Chronic Cough and Obstructive Sleep Apnea.

Chronic cough, defined as a cough lasting more than 8 weeks, is a common medical condition occurring in 5% to 10% of the population. Its overlap with another highly prevalent disorder, obstructive sleep apnea (OSA), is therefore not surprising. The relationship between chronic cough and OSA extends beyond this overlap with higher prevalence of OSA in patients with chronic cough than in the general population. The use of continuous positive airway pressure can result in improvement in chronic cough although further studies are needed to understand which patients will experience benefit in their cough from the treatment of comorbid OSA.

Noninvasive Bolus Transit Detection in Cervical Esophagus Utilizing Ultrasound Characteristics.

This pilot study aims to identify characteristic A-mode ultrasound features relevant to noninvasive detection of esophageal bolus transit in the proximal esophagus. Ultrasound signals at a lateral neck site were obtained via a single-element ultrasonic transducer with synchronous videofluoroscopic swallowing studies images of swallows of differing viscosities in 21 adult dysphagia outpatients. Characteristic ultrasound features were extracted to differentiate a bolus-filled from a collapsed esophagus. From 21 subjects, 412 swallows exhibited 4 reproducible waveform patterns associated with bolus transit as displayed in a heatmap: (1) Strong Reflectors; (2) Echo Shifts; (3) Distal Acoustic Enhancement; and (4) Speckling: One or more of these features were observed in the swallow series for all 21 subjects. Distinct acoustic waveform features acquired by single-element ultrasonic transducers can identify bolus transit through the cervical esophagus.

Laryngeal Dysfunction Manifesting as Chronic Refractory Cough and Dyspnea: Laryngeal Physiology in Respiratory Health and Disease.

TOPIC IMPORTANCE: Laryngeal dysfunction as a cause of chronic refractory cough and episodic dyspnea is often missed, which results in unnecessary testing and delays in diagnosis. Understanding laryngeal roles in breathing and airway protection can help to appreciate the propensity to laryngeal dysfunction with aging, chronic lung disease, and sleep apnea. REVIEW FINDINGS: The human larynx is a complex muscular structure that is responsible for multiple roles of breathing, vocalization, coughing, and swallowing. To undertake these activities, the larynx has a high density of sensory and motor innervation. In addition to common embryological origins with the pharynx and esophagus, with which many laryngeal activities are shared, somatomotor and autonomic pathways regulate emotional, cognitive, and complex motor sequence-planning activities within the larynx. Due to its unique location, the larynx is susceptible to infectious and gastroesophageal reflux-related insults. Couple this with key roles in regulation of airflow and mediation of airway protective reflexes, it is not surprising that neuropathic abnormalities and muscle dysfunction frequently develop. The expression of laryngeal dysfunction as hypersensitivity to mechanical, thermal, chemical, and other stimuli leads to exaggerated airway protective reflexes (laryngeal adductor reflex and cough reflex) manifesting as dyspnea and cough. SUMMARY: Pulmonologists should incorporate assessment of laryngeal dysfunction during evaluation of chronic refractory cough and dyspnea. Recognition of laryngeal hypersensitivity in the patient with chronic refractory cough can identify patients who may benefit from cough suppression therapies. Similarly, timely identification of inducible laryngeal obstruction may not only resolve episodic dyspnea but lessen the need for unnecessary testing and treatments.

A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain.

In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that contribute to such functions (including the amygdala, basal forebrain and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei, do not directly project there. We show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to numerous forebrain regions. Suppressing the PC-PBN pathway influences many regions in the forebrain and is aversive. Molecular profiling shows that PCs directly inhibit numerous types of PBN neurons that control diverse behaviors that are not involved in motor control. Therefore, the PC-PBN pathway allows the cerebellum to directly regulate activity in the forebrain, and may be an important substrate for cerebellar disorders arising from damage to the posterior vermis.

Cerebellar granule cell signaling is indispensable for normal motor performance.

Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals. Remarkably, it is not known whether GCs are essential for normal motor function. Here we address this issue by selectively eliminating calcium channels that mediate transmission (CaV2.1, CaV2.2, and CaV2.3) in a combinatorial manner. We observe profound motor deficits but only when all CaV2 channels are eliminated. In these mice, the baseline rate and variability of PC firing are unaltered, and locomotion-dependent increases in PC firing are eliminated. We conclude that GCs are indispensable for normal motor performance and that disruption of MF-induced signals impairs motor performance.

Extracellular matrix deformations of the porcine recurrent laryngeal nerve in response to hydrostatic pressure.

Damage to the recurrent laryngeal nerve (RLN) caused by supraphysiological compression or tension imposed by adjacent tissue structures, such as the aorta, may contribute to onset of idiopathic unilateral vocal fold paralysis (iUVP) resulting in difficulty speaking, breathing, and swallowing. We previously demonstrated in adolescent pigs that the right RLN epineurium exhibits uniform composition of adipose tissue, with larger quantities along its length within the neck region in contrast to the left RLN that shows greater collagen composition in the thoracic region and greater quantities of adipose tissue in the neck region. In contrast, the epineurium in piglets was primarily composed of collagen tissue that remained uniform along the length of the left and right RLNs. Tensile testing of the left and right RLN in piglets and pigs showed associated differences in strain by RLN side and segment by age. The goal of this study was to investigate how external hydrostatic compression of the RLN affects the nerve's connective tissue and microstructure. RLN segments were harvested from the distal (cervical/neck) regions and proximal (subclavian for the right RLN, thoracic for the left RLN) regions from eight adolescent pigs and nine piglets. RLN segments were isolated and assessed under fluid compression to test hypotheses regarding epineurium composition and response to applied forces. Second harmonic generation (SHG) imaging of epineurial collagen was conducted at 0, 40, and 80 mmHg of compression. The cartesian strain tensor, principal strain (Eps1), and principal direction of the RLN collagen fibers were determined at each pressure step. Significantly larger values of the 1st principal strain occurred in the proximal segments of the pig left RLN when compared to the same segment in piglets (p = 0.001, pig = 0.0287 [IQR = 0.0161 - 0.0428], piglet = 0.0061 [IQR = 0.0033 - 0.0156]). Additionally, the median transverse strain Eyy) for the second pressure increment was larger in the right proximal segment of pigs compared to piglets (p < 0.001, pig = 0.0122 [IQR = 0.0033 - 0.0171], piglet = 0.0013 [IQR = 0.00001 - 0.0028]). Eyy values were significantly larger in the right proximal RLN versus the left proximal RLNs in pigs but not in piglets (p < 0.001). In contrast to piglets, histological analysis of pig RLN demonstrated increased axial alignment of epineurial and endoneurial collagen in response to compressive pressure. These findings support the hypothesis that the biomechanical response of the RLN to compressive pressure changed from being similar to being different between the right and left RLNs during development in the porcine model. Further investigation of these findings associated with age-related onset of idiopathic UVP may illuminate underlying etiologic mechanisms. STATEMENT OF SIGNIFICANCE: Damage to the recurrent laryngeal nerve (RLN) caused by compression imposed by the aorta may contribute to the onset of left-sided idiopathic unilateral vocal fold paralysis resulting in difficulty speaking, breathing, and swallowing. The goal of this study was to investigate how compression affects the connective tissue and microstructure of the RLN. We quantified the pressure induced deformation of the RLN using multiphoton imaging as a function of both location (proximal versus distal) and age (piglets, adolescent pigs). Our results demonstrate that the biomechanical response of the RLN to compression changes in the right versus left RLN throughout development, providing further evidence that the the left RLN is exposed to increasing dynamic loads with age.

Is laryngeal hypersensitivity the basis of unexplained or refractory chronic cough?

Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are common problems seen in primary care and subspecialty clinics. The role of cough hypersensitivity and laryngeal dysfunction in contributing to the persistence of cough in RCC/UCC is not well recognised. Data of patients with RCC and UCC evaluated in 2019 by an interdisciplinary cough clinic led by a pulmonologist and speech-language pathology team was reviewed. Patients completed validated questionnaires including the Leicester cough questionnaire (LCQ), voice handicap index (VHI) and dyspnoea index (DI) questionnaire at initial encounter. Presence of cough hypersensitivity was based upon a history of allotussia and hypertussia. Laryngeal dysfunction was diagnosed in those with a history of laryngeal paresthesias, throat clearing, voice abnormalities, upper airway dyspnoea and documentation of functional or anatomic laryngeal abnormalities on nasoendoscopy. Of the 60 UCC/RCC patients analysed, 75% of patients were female and 85% were over 40 years of age. Cough hypersensitivity was documented in all patients and multiple cough triggers occurred in 75% of patients. 95%, 50% and 25% of patients reported laryngeal paresthesias, voice abnormalities and upper airway dyspnoea, respectively. Significant associations between LCQ and VHI and DI scores occurred when adjusting for age, sex, ethnicity and body mass index. Laryngeal functional abnormalities were documented on 44 out of 60 patients on nasoendoscopy. Hypertussia, allotussia and laryngeal dysfunction are common in patients with RCC and UCC. Evaluation of UCC and RCC can delineate laryngeal hypersensitivity and allows appropriate treatment to be directed at this phenotype.

Vocalization with semi-occluded airways is favorable for optimizing sound production.

Vocalization in mammals, birds, reptiles, and amphibians occurs with airways that have wide openings to free-space for efficient sound radiation, but sound is also produced with occluded or semi-occluded airways that have small openings to free-space. It is hypothesized that pressures produced inside the airway with semi-occluded vocalizations have an overall widening effect on the airway. This overall widening then provides more opportunity to produce wide-narrow contrasts along the airway for variation in sound quality and loudness. For human vocalization described here, special emphasis is placed on the epilaryngeal airway, which can be adjusted for optimal aerodynamic power transfer and for optimal acoustic source-airway interaction. The methodology is three-fold, (1) geometric measurement of airway dimensions from CT scans, (2) aerodynamic and acoustic impedance calculation of the airways, and (3) simulation of acoustic signals with a self-oscillating computational model of the sound source and wave propagation.

Morphometric Differences in the Recurrent Laryngeal Nerve in Patients with Vocal Fold Paralysis.

OBJECTIVES: Injury to the recurrent laryngeal nerve (RLN), if severe enough, can result in vocal fold paralysis. Reinnervation surgery can improve patient outcomes, but previous studies have reported a negative correlation between time since onset of paralysis and surgical outcomes. The ability of the paralyzed nerve to serve as a conduit for donor nerve fibers may be a factor in the success of reinnervation; however, changes in RLN composition after paralysis have not been well studied. Therefore, we investigated the morphometric composition of explanted RLN sections from patients who had experienced vocal fold paralysis for varying length of times. METHODS: Nine nerve sections from unilateral vocal fold paralysis (UVP) patients and seven control nerve sections were analyzed for morphometric parameters including fascicular area, fiber count, fiber density, fiber packing, mean g-ratio, and fiber diameter distribution. Nerves from UVP patients were also compared as a function of time since UVP onset. RESULTS: In comparison to control nerves, paralyzed nerves were found to have significantly lower fiber densities and fiber packing, higher mean g-ratio values, and a shift in diameter distributions toward smaller diameter fibers. With respect to paralysis duration, no significant differences were observed except in fiber diameter distributions, where those with paralysis for >2 years had distributions that were significantly shifted toward smaller diameter fibers. CONCLUSIONS: The morphometric data presented here suggest that correlations between the time since onset of vocal fold paralysis and reinnervation outcomes may be due to fiber size changes in the paralyzed nerve over time.