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A. Physiological basis of sleep
5. Effects of acute and chronic sleep deprivation
HANS-PETER LANDOLT
1,2,3,4
, ALEXANDRA SOUSEK
1
and
SEBASTIAN C. HOLST
1
1
Institute of Pharmacology and Toxicology, University of Z€
urich, Z€
urich, Switzerland,
2
Z€
urich Center for Inter-Disciplinary Sleep Research (ZiS),
University of Z€
urich, Z€
urich, Switzerland,
3
Z€
urich Center for Integrative Human Physiology (ZIHP), University of Z€
urich, Z€
urich, Switzerland and
4
Neuroscience Center Z€
urich (ZNZ), University of Z€
urich and ETH Z€
urich, Z€
urich, Switzerland
Keywords
Xxxxx, xxxx
1
Correspondence
Hans-Peter Landolt, PhD, Institute of Pharmacology and Toxicology,
University of Z€
urich, Winterthurerstrasse 190, 8057 Z€
urich,
Switzerland.
Tel.: + 41-44-635-59-53;
fax: + 41-44-635-57-07;
e-mail: landolt@pharma.uzh.ch
KEY POINTS
•Sleep deprivation increases sleepiness, impairs mood
states and emotional processing and contributes to
altered risk-taking and decision-making behaviour.
•Long-term sleep restriction may lead to a reduced
sense of sleepiness despite continuing reductions in
cognitive performance capabilities.
•Important negative health outcome measures such as
weight gain, obesity, type 2 diabetes, cardiovascular
disease, hypertension and inflammation have been
associated with insufficient sleep.
•Several immune-related transcripts and markers of
infection are altered after sleep restriction, providing a
possible pathophysiological basis for the elevated risk
of falling sick after sleep loss.
•Insufficient sleep has been associated with elevated
mortality, enhanced accident risk and a generally
increased incidence of errors.
SUMMARY
Chronic sleep restriction and acute total sleep loss are
highly prevalent in the modern ‘24/7 society’and pose
significant risks for quality of life, mental wellbeing,
cognitive performance and physical health. The con-
sequences of acute and chronic sleep deprivation have
become a public health concern. Based on the cata-
logue of knowledge and skills for sleep medicine, this
chapter focuses on the effects of sleep deprivation on
emotional state, mood, cognition, physical health and
immune functions. We review the effect sizes of these
different consequences of lack of sleep and provide
insights into possible neuroanatomical and (neuro)
physiological underpinnings of how insufficient sleep
could impact upon these health outcomes. A better
understanding of these relationships is important,
because the avoidance of short and inadequate sleep
may be amenable to modification and help to save
increasingly high social, financial and health-related
costs for the affected individuals and for society.
INTRODUCTION
It is well established that enough and undisturbed sleep are
essential for an individual’s personal wellbeing and the
ability to perform correctly. With the increasing economic
and social demands of the modern ‘global 24/7 society’,
more and more people work and stay active outside the
regular day and curtail their sleep. The negative effects of
chronic sleep restriction on productivity and health have
begun to be appreciated as a public health concern, yet are
still often underestimated (Goel et al., 2009). Thus, sleep-
iness has surpassed alcohol and drugs as the greatest
identifiable and preventable cause of accidents in all modes
of transport.
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ª2014 European Sleep Research Society 1
JSR 12157
Dispatch: 31.3.14 CE: Lenard S.
Journal Code Manuscript No.
No. of pages: 13 PE: Sudhakar G
The most common measure reflecting insufficient sleep in
population-based studies is daytime sleepiness (Goel et al.,
2009). To determine the prevalence of daytime sleepiness in
a large public health database, 1007 randomly selected
adults aged 21–30 years were interviewed twice between
1989 and 1995. It was noted that low, medium and high
subjective sleepiness as quantified with a self-administered
instrument was related significantly to the hours of sleep on
weekdays, such that those individuals with the highest level
of sleepiness reported roughly 20 min shorter sleep (~ 6.5 h)
than those individuals with lower sleepiness levels (~ 6.8 h).
Laboratory studies began to model insufficient sleep
experienced by many individuals because of lifestyle and
medical disorders with scheduled sleep restricted to 4–7h
per 24 hours during several days. Such experiments
revealed that not only sleepiness, but also neurobehavioural
deficits, accumulate over time to severe levels (Dinges et al.,
1997; Van Dongen et al., 2003). Furthermore, after only two
nights of sleep restricted to 4 h, normal-weight young healthy
men exhibited reduced leptin, increased ghrelin and more
hunger when compared to 10 h of sleep (Spiegel et al.,
2004). These and other data have been supported by large-
scale, population-based epidemiological studies showing that
self-reported short sleep duration (often defined as ≤6h)is
commonly associated with negative health outcomes, includ-
ing impaired vigilance, weight gain, obesity, diabetes and
cardiovascular disease, as well as all-cause mortality
(Cappuccio et al., 2010).
Apart from partial sleep deprivation, short-term (≤45 h of
extended wakefulness) and long-term (>45 h of extended
wakefulness) total sleep deprivation also acutely affect
emotional, behavioural and physiological functions. Moder-
ately prolonged wakefulness can already produce psycho-
motor impairment that may be even more pronounced than
proscribed alcohol intoxication (Dawson and Reid, 1997). In a
seminal, controlled laboratory study, regression analysis
revealed a negative linear correlation between mean relative
performance on an unpredictable tracking task and the
duration of 10–26 h of sustained wakefulness. Intriguingly,
the correlation coefficient accounted for as much as 92% of
the variance in psychomotor performance. After only 17 h of
wakefulness, performance decreased to a level equivalent to
the performance impairment observed at a blood alcohol
concentration of 0.05%. This corresponds to the legal level of
alcohol intoxication in many western industrialized countries.
When wakefulness was prolonged into the night, perfor-
mance degraded further. A minimum was reached in the
early morning after 23–25 h of wakefulness, whereas a
moderate improvement was noted thereafter (Dawson and
Reid, 1997).
It is widely accepted that this time–course of performance
impairment during extended wakefulness reflects the com-
plex interaction of a sleep–wake-dependent homeostatic
process (process S) and the output of the endogenous
circadian clock (process C) (Achermann and Borb
ely, 2011).
These processes not only determine neurocognitive perfor-
mance (Goel et al., 2009), but also psychological and
physiological states, including sleepiness, emotions and
mood (Killgore, 2010), timing and quality of sleep and
important features of the sleep and waking electroencepha-
logram (EEG) (Achermann and Borb
ely, 2011). Reduced
sleep duration, increased wake time and circadian phase
affect all these aspects of wellbeing.
Several authoritative recent reviews have comprehensively
summarized distinct aspects of short sleep, chronic sleep
deprivation and an acute loss of sleep (Achermann and
Borb
ely, 2011; Goel et al., 2009; Imeri and Opp, 2009;
Knutson and Van Cauter, 2008; Landolt, 2008; Mullington
et al., 2010; Rasch and Born, 2013; Walker, 2009). Based
upon this work and according to the ‘catalogue of knowledge
and skills for sleep medicine’, this chapter summarizes
important possible risks for wellbeing, performance and
health associated with the lack of adequate sleep. A special
focus is put upon the effect sizes of the different conse-
quences of sleep loss, their implications for public health and
the possible neuroanatomical and (neuro)physiological
underpinnings of how insufficient sleep could impact upon
these distinct health outcomes.
EFFECTS OF SLEEP DEPRIVATION ON
EMOTIONAL STATE AND MOOD
The regulation of sleep, emotions and mood is closely
related. Ample evidence for this crucial interaction stems
from the common clinical observation that psychiatric dis-
eases and mood disorders are associated typically with
disturbed sleep. In addition, insomnia is a powerful predictor
of depression, suggesting that non-depressed insomniacs
have a roughly twofold risk of developing depression later
(Walker, 2009).
An early meta-analysis concluded that mood is even more
affected by sleep deprivation than either cognitive perfor-
mance or motor functions, and that the negative impact on
mood of partial sleep deprivation is even more pronounced
than either short-term or long-term complete sleep loss
(Pilcher and Huffcutt, 1996). Some of these conclusions have
since been contested, due to the development of more
appropriate experimental controls and more sensitive
assessments of the neurocognitive consequences of acute
and chronic sleep deprivation (Goel et al., 2009). Neverthe-
less, chronic restriction of sleep to roughly 5 h per night for
1 week resulted in robust cumulative impairment of emotional
wellbeing, including increased sleepiness, fatigue, confusion,
tension and total mood disturbance. These changes tended
to precede the negative impact on objective measures of
sustained vigilant attention by 1 day (Dinges et al., 1997).
Furthermore, recent work confirmed that subjective alertness
was generally more affected by both partial and total sleep
deprivation than performance across different cognitive
domains (Lo et al., 2012) (Fig. 1).
In healthy volunteers, virtually all forms of sleep deprivation
result in increased negative mood states, especially feelings
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of sleepiness, fatigue, loss of vigour, confusion and impaired
emotional processing, including frustration tolerance and
coping capacities (Killgore, 2010). Positron emission tomog-
raphy (PET) and functional magnetic resonance imaging
(fMRI) studies identified brain regions involved in these
effects of sleep deprivation. Among other findings, it was
found that activation of the prefrontal cortex (PFC) during
verbal learning correlated significantly with increased
subjective sleepiness in sleep-deprived subjects (Drummond
et al., 2000). Furthermore, activation of the amygdalae by
emotional stimuli was observed repeatedly to be altered upon
the lack of sleep. The amygdalae are part of the limbic
system and, importantly, involved in processing emotions.
For example, fMRI was used while exposing healthy individ-
uals to standardized emotional pictures (Walker, 2009). The
authors found that the amygdalae response to increasingly
aversive images was more pronounced, and activated a
larger area in sleep-deprived subjects than in rested controls.
Furthermore, relative to the sleep-control group, the func-
tional connectivity between amygdalae and ventromedial
PFC (vmPFC) was reduced in the group that was kept awake
in the night before scanning. By contrast, stronger connec-
tivity was found to autonomic brain stem regions, including
the locus coeruleus. These findings indicate that top–down
prefrontal control of emotional challenges is impaired follow-
ing sleep deprivation.
While the earlier studies highlighted increased reactivity
towards negative stimuli, more recent work also revealed
elevated reactivity in response to pleasure-evoking stimuli.
Collectively, the data suggest a ‘bi-directional affective
imbalance’upon insufficient sleep. Positive stimuli in sleep-
deprived individuals appear to amplify reactivity in mesolim-
bic reward networks, in particular ventral tegmental areas
and putamen (Gujar et al., 2011). This change was associ-
ated with increased functional connectivity in extended limbic
regions and decreased connectivity to mediofrontal and
orbitofrontal areas. Taken together, the amplified behavioural
reactivity towards both negative and positive emotional
stimuli, as well as the sleep deprivation-induced functional
changes in emotional brain networks, may contribute to
altered mood regulation, risk-taking and decision-making on
the loss of sleep (see below).
With respect to the different sleep states, it has been
traditionally assumed that deprivation of REM sleep affects
emotional reactivity and mood, due partly to the suggested
role of rapid eye movement (REM) sleep in adaptation and
attenuation of the emotional tone of previous experiences
(Walker, 2009). Interestingly, however, a recent partial REM
sleep deprivation study indicated unexpectedly that REM
sleep may attenuate adaptation and enhance morning
reactivity to negative emotional stimuli.
In contrast to the general mood impairment in healthy
individuals, total and partial sleep deprivation (‘wake ther-
apy’) have been known for decades as rapidly acting and
effective antidepressant interventions in many patients with
major depression. The mechanisms of the antidepressant
action of wake therapy are largely unknown. Clinically used
antidepressant medications, including monoamine oxidase
(MAO) inhibitors and blockers of monoamine reuptake,
typically inhibit REM sleep in depressed patients, who often
present with reduced REM sleep latency and elevated REM
density. Nevertheless, antidepressant response to the potent
classical MAO inhibitor, phenelzine, did not depend upon the
(a)
(b)
(c)
Figure 1. Comparison of effect sizes for subjective alertness,
sustained attention and working memory of (a) repeated partial
sleep deprivation, (b) acute total sleep deprivation on performance
during the circadian day and (c) acute total sleep deprivation on
performance during the circadian night. Horizontal dashed lines
indicate cut-offs for small, medium and large effect sizes; note the
different scaling in the y-axes in (a), (b) and (c). Figure reprinted with
permission from Lo et al. (2012).
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selective, complete elimination of REM sleep (Landolt et al.,
2001). Recently, suppression of slow wave sleep (SWS) was
also reported to ameliorate depressive symptoms (Lands-
ness et al., 2011). In general, the sleep deprivation-induced
improvement of mood often vanishes after recovery sleep
and cannot be maintained over time. It is hoped that a better
understanding of the tight neurobiological relationships
between sleep and mood regulation may pave the way to
the identification of biomarkers of antidepressant response,
and the development of rapid and more effective novel
treatments of depression that are eagerly searched for.
EFFECTS OF SLEEP DEPRIVATION ON
NEUROCOGNITIVE FUNCTIONS
The detrimental impact of sleep loss on human cognitive
functions has long been recognized. More recent data
demonstrate that the deficits produced by a lack of sleep
depend strongly upon the nature of the cognitive skills
examined. The current literature suggests that exposure to
partial and total sleep deprivation impairs primarily behavio-
ural alertness (sustained attention) and cognitive processing
capabilities (working memory) with measurable effect sizes
(Lo et al., 2012). Generally, sustained attention is more
affected than other cognitive domains and tasks, including
working memory, even when implemented with a high
executive load (Fig. 1).
Effects of sleep deprivation on sustained attention
The dominant assay of sustained attention in paradigms of
sleep loss is the psychomotor vigilance task (PVT) (Dinges
et al., 1997). This task has been used widely in human
studies to detect the neurobehavioural deficits associated
with chronic sleep restriction and acute total lack of sleep
(Belenky et al., 2003; Van Dongen et al., 2003). The task is
highly sensitive to sleep loss, independent of aptitude, devoid
of learning effects, and its reliability and validity have been
amply demonstrated. The PVT is a simple reaction-time task
to a visual cue that is typically presented roughly 100 times at
random intervals during 10 min. According to the ‘wake state
instability’hypothesis (see Goel et al., 2009 for review),
performance on the PVT becomes increasingly variable
under the influence of elevated sleep pressure due to
inadvertent microsleep episodes, with brief moments of low
arousal that make it difficult to sustain attention. This unstable
state, which fluctuates from second to second, is character-
ized by an increased number of lapses, errors in response
and increased compensatory efforts resulting in normal
reaction times for a short period of time.
The effect on sustained attention of controlled sleep
restriction allowing 9, 7, 5 or 3 h of sleep during 7 consec-
utive nights was studied by Belenky et al. (2003). While in the
3-h condition, a continuous slowing and a steady increase in
the number of lapses on the PVT was observed; response
speed in the 5- and 7-h conditions remained stable after the
initial drop in performance when sleep duration was first
reduced. Similar observations were made in another dose–
response experiment of chronic sleep restriction, investigat-
ing the neurocognitive effects of 14 days of sleep limitation to
8, 6 or 4 h time in bed (Van Dongen et al., 2003). No
cognitive deficits, including sustained attention, working
memory and ‘cognitive throughput’, occurred following 8 h
in bed for sleep each night. After 2 weeks of sleep restriction
to 6 h, however, deficits in all these skills were equivalent to
those seen after 1 night of total sleep loss. Two weeks of
sleep restriction to 4 h resulted in cognitive deficits similar to
those after 2 nights without sleep. Importantly, the cognitive
deficits accumulated much faster when no sleep was allowed
than when the same amount of sleep was lost more gradually
over days of sleep restriction. Based on these findings, the
authors proposed that the critical factor in producing daytime
cognitive performance deficits was the cumulative amount of
time subjects spent awake in excess of their usual wakeful-
ness period (Van Dongen et al., 2003).
In contrast to other studies (see above), sleepiness ratings
in this experiment showed much smaller increases during
sleep restriction than the cognitive impairments, suggesting
an escalating dissociation between the subjective perception
of sleepiness and the actual cognitive performance capability
(Van Dongen et al., 2003). Furthermore, EEG slow wave
(‘delta’) activity (SWA) in non-rapid eye movement (NREM)
sleep, the most reliable physiological marker of homeostatic
sleep pressure after total sleep loss (Achermann and
Borb
ely, 2011), showed no statistically reliable progressive
changes across days of sleep restriction in any of the chronic
sleep restriction conditions (Van Dongen et al., 2003). It was
concluded that, as long as at least 4 h sleep per night are
permitted, SWA does not reflect the homeostatic need for
sleep during wakefulness (Van Dongen et al., 2003). A
subsequent study, however, demonstrated robust homeo-
static responses in EEG SWA to sleep restriction (Akerstedt
et al., 2009). In this study, sleep was restricted to 4 h of sleep
across 5 days, followed by 3 nights of recovery sleep. Sleep
restriction indeed resulted in dynamic changes in the EEG
low-frequency activity (1.25–7.0 Hz band) in NREM sleep.
The increase was particularly evident during the first 4 h of
sleep, and returned to baseline by night 2 of recovery sleep.
Sustained attention is also largely impaired after total sleep
deprivation (Fig. 1). Collectively, four dominant findings have
emerged from the use of the PVT in sleep deprivation
protocols. First, the evolution of PVT performance during
extended wakefulness reveals the presence of the interacting
homeostatic and circadian sleep-regulatory processes
(Fig. 2). Secondly, sleep deprivation results in an overall
slowing of responses. Thirdly, sleep deprivation increases
the propensity of individuals to lapse for lengthy periods
(>500 ms), as well as to make false starts. Both restricted
sleep and total lack of sleep impair PVT performance in a
dose-dependent manner. Finally, sleep deprivation enhances
the time-on-task effect, the phenomenon whereby perfor-
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mance worsens during the course of a cognitive task owing to
fatigue and reduced motivation.
Effects of sleep deprivation on executive functioning and
decision-making
Although less consistent than changes in emotional process-
ing, impairments in sustained attention and increased EEG
low-frequency activity in wakefulness and sleep, sleep loss
was shown repeatedly to impact adversely on higher-order
cognitive skills. For example, learning, working memory,
decision-making, expectation of reward, adapting and revis-
ing plans, divergent thinking, reasoning, behavioural inhibi-
tion and problem-solving were all reported to be impaired
after sleep deprivation (Goel et al., 2009). Nevertheless, it is
still controversial whether this impairment merely reflects the
negative impact of sleep loss on underlying basic cognitive
capacities such as vigilant attention or, alternatively, whether
sleep deprivation distinctly affects specific higher-order cog-
nitive functions beyond reduced attention.
Increasing evidence suggests that the latter possibility is
the case. Already, 24 h of prolonged wakefulness caused a
global decrease in absolute cerebral glucose metabolic rate
during performance of a computer-based serial addition/
subtraction task in thalamus, PFC, posterial parietal cortices
and basal ganglia together with impaired vigilance (Thomas
et al., 2000). By contrast, sleep-deprived individuals showed
distinctly different cerebral responses in these brain areas
when performing other cognitive tasks (Drummond et al.,
2000). For example, during arithmetic tasks, sleep loss
decreased activation of PFC and parietal lobes. During verbal
learning, the temporal lobe was activated after normal sleep
but not after a night without sleep, whereas the parietal lobes
were activated after sleep deprivation in contrast to the rested
control condition. Finally, a divided attention task comprising
arithmetic aspects and verbal learning performed after 35 h
sustained wakefulness led to enhanced activation of PFC
and parietal lobes. The activation in these brain areas
correlated with memory performance. Taken together, the
findings indicate that dynamic, task-related and region-
specific changes in cerebral activation maintain performance
on distinct neurocognitive tasks after sleep deprivation. In
particular, complex rule-based, convergent logical tasks
appear to show little change following sleep loss. Conversely,
divergent skills such as flexible thinking, taking decisions in
the light of unexpected new information, innovation, revising
plans and preventing distraction may be substantially
affected by excess wakefulness (Harrison and Horne, 2000).
Implicit in divergent thinking abilities and decision-making
is the important reliance on executive functions that draw
heavily upon resources in the PFC (Goel et al., 2009).
Various pharmacological studies aimed at disentangling the
relationships between reduced vigilance and attention and
deteriorated executive functions after sleep loss. It was found
repeatedly that caffeine, modafinil and dextroamphetamine
diminish the negative impact of short- and long-term sleep
deprivation on subjective sleepiness, arousal, attention and
basic cognitive skills (Landolt, 2008). By contrast, the ability
to integrate emotion with cognition to guide decisions was
typically unimproved by moderate doses of these wake-
promoting agents. These findings further support the notion
that the sleep deprivation-induced impairments of executive
functions are separate from simple arousal and alertness
systems.
In patients with damage to the vmPFC, decision-making is
typically impaired such that focus is shifted towards short-
term outcomes. A similar behaviour is often seen in sleep-
deprived individuals in whom risk assessment and valuation
d d
****
d
d d
Figure 2. Time–course of performance on the psychomotor vigilance task (PVT) across 40 h prolonged wakefulness in young caffeine-
sensitive (n= 12, green and olive dots), young caffeine-insensitive (n= 10, dark blue and light blue diamonds) and middle-aged (n= 10, black
and grey squares) men. The evolution of performance reveals the interaction of homeostatic and circadian sleep regulatory processes. Means
standard error of the mean of the slowest 10th percentile of reaction times, a sensitive marker for sleep loss, is plotted. The 10–min PVT
sessions were administered every 3 h beginning 30 min after awakening from the baseline night. Ticks on the x-axes were rounded to the
previous hour. Caffeine (200 mg) and placebo were administered 11 and 23 h into the scheduled waking period (arrows) according to a
randomized, double-blind, cross-over study design. Self-rated caffeine sensitive individuals are most impaired by sleep loss, yet benefit the
most from caffeine. Data were replotted from Landolt et al. (2012). *P< 0.05 (false discovery rate).
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during decision-making also appears to be altered. Thus,
sleep deprivation prompted healthy volunteers to take more
risks in a gambling task compared to when they were well-
rested, in particular when the possible outcomes were framed
in terms of potential gains. By contrast, when the same task
was presented in terms of potential losses, lack of sleep led
them to take fewer risks than usual. Functional neuroimaging
studies have highlighted that sleep-deprived individuals show
differences within brain-reward circuitry during risky decision-
making (Venkatraman et al., 2007). Specifically, increased
nucleus accumbens activation following risky choices and
reduced neural responses in insular and orbitofrontal cortices
following losses may bias them towards expectation of gains
while reducing their focus on losses.
Such findings further indicate that sleep-deprived individ-
uals place reduced weight on new information when making
choices. Instead, they rely more upon pre-existing cognitive
biases and tend to adhere to automatic, stereotypical and
redundant forms of cognitive processing. Emotional biasing is
a form of automatic processing that may influence decision-
making by emotional ‘gut reactions’, which prime people to
make choices based on how rewarding or unpleasant they
perceived a previous similar experience to be. In an exper-
imental setting, this emotion-guided decision-making can be
investigated using the Iowa Gambling Task (IGT). During this
task, on a computer screen, participants are presented with
four decks of cards placed face down. Players are required to
select 100 cards from these four available packs. On card
selection, they are immediately informed as to whether the
card they selected results in a monetary gain or a monetary
loss. Unknown to the subjects, two of the decks are ‘good’
decks and lead to small but consistent net gains. The other
two decks are ‘bad’decks and comprise large short-term
gains but consistent long-term losses. Healthy, well-rested
individuals usually learn from the trial-by-trial feedback and
adjust their playing strategy to avoid the risky bad decks in
favour of the modest, but consistently advantageous, good
decks. However, following 49 and 75 h of prolonged wake-
fulness, study participants showed a significant decline in
performance. Specifically, they became progressively more
risk-taking and short-sighted in decision-making, tending to
prefer risky short-term gains at the expense of incurring long-
term losses (Killgore, 2010). Such findings are in line with
evidence that damage to the vmPFC leads to shortsighted-
ness for the future, as well as neuroimaging data that indicate
that this brain region plays a key role in the decision-making
process of the IGT.
Effects of sleep deprivation on neurophysiological
markers of cortical functioning
As stated above, the vmPFC belongs to those brain regions
that are particularly affected by sleep deprivation. Metabolic
activity of the vmPFC is drastically reduced after a night of
sleep loss (Thomas et al., 2000). Furthermore, PET mea-
sures of vmPFC activity (i.e. cerebral blood flow) correlate
with EEG SWA (0.75–4.5 Hz range) in NREM sleep. Con-
sistent with this finding, not only the increase in SWA in
NREM sleep, but also the rise in EEG theta (~ 5–9 Hz range)
activity after prolonged wakefulness is larger over anterior
than posterior cortical areas (Achermann and Borb
ely, 2011).
Taken together, behavioural, pharmacological, neuroimaging
and neurophysiological data suggest consistently that the
vmPFC and higher-order cognitive processes associated
with this brain area are specifically affected by sleep
deprivation. Nevertheless, particularly during shorter dura-
tions, such as 1 night of sleep deprivation, deficits in
executive functions have not been observed universally.
This suggests that the brain’s executive function systems
may compensate temporarily for brief sleep loss by utilizing
additional cognitive resources via activation of alternative
brain regions (Drummond et al., 2000).
Effects of sleep deprivation on learning and memory
A highly active area of research during the past decade
investigated the role for sleep in encoding, consolidation and
retrieval of declarative and procedural memories (Rasch and
Born, 2013). To this end, various sleep deprivation protocols
were conducted, including sleep restriction before and after
learning, early and late partial sleep deprivation and selective
(partial) SWS and REM sleep deprivation. The possible
beneficial effects of nap sleep for learning and memory were
also studied. Although the exact nature and a causal role for
sleep in the relationship between sleep and memory consol-
idation still need to be clarified, the simplified current state of
this research may be summarized briefly as follows: (i) sleep
promotes the consolidation of memories, i.e. the transforma-
tion of newly encountered labile information into stable
representations integrated in pre-existing networks;
(ii) SWS benefits the promotion of hippocampus-dependent,
declarative memories; and (iii) REM sleep benefits the
promotion of procedural memories. For a more comprehen-
sive discussion of the relationships between sleep and
memory, please refer to chapter 2[...] of this textbook. Very
recently, the hypothesis that sleep may serve the selective
erasure of (negative) memories have also received some
experimental support. Critical evaluation of the literature,
however, reveals that effect sizes are often small and that the
underlying mechanisms and possible contribution of the
different sleep states to distinct aspects of learning and
memory remain controversial.
Apart from being a whole-brain phenomenon, it is increas-
ingly accepted that sleep and the homeostatic regulation of
sleep also entail local and use-dependent aspects (Acher-
mann and Borb
ely, 2011). Thus, sleep slow waves occur with
increased prevalence over brain regions activated and used
preferentially during waking experiences. It has been sug-
gested that slow waves, in particular the ‘neocortical’slow
oscillation, together with hippocampal sharp-wave ripples
and thalamocortical spindles, reflect the reactivation and
consolidation of memories. These sleep oscillations may
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promote the transformation and integration of recently
encoded neuronal memory representations into long-term
memory (‘active system consolidation’) (Rasch and Born,
2013). Alternatively, the ‘synaptic homeostasis hypothesis’
proposed by Tononi and Cirelli (2006) assumes that sleep
slow waves serve to normalize global synaptic strength
potentiated in the course of information encoding during
wakefulness. According to this concept, linear synaptic down-
scaling enhances the signal-to-noise ratio and strengthens
learning and important memories indirectly by nullifying
connections that were not or only weakly potentiated during
previous waking experiences. The two hypotheses may not
be mutually exclusive. Thus, supporting evidence for and
concerns against both these theories as the sole mechanism
underlying sleep-dependent memory benefits have been
brought forward.
While recent research has focused on the role for SWS
in memory consolidation, the contribution of REM sleep to
learning and memory has gained less attention. Tradition-
ally, REM sleep was associated with retention of emotional
memories, yet the findings about the role of REM sleep in
human memory processing are inconsistent (Rasch and
Born, 2013). An important argument against a critical
contribution of REM sleep to memory processes is the lack
of any documented memory deficits in depressed
patients who may experience long-term, almost complete
pharmacological REM sleep suppression during therapy
with certain antidepressant medications (Landolt et al.,
2001).
As introduced above, multiple studies reported altered
task-related brain activation in sleep-deprived individuals
when memory for contents with different emotional values
was tested. In one study, recognition memory was probed
72 h after encoding of emotional and neutral information
(Sterpenich et al., 2007). During the night after encoding,
subjects were either kept awake or allowed to sleep. Sleep
deprivation resulted in the reduced activation of vmPFC,
amygdalae and occipital cortex during recognition, although
performance was tested in a well-rested condition. The
connectivity among these areas was also altered between
the sleep and sleep-deprivation groups (Sterpenich et al.,
2007). In the sleep group, retention of emotional memories
was associated with greater activation of hippocampus and
medial PFC, as well as enhanced connectivity between these
brain areas. In the sleep deprivation group, retention of
negative memories elicited greater response in amygdalae
and occipital areas. Sleep loss prior to learning also showed
differential effects depending on the valence of information
(Walker, 2009). While, in the sleep condition, positive and
negative emotions were more efficiently encoded, sleep
deprivation caused a decline in memory of neutral and
positive contents. On the contrary, retrieval of negative cues
was less impaired by sleep deprivation. These findings
indicate that different mechanisms are involved in the
processing of emotionally relevant information. It was sug-
gested that activation of an alternative amygdalae–cortical
network permits the retention of negative, possibly threaten-
ing, information, even under suboptimal, sleep-deprived,
conditions.
EFFECTS OF SLEEP DEPRIVATION ON
PHYSICAL HEALTH
Classic studies dating back to more than a century ago had
already reported that several weeks of sleep deprivation in
dogs disrupted temperature regulation and metabolism,
increased appetite and enhanced risk of infections, and led
ultimately to the death of the laboratory animals. Although the
exact underlying mechanisms remained unknown and severe
stress associated with such experiments probably contrib-
uted to the outcome, the main findings were later replicated in
rats under more controlled conditions, following both pro-
longed total sleep deprivation as well as selective REM sleep
deprivation (Rechtschaffen and Bergmann, 2002). Together,
the studies indicate that long-term chronic sleep loss may be
fatal.
In humans, research over the last few decades has
provided growing evidence that lack of sleep exerts detect-
able, deleterious changes in endocrine, metabolic and
immune pathways. A recent meta-analysis of large prospec-
tive, population-based studies revealed that people reporting
consistently sleeping ≤5 h per night have a 12% increased
risk for all-cause mortality when compared with 6–8h of
sleep per night (Cappuccio et al., 2010). Based on the
currently available evidence, it is possible that sleep depri-
vation triggers biological mechanisms which contribute to the
deterioration of health status and increased morbidity,
including obesity, reduced glucose tolerance, insulin resis-
tance, diabetes, cardiovascular vulnerability, hypertension
and infectious diseases.
Effects of sleep deprivation on appetite and body mass
homeostasis
Chronic sleep restriction is increasingly common in our hectic
modern society, due to lifestyle choices, work and family
demands and/or physical or psychological problems. It
appears that during the past 50 years sleep duration in
adults and teenagers has decreased by almost 2 h per night.
It may be important to note that this decrease has coincided
with the progression of obesity and type 2 diabetes (T2D) in
western industrialized societies. These developments con-
stitute important public health concerns, and interventions
designed to prevent the onset and progression of obesity and
T2D are essential. Given that short duration and poor quality
of sleep provide newly identified, possibly preventable risk
factors for metabolic disease, a wealth of cross-sectional, as
well as prospective, epidemiological studies recently exam-
ined the possible metabolic consequences of short and
insufficient sleep and total sleep loss. Although discrepant
findings cannot be ignored (Tare et al., 2014) 3, the literature
generally suggests that inadequate sleep indeed provides a
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risk factor for the development of obesity, impaired glucose
tolerance and T2D (Knutson and Van Cauter, 2008).
For example, after only 2 days of sleep curtailment from 10
to 4 h time in bed, leptin levels in lean healthy volunteers
were found to decrease, whereas ghrelin levels, hunger and
appetite were found to increase (Spiegel et al., 2004). The
changes were remarkably pronounced, equalling between 18
and 33% (Fig. 3). Together with insulin, the hormones leptin
and ghrelin play important roles in regulating food intake and
appetite. Their changes after sleep restriction could contrib-
ute to a physiological mechanism underlying the proposed
adverse impact of insufficient sleep on body mass homeo-
stasis (Knutson and Van Cauter, 2008). Leptin is released
from adipocytes after food intake and mediates the percep-
tion of satiety. Ghrelin is produced in cells of the stomach and
the intestines; its levels rise before meals and during fasting
and fall rapidly after food intake. Both leptin and ghrelin
influence the central nervous system via different receptor
systems in the ‘appetite centre’of the brain that controls
homeostatic food intake: the ventromedial and arcuate nuclei
of the hypothalamus (Knutson and Van Cauter, 2008). Leptin
inhibits and ghrelin activates neurones of the arcuate
nucleus.
Leptin and ghrelin also influence the activity of the
hypocretin (or orexin) system that integrates the control of
feeding, energy homeostasis and the stabilization of con-
solidated wakefulness and sleep. Hypocretin is produced by
a small cluster of 10 000–20 000 neurones in the lateral
hypothalamus, which innervates not only the arcuate
nucleus, but also the paraventricular nucleus (PVN), the
nucleus tractus solitarius (NTS), the nucleus accumbens,
the ventral tegmental area (VTA), the cerebral cortex and
other areas of the ascending arousal system (ARAS)
(Knutson and Van Cauter, 2008). Neurones within PVN
and NTS are important for satiety, taste and autonomic
functions controlling energy balance, whereas the dopami-
nergic nucleus accumbens and VTA are ‘reward and
motivation’centres that modulate hedonic, non-homeostatic
food intake. Finally, the cerebral cortex and the ARAS
maintain and regulate higher-order cognitive functions,
arousal and vigilance, as well as wakefulness and sleep.
Given that hypocretin neurones are functionally inhibited by
leptin and functionally excited by ghrelin, the sleep depriva-
tion-induced alterations in leptin and ghrelin will lead to
enhanced hypocretin activity. This system appears, thus, to
be ideally placed to link inadequate sleep and excess
feeding (Fig. 4).
Another possible brain mechanism by which insufficient
sleep may contribute to the development and maintenance of
obesity was proposed recently on the basis of an fMRI study
(Greer et al., 2013). Healthy, normal-weight participants
completed a counterbalanced, cross-over study protocol
involving a night of normal rested sleep (average 8.2 h
asleep) and a night of monitored total sleep deprivation
(average 24.6 h awake), separated by at least 1 week.
There were no differences in self-reported hunger. When
compared to the sleep-rested state, however, sleep depri-
vation using a food-desire task resulted in a significant
increase in the proportion of ‘wanted’high-caloric food items.
Specifically, participants saw and rated 80 food items on a
scale from 1 to 4, according to how much they wanted the
food item during fMRI scanning. As food desire progressively
increased, sleep deprivation diminished activity in anterior
cingulate cortex, lateral orbitofrontal cortex and anterior
insular cortex (Greer et al., 2013). Interestingly, the reduced
activity in these cortical appetitive evaluation regions after
the lack of sleep was accompanied by increased respon-
siveness of the amygdalae to desirable food items. The
findings may suggest that increased food craving after sleep
loss is associated with reduced activity in frontal cortex,
combined with a converse amplification of activity within the
amygdalae that are known to signal food salience in the
context of appetitive choices.
Sleep deprivation and T2D
Because both hyperglycaemia and hypoglycaemia pose
severe health risks to the organism, blood glucose levels
need to be regulated tightly. Brain glucose utilization is the
rate at which glucose is metabolized in brain tissue. It is
related closely to glucose tolerance, a measure of how
rapidly blood glucose levels are normalized following intra-
venous glucose injection or ingestion of a standardized
(carbohydrate-rich) meal. Glucose tolerance reflects how
efficiently insulin-dependent and insulin-independent tissues
respond to and metabolize increased blood glucose levels.
Glucose regulation and insulin secretion undergo strong
circadian and sleep-dependent influences, such that glucose
tolerance is lowest in the middle of the habitual sleep period
(Spiegel et al., 1999). Sleep restriction and acute and chronic
sleep loss have been associated with increased blood
glucose levels, and larger field studies support this associ-
ation derived from controlled laboratory experiments. For
example, in a cross-sectional sample of 740 young and
Figure 3. Change in daytime levels of leptin, ghrelin, hunger and
appetite after 2 days of curtailed sleep from 10 to 4 h bedtime in 12
healthy lean volunteers. Data were replotted from Spiegel et al.
(2004). *P< 0.05; **P≤0.01 (Wilcoxon’s matched-pairs signed-
rank tests). Hunger and appetite were measured on visual analogue
scales.
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middle-aged adults, fasting glucose levels were significantly
higher in short-sleeping men and women reporting 5–6hof
sleep per night when compared to ‘normal’(7–8 h) and ‘long’
(9–10 h) sleepers (Chaput et al., 2007). Furthermore, the
prevalence of impaired glucose tolerance, quantified by the
widely validated homeostatic model assessment (HOMA)
levels, was increased by 58% in the short sleepers in
comparison to the ‘normal’sleeping reference group. The
data suggest collectively that short sleep duration and
inadequate sleep, either behavioural or related to sleep
disorders, are deleterious for glucose utilization and meta-
bolism.
Deep SWS is associated with a decrease in brain glucose
metabolism. In addition, SWS exerts major modulatory
effects on endocrine release. The release of growth hormone
(GH) and prolactin is increased, whereas the release of other
hormones of the hypothalamic–pituitary–adrenal (HPA) axis,
such as thyrotrophin and cortisol, is inhibited. Both GH and
cortisol have important roles in glucose metabolism. In
particular, the secretion of GH is dependent upon the
occurrence and quality of sleep, such that the most repro-
ducible GH pulse occurs shortly after sleep onset (Knutson
and Van Cauter, 2008). The GH stimulates muscle build-up,
lipolysis and gluconeogenesis in the liver. By contrast, the
steroid hormone, cortisol, is released primarily in response to
stress and stimulates glycogenolysis, i.e. the breakdown of
glycogen to glucose. In normal sleepers, nocturnal GH
release was shown to be reduced during total sleep depri-
vation, but subsequently increased in daytime recovery sleep
(Knutson and Van Cauter, 2008). Cortisol was affected
adversely by acute total sleep loss. Based on these and other
studies, it has been suggested that sleep deprivation results
in increased sympathetic nervous activity, increased levels of
GH in the daytime and increased levels of cortisol in the
evening. These effects could lead to reduced glucose
tolerance (Fig. 4).
Chronic high blood glucose concentration constitutes a key
symptom of T2D, which is mediated by insulin resistance, i.e.
the inability of insulin-sensitive tissues to respond adequately
to insulin. The effects of chronic sleep restriction on blood
glucose regulation and T2D risk was examined in healthy
subjects who gained <4 h of sleep during 6 consecutive
nights, followed by 6 recovery nights with a 12-h sleep
opportunity (Spiegel et al., 1999). At the end of each study
block, an intravenous glucose tolerance test was adminis-
tered followed by 24-h blood sampling at regular intervals.
When compared to the recovery condition, sleep restriction
induced a 40% reduction in glucose tolerance, a 30%
reduction in insulin-independent glucose disposal and a
30% reduction in acute insulin response (Spiegel et al.,
1999). These findings are consistent with cross-sectional, as
well as prospective, epidemiological studies indicating that
short sleep duration and acute total sleep deprivation, as well
as self-reported sleep problems or the presence of obstruc-
tive sleep apnea and insomnia, predict increased insulin
resistance and increased risk of developing T2D (Fig. 4).
However, it should be kept in mind that there are reported
differences in the hormonal effects of acute total sleep loss
Figure 4. Simplified schematic of putative pathways leading from sleep deprivation and insufficient sleep to weight gain, obesity, type 2
diabetes, cardiovascular vulnerability and hypertension. Figure adapted and extended from Knutson and Van Cauter (2008). Other possible
consequences of sleep loss contributing to changes in metabolism, such as more time to eat or reduced energy expenditure, are not depicted.
COLOR
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compared to recurrent partial sleep deprivation (Knutson and
Van Cauter, 2008). Further research is thus required to
elucidate the mechanisms and causality of these suggested
relationships.
Effects of sleep deprivation on cardiovascular
vulnerability and hypertension
The autonomic nervous system (ANS) controls ‘fight-or-flight’
reactions. Increased activity of the sympathetic nervous
system is responsible for reduced pancreatic insulin secre-
tion, increased contractile force of the heart, constriction of
blood vessels and dilation of bronchioles of the lungs. Heart
rate and heart-rate variability have proved useful in sleep
research and chronobiology to estimate the sympathetic/
parasympathetic balance after challenges to the sleep–wake
system. Recent data show that acute sleep deprivation leads
to greater sympathetic influence on the autonomic control of
the heart (Viola et al., 2008). Furthermore, sympathetic
predominance increases and parasympathetic indexes
decrease during recovery sleep after prolonged wakefulness.
From the perspective of the heart, such recovery sleep
appears not to have the characteristics of physiologically
restorative sleep, i.e. low sympathetic predominance.
Increased sympathetic nervous activity also leads to hyper-
tension. These findings suggest that insufficient sleep could
increase cardiovascular vulnerability (Fig. 4). However, a
systematic review and meta-analysis of 15 prospective
studies including almost 475 000 people did not support this
notion unequivocally (Cappuccio et al., 2011). Short sleep
duration (≤5–6 h per night) was not associated significantly
with total cardiovascular disease, yet was associated with a
48% enhanced risk of developing or dying of coronary heart
disease and a 15% enhanced risk of stroke. By contrast, long
sleep duration (>8–9 h per night) predicted all three cardio-
vascular outcomes. It was concluded that people reporting
consistently sleeping 5 h or less per night should be regarded
as a higher-risk group for cardiovascular morbidity and
mortality, whereas sleeping 9 h or more per night may
represent a diagnostic tool for detecting subclinical or
undiagnosed comorbidity.
EFFECTS OF SLEEP DEPRIVATION ON IMMUNE
FUNCTIONS
The increased risk of sleep-deprived people to develop
obesity, diabetes and cardiovascular disease has one com-
ponent in common: all these health problems reflect, at least
in part, the occurrence of inflammatory processes (Mullington
et al., 2010). Pioneering early studies revealed that the
cerebrospinal fluid of sleep-deprived animals caused other
animals to fall asleep. In an attempt to identify the underlying
‘hypnotoxin’,an‘endogenous factor S’was isolated and
characterized as a bacterial cell wall peptide, muramyl
dipeptide. This peptide and purified endotoxin fragments in
humans induce the production of primary cytokines of the
inflammatory system, including interleukin (IL)-1, tumour
necrosis factor (TNF) and nuclear factor kappa B (NF-jB)
(Imeri and Opp, 2009; Krueger et al., 1984; Mullington et al.,
2010). Together with other neurochemicals such as adeno-
sine, nitric oxide, prostaglandin D
2
and GH-releasing
hormone, these cytokines are widely accepted to play an
important role in the physiological regulation of NREM sleep
duration and intensity. Indeed, as most people have expe-
rienced themselves, sleep is altered during infections and
general disease. In the laboratory, an immune challenge
increases the duration and intensity of NREM sleep dose-
dependently, as quantified by EEG SWA, and reduces REM
sleep (Mullington et al., 2010).
In simplified terms, the immune system protects its host
from pathogens and infections and consists of two main
parts, the innate immune system and the adaptive immune
system. The innate immune system is non-specific and more
or less functional immediately after birth. It includes the
physical and chemical protection mechanisms of the organ-
ism, such as skin, mucosae, saliva and resident bioflora. In
principle, enhanced cortisol levels after sleep deprivation
could lead to the breakdown of skin collagen and thereby
reduce the protective function of the innate immune system. If
a pathogen penetrates the physical barriers of the body, the
innate immune system also activates non-specific immune
cells, including lymphocytes, macrophages, cytokines and
the complement system. These cells can trigger fever and
inflammatory processes. Furthermore, the adaptive immune
system is also activated. It is slower, yet highly potent and
very specific. It consists of B and T cell-type lymphocytes,
which are able to present antigens, detect and eliminate
pathogens and finally ‘remember’the eliminated pathogen,
which allows for more rapid elimination if encountered again
later.
The acute-phase response refers to the rapid and early
activation of an immune cascade in response to injury and
infection. This response involves activation of Toll-like
receptors that trigger genetic transcription of NF-jB and
leads to the production of IL-1b, TNF-aand IL-6 (Mullington
et al., 2010). Recent genetic studies in humans demonstrate
that these established markers of the acute inflammatory
system respond strongly to sleep loss induced by either
partial sleep restriction or acute total sleep deprivation (Aho
et al., 2013; Moller-Levet et al., 2013). For example, Aho
et al. (2013) analysed gene expression in peripheral blood
mononuclear cells taken from sleep-deprived healthy volun-
teers following 5 days of sleep restriction to 4 h per day
(n= 9). Genome-wide microarrays were compared to a
rested control group (n= 8) and a population-based epide-
miological cohort (n= 472) with ‘self-reported sufficient
sleep’or ‘self-reported insufficient sleep’. The study revealed
that sleep restriction altered the expression of 117 genes. In
another study, 26 participants were exposed to two exper-
imental conditions, 1 week with insufficient sleep (~ 5.7 h per
24 h) and 1 week with sufficient sleep (~ 8.5 h per 24 h)
(Moller-Levet et al., 2013). Immediately after each condition,
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whole-blood RNA samples were collected from each partic-
ipant. Transcriptome analyses revealed that 711 genes were
up- or down-regulated by insufficient sleep. While different
biological processes were affected (e.g. sleep homeostasis,
circadian rhythms, stress, metabolism), the studies showed
collectively that many among the most up-regulated tran-
scripts were indeed related to the immune system, including
Toll-like receptors, proinflammatory cytokine production and
B cell activation (Aho et al., 2013; Moller-Levet et al., 2013).
This notion was supported further by similar findings in the
population sample in which, in men, a significant association
was noted between self-reported insufficient sleep and the
levels of the well-known inflammation marker, C-reactive
protein (Aho et al., 2013). Related findings from other studies
suggest that short sleep following a rhinovirus infection
increases the risk of catching the common cold by almost
threefold.
Another interesting aspect of insufficient sleep is related to
the adaptive immune system and the response to vaccina-
tions. A recent study investigated a role for sleep in boosting
immunological memory, and followed the T helper cell and
antibody response to hepatitis A and B inoculations over
1 year (Lange et al., 2011). The study enrolled 27 healthy
men divided into two groups, assigned randomly to either
stay awake (n= 14) or to sleep (n= 13) during the night
following each vaccination injection. Three injections of
hepatitis A combined with hepatitis B vaccine were admin-
istered at weeks 0, 8 and 16. Polysomnographic EEG was
recorded in the group that was allowed to sleep. Sleep during
the post-vaccination nights was characterized by high SWA
and accompanying levels of immunoregulatory hormones
(e.g. increased GH and prolactin and decreased cortisol).
When compared to the sleep deprivation group, the level of
hepatitis A virus-specific T helper cell response to vaccina-
tion was almost doubled 4 weeks after the first injection of the
vaccine. This effect even persisted until follow-up after
1 year. In addition, both at the time of the third inoculation
as well as at follow-up, EEG SWA in NREM sleep was
correlated strongly with the hepatitis A virus-specific T helper
cell response to the vaccine (Lange et al., 2011).
Taken together, the available findings amply demonstrate
that sleep deprivation impairs the immune response in
humans. Conversely, changes in inflammatory cytokines
during an infection not only lead to fever but also promote
deep sleep. It has been proposed that these changes may
serve an evolutionary purpose, thus reducing the risk of
spreading the infection and at the same time keeping the
infected individual immobilized at home and in a safe
environment (Imeri and Opp, 2009).
OTHER EFFECTS OF SLEEP DEPRIVATION
The possible consequences of acute and chronic sleep
deprivation also include an elevated risk of accidents in
traffic, at work and during leisure (Goel et al., 2009). For
example, sleep-related accidents while driving may be the
underlying cause of about 30% of fatal motor vehicle crashes
in Europe and the United States, yet the exact numbers are
difficult to estimate. Similarly, the risk of occupational
accidents, including medical errors and adverse events by
residents, are more frequent when working sleep-deprived.
Some of the major accidents in history have been linked to
human error due to the lack of sleep. Such disastrous
examples include the explosion in the nuclear plant ‘Three
Mile Island’(1979), the nuclear meltdown in Chernobyl
(1986) and the Exxon Valdez oil spill (1989). The occurrence
of insufficient sleep can reflect lifestyle choices, overwhelm-
ing occupational, family or social demands or medical
problems. Thus, a recent screening for sleep disorders in
almost 5000 American police officers revealed a >40%
prevalence of at least one type of sleep disorder (Rajaratnam
et al., 2011). Bad sleep quality was associated significantly
with adverse performance, safety and health outcomes.
These findings highlight the possible importance of aware-
ness, screening, prevention and treatment programmes to
improve the quantity and quality of sleep in society to reduce
these risks.
CONCLUDING REMARKS
It has become increasingly apparent that acute and chronic
sleep deprivation pose significant risks for quality of life,
performance and mental and physical health in society.
Nevertheless, in particular with respect to neurocognitive
performance, research over the last decade has demon-
strated that decrements in performance after sleep loss
depend upon the task examined. Furthermore, they also
reflect differential individual vulnerability to the consequences
of sleep loss. Accumulating data suggest that these differ-
ences are trait-like and, at least in part, genetically deter-
mined. Ongoing research has begun to examine the distinct
underlying genetic influences (Goel et al., 2009; Landolt,
2008). Some of the first results revealed that genetic variants
modulating adenosine receptor-mediated neurotransmission
contribute to individual differences in PVT performance in
rested and sleep-deprived states. This conclusion is sup-
ported by different, stimulant actions of the adenosine
receptor antagonist caffeine (Landolt, 2008). Interestingly,
when compared to young subjects, PVT performance in
healthy adults of older age is consistently less impaired by
acute sleep loss, especially in the morning after the night
without sleep. In fact, the age-related differences in sleep
loss-induced impairment in neurobehavioural function are
mimicked in young individuals of low and high sensitivity to
the stimulant effects of caffeine (Fig. 2). Based on these
data, it was hypothesized that age-related differences in
adenosine receptor-mediated signal transduction contributes
to the age-related changes in vulnerability to acute sleep
deprivation. It can be expected that such a research
approach will disclose molecular mechanisms of human
sleep–wake regulation, provide insights into their changes in
normal older age and sleep–wake disorders and may assist
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in the evidence-based search for new treatments of impaired
wakefulness and sleep.
Not only vulnerability to sleep loss, but also sleep need,
differ widely among healthy individuals (i.e. there exist both
physiological long and short sleepers). Keeping this in mind,
the available literature suggests strongly that individuals who
do not obtain sufficient sleep due to chronic sleep restriction
or acute sleep deprivation often experience negative health
outcomes, including a 12% elevated risk for all-cause
mortality (Cappuccio et al., 2010). Nevertheless, causal
inference is often difficult because confounders, e.g. pre-
existing illness, or possible reversed causation may be
present in epidemiological studies. Thus, long sleep (>9 h)
has also been associated consistently with increased mor-
tality. Future studies will have to answer the question of
whether sleep duration is a cause or simply a marker of ill
health. In addition, research should aim at identifying the
mechanisms by which sleep loss impairs health outcomes.
This is important because avoidance of short and inadequate
sleep may be amenable to modifications through education,
counselling and measures of public health, as well as newly
developed evidence-based treatments of disease-related
insufficient sleep.
ACKNOWLEDGEMENTS
The research conducted in the laboratory discussed in this
chapter was supported by the University of Z€
urich, the
Clinical Research Priority Program ‘Sleep and Health’of the
University of Z€
urich, the Swiss National Science Foundation,
the Z€
urich Center for Integrative Human Physiology and the
Neuroscience Center Z€
urich.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest, financial or
otherwise.
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