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Thyrotropin-releasing hormone (TRH) is produced by the hypothalamus but most brain TRH is located elsewhere where it acts as a neuromodulator. TRH-positive neurons project to the hypoglossal motoneuron pool where TRH receptor RNA shows a high degree of differential expression compared with the rest of the brain. Strategies to modulate hypoglossal motor activity are of physiological and clinical interest given the potential for pharmacotherapy for obstructive sleep apnea (OSA), a common and serious respiratory disorder. Here, we identified the effects on tongue motor activity of TRH and a specific analog (taltirelin) applied locally to the hypoglossal motoneuron pool and systemically in vivo. Studies were performed under isoflurane anesthesia and across sleep–wake states in rats. In anesthetized rats, microperfusion of TRH (n = 8) or taltirelin (n = 9) into the hypoglossal motoneuron pool caused dose-dependent increases in tonic and phasic tongue motor activity (both p < 0.001). However, the motor responses to TRH were biphasic, being significantly larger “early” in the response versus at the end of the intervention (p ≤ 0.022). In contrast, responses to taltirelin were similar “early” versus “late” (p ≥ 0.107); i.e. once elicited, the motor responses to taltirelin were sustained and maintained. In freely behaving conscious rats (n = 10), microperfusion of 10 μM taltirelin into the hypoglossal motoneuron pool increased tonic and phasic tongue motor activity in non-rapid-eye-movement (REM) sleep (p ≤ 0.038). Intraperitoneal injection of taltirelin (1 mg/kg, n = 16 rats) also increased tonic tongue motor activity across sleep–wake states (p = 0.010). These findings inform the studies in humans to identify the potential beneficial effects of taltirelin for breathing during sleep and OSA.

AIM The mylohyoid muscle is often believed to exhibit high physiologic fluoro-deoxy-glucose (FDG) uptake. Aim of this study was to use PET/MR for adequately assessing the normal FDG distribution in floor of the mouth (FOM) muscles and neighboring major salivary glands. MATERIALS AND METHODS Patients scanned with a simultaneous PET/MRI system for initial staging or follow-up of head and neck tumors, with no malignant lesions in salivary glands or in FOM, were included. Volumes-of-interest (VOIs) were positioned separately for bilateral mylohyoid, digastric, genioglossus, and geniohyoid muscles, based on T2-weighted and T1-weighted images, and for bilateral parotid, submandibular, and sublingual glands in the same way. SUVmax was measured for each VOI. RESULTS Six hundred and ninety-two VOIs were positioned. FDG uptake in mylohyoid (SUVmax = 1.94 ± 0.37) and digastric muscles (SUVmax = 2.01 ± 0.37) were significantly higher compared to that in geniohyoid (SUVmax = 1.67 ± 0.53) and genioglossus muscles (SUVmax = 1.75 ± 0.54) (Friedman's test; P

Made available in DSpace on 2020-12-12T02:37:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-03-01 The genioglossus advancement muscle is a technique used to treat obstructive sleep apnea and depends on the precise location of the muscle insertion into the geniotubercle. The aim of this article was to present a case report about a 38-year-old male patient with obstructive sleep apnea even after undergoing uvulopalatopharyngoplasty and mentoplasty. A maxillo-mandibular advancement and genioglossus was proposed, for this a virtual planning of the surgical guide was done using a specialized software. The great advantage is to reduce the osteotomy by focusing precisely on the insertion of the muscle. The cutting guide facilitated the surgical procedure in all aspects and brought safety. Oral and Maxillofacial Surgery Department of Surgery and Integrated Clinic São Paulo State University (UNESP) School of Dentistry Division of Dentistry-Oral and Maxillofacial Surgery Medical School (USP) Hospital das Clínicas Oral and Maxillofacial Surgery Department of Surgery and Integrated Clinic São Paulo State University (UNESP) School of Dentistry

Purpose In the Union for International Cancer Control classification, extrinsic muscle involvement in oropharyngeal cancers is systematically defined as a T4a tumor, although the term extrinsic may incorrectly imply that these muscles are outside the tongue. Our aim was to describe the topography of extrinsic tongue muscles and show that their involvement in oropharyngeal cancers does not always correspond to T4a staging. Methods This cadaveric study was based on dissections of the tongues of ten healthy subjects. Dissections were carried out using sections, and careful macroscopic examination with a 3.5-diopter magnifying glass allowed the identification of muscles from their origin to their termination. Imagery and histology were excluded to stay as close as possible to the clinical evaluation. Results The sample comprised seven men and three women, with a mean age 82 years. In all the ten cases, the extrinsic muscles were located at the periphery of the tongue. The genioglossus was the only deep extrinsic muscle, extending to the periphery and under the mucous membrane of the tongue. As a result, a T1 tumor can invade the mucous membrane and affect the extrinsic muscles without transforming into a T4a tumor. Conclusion As extrinsic tongue muscles are peripheral and submucosal, the use of the term “deep” is erroneous, as is the systematic usage of extrinsic muscles to define T4a oropharyngeal cancers. This study attempts to explain this error, which is recurrent in the different editions of the Union for International Cancer Control and American Joint Committee on Cancer.

STUDY OBJECTIVES: Hypoglossal nerve stimulation (HNS) is an effective surgical alternative for patients with obstructive sleep apnea (OSA). HNS therapy relies on the stimulation of the hypoglossal nerve to open the upper airways. This stimulation could lead to alterations in tongue strength and fatigability, which could alter treatment outcome over time. The aim of the study was to investigate whether HNS alters tongue strength and fatigability. METHODS: Tongue protrusion strength (peak pressure in kPa) and fatigability (time to task failure during 50% of peak pressure contraction) were measured with a pressure transducer at least 2 months after HNS implantation (n = 30). These results were compared to a group of patients with OSA (n = 38) and a non-OSA control group (n = 35). RESULTS: Median tongue protrusion strength was lower (54.7 [43.8, 63.0] versus 60.7 [53.7, 66.0] kPa, P = .013) and fatigue occurred more quickly (21.3 [17.4, 26.3] versus 26.0 [19.3, 31.3] seconds, P = .017) in the patients with OSA compared to the non-OSA control group. In multiple regression analysis, age was a significant factor for tongue strength and diagnosis of OSA for tongue fatigability. Tongue strength and fatigability did not differ between patients with OSA with conservative therapy or observation versus after HNS implantation (51.8 [41.3, 63.4] versus 56.3 [45.0, 62.3] kPa, P = .502; 20.8 [16.3, 26.2] versus 21.8 [18.3, 26.8] seconds, P = .418). CONCLUSIONS: Tongue strength decreases with age. Tongue fatigability is more pronounced in people with OSA. However, approximately 1.5 years of HNS therapy on average does not alter tongue strength or fatigability compared to an OSA control group. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Change in Tongue Strength and Fatigue After Upper Airway Stimulation Therapy; Identifier: NCT03980158 CITATION: Wirth M, Unterhuber D, von Meyer F, et al. Hypoglossal nerve stimulation therapy does not alter tongue protrusion strength and fatigability in obstructive sleep apnea. J Clin Sleep Med. 2020;16(2):285–292.

BackgroundBulbar involvement is a hallmark of amyotrophic lateral sclerosis (ALS), but surprisingly very few studies have addressed the frequency, pattern and clinical relevance of laryngeal involvement in the disease.MethodsTwenty-six patients with spinal-onset ALS underwent nasofibroscopy (NF), followed by laryngeal electromyography (LEMG). We also studied resting activity and motor unit potentials of the genioglossus and masseter muscles.ResultsTwenty-four patients presented neurogenic changes in at least one laryngeal muscle. There were fibrillation and/or fasciculation potentials associated with chronic neurogenic changes in the same muscle in 16 patients; of these, 9 had no alteration in the genioglossus. We found no patient with tongue neurogenic changes and normal LEMG. NF was abnormal in 14 patients; in the remaining 12, LEMG identified neurogenic changes in 11 of them.ConclusionLEMG is able to identify laryngeal denervation in patients with ALS, sometimes before clinical manifestations are noticed. This technique may be a useful diagnostic tool for selected patients with suspicion of ALS.

Background The classical anatomical representation of the lingual relief of the mental region of the mandible reflects the presence of geniohyoid as well as genioglossus attachment areas, which are divided into two or single areas. The International Anatomical Terminology (contains references to the presence of upper and lower spinae mentales, but the terminology does not reflect the content of these structures. The aim of this study was to examine and classify the lingual canals of the mental region. Materials and methods Using a Sirona ORTHOPHOS XG 3D tomograph (isotropic voxel size 0.1 in high-resolution mode) and KaVo 3D eXam cone beam computed tomography, the mental region of the mandible was analyzed in 561 patients aged 18–75 years with regard to bone density and the occurrence of a canal opening on the lingual side of the mandible. In order to visualize the mental spine area, another 50 mandibles were analyzed, divided into two groups of 25 mandibels each: 25 native and 25 dry preparations. Results By prevalence the following channel types were classified: in 33% type I (narrow); in 32% type II (double) and of these in 17.5% (convergent) and type IIb in 14.5% a type IIb subtype (non-convergent); in 14% type III (wide); in 12% type IV (hook-shaped) and in 9% type V (diverging channel), identifying three combined components: the system of channels of the superior and inferior mental spine, and the transversal intraosseous canal of the mental region of the mandible. Conclusions Our anatomical and radiological approach allowed us to suggest a new classification of intraosseous organization of the anterior part of the human mandible. As a result of studying X-ray anatomical and anatomical-topographical, constitutional-based, structural features of the mandible, intraosseous structures of the anterior mandible were clarified and classified, which solve not only terminological disputes, but also are important clinical guidelines for bone surgery, prosthetics, traumatology, endodontic treatment, dental implantation and local anesthesia.

The aim of this study was to evaluate the association between genioglossus activity during sleep onset and the outcome of uvulopalatopharyngoplasty (UPPP) in patients with obstructive sleep apnea.Case series with planned data collection.Sleep medical center.Forty-four patients with obstructive sleep apnea underwent overnight polysomnography with synchronous genioglossus electromyography (GGEMG) with intraoral electrodes. In addition, all patients underwent revised UPPP with uvula preservation and were followed up with polysomnography at least 3 months after surgery.Twenty-five patients (56.8%) were responders. Multiple regression analysis revealed that increasing tonsil size (odds ratio [OR], 0.086;Sleep-onset GGEMG and tonsil size are both important in deciding outcomes of UPPP. Patients with tonsil size III or IV and higher sleep onset may be more suitable candidates for UPPP because of the higher probability of surgical success.

Aging of population brings related social problems, such as muscle attenuation and regeneration barriers with increased aging. Muscle repair and regeneration depend on muscle stem cells (MuSCs). Obstructive sleep apnea (OSA) rises in the aging population. OSA leads to hypoxia and upper airway muscle injury. However, little is known about the effect of increasing age and hypoxia to the upper airway muscle. The genioglossus (GG) is the major dilator muscle to keep the upper airway open. Here, we reported that muscle fiber and MuSC function declined with aging in GG. Increasing age also decreased the migration and proliferation of GG MuSCs. p53 and p21 were high expressions both in muscle tissue and in GG MuSCs. We further found that hypoxia inhibited GG MuSC proliferation and decreased myogenic differentiation. Then, hypoxia enhanced the inhibition effect of aging to proliferation and differentiation. Finally, we investigated that hypoxia and aging interact to form a vicious circle with upregulation of p53 and p21. This vicious hypoxia plus aging damage accelerated upper airway muscle injury. Aging and hypoxia are the major damage elements in OSA patients, and we propose that the damage mechanism of hypoxia and aging in GG MuSCs will help to improve upper airway muscle regeneration.

PurposeWe performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer.Patients and MethodsEleven patients (age 49 to 86 years) with newly diagnosed or recurrent oral and oropharyngeal cancer were injected intravenously with 18F-PARPi (331 ± 42 MBq) and dynamic PET/CT imaging was performed between 0 min and 25 min post-injection. Static PET/CT scans were obtained at 30 min, 60 min and 120 min p.i. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry and CBC were obtained before and after administration of 18F-PARPi.Results18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG negative lymph nodes of three patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. Contrast for 18F-PARPi and 18F-FDG was comparable (SUVmax(lesion)/SUVmax(genioglossus) = 3.3 and 3.0, respectively; p = 0.23), and SUVmax values for 18F-PARPi were less variable compared to 18F-FDG (1.3 versus 6.0, p = 0.001).ConclusionsImaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction caused by a loss of upper airway dilator muscle tone during sleep and an inadequate compensatory response by these muscles in the context of an anatomically compromised airway. The genioglossus (GG) is the main upper airway dilator muscle. Currently, continuous positive airway pressure is the first-line treatment for OSA. Nevertheless, problems related to poor adherence have been described in some groups of patients. In recent years, new OSA treatment strategies have been developed to improve GG function. (A) Hypoglossal nerve electrical stimulation leads to significant improvements in objective (apnea-hypopnea index, or AHI) and subjective measurements of OSA severity, but its invasive nature limits its application. (B) A recently introduced combination of drugs administered orally before bedtime reduces AHI and improves the responsiveness of the GG. (C) Finally, myofunctional therapy also decreases AHI, and it might be considered in combination with other treatments. Our objective is to review these therapies in order to advance current understanding of the prospects for alternative OSA treatments. The authors thank Ana Belen Martínez and Juan Solis for their work on the illustrations.

The incidence of Sleeping-Disorder Breathing (SDB) is getting higher and higher, which is the source of chronic diseases in internal medicine, and brings a heavy social and economic burden. Noninvasive positive pressure ventilation, it's current standard treatment, still has many disadvantages, like high price, low compliance, ineffectiveness treatment of central suspension and so on. By detecting respiratory pressure and temperature, oxygen saturation (SpO2) and heart rate to judge if residual occlusion events are happening, then stimulate the hypoglossal nerve to contract the genioglossus, this paper proposes a respiratory mask based on hypoglossal nerve stimulation. In the next step, the mask is tested for safety and accuracy. The nerve electrical stimulation module, blood oxygen saturation, heart rate, respiratory pressure and temperature can be detected accurately. And the sleep breathing state is judged by the above parameters. Corresponding electrical stimulation is provided during sleep apnea, and this design is expected to provide a new non-invasive treatment for sleep-disordered breathing.

Background 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 (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness. Research Question This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment. Study Design and Methods 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 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg 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. Results 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. Interpretation 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. Trial Registry Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au

There are increased risks for deglutition disorders in people with Down syndrome (DS). Although mouse models have been used to study the biological underpinnings of DS in other areas, relatively little is known about swallowing phenotypes in these models. We hypothesized that swallowing performance would be affected in adult mouse models of DS, relative to typical control mice. Videofluoroscopic swallow studies (VFSS) were conducted on adults of two mouse models of DS: Ts65Dn and Dp(16)1Yey, and evaluated in comparison with age-matched controls. Relative to other groups, adult Ts65Dn showed significantly slower swallow rates, longer inter-swallow intervals (ISI), and greater numbers of jaw excursion cycles preceding each swallow. In contrast, adult Dp(16)1Yey mice showed swallowing performance similar to control mice. Exploratory quantitative analyses of the intrinsic tongue (transverse muscle), and extrinsic tongue muscles [genioglossus (GG), styloglossus (SG), and hyoglossus (HG)] showed no significant differences between genotype groups in myosin heavy chain isoform profiles. Collectively, these findings suggest that while swallowing is typical in adult Dp(16)1Yey, swallowing in adult Ts65Dn is atypical due to unknown causes. The finding that adult Ts65Dn may have utility as a model of dysphagia provides new opportunities to elucidate biological underpinnings of dysphagia associated with DS.

This study investigated whether a change in posture affected the activity of the upper-airway dilator muscle genioglossus in participants with and without obstructive sleep apnea (OSA). During wakefulness, a monopolar needle electrode was used to record single motor unit activity in genioglossus in supine and upright positions to alter the gravitational load that causes narrowing of the upper airway. Activity from 472 motor units was recorded during quiet breathing in 17 males, nine of whom had OSA. The mean number of motor units for each participant was 11.8 (SD 3.4) in the upright and 16.0 (SD 4.2) in the supine posture. For respiratory-modulated motor units, there were no significant differences in discharge frequencies between healthy controls and participants with OSA. Within each breath, genioglossus activity increased through the recruitment of phasic motor units and an increase in firing rate, with an overall increase of ~6 Hz (50%) across both postures and participant groups. However, the supine posture did not lead to compensatory increases in the peak discharge frequencies of inspiratory and expiratory motor units, despite the increase in gravitational load on the upper airway. Posture also had no significant effect on the discharge frequency of motor units that showed no respiratory modulation during quiet breathing. We postulate that, in wakefulness, any increase in genioglossus activity to compensate for the gravitational effects on the upper airway is achieved primarily through the recruitment of additional motor units in both healthy controls and participants with OSA.

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive sleep-related losses of upper airway patency that occur most frequently during rapid eye movement (REM) sleep. Hypoglossal motoneurons play a key role in regulating upper airway muscle tone and patency during sleep. REM sleep activates GABA and glycine neurons in the ventral medulla (VM) to induce cortical desynchronization and skeletal muscle atonia during REM sleep; however, the role of this brain region in modulating hypoglossal motor activity is unknown. We combined optogenetic and chemogenetic approaches with in-vitro and in-vivo electrophysiology, respectfully, in GAD2-Cre mice of both sexes to test the hypothesis that VM GABA/glycine neurons control the activity of hypoglossal motoneurons and tongue muscles. Here, we show that there is a pathway originating from GABA/glycine neurons in the VM that monosynaptically inhibits brainstem hypoglossal motoneurons innervating both tongue protruder genioglossus (GMNs) and retractor (RMNs) muscles. Optogenetic activation of ChR2-expressing fibers induced a greater postsynaptic inhibition in RMNs than in GMNs. In-vivo chemogenetic activation of VM GABA/glycine neurons produced an inhibitory effect on tongue electromyographic (EMG) activity, decreasing both the amplitude and duration of inspiratory-related EMG bursts without any change in respiratory rate. These results indicate that activation of GABA/glycine neurons from the VM inhibits tongue muscles via a direct pathway to both GMNs and RMNs. This inhibition may play a role in REM sleep associated upper airway obstructions that occur in patients with OSA.

KEY POINTS 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. ABSTRACT 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 (∼250 ms) pressure pulses (∼-11 cmH2 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 100 ms 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

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

Objectives/hypothesis Upper airway stimulation for obstructive sleep apnea (OSA) via implantable hypoglossal nerve stimulation (HGNS) reduces airway obstruction by selectively stimulating nerve fibers that innervate muscles that produce tongue protrusion, while avoiding fibers that produce tongue retraction. This selective stimulation likely depends upon the location, intensity, and type of electrical stimulation delivered. This study investigates the impact of changing stimulation parameters on tongue muscle activation during HGNS using intraoperative nerve integrity monitoring in conjunction with electromyography (EMG). Study design Prospective case series. Methods Ten patients undergoing unilateral HGNS implantation for OSA in a university hospital setting were studied. Data included EMG responses in tongue muscles that produce protrusion (genioglossus), retraction (styloglossus/hyoglossus), and stiffening (transverse/vertical) in response to intraoperative bipolar probe electrical stimulation of lateral and medial branches of the hypoglossal nerve (HGN) and to implantable pulse generator (IPG) unipolar and bipolar settings after placement of the stimulation cuff. Results Stimulation of medial division HGN branches resulted in EMG responses in genioglossus muscles, but not in styloglossus/hyoglossus muscles, whereas stimulation of the lateral division HGN branches drove responses in styloglossus/hyoglossus muscles. Variable responses in transverse/vertical muscles were observed with stimulation of lateral and medial division branches. After electrode cuff placement, unipolar and bipolar HGN stimulation configurations of IPG resulted in unique patterns of muscle activation. Conclusions The relative activation of extrinsic and intrinsic tongue musculature by HGNS is determined by stimulus location, intensity, and type. Intraoperative neurophysiological monitoring of tongue muscle activation enables proper electrode cuff placement and may provide essential data for stimulus optimization. Level of evidence 4 Laryngoscope, 130:1836-1843, 2020.

In the cat four different types of vocalization, mews, howls, cries, and hisses were generated by microstimulation in different parts of the periaqueductal gray (PAG). While mews imply positive vocal expressions, howls, hisses, and cries represent negative vocal expressions. In the intermediate PAG, mews were generated in the lateral column, howls, and hisses in the ventrolateral column. Cries were generated in two other regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. In order to define the specific motor patterns of the mews, howls, and cries, the following muscles were recorded during these vocalizations; larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration muscles (diaphragm, internal intercostal, external, and internal abdominal oblique). During these mews, howls, and cries we analyzed the frequency, intensity, activation cascades power density, turns, and amplitude analysis of the electromyograms (EMGs). It appeared that each type of vocalization consists of a specific circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla is known to serve as the final premotor interneuronal output system for vocalization. Although neurochemical microstimulation in the NRA itself also generated vocalizations, they only consisted of guttural sounds, the EMGs of which involved only small parts of the EMGs of the mews, howls, and cries generated by neurochemical stimulation in the PAG. These results demonstrate that positive and negative vocalizations are generated in different parts of the PAG. These parts have access to different groups of premotoneurons in the NRA, that, in turn, have access to different groups of motoneurons in the brainstem and spinal cord, resulting in different vocalizations. The findings would serve a valuable model for diagnostic assessment of voice disorders in humans.

Oral appliance (OA) can effectively treat obstructive sleep apnea; however, numerous types of oral appliances and designs are variable and the precise mechanisms behind differences in treatment outcomes are uncertain. The objective of this study was to evaluate the effects of different degrees of mandibular position [4° of bite openings (BO): 2, 4, 8 and 12 mm; and protrusion (P): 0, 50%, MAX], for both the upright and supine positions: BO2 mm_P0%, BO4 mm_P0%, BO4 mm_P50%, BO4 mm_PMAX, BO8 mm_P0%, BO12 mm_P0%; with an OA on the: (1) activity of the genioglossus (GG) muscle by electromyogram, (2) inspiration by airflow sensor, and (3) recording mandibular movements (incisor and mandibular condyle point) in each position. Nine healthy male adults (age 27.5 ± 1.30 years) were recruited. The results show that GG muscle activity increased significantly from BO 4 mm_P0% to BO12 mm_P0% during the supine position, and the strongest signal was found in BO4 mm_PMAX, compared to all of the other positions, and GG muscle activity in BO4 mm_P0% tended to be lower. From supine to upright position the inspiration increased significantly but GG muscle activity did not. These results might be a stimulus to augment a compensatory mechanism of GG muscle induced by OA, however, mainly in protrusion position. The increase of BO (2–12 mm) and even maximum protrusion might not negatively affect the temporomandibular joint.

Surgical intervention for obstructive sleep apnea (OSA) is a complex topic. The discussion involves intricate procedures targeting specific areas of the upper airway. Because of the wide variety of physiologic and anatomic causes of this disorder it is important to tailor the treatment to offer the patient the best possible outcome. Genioglossus, hyoid, and tongue base procedures should be considered among theses treatment options.

Study objectives Arousals from sleep vary in duration and intensity. Accordingly, the physiological consequences of different types of arousals may also vary. Factors that influence arousal intensity are only partly understood. This study aimed to determine if arousal intensity is mediated by the strength of the preceding respiratory stimulus, and investigate other factors mediating arousal intensity and its role on post-arousal ventilatory and pharyngeal muscle responses. Methods Data were acquired in 71 adults (17 controls, 54 obstructive sleep apnea patients) instrumented with polysomnography equipment plus genioglossus and tensor palatini electromyography (EMG), a nasal mask and pneumotachograph, and an epiglottic pressure sensor. Transient reductions in CPAP were delivered during sleep to induce respiratory-related arousals. Arousal intensity was measured using a validated 10-point scale. Results Average arousal intensity was not related to the magnitude of the preceding respiratory stimuli but was positively associated with arousal duration, time to arousal, rate of change in epiglottic pressure and negatively with BMI (R2 > 0.10, P ≤ 0.006). High (> 5) intensity arousals caused greater ventilatory responses than low (≤ 5) intensity arousals (10.9 [6.8-14.5] vs. 7.8 [4.7-12.9] L/min; P = 0.036) and greater increases in tensor palatini EMG (10 [3-17] vs. 6 [2-11]%max; P = 0.031), with less pronounced increases in genioglossus EMG. Conclusions Average arousal intensity is independent of the preceding respiratory stimulus. This is consistent with arousal intensity being a distinct trait. Respiratory and pharyngeal muscle responses increase with arousal intensity. Thus, patients with higher arousal intensities may be more prone to respiratory control instability. These findings are important for sleep apnea pathogenesis.

Objectives/Hypothesis To assess the effect of genioglossus, geniohyoid, and anterior digastric muscle advancement on base of tongue and hyoid position. Study Design Cadaver experiments. Methods In fresh cadavers, the mandibular attachments of the genioglossus, geniohyoid, and anterior digastric muscles were advanced anteriorly by 6, 10, or 14 mm, and the anterior displacement of the base of tongue and hyoid was measured. The degrees of displacement of the tongue base and hyoid by the individual muscles and combinations of muscles were compared to one another. Results In 11 cadavers, 462 measurements were taken. Genioglossus advancement alone produced significantly greater tongue base advancement than any other muscle (P < .001). No combination of muscles produced significantly more tongue base advancement than the genioglossus alone. Geniohyoid (P < .001) and anterior digastric muscle (P < .001) advancement both produced significantly greater hyoid advancement than the genioglossus, but there was no difference between the two (p = .615). No combination of muscles produced significantly more hyoid advancement than the geniohyoid or anterior digastric alone. Conclusions Genioglossus muscle advancement produces the greatest base of tongue advancement. Geniohyoid or anterior digastric muscle advancement produces the greatest hyoid advancement. Advancement of neither base of tongue nor hyoid was superior when combinations of muscles were moved. Level of Evidence NA Laryngoscope, 127:1938–1942, 2017

There is too much individual patient variation in mandibular anatomy for any single described genioglossus advancement technique to be used consistently. Virtual surgical planning allows surgeons to design genioglossus osteotomy that captures the structures of interest. Intraoperative osteotomy and positioning guides mitigate known risks of the procedure while maximizing the reproducibility and efficacy of the procedure. In this report, we demonstrate the protocol step by step as it had been used on 10 patients, and we highlight 3 clinical scenarios that exemplify its utility.

Obstructive sleep apnea (OSA) is characterized by repeated involuntary closure of the pharyngeal airspace during sleep. Normal activity of the genioglossus (GG) muscle is important in maintaining airway patency, and inhibition of GG activity can contribute to airway closure. Neurons in the hypoglossal motor nucleus (HMN) regulate GG activity. Adrenergic tone is an important regulator of HMN neuronal excitability. In laboratory models α1-adrenergic antagonists inhibit HMN neurons and GG activity, suggesting that α1-adrenergic antagonism might adversely affect patients with OSA. To date there has been no report of such a case. Case Summary: The patient was a 67-year old man with a 27-month history of obstructive sleep apnea. Diagnostic polysomnography demonstrated a baseline apnea-hypopnea index (AHI) of 21.3 and a trough oxygen saturation of 84%. Treatment with continuous positive airway pressure (CPAP) was initiated. The AHI in year 1 averaged 1.0 ± 0.1 (mean ± SD) and 0.8 ± 0.1 in year 2. Other medical conditions included hypertension controlled with losartan and benign prostatic hypertrophy not well controlled by finasteride monotherapy. The α1-adrenergic receptor antagonist tamsulosin 0.4 mg daily was added. Shortly after initiation of tamsulosin, subjective sleep quality deteriorated. Significant surges in obstructive events, apneic episodes, and AHI were also recorded, and nocturnal airway pressure was frequently sustained at the CPAP device maximum of 20 cm H2O. Tamsulosin was discontinued. CPAP parameters and sleep quality returned to the pre-tamsulosin baselines within 10 days. These findings suggest that α1-adrenergic blockade with tamsulosin may exacerbate sleep-disordered breathing in susceptible patients.

Objective To examine the suitability of commonly used agents for drug-induced sleep endoscopy (DISE) based on agent-specific neuropharmacology. Data Sources PubMed. Review Methods A literature search of the PubMed database was performed on January 1, 2016. A two-layered search strategy was performed to identify relevant pharmacologic agents and articles related to neuropharmacology for these agents. The first search identified relevant pharmacologic agents; the second search examined agents with greater than five results from search 1, along with medical subject headings “respiration,” “sleep,” “pharmacology,” and/or “[respective agent] (e.g., propofol).” Articles not in English were excluded. Bibliographies of pertinent articles were hand-searched for additional articles. Results Three agents were commonly identified from search 1: propofol, midazolam, and dexmedetomidine with 44, 13, and 6 results, respectively. Of note, 11 results utilized coinduction with midazolam and propofol. Search 2 for propofol, midazolam, and dexmedetomidine retrieved 219, 220, and 26 results, respectively. Eleven results for propofol, 4 for midazolam, and 9 for dexmedetomidine were found to be related to their neuropharmacology. Conclusion The current review demonstrates relatively few investigations seeking to characterize the neuropharmacologic suitability of DISE agents. Compared to propofol and midazolam, dexmedetomidine's mechanism of action appears most likely to induce natural sleep pathways. Further study of its effect on upper airway collapsibility (critical closing pressure) and pharyngeal muscle tone (genioglossus electrode electromyography) are needed. Laryngoscope, 2016 Laryngoscope, 127:273–279, 2017

Study objectives To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. Methods Twelve patients with OSA (apnea-hypopnea index = 41 ± 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness. Results Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 ± 5.6 versus -26.4 ± 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 ± 0.2 versus -0.44 ± 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns. Conclusions In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others. Clinical trial registration Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.

Parkinson disease (PD) is associated with speech and swallowing difficulties likely due to pathology in widespread brain and nervous system regions. In post-mortem studies of PD, pathology has been reported in pharyngeal and laryngeal nerves and muscles. However, it is unknown whether PD is associated with neuromuscular changes in the tongue. Prior work in a rat model of PD (Pink1-/-) showed oromotor and swallowing deficits in the premanifest stage which suggested sensorimotor impairments of these functions. The present study tested the hypothesis that Pink1-/- rats show altered tongue function coinciding with neuromuscular differences within tongue muscles compared to wildtype (WT). Male Pink1-/- and WT rats underwent behavioral tongue function assays at 4 and 6 months of age (n = 7-8 rats per group), which are time points early in the disease. At 6 months, genioglossus (GG) and styloglossus (SG) muscles were analyzed for myosin heavy chain isoforms (MyHC), α-synuclein levels, myofiber size, centrally nucleated myofibers, and neuromuscular junction (NMJ) innervation. Pink1-/- showed greater tongue press force variability, and greater tongue press forces and rates as compared to WT. Additionally, Pink1-/- showed relative increases of MyHC 2a in SG, but typical MyHC profiles in GG. Western blots revealed Pink1-/- had more α-synuclein protein than WT in GG, but not in SG. There were no differences between Pink1-/- and WT in myofiber size, centrally-nucleated myofibers, or NMJ innervation. α-synuclein protein was observed in nerves, NMJ, and vessels in both genotypes. Findings at these early disease stages suggest small changes or no changes in several peripheral biological measures, and intact motor innervation of tongue muscles. Future work should evaluate these measures at later disease stages to determine when robust pathological peripheral change contributes to functional change, and what CNS deficits cause behavioral changes. Understanding how PD affects central and peripheral mechanisms will help determine therapy targets for speech and swallowing disorders.

STUDY OBJECTIVES Mandibular advancement splints (MAS) are the leading treatment alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). However, not all patients experience clinical benefit and treatment prediction remains challenging. Understanding the effects of mandibular advancement on pharyngeal collapsibility and muscle function may provide valuable information on the mechanisms of MAS, and thereby help to develop novel approaches for patient selection. Thus, we aimed to determine dose-dependent effects of mandibular advancement on pharyngeal collapsibility and muscle function concurrently in OSA patients undergoing MAS therapy. METHODS Twelve (11 male) MAS-naive patients underwent a detailed physiology sleep study (polysomnography) to quantify pharyngeal collapsibility (PCRIT), pharyngeal muscle responsiveness to negative pharyngeal pressure (via genioglossus intramuscular electromyography and an epiglottic pressure sensor) and effectiveness to restore airflow and minute ventilation (Vi) after 1-minute transient CPAP reductions (induced airflow-limitation) at three mandibular advancement positions: 0% (habitual bite), 50% and 100% of the maximum comfortable mandibular advancement. Standard clinical polysomnography after MAS therapy optimization was performed to determine treatment outcome. RESULTS Overall, participants were obese with severe OSA (mean ± SD: BMI = 31 ± 4 kg/m2, apnea-hypopnea index [AHI] = 33 ± 14 events/hour). PCRIT decreased with mandibular advancement in a dose-dependent manner (1.8 ± 3.9 vs. -0.9 ± 2.9 vs. -4.0 ± 3.6 cmH2O; p < 0.001). There was no systematic change in genioglossus muscle responsiveness (p = 0.09) or effectiveness to restore peak airflow (p = 0.4) or Vi (p = 0.7) with mandibular advancement. CONCLUSIONS Mandibular advancement reduces pharyngeal collapsibility in a dose-dependent manner without systematically changing genioglossus muscle function in a predominantly obese and severe OSA population. This indicates that the primary mode of action of MAS therapy is via improvement in passive pharyngeal anatomy.

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

New Findings: What is the central question of this study? Moving to supine induces upper airway modifications and a fluid shift to the neck, which represent inspiratory load that predisposes to upper airway collapse.Is there cortical participation in the response to the load induced by transition to a supine posturein awake healthy subjects? What is the main finding and its importance? Moving to supine induces transient cortical activation in awake healthy subjects, with greater fluid shift, supporting possible cortical participation in the response to upper airway load induced by transition to a supine posture. Our findings open new perspectives in the understanding of the pathogenesis of obstructive sleep apnoea. Abstract: Moving from sitting upright to lying supine causes anatomical modifications and a fluid shift to the neck, which represent inspiratory loads that predispose to upper airway collapse. The pre-inspiratory potential (PIP) corresponds to the cortical activity observed during inspiratory load. In the sitting position during wakefulness, some obstructive sleep apnoea patients exhibit PIP, probably in relationship to upper airway abnormalities. The aim of this study was to investigate whether moving to the supine position induces respiratory-related cortical activation (PIP) in awake healthy subjects. The ECG was analysed to detect PIP, and EMG activity of the genioglossus muscle and ventilation were measured in the sitting position, immediately after moving to the supine position, and during application of leg positive pressure in the supine position to promote fluid shift, which was measured by bioelectrical impedance. Twenty-four subjects were included. From sitting to lying, PIP prevalence increased from 1/24 to 11/24 (P=0.002), and ventilation decreased with no change in genioglossus activity. The fluid shift from sitting to supine was higher in the subjects exhibiting PIP while supine compared with the subjects without PIP [median (25th; 75th centiles) 440(430; 520) versus 320(275; 385)ml, P=0.018], without any other differences. From before to during leg positive pressure, PIP disappeared (P=0.006). These results indicate that moving from sitting to lying induces transient respiratory-related cortical activity in awake healthy subjects with greater fluid shift, supporting possible cortical participation in the response to upper airway loading induced by moving from sitting upright to lying supine. This study offers new perspectives in the understanding of obstructive sleep apnoea pathogenesis.

Lingual dystonia is a debilitating type of oromandibular dystonia characterized by involuntary, often task-specific, contractions of the tongue muscle activated by speaking or eating. Botulinum neurotoxin (BoNT) has been used to treat lingual dystonia, however, it is known to cause serious complications, such as dysphasia and aspiration. The purpose of this study was to evaluate the efficacy and adverse effects of individualized BoNT therapy for lingual dystonia. One-hundred-and-seventy-two patients (102 females and 70 males, mean age: 46.2 years) with lingual dystonia were classified into four subtypes based on symptoms of involuntary tongue movements: protrusion (68.6%), retraction (16.9%), curling (7.6%), and laterotrusion (7.0%). Patients were treated with BoNT injection into the genioglossus and/or intrinsic muscles via individualized submandibular and/or intraoral routes. Results were compared before and after BoNT therapy. Botulinum neurotoxin was injected in 136 patients (mean: 4.8 injections). Clinical sub-scores (mastication, speech, pain, and discomfort) in a disease-specific rating scale were reduced significantly (p &lt, 0.001) after administration. Comprehensive improvement after BoNT injection, assessed using the rating scale, was 77.6%. The curling type (81.9%) showed the greatest improvement, while the retraction type showed the least improvement (67.9%). Mild and transient dysphasia occurred in 12.5% of patients (3.7% of total injections) but disappeared spontaneously within several days to two weeks. No serious side effects were observed. With careful diagnosis of subtypes and a detailed understanding of lingual muscle anatomy, individualized BoNT injection into dystonic lingual muscles can be effective and safe.

Introduction Obstructive sleep apnea (OSA) is characterized by repetitive episodes of pharyngeal collapse. The genioglossus is a major upper airway dilator muscle thought to be important in OSA pathogenesis. Upper airway (UA) muscle training has reported benefits in some OSA patients. Our goal was to assess the effect of upper airway muscle training on OSA outcomes. Methods Sixty five patients with OSA (AHI>10/h) were divided in three subgroups: 1) Treated with auto-CPAP (n=21), 2) Previously failed or refused CPAP therapy (no treatment), (n=24), 3) Currently treated with an oral appliance who still have residual OSA (AHI>10/h), (n=20). All subjects were given a custom-made tongue strengthening device. Within each group we conducted a prospective, randomized, controlled study examining the effect of upper airway muscle training. In each subgroup, subjects were randomized to UA muscle training (volitional protrusion against resistance) or sham group (negligible resistance), with 1:1 ratio over 6 weeks of treatment (twice daily for 20 min/session). In the baseline and the final visit, subjects completed home sleep testing, questionnaires (ESS, PSQI), acoustic pharynogometry, Iowa Oral Performance Instrument (IOPI), and Psychomotor Vigilance Test (PVT). Results Results remain blinded; 33 patients received treatment Y and 32 patients received treatment Z. To date, we have not observed a main effect of treatment group on several measures of OSA severity. Some changes in subjective measures over time were observed but difficult to interpret until unblinding occurs. Conclusion Treatment of OSA using upper airway muscle training exercises requires further study. Whether muscle training is a viable approach for a definable subset of OSA patients remains unclear. Support R01HL085188-05A1 (U.S. NIH Grant/Contract)