Curr Neurol Neurosci Rep (2015) 15: 12

DOI 10.1007/s11910-015-0537-1

SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)

Neurogenic Changes in the Upper Airway

of Obstructive Sleep Apnoea
Julian P. Saboisky & Jane E. Butler & Billy L. Luu &
Simon C. Gandevia

Published online: 24 February 2015

# Springer Science+Business Media New York 2015

Abstract Obstructive sleep apnoea (OSA) is linked to local

neural injury that evokes airway muscle remodelling. The upper airway muscles of patients with OSA are exposed to intermittent hypoxia as well as vibration induced by snoring. A
range of electrophysiological and other studies have
established altered motor and sensory function of the airway
in OSA. The extent to which these changes impair upper airway muscle function and their relationship to the progression
of OSA remains undefined. This review will collate the evidence for upper airway remodelling in OSA, particularly the
electromyographic changes in upper airway muscles of patients with OSA.
Keywords Remodelling . Reinnervation . Denervation .
Genioglossus . Tongue . Respiratory . Fibre density .
Motor unit potential . Electromyography . Quantitative EMG
Introduction
Obstructive sleep apnoea (OSA) is a common sleep disorder
with serious consequences including fragmented sleep, recurrent hypoxemia, greater risk of cardiovascular mortality, excessive daytime sleepiness, depression, impaired learning and
memory, as well as an increased risk of accidents [e.g. 14].
Factors that contribute to frequent collapse of the upper airway
in sleep include constricted space due to poor upper airway
anatomy, insufficient neuromuscular drive, high intraluminal
negative pressure and external influences on the pharyngeal
space such as increased fat [5, 6]. Continuous positive airway
This article is a part of the Topical Collection on Sleep
J. P. Saboisky (*) : J. E. Butler : B. L. Luu : S. C. Gandevia
Neuroscience Research Australia, University of New South Wales,
Barker Street, PO Box 1165, Randwick Sydney,
NSW 2031, Australia
e-mail: J.SABOISKY@neura.edu.au

pressure (CPAP) is regarded as the best standard treatment for

OSA. It reduces apnoeas and hypopnoeas and can decrease
mean arterial blood pressure [7]. CPAP has little risk for the
patient, but it has relatively poor adherence (50 %) [e.g. 8, 9].
In preventing sleep apnoea, CPAP acts to splint the airway
open such that less muscle activation is required to maintain
airway patency [10, 11].
This review will focus on the evidence for remodelling of
upper airway muscles in OSA due to neurogenic change. They
are associated with denervation, collateral sprouting and reinnervation of upper airway dilator muscles. These changes alter
the multiunit electromyographic (EMG) signal, and this needs
to be considered when EMG signals are an outcome variable.
Anatomy of Pharyngeal Airway
The human pharyngeal airway is by any standard dynamically
complex. Unique demands placed on this relatively small conduit have seen it evolve and adapt to swallowing, vocalisation
and importantly breathing. To achieve this range of tasks, the
conduit is not a simple stable rigid tube [12]. The human upper
airway comprises more than 20 muscles and can be divided
into three segments: the velopharynx, oropharynx and hypopharynx. Each segment is walled by muscles and is a potential
site of airway obstruction. The velopharynx is the most collapsible segment of the upper airway and is usually the site of
most constriction [13]. There are five pairs of muscles which
control the velopharyngeal airway, and they interact dynamically with muscles in the oropharynx. In the oropharynx, eight
intrinsic and eight extrinsic muscles collectively form a muscular hydrostat known as the tongue [1416]. Some muscles
contract rhythmically in stable quiet breathing [10, 1719],
but they can also be activated to generate other tongue movements [14, 20]. The hyoid arch forms the lower margin of the
hypopharynx and is suspended by 12 muscles from the tongue
and it links to the infrahyoid muscles. The floating hyoid in

12 Page 2 of 7

humans has likely contributed indirectly to the evolution of

language but it also affects the patency of the airway particularly at the level of the hypopharynx [21]. The upper airway
muscles in humans have a relatively high density of nerve
fibres and terminals [22].
The shape of the airway has been compared between patients with OSA and healthy control subjects, with dynamic
imaging revealing that the upper airway size varies throughout
the respiratory cycle [e.g. 13, 20, 2325]. While the oropharyngeal and hypopharyngeal spaces of patients with OSA are
similar in size to the those of the control subjects [13], the
velopharynx is not. The velopharyngeal space (measured in
expiration) has a ~40 % smaller cross-sectional area in patients
with OSA compared to matched control subjects (30 vs
106 mm2, respectively) [13, 26, 27]. Therefore, it is possible
that the mechanical coupling to the velopharyngeal space
from the genioglossus via the palatopharyngeus muscles is
important for control of the reduced cross-sectional area in
patients with OSA. Some of the neurophysiological changes
considered below may further impair this neuromechanical
control of the upper airway.

Neuropathic Change in Upper Airway Muscles in OSA

Electrophysiological evidence for a link between upper airway remodelling and OSA derives from several studies. Studies that relate to neurogenic changes in upper airway muscles
are summarised in Table 1. It shows general hypotheses, the
overall findings and possible underlying mechanisms. The
studies have used intramuscular EMG techniques to determine
whether there are changes in the upper airway musculature in
humans with OSA. The first indication of a possible abnormality was provided by Mezzanotte and colleagues [28] and
subsequently reinvestigated by Fogel and colleagues [29].
Both studies quantified intramuscular multiunit EMG in quiet
breathing and expressed it as a percentage of a maximal value
obtained in a voluntary contraction [28, 29]. Mezzanotte and
colleagues reported a ~3-fold (40.6 % vs 12.7 % maximum,
respectively) increase in genioglossus activation in patients
with OSA compared to healthy subjects during quiet breathing
(Table 1). Based on these data, they hypothesised that there
was a neuromuscular compensatory mechanism to maintain
or improve airway patency during wakefulness [28, 29]. Fogel
and colleagues [29] reported a ~2-fold increase in activity in
patients with OSA compared to control subjects but with comparatively low levels of muscle activity (11.0 % vs 6.4 %
maximum, respectively). Similarly, Katz and White [30]
found a ~2-fold increase in genioglossus EMG in children
with OSA compared to control subjects using surface intraoral
electrodes (3.6 % vs 1.6 % maximum, respectively). Surface
electromyography with submental electrodes, in adults, also
revealed increased activity in patients with OSA [31]. Muscle

Curr Neurol Neurosci Rep (2015) 15: 12

conduction velocity in genioglossus is higher in patients with

OSA [32], a change which can occur in repeated exercise
bouts [33], but the mechanism of this effect in OSA has not
been studied in detail. Furthermore, studies using intramuscular EMG have revealed that inspiratory activation is maintained during stable NREM sleep [3437] and that there is
an impaired reflex response to induced airway obstruction
during sleep in patients with OSA [38].
To examine the compensatory drive hypothesis and to
assess directly if there was an increase in hypoglossal
motoneurone output, the behaviour of single motor units in
quiet breathing has been examined. Initially, investigations
sought to assess if there was increased neural drive in patients
with OSA by comparing the discharge frequencies of populations of single motor units. There are six firing patterns of
genioglossus motor units in quiet breathing [17], and they
were similar in proportion in both normal and OSA groups
[39]. Further, the discharge rates of these genioglossus units
were not consistently higher in OSA patients than those in
healthy control subjects [39]. The similarity in motor unit
discharge rates argues against a compensatory increase in neural drive [10, 39], at least during wakefulness. In addition, the
number of motor units recorded at each site in quiet breathing
was not different, suggesting comparable levels of recruitment
[39, 40]. However, the genioglossus motor units in patients
with OSA were recruited ~100 ms earlier (inspiratory phasic
units 91 ms and inspiratory tonic units 106 ms earlier) than
those in control subjects relative to inspiratory airflow, consistent with previous multiunit EMG recordings (see Table 1)
[39]. The advanced activation of the genioglossus in patients
with OSA may reflect advanced descending drive from the
medulla. However, obese subjects have delayed onset of airflow compared to timing of diaphragm activation [41]. Therefore, a limitation of recording from a single upper airway
(genioglossus) muscle is the uncertainty as to whether the
early recruitment of its motor units reflects earlier central respiratory drive or if airflow was delayed due to the increased
inertia of the airway and thoracoabdominal structures.
In addition to the analysis of rate coding and recruitment of
single genioglossus motor units, measurements of the morphology of motor unit potentials has been performed in two
independent studies with intramuscular needle electrodes [39,
40]. Needle EMG recordings were made at multiple sites in
genioglossus when supine awake subjects were breathing quietly. Genioglossus motor unit potentials in patients with OSA
had similar peak-to-peak amplitudes compared to control subjects (398 vs 383 V, respectively). However, the motor unit
potentials in the patients with OSA were ~23 % longer in
duration, 14.6 % greater in area [39] and had a 33 % increase
in complexity (reflecting the number of phase changes in the
motor unit potential) compared to control subjects [40]. Recently, Zhang and colleagues [42] extended these findings and
reported that motor units in the posterior regions of the

Compensatory drive
in OSA
Compensatory drive
in OSA

Neurogenic changes in
palatopharyngeus

Katz & White

2003 [30]
Saboisky et al.
2007 [39]

Hagander, 2006 [44]

Motor unit potential morphology

Motor unit potential duration
sub-analysis controls (older vs younger)
14.10.7 vs 10.50.3 ms

Age effects and neurogenic

changes

Saboisky et al.
2014 [49]

Denervation and collateral spouting

Denervation and collateral spouting

Remodelled muscle fibresdecrease

muscle fibre conduction velocity

Denervation and collateral spouting

Denervation and collateral spouting

Denervation and collateral spouting

Onset of airflow may be altered

due to increased body weight

rate coding and recruitment

Early motor unit recruitment
Motor units saturated as already
discharging quickly
Drive not increased

Early motor unit recruitment

rate coding and recruitment

Possible underlying mechanism

Do hypoglossal motoneurons show

alterations in rate coding or rate
modulation in anterior
versus posterior genioglossus?
Do discharge rates of hypoglossal
motoneurons show alterations in rate
coding or rate modulation with age?

Studies conducted during quiet

breathing. Is recruitment similar
in voluntary breathing?
Estimation of remaining motor unit
numbers
External stimulation of hypoglossal
nerve?

Studies conducted during voluntary

contractions
Which other muscles are affected
Studies conducted during voluntary
contractions

Did not compare timing of diaphragm

activation with genioglossus

Can units respond with increased

discharge rates?

Do children have neurogenic changes?

Adequacy of multiunit EMG to

reveal changes in drive
Is the neural drive intact during
sleep in OSA

Limitations and questions

= increase, = no change

Reference Podnar & Dolenc Groselj, 2010 [81] only appears in abstract form; it shows isolated neurogenic changes in the upper airway which has not been published

Regional neurogenic
changes

11.50.1 vs 10.30.1 ms

Zhang et al.
2014 [42]

EMG median frequency no difference

OSA vs. control (144 vs. 155 Hz)
Muscle fibre conduction velocity in OSA
vs control subjects (4.1 vs 1.9 m/s, P<0.04)
Motor unit potential morphology
Duration OSA (anterior vs posterior)
7.02.6 vs 8.63.3 ms

Neurogenic changes
Changes correlated
with nadir O2

Motor unit potential morphology

68 % of patients had neuropathic
changes in genioglossus
Motor unit potential morphology
11.33.5 vs 9.22.5 ms

Conduction velocity fatigue

Saboisky et al.
2012 [40]
McSharry et al.
2012 [32]

Saboisky et al.
2007 [39]

Inspiratory phasic 221 vs 191 Hz

Inspiratory tonic 251 vs 281 Hz
Timing of motor units earlier
Inspiratory phasic 3227 vs +12330 ms
Inspiratory tonic 22736 vs 12139 ms
Motor unit potential morphology
Increased duration in 6/10 patients

Global genioglossus activity

40.65.6 vs 12.71.7 %max
Main analysis (all subjects)
11.01.4 vs 6.41.4 %max, P=0.03
Age matched sub-analysis EMG not increased
11.22.1 vs 6.20.9 %max, P=0.25
Global genioglossus activity
3.61.8 vs 1.61.8 %max
No increase in rate coding

Finding (OSA vs control subjects)

or

Neurogenic changes

localised to upper airway

Compensatory drive
in OSA

Mezzanotte et al.
1992 [28]
Fogel et al.
2001 [29]

Svanborg, 2005 [43]

Podnar & Dolenc
Groselj, 2010 [81]

Hypothesis

Electrophysiological evidence for upper airway remodelling and OSA

Authors

Table 1

Curr Neurol Neurosci Rep (2015) 15: 12

Page 3 of 7 12

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genioglossus in patients with OSA had increased amplitude

(14 %), duration (23 %), area (30 %) and size index (which
controls for the influence of needle position) (50 %) compared
to those in anterior regions of the genioglossus. This regional
difference was not observed in healthy subjects in their study
(see Table 1). There are also reports of long polyphasic EMG
potentials in the palatopharyngeus muscle in patients with
OSA [43, 44]. For single units, the increase in their duration,
area and complexity in patients with OSA is consistent with
peripheral motor axonal sprouting to reinnervate orphaned
muscle fibres following denervation. Using a different approach, Kim and colleagues (2014) found that glucose uptake
by genioglossus was decreased in patients with OSA, a finding which they suggest argues against a compensatory increase in neural drive to genioglossus [45].
As a result of the growing evidence for motor unit remodelling, it is interesting to speculate that the increased prevalence of OSA in older individuals is linked to age-related
neurogenic changes. Although the links between aging and
OSA have been explored extensively [e.g. 46, 47], the role
of motor unit remodelling in upper airway pathology has not
been considered [e.g. 48, 49]. In individuals over 55 years of
age without OSA, Saboisky and colleagues [49] found a 3-ms
increase (34 %) in duration of motor unit potentials in the
genioglossus and fewer motor units per recording site (see
Table 1). In the older patients with OSA (with larger motor
unit potential duration and areas), the complexity of
genioglossus motor units was decreased compared to younger
patients with OSA, which may reflect stable long-term reinnervation of motor units. The MACRO EMG potentials,
which are recorded from a nonselective electrode and reflect
the total territory of the motor unit, had a larger area in patients
with OSA compared to healthy controls (37 % larger in the
younger OSA subjects and 58 % larger in the older OSA
subjects). The MACRO potential area increases with the number of fibres in the motor unit [50], and hence the larger area in
patients with OSA may indicate that the genioglossus units
generate greater twitches and tetanic forces. This possibility
has not been measured formally for genioglossus.
The presence of remodelled motor units in the upper airway
muscles of OSA patients is supported by Boyd and colleagues
[51] who found overexpression of a neural cell adhesion
molecule (N-CAM) in palatal muscles of patients with OSA.
This implies that there is active collateral sprouting associated
with reinnervation of muscle fibres.
Factors that may Influence Remodelling
The mechanisms that underlie neuropathic pathology in OSA
have been debated [52, 53]. It is unlikely that a single mechanism can explain all the changes. The most plausible explanation is that the changes reflect the effect of repeated exposure to hypoxia, vibration, abnormal movement or

Curr Neurol Neurosci Rep (2015) 15: 12

compression of the pharyngeal musculature that may impair

the function of both motor and sensory nerves through axonal
damage [51]. Repeated vibration due to snoring may also
induce focal trauma via localised inflammation [for review
see: 54]. Mechanical vibration induced neuropathies can
evoke increased pressure within the nerve, resulting in reduced sensory and motor conduction velocities [55, 56]. Exposure to hypoxia from in vivo animal studies reveals the
vulnerability of motor nerve terminals, with rapid changes in
nerve terminal form and function even without ischemia [57,
58]. Furthermore, the effects of plasticity may extend beyond
the nerve to muscle function, where the force frequency and
fatigue of upper airway muscles can be vulnerable in critical
periods of development [58].

Questions and Consequences

A number of questions remain about various influences on the
multiunit genioglossus EMG signal. First, inflammation of the
airway [51, 59, 60] alters muscle fibre cross-sectional area
[61], and tissue properties may also affect the size of the multiunit EMG signal, but these have not been studied in OSA. In
addition, previous investigations using multiunit EMG have
assumed that expression of EMG as a percentage of a maximum (usually in a swallow or tongue protrusion) allows
meaningful comparisons between healthy control subjects
and patients with OSA. However, the influence of electrophysiological abnormalities on the normalisation of multiunit
EMG and the resultant change in force output are difficult to
tease apart.
Muscles adapt to overuse, disuse, and injury, with changes
in muscle fibre size and fibre type usually leading to changes
in the muscle force output [for review see: 62]. Ultimately,
fewer motor axons may reinnervate the same number of muscle fibres to produce larger, longer and often more complex
motor unit potentials [63]. The extent of motor unit remodelling is illustrated by Kugelberg et al. (1970) who documented
in the rat an up to 7-fold increase in the number of muscle
fibres innervated by a single motor unit after recovery from
motor root transection [64]. In humans, early in motoneurone
disease, motor units can increase their force output 3-fold as a
result of reinnervation, a change which masks the effect of
motoneurone loss [65]. The active remodelling of motor units
can continue for decades, as it occurs in patients with prior
poliomyelitis [66].
It is possible that the neurogenic changes in the upper airway in OSA are maladaptive and lead directly to impaired
upper airway control. In patients with OSA studied awake,
there are altered movement patterns of the tongue in quiet
breathing that do not reflect the measured EMG activity
[67]. Paradoxically, despite the need for airway dilation, patients with severe OSA have little or no inspiratory dilatory

Curr Neurol Neurosci Rep (2015) 15: 12

movement of the lateral wall of the upper airway or anterior

movement of the posterior tongue [67]. However, in patients
with moderate OSA, there is often bidirectional movement of
genioglossus in the sagittal plane [67]. This results in unbalanced rotation of the posterior tongue, where contraction in
one region dilates the airway, but another region narrows before and during inspiratory flow [for review see: 12, 20]. Conversely, in those healthy subjects who have a small crosssectional area of the upper airway (at its narrowest point)
coordinated anterior displacement of the tongue during inspiration is relatively large [24]. It remains probable that the
altered coordination of the upper airway muscles in patients
with OSA is not due to neurogenic changes but rather results
from discoordinated neural drive.
The remodelled motor units in patients with severe OSA
are likely to have increased territories. There is also a shift to a
predominance of type II muscle fibres [e.g. 68] together with
increased fat within and around the upper airway muscles
[6972]. While more type II muscle fibres may facilitate opening of the airway following an obstruction, the increased fat
may impair contractile transmission [73]. Based on enlarged
remodelled genioglossus motor units in patients with OSA,
we would expect them to have impaired fine motor control
of the upper airway. Such physiological impairments in patients with OSA may contribute to their compromised
swallowing reflexes [7478]. After treatment for OSA, some
pathophysiological changes may be corrected such as the
changes in muscle fibre types [e.g. 68] and swallowing reflexes [e.g. 79]. In addition, novel treatments that are likely
to improve the motor coordination of the soft palate have been
promoted as alternative treatments to OSA, such as didgeridoo
playing [80].

Page 5 of 7 12
Compliance with Ethics Guidelines
Conflict of Interest Julian P. Saboisky, Jane E. Butler, Billy L. Luu and
Simon C. Gandevia have received a NHMRC grant.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.

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Conclusions
This short review covers the link between OSA and neurogenic changes in muscles of the upper airway. Motor unit
potentials are larger in area and duration and more complex
in OSA patients than those in healthy control subjects.
There is no evidence for increased rate coding of motor
units as a form of compensatory drive or for additional
motor unit recruitment in patients with OSA. Hence, the
previously described neural compensatory drive hypothesis [28, 29] may be explained principally by the larger
motor unit potentials. Airway muscle remodelling should
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changes in OSA. This will require attention to factors affecting the multiunit EMG such as phase cancellations,
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