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ABSTRACT Background Methods Results Conclusions Early treatment of mandibular advancement device (MAD) reverses the abnormal changes resulting from obstructive sleep apnoea (OSA), but the underlying mechanism is not clear. We analysed the changes of genioglossus function before and after MAD treatment in OSA rabbits and explored the mechanism of mitochondrial autophagy.Eighteen male New Zealand rabbits were randomised into three groups: the control group, Group OSA, and Group MAD. After successful modelling, all animals were induced sleep in supine positions for 4–6 h per day for 8 weeks. Cone beam computed tomography (CBCT) and polysomnography (PSG) were performed to record sleep conditions. The genioglossus contractile force and the levels of LC3‐I, LC3‐II, Beclin‐1, PINK1 and Parkin were detected in three groups. In vitro, C2C12 myoblast cells were cultured under normoxic or hypoxic conditions for 24 h, and then the changes in mitochondrial structure and accumulation of autolysosomes were detected by transmission electron microscopy (TEM).The contractile tension of the genioglossus in Group OSA was significantly lower than that in the control group. The ratio of LC3II/LC3I and the levels of Beclin‐1, PINK1 and Parkin were higher in Group OSA than that in the control group. And the abnormal changes were tended to be normal after MAD treatment. The mitochondrial structure was disrupted, and the number of autolysosomes increased in C2C12 after 24 h of hypoxia.MAD treatment in male rabbits may decrease the contractile tension of the genioglossus and increase the level of mitochondrial autophagy caused by OSA. And the mechanism of mitochondrial autophagy was mediated by the PINK1/Parkin pathway in male rabbits. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) patients often have dysphagia following surgical and/or chemoradiation treatment, which can lead to reduced quality of life. Some patients suffer from decreased tongue strength and mobility that may cause discomfort and difficulty with swallowing. Our group has developed a patented genioglossus muscle strength trainer (GMST) to increase tongue protrusive force that has been used in patients with sleep apnea. We hypothesized that the GMST device would increase tongue strength in the HNC population. Methods: We conducted an IRB approved, non-randomized, interventional clinical trial of HNC patients with dysphagia to determine the effect of GMST on tongue strength. Our secondary objective was to assess dysphagia quality of life, as determined by questionnaires. Genioglossus muscle strength measurements (measured in Newtons, N) and dysphagia quality of life scores (SWAL-QoL questionnaire) were obtained from enrolled patients at baseline and following 4 weeks of intervention. Treatment was at-home GMST exercise regimen 3 times daily, 5 days per week. Compliance was assessed via review of training logs. Two-sided paired t -tests at significance level α =.05 were performed to assess difference in mean GG muscle strength pre- and post-treatment. Results: Out of 10 patients initially enrolled, 7 patients completed the trial. Eighty-six percent were male and the average age was 60. About 5 patients had surgery plus adjuvant radiation and 2 patients had primary radiation. All patients had baseline dysphagia as determined by patient complaint and/or objective measurement (prior modified barium swallow). No adverse events were reported. We observed a statistically significant increase in genioglossus muscle strength (mean change: 4.0 N, 95% CI 1.1-6.9, P =.015) after 4 weeks of treatment. Patients reported reduced swallowing burden and feeling of stigma around eating based on SWAL-QoL results. Conclusions: Our data suggest that protrusive tongue-training exercises utilizing a novel tongue trainer device is well-tolerated and increases genioglossus muscle strength in treated HNC patients complaining of dysphagia. Patient-reported outcomes based on the SWAL-QoL survey indicate improvements in quality-of-life post-treatment, although our results are limited by small sample size. Larger studies are needed to see if this device could have clinically meaningful results for this difficult-to-treat patient population. [ABSTRACT FROM AUTHOR]

High activity of upper airway dilator muscles is thought to be critical in preventing sleep-related upper airway collapse. To date, most of the research regarding upper airway dilator muscles has focused on the genioglossus muscle, which protrudes the tongue and opens the retroglossal airway. However, collapse commonly occurs in the retropalatal region. We, therefore, aimed to examine the motor control of the palatoglossus muscle as well as investigate breathing route-related changes in genioglossus and palatoglossus motor units. Single motor unit recordings of the genioglossus and palatoglossus were made simultaneously in healthy individuals during wakefulness while breathing through the nose with the mouth closed (NMC), nose with mouth open (NMO), or orally (OMO). The palatoglossus was found to have all five motor unit firing patterns that have been observed in other upper airway dilator muscles, but during nasal breathing had a higher proportion of tonically active but inspiratory modulated motor units as compared with the genioglossus (67% vs. 30%). When still breathing nasally but with the mouth open, the units with an expiratory firing pattern in genioglossus, and all firing patterns in palatoglossus, increased their firing rates compared with nasal breathing with the mouth closed [genioglossus (GG): 17.8 ± 4.9 vs. 23.1 ± 4.8 Hz, palatoglossus (PG): 17.0 ± 4.0 vs. 19.3 ± 4.0 Hz]. Finally, oral breathing resulted in dramatic reductions in the number of palatoglossal motor units that were firing (35 units vs. 92 during nasal breathing). Palatoglossal activity may contribute importantly to airway collapsibility and may provide an alternate pathway for preventing sleep-related airway collapse. NEW & NOTEWORTHY: The firing patterns of motor units in the palatoglossus have until now not been investigated, and how they and motor units in the genioglossus change with breathing route alteration was not known. This study has shown that the palatoglossus contains motor units with all the firing patterns observed in the genioglossus but in different proportions. Furthermore, breathing route changes alter units with different firing patterns differentially in the two muscles. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a serious and potentially life‐threatening disease. Mandibular advancement device (MAD) has the characteristics of non‐invasive, comfortable, portable and low‐cost, making it the preferred treatment for mild‐to‐moderate OSAHS. Our previous studies found that abnormal contractility and fibre type distribution of the genioglossus could be caused by OSAHS. However, whether the mitochondria participate in these tissue changes is unclear. The effect of MAD treatment on the mitochondria of the genioglossus in OSAHS is also uncertain. Objective: To examine the morphology and function of mitochondria from the genioglossus in a rabbit model of obstructive sleep apnea–hypopnea syndrome (OSAHS), as well as these factors after insertion of a mandibular advancement device (MAD). Methods: Thirty male New Zealand white rabbits were randomised into three groups: control, OSAHS and MAD, with 10 rabbits in each group. Animals in Group OSAHS and Group MAD were induced to develop OSAHS by injection of gel into the submucosal muscular layer of the soft palate. The rabbits in Group MAD were fitted with a MAD. The animals in the control group were not treated. Further, polysomnography (PSG) and cone‐beam computed tomography (CBCT) scan were used to measure MAD effectiveness. CBCT of the upper airway and PSG suggested that MAD was effective. Rabbits in the three groups were induced to sleep for 4–6 h per day for eight consecutive weeks. The genioglossus was harvested and detected by optical microscopy and transmission electron microscopy. The mitochondrial membrane potential was determined by laser confocal microscopy and flow cytometry. Mitochondrial complex I and IV activities were detected by mitochondrial complex assay kits. Results: OSAHS‐like symptoms were induced successfully in Group OSAHS and rescued by MAD treatment. The relative values of the mitochondrial membrane potential, mitochondrial complex I activity and complex IV activity were significantly lower in Group OSAHS than in the control group; however, there was no significant difference between Group MAD and the control group. The OSAHS‐induced injury and the dysfunctional mitochondria of the genioglossus muscle were reduced by MAD treatment. Conclusion: Damaged mitochondrial structure and function were induced by OSAHS and could be attenuated by MAD treatment. [ABSTRACT FROM AUTHOR]

Difficulty relaxing the genioglossus muscle makes the evaluation of spontaneous activity problematic in patients with motor neuron disease (MND). We performed jitter analysis using conventional disposable concentric needle electrodes (CNEs) of the voluntarily activated genioglossus muscle in patients with and without MND to detect the denervation-reinnervation process. CNE jitter analysis was performed at the genioglossus muscle in 21 MND(+) patients and 22 MND(–) subjects. The jitter analysis was considered abnormal if the jitter values exceeded these limits for the mean consecutive difference (MCD) or the individual MCD in more than 10% of readings. Seventeen MND(+) patients (81%) had at least three abnormal individual jitter values whereas denervation findings were obtained in eleven of them during the needle electromyographic examination at genioglossus muscle. None of the MND(–) subjects showed CNE jitter abnormality. CNE jitter analysis of genioglossus muscle may provide an useful information that may be suggestive of a diagnosis of MND/ALS. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the correlation between median frequency (MF) as a measure of genioglossus (GG) fatigue and overnight repetitive respiratory events in male patients with severe obstructive sleep apnea (OSA). Methods: GG electromyography (EMG) data were collected synchronously with polysomnography (PSG). Overnight respiratory events were divided based on whether they occurred during the first or second halves of the total number of overnight respiratory events, and differences in MF in the respiratory phase were compared in the same segments. Events were then sampled in pairs to compare MF. The correlation between MF and the order of respiratory events, as well as interindividual differences, were analyzed. Results: Twenty-two male patients were enrolled in this study and 2210 respiratory events were recorded. Before and during respiratory events, MF decreased significantly in the second half, especially during the inspiratory phase (segments 1–4: P = 0.014, P < 0.001, P < 0.001, P < 0.001, respectively). This trend was observed in non-rapid eye movement sleep and lateral position, but not in rapid eye movement sleep or the supine position, and remained after pairing for duration, stage, and position. MF correlated negatively with the order of respiratory events during the inspiratory phase. The trend of decrease in MF only existed in patients with apnea–hypopnea index > 30 events/h. Conclusion: Overnight repetitive respiratory events were associated with increased GG fatigue, influenced by sleep stage and body position in male patients with severe OSA. GG fatigue depends on the order and frequency of respiratory events. [ABSTRACT FROM AUTHOR]

Objective: This study aims to develop a novel method to classify different genioglossus (GG) responses to upper airway (UA) negative pressure in obstructive sleep apnea (OSA) patients. Study Design: A single‐center, prospective, cohort study. Setting: Sleep Medical Center. Methods: Patients with OSA underwent drug‐induced sleep endoscopy with synchronous genioglossus electromyography (ggEMG) and UA pressure monitoring. In spontaneous obstructive apnea events, the value of epiglottis negative pressure at the end of inspiration (Pepi) and corresponding peak phasic ggEMG were recorded as pairing data for linear regression analysis to classify GG response modes: peak phasic ggEMG‐Pepi linear mode (P <.05) were classified as group 1; others (P ≥.05) were classified as group 2. Using nasopharyngeal tube (NPT) to reopen the palatopharyngeal cavity for comparing the improvement between the OSA patients with different GG response modes. Results: Sixty subjects were analyzed for GG response modes: 22 patients were in group 1 (r2 = 0.233‐0.867), and 38 patients were in group 2. The proportion of partial (63.16% vs 59.09%) or complete (36.84% vs 22.73%) collapse rate of the tongue base in group 2 was significantly higher (χ2 = 7.823, P =.020). The improvement of the apnea‐hypopnea index after NPT placement in group 2 was significantly lower than in group 1 (59.09% vs 31.58%, χ2 = 4.339, P =.037). Conclusion: This novel method is advantageous for distinguishing OSA patients with different GG response abilities to UA negative pressure, whose GG responses conforming to peak phasic ggEMG‐Pepi linear mode might be more suitable for palatopharyngeal surgery. [ABSTRACT FROM AUTHOR]

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

Obstructive Sleep Apnea (OSA) is exceedingly common but often under-treated. Continuous positive airway pressure (CPAP) has long been considered the gold standard of OSA therapy. Limitations to CPAP therapy include adherence and availability. The 2021 global CPAP shortage highlighted the need to tailor patient treatments beyond CPAP alone. Common CPAP alternative approaches include positional therapy, mandibular advancement devices, and upper airway surgery. Upper airway training consists of a variety of therapies, including exercise regimens, external neuromuscular electrical stimulation, and woodwind instruments. More invasive approaches include hypoglossal nerve stimulation devices. This review will focus on the approaches for modifying upper airway muscle behavior as a therapeutic modality in OSA. [ABSTRACT FROM AUTHOR]

Summary: Background: Hypoglossal nerve stimulation (HNS) for obstructive sleep apnoea (OSA) is a novel way to manage the condition. We hypothesised that in patients with OSA and limited adherence to continuous positive airway pressure (CPAP) therapy, domiciliary transcutaneous electrical stimulation (TESLA) would control sleep apnoea and provide health benefits. Methods: We undertook a single-centre, open-label, randomised, controlled phase III trial in patients with OSA (apnoea-hypopnoea-index [AHI] 5–35 h−1), a BMI of 18.5–32 kg∗m−2, and a documented lack of adherence to CPAP therapy (

Obstructive Sleep Apnea (OSA) is exceedingly common but often under-treated. Continuous positive airway pressure (CPAP) has long been considered the gold standard of OSA therapy. Limitations to CPAP therapy include adherence and availability. The 2021 global CPAP shortage highlighted the need to tailor patient treatments beyond CPAP alone. Common CPAP alternative approaches include positional therapy, mandibular advancement devices, and upper airway surgery. Upper airway training consists of a variety of therapies, including exercise regimens, external neuromuscular electrical stimulation, and woodwind instruments. More invasive approaches include hypoglossal nerve stimulation devices. This review will focus on the approaches for modifying upper airway muscle behavior as a therapeutic modality in OSA.

BACKGROUND: At present, the common treatment method for obstructive sleep apnea is mandibular advancement device. Scholars have reached a consensus that the abnormality of the genioglossus muscle can cause obstructive sleep apnea. However, insufficient attention has been paid to the mechanism that causes genioglossus muscle damage and dysfunction and the impact of relevant treatment methods on the genioglossus muscle. OBJECTIVE: To evaluate the effects of mandibular advancement device for obstructive sleep apnea on the genioglossus ultrastructure and explore whether oxidative stress pathway is the mechanism of obstructive sleep apnea causing skeletal muscle structure and function disorders. METHODS: Thirty rabbits were divided into three groups: control, obstructive sleep apnea, and mandibular advancement device groups. Rabbit models of obstructive sleep apnea were established in the latter two groups. Three days after modeling, all rabbits were induced to sleep in supine position. CT scans were performed to examine the changes in upper airway structure and polysomnography was used to monitor changes in blood oxygen saturation and respiratory sleep index. After 8 weeks, the ultrastructure of the genioglossus muscle was detected under transmission electron microscope. The level of malondialdehyde in the genioglossus muscle was measured by the thiobarbituric acid method, and the levels of 8-isoprostaglandin in the plasma and genioglossus muscle were measured by the enzyme-linked immunosorbent assay method. The level of glutathione and activities of catalase, total superoxide dismutase, copper-zinc superoxide dismutase, manganese superoxide dismutase, and succinate dehydrogenase were measured in strict accordance with the kit instructions. RESULTS AND CONCLUSION: The morphology and structure of genioglossus mitochondria were normal in the control group, and were seriously damaged in the obstructive sleep apnea group. Compared with the control group, the obstructive sleep apnea group had a higher level of 8-isoprostaglandin (P < 0.05); the level of malondialdehyde was increased significantly in the obstructive sleep apnea group compared with the other two groups (P < 0.05); the activities of total superoxide dismutase, copper-zinc superoxide dismutase and manganese superoxide dismutase decreased significantly in the obstructive sleep apnea group compared with the other two groups (P < 0.05); glutathione level and the activities of catalase and succinate dehydrogenase decreased significantly in the obstructive sleep apnea group compared with the control group (P < 0.05). However, there were no significant differeces between mandibular advancement device group and control group (P < 0.05). To conclude, obstructive sleep apnea -induced genioglossus mitochondria damage is related to oxidative stress. Mandibular advancement device can prevent or alleviate the damage of mitochondrial structure caused by obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

Current treatments for dysphagia in ALS do not target the underlying tongue weakness and denervation atrophy that is prevalent in spinal and bulbar ALS cases. To address this clinical gap, we studied the low copy number SOD1-G93A (LCN-SOD1) mouse model of ALS to quantify the impact of limb phenotype on tongue denervation atrophy, dysphagia penetrance, and survival time in preparation for future treatment-based studies. Two male LCN-SOD1 breeders and 125 offspring were followed for limb phenotype inheritance, of which 52 (30 LCN-SOD1 and 22 wild-type/WT, both sexes) underwent characterization of dysphagia penetrance (via videofluoroscopic swallow study; VFSS) and survival time at disease end-stage (15–20% body weight loss). From these, 16 mice (8/genotype) underwent postmortem histological analysis of the genioglossus for evidence of denervation atrophy. Results revealed that both breeders displayed a mixed (hindlimb and forelimb) ALS phenotype and sired equal proportions of hindlimb vs. mixed phenotype offspring. Dysphagia penetrance was complete for mixed (100%) versus incomplete for hindlimb (64%) phenotype mice; yet survival times were similar. Regardless of limb phenotype, LCN-SOD1 mice had significantly smaller genioglossus myofibers and more centralized myonuclei compared to WT mice (p < 0.05). These biomarkers of denervation atrophy were significantly correlated with VFSS metrics (lick and swallow rates, p < 0.05) but not survival time. In conclusion, both LCN-SOD1 phenotypes had significant tongue denervation atrophy, even hindlimb phenotype mice without dysphagia. This finding recapitulates human ALS, providing robust rationale for using this preclinical model to explore targeted treatments for tongue denervation atrophy and ensuing dysphagia. [ABSTRACT FROM AUTHOR]

Taltirelin is a stable, brain-penetrating thyrotropin-releasing hormone (TRH) analog with minimal endocrine activity and potential respiratory stimulant properties. Taltirelin's receptor target shows high differential expression at the hypoglossal motor nucleus, and local taltirelin microperfusion into the hypoglossal motor nucleus causes sustained tongue motor activation compared with the transient activating effects of TRH itself. Here, we performed a randomized, within-subject, repeated-measures design over six separate study days (separated by at least 72 h) in chronically instrumented male (n = 10) and female (n = 9) rats to identify effects on sleep and breathing. Vehicle controls or taltirelin (0.1 and 1 mg/kg) with and without trazodone (30 mg/kg) were administered by intraperitoneal injection. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. Systemically administered taltirelin (1 but not 0.1 mg/kg) increased tonic and within-breath phasic tonic muscle activity compared with vehicle controls (P ≤; 0.007), with little or no changes in diaphragm amplitude or respiratory rate. Taltirelin also suppressed nonrapid eye movement (non-REM) sleep and increased wakefulness (P ≤ 0.037). Other indices of taltirelin-induced central nervous system arousal included increased trapezius muscle tone in non-REM sleep and decreased total electroencephalogram power and δ (0.5-4 Hz) power (P ≤ 0.046). These effects were especially apparent in non-REM sleep and not prevented by trazodone. These preclinical findings identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties, traits that have potential favorable relevance to some respiratory disorders but not others. NEW & NOTEWORTHY One of the major goals for translational sleep science and medicine is to identify viable and tractable pharmacological targets for obstructive sleep apnea and other respiratory disorders of sleep or sedation. In the present preclinical study in rats, we performed a randomized, within-subject, repeated-measures design over six intervention study days in chronically instrumented male and female rats with systemic peripheral administration of vehicle controls, the thyrotropin-releasing hormone analog taltirelin at two doses, all with and without coadministered trazodone. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. These preclinical findings newly identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties. These traits have potential favorable relevance to some respiratory disorders but not others, as identified and discussed. [ABSTRACT FROM AUTHOR]

Qingqing Chen,1,2 Xinxin Han,2 Meihua Chen,2,3 Bingjiao Zhao,1,2 Bingjing Sun,1,2 Liangyan Sun,1,2 Weihua Zhang,1,2 Liming Yu,1,2 Yuehua Liu1,2 1Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, People’s Republic of China; 3Department of Periodontology, Shanghai Stomatological Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Yuehua Liu; Liming YuShanghai Stomatological Hospital, Fudan University, No. 356 East Beijing Road, Shanghai, 200001, People’s Republic of ChinaTel +86 2163298475Fax +86 2163614515Email liuyuehua@fudan.edu.cn; ylmphoebe@126.comPurpose: Obesity 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.Methods: Six-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.Results: Compared 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.Conclusion: Our 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.Keywords: obesity, obstructive sleep apnea, genioglossus, muscle, mitochondria

Hong Huang, Wenyang Li, Hongyu Jin, Lei Zhang, Zhijing Wei, Wei Wang Institute of Respiratory and Critical Care, The First Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Wei WangInstitute of Respiratory and Critical Care, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning, 110001, People’s Republic of ChinaTel +86 24 83282529Fax +86 2483282002Email wwbycmu@126.comPurpose: Tongue strength training (TST) has been shown to decrease the apnea-hypopnea index in some patients with obstructive sleep apnea (OSA). However, whether TST modulates the central regulation of genioglossus and influences the stability of the upper airway remains unknown. The purpose of this study was to dynamically assess the effect of TST on the upper airway.Methods: Sixteen adult male Sprague–Dawley rats were studied to explore the mechanism of TST improving the upper airway function. The rats were randomly assigned to the normal control (NC) and TST groups. The TST group underwent 8-week progressive resistance tongue exercise training. Transcranial magnetic stimulation (TMS) responses and EMG activities were consistently recorded for 2 h on days 0, 14, 28, and 56 of the experiments in both groups. Theoretical critical pressure (Pcrit) value was measured on days 0, 14, 28, and 56.Results: The TST group showed shorter TMS latency and higher genioglossus EMG activity, which lasted from 5 min to 80 min after training on day 56 of training, than the NC group. The TST group showed significantly lower theoretical Pcrit values on days 28 and 56 of training than the NC group (-4.07± 0.92 vs -3.12± 0.77 cmH2O, P< 0.05, -4.66± 0.74 vs -3.07± 0.38 cmH2O, P< 0.01).Conclusion: This study revealed that an 8-week TST could gradually and transiently increase corticomotor excitability of genioglossus, elevate the genioglossus EMG activity, and ultimately enhance the stability of the upper airway during daytime. Moreover, improved neuromuscular excitability occurred prior to the enhanced upper airway stability. These findings provide a theoretical foundation for TST as a promising treatment for OSA patients.Keywords: tongue strength training, genioglossus, upper airway critical pressure, transcranial magnetic stimulation, corticomotor excitability

The tongue has a wide variety of motor functions, which are driven by tongue muscle contractions and associated with movements of the hyoid bone (HB) connected to the tongue root. HB movement has been observed in many situations, including swallowing, breathing, and speech. However, the relationships between HB movement and tongue kinematic function have received little attention, and have not been considered in most previous biomechanical tongue modeling research, except studies of swallowing. The current study aimed to clarify the effects of HB movement on tongue kinematics during tongue forward protrusion, which is an essential tongue motor function associated with speech disorder. HB displacement during tongue forward protrusion was quantified using ultrasound imaging in four healthy controls. Furthermore, computational mechanical simulations of tongue forward protrusion were conducted with observed HB movements and active contraction of the genioglossus (GG) muscle, which is conventionally considered to be the driving muscle in tongue forward protrusion. Ultrasound imaging revealed anterosuperior HB displacement in tongue forward protrusion, with a similar magnitude in each direction (anterior: 6.3 ± 2.8 mm, superior: 5.8 ± 1.6 mm). Computational simulation demonstrated that the HB movement described above caused not only anterosuperior displacement, but also forward rotation of the tongue body, which was caused by kinematic constraints of GG. The resulting anterior displacement of the tongue tip was 1.5 times greater compared with that without HB movement. These findings indicate that the HB and associated tongue body movements play non-negligible roles in the tongue kinematics of forward protrusion. [ABSTRACT FROM AUTHOR]

The 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 (GG V) on the tongue and their EMG activity during wakefulness and sleep. The findings were compared to those of the longitudinal fibers (GG L), which, based on their orientation, are responsible for tongue protrusion. Fine-wire electrode pairs were placed into the GG V and GG L 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 CO 2 rebreathing during wakefulness. During sleep, repetitive flow limitation events were induced with low-level CPAP to augment GG activity. In all participants, electrical stimulation of GG L and GG V protruded and retracted the tongue, respectively. Respiratory stimulation increased GG activity, but GG V reached only 39 % and 23 % of peak GG L activity during high resistive loading and PCO 2 of 65 mmHg, respectively. Flow limitation during sleep increased GG L to levels that were considerably higher than awake baseline, but GG V activity remained tonic or with minimal phasic activity, reaching on average 15 % of GG L peak activity. Our electrical stimulation findings indicate that GG V 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 GG V 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 GG L activity to alleviate flow limitation. • Although the genioglossus muscle is considered to be the main tongue protrusor, this is correct only for the longitudinal fibers. The anterior-vertical fibers of the genioglossus actually cause retraction of the tongue. • In accordance with their different function, control and activation of these two parts of the genioglossus differ considerably during both wakefulness and sleep. [ABSTRACT FROM AUTHOR]

Neural mechanisms of obstructive sleep apnea, a common sleep-related breathing disorder, are incompletely understood. Hypoglossal motoneurons, which provide tonic and inspiratory activation of genioglossus (GG) muscle (a major upper airway dilator), receive catecholaminergic input from medullary A1/C1 neurons. We aimed to determine the contribution of A1/C1 neurons in control of GG muscle during sleep and wakefulness. To do so, we placed injections of a viral vector into DBH-cre mice to selectively express the hMD4i inhibitory chemoreceptors in A1/C1 neurons. Administration of the hM4Di ligand, clozapine-N-oxide (CNO), in these mice decreased GG muscle activity during NREM sleep (F1,1,3=17.1, p

Upper airway muscle activity is reportedly elevated during slow-wave sleep (SWS) when compared with lighter sleep stages. To uncover the possible mechanisms underlying this elevation, we explored the correlation between different indices of central and reflex inspiratory drive, such as the changes in airway pressure and end-expiratory CO2 and the changes in the genioglossus (GG) and tensor palatini (TP) muscle activity accompanying transitions from the lighter N2 to the deeper N3 stage of non-rapid eye movement (NREM) sleep in healthy young adult men. Forty-six GG and 38 TP continuous electromyographic recordings were obtained from 16 men [age: 20 ± 2.5 (SD) yr; body mass index: 22.5 ± 1.8 kg/m2] during 32 transitions from NREM stages N2 to N3. GG but not TP activity increased following transition into N3 sleep, and the increase was positively correlated with more negative airway pressure, increased end-tidal CO2, increased peak inspiratory flow, and increased minute ventilation. None of these correlations was statistically significant for TP. Complementary GG and TP single motor unit analysis revealed a mild recruitment of GG units and derecruitment of TP units during the N2 to N3 transitions. These findings suggest that, in healthy individuals, the increased GG activity during SWS is driven primarily by reflex stimulation of airway mechanoreceptors and central chemoreceptors.NEW & NOTEWORTHY The characteristic increase in the activity of the upper airway dilator muscle genioglossus during slow-wave sleep (SWS) in young healthy individuals was found to be related to increased stimulation of airway mechanoreceptors and central chemoreceptors. No evidence was found for the presence of a central SWS-specific drive stimulating genioglossus activity in young healthy individuals. However, it remains to be determined whether a central drive exists in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) incurs a huge individual, societal, and economic burden. Specific and selective targeting of hypoglossal motor neurons could be an effective means to treat OSA. Bioluminescent-optogenetics (BL-OG) is a novel genetic regulatory approach in which luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels, increase neuronal excitability when exposed to a suitable substrate. Here we develop and validate the feasibility of BL-OG for sleep-disordered breathing (SDB). Upon confirming that diet-induced obese mice represent an excellent SDB model, we employed a method of targeting the hypoglossal nucleus (12 N) by peripherally injecting retrogradely transported rAAV2/Retro. With AAV transduction, the eLMO3 protein is expressed in hypoglossal motor neurons (HMN); administration of CTZ results in production of bioluminescence that in turn activates the tethered channelrhodopsin, leading to an increase in the firing of HMN and a 2.7 ± 0.8-fold increase in phasic activity of the genioglossus muscle, a 7.6 ± 1.8-fold increase in tonic activity, and improvements in hypoventilation and apnea index without impacting sleep structure. This is therefore the first study to leverage the rAAV2/Retro vector to execute the BL-OG approach in SDB, which amplified genioglossus muscle discharge activity and increased airflow in mice after activation. This study marks the pioneering utilization of BL-OG in SDB research. [Display omitted] • Diet-induced obese (DIO) mice represent an excellent model of SDB. • Compared to rAAV2/9 and rAAV2/11, the rAAV2/Retro serotype has a higher retrograde infection efficiency. • The BL-OG approach, which was used for the first time in SDB research, has demonstrated a positive safety profile. • In virus-infected mice, CTZ administration increases muscle activity, improves hypoventilation and AI, without altering sleep structure. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is common in people with multiple sclerosis (MS). However, people with MS often do not have "typical" anatomical risk factors (i.e., nonobese and female predominance). Accordingly, nonanatomical factors such as impaired upper-airway muscle function may be particularly important for OSA pathogenesis in MS. Therefore, this study aimed to investigate genioglossus (largest upper-airway dilator muscle) reflex responses to brief pulses of upper-airway negative pressure in people with OSA and MS. Eleven people with MS and OSA and 10 OSA controls without MS matched for age, sex, and OSA severity were fitted with a nasal mask, pneumotachograph, choanal and epiglottic pressure sensors, and intramuscular electrodes into genioglossus. Approximately 60 brief (250 ms) negative pressure pulses (approximately ~12 cmH2O mask pressure) were delivered every 2-6 breaths at random during quiet nasal breathing during wakefulness to determine genioglossus electromyogram (EMGgg) reflex responses (timing, amplitude, and morphology). Where available, recent clinical MRI brain scans were evaluated for the number, size, and location of brainstem lesions in the group with MS. When present, genioglossus reflex excitation responses were similar between MS participants and controls (e.g., peak excitation amplitude = 229 ± 85% vs. 282 ± 98% baseline, P = 0.17). However, ~30% of people with MS had either an abnormal (predominantly inhibition) or no protective excitation reflex. Participants with MS without a reflex had multiple brainstem lesions including in the hypoglossal motor nucleus which may impair sensory processing and/or efferent output. Impaired pharyngeal reflex function may be an important contributor to OSA pathogenesis for a proportion of people with MS. [ABSTRACT FROM AUTHOR]

Anatomical and imaging evidence suggests neural control of oblique and horizontal compartments of the genioglossus differs. However, neurophysiological evidence for differential control remains elusive. This study aimed to determine whether there are differences in neural drive to the oblique and horizontal regions of the genioglossus during swallowing and tongue protrusion. Adult participants (n = 63; 48 M) were recruited from a sleep clinic; 41 had obstructive sleep apnea (OSA: 34 M, 8 F). Electromyographic (EMG) was recorded at rest (awake, supine) using four intramuscular fine-wire electrodes inserted percutaneously into the anterior oblique, posterior oblique, anterior horizontal, and posterior horizontal genioglossus. Epiglottic pressure and nasal airflow were also measured. During swallowing, two distinct EMG patterns were observed – a monophasic response (single EMG peak) and a biphasic response (2 bursts of EMG). Peak EMG and timing of the peak relative to epiglottic pressure were significantly different between patterns (linear mixed models, P < 0.001). Monophasic activation was more likely in the horizontal than oblique region during swallowing (OR = 6.83, CI = 3.46–13.53, P < 0.001). In contrast, during tongue protrusion, activation patterns and EMG magnitude were not different between regions. There were no systematic differences in EMG patterns during swallowing or tongue protrusion between OSA and non-OSA groups. These findings provide evidence for functional differences in the motoneuronal output to the oblique and horizontal compartments, enabling differential task-specific drive. Given this, it is important to identify the compartment from which EMG is acquired. We propose that the EMG patterns during swallowing may be used to identify the compartment where a recording electrode is located. [ABSTRACT FROM AUTHOR]

Abstract Objective Sleep apnea research cites that an oral appliance, which places the mandible in a more forward position and the genioglossus (tongue muscle) on the floor of the mouth, improves aspects of the pharyngeal opening. Exercise science research has cited improvements in airway dynamics and physiological variables with oral appliance use during exercise. Thus, the purpose of this study was to design an oral appliance that would act on the genioglossus and determine if there were effects on respiratory parameters while exercising. Materials and methods Seventeen healthy subjects ages 18–43 participated in this study. Prior to the exercise protocol, the order of the oral applicance (OA) or no oral appliance (no OA) condition was randomly assigned to subjects, with subjects completing both conditions. Respiratory parameters (respiratory rate, ventilation, oxygen, and carbon dioxide) were measured between conditions while subjects ran for 10 min at steady state. Results The results demonstrated that both respiratory rate (25.97 BPM, OA and 28.35 BPM, no OA) and ventilation (47.66 l/min, OA and 50.34 l/min, No OA) were significantly lowered (p < .01) in the OA condition. There were no differences in carbon dioxide (1.89 l/min, no OA and 1.88 l/min, OA) or oxygen outcomes (2.17 l/min, no OA and 2.17 l/min OA). Discussion The outcomes from this study suggest that the design of the oral appliance elicits an effect on the genioglossus, thereby resulting in lowered respiratory rate and ventilation with no negative effects on oxygen uptake during exercise.

• EMG genioglossus involvement at diagnosis is associated with a shorter disease duration in ALS. • Genioglossus EMG is a stronger prognostic factor that the presence of clinical bulbar lower motor neuron signs alone. • The prognostic value of genioglossus EMG is also confirmed in ALS patients without clinical bulbar lower motor neuron signs at diagnosis. To evaluate the prognostic value of needle electromyography (EMG) genioglossus involvement in patients with amyotrophic lateral sclerosis (ALS) at diagnosis. We separately explored the prognostic value of clinical bulbar lower motor neuron (LMN) signs and EMG genioglossus involvement using Cox proportional hazard models adjusted for age, gender, diagnostic delay, presence of bulbar upper motor neuron (UMN) signs, EMG cervical and lumbosacral region involvement, ALSFRS-R score and C9Orf72 gene status. Then, we compared the prognostic value of EMG masseter and genioglossus abnormalities in a subset of patients in whom both muscles were analysed. 103 ALS patients were included in the study. Neurophysiological genioglossus involvement was associated with a shorter survival (p = 0.002), a shorter time to moderate dysphagia (p = 0.0001) and to severe dysarthria (p = 0.012). Its prognostic value was still evident in patients without clinical bulbar LMN signs. Bulbar clinical LMN signs were only associated with an earlier onset of moderate dysphagia (p = 0.0001). EMG masseter abnormalities did not reach statistical significance with regard to all the clinical milestones. Genioglossus EMG at diagnosis could provide important information about ALS progression rate. The masseter muscle seems to be less involved in ALS. EMG genioglossus involvement is a prognostic factor in ALS. [ABSTRACT FROM AUTHOR]

The intrinsic and extrinsic tongue muscles manipulate the position and shape of the tongue and are activated during many oral and respiratory behaviors. In the present study, in 6-mo-old Fischer 344 rats, we examined mechanical and fatigue properties of tongue muscles in relation to their fiber type composition. In an ex vivo preparation, isometric force and fatigue was assessed by direct muscle stimulation. Tongue muscles were frozen in melting isopentane and transverse sections cut at 10 mm. In hematoxylin-eosin (H&E)-stained muscle sections, the relative fractions of muscle versus extracellular matrix were determined. Muscle fibers were classified as type I, IIa and IIx, and/or IIb based on immunoreactivity to specific myosin heavy chain isoform antibodies. Cross-sectional areas (CSAs) and proportions of different fiber types were used to calculate their relative contribution to total muscle CSAs. We found that the superior and inferior longitudinal intrinsic muscles (4.4 N/cm²) and genioglossus muscle (3.0 N/cm²) generated the greatest maximum isometric force compared with the transversalis muscle (0.9 N/cm²). The longitudinal muscles and the transversalis muscle displayed greater fatigue during repetitive stimulation consistent with the greater relative contribution of type IIx and/or IIb fibers. By contrast, the genioglossus, comprising a higher proportion of type I and IIa fibers, was more fatigue resistant. This study advances our understanding of the force, fatigue, and fiber type-specific properties of individual tongue musculature. The assessments and approach provide a readily accessible muscular readout for scenarios where motor control dysfunction or tongue weakness is evident. [ABSTRACT FROM AUTHOR]

The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50±10 years with a BMI of 35±6 kg/m(2) and severe OSA (apnea-hypopnea index=52±28 events/h) were studied. NED and phasic genioglossus muscle activity (EMG(GG)) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMG(GG) activity (p

Study objectivesRapid eye movement (REM)-induced hypotonia of the major upper airway dilating muscle (genioglossus) potentially contributes to the worsening of obstructive sleep apnea that occurs during this stage. No prior human single motor unit (SMU) study of genioglossus has examined this possibility to our knowledge. We hypothesized that genioglossus SMUs would reduce their activity during stable breathing in both tonic and phasic REM compared to stage N2 sleep. Further, we hypothesized that hypopneas occurring in REM would be associated with coincident reductions in genioglossus SMU activity.DesignThe activity of genioglossus SMUs was studied in (1) neighboring epochs of stage N2, and tonic and phasic REM; and (2) during hypopneas occurring in REM.SettingSleep laboratory.Participants29 subjects (38 ± 13 y) (17 male).InterventionNatural sleep, including REM sleep and REM hypopneas.Measurement and resultsSubjects slept overnight with genioglossus fine-wire intramuscular electrodes and full polysomnography. Forty-two SMUs firing during one or more of stage N2, tonic REM, or phasic REM were sorted. Twenty inspiratory phasic (IP), 17 inspiratory tonic (IT), and five expiratory tonic (ET) SMUs were characterized. Fewer units were active during phasic REM (23) compared to tonic REM (30) and stage N2 (33). During phasic REM sleep, genioglossus IP and IT SMUs discharged at slower rates and for shorter durations than during stage N2. For example, the SMU peak frequency during phasic REM 5.7 ± 6.6 Hz (mean ± standard deviation) was less than both tonic REM 12.3 ± 9.7 Hz and stage N2 16.1 ± 10.0 Hz (P < 0.001). The peak firing frequencies of IP/IT SMUs decreased from the last breath before to the first breath of a REM hypopnea (11.8 ± 10.9 Hz versus 5.7 ± 9.4 Hz; P = 0.001).ConclusionGenioglossus single motor unit activity is significantly reduced in REM sleep, particularly phasic REM. Single motor unit activity decreases abruptly at the onset of REM hypopneas.

STUDY OBJECTIVE: Obstructive sleep apnea is prevalent among people with asthma, but underlying mechanisms remain unknown. Inhaled corticosteroids may contribute. We tested the effects of orally inhaled fluticasone propionate (FP) on upper airway (UAW) during sleep and wakefulness. STUDY DESIGN: 16-week single-arm study. PARTICIPANTS: 18 (14 females, mean [ ± SD] age 26 ± 6 years) corticosteroid-naïve subjects with mild asthma (FEV1 89 ± 8% predicted). INTERVENTIONS: High dose (1,760 mcg/day) inhaled FP. MEASUREMENTS: (1) UAW collapsibility (passive critical closing pressure [Pcrit]); (2) tongue strength (maximum isometric pressure-Pmax, in KPa) and endurance-time (in seconds) able to maintain 50% Pmax across 3 trials (Ttot)-at anterior and posterior locations; (3) fat fraction and volume around UAW, measured by magnetic resonance imaging in three subjects. RESULTS: Pcrit overall improved (became more negative) (mean ± SE) (-8.2 ± 1.1 vs. -12.2 ± 2.2 cm H2O, p = 0.04); the response was dependent upon baseline characteristics, with older, male gender, and worse asthma control predicting Pcrit deterioration (less negative). Overall, Pmax increased (anterior p = 0.02; posterior p = 0.002), but Ttot generally subsided (anterior p = 0.0007; posterior p = 0.06), unrelated to Pcrit response. In subjects studied with MRI, fat fraction and volume increased by 20.6% and 15.4%, respectively, without Pcrit changes, while asthma control appeared improved. CONCLUSIONS: In this study of young, predominantly female, otherwise healthy subjects with well-controlled asthma and stiff upper airways, 16-week high dose FP treatment elicited Pcrit changes which may be dependent upon baseline characteristics, and determined by synchronous and reciprocally counteracting local and lower airway effects. The long-term implications of these changes on sleep disordered breathing severity remain to be determined.

Purpose: Dysfunction of the genioglossus muscle is important in the pathogenesis of obstructive sleep apnea due to chronic intermittent hypoxia (CIH). Mitochondrial impairment resulting from hypoxia is mitigated by mitophagy to avoid cell apoptosis in cardiomyocytes. This project was designed to explore the effects of CIH on mitophagy in the genioglossus muscle and the impact of adiponectin (Ad). Methods: One hundred eighty male SD rats were randomly divided into 3 groups (normal control [NC], CIH, and CIH + Ad groups), with 60 rats in each group observed for 5 weeks. Comparisons of serum Ad levels, mitochondrial structure and function, mitophagy, and cell apoptosis in the genioglossus were made at different time points. Results: (1) The CIH group was significantly different from the NC group as follows: During the first 3 weeks, serum Ad levels, the reactive oxygen species (ROS), relative proteins and mRNA of mitophagy, autophagy biomarker LC3-II, and autophagosomes increased, while during the last 2 weeks, most parameters decreased. (2) There was no difference among the 3 groups in mitochondrial structure and function-associated mRNA during the first 3 weeks, while damaged mitochondrial structures were growing during the last 2 weeks. Exacerbation of apoptosis was also detected in the last 2 weeks. (3) All of the damage was partially alleviated in the CIH + Ad group in contrast to CIH group at the end of this study. Conclusion: Disturbances of genioglossal mitophagy could be related to damaged mitochondrial structure and function induced by CIH, which could be alleviated by supplementation of exogenous Ad via increasing mitophagy. [ABSTRACT FROM AUTHOR]

The article published in the Journal of Physiology explores the relationship between genioglossus muscle activation and tongue movement in individuals with and without obstructive sleep apnoea (OSA). The study found that there is a complex relationship between genioglossus muscle activity and tongue movement, with a significant uncoupling observed in people with OSA. The research suggests that airway dilatation cannot be reliably predicted from genioglossus EMG activity alone, highlighting the need for a more comprehensive assessment of upper airway muscles in understanding airway mechanics. The findings contribute to advancing our understanding of the multifactorial contributors to airway occlusion in sleep, potentially leading to tailored therapies for individuals with OSA. [Extracted from the article]

Jennifer M Cori,1 Fergal J O’Donoghue,1 Amy S Jordan2 1Department of Respiratory and Sleep Medicine, Institute for Breathing and Sleep, Austin Hospital, Heidelberg, VIC, Australia; 2Department of Psychology, Melbourne School of Psychological Sciences, University of Melbourne, Parkville, VIC, Australia Abstract: The focus of this review was on the genioglossus (GG) muscle and its role in maintaining upper airway patency in both healthy individuals and obstructive sleep apnea (OSA) patients. This review provided an overview of GG anatomy and GG control and function during both wakefulness and sleep in healthy individuals and in those with OSA. We reviewed evidence for the role of the GG in OSA pathogenesis and also highlighted abnormalities in GG morphology, responsiveness, tissue movement patterns and neurogenic control that may contribute to or result from OSA. We summarized the different methods for improving GG function and/or activity in OSA and their efficacy. In addition, we discussed the possibility that assessing the synergistic activation of multiple upper airway dilator muscles may provide greater insight into upper airway function and OSA pathogenesis, rather than assessing the GG in isolation. Keywords: pharyngeal dilators, upper airway, airway obstruction, airway collapsibility and sleep

Objectives: To reveal the characteristics of genioglossus (GG) activation in moderate and severe obstructive sleep apnea (OSA) patients during rapid eye movement (REM) sleep compared with non-rapid eye movement (NREM) sleep and to determine whether continuous positive airway pressure (CPAP) could improve GG activation in OSA patients during sleep. Methods: All subjects underwent polysomnography (PSG) with synchronous GG electromyography (GGEMG) recording with intra-oral surface electrodes at baseline on the first night. Only those subjects diagnosed with moderate and severe OSA were included and were manually titrated with CPAP to achieve a therapeutic pressure (Pt) with GGEMG recording on the second night. Results: Nine OSA patients and six normal controls were analyzed in this study. The tonic GGEMG was higher in OSA patients during wakefulness (p = 0.003) and NREM sleep (p = 0.015), but it was not higher in REM sleep (p = 0.862). The average phasic activity of OSA patients was significantly higher in all stages, including wakefulness (p = 0.007), NREM sleep (p = 0.005), and REM sleep (p = 0.021). The peak phasic GGEMG was not different in wakefulness compared with normal controls (p = 0.240), but it was higher in OSA patients in NREM sleep (p = 0.001) and REM sleep (p = 0.021), and it was significantly reduced by using CPAP during sleep (NREM sleep: p = 0.027; REM sleep: p = 0.001). Conclusions: Our results demonstrate that GG activation during NREM and REM sleep is associated with component differences. The tonic component of GGEMG exhibited less of a compensatory increase compared with the phasic component in REM sleep, suggesting that it may be one of the pathological mechanisms of UA collapsibility in REM sleep. In addition, treatment with CPAP can normalize GGEMG activity and mostly reduced the peak phasic GGEMG during sleep. [ABSTRACT FROM AUTHOR]

Introduction: Supra-selective stimulation of the branches destined for the horizontal part of genioglossus muscle (GGh) could be a target of choice in the treatment of mild-to-severe obstructive sleep apnea syndrome. The main aim of our study was to assess a percutaneous method for the three-dimensional localisation of the terminal branches destined to GGh. Materials and methods: Twenty cadaveric hypoglossal nerves were dissected and included in the injection protocol. The distance between the posterior edge of the mandibular symphysis and the hyoid bone on the sagittal midline as the approximated distance of the geniohyoid muscle (dGH) was measured before any dissection. Methylene blue mixed with a thickening agent, was injected. The injection point was defined in relation to dGH, in an orthonormal coordinate system. For each dissection, we recorded the theoretical and the real (X, Y, Z) coordinates of GGh motor points and measured their distance to each other. Results: X was accurately estimated. Y and Z were overestimated by + 5.34 ± 5.21 mm ( 0.1075 ± 0.1039 dGH ) and + 4.79 ± 3.99 mm ( 0.0928 ± 0.0817 dGH ) on average, respectively. We found a more significant difference between the theoretical and real Y and Z coordinates in the subgroup BMI < 25 kg/m2 (8.6 ± 4.5 mm and 6.9 ± 2.5 mm, respectively, p = 0.0009), and of Z in subgroup with dGH ≥ 50 mm (6.89 ± 3.26 mm, p = 0.0494). Conclusions: X can be estimated accurately using the relationship X = 0.2 dGH . Y seems to be related to BMI and Z may be estimated with the relationship Z = 0.55 dGH . This three-dimensional localisation could be very helpful to facilitate placement of cuff electrodes to manage refractory sleep apnea. [ABSTRACT FROM AUTHOR]

Objective: Sleep apnea research cites that an oral appliance, which places the mandible in a more forward position and the genioglossus (tongue muscle) on the floor of the mouth, improves aspects of the pharyngeal opening. Exercise science research has cited improvements in airway dynamics and physiological variables with oral appliance use during exercise. Thus, the purpose of this study was to design an oral appliance that would act on the genioglossus and determine if there were effects on respiratory parameters while exercising. Materials and methods: Seventeen healthy subjects ages 18–43 participated in this study. Prior to the exercise protocol, the order of the oral applicance (OA) or no oral appliance (no OA) condition was randomly assigned to subjects, with subjects completing both conditions. Respiratory parameters (respiratory rate, ventilation, oxygen, and carbon dioxide) were measured between conditions while subjects ran for 10 min at steady state. Results: The results demonstrated that both respiratory rate (25.97 BPM, OA and 28.35 BPM, no OA) and ventilation (47.66 l/min, OA and 50.34 l/min, No OA) were significantly lowered (p <.01) in the OA condition. There were no differences in carbon dioxide (1.89 l/min, no OA and 1.88 l/min, OA) or oxygen outcomes (2.17 l/min, no OA and 2.17 l/min OA). Discussion The outcomes from this study suggest that the design of the oral appliance elicits an effect on the genioglossus, thereby resulting in lowered respiratory rate and ventilation with no negative effects on oxygen uptake during exercise. [ABSTRACT FROM AUTHOR]

Background: Chronic intermittent hypoxia is the most remarkable feature of obstructive sleep apnea/hypopnea syndrome and it can induce the change of hypoxia-inducible factor-1α (HIF-1α) expression and contractile properties in the genioglossus. To clarify the role of HIF-1α in contractile properties of the genioglossus, this study generated and compared high-throughput RNA-sequencing data from genioglossus between HIF-1α conditional knockout (KO) mice and littermate wild-type (WT) mice. Methods: KO mice were generated with cre-loxP strategy. Gene expression profile analysis was performed using gene enrichment analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of differently expressed messenger RNAs were performed to identify the related pathways and biological functions. Six differentially expressed genes (DEGs) were validated by qualitative reverse transcription polymerase chain reaction. Results: A total of 142 (77 upregulated and 65 downregulated) transcripts were found to exhibit statistically significant difference between the HIF-1α-KO and WT mice. GO and KEGG analyses indicated that DEGs included genes involved in “skeletal muscle cell differentiation,” “muscle organ development,” “glucose metabolic process,” “glycogen biosynthetic and metabolic process,” etc. Conclusion: This study might provide evidence that HIF-1α affects the expression of multiple genes involved in the myogenesis, muscle development, and carbohydrate metabolism through transcriptome analysis in conditional HIF-1α-KO mice.

The sleep-breathing condition obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse, which can exacerbate oxidative stress and free radical generation, thereby detrimentally impacting both motor and sensory nerve function and inducing muscular damage. OSA development is promoted by increasing proportions of fast-twitch muscle fibers in the genioglossus. Orientin, a water-soluble dietary C-glycosyl flavonoid with antioxidant properties, increased the expression of slow myosin heavy chain (MyHC) and signaling factors associated with AMP-activated protein kinase (AMPK) activation both in vivo and in vitro . Inhibiting AMPK signaling diminished the effects of orientin on slow MyHC, fast MyHC, and Sirt1 expression. Overall, orientin enhanced type I muscle fibers in the genioglossus, enhanced antioxidant capacity, increased mitochondrial biogenesis through AMPK signaling, and ultimately improved fatigue resistance in C2C12 myotubes and mouse genioglossus. These findings suggest that orientin may contribute to upper airway stability in patients with OSA, potentially preventing airway collapse.

This study aimed to determine whether there is impairment of genioglossus neuromuscular responses to small negative pressure respiratory stimuli, close to the conscious detection threshold, in obstructive sleep apnea (OSA). We compared genioglossus electromyogram (EMGgg) responses to midinspiratory resistive loads of varying intensity (≈1.2-6.2 cmH2O⋅L-1⋅s), delivered via a nasal mask, between 16 severe OSA and 17 control participants while the subjects were awake and in a seated upright position. We examined the relationship between stimulus intensity and peak EMGgg amplitude in a 200-ms poststimulus window and hypothesized that OSA patients would have an increased activation threshold and reduced sensitivity in the relationship between EMGgg activation and stimulus intensity. There was no significant difference between control and OSA participants in the threshold (P = 0.545) or the sensitivity (P = 0.482) of the EMGgg amplitude vs. stimulus intensity relationship, where change in epiglottic pressure relative to background epiglottic pressure represented stimulus intensity. These results do not support the hypothesis that deficits in neuromuscular response to negative upper airway pressure exist in OSA during wakefulness; however, the results are likely influenced by a counterintuitive and novel genioglossus muscle suppression response observed in a significant proportion of both OSA and healthy control participants. This suppression response may relate to the inhibition seen in inspiratory muscles such as the diaphragm in response to sudden-onset negative pressure, and its presence provides new insight into the upper airway neuromuscular response to the collapsing force of negative pressure. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Genioglossus advancement is performed in select patients with obstructive sleep apnea. Surgical techniques attempt to capture the genial tubercle of the mandible; however, measurements of the genioglossus, geniohyoid, and digastric muscles are poorly delineated. This investigation is the largest anatomic study exploring the muscles of genial advancement surgery and the first to quantitatively characterize muscular attachments relative to the tubercle, providing new insights from an anatomic perspective on optimizing muscular advancement.Study Design: Cadaveric study.Methods: Fifty-three fresh cadaveric mandibles underwent dissection of the genial tubercle and genioglossus, geniohyoid, and digastric muscles.Results: Genial tubercle, geniohyoid, and genioglossus mean height was 7.78 mm, 5.15 mm, and 6.11 mm, respectively. On average, the geniohyoid began 4.88 mm and ended 10.03 mm from the inferior border of the mandible; the genioglossus 11.91 mm and 18.01 mm, similarly. Intermuscular distance, if present, was 2.67 mm; the muscles overlapped in 28% of cadavers. The combined vertical height of the muscles at their mandibular attachment was 13.94 mm, significantly differing from the height of the genial tubercle. The left and right lateral insertion of the digastric muscles was 19.34 mm and 19.31 mm, respectively, from midline.Conclusions: The variable range of muscle attachments suggests that genioglossal and geniohyoid attachments extend beyond the genial tubercle and may not originate concentrically from the tubercle, but overlap and lie in very close proximity. Mandibular anterior muscle attachments require anatomic accuracy and an effective operative evaluation of advancement before reproducible, clinically effective osteotomies can be recommended.Level Of Evidence: NA Laryngoscope, 129:2424-2429, 2019. [ABSTRACT FROM AUTHOR]

The extrinsic tongue muscles are activated in coordination with pharyngeal muscles to dilate the airways as needed during breathing. The genioglossus (GG) activity is known to be modulated by several reflexes evoked via the mechanoreceptors of the upper airways. The primary objective of this paper was to investigate the effectiveness of activating these reflex pathways using mechanical stimulation of the mandible or the submandibular muscles. In eight healthy subjects, 3-s long, 5-mm vertical mechanical vibrations were delivered at 8 and 12 Hz to the lower jaw in a seated position, while the GG EMG was recorded using a custom-made sublingual electrode, along with the activity of the masseter (MS) and mylohyoid (MH). All three muscle activities were significantly higher during stimulation compared with the baseline (P < 0.02), and the increase was larger at 12 Hz versus 8 Hz (P < 0.02). All three muscle responses had components that synchronized with the mechanical stimuli, but those of MS were much more strongly phase-locked to the vibrational cycle. In 10 healthy subjects, we also applied mechanical vibrations to the submandibular muscles at three different stimulation intensities, while subjects were lying in a supine position. The GG activity increased significantly above the baseline (P = 0.026) in 9 out of 10 subjects, and the elevated activity persisted after termination of the stimulus for a few seconds. The results demonstrate that GG muscle responses can be evoked with mechanical vibrations applied to the lower jaw or the submandibular muscles in healthy subjects during wakefulness. [ABSTRACT FROM AUTHOR]

Highlights • Dyscoordination of dilator muscles during sleep contributes to pharyngeal collapse. • We found a sleep-dependent shift in peri-pharyngeal muscles power spectrum. • This finding suggests a state-dependent alteration in dilators motor unit activation. • We speculate that this change may lessen dilator muscles' mechanical efficiency. Abstract Introduction In addition to dyscoordination of upper airway dilator muscles activity, sleep may also alter the pattern of intra-muscular activation of single motor units (SMUs). Such changes should be identifiable by a state dependent change in EMG power spectrum, i.e., a shift in centroid frequency (ƒc) during sleep. Methods EMGs of the genioglossus and four other peri-pharyngeal muscles were recorded in OSA patients (n = 8), age-matched healthy subjects (n = 7), and 5 young healthy subjects, and ƒc was calculated for wakefulness and sleep periods. Results ƒc decreased with the onset of sleep and returned to baseline levels after arousal. ƒc of all muscles decreased similarly and significantly during sleep in the OSA and the age-matched healthy subjects, but not in the young subjects. Conclusions The pattern of decrease in ƒc is compatible with altered synchronization of SMUs during sleep. We speculate that these changes may contribute to the failure of dilator muscles to improve flow limitation during sleep in older subjects. [ABSTRACT FROM AUTHOR]

Obstructive Sleep Apnea (OSA) is a common sleep-related respiratory disorder that is associated with cognitive, cardiovascular, and metabolic morbidities. The major cause of OSA is the sleep-related reduction of upper airway muscle tone that leads to airway obstructions in individuals with anatomically narrow upper airway. This reduction is mainly due to the suppressant effect of sleep on hypoglossal motoneurons that innervate upper airway muscles. The hypoglossal motoneurons have state-dependent activity, which is decreased during the transition from wakefulness to non-rapid eye movement sleep and is further suppressed during rapid eye movement sleep. Multiple neurotransmitters and their receptors have been implicated in the control of hypoglossal motoneuron activity across the sleep-wake states. However, to date, the results of the rigorous testing show that withdrawal of noradrenergic excitation and cholinergic inhibition essentially contribute to the depression of hypoglossal motoneuron activity during sleep. The present review will focus on origins of noradrenergic and cholinergic innervation of hypoglossal motoneurons and the functional role of these neurons in the state-dependent activity of hypoglossal motoneurons.

The sleep-related depression of excitability of upper airway motoneurons is a major neurological cause of obstructive sleep apnea whereas a disruption in the inhibition of spinal motoneurons during rapid eye movement (REM) sleep causes the REM sleep behavioral disorder. The large amount of experimental data has been obtained that deal with neurochemical mechanisms that are responsible for sleep-related depression of various motoneuron groups. However, there is a disagreement regarding the outcome of these studies primarily due to the use of different animal models and approaches, as well as due to differences in quantification and interpretation of obtained results. In this study, we sought to apply the same calculation methodology in order to uniformly quantify and compare the relative contribution of excitatory or inhibitory inputs to the decrease of excitability of different motoneuronal pools during REM and/or non-REM sleep. We analyzed only published quantitative data that were obtained by using receptor antagonists or chemogenetic approach to block receptors or silence neuronal populations. The outcomes of this analysis highlight the differences in the neurotransmitter mechanisms of sleep-related motoneuron depression between different motoneuronal pools and demonstrate the consistency of these mechanisms for hypoglossal motoneurons among various animal models.

Keywords: alcohol; genioglossus; motor unit; upper airway EN alcohol genioglossus motor unit upper airway 331 332 2 03/03/23 20230301 NES 230301 The human pharynx is a compliant conduit for airflow, vulnerable at times to collapse, owing to suction forces generated during inspiration. Therefore, studies of the effects of alcohol on genioglossus EMG and motor unit activity throughout the sleep-wake cycle in healthy participants and people with OSAS are warranted. [Extracted from the article]