Quantitative Electroencephalogram Measures in Adult Obstructive Sleep Apnea - Potential Biomarkers of Neurobehavioural Functioning - ScienceDirect

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Outline
Summary
Keywords
Abbreviations
Introduction
Method
Quantitative EEG measures during wakefulness in OSA
Quantitative EEG measures during sleep in OSA
Potential mechanisms for wake and sleep EEG abnormalities and neurobehavioural deficits in OSA
Conclusion
Conflict of interest
Acknowledgments
References∗
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Tables (2)
Table 1
Table 2
Sleep Medicine Reviews

Volume 36, December 2017, Pages 29-42
Clinical Review
Quantitative electroencephalogram measures in adult obstructive sleep apnea – Potential biomarkers

of neurobehavioural functioning
Angela L. D'Rozario a, b, c , Nathan E. Cross a, 1, Andrew Vakulin a, d, Delwyn J. Bartlett a, e, Keith K.H. Wong a, c , e, David Wang a, c , e, Ronald R. Grunstein a, c , e
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https://doi.org/10.1016/j.smrv.2016.10.003 Get rights and content
Summary
Obstructive sleep apnea (OSA) results in significantly impaired cognitive functioning and increased daytime sleepiness in some patients leading to
increased risk of motor vehicle and workplace accidents and reduced productivity. Clinicians often face difficulty in identifying which patients are at
risk of neurobehavioural dysfunction due to wide inter-individual variability, and disparity between symptoms and conventional metrics of disease
severity such as the apnea hypopnea index. Quantitative electroencephalogram (EEG) measures are determinants of awake neurobehavioural
function in healthy subjects. However, the potential value of quantitative EEG (qEEG) measurements as biomarkers of neurobehavioural function in
patients with OSA has not been examined. This review summarises the existing literature examining qEEG in OSA patients including changes in
brain activity during wake and sleep states, in relation to daytime sleepiness, cognitive impairment and OSA treatment. It will speculate on the
mechanisms which may underlie changes in EEG activity and discuss the potential utility of qEEG as a clinically useful predictor of neurobehavioural
function in OSA.
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Keywords
Quantitative EEG analysis; Power spectral analysis; Signal processing; Sleep disordered breathing; Cognition; Performance
Abbreviations
ABG
arterial blood gas
AHI
apnea hypopnea index
COPD
chronic obstructive pulmonary disease
CPAP
continuous positive airway pressure
DFA
detrended fluctuation analysis
DS%
deep sleep percentage
EEG
electroencephalogram/electroencephalography
ESS
Epworth sleepiness scale
FFT
fast Fourier transform
KSS
Karolinska sleepiness scale
MSLT
multiple sleep latency test
MWT
maintenance of wakefulness test
NREM
non-rapid eye movement
ODI
oxygen desaturation index
OSA
obstructive sleep apnea
PFC
prefrontal cortex
PSA
power spectral analysis
PVT
psychomotor vigilance task
qEEG
quantitative electroencephalography
REM
rapid eye movement
RCT
randomized control trial
SaO2
arterial oxyhaemoglobin saturation
SWA
slow wave activity
SWS
slow wave sleep
Introduction
Obstructive sleep apnea (OSA) is a frequently under-recognised sleep breathing disorder [1], and is highly prevalent affecting almost a quarter of
middle-aged women and half of middle-aged men in the general community [2], with increasing prevalence tied to the rise in obesity [3]. Untreated
OSA is associated with increased daytime sleepiness, problems with attention and cognitive functioning, and increased risk of motor vehicle and
workplace accidents [4]. This is a significant problem in high-risk populations such as in transport workers where vigilance failure has serious safety
consequences [5,6]. Importantly, there is wide inter-individual variability in the risk of vigilance failure as not all OSA patients are sleepy or show
functional impairments [7]. Moreover, sleepiness in transport workers may be underestimated [8]. Current clinical metrics of disease severity (apnea
hypopnea index, AHI and oxygen saturation indices) do not strongly and consistently relate to functional impairment [9–11], leaving physicians in a
quandary when assessing patients regarding driving risk and need for treatment.
Electroencephalogram (EEG) recordings can be quantitatively analysed revealing variations in brain activity which are modulated by homeostatic and
circadian processes, these two distinct biological mechanisms and their interactions are modelled by the two-process model of sleep-wake
regulation [12,13]. Circadian regulation (process C) of the sleep-wake cycle is influenced by the intrinsic biological clock located in the
suprachiasmatic nucleus of the hypothalamus, while the homeostatic process S represents sleep propensity or ‘sleep drive’ that intensifies with
increasing time awake and dissipates with time spent asleep. Previous work in healthy subjects has shown relationships between quantitative EEG
characteristics of NREM sleep and daytime performance and sleep propensity highlighting the potential value of EEG measures as biomarkers of
sleepiness and cognitive function in OSA [14]. However the relationships between EEG activity and daytime sleepiness and cognitive impairment in
OSA have not been well elucidated, a gap addressed with this review.
EEG characteristics of wake and sleep

Thalamocortical networks are largely responsible for the distinct patterns of neuronal firing on the EEG which differentiates wake from distinct stages
of sleep [15]. Wakefulness and REM sleep exhibit similar EEG features, characterised by low-voltage fast-frequency ‘desynchronised’ activity. The
EEG characteristics of NREM sleep vary significantly with sleep stage. N2 sleep is characterised by K-complexes (slow oscillations <1 Hz) and sleep
spindles (waxing and waning oscillations of 0.5–3 s, usually within the frequency range of 11–16 Hz) and N3 or SWS is dominated by high-voltage,
slow wave activity (SWA) in the delta (typically 0.5–4.5 Hz) frequency range.
EEG power spectral analysis

The sinusoidal waveforms of the EEG are often defined by their frequency i.e., waveforms in the theta band have frequencies of 4.5–8 Hz; alpha
waves have a frequency of 8–12 Hz, etc. In reality, the EEG recorded during wake or sleep is often a complex mixture of different waveforms
superimposed on one another. The complex patterns of the EEG can be created by adding together simpler sine waves of different frequencies,
amplitudes and phase relationships. Conversely, the EEG can be deconstructed into waveforms with different frequency components. Power spectral
analysis (PSA) based on fast Fourier transform (FFT) is the most common method for processing the EEG signal in the current literature. The EEG is
transformed from the time domain (amplitude versus time) to the frequency domain (amplitude versus frequency) [16]. This process allows for greater
insight into brain activity during sleep which would otherwise be masked when using conventional sleep staging criteria. PSA quantifies the amplitude
and prevalence of the different frequency sine waves, which compose the EEG waveform [17]. The amplitude or magnitude of the components for a
specified frequency is then plotted as a power spectrum with frequency on the x-axis and amplitude on the y-axis and is expressed in mean square
values (absolute power) representing the contribution of that particular frequency to the composite EEG waveform [17]. Relative EEG power (often
called power density) is defined as the absolute power of a given frequency band divided by the total absolute power across all frequencies. Relative
power provides a calculation of the contribution of EEG activity within a given frequency range based on an individual's distinct EEG composition.
Quantitative EEG measures as determinants of neurobehavioural function in healthy adults

In healthy people, resting wake EEG power varies with increasing time awake [18–20]; shows circadian variation [21,22]; and relates to measures of
performance and sleepiness [19,23,24]. Slowing of the EEG is reflected in increased activity in the delta, theta and alpha frequency ranges during
prolonged periods of wakefulness. This EEG slowing has been linked to greater subjectively-rated levels of sleepiness and fatigue [18,24] and
objectively-measured lapses in attention and vigilance failure [25,26]. EEG frequencies are altered with circadian timing, and these correspond with
changes in cognitive processing [22,27,28].
Sleep EEG activity also relates to sleepiness and cognitive performance. In young healthy subjects, reduced theta activity in non-rapid eye movement
(NREM) sleep predicts increased daytime sleepiness measured by the multiple sleep latency test (MSLT) [29], while greater SWA during slow wave
sleep (SWS) relates to improved declarative memory, procedural learning and faster reaction times [30]. A similar relationship was found between
SWA during sleep and awake neurobehavioural function specific to the pre-frontal cortex (PFC) in healthy older adults [31]. Research also supports
the functional role of sleep spindles in sleep-dependent memory processes with increased sleep spindle density and sigma (12–16 Hz) EEG power
related to improved learning and memory consolidation [32]. Reductions in these sleep EEG features in older adults have been implicated in the
weakening of sleep-dependent learning and memory processes observed in ageing [33].
The relationship between EEG and neurobehavioural function described in healthy adults underscores the potential clinical value of EEG-based
candidate biomarkers in OSA. EEG biomarkers may accurately and reliably phenotype patient groups cross-sectionally to indicate disease/non-
disease states or predict treatment or other future outcomes. While a growing number of studies have examined quantitative EEG (qEEG) activity in
OSA, the reported findings have not been well summarised. The review describes differences in brain activity during sleep and awake states in OSA
patients and controls. It further examines how abnormal EEG profiles in OSA manifest, and the utility of qEEG measures as candidate biomarkers of
neurobehavioral dysfunction.
Method
An electronic search using PubMed and Scopus databases was conducted. We included original research papers published up to December 2015.
The keywords utilised in the systematic search were ‘EEG spectral power’, ‘EEG spectral analysis’, ‘EEG power’, ‘quantitative EEG’, ‘EEG
topography’, ‘EEG spectra’, and these were combined with either ‘obstructive sleep apnea’, ‘sleep disordered breathing’, or ‘continuous positive
airway pressure’.
The search was limited to include full-text and English language publications. References of the selected studies were reviewed to identify additional
relevant studies that were not found in the initial search. We included all observational studies (n = 2), case-controlled studies (n = 13) and continuous
positive airway pressure (CPAP) studies (n = 9) which quantitatively analysed EEG data sampled during wake (eyes open and eyes closed states)
and sleep (NREM and REM sleep from polysomnography (PSG) recordings) using power spectral analysis in adults with OSA to evaluate qEEG
activity as markers of daytime sleepiness and cognitive performance, and/or differences in OSA and controls. We excluded any publications including
participants under 18 y of age or with significant co-morbidities (e.g., stroke, epilepsy).
Quantitative EEG measures during wakefulness in OSA

This section examines the evidence for EEG-based measures during wakefulness to discriminate OSA patients from healthy controls, and how
waking EEG activity relates to neurobehavioural functioning focusing on the common symptoms of daytime sleepiness and cognitive impairment.
Furthermore, we examine the effects of CPAP treatment on waking EEG profiles to critically evaluate the potential of qEEG as biomarkers of
neurobehavioural function (daytime sleepiness and cognitive performance).
Differentiating OSA patients from controls using wake qEEG measures

Seven studies [34–40] have directly analysed differences in awake EEG spectral power between OSA patients and healthy subjects, see Table 1. In
OSA patients, increased EEG activity in slower frequencies during wakefulness was found in six of the seven studies, predominantly in the frontal and
central regions [34,36–40], while one study showed no between group differences in EEG spectral power [35]. EEG slowing during wake in OSA was
reflected by higher absolute and relative EEG power within slower frequency bands (delta and theta) in five studies [34,37–40], while four studies
reported a higher ratio of slow to fast frequency EEG activity (EEG slowing ratio = (delta + theta)/(alpha + beta) absolute power), see Table 1. These
findings were robust even when controlling for age [36]. One study also reported an increase in faster frequency (absolute beta) EEG power during
sustained wakefulness, which possibly reflects a greater cortical resource requirement to maintain wakefulness as a compensatory mechanism [37].
Table 1. Quantitative EEG measures during wakefulness in OSA.
Study Subjects EEG EEG measures qEEG in Did the qEEG biomarker correlate with PSG measures of OSA Effect of Comments
(sample size; analysis [condition] OSA, severity or daytime symptoms? CPAP
n) [age (y); method compared
mean ± SD] to controls Daytime Cognitive Sleep Respiratory Oxygen
(electrode sleepiness function Fragmentation Events Saturation
sites)
Morisson OSA, severe PSA Absolute δ, θ, α, ↑ δ, θ activity No* (NS) No# *MSLT
et al. (21) [44 ± 7] β power, ratio of (frontal) #↑SR was
(1998) Controls (10) fast frequencies ↑ SR (frontal, significantly
[40] [44 ± 6] to slow central, associated with
frequencies (EEG parietal, ↓ SaO2 (NS
slowing ratio: occipital, after correction
(δ+θ)/(α+β)) temporal) for multiple
[eyes closed] comparisons)
Morisson OSA, severe PSA Absolute and ↑ δ absolute No* (NS) No‡ (NS) No# (NS) ↓δ&θ *MSLT
et al. (14) [45 ± 6.4] relative δ, θ, α, β activity in activity ‡AHI
(2001) Controls (10) power, (EEG OSA (frontal) ↓ # SaO2 time
[34] [44.2 ± 6.1] slowing ratio: ↑ SR (frontal, [(δ+θ)/(α+β)] spent <90%,
(δ+θ)/(α+β)) central) SaO2 minimum
[eyes closed]
Sforza OSA, snorers PSA Ratio of mean – No* (NS) No** (NS) No‡ (NS) No# (NS) *ESS, VAS,
et al. and mild, eyes-closed to SSS & MWT
(2002) moderate and mean eyes open ** number of
[42] severe alpha activity arousals,
[49.4 ± 1.9] (ACC) awakenings,
Absolute θ, α, β and sleep state
power (δ power transitions
not computed) ‡AHI
[eyes open and # SaO2 <90%,
eyes closed] SaO2 minimum
No significant
differences in
waking qEEG
between
snorers and
OSA
Mathieu OSA, PSA EEG slowing ↑ SR (frontal, No† (NS) Yes** Yes‡ †attention
et al. moderate- ratio: (δ+θ)/(α+β) central, (FCRTT)
(2007) severe [young] [eyes closed] parietal, **↑ SR
[36] (12) occipital, associated with
[38.2 ± 6.4] temporal) in ↑ ArI
Controls both young ‡ ↑ SR
[young] (13) and old associated with
[35.8 ± 8.9] groups ↑ AHI (parietal)
OSA,
moderate-
severe [old]
(13)
[62.2 ± 5.6]
Controls [old]
(14)
[60.2 ± 6.4]
Grenèche OSA, severe PSA Absolute δ, θ, α, ↑ δ, θ, β No* (NS) *KSS, VAS

et al. (12) β power [eyes power
(2008a) [51.2 ± 2.5] open and closed] Sharper rise
[37] Controls (8) EEG measured in δ power
[49.4 ± 3.4] every hour during across 24-h
24-hours of awake
sustained
wakefulness
Grenèche OSA, severe PSA Absolute δ, θ, α, – No** (NS) Yes‡ Yes# ∗∗ArI
et al. (12) β power [eyes ‡ ↑ α power
2008b [51.2 ± 2.5] open and closed] significantly
[41] EEG measured associated with
during 24-h ↑ AHI and AI, ↑
awake at baseline β was
associated with
↑ AI
# ↑ α, θ powers
significantly
associated with
↑ ODI; ↑ β
associated with
↓ SaO2
minimum; ↑ θ,
α, β associated
with ↑ SaO2
<90%
Xiromeritis OSA, mild (28) PSA Relative δ, θ, α, β ↑ θ and δ Yes* No (NS)** Yes# CPAP in a *↑ θ, δ was
et al. [46.2 ± 11.4] power [vigilant power subset significantly
(2010) OSA, EEG, condition (occipital, (n=29) associated with
[38] moderate (35) not specified] temporal, ↓ θ and α ↑ESS; ↑ α
[51.3 ± 8.5] parietal) power associated with
OSA, severe (frontal) ↓ESS (all
(68) [49.6 ± 10] ↑ δ and β regions)
Controls (30) power (all) **ArI
[46.7 ± 11.8] # ↑ θ, δ
associated with
↑ODI,↓minimum
SaO2, ↓mean
SaO2(all
regions)
Grenèche OSA, severe PSA Absolute δ, θ, α, – No* (NS) No (NS)** ↓ θ power *KSS
et al. (12) β power [eyes after 3 mo **ArI
(2011) [51.2 ± 2.5] open and closed] CPAP
[43] EEG measured ↑ β power
during 24-h after 6 mo
awake at baseline CPAP
and after three
and six months of
CPAP
Lee et al. OSA, severe PSA EEG slowing – Yes* Yes† ↓ absolute δ * ↓ δ power
(2012) Own control, ratio: (δ+θ)/(α+β) power (after CPAP)
[50] before and Absolute δ power (frontal, was
after CPAP [eyes closed] central, significantly
therapy (13) parietal and associated with
[49.9 ± 7.0] temporal) ↓ESS
↓ † ↓ δ power
[(δ+θ)/(α+β)] (after CPAP)
associated with
↑ recall &
executive
function
Baril et al. OSA, PSA Absolute and ↔ α, δ Yes* *↑ θ was

(2013) moderate- ERP relative δ, θ, α, β1 significantly
[35] severe (12) β2 power associated with
[47.9 ± 13.70] EEG slowing ↑P300
Controls (12) ratio: amplitude, ↑ β
[44.4 ± 9.5] (δ+θ)/(α+β1+ β2) associated with
[eyes closed] ↑P3a amplitude
D'Rozario OSA, PSA Relative δ, θ, α, β ↑ DFA Yes* Yes† *↑θ,δ,α was
et al. moderate- DFA power scaling significantly
(2013) severe (8) DFA scaling exponent associated with
[39] [44.6 ± 8.4] exponent [eyes ↑ δ power ↑KSS, ↑RT on
Controls (9) open and closed] ↓ α power the PVT
[27.8 ± 3.7] [eyes closed] (central)
†↑δ associated
with ↓simulated
driving (AusEd;
central)
Wang OSA, PSA Absolute δ, θ, α, After Yes* Yes† * ↑α/δ ratio,

et al. moderate- DFA β power, α/δ modafinil: ↑ ↑fast ratio &
(2015) severe ratio, fast ratio: α/δ ratio and ↑DFA was
[44] Own control, (α+β)/(δ+θ) fast ratio, significantly
cross-over, DFA scaling ↓DFA associated with
receiving real exponent [eyes ↑KSS & ↓RT on
and placebo open and closed] the PVT
modafinil (23) †↑α/δ ratio
[55 ± 8] associated with
↓driving
performance
(AusEd)
↔, no change; ↓, reduced; ↑, increased; spectral power frequency band symbols: δ, delta; θ, theta; α, alpha; β, beta; ACC, alpha attenuation coefficient; AHI, apnea
hypopnea index; AI, apnea index; ArI, arousal index; AusEd, AusEd driving simulator task; CPAP, continuous positive airway pressure; DFA, detrended fluctuation analysis;
EC, eyes closed; EEG, electroencephalogram; ERP, evoked response potential; ESS, Epworth sleepiness scale; FCRTT, four choice reaction time test; KSS, Karolinska
sleepiness scale; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; NS, not significant; ODI, oxygen desaturation index; OSA, obstructive sleep
apnea; PSA, power spectral analysis; PVT, psychomotor vigilance test; RT, reaction time; SaO2, saturation of blood oxygen; SD, standard deviation; SR, EEG slowing ratio
([δ+θ]/[α+β]); SSS, Stanford sleepiness scale; VAS, visual analogue scale. N.B. All three publications by Grenèche et al. are from the same study; In Morisson et al. 2001,
a subset of 14 OSA patients from Morrison et al. 1998 received 6 mo of CPAP therapy.
Changes in waking EEG power are inconsistently related to PSG metrics of OSA severity, see Table 1. In severe OSA patients AHI, ODI and
minimum SaO2 were not related to delta power but were positively correlated to alpha power whilst theta and beta power correlated with worse
hypoxaemia [41]. In another study of severe OSA patients, a greater EEG slowing ratio was associated with higher arousal index (frontal, central,
temporal, parietal and occipital regions: all r between 0.41 and 0.48, all p < 0.05) and higher AHI (parietal region: r = 0.44, p = 0.028, trends for all
other cortical regions) [36]. In a more diverse group of mild to severe OSA patients, increased relative delta and theta power were related to worse
hypoxemia [38]. A difference in absolute waking EEG power was only observed between severe OSA patients and controls in this study, suggesting
altered waking EEG activity is dependent on OSA severity [38]. Other studies have failed to find any association between PSG-derived OSA severity
measures and waking EEG power [34,40,42,43].
Overall, these observations strongly suggest there is a general slowing of the EEG, observed as greater power in the slower frequency bands, during
wakefulness in OSA patients compared with controls. It is less clear how these EEG changes relate to PSG-derived metrics of sleep-disordered
breathing.
Relationship between wake qEEG and daytime sleepiness in OSA

Seven studies examined the relationship between wake qEEG and daytime sleepiness in OSA patients [36–40,42,44], with inconsistent results.
Three of these studies [38,39,44] assessed self-rated sleepiness and found a significant relationship with PSA-derived qEEG measures during
wakefulness, see Table 1. Greater sleepiness (higher Epworth sleepiness scale (ESS) score) was correlated with lower relative alpha power and
higher relative delta and theta power across all brain regions [38]. Another study identified a relationship between greater sleepiness (higher
Karolinska sleepiness scale (KSS) score) and higher relative delta, theta and alpha power during eyes open and higher relative delta and alpha
power during eyes closed at the central derivation [39]. Similarly in a third study, a randomized control trial (RCT) design investigating the effects of
modafinil in CPAP withdrawal, found a higher KSS score was significantly correlated with higher awake alpha/delta ratio, fast ratio
(alpha + beta)/(delta + theta) in OSA patients during CPAP withdrawal [44]. In contrast, measures of EEG slowing during wake failed to differentiate
sleepy from non-sleepy patients using the ESS at a cut-off score of 10 [42]. Using the MSLT or maintenance of wakefulness test (MWT) to objectively
measure daytime sleepiness in OSA patients, no significant relationships were found with waking EEG measures and sleepiness [34,40,42].
These inconsistent findings between sleepiness measures and waking EEG may be explained by the small samples, differences in subjective and
objective tests, as well as the timing of the administration of the test (i.e., the influence of circadian or homeostatic factors). The condition in which the
EEG was recorded e.g., eyes open, eyes closed or averaged across both conditions, and whether the spectral power was presented as absolute or
relative values or as a ratio of slow to fast frequency activity may also explain discrepant findings.
Overall, increased slow frequency EEG activity (delta, theta ranges) during wakefulness appears to correlate with greater subjective sleepiness, yet
there are no established relationships between qEEG and objectively-measured sleepiness to date. This may be due to limitations in how these tests
measure and define sleepiness; and the lack of a gold-standard test for measuring sleepiness in OSA. Though the MWT is promoted as an objective
test of daytime sleepiness and treatment efficacy, its utility to accurately identify OSA patients at risk of neurobehavioural dysfunction is limited [45].
More studies with larger sample sizes and consistent methodologies are required to investigate the complex relationships of the waking EEG and
daytime sleepiness in OSA. This in turn will determine whether wake qEEG slowing is a candidate biomarker for sleepiness in OSA and can
differentiate a subset of patients with a high risk- ‘alertness failure’ phenotype.
Relationship between wake qEEG and cognitive performance in OSA

Increased theta and delta EEG activity, and decreased beta activity during wake are associated with attentional performance lapses and vigilance
failure in healthy subjects [23,25,46,47]. To date, there is limited direct evidence examining links between the waking brain activity and cognitive
performance in OSA [36,39,44]. Waking qEEG (eyes closed) was not associated with attention using the four choice reaction time test in OSA
patients while associations between wake EEG and performance were not assessed in the control group [36]. In contrast, a relationship was found
between brain activity and performance on a psychomotor vigilance task (PVT) and a driving simulator task in both OSA and healthy volunteers
across 40 h of extended wakefulness [39]. Poorer driving performance and vigilance was correlated with higher delta, theta and alpha EEG power
(eyes closed) and increased theta power (eyes open) [39], see Table 1. In addition to PSA, this study used a technique for analysing non-stationary
physiological data called detrended fluctuation analysis (DFA) [48,49]. The DFA method quantifies fluctuations in the EEG and provides a single
measure called the scaling exponent. The DFA scaling exponent of the resting wake EEG measured at baseline predicted impaired driving after 24-
hr awake in OSA whilst conventional PSA measures did not. Both standard and novel signal processing techniques are needed to confirm the utility
of qEEG biomarkers. In a recent study employing similar techniques, significant associations were reported between increased awake EEG
alpha/delta ratio and poorer driving simulator and PVT performance in 23 OSA patients during a CPAP withdrawal RCT cross-over study [44].
Furthermore, a higher DFA scaling exponent positively correlated with PVT lapses, and negatively correlated with PVT reciprocal reaction time [44].
The effect of CPAP on wake qEEG

Five studies have evaluated the effects of CPAP treatment on waking EEG [34,38,43,50,51]. The most consistent finding was the reduction of theta
power, whilst the effects on delta power were inconsistent. In three studies a decrease in delta power with CPAP was evident [34,50,51], whilst
another study found an increase [38], with no change reported in the fifth study [43]. There are mixed findings on whether the changes in EEG activity
observed after CPAP treatment impact on sleepiness. Some studies report no associations between EEG changes and sleepiness either using
subjective (ESS or KSS) [43] or objective (MSLT) measures [34]. Supporting a link between awake delta power and sleepiness is work showing that
a reduction of frontal delta power and EEG slowing ratio across all regions (both eyes open and closed) [50], and significant reductions in delta power
(%) and delta/alpha ratio with increased alpha power (%) measured centrally [51] after CPAP treatment were all associated with improvements in
subjective sleepiness (ESS). Furthermore, reduced theta power during wake following CPAP correlated with improved memory (immediate recall on
a verbal learning task) and executive functioning (faster trail making) [50]. However, the limited studies with small sample sizes highlight the need for
larger studies designed to investigate the relationship between qEEG biomarkers and neurobehavioural function in untreated and treated OSA.
Quantitative EEG measures during sleep in OSA
In healthy subjects the temporal profile of the EEG during sleep is governed by both circadian and homeostatic regulation which in turn is linked to
performance and daytime sleepiness. Experimental studies of SWS suppression leads to increased daytime sleepiness and performance deficits in
healthy adults [52] and significantly lower SWS has been reported in OSA patients compared to controls using traditional PSG [53,54]. This section
first describes the sleep qEEG features in OSA patients which differentiate them from healthy sleepers. We then examine how these features relate to
daytime symptoms and discuss their utility to identify different neuro-phenotypes in OSA in terms of vulnerability to neurobehavioural impairment.
Differentiating OSA patients from controls using sleep qEEG measures

EEG spectral power during sleep in OSA patients and controls (including self-controlled interventional studies) has been examined in a number of
studies with inconsistent results [34,40,51,55–60], see Table 2. Interpretation of data of EEG profiles in OSA is problematic due to inconsistent
methodological approaches used for EEG sampling, signal pre-processing and quantitative analysis techniques employed across studies. Some
studies focused solely on SWA (1–4 Hz) in NREM [57,58] and either did not examine faster EEG frequency activity in NREM or EEG during REM
sleep. While other studies only examined EEG power during REM sleep [34,40]. Only four studies have applied PSA to the entire sleep period
(NREM and REM) and explored a range of EEG frequencies [51,55,59,60].
Table 2. Quantitative EEG measures during sleep in OSA.
Study Subjects EEG EEG measure, qEEG in Sleep stage Did the qEEG biomarker correlate with PSG measures of OSA Effect of Com
(sample analysis frequency bands OSA qEEG severity or daytime symptoms? CPAP
size; n) method (electrode sites) in OSA,
Daytime Cognitive Sleep Respiratory Oxygen
[age (y); compared
sleepiness function fragmentation Events Saturation
mean ± SD] to controls
Morisson OSA, PSA EEG slowing ratio ↑ SR and δ REM No*(NS) No‡(NS) No#(NS) *MS
et al. (1998) severe (21) (SR): (δ+θ)/(α+β) activity in ‡AH
[40] [44 ± 7] and absolute frontal, #Min
Controls power δ, θ, α, σ, β central and SaO
(10) [44 ± 6] (frontal, central, parietal <90%
parietal, temporal, regions.
occipital)
Morrison OSA, PSA ↑ SR in REM No*(NS) Yes‡ No#(NS) ↓δ&θ *MS
et al. (2001) severe (14) frontal and activity ‡AH
[34] [45 ± 6.4] central ↓ #Min
Controls regions [(δ+θ)/(α+β)] SaO
(10) <90%
[44.2 ± 6.1]
Guilleminault OSA, PSA Absolute power δ ↓ SWA REM; NREM; OSA

et al. (2001) moderate- (0.75–3.75 Hz), θ, and δ sleep cycles patie
[55] severe, non- α, σ, β and SWA power ↓ SW
obese (12) (0–3.5 Hz) across all cont
[42 ± 7.1] (central) sleep UAR
Controls stages patie
(12) ↑ absolute OSA
[41.9 ± 7.1] β, α and ↓ show
UARS σ in NREM ↑ES
(12) asso
[42 ± 7.1] with
mea
were
exam
Heinzer OSA, PSA SWA (absolute ↔ in SWA NREM; sleep Yes* Yes** No‡(NS) No#(NS) ↑ levels of *↑S
et al. (2001) severe (10) power 0.75– cycles SWA (i.e., 1st N
[57] [42.7 ± 1.9] 4.5 Hz) (central) δ) cycl
Controls sign
(10) asso
[43.9 ± 2.2] with
at ba
(cen
occi
** ↑
1st N
cycl
sign
asso
with
(cen
occi
‡AH
#Min
SaO
<90%
Himanen OSA, mild - PSA SWA (0.75–4 Hz, ↔ SWA NREM OSA
et al. (2003) moderate normalised show
[58] (12) [48] μV2/30-s) (central) ↑ AH
Controls their
(12) [43] asso
with
mea
were
exam
Ondze et al. OSA, mild PSA Absolute power δ, ↓ Lower θ NREM; sleep Yes** **↓S
(2003) [59] (18) θ, α, σ, β and and σ cycles expo
[35.5 ± 10.8] SWA (0.5 – 2 Hz) power in deca
Controls and sleep each sleep was
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et al. (2009) moderate- based percentage (DS%, (frontal, left show
[61] severe (15) < 4 Hz) (frontal, central, hemisphere. ↓visu
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et al. (2010) moderate- power δ, θ, α, σ, β α,θ show
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Jones et al. OSA, PSA Absolute and ↓ REM; NREM; No**(NS) No‡(NS) No#(NS) ** A
(2014) [60] moderate- normalised power normalised stages ‡In t
severe (9) δ (SWA, 1– power in all N1,2,3; grou
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Wang et al. Hypercapnic PSA Absolute power δ, – Sleep + wake Yes* Yes** No‡(NS) No#(NS) ↓ δ/α ratio, * ↓δ
(2014) [51] OSA, θ, α, σ, β and δ/α during PSG; ↑ α% and ↓ ↓δ%
severe ratio (central) wake; N2 β in N2 ↑α%
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et al. (2016) severe (76) DFA θ, α, σ, β & total entire sleep †↑δ
[71] [42.8 ± 10.6] power; EEG SR period σ, β
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↔, no change; ↓, reduced; ↑, increased; spectral power frequency band symbols: δ, delta; θ, theta; α, alpha; σ, sigma; β, beta; AHI, apnea hypopnea index; ArI, arousal
index; DS%, deep sleep percentage; CPAP, continuous positive airway pressure treatment; EEG, electroencephalogram; ESS, Epworth sleepiness scale; FFT, fast Fourier
transform; MSLT, multiple sleep latency test; NREM, non-rapid eye movement; N2, stage 2 sleep; NS, not significant; PAP, positive airway pressure treatment; PSA, power
spectral analysis; PSG, polysomnography; OSA, obstructive sleep apnea; qEEG, quantitative EEG; REM, rapid eye movement; SaO2, saturation of blood oxygen; SD,
standard deviation; SSI, sleep spindle index; SWA, slow wave activity; SWE, slow wave energy; TST, total sleep time. N.B. In Morisson et al. 2001, a subset of 14 OSA
patients from Morrison et al. 1998 received 6 mo of CPAP therapy.
Most investigations of sleep EEG in OSA have focused on SWA during NREM sleep and its dynamics across the night. SWA during sleep in OSA
patients was shown to be significantly reduced compared with controls [56] and patients with upper airway resistance syndrome [55]. An FFT-based
computational measure of the amount of deep sleep consisting of an EEG frequency below 4.0 Hz (deep sleep percentage, DS%) showed
significantly reduced DS% across frontal, central and occipital derivations as well as interhemispheric differences in OSA patients [61]. Using high
density EEG, regional reductions in total EEG power were observed during NREM sleep in OSA and were most pronounced for SWA in regions
overlaying the parietal cortex [60]. Three other controlled studies did not show any significant differences in SWA in NREM between groups [57–59].
However, one of these negative studies did show a significant response to treatment with increased SWA after 9 mo of CPAP [57], and the other two
studies reported lower SWA in OSA patients which did not reach the threshold for statistical significance [58,59].
In contrast to the reported reductions in SWA/SWS, OSA patients with hypercapnia, particularly those with obesity hypoventilation syndrome or
overlap syndrome (chronic obstructive pulmonary disease (COPD) + OSA), have significantly increased SWS/SWA during sleep [51,62]. A high
percentage of SWS (33%) was reported in a study of 97 hypercapnic OSA patients [62]. A further interventional study in this patient group assessed
sleep qEEG measures and showed that the augmented SWA can be reversed after 3-month CPAP/BiPAP therapy with associated improvements in
daytime sleepiness [51]. These limited data suggest that hypercapnia may slow brain activity and adversely affect neurobehavioural function in this
OSA patient phenotype [63]. The functional role of these slow waves during sleep and how they may differ from “healthy” homeostatic slow waves
remains to be elucidated. Though the mechanisms underlying these EEG changes are unclear, imaging insights have showed that breathing 5% CO2
significantly reduces functional connectivity MRI indices during the resting-state and suppresses cerebral metabolic rate of oxygen in healthy subjects
[64].
In studies examining the time course of SWA during sleep as the putative marker of sleep homeostasis, a slower decay rate of the dissipation of
SWA (%) across consecutive NREM–REM sleep cycles was reported in OSA patients (n = 18, mean age 36 y) compared to controls [59], while
another study found no difference in SWA (absolute power) dissipation between a smaller group of OSA patients (n = 10, mean age 48 y) and
controls [57]. These discrepant findings are most likely explained by the different methodologies and small sample size. Ondze and colleagues
utilised filtered delta power using a 75 μV amplitude discriminator and fitted an exponential function to four sleep cycles [59], while Heinzer and
colleagues did not use an amplitude criterion and used three sleep cycles to measure the time course of SWA [57]. Traditional methods of defining
sleep cycles [65] may be not be appropriate for untreated OSA patients who often do not have the classic profile of NREM-REM periodicity seen in
healthy sleepers. New analytical approaches to more accurately measure process S and examine how disrupted sleep homeostasis may contribute
to sleepiness and cognitive impairment in OSA and different phenotypes are needed.
Reduced spindle activity reflected by decreased sigma power in NREM sleep appears to be a consistent finding in OSA patients [55,56,59,60].
Sigma EEG power and sleep spindle density were significantly lower in OSA patients compared to controls across each sleep cycle and the whole
night, with these findings attributed to the high degree of sleep fragmentation in the patient group [59]. A recent review of spindle activity in sleep
disorders, quantified using event-based detection methods as well as sigma EEG power, surmised that OSA patients had less spindle activity and
slower sleep spindle frequencies than controls [66]. Altered spindle activity may indicate frontal thalamocortical dysfunction and underlie OSA-related
memory deficits [67].
Quantitative analysis of REM sleep has revealed slowing of the EEG in untreated OSA patients compared to controls with a higher EEG slowing ratio
and delta power over frontal, central and parietal regions [34,40]. Artefact-free EEG was sampled during the middle of apneas to avoid EEG changes
associated with arousals. However only a short 96-second EEG sample from REM sleep for each participant was analysed. Future studies examining
longer EEG segments selected from REM periods across the night are required to confirm these findings and further explore these sleep EEG
abnormalities.
One significant issue with analysing sleep EEG activity in OSA is how artefact is processed, and in particular how frequent arousals from sleep may
affect quantitative EEG measures. For example, artefact rejection of bursts of delta activity that often occur before and surrounding the end of apneic
events may mask characteristics that are important for determining qEEG biomarkers of neurobehavioural function. Future qEEG research should
consider how discrete EEG events or bursts of EEG waves closely tied to periods of apneic breathing [68] and the composition of associated EEG
arousals [69] relate to daytime dysfunction.
In summary, despite substantial inconsistencies in qEEG methodologies, significant differences in sleep EEG microstructure reported in OSA include
reduced SWA and sigma power during NREM sleep and slowing of the EEG during REM sleep. Studies utilising standardised methods of qEEG
analysis in larger sample sizes are required to determine whether these inconsistencies are due to methods of analysis, or rather reflect different
phenotypes of OSA. Sleep EEG is routinely measured in OSA patients through clinical PSG and supplementing conventional sleep scoring with
EEG-based signal analysis is attractive if there are significant predictive links between sleep EEG and daytime dysfunction.
Relationship between sleep qEEG and daytime sleepiness in OSA

The links between sleep EEG activity and daytime sleepiness have also been examined [34,40,57,70] with inconsistent and relatively modest
relationships reported. Two of these early studies [34,40] found no significant relationship between EEG spectral power or EEG slowing ratio
sampled from 96-s of REM sleep and objectively measured daytime sleepiness (MSLT), see Table 2. In contrast, reduced SWA in the first NREM
cycle was significantly associated with shorter mean sleep latency on the MSLT in untreated OSA patients [57].
Intricate analysis of respiratory cycle-related EEG changes (RCRECs) in adult patients with OSA have shown increased sigma EEG power with a
simultaneous decrease in delta EEG power during inspiration [70]. Using this method, the rate at which EEG activity varies in synchrony with the
respiratory cycle predicted sleepiness the next day as measured by MSLT better than PSG measures of disease severity such as minimum oxygen
saturation or the AHI [70]. Given the different methodologies employed in the small number of studies to date, additional qEEG studies that
systematically evaluate the relationship between sleep EEG and daytime sleepiness in OSA patients are necessary.
Relationship between sleep qEEG and cognitive performance in OSA

Although studies have examined qEEG measures during sleep in OSA [34,40,51,55–61,71], see Table 2, most have not investigated the relationship
between sleep EEG activity and cognitive function. In fact, only one recent study has evaluated EEG spectral power derived from routine diagnostic
PSGs in relation to performance. This study of 76 patients with OSA found that higher absolute delta EEG power in REM and higher beta power in
NREM sleep were significant predictors of worse steering deviation on a 30 min driving simulator task, while routine OSA metrics of AHI and
hypoxemia were not informative [71].
The effects of CPAP on sleep qEEG

Five studies have evaluated the effect of CPAP treatment on sleep qEEG [34,51,57,61,72], and three of these investigated the relationship with
daytime sleepiness. Morrison and colleagues [34] reported a decrease in delta and theta EEG power as well as a reduction in the EEG slowing ratio
in REM sleep following CPAP treatment in OSA; however pre and post treatment values of qEEG measures and daytime sleepiness assessed by
MSLT were not correlated. SWA during the first and second NREM sleep cycle increased following CPAP treatment, and SWA in the first NREM
cycle was positively correlated with MSLT sleep latency before treatment [57]. However no associations between SWA and daytime sleepiness were
observed following treatment [57]. Six months of CPAP enhanced sleep depth with increased DS% observed at frontal and central brain regions
compared to pre-treatment, with DS% in some regions normalising to levels observed in control subjects [61]. Chervin and colleagues found that
RCRECs in non-apneic sleep were diminished with CPAP treatment [72], while changes in daytime sleepiness following CPAP was not examined.
Three months of CPAP/BiPAP therapy in hypercapnic OSA patients led to significantly faster overnight EEG with increased alpha power (%) and
decreased delta/alpha ratio [51]. These qEEG changes significantly correlated with improvements in subjective daytime sleepiness/ESS and arterial
blood gas (ABG) carbon dioxide partial pressure (PCO2) [51]. To our knowledge, there are no CPAP treatment studies reporting on qEEG and
cognitive measures.
Potential mechanisms for wake and sleep EEG abnormalities and neurobehavioural deficits in OSA
Links between nocturnal hypoxemia/hypercapnia, sleep fragmentation and wake EEG

The pathophysiology underlying the neurobehavioural sequelae in OSA are complex and poorly understood, but may involve the intricate interplay of
intermittent hypoxia, re-oxygenation, hypercapnia, changes in cerebral blood flow and sleep fragmentation [73]. Intermittent hypoxia during sleep has
long been considered as a significant mediator of OSA-related neurobehavioural dysfunction by potentially disrupting the restorative cellular
processes leading to PFC dysfunction [74]. Worse nocturnal hypoxemia during PSG has also been associated with EEG slowing during wakefulness
in OSA with increased slow frequency activity significantly correlated with lower minimum oxygen saturation levels [38], especially when oxygen
saturation was below 90% [40]. The modest relationship in the latter study was not robust following adjustment for multiple comparisons [40]. Greater
AHI and worse sleep fragmentation have also been associated with a higher EEG slowing ratio during wake the next day [36]. A number of studies
using acoustic stimuli to suppress SWA during SWS in healthy subjects suggest that SWA/SWS deficits are carried forward to the next waking period
[14]. It is plausible that the chronic sleep disruption in OSA patients may overload the brain's functional capacity resulting in periods of local sleep
during wakefulness. Human and animal studies have shown that transient neuronal off periods (local sleep) occur with prolonged time awake, and are
characterised by increased slow/theta waves which are temporally associated with performance errors [75,76]. These proposed episodes of ‘network
overload’ may manifest as increased slow frequency EEG activity during wakefulness in OSA but this is speculative and further studies investigating
links between local sleep and neurobehavioural consequences should be undertaken.
Though studies have implicated intermittent hypoxemia in OSA-related EEG slowing, most studies did not properly control for the effect of CO2 on
EEG slowing. In a recent clinical experiment comparing the effect of hypercapnia and hypoxia on awake EEG activation in 20 healthy volunteers [77],
progressive hypercapnia during a 5-minute rebreathing session (PO2 was kept constant) correlated with EEG slowing during wakefulness in healthy
subjects. In contrast, progressive hypoxia alone (controlled for PCO2) did not show any effect on EEG power spectra [77]. In addition, another session
with mixed hypercapnia and hypoxia showed a stronger EEG slowing effect than hypercapnia alone, suggesting a potential additive effect of hypoxia
on top of hypercapnia in slowing brain activity [77]. Furthermore, in undersea diver-related experimental studies, a dose-response relationship
between higher CO2 tensions and impaired cognitive and psychomotor performance were found [78,79]. In contrast, neither 2 wk of high altitude
hypoxia (13,000 feet) nor 4 wk of nocturnal intermittent hypoxia have been shown to change neurocognitive functions in healthy volunteers [80,81]. The
effect of hypercapnia on neuro-outcomes in OSA has been largely under-investigated and further technological advancements in carbon dioxide
measurement during sleep are needed in order to validate and support this premise [63].
Links between nocturnal hypoxemia/hypercapnia, sleep fragmentation and sleep EEG
Animal data suggest that compared to room air, intermittent hypoxic stimuli during sleep leads to increased time awake after sleep onset, reduced
REM sleep and a non-significant reduction in NREM sleep in rodents, whilst reducing overall slower frequencies and increasing faster frequencies in
the sleep EEG [82–84]. The effects of sleep fragmentation have also been attributed to changes in sleep EEG with decreases observed in
SWS/SWA [84]. Animal data further suggest that both intermittent hypoxemia and sleep fragmentation, independently and synergistically, disrupt
sleep architecture and impact the integrity of the sleep homeostatic process in OSA patients, with resultant abnormalities in sleep EEG, impaired
daytime function and increased sleepiness [84–87]. In a recent study in rodents with EEG electrodes implanted in frontal and parietal regions, Funk
and colleagues showed that slow waves, traditionally considered a feature of NREM sleep, also occurred during REM sleep in primary sensory and
motor areas [88]. The functional role of SWA in REM sleep is unknown but sleep deprivation data suggest that it is not regulated by sleep
homeostatic processes unlike SWA in NREM sleep but may serve as a mechanism for promoting sensory disconnection during REM sleep.
In human clinical studies examining sleep qEEG in OSA patients, none have found significant relationships between EEG measures and severity of
nocturnal hypoxemia during PSG [34,40,51,57,60]. Three studies have examined the relationship between SWA in NREM and sleep fragmentation
[57,59,60]. One study reported a significant correlation between greater SWA and fewer arousals [57], while another failed to show any relationship
between these variables [60]. The third study found a significantly slowed rate of SWA dissipation during the night was associated with increased
awakenings (<1 min) [59]. Two studies have investigated the role of hypercapnia on qEEG measures derived during sleep in adult OSA. Firstly,
awake arterial blood PCO2 and sleep fragmentation were the top two significant predictors for significantly higher levels of SWS seen in OSA
patients with respiratory failure, while hypoxia-related parameters were not significant predictors [62]. Secondly, following 3 mo of CPAP treatment,
hypercapnic OSA patients exhibited faster EEG activity during sleep (reduced delta/alpha ratio) and reduced daytime sleepiness compared to
baseline, and PCO2 was the only significant predictor of these changes [51].
In summary, there appears to be a complex interaction between hypercapnia, hypoxia, sleep fragmentation and cerebral blood flow changes which
may affect brain EEG activity and neurocognitive outcomes [63,73]. Further studies are needed to elucidate the differential contribution of these
factors to abnormal EEG profiles in OSA and importantly how this relates to individual risk of neurobehavioural dysfunction.
Links between brain structure and function, EEG abnormalities and neurobehavioural deficits in OSA
Underlying pathophysiology in the brain may be driving the EEG abnormalities observed in OSA but there are limited studies combining high density
EEG and brain mapping to address these mechanistic questions. The existing brain imaging studies in OSA report altered cortical activation and
compromised grey and white matter integrity across multiple brain regions (frontal and parietal cortex, temporal lobe, anterior cingulate,
hippocampus, and cerebellum) [89–92].
In general, when topographical distributions of brain activity are assessed, EEG abnormalities during wake occur in frontal and central brain regions
[34,36–40]. The majority of the sleep qEEG studies used a single EEG derivation for PSA, but in three studies using multiple electrode sites
(including 256-channel high density EEG), sleep EEG abnormalities were present across multiple brain regions including the frontal, central and
parietal lobes [34,40,60]. High density EEG acquisitions allow for more detailed observations of the local, use-dependent changes of sleep EEG
rhythms [93]. In future studies, source localisation modelling of high density EEG data during sleep will likely provide greater insight into specific brain
regions or networks differentially affected in OSA [94]. This method has the potential to elucidate links between abnormal sleep and wake EEG
profiles, sleep-dependent cognitive processes, inter-individual variability in neurobehavioural function and any associated neural compensatory
mechanisms in OSA patients.
Possibly the most significant area for OSA-related EEG and neurobehavioural abnormalities is the PFC, a critical structure in the anterior and
posterior “attention control” brain network [95] mediating higher order cognitive function such as goal directed executive function, attention, vigilance
and working memory [96]. The PFC appears to be more vulnerable to central nervous system stressors such as sleep deprivation or sleep
fragmentation [97–99] and hypoxic damage compared with other brain regions [100]. This compromised integrity and vulnerability of the PFC in OSA
patients may manifest as altered sleep/wake EEG activity and consequential neurobehavioural dysfunction. It is possible that structural or functional
changes in thalamocortical networks may also underlie altered EEG profiles in OSA by compromising the ability to generate specific EEG activity
(such as slow oscillations or sleep spindles), resulting in impaired memory consolidation and poor sleep quality but data are lacking (for theoretical
review, see Lu and Goder 2012 [101]).
OSA may exacerbate brain ageing

OSA and its associated sleep fragmentation and intermittent hypoxemia/hypercapnia may further exacerbate alterations in brain function and
structure that naturally occur with ageing [102]. For example, significantly greater delta activity has been observed during wakefulness in older
individuals (mean age 70 y) compared to younger controls (23 y) [103]. The combined effects of increasing age and OSA may increase PFC
dysfunction amplifying abnormalities observed in brain activity, with ensuing deficits in daytime performance. When evaluating the combined effects of
increasing age and the presence of OSA on waking EEG activity, it has been reported that both older and younger OSA patients exhibit higher
slowing EEG ratios across all brain regions than their age-matched control counterparts [36]. Evidence also points to associations between
increasing age, reduced SWA during NREM sleep, prefrontal atrophy, functional changes in the PFC and consequential impaired long-term memory
performance [104].
Furthermore, EEG slowing during REM and wakefulness has been observed in mild to moderate Alzheimer's disease, possibly reflecting the
degeneration of neuronal systems that modulate cortical activation during wake and REM sleep [105]. Recent evidence has also shown that EEG
slowing in frontal regions during REM sleep was able to significantly discriminate patients with amnestic mild cognitive impairment (MCI) from those
with the non-amnestic type and healthy older controls [106]. Patients with amnestic MCI are at a greater risk of developing dementia. From this
evidence it is plausible that EEG slowing during REM in OSA patients could reflect some degree of neuronal degeneration due to severely disrupted
sleep by repeated arousals and long-term intermittent hypoxemia/hypercapnia at night. This is an important area for ageing research, given that
numerous studies have linked OSA with cognitive decline and neurodegenerative processes such as Alzheimer's disease [107,108]. Longitudinal
studies to determine if early intervention in middle-aged OSA patients could help prevent or delay neurocognitive decline into older age are needed.
In addition, interpretation of EEG activity in the context of other neural correlates i.e., neuroimaging, or by using advanced topographic analysis
techniques, may add to a better understanding of the mechanisms underlying any relationship between abnormal EEG activity in OSA and the
detrimental impact on brain integrity with ageing.
Conclusion
In summary, there is consistent evidence that OSA patients exhibit greater overall EEG slowing during wakefulness compared to healthy controls. This
dominance of slow frequency EEG activity during wake relates to worsening vigilance (sustained attention) and driving simulator performance,
greater subjective sleepiness but not objective sleepiness (MSLT or MWT). This may be due to the limited sensitivity of stand-alone tests currently
used to clinically assess daytime sleepiness.
Of the current evidence surrounding qEEG measures during sleep, there are substantial inconsistencies in the methodologies and a paucity of data,
which makes drawing conclusions difficult. Despite this, the studies to date show that OSA patients demonstrate increased slow frequency EEG
activity during REM sleep and reduced SWA and spindle frequency (sigma power) activity during NREM sleep. In contrast, OSA patients with
hypercapnia show augmented SWA in NREM sleep at baseline which is reduced following treatment with associated improvements in daytime
sleepiness. The underlying mechanisms of these differential sleep EEG profiles remain to be fully elucidated and further research is required to better
define qEEG markers of neurobehavioural function in phenotypically different OSA patients.
CPAP treatment appears to improve wake and sleep EEG microstructure by partially reversing EEG abnormalities observed pre-treatment, but
changes in EEG activity do not always correlate with reduced daytime sleepiness levels. To date no studies have assessed sleep EEG changes after
CPAP in relation to cognitive performance. Relationships between abnormal wake and sleep EEG profiles and complex neurobehavioral tasks such
as driving are highly relevant to clinical assessments of fitness to drive in OSA patients.
Clinicians are often limited with the objective tools they can use to accurately measure daytime dysfunction in patients, and often clinical history
assessment and symptom reports are relied upon. There is no gold-standard measure of sleepiness and cognitive impairment currently available in
OSA and this presents problems when bench marking the utility of qEEG measures. Current clinical sleepiness measures are limited, particularly
where concern for loss of drivers licence and a high degree of inter-individual variability are significant factors in determining the sensitivity of the
tests.
Research efforts in this area are limited to identifying new candidate biomarkers by relating them to known measures such as symptom ratings and
performance on cognitive tasks, which are themselves imperfect measures and are not always strongly inter-related [7,9,109]. In the end the
development of automatically-analysed, simple candidate markers will permit larger studies to be conducted to validate their clinical utility, alone or in
combination with assessments like daytime cognitive testing or MWT, and then ultimately relate them to risk of real world events like fall asleep errors.
Neurobehavioural dysfunction varies greatly between OSA patients [7]. Not all OSA patients exhibit impaired alertness and many function normally
during the day. One way to unmask an individual's vulnerability to alertness failure is to expose them to extended wakefulness challenge (i.e., sleep
deprivation/restriction) [110] and test their performance at a period of circadian disadvantage i.e., middle of the night. Future studies should employ
this “sleep stress” methodology to test the accuracy of candidate markers to identify the vulnerable OSA patients who have an excessive and clinically
meaningful risk of alertness failure. A personalised neuro-phenotyping approach to characterise key EEG features as biomarkers of functional
impairment may help identify those patients at high vs low risk of alertness failure. Moreover it would be important if EEG based biomarkers could
provide meaningful and relevant assessments of daytime sleepiness and functional performance following treatment.
Future studies using standardised approaches and combined modalities such as high density EEG, brain mapping techniques and neuroimaging will
help identify the brain regions most impacted by OSA, and elucidate the neural mechanisms and pathways which underlie EEG abnormalities and
how they relate to neurobehavioural dysfunction. More studies are needed to clarify the complex interactions between hypercapnia, hypoxia, sleep
fragmentation and EEG activity and cognitive consequences in OSA. A clearer understanding of those mechanisms may provide the potential to
phenotype individual vulnerability to OSA-related neurobehavioural impairment, and provide targeted solutions for effective clinical management of
patients.
Practice points
• Untreated OSA is associated with increased slow frequency EEG activity during wake and REM sleep in frontal, central and parietal
brain regions; and reduced SWA and spindle frequency activity in NREM sleep. Limited evidence suggests that these EEG changes
are related to cognitive dysfunction and excessive sleepiness.
• CPAP therapy improves EEG abnormalities during wake and sleep, but does not always reflect changes in neurobehavioural
function, and not all individuals may respond the same to treatment.
• EEG-based biomarkers have potential clinical utility to identify OSA patients more susceptible to functional impairment.
Research agenda
• Establish robust and validated EEG markers for predicting those OSA patients who are more likely to experience excessive daytime
sleepiness and neurocognitive deficits, and those patients more likely to benefit from CPAP treatment.
• Establish standardised wake and sleep qEEG methodologies and develop more accurate neurobehavioural outcomes relevant to
operational vigilance-dependent performance and real-world outcomes (e.g., traffic and workplace accidents).
• Utilise advancements in technology such as topographic acquisition (e.g., high density EEG) or analyse qEEG in context with other
neural correlates (e.g., MRI), to further our understanding of the brain regions compromised in OSA in relation to neurobehavioural
dysfunction and establish clinically useful EEG-based markers.
•
Clarify the roles of nocturnal intermittent hypoxemia, hypercapnia and sleep fragmentation in EEG slowing during wakefulness and
sleep in OSA.
• Understand the sleep homeostatic response in OSA and differential components of slow frequency EEG activity in NREM sleep.
• Further research examining links between spindle abnormalities and neurobehavioural dysfunction in OSA should be undertaken.
• Extended research into the mechanisms and functional role of increased slow frequency EEG activity in REM detected at the scalp in
OSA patients.
• Elucidate the impact of OSA on brain ageing processes in relation to cognitive decline in older age.
• Harness the full potential of EEG-based assessments for predicting vulnerability to performance deficits by ensuring testing is
personalized and based on the EEG phenotype of each individual.
Conflict of interest
The authors do not have any conflicts of interest to disclose.
Acknowledgments
This work was supported by NeuroSleep, Centre of Research Excellence in Interdisciplinary Sleep Health funded by the Australian National Health &
Medical Research Council (NHRMC, APP1060992), and CIRUS (APP571421), Centre for Sleep and Chronobiology at the Woolcock Institute of
Medial Research. A Dora Lush Priority NHMRC Scholarship (ALD), Australian Postgraduate Award (NEC) and Australian NHMRC Research
Fellowships (RRG, AV, DW) funded researchers who undertook this review.
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Sleep Medicine Reviews

Quantitative electroencephalogram measures in adult obstructive sleep apnea – Potential biomarkers

https://doi.org/10.1016/j.smrv.2016.10.003 Get rights and content

Previous article Next article

EEG characteristics of wake and sleep

EEG power spectral analysis

Quantitative EEG measures as determinants of neurobehavioural function in healthy adults

Quantitative EEG measures during wakefulness in OSA

Differentiating OSA patients from controls using wake qEEG measures

Table 1. Quantitative EEG measures during wakefulness in OSA.

Grenèche OSA, severe PSA Absolute δ, θ, α, ↑ δ, θ, β No* (NS) *KSS, VAS

Baril et al. OSA, PSA Absolute and ↔ α, δ Yes* *↑ θ was

Wang OSA, PSA Absolute δ, θ, α, After Yes* Yes† * ↑α/δ ratio,

Relationship between wake qEEG and daytime sleepiness in OSA

Relationship between wake qEEG and cognitive performance in OSA

The effect of CPAP on wake qEEG

Differentiating OSA patients from controls using sleep qEEG measures

Table 2. Quantitative EEG measures during sleep in OSA.

Guilleminault OSA, PSA Absolute power δ ↓ SWA REM; NREM; OSA

Abdullah OSA, PSA Absolute + relative ↓absolute NREM OSA

Relationship between sleep qEEG and daytime sleepiness in OSA

Relationship between sleep qEEG and cognitive performance in OSA

The effects of CPAP on sleep qEEG

Links between nocturnal hypoxemia/hypercapnia, sleep fragmentation and wake EEG

OSA may exacerbate brain ageing

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