Regional associations between inspiratory tongue dilatory movement and genioglossus activity during wakefulness in people with obstructive sleep apnoea.

Inspiratory tongue dilatory movement is believed to be mediated via changes in neural drive to genioglossus. However, this has not been studied during quiet breathing in humans. Therefore, this study investigated this relationship and its potential role in obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue dilatory movement, quantified with tagged magnetic resonance imaging, and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in nine controls [apnoea-hypopnea index (AHI) ≤5 events/h] and 37 people with untreated OSA (AHI >5 events/h). Measurements were obtained for 156 neuromuscular compartments (85%). Analysis was adjusted for nadir epiglottic pressure during inspiration. Only for 106 compartments (68%) was a larger anterior (dilatory) movement associated with a higher phasic EMG [mixed linear regression, beta = 0.089, 95% CI [0.000, 0.178], t(99) = 1.995, P = 0.049, hereafter EMG↗/mvt↗]. For the remaining 50 (32%) compartments, a larger dilatory movement was associated with a lower phasic EMG [mixed linear regression, beta = -0.123, 95% CI [-0.224, -0.022], t(43) = -2.458, P = 0.018, hereafter EMG↘/mvt↗]. OSA participants had a higher odds of having at least one decoupled EMG↘/mvt↗ compartment (binary logistic regression, odds ratio [95% CI]: 7.53 [1.19, 47.47] (P = 0.032). Dilatory tongue movement was minimal (>1 mm) in nearly all participants with only EMG↗/mvt↗ compartments (86%, 18/21). These results demonstrate that upper airway dilatory mechanics cannot be predicted from genioglossus EMG, particularly in people with OSA. Tongue movement associated with minimal genioglossus activity suggests co-activation of other airway dilator muscles. KEY POINTS: Inspiratory tongue movement is thought to be mediated through changes in genioglossus activity. However, it is unknown if this relationship is altered by obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue movement, quantified with tagged magnetic resonance imaging (MRI), and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in four tongue compartments of people with and without OSA. Larger tongue anterior (dilatory) movement was associated with higher phasic genioglossus EMG for 68% of compartments. OSA participants had an ∼7-times higher odds of having at least one compartment for which a larger anterior tongue movement was not associated with a higher phasic EMG than controls. Therefore, higher genioglossus phasic EMG does not consistently translate into tongue dilatory movement, particularly in people with OSA. Large dilatory tongue movements can occur despite minimal genioglossus inspiratory activity, suggesting co-activation of other pharyngeal muscles.

Regional respiratory movement of the tongue is coordinated during wakefulness and is larger in severe obstructive sleep apnoea.

KEY POINTS: Coordination of the neuromuscular compartments of the tongue is critical to maintain airway patency. Currently, little is known about the extent to which regional tongue dilatory motion is coordinated in heathy people and if this coordination is altered in people with obstructive sleep apnoea (OSA). We show that regional tongue muscle coordination in people with and without OSA during wakefulness is associated with effective airway dilatation during inspiration, using dynamic tagged magnetic resonance imaging. The maximal movement of four compartments of the tongue were correlated and occurred concurrently towards the end of inspiration. If tongue movement was observed, people with more severe OSA had larger movement and moved more compartments (up to four) to maintain airway patency, while people without OSA moved only one compartment. These results suggest that airway patency is preserved during wakefulness in people with OSA via active dilatory movement of the genioglossus. ABSTRACT: Maintaining airway patency when supine requires neural drive to the genioglossus horizontal and oblique neuromuscular compartments (superior fan-like and inferior horizontal genioglossus, regions that are innervated by different branches of the hypoglossal nerve) to be coordinated during breathing, but it is unknown if this coordination is altered in obstructive sleep apnoea (OSA). This study aimed to assess coordination of airway dilatory motion across four mid-sagittal tongue compartments during inspiration (i.e. anterior and posterior of the horizontal and oblique compartments), and compare it in controls and OSA patients. Fifty-four participants (12 women, aged 20-73 years) underwent dynamic 'tagged' magnetic resonance imaging during wakefulness. Ten participants had no OSA [apnoea hypopnoea index (AHI) < 5 events h-1 ], 14 had mild OSA (5 < AHI ≤ 15 events h-1 ), 12 had moderate OSA (15 < AHI ≤ 30 events h-1 ) and 18 had severe OSA (AHI > 30 events h-1 ). A higher AHI was associated with a greater anterior movement of the anterior and posterior horizontal compartments (Spearman, r = -0.32, P = 0.02 for both), but not in the oblique compartments. If movement was observed, higher OSA severity was associated with an anterior movement of a greater number of compartments. Controls only moved the posterior horizontal compartment while the anterior horizontal compartment also moved in OSA participants. Oblique compartments moved only in people with severe OSA. The maximal anterior inspiratory movement of the four compartments was highly correlated (Spearman, P < 0.001) and occurred concurrently. The posterior horizontal compartment had the greatest anterior motion. These results suggest that airway patency is preserved during wakefulness in people with OSA via active dilatory movement of the genioglossus.

Optogenetic Control of Muscles: Potential Uses and Limitations.

Optogenetics is a technique where a cell is transduced with a light-sensitive ion channel. This technique can be used to control muscle cell contraction in conjunction with commonly used viral vectors. However, this technique has not yet become widely applied. In this study, we discuss the mechanisms and techniques involved in opsin transfer to muscle tissue, the clinical applicability of these approaches, and the major limitations facing this technique.

Direct optogenetic activation of upper airway muscles in an acute model of upper airway hypotonia mimicking sleep onset.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA), where the upper airway collapses repeatedly during sleep due to inadequate dilator muscle tone, is challenging to treat as current therapies are poorly tolerated or have variable and unpredictable efficacy. We propose a novel, optogenetics-based therapy, that stimulates upper airway dilator muscle contractions in response to light. To determine the feasibility of a novel optogenetics-based OSA therapy, we developed a rodent model of human sleep-related upper airway muscle atonia. Using this model, we evaluated intralingual delivery of candidate optogenetic constructs, notably a muscle-targeted approach that will likely have a favorable safety profile. METHODS: rAAV serotype 9 viral vectors expressing a channelrhodopsin-2 variant, driven by a muscle-specific or nonspecific promoter were injected into rat tongues to compare strength and specificity of opsin expression. Light-evoked electromyographic responses were recorded in an acute, rodent model of OSA. Airway dilation was captured with ultrasound. RESULTS: The muscle-specific promoter produced sufficient opsin expression for light stimulation to restore and/or enhance electromyographic signals (linear mixed model, F = 140.0, p < 0.001) and induce visible tongue contraction and airway dilation. The muscle-specific promoter induced stronger (RM-ANOVA, F(1,8) = 10.0, p = 0.013) and more specific opsin expression than the nonspecific promoter in an otherwise equivalent construct. Viral DNA and RNA were robust in the tongue, but low or absent in all other tissues. CONCLUSIONS: Significant functional responses to direct optogenetic muscle activation were achieved following muscle-specific promoter-driven rAAV-mediated transduction, providing proof-of-concept for an optogenetic therapy for patients with inadequate dilator muscle activity during sleep.

Task-dependent neural control of regions within human genioglossus.

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

The relationship between mandibular advancement, tongue movement, and treatment outcome in obstructive sleep apnea.

STUDY OBJECTIVES: To characterize how mandibular advancement enlarges the upper airway via posterior tongue advancement in people with obstructive sleep apnea (OSA) and whether this is associated with mandibular advancement splint (MAS) treatment outcome. METHODS: One-hundred and one untreated people with OSA underwent a 3T magnetic resonance (MRI) scan. Dynamic mid-sagittal posterior tongue and mandible movements during passive jaw advancement were measured with tagged MRI. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of maximum advancement. Treatment outcome was determined after a minimum of 9 weeks of therapy. RESULTS: Seventy-one participants completed the study: 33 were responders (AHI<5 or AHI≤10 events/hr with >50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 nonresponders (AHI reduction<50% and AHI≥10 events/hr). Responders had the greatest naso- and oropharyngeal tongue anterior movement (0.40 ± 0.08 and 0.47 ± 0.13 mm, respectively) and oropharyngeal cross-sectional area enlargement (6.41 ± 2.12%) per millimeter of mandibular advancement. A multivariate model that included tongue movement and percentage of airway enlargement per millimeter of mandibular advancement along with baseline AHI correctly classified 69.2% (5-fold cross-validated 62.5%, n = 39) of participants in response categories when the jaw was advanced in the range that would usually be regarded as sufficient for clinical efficacy (> 4 mm). In comparison, a model using only baseline AHI correctly classified 50.0% of patients (5-fold cross-validated 52.5%, n = 40). CONCLUSIONS: Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improve treatment response categorization to a satisfactory level (69.2%, 5-fold cross-validated 62.5%).

Effect of upper airway fat on tongue dilation during inspiration in awake people with obstructive sleep apnea.

STUDY OBJECTIVES: To investigate the effect of upper airway fat composition on tongue inspiratory movement and obstructive sleep apnea (OSA). METHODS: Participants without or with untreated OSA underwent a 3T magnetic resonance imaging (MRI) scan. Anatomical measurements were obtained from T2-weighted images. Mid-sagittal inspiratory tongue movements were imaged using tagged MRI during wakefulness. Tissue volumes and percentages of fat were quantified using an mDIXON scan. RESULTS: Forty predominantly overweight participants with OSA were compared to 10 predominantly normal weight controls. After adjusting for age, BMI, and gender, the percentage of fat in the tongue was not different between groups (analysis of covariance [ANCOVA], p = 0.45), but apnoeic patients had a greater tongue volume (ANCOVA, p = 0.025). After adjusting for age, BMI, and gender, higher OSA severity was associated with larger whole tongue volume (r = 0.51, p < 0.001), and greater dilatory motion of the anterior horizontal tongue compartment (r = -0.33, p = 0.023), but not with upper airway fat percentage. Higher tongue fat percentage was associated with higher BMI and older age (Spearman r = 0.43, p = 0.002, and r =0.44, p = 0.001, respectively), but not with inspiratory tongue movements. Greater inspiratory tongue movement was associated with larger tongue volume (e.g. horizontal posterior compartment, r = -0.44, p = 0.002) and smaller nasopharyngeal airway (e.g. oblique compartment, r = 0.29, p = 0.040). CONCLUSIONS: Larger tongue volume and a smaller nasopharynx are associated with increased inspiratory tongue dilation during wakefulness in people with and without OSA. This compensatory response was not influenced by higher tongue fat content. Whether this is also true in more obese patient populations requires further investigation.

Mandibular advancement splint response is associated with the pterygomandibular raphe.

STUDY OBJECTIVES: To investigate whether the presence of tendinous PMR could predict treatment outcome and how it affects lateral wall mechanical properties. Mandibular advancement increases the lateral dimensions of the nasopharyngeal airway via a direct connection from the airway to the ramus of the mandible. The anatomical structure in this region is the pterygomandibular raphe (PMR), but a tendinous component is not always present. Whether tendon presence influences treatment outcome is unknown. METHODS: In total, 105 participants with obstructive sleep apnea completed detailed anatomical magnetic resonance imaging with and without mandibular advancement. The study design was case-control. Variables were compared between participants with and without the tendon present. RESULTS: The amount of maximum mandibular advancement decreased when pterygomandibular tendon was present (4.0 ± 1.2 mm present versus 4.6 ± 1.4 mm absent, p = 0.04). PMR tendon-absent participants had a lower posttreatment apnea hypopnea index (16 ± 12 events/hour tendon present versus 9 ± 9 events/hour absent, p = 0.007) and were more likely to have complete response (63% versus 36%, p = 0.02). However, tendon-absent participants were more likely to not complete the study (χ 2 (3) = 10.578, p = 0.014). Tendon-absent participants had a greater increase in midline anteroposterior airway diameter (1.6 ± 1.7 mm versus 0.6 ± 2.3 mm, p = 0.04). CONCLUSION: When PMR tendon is absent, treatment response and amount of maximum advancement improve, possibly at the expense of reduced splint tolerability. Tendon presence may help predict a group less likely to respond to mandibular advancement splint therapy.

Influence of mandibular advancement on tongue dilatory movement during wakefulness and how this is related to oral appliance therapy outcome for obstructive sleep apnea.

STUDY OBJECTIVES: To characterize how mandibular advancement splint (MAS) alters inspiratory tongue movement in people with obstructive sleep apnea (OSA) during wakefulness and whether this is associated with MAS treatment outcome. METHODS: A total of 87 untreated OSA participants (20 women, apnea-hypopnea index (AHI) 7-102 events/h, aged 19-76 years) underwent a 3T MRI with a MAS in situ. Mid-sagittal tagged images quantified inspiratory tongue movement with the mandible in a neutral position and advanced to 70% of the maximum. Movement was quantified with harmonic phase methods. Treatment outcome was determined after at least 9 weeks of therapy. RESULTS: A total of 72 participants completed the study: 34 were responders (AHI < 5 or AHI ≤ 10events/h with >50% reduction in AHI), 9 were partial responders (>50% reduction in AHI but AHI > 10 events/h), and 29 nonresponders (change in AHI <50% and AHI ≥ 10 events/h). About 62% (45/72) of participants had minimal inspiratory tongue movement (<1 mm) in the neutral position, and this increased to 72% (52/72) after advancing the mandible. Mandibular advancement altered inspiratory tongue movement pattern for 40% (29/72) of participants. When tongue dilatory patterns altered with advancement, 80% (4/5) of those who changed to a counterproductive movement pattern (posterior movement >1 mm) were nonresponders and 71% (5/7) of those who changed to beneficial (anterior movement >1 mm) were partial or complete responders. CONCLUSIONS: The mandibular advancement action on upper airway dilator muscles differs between individuals. When mandibular advancement alters inspiratory tongue movement, therapeutic response to MAS therapy was more common among those who convert to a beneficial movement pattern.