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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.

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

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.

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

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.

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.

Neuromuscular compensation of the genioglossus muscle can be induced by chronic intermittent hypoxia (CIH) in obstructive sleep apnea to maintain upper airway stability. Noradrenergic activation of hypoglossal nucleus plays a critical role in the central control of the genioglossus. However, it remains unknown whether norepinephrine takes part in the central regulation of the genioglossus during CIH. Adult male Wistar rats (n = 32) were studied to explore the influence of noradrenergic activation of hypoglossal nucleus on the central control of the genioglossus at different stages of CIH. The rats were divided into four groups: normal control or normoxic (NO) group, CIH group, CIH + normal saline (NS) group, and CIH + prazosin (PZ, α1-adrenergic antagonist) group. PZ (0.2 mM, 60 nl) and NS (0.9%, 60 nl) were microinjected into the hypoglossal nucleus. The responses of the genioglossus corticomotor area to transcranial magnetic stimulation (TMS) were recorded on the 1st, 7th, 14th, and 21st day of CIH. The CIH group showed significantly shorter TMS latencies on days 1, 7, and 14 (3.85 ± 0.37 vs. 4.58 ± 0.42, 3.93 ± 0.17 vs. 4.49 ± 0.55, 3.79 ± 0.38 vs. 4.39 ± 0.30 ms, P

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

Genial tubercles are tiny bony projections located bilaterally around the lingual foramen, on the lingual surface of the mandible giving attachment to geniohyoid inferiorly & genioglossus superiorly. Due to delayed prosthetic rehabilitation & lack of balanced mastication excessive resorption of alveolar processes take place thereby leaving genial tubercles as elevated bony projections. This may pose problems in speech, deglutition & prosthetic rehabilitation. Excessive mobility of tongue may also contribute to enlargement of genial tubercles to such an extent that they may extend beyond the crest of alveolar ridges leaving them vulnerable to spontaneous fracture. This report presents a rare case of excessive enlargement of genial tubercles and its surgical management using a novel technique. This technique not only addresses the removal of the enlarged genial tubercles but also aims at reattachment of muscles attached to these tubercles, in a simple non morbid manner.

Obstructive sleep apnea (OSA) patients have increased upper airway muscle activity, including such lingual muscles as the genioglossus (GG), geniohyoid (GH) and hyoglossus (HG). This adaptation partially protects their upper airway against obstructions. Rodents are used to study the central neural control of sleep and breathing but they do not naturally exhibit OSA. We investigated whether, in chronically instrumented, behaving rats, disconnecting the GH and HG muscles from the hyoid (H) apparatus would result in a compensatory increase of other upper airway muscle activity (EMG) and/or other signs of upper airway instability. We first determined that, in intact rats, lingual (GG and intrinsic) muscles maintained stable activity levels when quantified based on 2 h-long recordings conducted on days 6 through 22 after instrumentation. We then studied 5 rats in which the tendons connecting the GH and HG muscles to the H apparatus were experimentally severed. When quantified across all recording days, lingual EMG during SWS was modestly but significantly increased in rats with surgically altered upper airway (8.6% ±0.7(SE) vs. 6.2% ±0.7 of the mean during wakefulness; p=0.012). Respiratory modulation of lingual EMG occurred mainly during SWS and was similarly infrequent in both groups, and the incidence of sighs and central apneas also was similar. Thus, a weakened action of selected lingual muscles did not produce sleep-disordered breathing but resulted in a relatively elevated activity in other lingual muscles during SWS. These results encourage more extensive surgical manipulations with the aim to obtain a rodent model with collapsible upper airway.

Abstract Obstructive sleep apnoea is a common and serious breathing problem that is caused by effects of sleep on pharyngeal muscle tone in individuals with narrow upper airways. There has been increasing focus on delineating the brain mechanisms that modulate pharyngeal muscle activity in the awake and asleep states in order to understand the pathogenesis of obstructive apnoeas and to develop novel neurochemical treatments. Although initial clinical studies have met with only limited success, it is proposed that more rational and realistic approaches may be devised for neurochemical modulation of pharyngeal muscle tone as the relevant neurotransmitters and receptors that are involved in sleep-dependent modulation are identified following basic experiments.