Pharyngeal Muscle Activity Research Articles

Atomoxetine and spironolactone combine to reduce obstructive sleep apnea severity and blood pressure in hypertensive patients.

Norepinephrine reuptake inhibitors such as atomoxetine (ato) can improve OSA by increasing pharyngeal muscle activity. Mineralocorticoid antagonists such as spironolactone, may potentiate the reduction of OSA severity and reduce blood pressure. We evaluated whether adding spironolactone to atomoxetine (ato-spiro) improved responses in hypertensive OSA patients. Twenty-one patients with an apnea-hypopnea index (AHI) between 10 and 50 events/h and a history of hypertension were recruited and crossed-over in random order to ato 80mg and ato-spiro 80/50mg for 1 week after a 3-day low dose run-in period. Two dropped out due to drug related side effects. Polysomnography and 24-hour blood pressure (BP) monitoring were performed at baseline and after each treatment period. AHI decreased on both ato and ato-spiro from a baseline median(IQR) of 20.3(18.8 to 28.5) to 8.2(7 to 13.1) and 6.2(5.7 to 14.1), respectively (p < 0.001 for both). Systolic BP (mmHg) fell by mean(95%CI) -4.5(-13.8 to 4.8, p = 0.33) on ato and - 10.3(-19.2 to -1.5, p = 0.02) on ato-spiro, and diastolic BP dropped by -3.0(-8.0 to 2.0, p = 0.23) on ato and - 5.0(-9.1 to -0.9; p = 0.02) on ato-spiro. Both ato and ato-spiro led to a significant shift from apnea to hypopnea predominance (p < 0.001), and significant reductions in hypoxic burden (p ≤ 0.001) and REM sleep (p ≤ 0.001). Both ato-spiro and ato alone decreased OSA severity similarly, but ato-spiro led to even greater, statistically significant and clinically meaningful falls in systolic and diastolic BP. BP reductions were likely due to ato-related improvements in upper airway patency and hypoxemia, and to spiro-related reduced fluid retention. These findings show promise for ato-spiro as an oral treatment for hypertensive OSA patients. REGISTERED AT CLINICALTRIALS.GOV: NCT04905979.

Adapting and optimizing GCaMP8f for use in Caenorhabditis elegans.

Improved genetically encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultrafast kinetics and high sensitivity was recently reported by Zhang et al. (2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics, and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types.

Effects of TAK-925 (danavorexton) a selective orexin 2 receptor agonist on upper airway collapsibility and pharyngeal muscle activity in adults with obstructive sleep apnea

Effects of TAK-925 (danavorexton) a selective orexin 2 receptor agonist on upper airway collapsibility and pharyngeal muscle activity in adults with obstructive sleep apnea

Tongue, palatal, hyoid and pharyngeal muscle activity during chewing, swallowing, and respiration

ObjectiveChewing, swallowing, and respiration are synchronized oropharyngeal functions. This study aimed to analyze the dynamics and coordination during natural chewing and swallowing in relation to respiratory phases. DesignEight oropharyngeal muscles in minipigs were recorded using electromyography, X-ray fluoroscopy, and nasopharyngeal dynamics. Chewing cycles and swallowing episodes were analyzed for timing and activity amplitude along respiratory cycles. Digastric and middle pharyngeal constrictor were used as zero-points for timing analysis in chewing cycles and swallowing episodes, respectively. The beginning of these cycles and episodes were used as the zero-point for timing analysis in respiration during feeding. ResultsThe timing of jaw closing (57.8%) was longer than opening (42.2%) during chewing. Muscle activity occurred 20% later than digastric onsets and 15% earlier than jaw closing phase. Duration of muscle activity was shorter in ipsilateral than contralateral sides except for palatal muscles. Pharyngeal, palatal, and hyoid muscles showed longer durations than tongue muscles in jaw opening (p < 0.05). Palatal and hyoid muscles showed 2-phased activity in chewing while hyoid muscles showed higher amplitude in chewing and swallowing than other muscles. About 80% of the chewing cycles and swallowing episodes occurred in expiration. Nasopharyngeal airflow velocity increased from jaw opening to swallowing while airflow pressure decreased. ConclusionThese findings indicate key activity of palatal and pharyngeal muscles mostly in chewing. The respiratory cycle changes in chewing and swallowing simultaneously with the activation of the tongue, palatal, and pharyngeal muscles. These findings will be useful for further understanding the mechanisms in swallowing and breathing disorders.

Optical and pharmacological manipulation of hypoglossal motor nucleus identifies differential effects of taltirelin on sleeping tonic motor activity and responsiveness

Pharyngeal muscle activity and responsiveness are key pathophysiological traits in human obstructive sleep apnea (OSA) and strong contributors to improvements with pharmacotherapy. The thyrotropin-releasing hormone (TRH) analog taltirelin is of high pre-clinical interest given its neuronal-stimulant properties, minimal endocrine activity, tongue muscle activation following microperfusion into the hypoglossal motor nucleus (HMN) or systemic delivery, and high TRH receptor expression at the HMN compared to rest of the brain. Here we test the hypothesis that taltirelin increases HMN activity and/or responsivity to excitatory stimuli applied across sleep–wake states in-vivo. To target hypoglossal motoneurons with simultaneous pharmacological and optical stimuli we used customized “opto-dialysis” probes and chronically implanted them in mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT–ChR2, n = 12) and wild-type mice lacking the opsin (n = 10). Both optical stimuli applied across a range of powers (P < 0.001) and microperfusion of taltirelin into the HMN (P < 0.020) increased tongue motor activity in sleeping ChAT–ChR2 mice. Notably, taltirelin increased tonic background tongue motor activity (P < 0.001) but not responsivity to excitatory optical stimuli across sleep–wake states (P > 0.098). This differential effect on tonic motor activity versus responsivity informs human studies of the potential beneficial effects of taltirelin on pharyngeal motor control and OSA pharmacotherapy.

Stepwise Add-on and Endotype-informed Targeted Combination Therapy to Treat Obstructive Sleep Apnea: A Proof-of-Concept Study.

Oral appliance therapy (OAT) is an effective treatment for many people with obstructive sleep apnea (OSA). However, OSA pathogenesis is heterogenous and in ~50% of cases, OAT does not fully control OSA. This study aimed to control OSA in individuals with an incomplete response to OAT alone by using additional targeted therapies informed by OSA endotype characterization. Twenty-three people with OSA (apnea-hypopnea index (AHI): 41+19 events/h) not fully resolved (AHI>10 events/h) with oral appliance therapy alone were prospectively recruited. OSA endotypes were characterized pre-therapy during a detailed physiology study night. Initially, an expiratory positive airway pressure valve (EPAP) and supine-avoidance device therapy were added to target the impaired anatomical endotype. Those with residual OSA (AHI>10 events/h) then received one or more non-anatomical interventions based on endotype characterization. This included O2 (4L/min) to reduce high loop gain (unstable respiratory control) and 80/5mg atomoxetine-oxybutynin to increase pharyngeal muscle activity. Finally, if required, OAT was combined with EPAP and CPAP therapy. Twenty participants completed the study. OSA was successfully controlled (AHI<10 events/h) with combination therapy in all but one participant (17/20 without CPAP). OAT plus EPAP and supine-avoidance therapy treated OSA in 10 (50%) participants. OSA was controlled in five (25%) participants with the addition of O2 therapy, one with atomoxetine-oxybutynin and one required O2 plus atomoxetine-oxybutynin. Two participants required CPAP for their OSA, another was CPAP intolerant. These novel prospective findings highlight the potential of precision medicine to inform targeted combination therapy to treat OSA. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN12618001995268).

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.

P080 State-dependency of nocturnal swallowing in healthy adults: Incidence, motor function and coordination with breathing

Abstract Introduction Swallowing involves a complex motor pattern and coordination with breathing and other oro-motor behaviors. Sleep has major depressive effect on many of the motor neuronal pools that facilitate swallowing, particularly upper airway muscles. This study examines the state-depedence of the swallow motor program and coordination with breathing. Methods Adult subjects recruited from community undertook an overnight sleep laboratory study. Subjects were instrumented to monitor sleep (EEG), breathing (nasal mask, pneumotach), swallowing / airway valving events (epiglottic pressure, submental EMG) and pharyngeal muscle activity (peroral genioglosuss EMG electrodes).We report preliminary findings (N=5; 2 female; age: 23-57 yrs) from an ongoing study. Data reported mean ± SD. Results Nocturnal swallowing occurred intermittently thoughout the night, the majority triggered during an arousal from sleep (43-98% of all nocturnal swallows). Pharyngeal swallowing pressure was 147±44 cmH2O during quiet wake, 137±25 cmH2O during arousal from sleep, and 78 ± 23 cmH2O in stable sleep (p=0.02, RM-ANOVA). Swallows generated a brief, near-maximal burst of genioglossus EMG activity during quiet wake (90 ± 2 %, N=2) and during arousal from sleep (107 ± 24 %). In stable sleep, swallow EMG activity was 34 ± 1 %. Swallows during wakefulness occurred during expiration, the vast majority bracketed by expiration (Ex/Ex). Swallows in sleep, or during arousal from sleep, occurred in all phases of the respiratory cycle. Conclusions Swallows elicited during arousal from sleep generate ballistic EMG and pharyngeal pressures equivalent to wake state. In contrast, swallowing in stable sleep produces a markedly attenuated EMG and pharyngeal pressure.

Thyrotropin-releasing hormone analog as a stable upper airway-preferring respiratory stimulant with arousal properties.

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.

0754 Effects of Atomoxetine plus a Hypnotic on Obstructive Sleep Apnea (OSA) Severity in Patients with a Moderately Collapsible Pharyngeal Airway

Abstract Introduction The combination of atomoxetine and oxybutynin has demonstrated efficacy in the treatment of OSA. Oxybutynin may play a role as an upper airway dilator muscle activator and/or a hypnotic to improve sleep quality. We assessed the effectiveness of atomoxetine when combined with one of two hypnotics. Trazodone is a known hypnotic with possible effects on pharyngeal muscle activity. The other is lemborexant, an orexin antagonist. The effects of both combinations were assessed in patients with OSA and a moderately collapsible pharyngeal airway. Methods Recruited patients were 18 – 65 years of age, with an AHI 4 (4% desaturation criteria) of 10 – 55 and a BMI &amp;lt; 40 kg/m2. Each had to have a moderately collapsible pharyngeal airway using previously defined criteria based on the average percent desaturation during obstructive events (&amp;lt; 8%) and the ratio of hypopneas to total events (&amp;gt; 50%). After a qualifying PSG, each patient spent three nights in the sleep laboratory with approximately one week between studies. Nights were randomized to placebo, atomoxetine 80 mg plus trazodone 100 mg, and atomoxetine 80 mg plus lemborexant 10 mg. Primary outcomes were AHI 4 and the sleep apnea specific hypoxic burden (HB), the area under the SpO2 curve associated with disordered breathing events. Results Fifteen patients completed the trial (median [interquartile range] age was 52 [48-55] and BMI was 33.6 [30 – 35.1] kg/m2. Atomoxetine plus trazodone showed a strong trend for AHI 4 reduction from placebo (from 18.2 [11.8 – 31.3] to 7.4 [5.4 – 16.1] events/h, p=0.064), a significant reduction in HB from placebo (from 48.2 [31.2 – 79.6] to 18.7 [14.9 – 43.5] % min/h) and a trend for a reduction in HB with atomoxetine plus lemborexant (from 34.1 [12.1 – 128.8] to 18.7 [14.9 – 43.5] % min/h, p=0.055). There was no change in total sleep time or arousal index between treatment arms. Mild adverse events were reported on atomoxetine plus trazodone (2/15 sinusitis, 1/15 heartburn). Conclusion In OSA patients with a moderately collapsible upper airway, the combination of atomoxetine plus trazodone yielded clinically meaningful improvements in measures of sleep disordered breathing and oxygenation while atomoxetine plus lemborexant produced smaller effects. Support (If Any) This study was supported by Apnimed.

Fibroadipogenic Progenitors Regulate the Basal Proliferation of Satellite Cells and Homeostasis of Pharyngeal Muscles via HGF Secretion.

Skeletal muscle stem cells, known as satellite cells (SCs), are quiescent in normal adult limb muscles. Injury stimulates SC proliferation, differentiation, and fusion to regenerate muscle structure. In pharyngeal muscles, which are critical for swallowing foods and liquids, SCs proliferate and fuse in the absence of injury. It is unknown what factors drive increased basal activity of pharyngeal SCs. Here, we determined how niche factors influence the status of pharyngeal versus limb SCs. In vivo, a subset of pharyngeal SCs present features of activated SCs, including large cell size and increased mitochondrial content. In this study, we discovered that the pharyngeal muscle contains high levels of active hepatocyte growth factor (HGF), which is known to activate SCs in mice and humans. We found that fibroadipogenic progenitors (FAPs) are the major cell type providing HGF and are thus responsible for basal proliferation of SCs in pharyngeal muscles. Lastly, we confirmed the critical role of FAPs for pharyngeal muscle function and maintenance. This study gives new insights to explain the distinctive SC activity of pharyngeal muscles.

Physiological responses and perceived comfort to high-flow nasal cannula therapy in awake adults: effects of flow magnitude and temperature.

Clinical use of heated, high-flow nasal cannula (HFNC) for noninvasive respiratory support is increasing and may have a therapeutic role in stabilizing the upper airway in obstructive sleep apnea (OSA). However, physiological mechanisms by which HFNC therapy may improve upper airway function and effects of different temperature modes are unclear. Accordingly, this study aimed to determine effects of incremental flows and temperature modes (heated and nonheated) of HFNC on upper airway muscle activity (genioglossus), pharyngeal airway pressure, breathing parameters, and perceived comfort. Six participants (2 females, aged 35 ± 14 yr) were studied during wakefulness in the supine position and received HFNC at variable flows (0-60 L/min) during heated (37°C) and nonheated (21°C) modes. Breathing parameters via calibrated Respitrace inductance bands (chest and abdomen), upper airway pressures via airway transducers, and genioglossus muscle activity via intramuscular bipolar fine wire electrodes were measured. Comfort levels during HFNC were quantified using a visual analog scale. Increasing HFNC flows did not increase genioglossus muscle activation despite increased negative epiglottic pressure swings (P = 0.009). HFNC provided ∼7 cmH2O positive airway pressure at 60 L/min in nonheated and heated modes. In addition, increasing the magnitude of HFNC flow reduced breathing frequency (P = 0.045), increased expiratory time (P = 0.040), increased peak inspiratory flow (P = 0.002), and increased discomfort (P = 0.004). Greater discomfort occurred at higher flows in the nonheated versus the heated mode (P = 0.034). These findings provide novel insight into key physiological changes that occur with HFNC for respiratory support and indicate that the primary mechanism for improved upper airway stability is positive airway pressure, not increased pharyngeal muscle activity.NEW & NOTEWORTHY This study evaluated upper airway muscle function, breathing, and comfort across different HFNC flows and temperatures. There were no increases in genioglossus muscle activity at higher flows despite greater negative epiglottic pressure swings. Increasing negative pressure swings was associated with increasing discomfort in the nonheated mode. HFNC was associated with ∼7 cmH2O increase in positive airway pressure, which may be the primary mechanism for upper airway stability with HFNC rather than increases in pharyngeal muscle activity.

Olfactory Stimulation Successfully Improves Swallowing Function of Aged Rats Through Activating Central Neuronal Networks and Downstream DHPR-RyR-mediated Neuromuscular Activities.

Presbyphagia is age-related changes in swallowing function, which imposes a high risk of aspiration in older adults. Considering olfactory stimulation (OS) can influence behavioral activities by modulating neuronal excitability, the present study aims to determine whether OS could improve the swallowing function of aged rats through activating the central neuronal networks and downstream muscular activities participated in the control of swallowing. Aged male Wistar rats received OS by inhaling a mixture of plant-based volatile molecules twice a day for 12 days were subjected to functional magnetic resonance imaging (fMRI) and c-fos, choline acetyltransferase (ChAT) immunostaining to detect the neuronal activities of the orbitofrontal cortex (OFC) and medullary nuclei engaged in swallowing control, respectively. The functional effects of OS on downstream pharyngeal muscle activity were examined by evaluating the dihydropyridine receptor-ryanodine receptor (DHPR-RyR)-mediated intramuscular Ca2+ expression, and analyzing the amplitude/frequency of muscle contraction, respectively. In untreated rats, only moderate signal of fMRI and mild c-fos/ChAT expression was detected in the OFC and medullary nuclei, respectively. However, following OS, intense signals of fMRI and immunostaining were clearly expressed in the orbitofronto-medullary networks. Functional data corresponded well with above findings in which OS significantly enhanced DHPR-RyR-mediated intramuscular Ca2+ expression, effectively facilitated a larger amplitude of pharyngeal muscle contraction, and exhibited better performance in consuming larger amounts of daily dietary. As OS successfully activates the neuromuscular activities participated in the control of swallowing, applying OS may serve as an effective, easy, and safe strategy to greatly improve the swallow function of aging populations.

The "respiratory REM sleep without atonia benefit" on coexisting REM sleep behavior disorder - obstructive sleep apnea.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. In patients with RBD, obstructive sleep apneas syndrome (OSAS) frequently occurs as a comorbid entity. It has been reported that the presence of muscle tone during REM sleep (REM sleep without atonia-RSWA) could play a protective role in patients with OSAS RBD. In OSAS, recurrent episodes of complete or partial collapse of the upper airway occur during both, NREM and REM sleep. Particularly during sleep, the withdrawal of excitatory noradrenergic and serotoninergic inputs to the upper airway motor neurons deeply reduces the pharyngeal muscle activity, increasing the propensity for superior airway collapse. The present study compared for the first time the impact of OSAS in RBD patients with a subtype of OSAS patients with predominantly or isolated REM sleep-related OSAS (OSAS REM group) in the search of an adequate model to evaluate future therapeutic strategies. Our study found a significant lower nadir of oximetry values in OSAS RBD in comparison with the OSAS REM group. This reduction, that we called the “respiratory RSWA benefit”, is in accordance with the decrease of the nadir oximetry values observed in patients with Parkinson disease and OSAS with or without RBD. We suggest that the group of OSAS REM patients is a natural model to evaluate the respiratory protective role of RSWA in patients with coexisting RBD-OSAS and Parkinson’s disease.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10mgzolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6±12.3 vs. 40.3±16.4events/h (means±SD), p=0.938) or nadir oxyhaemoglobin saturation (79.6±6.6 vs. 79.7±7.4%,p=0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9±14%(83±11 vs. 73±17%, p=0.010). Arousal threshold increased by 15±5% with zolpidem throughout all sleep stages (p=0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

Randomized Trial on the Effects of High-Dose Zopiclone on OSA Severity, Upper Airway Physiology, and Alertness

Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5mg) modestly reduced the AHI vsbaseline without changing other sleep parameters or next-day sleepiness. This study aimed to determine the effects of high-dose zopiclone(15mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds withoutmajor overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI butmay come at the expense of increased hypoxemia and next-day impairment. Twenty-eight participants (AHI= 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed. The AHI did not change from placebo to zopiclone (-1.5 events/h; 95%CI,-6.6 to 3.5 events/h; P= .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone. A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation. Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au.

Adaptations to Oral and Pharyngeal Swallowing Function Induced by Injury to the Mylohyoid Muscle.

Muscle injury is a frequent side effect of radiation treatment for head and neck cancer. To understand the pathophysiology of injury-related dysfunction, we investigated the effects of a single muscle injury to the mylohyoid on oropharyngeal swallowing function in the rat. The mylohyoid protects the airway from food/liquid via hyolaryngeal elevation and plays an active role during both oral and pharyngeal swallowing. We hypothesized (1) that fibrosis to the mylohyoid alters swallowing bolus flow and licking patterns and (2) that injury to the mylohyoid changes normal activity of submental, laryngeal, and pharyngeal muscles during swallowing. A chilled cryoprobe was applied to the rat mylohyoid muscle to create a localized injury. One and two weeks after injury, swallowing bolus transit was assessed via videofluoroscopy and licking behavior via an electrical lick sensor. The motor activity of five swallow-related muscles was analyzed immediately after injury using electromyography (EMG). Comparisons were made pre- and post-injury. Fibrosis was confirmed in the mylohyoid at 2 weeks after injury by measuring collagen content. One week after injury, bolus size decreased, swallowing rate reduced, and licking patterns were altered. Immediately post-injury, there was a significant depression in mylohyoid and thyropharyngeus EMG amplitudes during swallowing. Our results demonstrated that injury to the mylohyoid is sufficient to cause changes in deglutition. These disruptions in oral and pharyngeal swallowing were detected prior to long-term fibrotic changes, including delays in tongue movement, alterations in bolus flow, and changes in sensorimotor function. Therefore, injuring a single important swallowing muscle can have dramatic clinical effects.

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.

Expiratory muscle strength training evaluated with simultaneous high-resolution manometry and electromyography.

To examine feasibility of a simultaneous high-resolution pharyngeal manometry (HRM) and electromyography (EMG) experimental paradigm to detect swallowing-related patterns of palatal, laryngeal, and pharyngeal muscle activity during expiratory training. Technical report. Simultaneous HRM, surface submental, and intramuscular EMG were acquired in two healthy participants during five tasks: 10-cc water swallow, maximum expiratory pressure (MEP) testing, and expiratory muscle strength training (EMST) at three pressure levels (sham, 50%, and 75% MEP). Experimental conditions were feasible. Velopharyngeal closing pressure, palate EMG activity, and pharyngeal EMG activity increased as expiratory load increased. In contrast, thyroarytenoid EMG activity was low during the expiratory task, consistent with glottic opening during exhalation. Submental EMG patterns were more variable during expiratory tasks. Intraluminal air pressures recorded with HRM were correlated with measured expiratory pressures and target valve-opening pressures of the EMST device. Results suggest that a simultaneous HRM/EMG/EMST paradigm may be used to detect previously unquantified swallowing-related muscle activity during EMST, particularly in the palate and pharynx. Our approach and initial findings will be helpful to guide future hypothesis-driven studies and may enable investigators to evaluate other muscle groups active during these tasks. Defining mechanisms of action is a critical next step toward refining therapeutic algorithms using EMST and other targeted treatments for populations with dysphagia and airway disorders. 4. Laryngoscope, 127:797-804, 2017.

Evaluation of pharyngeal muscle activity through nasopharyngeal surface electromyography in a cohort of dysphagic patients with acute ischaemic stroke.

SUMMARYOro-pharyngeal dysphagia is frequently present during the acute phase of stroke. The aim of the present study was to evaluate whether the recording of surface EMG using a nasopharyngeal (NP) electrode could be applied to evaluation of pharyngeal muscle activity in acute stroke patients and if this neurophysiological measure is related with clinical assessment of swallowing. Patients were examined and clinical severity was assessed with the National Institute of Health Stroke Scale (NIHSS) score; dysphagia was evaluated through bedside screening test using the Gugging Swallowing Scale (GUSS). Extension of the ischaemic lesion was measured by quantitative score, based on CT scan [Alberta Stroke Programme Early CT Score (ASPECTS)]. We analysed 70 patients; 50 were classified as dysphagic (Dys+), and 20 as non-dysphagic (Dys–). Each participant underwent a surface NP EMG recording performed with a NP electrode, made of a Teflon isolated steel catheter, with a length of 16 cm and a tip diameter of 1.5 mm. The electrode was inserted through the nasal cavity, rotated and positioned approximately 3 mm anteroinferior to the salpingo-palatine fold. At least four consecutive swallowing-induced EMG bursts were recorded and analysed for each participant. Swallowing always induced a repetitive, polyphasic burst of activation of the EMG, lasting around 0.25 to 1 sec, with an amplitude of around 100-600mV. Two parameters of the EMG potentials recorded with the NP electrode were analyzed: duration and amplitude. The duration of the EMG burst was increased in Dys+ patients with a statistically significant difference compared to Dys- patients (p < 0.001). The amplitude was slightly reduced in the Dys+ group, but statistically significant differences were not observed (p = 0,775). Nevertheless, the burst amplitude showed a significant inverse correlation with NIHSS [r(48) = –0.31; p < 0.05] and ASPECTS scores [r(48) = –0.27; p < 0.05], meaning that the burst amplitude progressively reduced with an increase of clinical severity (NIHSS) and topographic extension of brain lesions in CT (ASPECTS). These results suggest that NP recordings can give a semi-quantitative measure of swallowing difficulties originating from pharyngeal dysfunction, in fact, electromyographic findings suggest reduced pharyngeal motility.