use (polysomnography) also electrocardiogram (EKG), respiration
and body position are measured.
The Human EEG in Wakefulness and Sleep
Sleep is traditionally categorized into non-rapid eye movement (NREM) sleep and REM
sleep. Human NREM sleep, in turn, is divided into stages N2 and N3.
EEG Sleep Stages: Wakefulness
Dominated by waves of low amplitude and high frequency (low-voltage fast
activity), including beta (16-25 Hz) and gamma (>25 Hz) oscillations.
When eyes close in preparation for sleep, EEG alpha activity (8–13 Hz)
becomes prominent, particularly in occipital regions (‘ idling’ rhythm in visual
The waking EOG reveals frequent voluntary eye movements and eye blinks.
The EMG reveals tonic muscle activity with additional phasic activity related
to voluntary movements.
EEG Sleep Stages: Stage N1
Characterized by loss of alpha activity and appearance of a low-voltage
mixed frequency EEG pattern with prominent theta activity (3–7 Hz).
Eye movements become slow and rolling, and muscle tone relaxes.
Although there is decreased awareness of sensory stimuli, a subject in stage
N1 may deny that he was asleep.
Motor activity may persist for a number of seconds during stage N1.
Occasionally individuals experience sudden muscle contractions (hypnic
jerks), sometimes accompanied by a sense of falling and dream-like imagery.
EEG Sleep Stages: Stage N2
Stage N2 is heralded in the EEG by the appearance of K-complexes and sleep
spindles, which are especially evident over central regions.
K-complexes are made up of a high-amplitude negative sharp wave followed
by a positive slow wave, and are often triggered by external stimuli.
Sleep spindles are waxing and waning oscillations at around 12–15 Hz that
last about 1 second and occur 5–10 times a minute.
Eye movements and muscle tone are much reduced. Individuals are partially
disconnected from the environment (increased arousal threshold)
EEG Sleep Stages: Stage N3
The EEG shows prominent Slow Waves in the delta range (1-4 Hz, 75 μV
amplitude in humans).
Eye movements cease during stage N3 and EMG activity decreases further.
The threshold for arousal is higher than in stage N2. The process of
awakening from slow wave sleep is drawn out, and subjects often remain
confused for some time (sleep inertia).
Sleep Hallmarks: Slow Waves (and K-Complexes)
Changes in neuromodulators during NREM sleep (in particular reduced levels
of arousal-related neurotransmitters) lead cortical and thalamic neurons to
enter in a “bistable” state. In this condition, a spontaneous or induced
opening of leakage K+ channels triggers a series of membrane currents that
produce the slow oscillation.
The slow oscillation is characterized by a
hyperpolarization phase or down-state
(neuronal silence, 1), which lasts a few
hundreds of milliseconds, and a slightly
longer depolarization phase or up-state
(neuronal spikes of activity, 2).
The slow oscillation is synchronized across the cortical mantle by corticocortical and thalamo-cortical connections.
Sleep Hallmarks: Slow Waves (and K-Complexes)
Topographically, slow waves are especially prominent over medial and lateral
prefrontal cortex.
K-complexes are high-amplitude
slow oscillations usually (but
not always) triggered by
external stimuli. They are most
likely the EEG correlate of global
slow oscillations due to the
near-synchronous activation of
the cortical mantle by the RAS
(as opposed to a single cortical
Sleep Hallmarks: Spindles
Spindles are generated in thalamic circuits as a consequence of cortical firing.
When the cortex enters an up-state, strong cortical firing excites GABAergic
neurons in the reticular nucleus of the thalamus.
These in turn strongly inhibit thalamocortical neurons, triggering intrinsic
currents that produce a rebound burst of action potentials. These bursts
percolate within local thalamoreticular circuits and produce oscillatory firing
at around 12–15 Hz.
Thalamic spindle sequences reach back to the cortex and are globally
synchronized by corticothalamic circuits, where they appear in the EEG as
sleep spindles.
EEG Sleep Stages: REM
After deepening through stages N2 to N3, NREM sleep lightens
and returns to stage N2, after which the sleeper enters REM
sleep (“paradoxical sleep”: the EEG trace is “similar” to the
activated EEG of waking or of stage N1).
The EEG is characterized by low-voltage fast-activity, often with
increased power in the theta band (3–7 Hz). So called sawtooth
waves (2-5 Hz) tipically occur in bursts, especially before the
appearance of Rapid Eye Movements (REMs)
EEG Sleep Stages: Tonic and Phasic components of REM
Tonic aspects of REM sleep include the activated EEG and a
generalized loss of muscle tone, except for the extraocular
muscles and the diaphragm. REM sleep is also accompanied by
penile erections.
Phasic features of REM include irregular bursts of REMs and
muscle twitches.
Sleep Regulation
Changes in Neuromodulation During Sleep
Wakefulness promoting structures
• Reticular formation: glutamatergic neurons
• Locus coeruleus: noradrenaline
• Pedunculopontine nucleus and laterodorsal tegmental
nucleus: acetylcholine
• Raphe neurons: serotonine
• Ventral periacqueductal grey: dopamine
• Nucleus basalis: acetylcholine
• Tuberomammillary neurons: histamine
• Posterior hypothalamus: orexin (hypocretin)
Ascending reticular activating system
• Wakefulness maintained by multiple neuronal systems with different
• Systems are partially redundant, no one system appears to be necessary or
sufficient for wakefulness
• Widespread projections to cortex, subcortical relays and brainstem or spinal
cord, mutually excitatory influences on each other
Sleep Cycles
The succession of NREM sleep stages followed by an episode of REM sleep is called a
sleep cycle, and lasts approximately 90–110 minutes in humans. There are a total of 4–
5 cycles per night.
Slow wave sleep (N3) is prominent early in the night, especially during the first sleep
cycle, and diminishes as the night progresses. As slow wave sleep wanes, periods of
REM sleep lengthen and show greater phasic activity.
A healthy young adult typically spends about 5% of the sleep period in stage N1, about
50% in stage N2, 20–25% in stage N3, and 20–25% in REM sleep.
A Two Process Model of Sleep Regulaton
The two-process model of sleep regulation posits that the interaction of its two
constituent processes a homeostatic Process S and a circadian Process C
determines the timing of sleep and waking.
(Process S)
(Process C)
The time course of Process S is derived from a physiological variable: EEG slowwave activity.
Borbély et al., Hum. Neurobiol., 1982
Slow Wave Activity as an index of Sleep Pressure
Slow-Wave Activity (SWA) is
classically calculated as the mean
power spectral density in the 0.54.0 Hz frequency range.
The figure shows the SWA profile in
NREM sleep during the night for an
individual subject (average 1-min
values, % of the mean of 4 NREM
episodes). Rapid eye movement
(REM) episodes are indicated by
hatched areas.
Riedner et al., Sleep, 2007
Slow Wave Activity as an index of Sleep Pressure
During late NREM sleep, when compared with early NREM sleep, are commonly
observed: (1) reduced SWA, (2) fewer large-amplitude slow waves, (3) decreased wave
slopes, (4) more frequent multipeak waves
Riedner et al., Sleep, 2007
Possible Significance of Slow Wave parameters
peak-to-peak amplitude
real slow waves are nothing like
«theoretical» waves
Amplitude: Extent of the neuronal population recruited in the down-state (i.e., small
SWs are based on the recruitment of fewer neurons as compared to large SWs).
Slope: This parameter may reflect synaptic strength (i.e., steeper slow waves are
generated when neuronal populations are rapidly and efficiently synchronized).
Negative Peaks: The presence of multiple peaks may indicate a sub-optimal
synchronization of distinct neuronal populations (partially asynchronous local waves).
Riedner et al., Sleep, 2007
Sleep Intensity is Locally (Homeostatically) Regulated
Motor Learning
Arm Immobilization
High SWA
Huber et al., 2002, Nature
Huber et al., 2006, Nature Neuroscience
Sleep intensity is locally regulated on a use-dependent basis
Possible Relationship between Sleep and Plasticity
Given the association between wake-dependent activities and networkspecific changes in sleep features (in particular, SWA), several authors
suggested that sleep may be involved in the regulation of learning and brain
In particular…
The synaptic homeostasis hypothesis suggests that wake activities are
associated with a potentiation of synaptic connections, and that sleep may
have a role in re-normalizing synapses (down-scaling), allowing for a new
learning cycle.
The hypothesis of synaptic potentiations suggests that locally regulated
sleep-related events may help potentiating (up-scaling) specific connections
in order to favor memory consolidation.
Changes in Brain Functioning
during deep sleep and REM
Changes in brain activity during NREM sleep
During deep NREM sleep, metabolic activity can be reduced as much as 40% relative to
resting wakefulness. Activation is especially reduced in the thalamus due to its profound
hyperpolarization during NREM sleep. In the cerebral cortex, activation is reduced in
dorsolateral prefrontal cortex, orbitofrontal and anterior cingulate cortex (slow waves are
especially prominent in these regions).
Maquet et al., Journ. Neurosci, 1997
Changes in DMN During NREM Sleep
Deep Sleep
Sleep-induced changes in consciousness are reflected in reduced correlations
between frontal and posterior areas of the DMN during deep sleep
Horovitz et al., PNAS, 2009
Changes in «Resting State» Connectivity During NREM Sleep
Wake VS N1
Wake VS N2
Wake < Sleep
Wake VS N3
Wake > Sleep
The net reduction in connectivity observed during deep sleep reflect a reduction in
brain interregional cross talk, i.e., a loss of global integration well in line with a
phenotypically concomitant reduction in consciousness. Modularity, a spatial measure
of functional segregation, generally increased across the brain with deepening sleep.
Tagliazucchi & Laufs, Nueron, 2014
Brain Activity in REM sleep (Meta-analysis of PET studies)
Decreased activity in REM
Increased activity in REM
Nir & Tononi, Trends Cogn. Sci., 2010
Brain Activity in REM sleep (Meta-analysis of PET studies)
During REM sleep, absolute levels of
blood flow and metabolic activity are
high, reaching levels similar to those
seen during wakefulness.
Some areas appear to be more active
in REM sleep than in wakefulness:
e.g., amygdala, parahippocampal
cortex, anterior cingulate, parietal
lobule and extrastriate areas.
By contrast, the rest of parietal cortex, precuneus, posterior cingulate cortex and
dorsolateral prefrontal cortex are relatively deactivated.
Nir & Tononi, Trends Cogn. Sci., 2010
Breakdown of Cortical Effective Connectivity During Sleep
The fading of consciousness
during certain stages of sleep
may be related to a breakdown in
cortical effective connectivity
Massimini et al., Cogn Neurosci., 2011
Dissociated States
Local Sleep and Local Wakefulness
Local Sleep during Wakefulness
After a long period in an awake state, cortical
neurons can go briefly ‘offline’ as in sleep,
accompanied by slow waves in the local EEG.
Neurons often go offline in one cortical area but
not in another [Local Sleep]
When local OFF periods happen in areas
relevant for behavior (i.e. motor cortex during a
reaching task) they lead to performance errors!
Vyazovskiy et al., J. Nature., 2011
Evidences for Local Sleep in Humans
Theta Power Contrast
Hung, Sarasso et al., Sleep, 2013
Local Sleep vs Micro Sleep
Local Sleep
Spatially circumscribed intrusion of sleep during
Involves only relatively small areas while most of the
brain shows activity patterns typical of wakefulness
Temporally circumscribed intrusion of (global) sleep
during wakefulness
Involves most brain regions and may last from a
fraction of a second to several seconds
Dissociated States: Local Wakefulness in Sleeping Individuals?
Local activations in the MC may be associated
with a parallel deepening of sleep in other regions
(increase of slow waves in the DLPFC).
Electrodes in MC and DLPFC
These results suggest that human sleep can be
characterized by the coexistence of wake-like and
sleep-like electroencephalographic patterns in
different cortical areas, supporting the hypothesis
that unusual phenomena, such as NREM
parasomnias, could result from an imbalance of
these two states.
Nobili et al., NeuroImage, 2011
Dissociated States: Wake-Sleep Transition
Falling Asleep
deep sleep
Slow wave density during the falling asleep process
Slow wave origin distribution during the falling asleep process
Siclari, Bernardi et al., SLEEP, 2014
Dissociated States: Wake-Sleep Transition
In the early phase of the falling-asleep
period, slow waves typically involve some
regions more than others:
Slow Wave Cortical Involvement
• The primary visual cortex and the medial
and lateral parietotemporal areas are
less affected by slow waves, and thus
“more awake”  Conscious experiences
are highly visual and frequently
characterized by vestibular sensations
• The prefrontal regions are more involved
by slow waves and thus “more asleep” 
The dreamer generally lacks insight into
the hallucinatory character of the
RED areas show more slow wave
activity at the beginning of the
falling asleep period. BLUE areas
show more activity when the
sleeper enters in deep sleep.
Islands of sleep and wakefulness can coexist across distinct brain areas
Siclari, Bernardi et al., SLEEP, 2014
Dissociated States: Sleep-Wake Transition and Sleep Inertia
Upon awakening, blood flow is rapidly re-established in brainstem and
thalamus, as well as in the anterior cingulate cortex. However, it can take up
to 20 min for blood flow to be fully re-established in other brain areas.
Sleep Inertia: physiological state of impaired alertness that follows an
awakening from sleep (especially, deep NREM sleep).
5’ post awakening
20’ post awakening
Balkin et al. BRAIN 2002
Dissociated States: Arousal Disorders
Confusional Arousal
Bassetti et al. Lancet 2005; Terzaghi et al. Sleep 2009, Mahowald and Schenck Nature 2005
Dreams, or Conscious Experiences
during different stages of sleep
1950s: Dreaming = REM sleep
‘Tell me whether you had a dream’
• Periods of ocular motility: yes 74%
• Periods of ocular inactivity: yes 17%
1960s onwards: NREM dreaming
‘Tell me wheter you had a dream’
‘What was going through your mind before you woke up ?’
How are conscious experiences distributed in sleep?
What was the last thing going through your mind prior to the alarm sound?
CE= Conscious Experience
CEWR = Conscious Experience Without Recall
NCE = No Conscious Experience
Siclari et al, Frontiers Psy., 2013
Combined TMS-EEG Studies of Sleep
NREM sleep
REM sleep
Type of
Typical Features
Mainly thoughts. Dreamlike in
up to 25%.
Independent of external stimuli (by
definition). Compared to REM: more
abrupt topic changes.
Short static images
(snapshots) or brief
sequences of disconnected
frames. Sensation of falling.
Sometimes influenced by
activities performed prior to
Compared to other sleep stages: fewer
emotions, fewer characters, less selfrepresentation, less bizarre, closer to
Early in the night: thoughtlike and conceptual. Later in
the night vivid and
hallucinatory experiences.
Compared to REM: shorter, less
dreamlike, more thought-like, less
vivid, more conceptual, under greater
volitional control, more plausible, more
related to current concerns, less
emotional. Late in the night sometimes
indistinguishable from REM reports.
Vivid, hallucinatory
Compared to wakefulness: singlemindedness, reduced self-awareness,
reduced executive control, high degree
of emotionality, altered mnemonic
Siclari et al, SAoNaP, 2012
Variability in Conscious Experiences during Sleep
NREM sleep N2, 6:09 AM
I was thinking about perfume and fragrance.
The very last word was ‘fragrance’.
Siclari et al, Frontiers Psy., 2013
Variability in Conscious Experiences during Sleep
NREM sleep N3, 6:09 AM
The last thing was raspberries,
a pint of raspberries.
Siclari et al, Frontiers Psy., 2013
Variability in Conscious Experiences during Sleep
REM sleep, 3:28 AM
I was doing this experiment with another girl. I
asked her what time it was and she said 7:07.
No, she actually said 6:55. Her boyfriend was
in the room, too. The last scene was just her
face. It was quite a long dream before that.
Siclari et al, Frontiers Psy., 2013
Investigating the correlates of consciousness in sleep…
fMRI data were acquired from sleeping participants simultaneously with polysomnography.
Participants were awakened during sleep stage 1 or 2 (red dashed line) and verbally reported
their visual experience. fMRI data immediately before awakening (= 9 s) were used as the
input for main decoding analyses. Words describing visual objects or scenes (in red) were
extracted. The visual contents were predicted using machine learning decoders trained on
fMRI responses to natural images.
Horikawa et al, Science, 2013
Investigating the correlates of consciousness in sleep…
“What I was just looking at was some kind of characters. There was something like a writing
paper for composing an essay, and I was looking at the characters from the essay or
whatever it was. It was in black and white and the writing paper was the only thing that was
Horikawa et al, Science, 2013
Investigating the correlates of consciousness in sleep…
Did the experience take place
indoors or outdoors?
High frequency activity (25-50 Hz) in REM sleep
Setting > No settting (p<0.05)
Setting > No settting (p<0.1)
Siclari et al, Under Review
Investigating the correlates of consciousness in sleep…
Were you moving?
High frequency activity (25-50 Hz) in REM sleep
Setting > No settting (p<0.05)
Setting > No settting (p<0.1)
Siclari et al, Under Review
Investigating the correlates of consciousness in sleep…
Was anyone speaking?
High frequency activity (25-50 Hz) in REM sleep
Setting > No settting (p<0.05)
Setting > No settting (p<0.1)
Siclari et al, Under Review
• Sleep is typically evaluated and classified using EEG
(preferably also with EMG and EOG)
• Sleep is accompanied by changes in regional brain
metabolism detectable using PET and fMRI
• Sleep deepening is associated with relevant changes in brain
interregional connectivity (reduction)
• Several sleep parameters are homeostatically regulated,
potentially reflecting/influencing wake-dependent plasticity
• Islands of wake and sleep may potentially coexist during
either behavioral states (potential explanation for dreams?)
Suggested Reading
Tononi, G., & Siclari, F. (2015). Sleep and Dreaming. The Neurology of
Consciousness 2nd Edition. Academic Press. Scientific American, 89-105.
Tononi, G., & Cirelli, C. (2014). Sleep and the price of plasticity: from synaptic and
cellular homeostasis to memory consolidation and integration. Neuron, 81(1), 1234.
Nir, Y., & Tononi, G. (2010). Dreaming and the brain: from phenomenology to
neurophysiology. Trends in Cognitive Sciences, 14(2), 88-100
Siclari, F., Bernardi, G., Riedner, B. A., LaRocque, J. J., Benca, R. M., & Tononi, G.
(2014). Two distinct synchronization processes in the transition to sleep: a highdensity electroencephalographic study. SLEEP, 37(10), 1621-1637.
Sarasso, S., Pigorini, A., Proserpio, P., Gibbs, S. A., Massimini, M., & Nobili, L. (2014).
Fluid boundaries between wake and sleep: experimental evidence from Stereo-EEG
recordings. Archives italiennes de biologie, 152(2/3), 169-177.