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 4

Cognitive recovery following positive airway

pressure (PAP) in sleep apnea

Ellyn E. Matthews{ and Mark S. Aloia{,*

{
College of Nursing, University of Colorado, Aurora, CO, USA
{
Department of Medicine, National Jewish Health, Denver, CO, USA

Abstract: Obstructive sleep apnea–hypopnea syndrome (OSAHS) is a common sleep disorder that is
characterized by repeated episodes of complete or partial cessation of breathing while sleeping. These
recurrent breathing events result in fragmented sleep and recurrent hypoxemia. Distressing daytime
sequelae reported by OSAHS patients include excessive daytime sleepiness, self-reported changes in mood,
and cognitive problems. It has been well established that OSAHS can negatively impact functioning in
multiple cognitive domains, such as attention and memory. In this chapter, neurobehavioral deficits in
OSAHS are discussed, and proposed models of cognitive dysfunction are summarized. Current studies
examining cognitive recovery with positive airway pressure treatment are presented. It appears that the
cognitive dysfunction of OSAHS is not likely to be due to a single mediating mechanism, nor is it pervasive
across all patients. Future research should attempt to identify these moderators for cognitive dysfunction in
OSAHS and to highlight the mechanisms of dysfunction by cognitive domain.

Keywords: sleep apnea; cognition; daytime sleepiness; neuropsychology; positive airway pressure.

Introduction OSAHS is characterized by repeated complete

Population-based epidemiologic studies have
underscored the high prevalence of obstructive
sleep apnea–hypopnea syndrome (OSAHS),
occurring in 5% of the general population
(Young et al., 2002). The pathophysiology of
*Corresponding author.
Tel.: þ 303 270 2386; Fax: þ 303 270 2115
E-mail: aloiam@njhealth.org
(apnea) or partial (hypopnea) cessations of
breathing most typically caused by a narrowing
at various potential sites along the upper airway.
During these breathing events, arterial oxygen
saturation can drop to dangerously low levels
(desaturation), resulting in increased respiratory
effort and arousals from sleep to resume breath-
ing. Recurrent hypoxemia, hypercapnia, and
fragmented sleep are direct consequences of

DOI: 10.1016/B978-0-444-53817-8.00004-9 71
72
OSAHS that can impact neurobehavioral perfor-
mance (Dempsey et al., 2010).
The primary daytime sequelae of OSAHS
include excessive daytime sleepiness, self-
reported changes in mood, and cognitive pro-
blems. Decreased cognitive acuity can have signif-
icant negative consequences for occupational
performance, driving safety, educational pursuits,
and global functioning. For example, the risk of
being involved in a motor vehicle accident is sub-
stantially higher as the severity of OSAHS
increases (Tregear et al., 2009). Moreover,
OSAHS has been associated with an increased
risk of comorbid medical illnesses, particularly
vascular diseases, such as hypertension, heart dis-
ease, and stroke (Dempsey et al., 2010). Psychiat-
ric disorders including depression and anxiety
have also been linked to OSAHS (Saunamaki
and Jehkonen, 2007) with accompanying func-
tional consequences that can be severe.
OSAHS treatment
Although surgical and behavioral (e.g., weight
loss) options exist for the clinical management of
OSAHS, positive airway pressure (PAP) is con-
sidered the treatment of choice (Giles et al.,
2006). PAP consists of a nasal mask attached to
a pneumatic pump by a flexible air tube, and held
in place by a harness that fits over the head. The
pump supplies positive air pressure to the upper
airway, preventing it from collapsing during sleep.
Once the appropriate pressure is determined,
PAP generally eliminates most or all nocturnal
breathing disturbances (American Thoracic Soci-
ety, 1994). With proper use, PAP has been found
to diminish sleep fragmentation, increase noctur-
nal oxygen saturation, and improve cognitive
functioning (Giles et al., 2006). Despite these
benefits, PAP is not a cure, but provides only a
“pneumatic splint” to prevent collapse of the
upper airway each night. Unfortunately, research
has revealed that long-term adherence to PAP is
less than optimal for reasons that remain to be
fully elucidated, but which include barriers
associated with the equipment (e.g., mask discom-
fort, nasal congestion, nasal dryness) and psycho-
logical barriers to behavior change (Aloia et al.,
2005; Matthews and Aloia, 2009). Adherence
may indeed have implications for the magnitude
of cognitive improvements with treatment.
Neurobehavioral deficits in OSAHS
Neurobehavioral functioning is a broad term that
includes several specific cognitive functions
(Beebe, 2005). Numerous studies of OSAHS have
examined cognitive deficits, a broad term that
describes cognitive performance outside of
expected normal values in both global and spe-
cific cognitive domains. The cognitive domains
will be summarized later in this chapter.
Neurobehavioral testing is common in studies
of OSAHS; however, cognitive sequelae remain
difficult to interpret given the wide diversity of
tests, and lack of standardized characterization
of disease severity (Aloia et al., 2004; Beebe
et al., 2003). Until recently, many investigations
focused on selected cognitive deficits, and few
studies employed comprehensive neuro-
behavioral test batteries. Fortunately, the number
of studies examining cognitive deficits is
expanding and advanced neuroimaging methods
are improving our understanding of brain struc-
ture and function in OSAHS (Zimmerman and
Aloia, 2006). Studies of cognitive deficits in adult
OSAHS participants typically fall into three main
areas: pretreatment group comparisons of
OSAHS patients compared to healthy controls;
OSAHS patients compared on levels of disease
severity; and cognitive impairments before and
after treatment, most often PAP.
Apnea patients may exhibit fewer global cogni-
tive impairments when compared to normal
controls because the various components of the
global score may mask specific deficits. Studies
assessing specific cognitive domains have been
more revealing, although cognitive domains are

not mutually exclusive. Cognitive abilities most
frequently found to be affected by OSAHS are
selective attention (concentration), sustained
attention (vigilance), short-term or working mem-
ory, executive functioning, and motor functioning,
with negligible impact on intellectual and
language functioning (Beebe et al., 2003).
Cognitive domains and OSAHS
The most commonly investigated cognitive
domains in OSAHS have been vigilance and
attention. Although vigilance and attention are
different constructs, apnea researchers do not
always differentiate between them, and tend to
favor tests of vigilance. Deficits in vigilance
include sustained attention, controlled attention,
information processing, and response time over
long periods. This appears to be the domain that
is most consistently affected in OSAHS patients
and it has been suggested that vigilance and
attention deficits are central to all aspects of
higher order cognitive functioning (Verstraeten
et al., 2004). Attention deficits in OSAHS
patients may affect the ability to both remain
awake in monotonous situations and manage
information in more stimulating conditions
(Mazza et al., 2005). This has implications for
clinical practice and highlights the importance of
conducting an adequate panel of vigilance tests.
Recent studies have suggested that attention and
alertness in OSAHS patients may be moderated
by intelligence and age. For example, one study
revealed that OSAHS patients with normal intel-
ligence had greater deficits in selective and per-
manent attention compared with controls
matched for age and intelligence, and these
deficits were fully corrected after 1 year of PAP.
High-intelligence OSAHS patients, however, had
no greater attention deficits compared with con-
trols of corresponding age and intelligence even
before PAP treatment (Alchanatis et al., 2005).
Measures of memory and executive function in
OSAHS have been less thoroughly studied, due
73
in part to the challenging complexity of these
domains. Memory is a broad domain comprised
of long- and short-term memory functions that
are associated with different memory processes.
For example, long-term memory includes an epi-
sodic memory component (recollection of specific
experiences) and a procedural memory compo-
nent (learning skills). The construct of a short-term
memory has evolved to include a multicomponent
“working memory” subdomain. Working memory
involves temporary storage and management of
limited information required to carry out complex
cognitive tasks such as learning and reasoning.
Although interrelated, memory subdomains
can be measured by a variety of specific tests.
Limitations in memory testing have been
attributed to complications in initial learning, free
recall, or long-term forgetfulness (Aloia et al.,
2004). Sleep apnea researchers do not always iden-
tify the precise memory subdomain and processes
that are affected by OSAHS, which has led to diffi-
culty interpreting discrepant memory-test findings
across studies (Beebe et al., 2003).
Impaired memory has been found in patients
with moderate and severe OSAHS as well as
older adults with OSAHS, relative to healthy
controls. Greater impairment of information
retrieval, and verbal and visual episodic memory
subdomains have been demonstrated in OSAHS
patients compared to healthy controls (Ferini-
Strambi et al., 2003; Naegele et al., 2006). Deficits
of working memory in OSAHS patients have
been reported in some studies (Redline et al.,
1997; Salorio et al., 2002; Thomas et al., 2005);
however, other studies have failed to demonstrate
this impairment in OSAHS patients (Ferini-
Strambi et al., 2003; Lee et al., 1999). In a large
sample of moderate to severe OSAHS patients
and closely matched healthy controls, Naegele
and colleagues (2006) recently reported that
OSAHS patients had mild but significant memory
impairment affecting episodic, procedural, and
working memory relative to controls. Specifically,
OSAHS patients demonstrated a retrieval deficit
of episodic memory but intact subdomains of
74
maintenance, recognition, and forgetfulness.
Taken together, these studies underscore the
importance of extensive testing of specific mem-
ory subdomains to fully understand deficits in
OSAHS. Comprehensive testing may provide
clues about the affected brain regions and guide
functional brain imaging.
Findings from a study of impaired performance
and decreased brain activation in OSAHS
patients during a working memory task relative
to health controls suggest that compromised brain
function in response to cognitive challenges may
underlie some of the cognitive deficits seen in
patients with OSAHS (Ayalon et al., 2009).
Archbold and colleagues (2009) found that with
greater OSAHS severity, neuronal activation dur-
ing working memory tasks was increased in the
right parietal lobe, but decreased in the cerebellar
vermis indicating that the severity of OSA may
correlate with neural activation during tasks of
working memory (Archbold et al., 2009).
Executive function refers to the ability to develop
and sustain an organized, goal-directed, and flexible
approach to problem solving using basic cognitive
skills such as working memory, mental flexibility,
planning, and, to some degree, core language skills.
The broadness of the executive function construct
makes it difficult to accurately describe the deficits,
assign causation, and distinguish executive dysfunc-
tion from impaired attention. Executive function is
often operationalized as a measure of working
memory (e.g., Wisconsin Card Sorting Test), set
shifting (e.g., Trails B), or verbal fluency (e.g.,
Controlled Oral Word Association), in addition
to testing behavioral inhibition, mental flexibility,
planning, organizations, and problem solving.
Despite the broadness of the concept and
its measurement, OSAHS patients consistently
underperform on tests of executive function rela-
tive to healthy controls. This includes a decreased
ability to initiate new mental processes and to
inhibit automatic ones relative to controls. In one
study, OSAHS patients exhibited less-efficient
use of semantic clustering, and poorer use of
semantic cues compared to healthy controls. With
the exception of letter fluency, deficits were not
observed in general executive control, and reten-
tion of previously encoded information and recog-
nition was intact (Salorio et al., 2002).
Psychomotor functions are characterized by fine
motor coordination and psychomotor speed.
Although the exact mechanism is unclear, OSAHS
patients appear to perform more poorly on tests of
psychomotor skills compared to healthy controls
(see Aloia et al., 2004 for review). The deficits
seem to be linked to fine motor coordination
abilities rather than to motor speed. There has
been comparatively less discussion about
psychomotor deficits compared to other cognitive
domains in OSAHS, in part because of the poten-
tial overlap with daytime sleepiness; however, this
does not account for the difference between tests
of fine motor skills and motor speed.
Cognitive performance has been linked to
severity of OSAHS. Most studies have found
that OSAHS severity as measured by the
apnea–hypopnea index (AHI) is associated with
prolonged reaction times, impaired sustained
attention, and monitoring information. Other
studies have examined specific cognitive domains
in relation to the severity of sleep fragmentation
and hypoxemia. Contrary to expectation that psy-
chomotor functioning would be associated with
hypoxemia, the findings have been inconsistent.
Moreover, psychomotor functioning appears to
be resistant to PAP treatment, suggesting the
possibility of an irreversible central nervous
system damage in severe OSAHS.
Models of neuropsychological deficits in OSAHS
Brain operations responsible for cognitive func-
tion occur primarily in the cerebral cortex (gray
matter layer covering the frontal lobes of the
brain) and its subcortical structures (e.g., the hip-
pocampus and lenticular nuclei). Various discrete
mechanisms of cognitive dysfunction in OSAHS

have been proposed, including the effects of sleep
fragmentation, chronic sleep deprivation, neuro-
nal cell loss due to hypoxemia, cerebral vascular
compromise (Aloia et al., 2004; Beebe, 2005;
Lanfranchi and Somers, 2001; Verstraeten and
Cluydts, 2004), and, most recently, inflammatory
processes (Haensel et al., 2009). Four models will
be summarized below.
Cumulative evidence in animal and human
studies suggests that the frontal lobes of the brain
are most affected by OSAHS. Beebe and Gozal
(2002) have proposed a model with two primary
mechanisms, sleep fragmentation, and hypox-
emia. Sleep fragmentation is thought to preferen-
tially affect the frontal lobes by disrupting the
normal restorative processes of sleep, while hyp-
oxemia results in cellular changes in the prefron-
tal cortex. This model is supported by basic and
clinical studies, particularly studies of the execu-
tive domain. Limitations of this model include
exclusion of brain regions other than the frontal
lobes and little discussion of the nuances of
executive functions. The authors are credited,
however, with the early development of one of
the first neurofunctional models of OSAHS
(Beebe and Gozal, 2002).
A second “hierarchical” model posits that
knowledge of lower order deficits (e.g., attention)
that underlie more complex deficits (e.g., execu-
tive functioning) can provide better understand-
ing of the cognitive mechanisms in OSAHS
(Verstraeten et al., 2004). Previous studies have
demonstrated that sleep disruption has a pro-
found effect on arousal, processing speed, and
attentional ability. Verstraeten and Cluydts
(2004) hypothesized that higher order cognitive
dysfunction in OSAHS can be explained by
impairment in both attention decrements and
slowed mental processing due to sleep disruption.
The authors suggest that theoretical frameworks
are helpful in guiding both the choice and inter-
pretation of higher order cognitive tests. They
conducted a study which provides support for this
model by controlling for basic attentional
75
performance when evaluating executive attention
in patients with severe OSAHS. Attention, vigi-
lance, and executive functions were assessed
using a battery of established neuropsychological
tests including Trail Making Test A,B; Stroop;
and Symbol Digit Modalities Test. The authors
concluded that cognitive performance was com-
parable to the decline found after sleep loss, but
qualitatively different from patients with chronic
obstructive pulmonary disease. Verstraeten and
colleagues (2004) suggest that sleepiness is the
primary factor in cognitive deficits in sleep apnea,
without the need to assume prefrontal brain dam-
age. It is suggested that future studies systemati-
cally control for lower order functions when
assessing executive tasks in OSAHS patients with
arousal and attention difficulties. Justification for
a cognitive hierarchy is compelling; however,
discussion of sleep fragmentation and hypoxemia
is limited in this model.
A third model, the microvascular theory, was
put forth by Aloia and colleagues in 2004. This
model is based on the work of Lanfranchi and
Somers (2001), and extensive cardiovascular and
hypoxia literature establishing a link between car-
diovascular dysfunction and OSAHS. Thus, it was
plausible to suggest (1) vascular compromise
might also exist in the small vessels of the brain,
and (2) intermittent hypoxemia of OSAHS would
preferentially affect the regions of the brain that
were metabolically active during hypoxemia
events. Damage to the vulnerable small vessels
may result in a predictable pattern of cognitive
deficits of attention, mental processing, memory,
executive abilities, motor speed, and coordina-
tion. With sufficient underpinning in the litera-
ture, Aloia et al. (2004) proposed that this
pattern of cognitive dysfunction was present in
OSAHS, and represented microvascular disease
of the small vessels feeding the white matter of
the brain. Several studies highlighting the involve-
ment of subcortical white matter of the brain
using magnetic resonance imaging (MRI) were
presented to support the model. The authors
76
demonstrated evidence in a small sample that
microvascular diseases could be seen on brain
MRI in OSAHS. More recent studies have
demonstrated a significant decrease in the brain's
white-matter volume in OSAHS patients
attributed to decreased myelin and a reduction
in the number of axons which could induce
alterations in mood and cognition (Macey et al.,
2008), while others have failed to find an associa-
tion between white matter ischemia and OSAHS.
A strength of this model is the ability to merge an
established mechanism in OSAHS, vascular com-
promise, with the cognitive aspects of sleep
apnea. Similar to Verstraeten and Cluydts’ hierar-
chical model, however, sleep fragmentation and
hypoxemia are not well integrated into the model.
Further research is needed to test and expand this
model and relate vascular compromise to com-
plaints of fatigue and daytime sleepiness.
Recently, Beebe (2005) developed a comprehen-
sive heuristic model in which multiple factors are
proposed to affect neurobehavioral functioning
among individuals with OSAHS. Beebe proposed
that the effects of sleep fragmentation and hypox-
emia are intermingled and may even be synergistic.
He hypothesized that these synergistic mechanisms
interact with vulnerable brain regions (e.g., the hip-
pocampus, prefrontal cortex, subcortical gray and
white matter), suggesting the potential involvement
of small vessels in the brain (Beebe, 2005).
Addressing the complexity of higher order cognitive
abilities, this model suggests that the mechanisms of
executive functions may be dependent on task
demands or the testing environment, and deficits
may be specific to some tasks but not others. Finally,
this model addresses extraneous variables that
should be considered in the mechanisms of cogni-
tive dysfunction of OSAHS: (1) genetic endow-
ment, (2) prior testing experience, and (3)
sociodemographic factors. Although testing of
this model is needed, it is a useful guide for future
research, and provides a comprehensive approach
to understanding the wide variation OSAHS
cognitive dysfunction, including moderating factors.
Alteration in brain morphology and
cognitive function
The pathophysiology of alterations in the brain
due to OSAHS may involve both chronic and
acute insults on the cerebral vascular structure
and function. As proposed in the microvascular
model of OSAHS-related cognitive dysfunction
(Aloia et al., 2004), these vascular changes may
lead to alterations in the structure and function
of the brain. Studies utilizing neuroimaging in
OSAHS are increasing, and may provide unique
information about brain structures, function, and
metabolic composition that are affected by
OSAHS (Zimmerman et al., 2006). Several of
these studies will be summarized below.
Subcortical brain systems play an important role
in the regulation of cognitive and emotional pro-
cesses, and frontal–subcortical circuits are a major
organizing neural network of the brain. Changes
in subcortical white matter and deep gray matter
nuclei, often noted in older adults, appear as foci
of increase signal intensity on certain pulse
sequences of MRI. Current data suggest subcorti-
cal hyperintensities may reflect a spectrum of struc-
tural changes resulting from hypoperfusion of
these subcortical regions (Campbell and Coffey,
2001). In one study of OSAHS patients, Colrain
and colleagues (2002) demonstrated a relationship
between severity of subcortical white matter
hyperintensities and level of hypoxemia (Colrain
et al., 2002). In another study, older adults with
severe OSAHS had more subcortical white matter
hyperintensities on brain MRI (functional MRI,
fMRI) relative to those with minimal apnea, and
there was a trend for a negative association
between subcortical hyperintensities and free
recall of a word list (Aloia et al., 2001). These sub-
cortical hyperintensities suggest the involvement
of small vessel damage in regions where hypo-
perfusion is more prevalent, however, that damage
to these small vessels can result in a number of cog-
nitive problems without specificity of any explicit
domain (Aloia et al., 2004).

Structural volume changes have been demon-
strated in brain regions including areas that regu-
late memory, executive function, and affect (e.g.,
frontal cortex, anterior cingulate, and hippocam-
pus). Several studies utilized MRI to assess gray
matter volume, which decreases with atrophy
and cell death, in regions of the brain involved
in motor regulation of the upper airway and cog-
nitive function. For example, one study compared
gray matter in 21 males with OSAHS with 21 con-
trols, and found significant reductions in gray
matter in several brain regions (i.e., anterior cin-
gulate, hippocampus, frontal, parietal, and tempo-
ral lobes) that correlated with OSAHS severity
(Macey et al., 2002). In another study, gray mat-
ter loss was demonstrated in the hippocampus, a
key area for cognitive processing (Morrell et al.,
2003). In contrast, one study did not find a signifi-
cant loss of gray matter in 27 males with OSAHS
relative to 24 controls (O’Donoghue et al., 2005).
These negative results may be due to recruitment
of a younger, healthier sample.
Regional brain metabolism may provide insight
into abnormalities in neurochemical transmission
that may reflect pathologic insults to brain integ-
rity. One study using positron emission tomogra-
phy (PET) in OSAHS patients with residual
daytime sleepiness despite effective PAP treat-
ment revealed five of seven participants had
impaired glucose utilization in the frontal, tempo-
ral, and/or parietal cortex (Antczak et al., 2007).
Magnetic resonance spectroscopy (MRS) provides
a measure of metabolic change through the chemi-
cal activity of neurotransmitters and amino acids
(e.g., N-acetylaspartate [NAA], choline [Cho], cre-
atine) that may reflect neural injury. Kamba and
colleagues conducted two studies using MRS. In
the first study, they reported that metabolic
changes occur in normal-appearing white matter
of patients with moderate to severe OSA (Kamba
et al., 1997). A follow-up study addressed the
effects of potentially confounding comorbid
conditions. Fifty-five patients with severe OSAHS
underwent MRS. The NAA/Cho ratio in the
77
cerebral cortex decreased with age, which is indica-
tive of cerebral metabolic injury. The severity of
OSAHS was found to have a significant negative
association with the NAA/Cho ratio for normal-
appearing white matter that was independent of
age or comorbid condition, suggesting the severity
of OSAHS may be associated with the degree of
white matter metabolic impairment and this
impairment may be due to cerebrovascular risk
factors (Kamba et al., 2001).
Previous studies have revealed that OSAHS
might compromise the recruitment of task-related
brain regions compared with controls. Using MRI
signal in OSAHS patients while performing a cog-
nitive challenge, both over- and underactivation
of specific brain regions have been reported
(Ayalon et al., 2009). Thomas and colleagues
(2005) found a lack of task-related signal activity
in the dorsolateral prefrontal cortex in 16
untreated OSAHS patients compared with
matched normal controls during a working mem-
ory challenge. In another study using fMRI,
OSAHS patients had an increased activation
response in several brain regions involved in atten-
tion tasks compared with controls on a verbal
learning task. Notably, OSAHS patients recruited
greater brain volume in task-related areas (e.g.,
cingulate, frontal) and other regions, suggesting
the need for compensatory resources (Ayalon
et al., 2009a).
In summary, the pathophysiology of OSAHS-
related cognitive deficits is controversial and
multifactorial. OSAHS brings with it disturbances
in sleep stages, blood oxygenation, and sympa-
thetic nervous system regulation. Since OSAHS
appears to affect multiple brain regions, brain
changes may reflect damage resulting from
several etiologies, including hypoxemia, small
vessel damage, cerebral circulation oscillations,
chronic inflammation, all of which can result in
local ischemia. This damage suggests an ongoing
series of accumulated injuries leading to gradual
cognitive changes that may be unrecognized by
patients and clinicians for some time.
78
Neurobehavioral recovery after PAP
PAP normalizes both sleep disruption and oxygen
desaturation and has been found to dramatically
reduce morbidity and mortality in a variety of
populations. Owing to these encouraging findings,
the effect of PAP on cognitive function has been
an area of interest for many apnea researchers.
In the 1980s, a cadre of researchers provided
early evidence of short-term effect of PAP on
improvement in a variety of cognitive deficits. In
a review of PAP treatment studies in peer-
reviewed journals from 1985 to 2002, Aloia et al.
(2004) examined whether pretreatment cognitive
impairments were permanent or if they remitted
with PAP (Aloia et al., 2004). Overall, studies of
OSAHS and PAP reported a positive association
between treatment adherence and improved
cognitive performance. The review revealed
attention/vigilance improved in the majority of
studies, but changes in global functioning, execu-
tive functioning, and memory improved in about
half of the studies. Tests of psychomotor function
and construction, however, failed to improve with
PAP in most studies. The authors noted that results
may be dependent on the selected neuropsycho-
logical tests, which may vary in sensitivity to
the effects of treatment, just as some may be more
sensitive to specific cognitive deficits. Since the
publication of the review, additional studies have
provided greater understanding of cognitive recov-
ery after effective PAP treatment (see Table 1).
Recent studies have concluded that adherence
to PAP, as measured by hours per night, is an
important factor when evaluating cognitive out-
comes. Zimmerman and colleagues (2006) com-
pared three groups of memory impaired OSAHS
patients based on average PAP use (poor, moder-
ate, optimal users) at 3 months. At baseline,
groups were similar with regard to demographic
variables and verbal memory performance. Mod-
erate users (2–5 h of use nightly) were three times
as likely to develop normal memory after
3 months of PAP compared to poor users (< 2 h
of use nightly); however, the difference did not
reach significance. Optimal users (> 6 h of use
nightly) were eight times more likely to exhibited
normalization of memory function compared with
poor users at 3 months. These findings suggest that
memory performance may be reversible with opti-
mal levels of PAP treatment, and OSAHS patients
with memory deficits at baseline may need 6 h
of use per night to experience meaningful benefit
in memory abilities (Zimmerman et al., 2006).
In a multisite study of adherence in 149 OSAHS
patients, Weaver and colleagues (2007) demon-
strated that subjective sleepiness as measured by
the Epworth Sleepiness Scale can improve with as
few as 4 h of PAP use per night. Objective sleepi-
ness as measure by the Multiple Sleep Latency Test
(MSLT) may require 6 h of use and functional out-
comes associated with sleepiness may take over
7 h. These studies, among others, show that adher-
ence as well as test sensitivity must be considered in
the design of efficacy trials (Weaver et al., 2007).
Changes in brain structure and function
after PAP
Growing evidence suggest the OSAHS-related
changes in brain morphology may improve with
PAP use. Neuroimaging studies performed during
cognitive testing have provided insight into PAP’s
effect on function of neuroanatomical circuits in
the brain. A recent study of the effects of acute with-
drawal of PAP on brain function in nine individuals
with OSAHS revealed significant treatment effects
on working memory and recruitment of task-related
brain regions during fMRI (Aloia et al., 2009).This
study is clinically relevant because it mimics the
common treatment holidays of many PAP users.
Although neuroradiography can provide important
insights into the structural and functional
differences associated with OSAHS, one of the
challenges is to interpret the findings in light of
comorbid conditions that also cause neural injury.
A second challenge in cross-sectional studies is the
timing of neural injury: whether it preceded
OSAHS or vice versa (Dempsey et al., 2010).
Table 1. Cognitive recovery after PAP for OSAHS (published in the past decade)

Sample

Total # (# men) OSAHS severity

Reference groups Age M (SD) M (SD) Study variables Key findings

Alchanatis et al. 83 OSAHS: AHI: Attention (selective and  The HI and NI OSAHS patient groups
(2005) 47 OSAHS (22 HI 47.3 (7.9) OSAHS: permanent), alertness did not differ with regard to OSAHS
HI, 20 NI) NI 50.3 (7.6) HI 62.8 (22.6) before PAP use and severity or sleepiness
36 healthy Controls: NI 69.6 (22.2) 1 year later  HI patients showed the same attention/
controls HI 49.3 (2.9) Controls: alertness performance compared with HI
(15 HI, 21 NI) NI 48.4 (4.1) HI 4.52 (1.4) controls suggesting a protective effect
NI 3.95 (1.72) against OSAHS cognitive decline
 NI patients showed deficits of reaction
time, and selective and permanent
attention decline compared with NI
controls
 At 1-year follow-up, neither patient
group showed any differences regarding
attention and alertness compared with
the control groups

Aloia et al. 12 64.8 (4.5) RDI: 51.2 (19.8) Attention, constructional  RDI at baseline was associated with
(2003) adherent abilities, motor speed, delayed verbal recall, while oxygen
45.9 (21.7) memory, language, desaturation was associated with both
nonadherent executive functioning delayed recall and constructional abilities
before and 3 months after  Compliant use of CPAP at 3 months was
CPAP associated with greater improvements in
attention, psychomotor speed, executive
functioning, and nonverbal delayed recall
 Attention measures predicted
compliance at 3 months

(Continued)

79
Table 1. Cognitive recovery after PAP for OSAHS (published in the past decade) (Continued)

80
Sample

Total # (# men) OSAHS severity

Reference groups Age M (SD) M (SD) Study variables Key findings

Aloia et al. 9 (5 men) 51.1 (9.3) AHI: 42.4 (28.2) Verbal working memory  Treatment effects on working memory-
(2009) during repeated fMRI related brain activity were significant,
under conditions of PAP with greater deactivation in the right
treatment (at least one posterior insula and overactivation in the
consecutive week) or right inferior parietal lobule
nontreatment (for two  The observed responses to PAP
consecutive nights) treatment withdrawal were more extreme
in all regions of interest, such that
memory-related activity increased and
memory-related deactivation decreased
further relative to the control task

Ancoli-Israel 52 older adults 78.6 (6.8) AHI: 29.8 (16.1) Attention/vigilance,  A comparison of pre- and posttreatment
et al. (2008) with Alzheimer's CPAP CPAP psychomotor speed, neuropsychological test scores after
disease (39 men) 77.7 (7.7) 26.9 (15.5) verbal episodic memory, 3 weeks of therapeutic CPAP compared
27 CPAP Placebo Placebo executive functioning to placebo PAP in both groups showed a
25 placebo pretreatment, at 3 and 6 significant improvement in cognition
weeks  Post hoc examination of change scores
for individual tests suggested
improvements in episodic verbal learning
and memory and some aspects of
executive functioning such as cognitive
flexibility and mental processing speed

Barbe et al. 54 54 (2) AHI: 54 (3) Attention, vigilance,  After 6 weeks of CPAP or placebo, there
(2001) 29 CPAP Adherence to memory, information were no significant changes in objective
25 Placebo CPAP 5.0 processing, visual–motor sleepiness, vigilance, attention, memory,
(0.4) h/day coordination information processing, or visual–motor
Quality of life, objective coordination between the groups
sleepiness
Bardwell (2001) 36 PAP 47 (1.9) RDI: Attention, constructional  Only 1/22 cognitive test scores showed
20 PAP Placebo 48 Placebo abilities, motor speed, significant changes specific to PAP
16 placebo (2.2) 43.6 (6.4) memory, language, treatment: Digit Vigilance-Time
PAP executive functioning (p ¼ 0.035). The PAP group improved
56.8 (5.4) their time (from 7.5 to 6.9 min. p ¼ 0.013)
 The rank-sum test revealed that the PAP
group had significantly better overall
cognitive functioning posttreatment than
the placebo group (mean ranks of 17.8
vs. 20.2, respectively; p ¼ 0.022)
Castronovo et al. 28 (all men) 42.15 (6.64) 50.14 (24.84) Working memory,  Compared to controls, never-treated
(2009) 14 OSAHS patients patients learning, recall, OSAHS patients showed increased
patients 43.93 (7.78) 349.36 (34.15) min/ recognition memory; activations in the left frontal cortex,
14 healthy controls night adherence executive functions medial precuneus, and hippocampus, and
controls (inhibition, selective decreased activations in the caudal pons
attention), vigilance,  OSAHS patients showed decreases in
sleepiness activation in the left inferior frontal gyrus
and anterior cingulate cortex, and
bilaterally in the hippocampus after PAP
compared to baseline suggesting a neural
compensation mechanism, which is
reduced by effective treatment
 Except for the Stroop test,
neurocognitive domains, impaired at
baseline, showed significant
improvement after 3 months of PAP

Cooke et al. 10 (7 men) 75.7 (5.9) AHI: Cognitive decline ,  Compared to the PAP group, the
(2009) 5 sustained PAP 1.6 (2.3) on PAP depressive symptoms, and PAPþ group showed less cognitive
users (PAPþ) Sustained CPAP daytime somnolence decline with sustained CPAP use,
5 discontinued use 13.3 month stabilization of depressive symptoms and
PAP (PAP) (5.2) daytime somnolence, and significant
improvement in subjective sleep quality

Felver-Gant et al. 56 (39 men) 52.8 (11.2) AHI: Working memory,  High adherers showed small
(2007) 41.4 (22.1) executive functioning, improvements in both tests of working
Average motor speed prior to PAP memory (2-back: F46 ¼ 4.73, p < 0.04;
adherence ¼ 4 and at 3 months PASAT: F46 ¼ 4.92, p < 0.04), whereas
(2.22) h/night low adherers performed evidence a
decline in scores over time
 There were no treatment effects for other
cognitive measures of executive
functioning, motor speed

Ferini-Strambi 23 OSAHS 56.52 (6.13) AHI Attention, vigilance,  At baseline, OSAHS patients had a
et al. (2003) patients (21 Patient memory, learning, verbal significant impairment, compared to
men) 54.9 (13.37) ability, executive controls, in tests of sustained attention,
23 controls functions, motor, and visuospatial learning, executive function,
constructional abilities, motor performance, and constructional
sleepiness, depressive abilities
symptoms

(Continued)

81
 82
Table 1. Cognitive recovery after PAP for OSAHS (published in the past decade) (Continued)

Sample

Total # (# men) OSAHS severity

Reference groups Age M (SD) M (SD) Study variables Key findings

 After a 15-day PAP, attentive,

visuospatial learning, and motor
performances returned to normal levels
in 16 patients with adherence 5 h/night
 A 4-month PAP did not result in any
further improvement in cognitive tests
 Executive functions and constructional
abilities were not affected by short- and
long-term treatment with PAP

Lim et al. (2007) 46 46.7 (2.4) AHI: Attention, vigilance,  Pretreatment, OSAHS patients showed
17 CPAP PAP 63.5 (7.8), PAP working memory, diffuse impairments, particularly speed of
14 placebo 48.9 (3.2) 65.8 (8.2), Placebo executive functions, information processing, attention, and
15 oxygen placebo 58.6 (8.3), Oxygen psychomotor working memory, executive functioning,
47.1 (2.3) performance, speed of learning, and memory, alertness, and
oxygen information processing, sustained attention
global cognitive score  There was no significant
Time  Treatment interaction for the
global deficit score. When examining
individual neuropsychological test scores,
two thirds of them improved with time
regardless of treatment, although only
Digit Vigilance-Time (p ¼ 0.020) showed
significant improvement specific to
CPAP treatment
 2 weeks of CPAP or oxygen-
supplementation treatment was
insufficient to show overall beneficial
cognitive effects, as compared with
placebo-CPAP. However, 2 weeks of
CPAP treatment might be helpful in
terms of speed of information processing,
vigilance, or sustained attention and
alertness
Munoz et al. 160 patients (156 49 (1) AHI: Vigilance, reaction time,  Before treatment, OSAHS patients were
(2000) men) OSAHS 60 (2) OSAHS daytime sleepiness, significantly more somnolent, anxious,
80 OSAHS 46 (1) control patients depression, and anxiety at and depressed and had a longer reaction
80 healthy baseline and time and poorer vigilance relative to
controls 12  1 months controls
 The use of CPAP improved significantly
the levels of somnolence (p < 0.0001) and
vigilance (p < 0.01), but failed to modify
anxiety and depression

O'Donoghue 51 (all men) 45.7 (10.1) AHI: T1-weighted brain  No areas of gray matter volume change
et al. (2005) 27 OSAHS OSAHS 71.7 (17.0) imaging in a high- were found in OSAHS patients relative
patients 43.3 (9.4) OSAHS resolution MRI pre-PAP, to controls and no differences were seen
24 controls controls 5.9 (4.7) controls at 6 months in bilateral hippocampal, temporal lobe,
or whole brain volumes, assessed by
manual tracing of anatomical borders
 No longitudinal changes were seen in
gray matter density or regional volumes
after PAP treatment, but whole brain
volume decreased slightly without focal
changes after 6 months of continuous
PAP

Sweet et al. 10 (6 men) 51.1 (9.3) AHI: 42.4 (28.2) Working memory,  Compared to the treatment adherent
(2010) sleepiness baseline, significant memory-related
fMRI following regular deactivation was observed during the
CPAP use, and after two PAP withdrawal condition
nights of CPAP  The magnitude of deactivation during
withdrawal withdrawal was significantly associated
with better working memory
performance in the posterior cingulate
and right postcentral gyrus, and greater
sleepiness in the left and right medial
frontal gyrus

Thomas et al. 32 Verbal working memory  Working memory speed in OSAHS

(2005) 16 OSAHS task and fMRI to map patients was significantly slower than in
16 healthy cerebral activation controls, and a group average map
controls showed absence of dorsolateral
prefrontal activation, regardless of
nocturnal hypoxia

(Continued)

83
 84
Table 1. Cognitive recovery after PAP for OSAHS (published in the past decade) (Continued)

Sample

Total # (# men) OSAHS severity

Reference groups Age M (SD) M (SD) Study variables Key findings

 After treatment, resolution of subjective

sleepiness contrasted with no significant
change in behavioral performance,
persistent lack of prefrontal activation,
and partial recovery of posterior parietal
activation, suggesting that working
memory may be impaired in OSAHS and
that this impairment is associated with
disproportionate impairment of function
in the dorsolateral prefrontal cortex
 Nocturnal hypoxia may not be a
necessary determinant of cognitive
dysfunction, and sleep fragmentation
may be sufficient

Weaver et al. 149 (87% men) 46.8 (8.8) 64.1 (29.1) Sleepiness (subjective,  There were significant differences in
(2007) objective), functional mean nightly PAP duration between
status treatment responders and nonresponders
Pretreatment, after with regard to sleepiness and daily
3 months of PAP use functioning
 Thresholds above which further
improvements were less likely relative to
nightly duration of CPAP were identified
for Epworth Sleepiness Scale score (4 h),
Multiple Sleep Latency Test (6 h), and
Functional Outcomes associated with
Sleepiness Questionnaire (7.5 h)
 A linear dose-response relationship
(p < 0.01) between increased use and
achieving normal levels was shown for
daytime sleepiness, but only up to 7 h of
PAP use for functional status
Zimmerman 58 (49 men) 48.1 (10.1) 46.1 (27.9) Verbal memory prior to  Logistic regression analyses revealed that
et al. (2006) PAP use: the initiation of PAP the odds of optimal users exhibiting
14 poor treatment and at 3 normalization of memory function
25 moderate 19 months of PAP following 3 months of PAP therapy were
optimal users 7.9 times (p ¼ 0.01) the odds of poor
users exhibiting normalization of
memory abilities
 Overall, 21% of poor users, 44% of
moderate users, and 68% of optimal
users exhibited memory performance in
the clinically normal range following
3 months of PAP use (w(2) ¼ 7.27;
p ¼ 0.03)
 These preliminary findings indicate that
impaired verbal memory performance in
patients with OSA may be reversible
with optimal levels of PAP treatment.
OSA patients exhibiting verbal memory
impairments may experience a clinically
meaningful benefit in their memory
abilities when they use PAP for at least
6 h/night

M (SD), means (standard deviation); OSAHS, obstructive sleep apnea and hypoxia syndrome; HI, high intelligence; NI, normal intelligence; AHI, apnea/hypopnea index; RDI,
respiratory disturbance index; fMRI, functional magnetic resonance imaging.

85
86
Conclusions and future directions
In this brief review, the mechanisms of neuro-
behavioral dysfunction in OSAHS, and remit-
tance of these deficits through PAP treatments
have been discussed. Recent publications suggest
distinct but not mutually exclusive deficits in mul-
tiple cognitive domains. There have been exciting
new models outlining the mechanisms of cogni-
tive deficits in OSAHS, and findings based on
advanced neuroimaging methods. It appears that
the cognitive dysfunction of OSAHS is not likely
to be due to a single mediating mechanism, nor
is it pervasive across all patients. There has been
growing evidence for the effect of potential
moderating factors. For example, studies have
demonstrated that high cognitive reserves may
spare some OSAHS patients from developing
cognitive problems (Alchanatis et al., 2005).
Future research should attempt to identify
these moderators for cognitive dysfunction in
OSAHS and to highlight the mechanisms of
dysfunction by cognitive domain. Finally, as our
knowledge of the physiological consequences of
OSAHS increases, cognitive research should try
to develop parsimonious theories of cognitive
dysfunction that incorporate these physiological
mechanisms.
References
Alchanatis, M., Zias, N., Deligiorgis, N., Amfilochiou, A.,
Dionellis, G., & Orphanidou, D. (2005). Sleep apnea-related
cognitive deficits and intelligence: An implication of cogni-
tive reserve theory. Journal of Sleep Research, 14, 69–75.
Aloia, M. S., Arnedt, J. T., Davis, J., Malloy, P., Salloway, S.,
& Rogg, J. (2001). MRI white matter hyperintensities in
older adults with obstructive sleep apnea. Sleep, 24, A55.
Aloia, M. S., Arnedt, J. T., Davis, J. D., Riggs, R. L., &
Byrd, D. (2004). Neuropsychological sequelae of obstructive
sleep apnea-hypopnea syndrome: A critical review. Journal
of the International Neuropsychological Society, 10, 772–785.
Aloia, M. S., Arnedt, J. T., Stepnowsky, C., Hecht, J., &
Borrelli, B. (2005). Predicting treatment adherence in
obstructive sleep apnea using principles of behavior change.
Journal of Clinical Sleep Medicine, 1, 346–353.
Aloia, M. S., Ilniczky, N., Di, D. P., Perlis, M. L.,
Greenblatt, D. W., & Giles, D. E. (2003). Neuropsychologi-
cal changes and treatment compliance in older adults with
sleep apnea. Journal of Psychosomatic Research, 54, 71–76.
Aloia, M. S., Sweet, L. H., Jerskey, B. A., Zimmerman, M.,
Arnedt, J. T., & Millman, R. P. (2009). Treatment effects
on brain activity during a working memory task in obstruc-
tive sleep apnea. Journal of Sleep Research, 18, 404–410.
American Thoracic Society (1994). Indications and standards
for use of nasal continuous positive airway pressure (CPAP)
in sleep apnea syndromes. American Journal of Respiratory
and Critical Care Medicine, 150, 1738–1745.
Ancoli-Israel, S., Palmer, B. W., Cooke, J. R., Corey-
Bloom, J., Fiorentino, L., Natarajan, L., et al. (2008). Cogni-
tive effects of treating obstructive sleep apnea in
Alzheimer’s disease: A randomized controlled study. Jour-
nal of the American Geriatrics Society, 56, 2076–2081.
Antczak, J., Popp, R., Hajak, G., Zulley, J., Marienhagen, J.,
& Geisler, P. (2007). Positron emission tomography findings
in obstructive sleep apnea patients with residual sleepiness
treated with continuous positive airway pressure. Journal
of Physiology and Pharmacology, 58(Suppl. 5), 25–35.
Archbold, K. H., Borghesani, P. R., Mahurin, R. K.,
Kapur, V. K., & Landis, C. A. (2009). Neural activation
patterns during working memory tasks and OSA disease
severity: Preliminary findings. Journal of Clinical Sleep Med-
icine, 5, 21–27.
Ayalon, L., Ancoli-Israel, S., & Drummond, S. P. (2009).
Altered brain activation during response inhibition in obstruc-
tive sleep apnea. Journal of Sleep Research, 18, 204–208.
Ayalon, L., Ancoli-Israel, S., Aka, A. A., McKenna, B. S., &
Drummond, S. P. (2009a). Relationship between obstructive
sleep apnea severity and brain activation during a sustained
attention task. Sleep, 32, 373–381.
Barbe, F., Mayoralas, L. R., Duran, J., Masa, J. F.,
Maimo, A., Montserrat, J. M., et al. (2001). Treatment
with continuous positive airway pressure is not effective
in patients with sleep apnea but no daytime sleepiness. A
randomized, controlled trial. Annals of Internal Medicine,
134, 1015–1023.
Bardwell, W. A., Ancoli-Israel, S., Berry, C. C., &
Dimsdale, J. E. (2001). Neuropsychological effects of one-
week continuous positive airway pressure treatment in
patients with obstructive sleep apnea: a placebo-controlled
study. Psychosomatic Medicine, 63, 579–584.
Beebe, D. W. (2005). Neurobehavioral effects of obstructive
sleep apnea: An overview and heuristic model. Current
Opinion in Pulmonary Medicine, 11, 494–500.
Beebe, D. W., & Gozal, D. (2002). Obstructive sleep apnea and
the prefrontal cortex: Towards a comprehensive model linking
nocturnal upper airway obstruction to daytime cognitive and
behavioral deficits. Journal of Sleep Research, 11, 1–16.

Beebe, D. W., Groesz, L., Wells, C., Nichols, A., & McGee, K.
(2003). The neuropsychological effects of obstructive sleep
apnea: A meta-analysis of norm-referenced and case-con-
trolled data. Sleep, 26, 298–307.
Campbell, J. J., III, & Coffey, C. E. (2001). Neuropsychiatric
significance of subcortical hyperintensity. The Journal of
Neuropsychiatry and Clinical Neurosciences, 13, 261–288.
Castronovo, V., Canessa, N., Strambi, L. F., Aloia, M. S.,
Consonni, M., Marelli, S., et al. (2009). Brain activation
changes before and after PAP treatment in obstructive sleep
apnea. Sleep, 32, 1161–1172.
Colrain, I. M., Bliwise, D., DeCarli, C., & Carmelli, D. (2002).
The contribution of oxygen desaturation to the development
of white matter hyperintensities in elderly male twins. Sleep,
25, A3.
Cooke, J. R., Ayalon, L., Palmer, B. W., Loredo, J. S., Corey-
Bloom, J., Natarajan, L., et al. (2009). Sustained use of CPAP
slows deterioration of cognition, sleep, and mood in patients
with Alzheimer's disease and obstructive sleep apnea: A pre-
liminary study. Journal of Clinical Sleep Medicine, 5, 305–309.
Dempsey, J. A., Veasey, S. C., Morgan, B. J., &
O'Donnell, C. P. (2010). Pathophysiology of sleep apnea.
Physiology Reviews, 90, 47–112.
Felver-Gant, J. C., Bruce, A. S., Zimmerman, M.,
Sweet, L. H., Millman, R. P., & Aloia, M. S. (2007). Work-
ing memory in obstructive sleep apnea: construct validity
and treatment effects. Journal of Clinical Sleep Medicine,
3, 589–594.
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.
Giles, T. L., Lasserson, T. J., Smith, B. H., White, J.,
Wright, J., & Cates, C. J. (2006). Continuous positive air-
ways pressure for obstructive sleep apnoea in adults.
Cochrane Database of Systematic Reviews, 3, CD001106.
Haensel, A., Bardwell, W. A., Mills, P. J., Loredo, J. S.,
Ancoli-Israel, S., Morgan, E. E., et al. (2009). Relationship
between inflammation and cognitive function in obstructive
sleep apnea. Sleep & Breathing, 13, 35–41.
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.
Kamba, M., Suto, Y., Ohta, Y., Inoue, Y., & Matsuda, E.
(1997). Cerebral metabolism in sleep apnea. Evaluation by
magnetic resonance spectroscopy. American Journal of
Respiratory and Critical Care Medicine, 156, 296–298.
Lanfranchi, P., & Somers, V. K. (2001). Obstructive sleep
apnea and vascular disease. Respiratory Research, 2, 315–319.
87
Lee, M. M., Strauss, M. E., Adams, N., & Redline, S. (1999).
Executive functions in persons with sleep apnea. Sleep &
Breathing, 3, 13–16.
Lim, W., Bardwell, W. A., Loredo, J. S., Kim, E. J., ncoli-
Israel, S., Morgan, E. E., et al. (2007). Neuropsychological
effects of 2-week continuous positive airway pressure treat-
ment and supplemental oxygen in patients with obstructive
sleep apnea: A randomized placebo-controlled study. Jour-
nal of Clinical Sleep Medicine, 3, 380–386.
Macey, P. M., Henderson, L. A., Macey, K. E., Alger, J. R.,
Frysinger, R. C., Woo, M. A., et al. (2002). Brain morphol-
ogy associated with obstructive sleep apnea. American
Journal of Respiratory and Critical Care Medicine, 166,
1382–1387.
Macey, P. M., Kumar, R., Woo, M. A., Valladares, E. M., Yan-
Go, F. L., & Harper, R. M. (2008). Brain structural changes
in obstructive sleep apnea. Sleep, 31, 967–977.
Matthews, E. E., & Aloia, M. S. (2009). Continuous positive
airway pressure treatment and adherence in obstructive
sleep apnea. Sleep Medicine Clinics, 4, 473–485.
Mazza, S., Pepin, J. L., Naegele, B., Plante, J., Deschaux, C., &
Levy, P. (2005). Most obstructive sleep apnoea patients
exhibit vigilance and attention deficits on an extended bat-
tery of tests. The European Respiratory Journal, 25, 75–80.
Morrell, M. J., McRobbie, D. W., Quest, R. A.,
Cummin, A. R., Ghiassi, R., & Corfield, D. R. (2003).
Changes in brain morphology associated with obstructive
sleep apnea. Sleep Medicine, 4, 451–454.
Munoz, A., Mayoralas, L. R., Barbe, F., Pericas, J., &
Agusti, A. G. (2000). Long-term effects of CPAP on day-
time functioning in patients with sleep apnoea syndrome.
The European Respiratory Journal, 15, 676–681.
Naegele, B., Launois, S. H., Mazza, S., Feuerstein, C.,
Pepin, J. L., & 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.
O'Donoghue, F. J., Briellmann, R. S., Rochford, P. D.,
Abbott, D. F., Pell, G. S., Chan, C. H., et al. (2005). Cere-
bral structural changes in severe obstructive sleep apnea.
American Journal of Respiratory and Critical Care Medicine,
171, 1185–1190.
Redline, S., Strauss, M. E., Adams, N., Winters, M., Roebuck, T.,
Spry, K., et al. (1997). Neuropsychological function in mild
sleep-disordered breathing. Sleep, 20, 160–167.
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.
Saunamaki, T., & Jehkonen, M. (2007). Depression and anxi-
ety in obstructive sleep apnea syndrome: A review. Acta
Neurologica Scandinavica, 116, 277–288.
88
Sweet, L. H., Jerskey, B. A., & Aloia, M. S. (2010). Default
network response to a working memory challenge after
withdrawal of continuous positive airway pressure treatment
for obstructive sleep apnea. Brain Imaging and Behavior, 4,
155–163.
Thomas, R. J., Rosen, B. R., Stern, C. E., Weiss, J. W., &
Kwong, K. K. (2005). Functional imaging of working mem-
ory in obstructive sleep-disordered breathing. Journal of
Applied Physiology, 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.
Verstraeten, E., & Cluydts, R. (2004). Executive control of atten-
tion in sleep apnea patients: Theoretical concepts and method-
ological considerations. Sleep Medicine Reviews, 8, 257–267.
Verstraeten, E., Cluydts, R., Pevernagie, D., & Hoffmann, G.
(2004). Executive function in sleep apnea: Controlling for
attentional capacity in assessing executive attention. Sleep,
27, 685–693.
Weaver, T. E., Maislin, G., Dinges, D. F., Bloxham, T.,
George, C. F., Greenberg, H., et al. (2007). Relationship
between hours of CPAP use and achieving normal levels
of sleepiness and daily functioning. Sleep, 30, 711–719.
Young, T., Peppard, P. E., & Gottlieb, D. J. (2002). Epidemi-
ology of obstructive sleep apnea: A population health per-
spective. American Journal of Respiratory and Critical Care
Medicine, 165, 1217–1239.
Zimmerman, M. E., & Aloia, M. S. (2006). A review of neuro-
imaging in obstructive sleep apnea. Journal of Clinical Sleep
Medicine, 2, 461–471.
Zimmerman, M. E., Arnedt, J. T., Stanchina, M.,
Millman, R. P., & Aloia, M. S. (2006). Normalization of
memory performance and positive airway pressure adher-
ence in memory-impaired patients with obstructive sleep
apnea. Chest, 130, 1772–1778.