Genioglossus Activity Research Articles

Differential neuromotor control of the vertical and longitudinal genioglossus muscle fibers: An overlooked tongue retractor

IntroductionThe genioglossus (GG) is known to be the main tongue protrusor, and therefore plays a major role in breathing. However, due to the fan shape of the GG fibers, it could be assumed that contraction of the anterior fibers of the GG do not cause tongue protrusion. In this study, we examined the effect of contraction of the anterior-vertical fibers of the GG (GGV) on the tongue and their EMG activity during wakefulness and sleep. The findings were compared to those of the longitudinal fibers (GGL), which, based on their orientation, are responsible for tongue protrusion. MethodsFine-wire electrode pairs were placed into the GGV and GGL in 11 patients with untreated OSA. Movement of the tongue during electrical stimulation at each site was videoed. The same electrodes were used to record EMG from both sites during respiratory stimulation by inspiratory loading and CO2 rebreathing during wakefulness. During sleep, repetitive flow limitation events were induced with low-level CPAP to augment GG activity. ResultsIn all participants, electrical stimulation of GGL and GGV protruded and retracted the tongue, respectively. Respiratory stimulation increased GG activity, but GGV reached only 39 % and 23 % of peak GGL activity during high resistive loading and PCO2 of 65 mmHg, respectively. Flow limitation during sleep increased GGL to levels that were considerably higher than awake baseline, but GGV activity remained tonic or with minimal phasic activity, reaching on average 15 % of GGL peak activity. ConclusionsOur electrical stimulation findings indicate that GGV is a tongue retractor and depressor. Tongue stimulation for OSA should avoid this area. The EMG results demonstrate that the anterior part of the GG is controlled very differently from the longitudinal protrusive fibers. The GGV responses are similar to those previously found in tongue retractors and peri-pharyngeal muscles other than the GG, in which diminished activation during sleep is likely to be involved in the failure of increasing GGL activity to alleviate flow limitation.

A Novel Design of an Oral Appliance for Monitoring Electromyograms of the Genioglossus Muscle in Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea (OSA) is a prevalent source of sleep-disordered breathing. OSA is most commonly associated with dysfunctions in the genioglossus (GG) muscle. In this study, we present the first version of a medical device that produces an electromyogram (EMG) of the GG. The prototype is composed of a (custom-made) 3D-printed mouthpiece. Impressions were taken for the lower arch and scanned with a lab scanner to be converted into digital impressions. ExoCad software was used to design the appliance. Fusion 360 software was then used to modify the design and create tubes to house the electrodes in a bilateral configuration to secure excellent and continuous contact with the GG muscle. Silver-silver chloride electrodes were incorporated within the appliance through the created tubes to produce a muscle EMG. In this preliminary prototype, an EMG amplifier was placed outside the mouth, and isolated electric wires were connected to the amplifier input. To test the design, we ran experiments to acquire EMG signals from a group of OSA patients and a control group in wakefulness. The GG EMGs were acquired from the participants for 60 s in a resting state whereby they rested their tongues without performing any movement. Then, the subjects pushed their tongues against the fontal teeth with steady force while keeping the mouth closed (active state). Several features were extracted from the acquired EMGs, and statistical tests were applied to evaluate the significant differences in these features between the two groups. The results showed that the mean power and standard deviation were higher in the control group than in the OSA group (p < 0.01). Regarding the wavelength during the active state, the control group had a significantly longer wavelength than the OSA group (p < 0.01). Meanwhile, the mean frequency was higher in the OSA group (p < 0.01) at rest. These findings support research that showed that impairment in GG activity continues in the daytime and does not only occur during sleep. Future research should focus on developing the device to be more user-friendly and easily used at home during wakefulness and sleep.

The effects of simulated gastroesophageal reflux on infant pig oropharyngeal feeding physiology.

The neural connectivity among the oral cavity, pharynx, and esophagus is a critical component of infant feeding physiology. Central integration of oral and pharyngeal afferents alters motor outputs to structures that power swallowing, but the potential effects of esophageal afferents on preesophageal feeding physiology are unclear. These effects may explain the prevalence of oropharyngeal dysphagia in infants suffering from gastroesophageal reflux (GER), though the mechanism underlying this relationship remains unknown. Here we use the validated infant pig model to assess the impacts of simulated GER on preesophageal feeding parameters. We used high-speed videofluoroscopy and electromyography to record bottle-feeding before and following the infusion of a capsaicin-containing solution into the lower esophagus. Sucking parameters were minimally affected by capsaicin exposure, such that genioglossus activity was unchanged and tongue kinematics were largely unaffected. Aspects of the pharyngeal swallow were altered with simulated GER, including increased thyrohyoid muscle activity, increased excursions of the hyoid and thyroid per swallow, decreased swallow frequency, and increased bolus sizes. These results suggest that esophageal afferents can elicit changes in pharyngeal swallowing. In addition, decreased swallowing frequency may be the mechanism by which esophageal pathologies induce oropharyngeal dysphagia. Although recent work indicates that oral or pharyngeal capsaicin may improve dysphagia symptoms, the decreased performance following esophageal capsaicin exposure highlights the importance of designing sensory interventions based upon neurophysiology and the mechanisms underlying disordered feeding. This mechanistic approach requires comprehensive data collection across the entirety of the feeding process, which can be achieved using models such as the infant pig.NEW & NOTEWORTHY Simulated gastroesophageal reflux (GER) in an infant pig model resulted in significant changes in pharyngeal swallowing, which suggests that esophageal afferents are centrally integrated to alter motor outputs to the pharynx. In addition, decreased swallow frequency and increased bolus sizes may be underlying mechanisms by which esophageal pathologies induce oropharyngeal dysphagia. The infant pig model used here allows for a mechanistic approach, which can facilitate the design of intervention strategies based on neurophysiology.

Interaction between Kölliker-Fuse/A7 and the parafacial respiratory region on the control of respiratory regulation

Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GGEMG). Blockade of the α1 adrenergic receptors (α1-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GGEMG without affecting inspiratory cessation. In contrast, blockade of α2-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GGEMG activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α1 and α2 adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.

Regional associations between inspiratory tongue dilatory movement and genioglossus activity during wakefulness in people with obstructive sleep apnoea.

Inspiratory tongue dilatory movement is believed to be mediated via changes in neural drive to genioglossus. However, this has not been studied during quiet breathing in humans. Therefore, this study investigated this relationship and its potential role in obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue dilatory movement, quantified with tagged magnetic resonance imaging, and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in nine controls [apnoea-hypopnea index (AHI) ≤5 events/h] and 37 people with untreated OSA (AHI >5 events/h). Measurements were obtained for 156 neuromuscular compartments (85%). Analysis was adjusted for nadir epiglottic pressure during inspiration. Only for 106 compartments (68%) was a larger anterior (dilatory) movement associated with a higher phasic EMG [mixed linear regression, beta=0.089, 95% CI [0.000, 0.178], t(99)=1.995, P=0.049, hereafter EMG↗/mvt↗]. For the remaining 50 (32%) compartments, a larger dilatory movement was associated with a lower phasic EMG [mixed linear regression, beta=-0.123, 95% CI [-0.224, -0.022], t(43)=-2.458, P=0.018, hereafter EMG↘/mvt↗]. OSA participants had a higher odds of having at least one decoupled EMG↘/mvt↗ compartment (binary logistic regression, odds ratio [95% CI]: 7.53 [1.19, 47.47] (P=0.032). Dilatory tongue movement was minimal (>1 mm) in nearly all participants with only EMG↗/mvt↗ compartments (86%, 18/21). These results demonstrate that upper airway dilatory mechanics cannot be predicted from genioglossus EMG, particularly in people with OSA. Tongue movement associated with minimal genioglossus activity suggests co-activation of other airway dilator muscles. KEY POINTS: Inspiratory tongue movement is thought to be mediated through changes in genioglossus activity. However, it is unknown if this relationship is altered by obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue movement, quantified with tagged magnetic resonance imaging (MRI), and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in four tongue compartments of people with and without OSA. Larger tongue anterior (dilatory) movement was associated with higher phasic genioglossus EMG for 68% of compartments. OSA participants had an ∼7-times higher odds of having at least one compartment for which a larger anterior tongue movement was not associated with a higher phasic EMG than controls. Therefore, higher genioglossus phasic EMG does not consistently translate into tongue dilatory movement, particularly in people with OSA. Large dilatory tongue movements can occur despite minimal genioglossus inspiratory activity, suggesting co-activation of other pharyngeal muscles.

P039 Genioglossus motor control during mandibular advancement.

Abstract Introduction High genioglossus muscle activity is thought to prevent/resolve upper airway collapse. Overall genioglossal activity results from the simultaneous firing of many motor units (MUs) which typically have one of 5 firing patterns: active only (IP) or at higher frequency (IT) during inspiration; active only (EP) or at higher frequency during expiration (ET); and constantly active without respiratory modulation (TT). To date, most experimental manipulations tested (e.g. hypoxia, hypercapnia, resistive loading) have influenced IP and IT MUs, with minimal changes in ET, EP and TT MUs. We hypothesized that IT/IP MUs respond to respiratory drive, whereas TT/EP/ET MUs will change in response to airway anatomical manipulations. Methods The number and firing frequencies of genioglossal MUs were assessed with intramuscular electrodes in healthy individuals during wakefulness, before and during mandibular advancement (MAD) to 80% of maximum with an myTAP device, to change airway anatomy but minimally alter respiratory drive. Results 201 MUs were identified from 55 trials in 14 participants. Ventilation did not differ between baseline and MAD. At baseline, 175 MUs were active: EP=0.6%, ET=12.6%, IP=14.9%, IT=48%, TT=24%. During MAD, 35 MUs ceased firing, but an additional 26 MUs began firing, with the resulting MUs proportions not differing from baseline: EP=0%, ET=10.2%, IP=21.1%, IT=36.7%, TT=31.9%, χ2(9)=12.0, p=.213. The mean firing frequency of MUs did not change during MAD (baseline=20.9±4.7Hz, MAD=21.9±5.4Hz). Discussion Contrary to the hypothesis, the firing patterns of genioglossal MUs did not differ from baseline during mandibular advancement. What controls the non-respiratory/expiratory MUs of the genioglossus remains unclear.

Characteristics of genioglossus neuromuscular activity in patients with obstructive sleep apnea during drug-induced sleep

Objective: To analyze genioglossus (GG) activation responses to the negative pressure of upper airway cavity during awake and different sleep stages in patients with different obstructive sleep apnea (OSA) graduation. Methods: This prospective cohort study started from August 2019 to January 2021, recruited 42 male OSA patients aged from 21 to 59 (38.77±8.42) years. After completing whole night polysomnography (PSG) and upper airway CT, each subject underwent drug-induced sleep with simultaneous monitoring of genioglossal electromyography (GGEMG) and pressure of epiglottis (Pepi). Subjects were divided into three groups of mild OSA(7 males), moderate OSA(12 males), and severe OSA(23 males). The differences in upper airway CT measurements, parameters of GGEMG and Pepi during awake and induced sleep were compared. Statistical analysis was conducted by SPSS 21.0. Results: There was no significant difference in the GGEMG parameters between the mild and moderate groups. In wakefulness, the peak phasic GGEMG of the severe group was higher than the mild group (t=1.249, P=0.025), with no statistically difference in the corresponding Pepi. In the sleep onset, the GGEMG parameters and Pepi in severe group were higher than the other two groups. Linear regression analysis of the maximum GGEMG and maximum Pepi at the end of obstructive apnea (OA) in all moderate plus severe patients (n=35) was shown nonlinear correlation (r=0.28, P=0.694). The airway length of the glossopharyngeal cavity was linearly correlated with the maximum Pepi of OA (r=0.468, R2=0.219, P=0.005). Conclusions: The individual difference of GG activation in OSA patients is related to the severity of the disease (frequency of respiratory events) and negative pressure stimulation. In moderate and severe OSA patients, GG activity is not in harmony with the corresponding negative pressure stimulation, which may be one of the mechanisms leading to the aggravation of OSA.

Difference in the Electromyographic Behavior of the Masticatory and Swallowing Muscles During Cued Versus Spontaneous Swallowing

The risk of dysphagia and/or aspiration is determined using screening tests, such as the repeated saliva swallowing test and modified water swallowing test, which evaluate cued swallowing. However, humans masticate and swallow foods with various consistencies, forms, and amounts, without conscious awareness. Therefore, this study aimed to examine the difference in the behavior of masticatory and swallowing muscles during spontaneous versus cued swallowing through a series of mastication and swallowing processes by evaluating surface electromyogram (sEMG) signals. The effect of the consistency and amount of food on the behavior of these muscles was also investigated. The sEMG recordings of the masseter muscles and anterior belly of the digastric muscle for 12 subjects, and genioglossus muscle for 5 subjects were obtained. The genioglossus activity was recorded using custom-made ball electrodes. The test foods were cookies and tofu, in amounts of 2 g and 4 g. The normalized muscle activity (integrated EMG), duration of the muscle activity, initial activation timepoint of each muscle, and total duration of swallowing were compared among four conditions. The activity of each muscle was significantly higher during the swallowing of cookies than tofu, for 4 g vs 2 g, and for cued versus spontaneous swallowing. The duration of each muscle activity, initial activation timepoint, and total duration of swallowing were significantly longer for cookies versus tofu, for 4 g vs 2 g, and for spontaneous versus cued swallowing. These results suggest that the behavior of the masticatory and swallowing muscles is affected by cued swallowing and by the consistency and amount of food.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, βdrive:βpressure; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half (n = 22 of 42) exhibited drive-dominant responses (i.e., βdrive:βpressure > 2:1), and one-quarter (n = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., βdrive:βpressure < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] %baseline/standard deviation of βdrive:βpressure; P = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Anatomical Basis of Obstructive Sleep Apnoea: A Review of Randomized Controlled Trials.

Repeated obstruction and closure of the upper airway, sporadic hypoxic episodes, and sympathetic activity are symptoms of obstructive sleep apnea (OSA). Obstructive sleep apnoea is due to a combination of altered upper airway structure and muscular function, a low arousal threshold and increased loop gain.Although recurrent upper airway (UA) collapse during sleep is the most frequent clinical hallmark of OSA, the exact cause of this collapse is unknown. Furthermore, while continuous positive airway pressure aids in the management of OSA, many patients find it intolerable. As a result, a better knowledge of the causes of OSA may result in more effective treatments. We did a review of randomized controlled trials that were done in this regard in the last 10 years and whose full-text version is available on the PubMed database. A total of 20 articles were finalized for review after applying our criteria. The articles have proposed different theories regarding the anatomical basis responsible for obstructive sleep apnoea. The theories proposed by different studies in the last decade include reduced genioglossus and hypoglossal nerve activity, the pharyngeal muscles' failure to keep the airway open or tighten it, tonsils and adenoid hypertrophy, an oversensitive ventilatory control system and low respiratory arousal threshold, mandibular position, pharyngeal muscles' high sympathetic drive, cephalometric alterations such as mandibular and hyoid bone position and the length of the soft palate, obesity, and neck fat and fluid re-distribution in the body, from the lower to the upper parts while reclining. Given the diverse etiological characteristics of OSA patients and to increase our knowledge of the condition, additional study into this group is required. Filling any knowledge gaps that may exist in the anatomical basis of the onset of OSA is the main objective of this review paper.

Mechanisms underlying the prolonged activation of the genioglossus following arousal from sleep.

Transient arousal from sleep has been shown to elicit a prolonged increase in genioglossus muscle activity that persists following the return to sleep and which may protect against subsequent airway collapse. We hypothesized that this increased genioglossal activity following return to sleep after an arousal is due to persistent firing of inspiratory-modulated motor units (MUs) that are recruited during the arousal. Thirty-four healthy participants were studied overnight while wearing a nasal mask with pneumotachograph to measure ventilation and with 4 intramuscular genioglossus EMG electrodes. During stable N2 and N3 sleep, auditory tones were played to induce brief (3-15s) AASM arousals. Ventilation and genioglossus MUs were quantified before the tone, during the arousal and for 10 breaths after the return to sleep. A total of 1089 auditory tones were played and gave rise to 239 MUs recorded across arousal and the return to sleep in 20 participants (aged 23 ± 4.2 years and BMI 22.5 ± 2.2 kg/m2). Ventilation was elevated above baseline during arousal and the first post-arousal breath (p < .001). Genioglossal activity was elevated for five breaths following the return to sleep, due to increased firing rate and recruitment of inspiratory modulated MUs, as well as a small increase in tonic MU firing frequency. The sustained increase in genioglossal activity that occurs on return to sleep after arousal is primarily a result of persistent activity of inspiratory-modulated MUs, with a slight contribution from tonic units. Harnessing genioglossal activation following arousal may potentially be useful for preventing obstructive respiratory events.

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility.

The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes. Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per VMIN and arousal threshold) were derived from validated algorithms. Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p=0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p=0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p=0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p=0.093). Ato-Feso lowered collapsibility (raised VMIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %VEUPNOEA , mean [CI], p=0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %VEUPNOEA , p=0.038). In post hoc analysis, 6/6 patients with milder collapsibility (VMIN > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia. While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals.

The impact of daytime transoral neuromuscular stimulation on upper airway physiology - A mechanistic clinical investigation.

There is a need for alternatives to positive airway pressure for the treatment of obstructive sleep apnea and snoring. Improving upper airway dilator function might alleviate upper airway obstruction. We hypothesized that transoral neuromuscular stimulation would reduce upper airway collapse in concert with improvement in genioglossal muscle function. Subjects with simple snoring and mild OSA (AHI < 15/h on screening) underwent in‐laboratory polysomnography with concurrent genioglossal electromyography (EMGgg) before and after 4–6 weeks of twice‐daily transoral neuromuscular stimulation. Twenty patients completed the study: Sixteen males, mean ± SD age 40 ± 13 years, and BMI 26.3 ± 3.8 kg/m2. Although there was no change in non‐rapid eye movement EMGgg phasic (p = 0.66) or tonic activity (p = 0.83), and no decrease in snoring or flow limitation, treatment was associated with improvements in tongue endurance, sleep quality, and sleep efficiency. In this protocol, transoral neurostimulation did not result in changes in genioglossal activity or upper airway collapse, but other beneficial effects were noted suggesting a need for additional mechanistic investigation.

Systemic Administration of Tempol, a Superoxide Dismutase Mimetic, Augments Upper Airway Muscle Activity in Obese Zucker Rats.

Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMGGG) and diaphragmatic (EMGDIA) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1–100 mg/kg) increased EMGGG without changing EMGDIA in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1–25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMGGG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMGGG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMGGG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.

High-Fat Diet-Induced Mitochondrial Dysfunction Promotes Genioglossus Injury - A Potential Mechanism for Obstructive Sleep Apnea with Obesity.

PurposeObesity is a worldwide metabolic disease and a critical risk factor for several chronic conditions. Obstructive sleep apnea (OSA) is an important complication of obesity. With the soaring morbidity of obesity, the prevalence of OSA has markedly increased. However, the underlying mechanism of the high relevance between obesity and OSA has not been elucidated. This study investigated the effects of obesity on the structure and function of the genioglossus to explore the possible mechanisms involved in OSA combined with obesity.MethodsSix-week-old male C57BL/6J mice were fed high-fat diet (HFD, 60% energy) or normal diet (Control, 10% energy) for 16 weeks. The muscle fibre structure and electromyography (EMG) activity of genioglossus were measured. The ultrastructure and function of mitochondrial, oxidative damage and apoptosis in genioglossus were detected by transmission electron microscopy (TEM), qPCR, Western blotting, immunohistochemistry and TUNEL staining. We further studied the influence of palmitic acid (PA) on the proliferation and myogenic differentiation of C2C12 myoblasts, as well as mitochondrial function, oxidative stress, and apoptosis in C2C12 myotubes.ResultsCompared with the control, the number of muscle fibres was decreased, the fibre type was remarkably changed, and the EMG activity had declined in genioglossus. In addition, a HFD also reduced mitochondria quantity and function, induced excessive oxidative stress and increased apoptosis in genioglossus. In vitro, PA treatment significantly inhibited the proliferation and myogenic differentiation of C2C12 myoblasts. Moreover, PA decreased the mitochondrial membrane potential, upregulated mitochondrial reactive oxygen species (ROS) levels, and activated the mitochondrial-related apoptotic pathway in myotubes.ConclusionOur findings suggest that a HFD caused genioglossus injury in obese mice. The mitochondrial dysfunction and the accompanying oxidative stress were involved in the genioglossus injury, which may provide potential therapeutic targets for OSA with obesity.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

O037 Genioglossus motor control following the return to sleep after brief arousal

Abstract Rationale Arousal from sleep has been shown to elicit a prolonged increase in genioglossus muscle activity that persists following the return to sleep and may protect against airway collapse. We hypothesised that this increased genioglossal activity following return to sleep after an arousal is due to persistent firing of inspiratory single motor units (SMUs) recruited during the arousal. Methods 34 healthy participants were studied overnight while wearing a nasal mask/pneumotachograph to measure ventilation and with 4 intramuscular genioglossus SMU electrodes. During stable N2 and N3 sleep, auditory tones were played to induce brief (3-15s) AASM arousals. Ventilation and genioglossus SMUs were quantified for 5 breaths before the tone, during the arousal and for 10 breaths after the return to sleep. Results A total of 1089 tones were played and gave rise to 236 SMUs recorded across arousal and the return to sleep in 20 participants (age 23±4.2 years and BMI 22.5±2.2kg/m2). Ventilation was elevated above baseline during arousal and the first post-arousal breath (p&amp;lt;0.001). The peak firing frequency of expiratory and tonic SMUs was unchanged during arousal and return to sleep, whereas inspiratory modulated SMUs were increased during the arousal and for 4 breaths following the return to sleep (p&amp;lt;0.001). Conclusions The prolonged increase in genioglossus activity that occurs on return to sleep after arousal is a result of persistent activity of inspiratory SMUs. Strategies to elevate inspiratory genioglossus SMU activity may be beneficial in preventing/treating obstructive sleep apnea.

P005 The effect of alcohol on the motor control of the genioglossus muscle

Abstract Rationale Alcohol is recognised to worsen snoring and obstructive sleep apnea (OSA). This effect is thought to be due to alcohol’s depressant effect on upper airway dilator muscles such as the genioglossus, but how alcohol reduces genioglossus activity is unknown. The aim of this study was to investigate alcohol’s effect on genioglossus single motor units (SMUs). Methods Healthy individuals visited the lab on two days (Alcohol: breath alcohol concentration ~0.08% or Placebo). They were instrumented with a nasal mask, 4 intramuscular genioglossus SMU EMG wires and an ear oximeter. They were exposed to 8–12 hypoxia trials (45-60s of 10%O2 followed by one breath of 100%O2) while awake. The SMUs were sorted according to their firing patterns with respect to respiration and were quantified during baseline, hypoxia, hyperoxia and recovery. Results The total number of SMUs recorded at baseline (68 and 67 respectively) and their distribution (ET: 29 vs 22, IP: 5 vs 10, IT: 8 vs 20 and TT: 26 vs 15 respectively) was similar between conditions. The discharge frequency did not differ between conditions (21Hz vs 22.4Hz, p&amp;gt;0.08). There was no difference between placebo and alcohol in the number (101 vs 88 respectively) and distribution (ET: 35 vs 32, IP: 22 vs 16, IT: 14 vs 22 and TT: 30 vs 17 respectively, p&amp;lt;0.05) of SMUs during hypoxia. Afterdischarge following hypoxia was also not different between conditions. Conclusion Alcohol has little effect on genioglossus SMUs and afterdischarge. OSA following alcohol may be related to increased upper airway resistance/nasal congestion.

DREADD Activation of Leptin Receptor Positive Neurons in The Nucleus of the Solitary Tract During Obstructive Sleep Apnea in Obese Mice

Introduction Obstructive sleep apnea (OSA) is periodic obstruction of the upper airway during sleep leading to intermittent hypoxemia, hypercapnia, and sleep fragmentation. OSA is highly prevalent, particularly in obesity. It leads to high neurocognitive and cardiovascular morbidity and mortality. The mechanisms alleviating OSA remain unknown. Previous studies have documented the role of leptin, an adipose tissue produced hormone, as a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected widely in the brain, especially in cell bodies within the nucleus of the solitary tract (NTS), an important region of the brainstem that processes afferent visceral information and controls breathing. We hypothesized that leptin acts on LepRb+ neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. Methods We selectively expressed AAV8-hSyn-hM3(Gq)-mCherry into the NTS in LepRb-Cre-GFP diet-induced obese (DIO) mice (fed with a high-fat diet for 12 weeks) and examined the effect of DREADD ligand, J60, on genioglossus activity and breathing during sleep. Results J60 did not stimulate breathing or upper airway in comparison with saline in obese mice during NREM and REM sleep. Conclusion We conclude that the mechanisms alleviating OSA in DIO mice are independent of LepRb+ neurons in the NTS.

Impact of histaminergic H3 receptor antagonist on hypoglossal nucleus in chronic intermittent hypoxia conditions

The hypoglossal nucleus (HN) controls the movement of the genioglossus (GG) muscle whose dysfunction leads to airway occlusion and occurrence of obstructive sleep apnea (OSA). Histamine produced by the tuberomammillary nucleus (TMN) has a potent excitatory action on GG muscle activity. The aim of the study was to investigate the role histaminergic neurons play in the regulation of the genioglossus. C57BL/6 mice were exposed to chronic intermittent hypoxia (CIH) for 3weeks to resemble OSA. The histamine H3 receptor (H3R) antagonist ciproxifan was applied to increase histamine in the brain. Histamine levels and GG activity were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and electromyogram (EMG) separately. Neuronal activity and repair ability of the HN and TMN and key proteins of histamine were analyzed by immunohistochemistry and western blots. Significant decline of histamine level and GG activity of the HN and TMN induced by CIH exposure could be ameliorated by ciproxifan. Application of ciproxifan could also partly reverse the decline of the histidine decarboxylase (HDC) by CIH. This investigation studied the impacts of ciproxifan on the HN and TMN in CIH conditions and revealed that the negative effects on the HN and TMN caused by CIH could be partly ameliorated by ciproxifan, which might open new perspectives for the development of pharmacological treatment for OSA.