Scholarly article on topic 'Tongue and upper airway function in subjects with and without obstructive sleep apnea'

Tongue and upper airway function in subjects with and without obstructive sleep apnea Academic research paper on "Medical engineering"

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Abstract of research paper on Medical engineering, author of scientific article — Takashi Ono

Summary Obstructive sleep apnea (OSA) is characterized by repeated occlusion of the oropharyngeal airway during sleep and can have a significant impact on quality of life. In this article, I review the current knowledge of the physiological and pathological functions of the tongue and the genioglossus muscle, one of the upper airway dilatory muscles, in subjects with OSA when they are awake and asleep. Research findings clearly reveal that the genioglossus muscle has important functions in maintenance of upper airway patency and in the pathophysiology of obstructive sleep apnea. Despite extensive study of the functional properties of the genioglossus muscle and its motor units, the availability of OSA prevention and treatment measures remains limited. This review indicates there is a need for further study on more effective prevention and treatment strategies.

Academic research paper on topic "Tongue and upper airway function in subjects with and without obstructive sleep apnea"

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Review article

Tongue and upper airway function in subjects with and without obstructive sleep apnea

Takashi Ono*

Orthodontic Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan Received 5 November 2011; received in revised form 26 December 2011; accepted 27 December 2011

KEYWORDS

Tongue;

Upper airway;

Obstructive sleep apnea;

Awake;

Sleep;

Genioglossus

Summary Obstructive sleep apnea (OSA) is characterized by repeated occlusion of the oropharyngeal airway during sleep and can have a significant impact on quality of life. In this article, I review the current knowledge of the physiological and pathological functions of the tongue and the genioglossus muscle, one of the upper airway dilatory muscles, in subjects with OSA when they are awake and asleep. Research findings clearly reveal that the genioglossus muscle has important functions in maintenance of upper airway patency and in the pathophysiology of obstructive sleep apnea. Despite extensive study of the functional properties of the genioglossus muscle and its motor units, the availability of OSA prevention and treatment measures remains limited. This review indicates there is a need for further study on more effective prevention and treatment strategies.

© 2012 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction............................................................................................................................................................72

2. Oropharyngeal anatomy and function: an overview................................................................................................72

3. Physiological GG muscle and tongue function in subjects without OSA....................................................................73

3.1. Activity while awake....................................................................................................................................73

3.2. Activity during sleep......................................................................................................................................75

4. Pathological GG muscle and tongue function in subjects with OSA..........................................................................76

4.1. Activity while awake....................................................................................................................................76

4.2. Activity during sleep......................................................................................................................................76

5. Conclusions............................................................................................................................................................78

References..............................................................................................................................................................78

* Tel.: +81 3 5803 5526; fax: +81 3 5803 5526. E-mail address: t.ono.orts@tmd.ac.jp.

1882-7616/$ — see front matter © 2012 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jdsr.2011.12.003

1. Introduction

Obstructive sleep apnea (OSA), one condition among sleep-disordered breathing (SDB) disorders, is characterized by recurrent occlusion of the oropharyngeal airway during sleep [1,2]. Many epidemiological studies have established the prevalence of OSA in United States and European countries [1—4], while limited data have been published for Asian countries [5—7]. Because of variation in the definition of OSA and methodology that has been employed, the prevalence of OSA in the Caucasian population reportedly ranges from3%to30%. In Asia, the prevalence of symptomatic OSA in middle-aged men and women was estimated to be 4.1—7.5% and 2.1—3.2%, respectively [8]. Several studies have suggested the involvement of ethnicity in the differential prevalence of OSA in Caucasian and non-Caucasian groups [9,10]. Obesity, an established major risk factor for OSA, is less common among Asians, and the reported values of body mass indices of Asians with OSA are lower than those in their Caucasian counterparts. However, these population-based studies have consistently demonstrated that obesity is still the major risk factor for OSA in Asians, while other studies have suggested that craniofacial structural factors may make a greater contribution toward development of OSA in Asians than in Caucasians [11].

Because subjects with OSA were more likely to be male and had a significantly greater prevalence of habitual snoring [12], Kurono et al. [13] first conducted a large-scale questionnaire survey for snoring among 7000 adult workers in a steel-making factory in Japan. They investigated the relationship between the severity of snoring and 17 items including age, obesity, family history of snoring, daytime sleepiness, hypertension, smoking, alcohol intake, and traffic accidents in three subgroups: non-snorers, mild snorers, and severe snorers. They found that age, obesity, smoking, and alcohol intake were risk factors for snoring. Compared with non-snorers, severe snorers were found to have a high incidence of family history of snoring, daytime sleepiness, and history of treatment of hypertension. The proportion of severe snorers over 40 years old with obesity, daytime sleepiness, and morning headache was 0.25%, representing the group that may have OSA. They thus speculated that the probable incidence of OSA in men might be considerably lower in Japan compared with that in either the United States or the Europe.

In a large cohort of subjects with OSA, O'Connor etal. [14] investigated the gender difference in polysomnographic findings. Male subjects had a higher apnea—hypopnea index than did females, and severe OSA was eight times more frequent in males. Apneas were more clustered during rapid eye movement (REM) sleep in women than in men. On the other hand, apneas that occurred predominantly in the supine position were almost restricted to male subjects with OSA. They thus concluded that female subjects had less severe OSA during non-REM sleep than did males, whereas females had a greater chance of oropharyngeal obstruction during REM sleep. Several interrelated factors that may explain the gender differences in the risk of OSA include oropharyngeal anatomy, function of oropharyngeal dilator muscles, distribution of adipose tissue, and hormonal status [6,15—19].

2. Oropharyngeal anatomy and function: an overview

The pharyngeal region (Fig. 1) has a complex musculature system that is closely related to many different and sophisticated behaviors such as speech, deglutition, and respiration [20—22]. Muscles in this region do not act independently, but rather work together to achieve equilibrium; otherwise, the patency of the upper airway (UA) would be jeopardized. A number of studies of UA muscle physiology and pathophysiology verify the importance of the pharyngeal region in the comprehension of respiratory disorders, with a particular interest on SDB conditions, including OSA. It is particularly important to emphasize that the force generated by UA dilator contraction represents the only adaptive dilating force that counterbalances the collapsing forces and stabilizes the UA. Thus, any alteration in the UA function and/or activation pattern and/or ability to produce force will interact with UA stability and therefore promote instability of the tube. The tongue, a muscular hydrostat in the oral cavity, plays important roles in sucking, chewing, swallowing, and breathing [23—25]. The central drives to control the tongue movement originate from several cortical and subcortical structures of the brain and converge onto the hypoglossal premotor and motoneurons in the brain stem [26—31].

Abnormal tongue function is clinically involved in oral respiration, adenoid face, constricted maxillary dental arch, and anterior open bite malocclusion. The three-dimensional position/movement of the tongue is robustly controlled by four extrinsic tongue muscles (genioglossus [GG], styloglossus [SG], hyoglossus [HG], and palatoglossus) and suprahyoid muscles such as the geniohyoid (GH) muscles. The GG muscle is the main protruder of the tongue body, which is a flat triangular muscle close to and parallel with the median plane; it originates from the mental spine of the mandible and inserts into the tongue and hyoid bone. It arises by a short tendon from the superior mental spine on the inner surface of the symphysis menti, immediately above the GH muscle, and from this point spreads out in a fan-like manner in the tongue. The inferior fibers extend downward to be attached by a thin aponeurosis to the upper part of the body of the hyoid bone. The middle fibers pass backward and the superior fibers pass upward and forward to enter the whole length of the undersurface of the tongue, from the root to the apex. The SG muscle is the main retruder of the tongue, the shortest and smallest of the three styloid muscles; it arises from the anterior and lateral surfaces of the styloid process, near its apex, and from the stylomandibular ligament. Passing downward and forward between the internal and external carotid arteries, it divides upon the side of the tongue near its dorsal surface, blending with the fibers of the intrinsic tongue muscle in front of the HG muscle; the other, the oblique, overlaps the HG muscle and decussates with its fibers. Sensation of the anterior two-thirds of the tongue is innervated by the lingual nerve that is the branch of the trigeminal nerve and chorda tympani branch of the facial nerve, and the posterior one-third is innervated by the glossopharyngeal nerve.

Figure 1 Anatomy of the upper airway and tongue. (A) Sagittal section of nose, mouth, pharynx, and larynx. (B) Extrinsic muscles of the tongue. Abbreviations: GG, genioglossus; SG, styloglossus; HG, hyoglossus. From Gray's Anatomy of the Human Body with permission.

3. Physiological GG muscle and tongue function in subjects without OSA 3.1. Activity while awake

The GG muscle demonstrates the rhythmical electromyo-graphic (EMG) activity related to respiratory oscillation (Fig. 2) in pace with the inspiratory drive [32]. In fact, a tagged magnetic resonance imaging (MRI) demonstrated respiratory-related motion of the GG muscle (Fig. 3) and soft tissue around the human UA during quiet breathing [33]. The maximal anteroposterior movement of a point tracked on the GG was 1.02 ± 0.54 mm (mean ± standard deviation [SD]). The GG muscle moved over the GH muscle with minimal movement in other muscles surrounding the airway at the level of the soft palate. Across the respiratory cycle, positive strains analyzed using two-dimensional strain maps within the GG reached peaks of 17.5% ± 9.3%, and negative strains reached peaks of -16.3% ± 9.3% relative to end inspiration. The patterns of strains were consistent with elongation and compression within a constant volume

structure. Hence, they concluded that even during respiration, the tongue behaves as a muscular hydrostat [34]. Thus, the GG muscle serves as a UA dilating muscle, and its contraction represents the adaptive dilating force that counterbalances the collapsing forces and stabilizes the UA. Any alteration in the GG activation pattern to produce force will interact with UA stability and therefore destabilize UA patency. In animal experiments, an increase in norepinephr-ine and serotonin terminal density and increased expression of a1-adrenergic receptors in the XII nucleus were elicited by chronic intermittent hypoxia [35]. The authors speculated that this may lead to augmentation of endogenous aminergic excitatory drives to XII motoneurons, thereby contributing to increased upper airway motor tone if the UA is jeopardized.

In a previous study [34], tongue pressure was recorded with a miniature pressure sensor incorporated in a custom-made intraoral appliance in different breathing modes (i.e., nasal and oral respiration) and body positions (i.e., upright and supine positions). The GG EMG activity and respiratory-related movement were recorded simultaneously. Tongue pressure showed respiratory-related cyclic oscillations with

Inspiration

gh n .......................................

Figure 2 Representative simultaneous recording of ribcage movement (Resp) and electromyographic activities of the gen-ioglossus (GG) and geniohyoid (GH) muscles during nasal breathing in the upright position in a subject [32]. Upward and downward arrows indicate inspiration and expiration, respectively. Vertical bar represents 50 mV for both the genioglossus and the geniohyoid muscle activities, and horizontal bar represents 3 s.

a maximum value during expiration and a minimum value during inspiration. In contrast, the GG EMG activity showed a maximum amplitude during inspiration and a minimum amplitude during expiration. The maximum tongue pressure during oral breathing was significantly greater than that during nasal breathing in both the upright and the supine positions. Changes in body position significantly affected the maximum tongue pressure during oral breathing. The GG EMG activity changed significantly with different breathing modes and body positions. Changes in the position of the hyoid bone

produced by changes in the breathing mode and body position appear to play a critical role in determining tongue pressure. This assumption was supported by an MRI study in normal awake subjects during nasal breathing [36]. In the retro-palatal region, there was a significant decrease in the lateral dimension in the lateral recumbent position compared with that in the supine position. The cross-sectional area in the retroglossal region was significantly increased in both the ''supine with the head rotated'' and the ''lateral recumbent'' positions. This change was accompanied by significant volumetric changes in the retroglossal region. Thus, the anatomical change in UA configuration is in concert with functional change in GG activity.

As indicated above, some GG fibers run perpendicular to the pharynx, and therefore activation of these fibers may result in both advancement of the base of the tongue and enlargement of the UA. Previous physiological studies have shown that the fibers of UA dilator muscles have faster contractile properties and less resistance to fatigue than those of the diaphragm [37,38]. In addition, the GG muscle contains type I, type IIa, and type IIb fibers [38,39]. However, it is not yet clear which type of motor unit is responsible for the respiratory-related activity of the GG muscle. It has recently been shown that there are at least two types of motor units with respiratory-related activity in the human GG muscle [40]: inspiratory motor units (IMUs), which show phasic firing during inspiration; and inspiratory/expiratory motor units (IEMUs), which fire during both inspiration and expiration, with a greater instantaneous firing frequency during inspiration. Their different patterns of firing activity indicate that these two types of motor units play different physiological roles with regard to respiratory-related control of tongue movement, but it is unclear whether the IMUs and IEMUs are heterogeneous. Unitary spike activity of GG

Figure 3 Movement of a grid of points on the tongue at four time points in the respiratory cycle in one subject [33]. Panels A and B each show a triangular mesh superimposed on the tagged image in the mid-sagittal plane and lower axial plane, respectively. The vertical and horizontal distance between grid points is 5 mm (panel A) and 8 mm (panel B). In each panel, the region of the tongue with distinct respiratory movements is enlarged. In both panels, there is movement of the posterior region of the genioglossus.

0 20 40 60 80 100 120

Figure 4 Mean interspike interval tSD points for 12 inspiratory motor units (IMU; open circles) and 12 inspiratory/expiratory motor units (IEMU; filled circles) [41]. t and SD were calculated during inspiration for the IMU and during both inspiration and expiration for the IEMU.

respiratory-related motor units were recorded in healthy subjects [41]. The mean interspike interval and the SD of successive spikes were calculated for IMUs and IEMUs, respectively. Scattergrams of the mean interspike interval versus SD were constructed for the two groups of motor units (Fig. 4). The effects of changes in head position on the firing activity and the patterns of distribution of the mean interspike interval versus its SD were significantly different between IMUs and IEMUs. These results suggest that IMUs and IEMUs play different functional roles in respiration; IMUs may be phasically active to counteract intraluminal negative pressure during inspiration, whereas IEMUs may be tonically active to maintain tongue posture.

Changing the body position exerts an unavoidable effect on the resistance of respiratory routes. In healthy subjects, nasal resistance was recorded when the chair was gradually

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Figure 5 Increases in genioglossus (GG) electromyographic (EMG) activity during progressive hypoxia in G-I (subjects aged 20-40 years; mean, 29.1 years) and G-II (subjects aged 4160 years; mean, 53.2 years) subjects [47]. The increases differed significantly between the two groups ( p < 0.01).

reclined from the sitting position to the supine position [42]. A significant increasein nasal resistance (as much as 30°) was found in the reclined position compared with the sitting position. Changing the body position from sitting or upright to supine increases the cardiac stroke volume and thereby the blood pressure. This change is detected by the aortal baroreceptor, and the baroreflex decreases the pulse rate and induces peripheral vasodilation. Vasodilation in the nasal mucous membrane elicits swelling associated with an increase in nasal resistance. Thus, a supine body position during sleep is disadvantageous for nasal breathing.

The divergent GG motor units with different responses to changes in head/body position [41] may counteract encroachment of the nasal pathway. The divergence of the GG motor units in relation to respiration were further investigated and classified into six types: inspiratory phasic, inspiratory tonic, expiratory phasic, expiratory tonic, tonic, and tonic other [43]. Different types of GG respiratory-related motor units show individual responses to chemical stimulation (i.e., hypercapnia) [44], and an increase in GG muscle activity in response to hypercapnia in healthy subjects is established by recruitment of previously inactive inspiratory modulated units [45]. Although GG EMG shows an increase in response to negative pressure in healthy adults [46], aging has a significant effect on activation of the GG muscle in response to chemical stimuli in healthy populations. Awake GG EMG activity was recorded under different oxygen saturations using rebreathing conditions in two groups of subjects: one was 20—40 years of age, and the other was 41—60 years of age [47]. As the percentage of oxygen saturation decreased, the GG EMG activity relative to the resting condition increased in both age groups. However, the increment in the older group was less than that in the younger group (Fig. 5). The age-related increase in UA collapsibility in healthy subjects was further confirmed using pneumotachography [48]. Thus, it appears that the biological mechanism to maintain UA patency is impaired with aging and predisposes elderly individuals to pharyngeal collapse.

3.2. Activity during sleep

Although most individuals usually sleep in the supine body position, the resistance of the nasal pathway changes in association with positional changes of the body. An increase in nasal resistance may trigger oral breathing. Indeed, oral breathing during sleep significantly increased the phasic EMG activity of the GG muscle and collapsibility of the UA [49]. This may be interpreted as follows: impairment of the nasal pathway forces oral breathing that is associated with increased negative pressure and induces augmented GG EMG activity. Thus, it is assumed that oral breathing modifies the normal mechanism for UA patency, and nasal breathing during sleep is not preferable from a physiological viewpoint.

Significant changes in oropharyngeal configuration occur during sleep. A cephalometric study performed during stage 1—2 sleep revealed significant changes compared with the awake state: the mandible rotated clockwise, the hyoid bone moved downward toward the thorax, the anteroposterior UA dimension decreased, and the cervical bone was displaced anteriorly toward the chin [50]. The posture of the mandible periodically changes according to the sleep stage across

stages 1—4 non-REM sleep to REM sleep in healthy subjects. As the sleep stage deepens from stages 1—2 to stages 3—4 and REM sleep, the amount of jaw opening increases [51]. Because the tongue position is reflexively controlled by muscle-spindle afferents in the temporal muscle, which determines the mandibular posture [52], jaw opening during sleep may induce GG EMG activity and protrude the tongue in healthy subjects. This reflexive protrusion of the tongue is reinforced by the negative pressure-driven increase in GG EMG activity [53].

4. Pathological GG muscle and tongue function in subjects with OSA

4.1. Activity while awake

It is known that the GG muscle in subjects with OSA is significantly augmented compared with that in subjects without OSA, while there are no significant differences in GG EMG activity during tongue protrusion, inspiratory effort, or swallowing [54] (Fig. 6). Fogel et al. also confirmed that GG EMG activity was greater in subjects with OSA in terms of tonic, phasic, and peak phasic activities [55]. In addition, they found that subjects with OSA generated a greater peak epiglottic pressure on a breath-by-breath basis. Although the relationship between GG EMG activity and epiglottic negative pressure was tight across all conditions in the OSA and control groups, there were no significant differences in the slope of this relationship between the two groups under any condition. Thus, it was concluded that the increased GG EMG activity seen in subjects with OSA during wakefulness appears to be a product of increased tonic activation of the muscle combined with increased negative pressure generation during inspiration [46]. The response of the GG muscle to chemical stimuli differs between subjects

with and without OSA. Kimura et al. investigated whether selective depression of GG EMG activity could be associated with hypoxic ventilatory depression, which develops in the late phase of the biphasic ventilatory response during sustained hypoxia, and suggested that a lack of compensatory response of the GG muscle to sustained hypoxia may be responsible for the pathogenesis of OSA [56].

In terms of identification of the properties of single GG motor units in subjects with OSA, a neurophysiological study was performed to test the hypothesis that the firing rate would be higher in subjects with OSA and that unit types with an inspiratory firing pattern would occur more frequently [57]. The investigators found that there were six types of GG respiratory motor units in subjects with OSA, as in the controls [43]. Inspiratory units were recruited earlier in OSA than in control subjects (Fig. 7). In control subjects, inspiratory tonic units peaked earlier than did inspiratory phasic units, while in OSA subjects, inspiratory tonic and phasic units peaked simultaneously. Onset frequencies did not differ between groups, but the peak discharge frequency for inspiratory phasic units was higher in OSA than in control subjects. Conversely, the peak discharge frequency of inspiratory tonic units was higher in control subjects. Based on these findings, they concluded that the differences in the timing and firing frequency of the inspiratory classes of GG motor units indicate that the output of the hypoglossal nucleus may have changed.

4.2. Activity during sleep

During the period of sleep onset, GG EMG activity declines in both subjects with and without OSA, but more so in subjects with OSA [58,59]. This suggests that compensatory reflex mechanisms are impaired during the transition period from wakefulness to sleep. It is widely known that a fall in arterial

Figure 6 Maneuvers to define maximum genioglossus (GG) electromyographic (EMG) activity [54]. Representative raw data from one patient with apnea (upper panels) and one normal control (lower panels) demonstrating the maneuvers used to determine maximal GG EMG activity in all subjects and patients. Each individual has his own scale of EMG activity (from electrical 0% to 100%). In addition, this figure demonstrates that basal EMG activity was a much greater percentage of the maximum in the patient with apnea than in the control.

Figure 7 Time and frequency plots of firing of single motor units in the human genioglossus (GG) muscle in control subjects and subjects with obstructive sleep apnea (OSA) during quiet breathing [57]. The motor units were sampled during the respiratory cycle, and their discharge times were normalized to inspiratory time (0—100% horizontal axis label). (A) Firing time for control subjects (n = 79 single motor units). (B) Firing time for each single motor unit for the GG muscle in subjects with OSA (n = 99 units). The darkest vertical lines in each panel represent the onset (0%) and end (100%) of inspiration measured from the flow signal. For units that discharged throughout both phases of the respiratory cycle, a continuous horizontal line indicates tonic firing. The time of the peak firing frequency is indicated by a black circle, and the mean peak frequency is indicated by the color of the thick horizontal line. The firing frequencies corresponding to each color are shown in the inset. The initial and final frequencies are represented by colored circles. The units are ordered within each category (phasic or tonic) according to their onset discharge time. The percentages for each type of unit were similar between the control and OSA subjects, and the onset time of inspiratory phasic and inspiratory tonic units was earlier in the OSA subjects.

oxygen saturation is more severe and that apneic events are more common during REM sleep than during non-REM sleep [60,61]. In a comparative study to clarify the differential effect of REM and non-REM sleep in subjects with OSA, it was demonstrated that GG EMG activity gradually increased in

the late apneic phase, peaked at the opening of the UA, then gradually decreased. There were no significant differences in GG EMG activity in either the ventilatory or the early apneic phases between non-REM sleep and REM sleep. On the other hand, GG EMG activity in the late apneic phase during REM

Figure 8 A series of obstructive hypopneas characterized by flow limitation on the nasal pressure tracing [63]. Genioglossus (GG) electromyographic (EMG) activity is minimal during obstructive breaths and increases markedly upon apnea termination.

sleep was significantly lower than that during non-REM sleep. They suggested that activation of the GG muscle in the later apneic phase during REM sleep was inhibited compared with that during non-REM sleep [62]. Another study reported that reduction in GG EMG activity is temporally associated with sleep apnea events and that REM sleep is associated with the lowest and most variable GG EMG activity [63] (Fig. 8).

Adachi et al. performed overnight monitoring to evaluate GG EMG activity during non-REM sleep [64]. The duration of inspiratory GG EMG activity, the total GG activity cycle, the duration of inspiration, and the duration of one total respiratory cycle were shorter in subjects with OSA. The commencement time lag between inspiratory GG EMG activity and the onset of inspiration was shorter in subjects with OSA during non-apneic breathing, which indicates that inspiratory GG EMG activity was activated relatively later in these patients. Furthermore, the inspira-tory GG EMG activity occurred after inspiration during apnea, but the timing of GG activity onset progressively advanced during the apnea. Earlier GG reactivation occurred before inspiration during the first non-occluded breath at the end of apnea. During subsequent tidal breathing, the timing of the GG onset progressively decreased after the onset of inspiration until the next episode of obstructive apnea occurred. Their observation suggests that the timing between GG inspiratory activity and inspiratory effort is of physiologic importance in the pathogenesis of OSA. Indeed, one of the oral appliances [65 that ameliorates the symptoms of OSA, the tongue-retaining device, was found to effectively reduce OSA severity, normalize the time lag, and counteract fluctuating GG EMG activity in subjects with OSA [66]. Interestingly, abnormal GG function is also normalized after treatment with continuous positive airway pressure [67].

5. Conclusions

The GG muscle, one of the UA dilating muscles, clearly plays an important role in physiological maintenance of UA patency and pathophysiology of sleep-disordered breathing conditions, including OSA. Much effort has been devoted to investigation of the biological background of UA dysfunction through an understanding of the functional properties of the GG muscle and its motor units in subjects with and without OSA. However, the options for prevention and the treatment strategy for OSA are still poorly developed. Continuous positive airway pressure is the golden standard for all levels of OSA, and the oral appliance is the only predictably effective alternative for mild to moderate OSA. Because OSA has a significant impact on quality of life through structural changes in the brain [68], it is important to establish an effective means for prevention and treatment of OSA.

Role of the funding source

The authors declare no funding for this study. Conflict of interest statement

The authors declare no conflicts of interest.

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