Michael J. Brennick

Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse

RATIONALE The effect of obesity on upper airway soft tissue structure and size was examined in the New Zealand Obese (NZO) mouse and in a control lean mouse, the New Zealand White (NZW). OBJECTIVES We hypothesized that the NZO mouse has increased volume of neck fat and upper airway soft tissues and decreased pharyngeal airway caliber. METHODS Pharyngeal airway size, volume of the upper airway soft tissue structures, and distribution of fat in the neck and body were measured using magnetic resonance imaging (MRI). Dynamic MRI was used to examine the differences in upper airway caliber between inspiration and expiration in NZO versus NZW mice. MEASUREMENTS AND MAIN RESULTS The data support the hypothesis that, in obese NZO versus lean NZW mice, airway caliber was significantly smaller (P < 0.03), with greater parapharyngeal fat pad volumes (P < 0.0001) and a greater volume of other upper airway soft tissue structures (tongue, P = 0.003; lateral pharyngeal walls, P = 0.01; soft palate, P = 0.02). Dynamic MRI showed that the airway of the obese NZO mouse dilated during inspiration, whereas in the lean NZW mouse, the upper airway was reduced in size during inspiration. CONCLUSIONS In addition to the increased volume of pharyngeal soft tissue structures, direct fat deposits within the tongue may contribute to airway compromise in obesity. Pharyngeal airway dilation during inspiration in NZO mice compared with narrowing in NZW mice suggests that airway compromise in obese mice may lead to muscle activation to defend upper airway patency during inspiration.

Pharyngeal airway wall mechanics using tagged magnetic resonance imaging during medial hypoglossal nerve stimulation in rats

To better understand pharyngeal airway mechanics as it relates to the pathogenesis and treatment of obstructive sleep apnoea, we have developed a novel application of magnetic resonance imaging (MRI) with non‐invasive tissue tagging to measure pharyngeal wall tissue motion during active dilatation of the airway. Eleven anaesthetized Sprague‐Dawley rats were surgically prepared with platinum electrodes for bilateral stimulation of the medial branch of the hypoglossus nerve that supplies motor output to the protrudor and intrinsic tongue muscles. Images of the pharyngeal airway were acquired before and during stimulation using a gated multislice, spoiled gradient recalled (SPGR) imaging protocol in a 4.7 T magnet. The tag pulses, applied before stimulation, created a grid pattern of magnetically imbedded dark lines that revealed tissue motion in images acquired during stimulation. Stimulation significantly increased cross‐sectional area, and anteroposterior and lateral dimensions in the oropharyngeal and velopharyngeal airways when results were averaged across the rostral, mid‐ and caudal pharynx (P < 0.001). Customized software for tissue motion‐tracking and finite element‐analysis showed that changes in airway size were associated with ventral displacement of  tissues in the ventral pharyngeal wall in the rostral, mid‐ and caudal pharyngeal regions (P < 0.0032) and ventral displacement of the lateral walls in the mid‐ and caudal regions (P < 0.0001). In addition, principal maximum stretch was significantly increased in the lateral walls (P < 0.023) in a ventral–lateral direction in the mid‐ and caudal pharyngeal regions and principal maximum compression (perpendicular to stretch) was significantly increased in the ventral walls in all regions (P < 0.0001). Stimulation did not cause lateral displacement of the lateral pharyngeal walls at any level. The results reveal that the increase in pharyngeal airway size resulting from stimulation of the medial branch of the hypoglossal nerve is predominantly due to ventral displacement of the ventral and lateral pharyngeal walls.

Modeling upper airway collapse by a finite element model with regional tissue properties

This study presents a new computational system for modeling the upper airway in rats that combines tagged magnetic resonance imaging (MRI) with tissue material properties to predict three-dimensional (3D) airway motion. The model is capable of predicting airway wall and tissue deformation under airway pressure loading up to airway collapse. The model demonstrates that oropharynx collapse pressure depends primarily on ventral wall (tongue muscle) elastic modulus and airway architecture. An iterative approach that involves substituting alternative possible tissue elastic moduli was used to improve model precision. The proposed 3D model accounts for stress-strain relationships in the complex upper airway that should present new opportunities for understanding pathogenesis of airway collapse, improving diagnosis and developing treatments.

Mechanical effects of genioglossus muscle stimulation on the pharyngeal airway by MRI in cats

To examine the regional mechanical effects of selective genioglossus muscle activation on pharyngeal airway size and function, magnetic resonance images of the pharyngeal airway were obtained in five paralyzed, anesthetized cats over a range of positive and negative pressures in an isolated, sealed upper airway. When all results across pressure levels and pharyngeal regions were analyzed, genioglossus stimulation significantly increased the cross-sectional area (CSA) of the nasopharyngeal airway. Within specific regions, stimulation tended toward significantly increasing cross-sectional airway area in the mid-nasopharynx. Despite its dilating effect, genioglossus muscle stimulation did not alter compliance in the nasopharyngeal airway, as evidenced by the similar slopes of the pressure versus cross-sectional area relationships with and without stimulation. Finally, airway shape in the mid pharynx became more circular with either increased airway pressure or genioglossus stimulation. The results indicate that selective stimulation of the genioglossus muscle dilates the nasopharynx and provide evidence that stimulation of the genioglossus alone does not alter airway compliance.

Tongue fat infiltration in obese versus lean Zucker rats.

STUDY OBJECTIVES Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats. DESIGN Animal study. SETTING Academic Medical Center. PARTICIPANTS OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats. INTERVENTIONS TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain). MEASUREMENTS AND RESULTS MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats. CONCLUSIONS Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.

Respiratory modulation of the pharyngeal airway in lean and obese mice

UNLABELLED Obesity is an important risk factor for pharyngeal airway collapse in obstructive sleep apnea (OSA). To examine the effect of obesity on pharyngeal airway size on inspiration and expiration, respiratory-gated MRI of the pharynx was compared in New Zealand obese (NZO) and New Zealand white (NZW) mice (weights: 50.4g vs. 34.7g, p<0.0001). RESULTS (1) pharyngeal airway cross-sectional area was greater during inspiration than expiration in NZO mice, but in NZW mice airway area was greater in expiration than inspiration; (2) inspiratory-to-expiratory changes in both mouse strains were largest in the caudal pharynx; and (3) during expiration, airway size tended to be larger, though non-significantly, in NZW than NZO mice. The respiratory pattern differences are likely attributable to obesity that is the main difference between NZO and NZW mice. The data support an hypothesis that pharyngeal airway patency in obesity is dependent on inspiratory dilation and may be vulnerable to loss of neuromuscular pharyngeal activation.

Genioglossal length and EMG responses to static upper airway pressures during hypercapnia in goats

Mechanoreflexes that activate genioglossus electromyogram (EMGgg) in response to negative upper airway pressure (UAP) may help defend airway patency in obstructive sleep apnea. Hypercapnia may affect mechanoreflexes by increasing EMGgg response to actively reduce genioglossus length (Lgg, measured by sonomicrometry). We hypothesized that during normocapnia, Lgg would be reduced at positive, and increased at negative UAP but hypercapnia would increase EMGgg responses to negative pressures and cause Lgg reductions. At 0, 3.5 and 7% inhaled CO2 (balance O2), Lgg and EMGgg were measured during static negative and positive UAP applied to the isolated upper airway in four unanesthetized goats. At 3.5 and 7% CO2 EMGgg was significantly increased and Lgg decreased with negative pressure while EMGgg was also greater at 7 than 0% CO2 (P<0.05). Non-significant pressure related Lgg changes were observed during normocapnia. These results suggest that hypercapnia may stimulate greater mechanoreflex EMGgg activation and consequent Lgg reduction in response to negative UAP application.

Kinematic MRI study of upper-airway biomechanics using electrical muscle stimulation

We have developed a new and powerful method to study the movement and function of upper airway muscles. Our method is to use direct electrical stimulation of individual upper airway muscles, while performing state of the art high resolution magnetic resonance imaging (MRI). We have adapted a paralyzed isolated UA cat model so that positive or negative static pressure in the UA can be controlled at specific levels while electrical muscle stimulation is applied during MRI. With these techniques we can assess the effect of muscle stimulation on airway cross-sectional area compliance and soft tissue motion. We are reporting the preliminary results and MRI techniques which have enabled us to examine changes in airway dimensions which result form electrical stimulation of specific upper airway dilator muscles. The results of this study will be relevant to the development of new clinical treatments for obstructive sleep apnea by providing new information as to exactly how upper airway muscles function to dilate the upper airway and the strength of stimulation required to prevent the airway obstruction when overall muscle tone may not be sufficient to maintain regular breathing.