H. P. A. Van Dongen and G. A. Kerkhof (Eds.

)
Progress in Brain Research, Vol. 190
ISSN: 0079-6123
Copyright Ó 2011 Elsevier B.V. All rights reserved.

CHAPTER 3

Cognition and daytime functioning in sleep-related

breathing disorders

Melinda L. Jackson{,*, Mark E. Howard{ and Maree Barnes{

{
Sleep and Performance Research Center, Washington State University, Spokane, WA, USA
{
Institute for Breathing and Sleep, Austin Health, Heidelberg, Melbourne, VIC, Australia

Abstract: Sleep-related breathing disorders encompass a range of disorders in which abnormal

ventilation occurs during sleep as a result of partial or complete obstruction of the upper airway,
altered respiratory drive, abnormal chest wall movement, or respiratory muscle function. The most
common of these is obstructive sleep apnea (OSA), occurring in both adults and children, and causing
significant cognitive and daytime dysfunction and reduced quality of life. OSA patients experience
repetitive brief cessation of breathing throughout the night, which causes intermittent hypoxemia
(reductions in hemoglobin oxygen levels) and fragmented sleep patterns. These nocturnal events result
in excessive daytime sleepiness, and changes in mood and cognition.
Chronic excessive sleepiness during the day is a common symptom of sleep-related breathing disorders,
which is assessed in sleep clinics both subjectively (questionnaire) and objectively (sleep latency tests).
Mood changes are often reported by patients, including irritability, fatigue, depression, and anxiety.
A wide range of cognitive deficits have been identified in untreated OSA patients, from attentional and
vigilance, to memory and executive functions, and more complex tasks such as simulated driving. These
changes are reflected in patient reports of difficulty in concentrating, increased forgetfulness, an inability
to make decisions, and falling asleep at the wheel of a motor vehicle. These cognitive changes can also
have significant downstream effects on daily functioning. Moderate to severe cases of the disorder are at
a higher risk of having a motor vehicle accident, and may also have difficulties at work or school.
A number of comorbidities may also influence the cognitive changes in OSA patients, including
hypertension, diabetes, and stroke. These diseases can cause changes to neural vasculature and result
in neural damage, leading to cognitive impairments. Examination of OSA patients using neuroimaging
techniques such as structural magnetic resonance imaging and proton magnetic resonance spectroscopy
has observed significant changes to brain structure and metabolism. The downstream effects of neural,

*Corresponding author.
Tel.: þ 1 509 358 5514; Fax: þ 1 509 358 7810
E-mail: jacksonm@wsu.edu

DOI: 10.1016/B978-0-444-53817-8.00003-7 53
54
cognitive, and daytime functional impairments can be significant if left untreated. A better understanding
of the cognitive effects of these disorders, and development of more effective assessment tools for
diagnosis, will aid early intervention and improve quality of life of the patient.
Keywords: sleep apnea; mood; sleepiness; attention; memory; executive function.
Introduction
Sleep-disordered breathing encompasses disorders
in which abnormal ventilation occurs during sleep
as a result of partial or complete obstruction of
the upper airway, altered respiratory drive, abnor-
mal chest wall movement, or respiratory muscle
function. There is a range of severity, from primary
snoring and upper airway resistance syndrome
through to sleep apnea and obesity hypo-
ventilation syndrome (OHS). Obstructive sleep
apnea (OSA) is characterized by obstruction of
the upper airway and the presence of continued
respiratory effort with normal central nervous sys-
tem drive for respiration during sleep (Patil et al.,
2007). Central sleep apnea (CSA) is characterized
by unstable ventilatory control with short periods
of absent or reduced central nervous system drive
to breath. This results in periods of reduced or
absent respiratory muscle activity and hence
reduced or absent respiration (Eckert et al.,
2007). Obstructive and CSA may occur in the same
individual (mixed apnea). CSA and mixed apnea,
like OSA, also cause arousals from sleep and hyp-
oxemia (decreased hemoglobin oxygen levels),
resulting in impaired daytime function. In OHS,
there is reduced ventilation during sleep and subse-
quently during wakefulness as a result of an exter-
nal restrictive effect due to mass loading of the
chest wall and abdomen, an increased incidence
of peripheral airflow obstruction (Schachter et al.,
2001) and narrowing of the upper airway, which is
worsened during sleep. This causes persistent hyp-
oxemia and hypercapnia (increased hemoglobin
carbon dioxide levels) during sleep, which persists
into wake. CSA makes up less than 10% of people
presenting with sleep apnea, and CSA and OHS
are relatively understudied; therefore, this chapter
primarily focuses on OSA.
OSA is found in 24% adult males and 9% adult
females, with 4% and 2%, respectively, being
symptomatic of this disorder (Young et al., 1993).
Children and adolescents may also be affected.
Age is a risk factor, with the proportion of OSA
patients averaging 30% after the age of 65.
Anatomical upper airway abnormalities, such as a
longer soft palate, occur more often in men, con-
tributing to the higher incidence of OSA in the
male population (Patil et al., 2007). Ethnicity also
influences the risk of OSA (Kripke et al., 1997).
The world wide increase in the prevalence of obe-
sity (McLellan, 2002) is likely to result in a rise in
the prevalence of OSA, as it is closely linked to
the occurrence of this disease. The most common
reason for an individual seeking a diagnosis is snor-
ing, which is usually reported by the bed partner,
often in association with the partner witnessing
episodes of apnea during sleep. Patients suffering
from OSA also may exhibit other nocturnal
symptoms such as excessive sweating, motor rest-
lessness, enuresis, and frequent awakenings with
gasping or choking (Patil et al., 2007). There are
also a number of daytime symptoms reported, such
as excessive daytime sleepiness (EDS), difficulties
concentrating, and changes in mood and cognition,
which combine to reduce patients’ enjoyment of
and participation in life (Barnes et al., 2004).
Mechanisms of cognitive impairment in OSA
What is unique about OSA compared to other
sleep disorders is that at least two primary noctur-
nal physiological abnormalities occur, which may
 55

be the underlying cause of cognitive daytime and intermittent hypoxemia also occur in
impairments: hypoxemia and sleep fragmentation. CSA and OHS, and are proposed causes of
Repetitive brief upper airway obstruction occurs daytime dysfunction in untreated patients (Colt
during sleep, resulting in apneas (complete cessa- et al., 1991).
tion of breathing) or hypopneas (a reduction in
breathing; Fig. 1). The major diagnostic criterion
Daytime function
for OSA is frequent periods of respiratory arrest
of 10 s or more during sleep. The apnea/
Sleepiness
hypopnea index (AHI; number of events per hour
of sleep) must be at least five to make a diagnosis
Chronic EDS is one of the hallmark features of
of OSA (AASM, 1999). Severe patients may
OSA, CSA, and OHS, and appears to result pre-
experience apneas that last over 3 min, or occur
dominantly from frequent arousal from sleep
hundreds of times per night. Apneas and
(Colt et al., 1991). Its clinical features are a strong
hypopneas often terminate with arousal from
feeling of abnormal daytime tiredness, and
sleep, with resultant fragmentation of sleep and
reduced wakefulness, and vigilance (Sauter
reduction in total sleep time. Additionally, hypox-
et al., 2000). The association between sleepiness
emia occurs during an apneic event, causing a dis-
and sleep-related breathing disorders has been
ruption in the biochemical and hemodynamic
demonstrated using both subjective and objective
state of the central nervous system (Patil et al.,
assessment of sleepiness.
2007). As discussed in the section Neural
impairment, some studies support the hypothesis
that hypoxemia ultimately results in structural Subjective sleepiness
neuronal damage. Patients diagnosed with severe
OSA may record arterial hemoglobin oxygen sat- The Epworth Sleepiness Scale (ESS) is a simple,
uration (SaO2) reductions to below 50% of widely used subjective measure of sleepiness,
preapneic levels. Multiple awakenings from sleep which asks about the likelihood of falling asleep

100

SaO2
%

50

THOR
x1

Ob.A Ob.A Ob.A Ob.A Ob.A Ob.A

ABDO
x1

Ob.A Ob.A Ob.A Ob.A Ob.A Ob.A

AIRFLOW
x1

EEG/DiEMG
62.5 mV

SOUND
x1

Fig. 1. Polysomnography trace of an individual with OSA. Blue squares indicate where an apnea has occurred. During an apneic
event, there is a reduction or cessation of respiratory drive (in ABDO and air flow traces), which causes a reduction in oxygen
saturations (SaO2). At the end of the apneic event, there is an arousal from sleep (in the EEG trace), and a gasping sound as
respiratory drive begins. This cycle continues constantly across the entire night, causing frequent intermitted hypoxemia and
arousals from sleep. EMG, electromyogram; EEG, electroencephalogram; SaO2, oxygen saturations; THOR, thoracic band;
ABDO, abdominal band.
56
in a variety of situations (Johns, 1991). Average
scores of 9.5, 11.5, and 16.0 were recorded in
patients with mild, moderate, and severe OSA
from a clinic population, compared to 5.9 in a
control group (potential range 0–24; Johns,
1991). Moderate to severe sleepiness was found
in a study of 54 patients with OHS, who had a
mean ESS of 16 (Perez de Llano et al., 2005).
Increased sleepiness on the ESS has also been
found in general population studies of OSA. In
the Sleep Heart Health study, the mean ESS
scores were 7.2, 7.8, 8.3, and 9.3 for subjects with
normal polysomnography, mild, moderate, and
severe OSA, respectively (Gottlieb et al., 1999).
The lesser sleepiness in the latter study may
relate to the different study populations (clinic
vs. general population). Other methods assessing
the propensity to fall asleep in different situations
have also identified increased sleepiness in OSA
subjects. In the Wisconsin sleep cohort, subjects
were described as excessively sleepy if they
"woke unrefreshed regardless of how long they
had slept," "felt excessively sleepy during the
day," and had "uncontrollable daytime sleepiness
that interfered with daytime living" at least 2 days
a week. Sixteen percent of men with OSA had all
three symptoms compared to only 3% of men
without OSA (Young et al., 1993). The functional
outcomes of sleep questionnaire (FOSQ) is a
sleep-specific quality of life tool, with subscales
related to activity level, vigilance, general produc-
tivity, social outcome, and intimate and sexual
relationships (Weaver et al., 1997). Subjects with
moderate OSA indicated significantly more diffi-
culty with sleepiness on all subscales of the FOSQ
and on the FOSQ global score. Increased sleepi-
ness on both the ESS and FOSQ is related to ele-
vated road crash risk (Howard et al., 2004), thus
signifying real-world relevance.
Objective sleepiness
Increased objectively measured sleepiness has
also been demonstrated in subjects with OSA.
Current recommended indices of chronic objec-
tive sleepiness measure sleep latency (the time
taken to fall asleep as measured by brain activity
on electroencephalography (EEG)) while in the
laboratory. In the multiple sleep latency test
(MSLT), sleep latency is measured while subjects
are lying down and told not to resist falling
asleep. In the maintenance of wakefulness test
(MWT), sleep latency is measured while subjects
are sitting passively in a comfortable chair in a
quiet dark room, but asked to try and remain
awake. In standard testing, four sleep latency
measurements are recorded at intervals during
the same day and the average sleep latency is
recorded. Sleep latency for both tests varies in
relation to sleep apnea severity and sleep restric-
tion (Banks et al., 2004; Chervin and Aldrich,
1998). In a group of patients with predominantly
severe OSA, mean sleep latency was markedly
reduced (2.6 min) compared to a matched control
group (12.9 min) on the MSLT (Roth et al.,
1980). Reduced sleep latency has also been
observed in subjects with severe OSA using the
MWT (Mazza et al., 2002). In patients with a
range of severity of OSA, Chervin and Aldrich
found that disease severity explained only 11%
of the variance of the mean sleep latency,
indicating that other factors have a significant
influence on sleep latency (Chervin and Aldrich,
1998). Other studies, assessing the relationship
between mild OSA and objective sleepiness, have
found variable results. One study found no differ-
ence in mean sleep latency between a group of
patients with mild OSA and a control group
(Redline et al., 1997). However, a more recent
study did find a weak relationship between sleep
latency on the MWT and AHI in subjects with
mild to moderate OSA (Banks et al., 2004). The
inclusion of subjects with moderate OSA may
have led to the finding in the latter study.
Increased objective sleepiness has been demon-
strated in professional drivers with OSA. Mean
sleep latency on the MSLT was related to severity
of OSA in a study of American truck drivers
(Dinges, 1998). Mean sleep latency was 5.76 and

4.36 min in drivers with moderate or severe OSA,
respectively, compared to 7.9 min in drivers with-
out OSA. Drivers with mild OSA were not differ-
ent from those without OSA. Hakkanen et al.
found a shorter sleep latency and increased blink
duration while driving in a group of bus drivers
with mild OSA compared to a control group
(Hakkanen et al., 1999).
In summary, the majority of studies support a
relationship between OSA and sleepiness, particu-
larly for subjects with moderate to severe disease.
Increased objective and subjective sleepiness has
been demonstrated, including subjective measures
that have been shown to relate to road crash risk.
These changes have been identified in both clinical
and general populations, with several studies
also identifying increased sleepiness in transport
drivers with sleep disorders.
Mood
Psychological and personality alterations are com-
monly reported in OSA patients, and often first
noted by their family members. These changes
generally stem from fragmented sleep patterns
and increased sleepiness levels. Patients with sig-
nificant daytime sleepiness may feel unmotivated,
lack energy, and report less enjoyment from daily
activities. They may experience irritability, impa-
tience, fatigue, moodiness, depression, anxiety
and in more severe cases, psychosis, paranoia,
and irrational behavior (Guilleminault et al.,
1978). In children with OSA, mood changes may
manifest as shyness and social withdrawal, aggres-
siveness, or hyperactivity which may reflect a
profile of attention deficit hyperactivity disorder.
In particular, there is considerable evidence
suggesting a high prevalence of depression and
anxiety symptomatology in OSA.
The prevalence of depression in clinical
samples of OSA is as high as 40% (Schroder
and O'Hara, 2005); this is compared to general
population estimates of 6% of males (American
Psychological Association, 1994). Studies of
57
clinical samples have generally found higher rates
of depression in OSA when compared to popula-
tion surveys. Variation in the prevalence of
depression in OSA may be due to different met-
hods and measurements for scoring depression
and different diagnostic criteria for selecting dis-
ease severity. Thus, it is difficult to compare these
studies and draw direct conclusions as to the
comorbid prevalence of these disorders. Another
confounding factor is gender. Depression is more
commonly reported in females in the general
population, and therefore the rates of depression
in OSA samples may depend on the proportion
of women included.
Correlational studies have reported mixed
findings as to the underlying mechanisms of
depression in OSA. Although the specific impact
of hypoxia versus sleep fragmentation on depres-
sive symptoms in OSA patients is unclear, it
appears that daytime sleepiness resulting from
fragmented sleep is the primary candidate. Inter-
estingly, OSA patients with depression have been
reported to have a higher rate of disordered
breathing events compared to their nondepressed
counterparts (Millman et al., 1989) suggesting a
causal relationship. However, changes in mood
have also been observed in primary snorers thus
the relationship between disease severity is not
clear cut (Aikens and Mendelson, 1999; Jackson
et al., 2010). This suggests that other aspects of
the disorder may also contribute to depression,
such as fatigue (Bardwell et al., 2007).
Reports of anxiety in OSA patients are less
common than depression, but are nonetheless
not unusual. As with depression, there is still
debate as to the prevalence of anxiety in OSA
patients, and its relationship to the nocturnal
symptoms of OSA. The association between
OSA and anxiety may be mediated by a patient's
quality of life, rather than the direct influence of
sleep variables (Sanchez et al., 2001).
The relationship between mood and OSA is far
from clear; it is yet to be resolved whether depres-
sion in OSA is a primary consequence, or if it
occurs as a secondary disorder associated with
58
OSA-related symptoms (e.g., sleepiness, fatigue,
and social withdrawal). Utilization of clinical
scales of fatigue and depression should be
included in the clinical interview for patients
presenting to sleep physicians. Although some
mood assessment tools have been validated for
patient populations, none have been validated for
use in OSA patients in whom many of the daytime
features also overlap with depression symptoms
(e.g., lethargy, lack of energy, and fatigue).
Depressive symptoms may also impact upon com-
pliance of treatment for OSA, such as continuous
positive airway pressure (CPAP) or weight loss.
These findings also have important clinical
implications for mental health professionals
reviewing patients with depression who may have
a concomitant sleep disorder. Difficulties with
sleep could exacerbate depressive symptoms, and
potentially affect the efficacy of treatment.
Cognition
Changes in cognition are one of the hallmark
features of OSA. For those patients who misper-
ceive their daytime sleepiness, cognitive complaints
of impaired concentration and forgetfulness, as well
as falling asleep at the wheel of a motor vehicle, may
be the key initial signs that they have the disorder.
Cognition in OSA patients has typically been exam-
ined in four clinically relevant domains: attention
and vigilance, memory and learning, executive
functions, and simulated driving. There have been
a number of clinical population studies examining
these areas of cognition and some theories and
speculations of the underlying mechanisms of these
deficits have been proposed, including sleep
fragmentation and recurrent cyclical nocturnal
hypoxia–reoxygenation.
Attention and vigilance
Attention is a multifaceted domain, which
involves focused attention (or concentration),
divided attention, sustained attention (or vigi-
lance), and alertness. An inability to maintain
concentration and attention is a commonly
reported symptom of untreated OSA patients,
which can have significant detrimental con-
sequences for occupational performance, motor
vehicle safety, and daily functioning. As a result,
attention is one of the most researched cognitive
domains in this population (Ayalon et al., 2009;
Bedard et al., 1991a; Redline et al., 1997). Deficits
in vigilance, attention, and psychomotor speed in
untreated patients appear to be the most consis-
tently reported cognitive domains. Electrophysio-
logical evidence supports the behavioral findings,
demonstrating increased P300 latency of event-
related potentials—an index or attentional alloca-
tion and processing speed—in OSA patients
(Kotterba et al., 1998).
Performance on attentional tasks in OSA
patients compared to a control group appears to
reflect a dose–response relationship with disease
severity (as measured by the AHI), with more
severe OSA patients displaying poorer attention
performance. For example, studies of mild OSA
patients report minor to no deficits in attention
performance (Redline et al., 1997), whereas stud-
ies examining sustained attention performance in
severe OSA patients using the psychomotor vigi-
lance test (PVT) and four choice reaction time
task report deficits in this particular attentional
domain (Barbe et al., 1998; Bedard et al.,
1991b). Studies examining focused and divided
attention performance in moderate OSA patients
have yielded mixed results; significant differences
between patients and controls have been reported
in some studies (Greenberg et al., 1987; Naegele
et al., 1995) but not others (Lee et al., 1999). Most
studies of moderate OSA patients, however, do
find impaired performance on at least one measure
of attention (Greenberg et al., 1987; Kotterba
et al., 1998; Naegele et al., 1995). However,
since the attentional deficits are not common
across all patients, it is possible that impairments
in attention may occur in some, but not all patients
with moderate forms of the disorder.

The underlying mechanisms of attentional
deficits in OSA patients have primarily been
linked to EDS associated with sleep disruption
and arousals (Ayalon et al., 2009; Naismith
et al., 2004). Evidence from functional magnetic
resonance imaging (MRI) also supports this con-
tention—OSA patients have reduced brain acti-
vation while performing the PVT compared to
healthy controls, and this activation pattern is
related to the number of arousals during sleep
and slower reaction times (Ayalon et al., 2009).
However, hypoxia may also play a role in atten-
tion deficits to some degree (Bedard et al.,
1991a; Greenberg et al., 1987). Greenberg
assessed neuropsychological function in a group
of subjects with sleep-disordered breathing, a
matched group with excessive sleepiness but with-
out sleep-disordered breathing and a control group
(Greenberg et al., 1987). The sleep-disordered
breathing group performed worse on most tasks
compared to both other groups and the degree of
hypoxemia was related to motor performance.
Deficits in vigilance and attention may also
mediate performance impairments in other cogni-
tive domains. For example, reduced vigilance has
been shown to contribute significantly to the ver-
bal memory impairment in untreated patients
(Naegele et al., 1995).
Memory and learning
Memory is a complex cognitive function, aspects
of which have been shown to be impaired in
OSA patients. Short-term memory is usually
described in terms of visual or verbal memory.
Long-term memory can be divided into two com-
ponents—procedural memory and declarative
memory. The former refers to unconscious
memories of how to do things (e.g., tie a shoe
lace). In contrast, declarative memory refers to
memories that are consciously recalled, either
facts (semantic memory, e.g., the names of differ-
ent types of roses) or events (episodic memory,
e.g., the first day of school). Thus, episodic
59
memory involves recall of personal events
whereas semantic memory involves recollection
of facts that may have been learnt at that event.
OSA patients have deficits in memory pro-
cesses, reflected in clinical complaints such as
forgetting names and phone numbers, and
learning difficulties are seen in children with
OSA. Despite extensive research in this area, it
remains unclear which aspects of memory are
affected by the disorder. Mild impairments in
short-term verbal (Naegele et al., 1995, 2006;
Twigg et al., 2010) and visual (Ferini-Strambi
et al., 2003; Naegele et al., 1995) memory have
been observed in some studies but not others
(Greenberg et al., 1987; Kim et al., 1997). Long-
term semantic memory impairment has also been
reported (Ferini-Strambi et al., 2003; Salorio
et al., 2002), but again the findings are not consis-
tent on all tests (Bedard et al., 1991b; Greenberg
et al., 1987; Naegele et al., 1995). Where proce-
dural memory has been investigated, this too has
produced inconsistent results (Naegele et al.,
2006; Rouleau et al., 2002). Taken together, these
studies suggest that memory impairments are
mild, and do not affect all aspects of memory.
Discrepancies in the field with regard to the spe-
cific memory impairments associated with OSA
may be due to the influence of other cognitive
factors such as vigilance on memory performance.
Recent studies that have utilized extensive memory
test batteries, while controlling for vigilance and
sleepiness, have reported that verbal episodic mem-
ory is the primary memory deficit seen in OSA
patients (Naegele et al., 2006; Twigg et al., 2010).
This suggests that memory deficits are related to
impairment of retrieval and not of learning or recog-
nition. Thus, OSA patients have a reduced capacity
to acquire new information but no difficulty in
retaining previously learned memories. Such
memory impairments may affect a patients’ ability
to take in important information, for example, relat-
ing to the correct use of their treatment. Since visual
memory seems to be preserved, the use of visual
information in training OSA patients in the use of
their treatment may be more effective.
60
Unlike attentional impairments, which stem
from sleep fragmentation and daytime sleepiness,
memory impairments appear to be related to
intermittent hypoxemia. The known vulnerability
of the hippocampus—a region associated with
memory processing—to intermittent hypoxia
(Gozal et al., 2001) has led to speculation that
neural cell loss associated with intermittent hyp-
oxemia may underlie aspects of memory
impairment (this is further discussed in the sec-
tion Neural impairment). Establishing a link
between aspects of memory impairment and any
single factor, such as intermittent hypoxemia, is
nonetheless hampered by the corelationship of
indices such as sleep fragmentation and daytime
sleepiness that are also likely to contribute to
memory deficits in OSA patients.
Memory impairment is not always a common
presenting complaint of patients with OSA; the
decline is often gradual in onset and deterioration
is slow, so compensatory mechanisms may mask
the memory loss. For example, OSA patients with
intact verbal encoding ability display increased
activation in prefrontal, temporal, and parietal
regions and the cerebellum on functional MRI
(Ayalon et al., 2006). Neuroimaging studies have
also revealed that during encoding of episodic
information, healthy sleep-deprived subjects
display significant reduction in activation of the
hippocampus, associated with reduced encoding
ability (Yoo et al., 2007). The findings suggest
that adequate sleep prior to learning is needed
for the proper functioning of brain regions
involved in encoding new memories. It could be
argued that this response may also occur in
OSA patients who experience fragmented sleep
patterns. Interestingly in healthy subjects, nega-
tive emotional stimuli seem to be relatively resis-
tant to encoding impairment from prior sleep
loss, as compared to positive stimuli (Walker
and Stickgold, 2006). As a consequence, sleep
insufficiency may produce a negative learning
bias, which may explain the higher rates of
comorbid mood disorder in OSA patients (Benca
et al., 1992).
Executive functions
Executive functioning is a loosely defined collec-
tion of brain processes responsible for planning,
problem-solving, mental flexibility, abstract think-
ing, rule acquisition, initiating appropriate
actions, inhibiting inappropriate actions, and
selecting relevant sensory information. Working
memory is the temporary storage and manipula-
tion of information, and is also part of the execu-
tive functioning of the brain. By the application of
these processes, people are able to function and
react appropriately in novel and changing
situations, selecting previously acquired informa-
tion, and manipulating, modifying, and applying
it to a new environment.
OSA patients may report decision-making
difficulties, increased errors, and poor judgment,
which can potentially affect their job performance
or educational pursuits. Other aspects of execu-
tive functioning performance, such as set shifting,
initiating new responses, planning and inhibition
of automatic responses have also been reported
in untreated sleep clinic populations (Bedard
et al., 1991b; Naegele et al., 1995). Some reports
of working memory impairment in OSA patients
include maintenance and manipulation of infor-
mation (Naegele et al., 2006; Redline et al.,
1997) but not dual task performance (Naegele
et al., 2006). Inconsistency in working memory
impairment between some studies (e.g. Naegele
et al., 2006; Twigg et al., 2010) may be due to
the influence of vigilance and concentration
impairments on working memory performance.
The disruption in executive function seen in both
children and adults with OSA has been proposed
to be due to a combination of sleep deprivation
due to sleep fragmentation and irreversible damage
due to the hypoxemia–reoxygenation cycles
(Bedard et al., 1991a; Naegele et al., 1995). The pat-
tern of deficits observed in OSA is consistent with
damage to the prefrontal and frontal lobe areas of
the brain. An elegant model linking upper airway
collapse to daytime functional impairment has been

proposed with the anatomical locus for the decre-
ment in executive function being the prefrontal cor-
tex (Beebe and Gozal, 2002). Prolonged latencies of
the P300 component of event-related potentials,
which are not reversed with CPAP treatment, have
also been demonstrated in OSA patients (Kotterba
et al., 1998). The P300 component is believed to be
generated by subcortical structures and the prefron-
tal cortex; thus, abnormalities in this brain response
may reflect damage to these regions in OSA
patients. Support for this model also arises from
functional MRI studies, which have reported
impaired performance on executive type functions
(response inhibition and working memory) is
associated with decreased activation of the prefron-
tal cortex (Ayalon et al., 2009; Thomas et al., 2005).
Simulated and on-road driving
Many patients with OSA have difficulty in
driving, and occasionally report falling asleep at
the wheel. Laboratory studies using simulated
driving or tracking tasks confirm that patients
with untreated or undiagnosed OSA have
impaired driving performance (George et al.,
1996). These impairments include a reduced abil-
ity to avoid obstacles; more errors for steering,
signaling, braking, and accelerating; greater track-
ing error; and slower reaction times (George
et al., 1996, Risser et al., 2000). These and other
studies of driving simulation have involved patients
with moderate to severe OSA compared to normal
controls. Performance impairments have been
shown to be worse than that of control subjects
who had ingested alcohol (mean blood-alcohol
concentration 0.09%; George et al., 1996).
Other factors that impair driving performance
appear to be more detrimental in OSA patients
than in normal subjects. In a study that evaluated
the effects of alcohol and sleep deprivation, OSA
patients had greater deterioration in steering per-
formance and more crashes than control subjects
following these interventions (Vakulin et al.,
61
2007). Examination of the relationship between
driving performance and OSA in professional
drivers, a particularly high-risk population, found
that driving impairment was related to severity of
OSA, but performance deterioration was only
evident for drivers with moderate to severe
disease (Dinges, 1998). These findings suggest
that untreated patients may be at a higher risk
of having a motor vehicle accident compared to
the general population.
Indeed, epidemiological evidence supports this
contention—people with OSA are at two to seven
times increased risk of road accidents (Teran-
Santos et al., 1999; Young et al., 1997) and a
two to three times increased risk of industrial
accidents (Lindberg et al., 2001) as a result of
sleepiness and altered cognitive function. A
recent meta-analysis found an increased accident
rate of 2.7 in those with OSA (Tregear et al.,
2009). It has been estimated that 800,000 OSA-
related motor vehicle accidents occur annually in
the United States at a cost of U.S. $15.9 billion
and 1400 lives lost (Sassani et al., 2004). In middle
aged (30–60 years) drivers, OSA is likely to be a
prominent cause of sleepiness-related crashes.
Findley et al. (1988) published the first con-
trolled data demonstrating the relationship
between OSA and crash risk (Findley et al.,
1988), comparing state accident records from 29
patients with OSA to those of matched control
subjects and the average accident statistics for
the state of Virginia (Table 1). There was a seven-
fold increased accident rate in patients compared
to controls and two and a half times increase in
the rate compared to the state average. Three
subsequent case–control studies found similar
associations between sleep-disordered breathing
and accidents (Barbe et al., 1998; George and
Smiley, 1999; Teran-Santos et al., 1999). One
large prospective, cohort study also supports the
association between sleep-disordered breathing
and accident risk found in the case–control stud-
ies (Young et al., 1997). This study was per-
formed in a general population of employed
62

Table 1. Sleep-disordered breathing and accident risk

Author/Year Study design Population Accident risk

Findley et al. (1988) Case–control Sleep clinic 7.0 RR

Aldrich (1989) Case–control Sleep clinic 1.0 OR
Wu et al. (1996) Cross-sectional Sleep clinic 3.0 OR
Young et al. (1997) Prospective cohort General population 4.2 OR
Barbe et al. (1998) Case–control Sleep clinic 2.3 OR
Teran-Santos et al. (1999) Case–control Drivers from traffic accidents 6.3 OR
Horstmann et al. (2000) Case–control Sleep clinic 8.7 RR
George (2001) Case–control Sleep clinic 3.0 RR
Shiomi et al. (2002) Case–control Sleep clinic 2.3 RR
Howard et al. (2004) Cross-sectional Commercial drivers 1.3 OR
Tregear et al. (2009) Meta-analysis – 2.7 RR

RR, rate ratio; OR, odds ratio.

adults. The odds ratio for having an accident was
4.2 in men with mild sleep-disordered breathing
and 3.4 for those with moderate to severe disease,
although the difference between the groups was
not statistically different. However, this suggests
that while the presence of sleep apnea is related
to accident risk, increasing severity of sleep apnea
(as measured by the AHI) is not predictive of
crash risk. Other factors, such as the degree of
associated sleepiness or cognitive impairment
may mediate the increase in risk. Although there
was no increased risk of having an accident in
women with sleep-disordered breathing, there
was a marked increased risk of having multiple
accidents in both women and men with sleep-
disordered breathing, which has also been
observed in other studies (Barbe et al., 1998).
Most studies have not found a relationship
between the severity of sleep-disordered breath-
ing and accident risk (Teran-Santos et al., 1999;
Young et al., 1997). However, a few studies have
suggested that it is predominantly patients with
severe OSA patients who have an increased acci-
dent risk. George found that the average accident
rate was 0.12 per year in those with severe disease
compared to 0.07 per year in control subjects
(George and Smiley, 1999). There was only a
minor increase in accident rate (0.08) in patients
with lesser degrees of sleep-disordered breathing.
In summary, moderate to severe OSA is
associated with impaired vigilance and driving
performance. The degree of impairment is similar
to that at high blood-alcohol levels, and is
associated with increased road accident risk.
Studies in both clinical populations with OSA
and subjects with OSA from general populations
have shown an increased risk of having a road
accident, which improves following treatment
(George, 2001; refer to Chapter 4 for more
details). Patients are also more likely to have mul-
tiple accidents. While some studies have found
a dose relationship between severity of sleep-
disordered breathing and accident risk, this is
not a universal finding.
Other factors associated with cognitive decline in
sleep-related breathing disorders
Comorbidities
There are several conditions that are strongly
associated with OSA and OHS that may also
influence cognitive function, including obesity,
diabetes mellitus, hypertension, and cardiovascu-
lar disease including stroke (Hajjar et al., 2010;
Shahar et al., 2001). This raises the possibility that
some of the cognitive impairment evident in OSA

is due to these confounding comorbidities.
However, OSA may in fact be causal in some of
these conditions by contributing to oxidative
stress, systemic inflammation, and sympathetic
activation through intermittent hypoxia and sleep
fragmentation (Pack and Gislason, 2009). Recent
cross-sectional data suggest that endothelial dys-
function and elevation of inflammatory
biomarkers are greater in OSA than controls
matched for obesity, and even higher in OHS
(Punjabi and Beamer, 2007). These abnormalities
are related to the presence of nocturnal hypoxia
and may explain the emergence and progression of
atherosclerosis, hypertension, and other
cardiovascular and metabolic disorders in these
conditions (Assmann et al., 2002). There is a reduc-
tion in the normal nocturnal dip in blood pressure in
OSA patients (Suzuki et al., 1996), and recently this
has been associated with brain atrophy (Hajjar
et al., 2010). In summary, there are several com-
orbidities related to OSA and OHS that may con-
tribute to cognitive impairment. Conversely, OSA
and OHS may also increase the risk of some of these
conditions, causing a vicious cycle of poor health
outcomes resulting from the disorder, leading to
unhealthy behaviors, which lead to worsening of
symptoms (Spruyt et al., 2010).
Neural impairment
The cognitive and functional impairment observed
in OSA patients suggests that there may be some
underlying changes in brain structure associated
with the disease. In a model of OSA in rats, inter-
mittent hypoxemia caused increased neuronal
death in the hippocampus, and this was associated
with impaired learning and memory in aging rats
(Gozal et al., 2001). This has led to speculation
that neural cell loss associated with intermittent
hypoxia may underlie aspects of memory
impairment in OSA in humans. Deficits in atten-
tion, vigilance, and verbal episodic memory in
hypoxic, compared to nonhypoxic patients,
support this contention (Findley et al., 1986).
63
In the past decade, a number of studies have
emerged describing neural cell loss and changes
in neurochemical levels of untreated OSA
patients, although there are inconsistencies in
the findings between studies. Some studies report
quantitative regional gray matter loss in the hip-
pocampus (Morrell et al., 2003), cerebellum, fron-
tal and parietal cortex, and the anterior cingulate
gyrus (Macey et al., 2002; Yaouhi et al., 2009),
whereas others report no difference in structural
volumes (O'Donoghue et al., 2005). These studies
had small sample sizes, included patients with
known comorbidities, and used different statisti-
cal thresholds which may explain the
discrepancies in findings between studies. A
recent study attempted to overcome these issues
by examining a relatively large sample of OSA
patients and controls, using standardized
improved methods of structural analysis (Morrell
et al., 2010). OSA patients, relative to controls,
had significant reductions in the right middle tem-
poral gyrus and left cerebellum—brain regions
involved in the motor regulation of the upper air-
ways, as well as in cognitive processing (Fig. 2).
Studies utilizing magnetic resonance spectros-
copy (MRS), a neuroimaging technique useful
for measuring brain metabolism, in patients
with untreated OSA have found metabolic
abnormalities in frontal white matter, associated
with the severity of OSA (AHI; Kamba et al.,
2001) and cognitive deficits (Bartlett et al., 2004).
These abnormalities appear to occur before any
structural changes are evident, and are reversible
with treatment. For instance, children with OSA
have no sign of structural neuronal damage, but
have reduced neural metabolites in hippocampus
and right frontal cortex, and exhibit impairments
in memory, learning, and executive functions
(Halbower et al., 2006).
Conclusion
The influence of sleep-related breathing disorders
on cognition and daytime functioning is complex,
64

(a)

5
4
3
2
1
0

(b)

3
SPM{T101}
2

Fig. 2. (a) Images show reductions in gray matter in right middle temporal gyrus of OSA patients compared with controls. Left panel
shows “glass brain” view, and right panel shows gray matter loss superimposed upon an MR template. Views, in neurological
orientation (left is left), from top left clockwise are, sagittal, coronal, and transverse. The voxel of maximum significance is marked
as arrow head in the left panel. On the right panel, the cross hairs (t ¼ 4.05—indicated by colored bar) are located on the right at
x ¼ 52, y ¼ 4, z ¼ 22 mm (Montreal Neurological Institute (MNI) coordinates relative to anterior commissure). The images are
thresholded to include clusters that survived the topological false detection rate threshold of p < 0.05. (b) Images show statistically
significant reductions in cerebellar gray matter in a subset of OSA patients compared with controls using a spatially unbiased
infratentorial template (SUIT). Left panel shows “glass brain” view, and right panel shows gray matter loss superimposed upon the
SUIT template. The image is displayed with a threshold of p < 0.05 uncorrected. The voxel of maximum significance survives
correction at p < 0.05 FWE corrected (t ¼ 4.62—indicated by colored bar) and is located on the left at x ¼ 14, y ¼ 51,
z ¼ 48 mm (MNI coordinates relative to anterior commissure). Two further maxima were located on the inferior edge of the
cerebellum (t ¼ 4.18, MNI: 50, 58, 55; t ¼ 3.99, MNI:  35, 53, 62). Note: the location of the cerebellum and the associated
gray matter reduction extends below the standard glass brain reference grid. Adapted from Morrell et al. (2010).

involving a number of overlapping physiological vigilance and other cognitive impairment on-road
and psychological processes. The downstream and occupational accidents can be significant if
effects of daytime functional impairments due to the disorder is left untreated.

The conflicting results of studies of
neurocognitive decrements in OSA are in part
related to the vast array of tests used. A number
of neurocognitive test batteries designed specifi-
cally for OSA patients have been proposed, which
would improve interpretation of the results of such
studies. There is also the issue of the validity of the
neurocognitive tasks and mood assessment tools
used in OSA patient studies, since most of these
were originally developed for head trauma
patients. Research in this area would also benefit
from standardized research diagnostic criteria.
Normal cognitive decline in older OSA patients
may mask or overwhelm decline that is due to sleep
apnea (Mathieu et al., 2008). Further to this, when
testing higher cognitive functions such as memory
and executive functions, it may be difficult to
delineate between the impairment due to reduced
vigilance, sleepiness, or poor motivation. It is
therefore essential that all these elements are
adequately measured and confounding factors are
accounted for, including age, educational level,
intelligence, and other medical illnesses may
contribute to neurocognitive deficits.
With the obesity epidemic growing throughout
the world (McLellan, 2002), the prevalence of
OSA is likely to increase, and with it a significant
public health burden. A better understanding of
the sequelae of OSA, as well as improved screen-
ing and diagnostic tools for assessment of these
daytime and cognitive impairments, will facilitate
early intervention and treatment to prevent per-
manent neurological damage, thereby reducing
the public health and economic consequences of
this disorder.
References
American Academy of Sleep Medicine Task Force (AASM)
(1999). Sleep-related breathing disorders in adults:
Recommendations for syndrome definition and measurement
techniques in clinical research. Sleep, 22, 667–689.
Aikens, J., & Mendelson, W. (1999). A matched comparison
of mmpi responses in patients with primary snoring or
obstructive sleep apnea. Sleep, 22, 355–359.
65
Aldrich, M. (1989). Automobile accidents in patients with
sleep disorders. Sleep, 12, 487–494.
American Psychological Association. (1994). Diagnostic and
statistical manual of mental disorders. Washington, DC:
American Psychiatric Association.
Assmann, G., Cullen, P., & Schulte, H. (2002). Simple scoring
scheme for calculating the risk of acute coronary events
based on the 10-year follow-up of the prospective cardiovas-
cular munster (procam) study. Circulation, 105, 310–315.
Ayalon, L. F., Ancoli-Israel, S., Aka, A. F., McKenna, B., &
Drummond, S. P. (2009). Relationship between obstructive
sleep apnea severity and brain activation during a sustained
attention task. Sleep, 32, 373–381.
Ayalon, L., Ancoli-Israel, S., Klemfuss, Z., Shalauta, M. D., &
Drummond, S. P. A. (2006). Increased brain activation dur-
ing verbal learning in obstructive sleep apnea. Neuroimage,
31, 1817–1825.
Banks, S., Barnes, M., Tarquinio, N., Pierce, R. J., Lack, L. C., &
Doug McEvoy, R. (2004). Factors associated with mainte-
nance of wakefulness test mean sleep latency in patients with
mild to moderate obstructive sleep apnoea and normal
subjects. Journal of Sleep Research, 13, 71–78.
Barbe, F., Pericas, J., Munoz, A., Findley, L., Anto, J. M., &
Agusti, A. G. (1998). Automobile accidents in patients with
sleep apnea syndrome. An epidemiological and mechanistic
study. American Journal of Respiratory and Critical Care
Medicine, 158, 18–22.
Bardwell, W. A., Ancoli-Israel, S., & Dimsdale, J. E. (2007).
Comparison of the effects of depressive symptoms and
apnea severity on fatigue in patients with obstructive sleep
apnea: A replication study. Journal of Affective Disorders,
97, 181–186.
Barnes, M., McEvoy, R. D., Banks, S., Tarquinio, N.,
Murray, C. G., Vowles, N., et al. (2004). Efficacy of positive
airways pressure and oral appliance in mild to moderate
obstructive sleep apnea. American Journal of Respiratory
and Critical Care Medicine, 170, 656–664.
Bartlett, D. J., Rae, C., Thompson, C. H., Byth, K.,
Joffe, D. A., Enright, T., et al. (2004). Hippocampal area
metabolites relate to severity and cognitive function in
obstructive sleep apnea. Sleep Medicine, 5, 593–596.
Bedard, M. A., Montplaisir, J., Richer, F., & Malo, J. (1991).
Nocturnal hypoxemia as a determinant of vigilance
impairment in sleep apnea syndrome. Chest, 100, 367–370.
Bedard, M. A., Montplaisir, J., Richer, F., Rouleau, I., &
Malo, J. (1991). Obstructive sleep apnea syndrome:
Pathogenesis of neuropsychological deficits. Journal of
Clinical and Experimental Neuropsychology, 13, 950–964.
Beebe, D. W., & Gozal, D. (2002). Obstructive sleep apnea
and the prefrontal cortex: Towards a comprehensive model
linking nocturnal upper airway obstruction to daytime cog-
nitive and behavioral deficits. Journal of Sleep Research,
11, 1–16.
66
Benca, R. M., Obermeyer, W. H., Thisted, R. A., & Gillin, J. C.
(1992). Sleep and psychiatric disorders: A meta-analysis.
Archives of General Psychiatry, 49, 651–668.
Chervin, R. D., & Aldrich, M. S. (1998). The relation between
multiple sleep latency test findings and the frequency of
apneic events in rem and non-rem sleep. Chest, 113, 980–984.
Colt, H. G., Haas, H., & Rich, G. B. (1991). Hypoxemia vs
sleep fragmentation as cause of excessive daytime sleepiness
in obstructive sleep apnea. Chest, 100, 1542–1548.
Dinges, D. (1998). Sleepiness and neurobehavioral functioning
in relation to apnea severity in a cohort of commercial
motor vehicle operators. Sleep, 21, 83.
Eckert, D., Jordan, A., Merchia, P., & Malhotra, A. (2007).
Central sleep apnea: Pathophysiology and treatment. Chest,
131, 595–607.
Ferini-Strambi, L., Baietto, C., Di Gioia, M. R., Castaldi, P.,
Castronovo, C., Zucconi, M., et al. (2003). Cognitive dys-
function in patients with obstructive sleep apnea (OSA):
Partial reversibility after continuous positive airway pres-
sure (CPAP). Brain Research Bulletin, 61, 87–92.
Findley, L., Barth, J., Powers, D., Wilhoit, S., Boyd, D., &
Suratt, P. (1986). Cognitive impairment in patients with
obstructive sleep apnea and associated hypoxemia. Chest,
90, 686–690.
Findley, L. J., Unverzagt, M. E., & Suratt, P. M. (1988). Auto-
mobile accidents involving patients with obstructive sleep
apnea. The American Review of Respiratory Disease, 138,
337–340.
George, C. F. (2001). Reduction in motor vehicle collisions fol-
lowing treatment of sleep apnoea with nasal CPAP. Thorax,
56, 508–512.
George, C. F., Boudreau, A. C., & Smiley, A. (1996).
Simulated driving performance in patients with obstructive
sleep apnea. American Journal of Respiratory and Critical
Care Medicine, 154, 175–181.
George, C., & Smiley, A. (1999). Sleep apnea and automobile
accidents. Sleep, 22, 790–795.
Gottlieb, D. J., Whitney, C. W., Bonekat, W. H., Iber, C.,
James, G. D., Lebowitz, M., et al. (1999). Relation of sleepi-
ness to respiratory disturbance index: The Sleep Heart
Health Study. American Journal of Respiratory and Critical
Care Medicine, 159, 502–507.
Gozal, D., Daniel, J. M., & Dohanich, G. P. (2001). Behavioral
and anatomical correlates of chronic episodic hypoxia during
sleep in the rat. The Journal of Neuroscience, 21, 2442–2450.
Greenberg, G. D., Watson, R. K., & Deptula, D. (1987).
Neuropsychological dysfunction in sleep apnea. Sleep, 10,
254–262.
Guilleminault, C., Van Den Hoed, J., & Mitler, M. (1978). Clin-
ical overview of the sleep apnea syndrome. In C. Guilleminult
& W. Dement (Eds.), Sleep apnea syndromes (pp. 1–12).
New York: Alan R. Liss.
Hajjar, I., Zhao, P., Alsop, D., & Al, E. (2010). Association of
blood pressure elevation and nocturnal dipping with brain
atrophy, perfusion and functional measures in stroke and
nonstroke individuals. American Journal of Hypertension,
23, 17–23.
Hakkanen, H., Summala, H., Partinen, M., Tiihonen, M., &
Silvo, J. (1999). Blink duration as an indicator of driver
sleepiness in professional bus drivers. Sleep, 22, 798–802.
Halbower, A. C., Degaonkar, M., Barker, P. B., Earley, C. J.,
Marcus, C. L., Smith, P. L., et al. (2006). Childhood obstruc-
tive sleep apnea associates with neuropsychological deficits
and neuronal brain injury. PLoS Medicine, 3, e301.
Horstmann, S., Hess, C. W., Bassetti, C., Gugger, M., &
Mathis, J. (2000). Sleepiness-related accidents in sleep
apnea patients. Sleep, 23, 383–389.
Howard, M. E., Desai, A. V., Grunstein, R. R., Hukins, C.,
Armstrong, J. G., Joffe, D., et al. (2004). Sleepiness, sleep-
disordered breathing, and accident risk factors in commer-
cial vehicle drivers. American Journal of Respiratory and
Critical Care Medicine, 170, 1014–1021.
Jackson, M., Stough, C., Howard, M., Spong, J., Downey, L.,
& Thompson, B. (2010). The contribution of fatigue and
sleepiness to depression in patients attending the sleep labo-
ratory for evaluation of obstructive sleep apnea. Sleep and
Breathing, online first, 1–7.
Johns, M. (1991). A new method for measuring daytime sleep-
iness: The Epworth Sleepiness Scale. Sleep, 14, 540–545.
Kamba, M., Inoue, Y., Higami, S., Suto, Y., Ogawa, T., &
Chen, W. (2001). Cerebral metabolic impairment in patients
with obstructive sleep apnoea: An independent association
of obstructive sleep apnoea with white matter change. Jour-
nal of Neurology, Neurosurgery and Psychiatry, 71, 334–339.
Kim, H. C., Young, T., Matthews, C. G., Weber, S. M.,
Woodward, A. R., & Palta, M. (1997). Sleep-disordered
breathing and neuropsychological deficits A population-
based study. American Journal of Respiratory and Critical
Care Medicine, 156, 1813–1819.
Kotterba, S., Rasche, K., Widdig, W., Duscha, C.,
Blombach, S., Schultze-Werninghaus, G., et al. (1998). Neu-
ropsychological investigations and event-related potentials
in obstructive sleep apnea syndrome before and during
cpap-therapy. Journal of the Neurological Sciences, 159,
45–50.
Kripke, D. F., Ancoli-Israel, S., Klauber, M. R.,
Wingard, D. L., Mason, W. J., & Mullaney, D. J. (1997).
Prevalence of sleep-disordered breathing in ages 40–64
years: A population-based survey. Sleep, 20, 65–76.
Lee, M., Strauss, M., Adams, N., & Redline, S. (1999).
Executive functions in persons with sleep apnea. Sleep and
Breathing, 3, 13–16.
Lindberg, E., Carter, N. G. T., & Janson, C. (2001). Role of
snoring and daytime sleepiness in occupational accidents.
American Journal of Respiratory and Critical Care Medicine,
164, 2031–2035.
Macey, P. M., Henderson, L. A., Macey, K. E., Alger, J. R.,
Frysinger, R. C., Woo, M. A., et al. (2002). Brain morphology

associated with obstructive sleep apnea. American Journal of
Respiratory and Critical Care Medicine, 166, 1382–1387.
Mathieu, A., Mazza, S., Décary, A., Massicotte-Marquez, J.,
Petit, D., Gosselin, N., et al. (2008). Effects of obstructive sleep
apnea on cognitive function: A comparison between younger
and older OSAS patients. Sleep Medicine, 9, 112–120.
Mazza, S., Pepin, J. L., Deschaux, C., Naegele, B., & Levy, P.
(2002). Analysis of error profiles occurring during the Osler
test: A sensitive mean of detecting fluctuations in vigilance in
patients with obstructive sleep apnea syndrome. American
Journal of Respiratory and Critical Care Medicine, 166,
474–478.
McLellan, F. (2002). Obesity rising to alarming levels around
the world. Lancet, 359, 1412.
Millman, R., Fogel, B., Mcnamara, M., & Carlisle, C. (1989).
Depression as a manifestation of obstructive sleep apnea:
Reversal with nasal continuous positive airway pressure.
The Journal of Clinical Psychiatry, 50, 348–351.
Morrell, M. J., Jackson, M. L., Twigg, G. L., Ghiassi, R.,
McRobbie, D. W., Quest, R. A., et al. (2010). Changes in
brain morphology in patients with obstructive sleep apnoea.
Thorax, 65, 908–914.
Morrell, M. J., Mcrobbie, D. W., Quest, R. A.,
Cummin, A. R. C., Ghiassi, R., & Corfield, D. R. (2003).
Changes in brain morphology associated with obstructive
sleep apnea. Sleep Medicine, 4, 451–454.
Naegele, B., Launois, S., Mazza, S., Feuerstein, C., Pepin, J., &
Levy, P. (2006). Which memory processes are affected in
patients with obstructive sleep apnea? An evaluation of 3
types of memory. Sleep, 29, 533–544.
Naegele, B., Thouvard, V., Pepin, J., Levy, P., Bonnet, C.,
Perret, J., et al. (1995). Deficits of cognitive executive functions
in patients with sleep apnea syndrome. Sleep, 18, 43–52.
Naismith, S., Winter, V., Gotsopoulos, H., Hickie, I., &
Cistulli, P. (2004). Neurobehavioral functioning in obstruc-
tive sleep apnea: Differential effects of sleep quality, hypox-
emia and subjective sleepiness. Journal of Clinical and
Experimental Neuropsychology, 26, 43–54.
O'Donoghue, F. J., Briellmann, R. S., Rochford, P. D.,
Abbott, D. F., Pell, G. S., Chan, C. H. P., et al. (2005). Cere-
bral structural changes in severe obstructive sleep apnea.
American Journal of Respiratory and Critical Care Medicine,
171, 1185–1190.
Pack, A., & Gislason, T. (2009). Obstructive sleep apnea and
cardiovascular disease: A perspective and future directions.
Progress in Cardiovascular Diseases, 5, 434–451.
Patil, S., Schneider, H., Schwartz, A., & Smith, P. (2007).
Adult obstructive sleep apnea: Pathophysiology and diagno-
sis. Chest, 132, 325–337.
Perez De Llano, L., Golpe, R., Ortiz Piquer, M., & Veres
Racamonde, A. (2005). Short-term and long-term effects
of nasal intermittent positive pressure ventilation in patients
with obesity-hypoventilation syndrome. Chest, 128, 587–594.
67
Punjabi, N., & Beamer, B. (2007). C-reactive protein is
associated with sleep disordered breathing independent of
adiposity. Sleep, 30, 29–34.
Redline, S., Strauss, M. E., Adams, N., Winters, M.,
Roebuck, T., Spry, K., et al. (1997). Neuropsychological func-
tion in mild sleep-disordered breathing. Sleep, 20, 160–167.
Risser, M. R., Ware, J. C., & Freeman, F. G. (2000). Driving
simulation with EEG monitoring in normal and obstructive
sleep apnea patients. Sleep, 23, 393–398.
Roth, T., Hartse, K. M., Zorick, F., & Conway, W. (1980).
Multiple naps and the evaluation of daytime sleepiness in
patients with upper airway sleep apnea. Sleep, 3, 425–439.
Rouleau, I., Décary, A., Chicoine, A., & Montplaisir, J. (2002).
Procedural skill learning in obstructive sleep apnea
syndrome. Sleep, 25, 404–411.
Salorio, C. F., White, D. A., Piccirillo, J., Duntley, S. P., &
Uhles, M. L. (2002). Learning, memory, and executive con-
trol in individuals with obstructive sleep apnea syndrome.
Journal of Clinical and Experimental Neuropsychology, 24,
93–100.
Sanchez, A., Buela-Casal, G., Bermudez, M., & Casas-
Maldonado, F. (2001). The effects of continuous positive air
pressure treatment on anxiety and depression levels in apnea
patients. Psychiatry and Clinical Neurosciences, 55, 641–646.
Sassani, A., Findley, L., Kryger, M. H., Goldlust, E.,
George, C., & Davidson, T. (2004). Reducing motor-vehicle
collisions, costs, and fatalities by treating obstructive sleep
apnea syndrome. Sleep, 27, 453–458.
Sauter, C., Asenbaum, S., Popovic, R., Bauer, H., Lamm, C.,
Klösch, G., et al. (2000). Excessive daytime sleepiness
in patients suffering from different levels of obstructive
sleep apnoea syndrome. Journal of Sleep Research, 9,
293–301.
Schachter, L., Salome, C., Peat, J., & Woolcock, A. (2001).
Obesity is a risk for asthma and wheeze but not airway
hyperresponsiveness. Thorax, 56, 4–8.
Schroder, C., & O'Hara, R. (2005). Depression and obstruc-
tive sleep apnea (OSA). Annals of General Psychiatry, 4, 13.
Shahar, E., Whitney, C. W., Redline, S., Lee, E. T.,
Newman, A. B., Javier Nieto, F., et al. (2001). Sleep-disor-
dered breathing and cardiovascular disease: Cross-sectional
results of the sleep heart health study. American Journal of
Respiratory and Critical Care Medicine, 163, 19–25.
Shiomi, T., Arita, A. T., Sasanabe, R., Banno, K.,
Yamakawa, H., Hasegawa, R., Ozeki, K., Okada, M., &
Ito, A. (2002). Falling asleep while driving and automobile
accidents among patients with obstructive sleep apnea-
hypopnea syndrome. Psychiatry & Clinical Neurosciences,
56, 333–334.
Spruyt, K., Capdevila, O. S., Serpero, L. D., Kheirandish-
Gozal, L., & Gozal, D. (2010). Dietary and physical activity
patterns in children with obstructive sleep apnea. Journal of
Pediatrics, 156, 724–730.
68
Suzuki, M., Guilleminault, C., Otsuka, K., & Shoimi, T. (1996).
Blood pressure “dipping” and “non-dipping” in obstructive
sleep apnea syndrome patients. Sleep, 19, 382–387.
Teran-Santos, J., Jimenez-Gomez, A., & Cordero-Guevara, J.
(1999). The association between sleep apnea and the risk
of traffic accidents Cooperative group burgos-santander.
The New England Journal of Medicine, 340, 847–851.
Thomas, R., Rosen, B., Stern, C., Weiss, J., & Kwong, K.
(2005). Functional imaging of working memory in obstruc-
tive sleep-disordered breathing. Journal of Applied Physiol-
ogy, 98, 2226–2234.
Tregear, S., Reston, J., Schoelles, K., & Phillips, B. (2009).
Obstructive sleep apnea and risk of motor vehicle crash:
Systematic review and meta-analysis. Journal of Clinical
Sleep Medicine, 5, 573–581.
Twigg, G. L., Papaioannou, I., Jackson, M., Ghiassi, R.,
Shaikh, Z., Jaye, J., et al. (2010). Obstructive sleep apnoea
syndrome is associated with deficits in verbal but not visual
memory. American Journal of Respiratory and Critical Care
Medicine, 182, 98–103.
Vakulin, A., Baulk, S. D., Catcheside, P. G., Anderson, R.,
Van Den Heuvel, C. J., Banks, S., et al. (2007). Effects of
moderate sleep deprivation and low-dose alcohol on driving
simulator performance and perception in young men. Sleep,
30, 1327–1333.
Walker, M., & Stickgold, R. (2006). Sleep, memory, and
plasticity. Annal Review of Psychology, 57, 139–166.
Weaver, T., Laizner, A., Evans, L., Maislin, G., Chugh, D.,
Lyon, K., et al. (1997). An instrument to measure functional
status outcomes for disorders of excessive sleepiness. Sleep,
20, 835–843.
Wu, H., & Yan-Go, F. (1996). Self-reported automobile
accidents involving patients with obstructive sleep apnea.
Neurology, 46, 1254–1257.
Yaouhi, K., Bertran, F., Clochon, P., Mézenge, F., Denise, P.,
Foret, J., et al. (2009). A combined neuropsychological and
brain imaging study of obstructive sleep apnea. Journal of
Sleep Research, 18, 36–48.
Yoo, S., Hu, P., Gujar, N., Jolesz, F., & Walker, M. (2007).
A deficit in the ability to form new human memories
without sleep. Nature Neuroscience, 10, 385–392.
Young, T., Blustein, J., Finn, L., & Palta, M. (1997). Sleep-
disordered breathing and motor vehicle accidents in a
population-based sample of employed adults. Sleep, 20,
608–613.
Young, T., Palta, M., Dempsey, J., Skatrud, J., Weber, S., &
Badr, S. (1993). The occurrence of sleep-disordered breath-
ing among middle-aged adults. The New England Journal of
Medicine, 328, 1230–1235.