Pharyngeal Dilator Muscle Research Articles

Sleep Apnea and Dental Implications -A Review

Obstructive sleep apnea (OSA) is an increasingly common, chronic, sleep-related breathing disorder.The prevalence of obstructive sleep apnea (OSA) continues to rise due to change in life patterns.The most common presenting symptom of OSA is excessive sleepiness and is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. The key contributors to OSA pathogenesis include a narrow, crowded, or collapsible upper airway “anatomical compromise” and “non-anatomical” contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. This review summarizes the latest knowledge ondifferent contributors to OSA with a focus on emerging clinical tools.

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

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

Role of Tongue Fat in The Pathogenesis of Obstructive Sleep Apnea: Review Article

Humans are fortunate to have sleep. A happy, fulfilling life depends on getting a restful night of sleep. Obstructive sleep apnea is a widespread sleep disorder is characterized by snoring loudly, difficulty breathing, and partial or complete lack of sleep. Systemic side effects from chronic obstructive sleep apnea may affect the cardiovascular system and other important body organs. Although the exact cause is unknown, a number of factors may contribute to this condition. Increased intramuscular fat may impair the tongue's capacity to act as a pharyngeal dilator muscle by changing its shape and decreasing its contractile force. More fat was found in apneic person at the base of the tongue, where the tongue's extrinsic muscles attach to the bone. Each extrinsic muscle's ability to position the tongue correctly away from the airway may be impacted by the increased fat.

Pro: can physiological risk factors for obstructive sleep apnea be determined by analysis of data obtained from routine polysomnography?

This article is a written debate between the author(s) of this article and the author(s) of the opposing argument [1]. The following argument was prepared in response to the question without the knowledge of the contents of the opposing argument. Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by heterogeneous underlying mechanisms and heterogeneous adverse outcomes. Over the last 20 years, investigators have described how OSA is manifest as a combination of several established physiological risk factors or “endotypic traits”: greater pharyngeal collapsibility, dampened pharyngeal dilator muscle compensation, hyper-responsive ventilatory control (elevated loop gain), and a low arousal threshold (increased arousability from sleep). Evidence for important roles of each pathophysiological pathway are extensive. Profoundly improving pharyngeal collapsibility with CPAP is highly efficacious for resolving OSA, and individuals without a collapsible pharynx (critical collapsing pressure <5 cmH2O) very rarely exhibit OSA [2, 3]; thus, a level of pharyngeal mechanical vulnerability is considered a requirement for OSA. Yet measures of collapsibility alone do not accurately predict the presence/absence of OSA, that is, for the same level of collapsibility some patients exhibit severe OSA and others do not. The two leading endotypic traits responsible for modifying OSA risk are reduced muscle compensation and elevated loop gain. Notably, obese individuals without OSA typically exhibit augmented muscle responses [4], and loop gain is elevated in OSA patients with less-severe collapsibility [5]. A lower arousal threshold is considered to contribute to more severe OSA within participants in lighter non-REM and REM [6].

Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial

Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 μg, 3 μg, and 30 μg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 μg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 μg), (2) half-dose nasal spray (80 μg), and (3) direct endoscopic application (160 μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 μg of BAY2586116 vsplacebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2cm H2O vsplacebo, regardless of topical application method and dose (P< .008, mixed model) in participants with OSA. Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. ClinicalTrials.gov; No.: NCT04236440; URL: www. gov.

What are we missing in adult obstructive sleep apnea clinical evaluation? Review of official guidelines

Purpose: This article presents a narrative review of current recommendations for the clinical evaluation and management of adult patients with obstructive sleep apnea (OSA) to identify points missing from a myofunctional perspective. Methods: The authors reviewed current official guidelines for adult patients with OSA, searching clinical evaluation and treatment recommendations for myofunctional therapy. Results: None of the current guidelines for evaluation of adult OSA recommend performing a myofunctional evaluation. Only two guidelines consider myofunctional therapy (MFT) as a treatment modality for adult patients with OSA. Conclusion: Despite the role of the pharyngeal dilator muscles as an essential contributor to the pathogenesis of OSA, this review has shown that myofunctional assessment is still not a standard recommendation in current guidelines for adult OSA. Recent guidelines occasionally include MFT as a therapeutic tool for OSA. To strengthen the knowledge base and evidence for including MFT treatment for adult patients with OSA, the authors encourage physicians to incorporate myofunctional evaluation into their regular clinical practice.

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

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

Upper airway muscles: influence on obstructive sleep apnoea pathophysiology and pharmacological and technical treatment options.

Obstructive sleep apnoea (OSA) is highly prevalent with numerous deleterious effects on neurocognitive and cardiovascular health. It is characterized by collapse of the upper airway during sleep, due to the decrease in both basal and compensatory UA muscle activities. However, the leading treatment, continuous positive airway pressure, is often poorly tolerated. This review presents latest works focusing on novel interventions targeting upper airway muscles to alleviate OSA severity. In the last years, researchers have focused on the development of alternative treatment strategies targeting UA muscle activation, including pharmacological and nonpharmacological interventions. Among the nonpharmacological treatments, hypoglossal nerve stimulation aims to increase upper airway muscle phasic activity during sleep through electrical stimulation, while myofunctional therapy improves the activity and coordination of upper airway dilator muscles.Regarding OSA pharmacotherapy, recent findings strongly suggest that selective norepinephrine reuptake inhibitors such as atomoxetine and reboxetine, when administered with antimuscarinics such as oxybutynin, can alleviate OSA in most patients increasing pharyngeal dilator muscles activity during sleep. New combinations of norepinephrine reuptake inhibitors and antimuscarinics have further been explored with variable success and animal models showed that leptin, thyrothropin releasing hormone analogues and gene therapy hold potential for the future of OSA pharmacotherapy.

First steps toward suctorial feeding in millipedes: Comparative morphology of the head of the Platydesmida (Diplopoda: Colobognatha)

AbstractAlthough most millipedes (Diplopoda) show a biting–chewing feeding mode, representatives of the so‐called Colobognatha (Platydesmida, Polyzoniida, Siphonocryptida, Siphonophorida), with their more or less reduced mouthparts, are assumed to have evolved a suctorial feeding mode, which enables them to exploit food sources like algal film and fungi hyphae. The Platydesmida are viewed as the key taxon for the understanding of mouthpart adaptations in Colobognatha, as their mouthpart elements still closely resemble those of biting–chewing millipedes. Studies of the skeletomuscular system of the Platydesmida are rare, impeding further understanding of the mouthpart evolution in millipedes. To overcome this impediment in the understanding of millipede evolution, we study the internal morphology of the head in specimens from four genera of Platydesmida: Brachycybe lecontii, Dolistenus spp., Gosodesmus claremontus, and Pseudodesmus spp. Although all Platydesmida show similarly structured skeletal elements and accompanying musculature, they are distinct from all other Diplopoda. Their head lacks eyes and organs of Tömösváry, and is pyriform and posteriorly bulging, overlapping the collum. The narrow mandibles are hidden underneath the broad genae. A previously described gnathochilarial postmentum is absent. Muscle attachment sites, such as the transverse mandibular tendon and the median septum, are reduced. The strong modifications of the head capsule, mandibles, and musculature limit the movability of the mandible for biting–chewing motions based on simulations of possible gape angles. Platydesmida likely show a scraping and slurping feeding mode, which is facilitated by the comparably well‐developed pharyngeal dilator muscles. We suggest that the Platydesmida show an intermediate state between the biting–chewing millipedes and the other suctorially feeding Colobognatha.

Tetraplegic obstructive sleep apnoea patients dilate the airway similarly to able-bodied obstructive sleep apnoea patients

Context/objective: Obstructive sleep apnoea (OSA) develops soon after cervical spinal cord injury (SCI) at rates higher than the general population, but the mechanisms are not understood. This study aimed to determine whether OSA in SCI is associated with altered pharyngeal muscle dilatory mechanics during quiet breathing, as has been observed in the non-SCI injured with obstructive sleep apnoea. Design: Cross sectional imaging study. Setting: Medical research institute. Participants: Eight cervical SCI patients with OSA were recruited and compared to 13 able-bodied OSA patients and 12 able-bodied healthy controls of similar age and BMI. Interventions and outcome measures: 3T MRI scans of upper airway anatomy and tagged-MRI to characterize airway muscle motion during quiet breathing were collected for analysis. Results: Considerable variation in the patterns of inspiratory airway muscle motion was observed in the SCI group, with some participants exhibiting large inspiratory airway dilatory motions, and others exhibiting counterproductive narrowing during inspiration. These patterns were not dissimilar to those observed in the able-bodied OSA participants. The increase in airway cross-sectional area of able-bodied control participants was proportional to increase in BMI, and a similar, but not significant, relationship was present in all groups. Conclusion: Despite the limited sample size, these data suggest that SCI OSA patients have heterogeneous pharyngeal dilator muscle responses to the negative pressures occurring during inspiration but, as a group, appear to be more similar to able-bodied OSA patients than healthy controls of similar age and BMI. This may reflect altered pharyngeal pressure reflex responses in at least some people with SCI.

Exercise as a treatment for sleep apnea

Citation:Lee-Iannotti JK, Parish JM. Exercise as a treatment for sleep apnea. J Clin Sleep Med. 2020;16(7):1005–1006.

Changes in pharyngeal collapsibility and genioglossus reflex responses to negative pressure during the respiratory cycle in obstructive sleep apnoea.

Impaired pharyngeal anatomy and increased airway collapsibility is a major cause of obstructive sleep apnoea (OSA) and a mediator of its severity. Upper airway reflexes to changes in airway pressure provide important protection against airway closure. This study shows increased pharyngeal collapsibility and attenuated genioglossus reflex responses during expiration in people with OSA. Upper airway collapse contributes to obstructive sleep apnoea (OSA) pathogenesis. Pharyngeal dilator muscle activity varies throughout the respiratory cycle and may contribute to dynamic changes in pharyngeal collapsibility. However, whether upper airway collapsibility and reflex responses to changes in airway pressure vary throughout the respiratory cycle in OSA is unclear. Thus, this study quantified differences in upper airway collapsibility and genioglossus electromyographic (EMG) activity and reflex responses during different phases of the respiratory cycle. Twelve middle-aged people with OSA (2 female) were fitted with standard polysomnography equipment: a nasal mask, pneumotachograph, two fine-wire intramuscular electrodes into the genioglossus, and a pressure catheter positioned at the epiglottis and a second at the choanae (the collapsible portion of the upper airway). At least 20 brief (∼250ms) pressure pulses (∼-11cmH2 O at the mask) were delivered every 2-10 breaths during four conditions: (1) early inspiration, (2) mid-inspiration, (3) early expiration, and (4) mid-expiration. Mean baseline genioglossus EMG activity 100ms prior to pulse delivery and genioglossus reflex responses were quantified for each condition. The upper airway collapsibility index (UACI), quantified as 100×(nadir choanal - epiglottic pressure)/nadir choanal pressure during negative pressure pulses, varied throughout the respiratory cycle (early inspiration=43±25%, mid-inspiration=29±19%, early expiration=83±19% and mid-expiration=95±11% (mean±SD) P<0.01). Genioglossus EMG activity was lower during expiration (e.g. mid-expiration vs. mid-inspiration=76±23vs. 127±41% of early-inspiration, P<0.001). Similarly, genioglossus reflex excitation was delayed (39±11vs. 23±7ms, P<0.001) and reflex excitation amplitude attenuated during mid-expiration versus early inspiration (209±36vs. 286±80%, P=0.009). These findings may provide insight into the physiological mechanisms of pharyngeal collapse in OSA.

Adult obstructive sleep apnoea: Pathogenesis, importance, diagnosis and imaging.

Obstructive sleep apnoea (OSA) is a serious worldwide health problem. Moderate-to-severe OSA has been found in up to 50% of men and 25% of women in the middle-aged population. It results in a fourfold increase in all causes of mortality. The prevalence of OSA is underestimated, partly due to absence of symptoms but also lack of knowledge amongst the population at large as well as sectors of the medical profession. Imaging, performed predominantly by clinicians and research scientists, has been integral to evaluating the anatomical basisof OSA. Increased nasal resistance and a narrowed and elongated oropharynx lead to increased collapsibility of the upper airway, predisposing to airway collapse and apnoea during sleep when there is reduction in tone of the pharyngeal dilator muscles. Unfortunately, a significantly narrowed upper airway is usually ignored by radiologists: it is not part of their reporting 'check-list'. The imaging findings in the upper airway that are strongly associated with OSA and its sequelae in various organ systems are discussed. Imaging can strongly suggest OSA; the diagnosis requires a polysomnogram for confirmation. Treatment of moderate-to-severe disease is primarily with positive airway pressure applied by a nasal or oral mask which splints the upper airway. Although highly effective, compliance is limited and other treatment modalities are increasingly being utilized.

Surgical treatment for obstructive sleep disordered breathing

The obstructive sleep apnea syndrome is a chronic condition characterized by repeated nocturnal pharyngeal collapse leading to poor-quality sleep and an increased risk of cardiovascular episodes. The classic management by continuous positive-pressure ventilation has its limitations and is not always well tolerated. The treatment alternative comprising an orthotic device is effective in 2/3 of cases, despite the dental limitations and risks inherent in long-term usage. Through a review of the literature, this paper describes the different surgical solutions used to correct obstructive sleep apnea syndrome in adults. The proposed corrections aim to maintain pharyngeal permeability during sleep either by reducing soft tissue volume or by enlarging the facial skeleton or, more recently, by acting on the tone of the pharyngeal dilator muscles. Among these different approaches, the highest success rate was reported for the maxillomandibular advancement procedure. This technique demands rigorous patient selection combined with an appropriate orthodontic work-up and management. Patient selection and the respective benefits and drawbacks of the different approaches are discussed. Indications are reported in the framework of current guidelines.

Surgical treatment for obstructive sleep disordered breathing

The obstructive sleep apnea syndrome is a chronic condition characterized by repeated nocturnal pharyngeal collapse leading to poor-quality sleep and an increased risk of cardiovascular episodes. The classic management by continuous positive-pressure ventilation has its limitations and is not always well tolerated. The treatment alternative comprising an orthotic device is effective in 2/3 of cases, despite the dental limitations and risks inherent in long-term usage. Through a review of the literature, this paper describes the different surgical solutions used to correct obstructive sleep apnea syndrome in adults. The proposed corrections aim to maintain pharyngeal permeability during sleep either by reducing soft tissue volume or by enlarging the facial skeleton or, more recently, by acting on the tone of the pharyngeal dilator muscles. Among these different approaches, the highest success rate was reported for the maxillomandibular advancement procedure. This technique demands rigorous patient selection combined with an appropriate orthodontic work-up and management. Patient selection and the respective benefits and drawbacks of the different approaches are discussed. Indications are reported in the framework of current guidelines.

Phenotypic approach to pharmacotherapy in the management of obstructive sleep apnoea.

To provide a concise synthesis of the current knowledge of obstructive sleep apnoea (OSA) phenotyping concepts and how this information is being used to develop and direct targeted pharmacotherapy for OSA. The causes of OSA vary between patients and therefore so too does the optimal therapy or therapies. Key phenotypic causes include impaired upper airway anatomy and non-anatomical contributors such as ineffective pharyngeal dilator muscles during sleep, waking up too easily to minor airway narrowing (low arousal threshold) and unstable respiratory control (high loop gain). Traditionally, heterogeneity of OSA pathophysiology was not considered in pharmacotherapy approaches for OSA. However, recent study has focussed on targeted pharmacotherapies directed towards specific OSA phenotypes. This, combined with advances in knowledge of the neurobiology of pharyngeal muscle control from animal studies that have recently been translated to human proof-of-concept studies by repurposing existing drugs that target the desired mechanisms, have opened up exciting new lines of investigation for OSA pharmacotherapy. There have been major recent advances in the development of new targeted approaches to pharmacotherapy for OSA. This study shows considerable promise for a viable and much needed pathway to drug therapy for this common chronic health condition.

Muscarinic Inhibition of Hypoglossal Motoneurons: Possible Implications for Upper Airway Muscle Hypotonia during REM Sleep.

Proper function of pharyngeal dilator muscles, including the genioglossus muscle of the tongue, is required to maintain upper airway patency. During sleep, the activity of these muscles is suppressed, and as a result individuals with obstructive sleep apnea experience repeated episodes of upper airway closure when they are asleep, in particular during rapid-eye-movement (REM) sleep. Blocking cholinergic transmission in the hypoglossal motor nucleus (MoXII) restores REM sleep genioglossus activity, highlighting the importance of cholinergic transmission in the inhibition of hypoglossal motor neurons (HMNs) during REM sleep. Glutamatergic afferent input from neurons in the parahypoglossal (PH) region to the HMNs is critical for MoXII respiratory motor output. We hypothesized that state-dependent cholinergic regulation may be mediated by this pathway. Here we studied the effects of cholinergic transmission in HMNs in adult male and female mice using patch-clamp recordings in brain slices. Using channelrhodopsin-2-assisted circuit mapping, we first demonstrated that PH glutamatergic neurons directly and robustly activate HMNs (PHGlut → HMNs). We then show that carbachol consistently depresses this input and that this effect is presynaptic. Additionally, carbachol directly affects HMNs by a variable combination of muscarinic-mediated excitatory and inhibitory responses. Altogether, our results suggest that cholinergic signaling impairs upper airway dilator muscle activity by suppressing glutamatergic input from PH premotoneurons to HMNs and by directly inhibiting HMNs. Our findings highlight the complexity of cholinergic control of HMNs at both the presynaptic and postsynaptic levels and provide a possible mechanism for REM sleep suppression of upper airway muscle activity.SIGNIFICANCE STATEMENT Individuals with obstructive sleep apnea can breathe adequately when awake but experience repeated episodes of upper airway closure when asleep, in particular during REM sleep. Similar to skeletal postural muscles, pharyngeal dilator muscles responsible for maintaining an open upper airway become hypotonic during REM sleep. Unlike spinal motoneurons controlling postural muscles that are inhibited by glycinergic transmission during REM sleep, hypoglossal motoneurons that control the upper airway muscles are inhibited in REM sleep by the combination of monoaminergic disfacilitation and cholinergic inhibition. In this study, we demonstrated how cholinergic signaling inhibits hypoglossal motoneurons through presynaptic and postsynaptic muscarinic receptors. Our results provide a potential mechanism for upper airway hypotonia during REM sleep.

Domiciliary use of transcutaneous electrical stimulation for patients with obstructive sleep apnoea: a conceptual framework for the TESLA home programme.

Obstructive sleep apnoea (OSA) is a global health problem of increasing prevalence. Effective treatments are available with continuous positive airway pressure (CPAP) therapy and mandibular advancement devices (MAD). However, there is limited long-term adherence to therapy, as CPAP and MAD require permanent usage to avoid recurrence of the symptoms and adverse ill health. Alternative treatments would aid in the treatment cascade to manage OSA effectively whenever standard therapy has been trialled and failed. Hypoglossal nerve stimulation (HNS), an invasive approach to stimulate the pharyngeal dilator muscles of the upper airway during sleep, has been approved for the treatment of OSA by several healthcare systems in recent years. In parallel to the development of HNS, a non-invasive approach has been developed to deliver electrical stimulation. Transcutaneous electrical stimulation in obstructive sleep apnoea (TESLA) uses non-invasive electrical stimulation to increase neuromuscular tone of the upper airway dilator muscles of patients with OSA during sleep. Data from previous feasibility studies and randomised controlled trials have helped to identify a subgroup of patients who are "responders" to this treatment. However, further investigations are required to assess usability, functionality and task accomplishment of this novel treatment. Consideration of these factors in the study design of future clinical trials will strengthen research methodology and protocols, improve patient related outcome measures and assessments, to optimise this emerging therapeutical option. In this review, we will introduce a conceptual framework for the TESLA home programme highlighting qualitative aspects and outcomes.

The effects of zolpidem in obstructive sleep apnea - An open-label pilot study.

New knowledge on hypnotics and their effects on the phenotypic causes of obstructive sleep apnea indicate that zolpidem has therapeutic potential for certain patients. Specifically, zolpidem increases the threshold for arousal threshold and pharyngeal dilator muscle responsiveness. However, the effects of a standard dose of zolpidem (10 mg) on obstructive sleep apnea severity and symptoms have not been investigated. In an open-label pilot study, 12 unselected people with obstructive sleep apnea were recruited following a diagnostic in-laboratory sleep study. Participants then returned for a single-night sleep study in which 10 mg of zolpidem was given just prior to sleep. Tolerability, next-day sleepiness and the effects of zolpidem on polysomnography variables were assessed. Zolpidem was well tolerated and significantly improved the sleep efficiency compared with the no-drug night (77 ± 12% versus 84 ± 9%, p = 0.005). Individual responses on obstructive sleep apnea severity to zolpidem in this unselected obstructive sleep apnea patient population were variable with no overall systematic difference in apnea-hypopnea index (29 ± 18.2 events per hr versus 33 ± 28 events per hr, p = 0.45) or other key respiratory parameters (e.g. event duration or hypoxemia). Next-day sleepiness assessed via the Karolinska Sleepiness Scale was not different between visits (4 ± 1 versus 4 ± 2, p = 0.85). These findings provide the first insight into the effects of a standard dose of zolpidem in obstructive sleep apnea, and highlight its tolerability and potential to improve sleep quality. The variable effects on obstructive sleep apnea severity observed in this pilot also underscore the need for larger trials that incorporate phenotypic characterisation (e.g. arousal threshold, Pcrit and muscle responsiveness) to understand inter-individual heterogeneity and the therapeutic potential of zolpidem for certain people with obstructive sleep apnea.

Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals.

Recent findings indicate that noradrenergic and antimuscarinic processes are crucial for sleep-related reductions in pharyngeal muscle activity. However, there are few human studies. Accordingly, this study aimed to determine if a combined noradrenergic and antimuscarinic intervention increases pharyngeal dilator muscle activity and improves airway function in sleeping humans. Genioglossus (GG) and tensor palatini electromyography (EMG), pharyngeal pressure, upper airway resistance, and breathing parameters were acquired in 10 healthy adults (5 female) during two overnight sleep studies after 4 mg of reboxetine (REB) plus 20 mg of hyoscine butylbromide (HBB) or placebo using a double-blind, placebo-controlled, randomized, cross-over design. Compared with placebo, peak and tonic GG EMG were lower (Mean ± SD: 83 ± 73 vs. 130 ± 75, p = 0.021 and 102 ± 102 vs. 147 ± 123 % wakefulness, p = 0.021, respectively) but the sleep-related reduction in tensor palatini was less (Median [25th, 75th centiles]: 53[45, 62] vs. 34[28, 38] % wakefulness, p = 0.008) with the drug combination during nonrapid eye movement (non-REM) sleep. These changes were accompanied by improved upper airway function including reduced pharyngeal pressure swings, airway resistance, respiratory load compensation, and increased breathing frequency during N2. REB and HBB significantly reduced rapid eye movement sleep compared with placebo (0.6 ± 1.1 vs. 14.5 ± 6.8 % total sleep time, p < 0.001). Contrary to our hypothesis, GG muscle activity (% wakefulness) during non-REM sleep was lower with REB and HBB. However, sleep-related reductions in tensor palatini activity were less and upper airway function improved. These findings provide mechanistic insight into the role of noradrenergic and antimuscarinic processes on upper airway function in humans and have therapeutic potential for obstructive sleep apnea. Australian New Zealand Clinical Trials Registry, https://www.anzctr.org.au, trial ID: ACTRN12616000469415.