Transient Receptor Potential Ankyrin 1 Channel Alters Transforming Growth Factor Beta 1/Smad Signaling in Rat Vocal Fold Fibroblasts.

Objectives: Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor-beta 1 (TGF-β1)-mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF-β1/Smad signaling in various organs.

Sustained Effects of Capsaicin Infusion into the Oropharynx on Swallowing in Perfused Rats.

Objectives: To examine the sustained effects of oropharyngeal capsaicin stimulation on the regulation of swallowing, we recorded the swallowing-related nerve activities during continuous infusion of capsaicin solution into the oropharynx.

Methods: In 33 in situ perfused brainstem preparation of rats, we recorded the activities of the vagus, hypoglossal, and phrenic nerves during fictive swallowing. The interburst intervals (IBIs) of the swallowing-related nerves during sequential pharyngeal swallowing (sPSW) elicited by electrical stimulation of the superior laryngeal nerve (SLN) during concurrent capsaicin stimulation of 10, 1, and 0.

Complementary Effect of Transcutaneous Cervical Stimulation by Interferential Current on Functional Dysphonia.

Objectives: Functional dysphonia (FD) varies in terms of vocal behavior and treatment efficacy. So-called hypofunctional dysphonia is characterized by insufficient subglottal pressure which causes a lack of driving power needed to vibrate the vocal folds leading to weak voice or aphonia in severe cases. While voice therapy is the initial treatment, some patients fail to respond to it.

Effect of pharmacological inhibition of the pontine respiratory group on swallowing interneurons in the dorsal medulla oblongata.

Objectives: To examine the role of neurons of the pontine respiratory group (PRG) overlapping with the Kölliker-Fuse nucleus in the regulation of swallowing, we compared the activity of swallowing motor activities and interneuron discharge in the dorsal swallowing group in the medulla before and after pharmacological inhibition of the PRG.

Methods: In 23 in situ perfused brainstem preparation of rats, we recorded the activities of the vagus (VNA), hypoglossal (HNA), and phrenic nerves (PNA), and swallowing interneurons of the dorsal medulla during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve or oral water injection. Subsequently, respiratory- and swallow-related motor activities and single unit cell discharge were assessed before and after local microinjection of the GABA-receptor agonist muscimol into the area of PRG ipsilateral to the recording sites of swallowing interneurons.

The Effects of Amniotic Membrane Transplantation on Vocal Fold Regeneration.

Objectives/hypothesis: Vocal fold (VF) scar and sulcus cause severe vocal problems, but optimal methods have not been established. Total replacement of the mucosa is required particularly for cases in which the whole lamina propria is occupied by severe fibrosis and vibratory function is totally lost. The amniotic membrane (AM) has been proven to have regenerative potential, as it contains stem cells and growth factors.

Anti-inflammatory and Antioxidant Effects of Japanese Herbal Medicine Kyoseihatekigan on Vocal Fold Wound Healing.

Objectives: The Japanese herbal medicine kyoseihatekigan (KHG) has been used to alleviate the symptoms of croaky voice and globus hystericus, and each of its components has anti-inflammatory and antioxidant effects. However, the mechanisms underlying these beneficial actions of KHG on the vocal folds remain largely unknown. We examined the effects of KHG on rat vocal fold wound healing and assessed its anti-inflammatory and antioxidant properties.

Firing characteristics of swallowing interneurons in the dorsal medulla during physiologically induced swallowing in perfused brainstem preparation in rats.

Oropharyngeal swallowing is centrally mediated by a swallowing central pattern generator (Sw-CPG) in the medulla oblongata. The activity of the Sw-CPG depends on the sensory inputs determined by physical and chemical bolus properties. Here we investigate the sensory-motor integration during swallowing arising from different sensory sources.

Physiological Effects of Voice Therapy for Aged Vocal Fold Atrophy Revealed by EMG Study.

Objectives: Age-related voice changes are characterized as breathy, weak and strained, and a deterioration in vocal function in the elderly has been putatively linked to a reduced intensity of speech. They contribute to undesirable voice changes known as presbyphonia. These changes are caused by histological alterations in the lamina propria of the vocal fold mucosa and atrophy of the thyroarytenoid muscle, as well as by decreased respiratory support.

Effects of Repeated Intracordal Glucocorticoid Injection on the Histology and Gene Expression of Rat Vocal Folds.

Objectives: Local injection of glucocorticoids (GCs) into the vocal folds has been used for treating the vocal fold lesions. While the positive effects on vocal fold nodules, polyps, or scarring have been clinically reported, some concern remains around the potential adverse effects such as vocal fold atrophy, and the mechanisms remain unclear. The present study examined the histology and gene expression of locally injected GC into the vocal folds in rats.

Mechanisms Underlying the Antifibrotic Potential of Estradiol for Vocal Fold Fibrosis.

Objectives/hypothesis: Vocal fold fibrosis remains a significant clinical challenge. Estrogens, steroid hormones predominantly responsible for secondary sexual characteristics in women, have been shown to alter wound healing and limit fibrosis, but the effects on vocal fold fibrosis are unknown. We sought to elucidate the expression of estrogen receptors and the effects of estrogens on TGF-β1 signaling in rat vocal fold fibroblasts (VFFs).

Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds.

Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-β and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling.

Influences of GABAergic Inhibition in the Dorsal Medulla on Contralateral Swallowing Neurons in Rats.

Objectives: We aimed to examine the effect of unilateral inhibition of the medullary dorsal swallowing networks on the activities of swallowing-related cranial motor nerves and swallowing interneurons.

Methods: In 25 juvenile rats, we recorded bilateral vagal nerve activity (VNA) as well as unilateral phrenic and hypoglossal activity (HNA) during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve during control and following microinjection of the GABA agonist muscimol into the caudal dorsal medulla oblongata in a perfused brainstem preparation. In 20 animals, swallowing interneurons contralateral to the muscimol injection side were simultaneously recorded extracellularly and their firing rates were analyzed during swallowing.

Intracordal Injection of Basic Fibroblast Growth Factor in 100 Cases of Vocal Fold Atrophy and Scar.

Objectives/hypothesis: Vocal fold atrophy, scar, and sulcus reduce the vibratory function of the vocal fold mucosa, which causes severe refractory dysphonia. We have reported encouraging preliminary results using an intracordal injection of basic fibroblast growth factor (bFGF) and showed improvement in phonatory parameters and voice. The present study summarizes our experience with 100 cases of stiffened vocal folds that were treated with bFGF injections.

Effects of Voice Therapy for Dysphonia due to Tension Imbalance in Unilateral Vocal Fold Paralysis and Paresis.

Objectives: Medialization procedures, such as type I thyroplasty, arytenoid adduction, and vocal fold injection, are popular treatments for dysphonia due to unilateral vocal fold paralysis (UVFP). However, dysphonia occasionally persists after medialization procedures owing to tension imbalance. This tension imbalance causes diplophonia, asymmetry and aperiodic vibrational flutter in travelling wave motion.

Implementing Efficient Peptoid-Mediated Delivery of RNA-Based Therapeutics to the Vocal Folds.

Objective: We hypothesize that Smad3 is a master regulator of fibrosis in the vocal folds (VFs) and RNA-based therapeutics targeting Smad3 hold therapeutic promise. Delivery remains challenging. We previously described a novel synthetic peptoid oligomer, lipitoid , complexed with siRNA to improve stability and cellular uptake.

Effect of Voice Therapy Using Semioccluded Vocal Tract Exercises in Singers and Nonsingers With Dysphonia.

Objectives: Voice therapy with semioccluded vocal tract exercises (SOVTE) has a long history of use in singers and nonsingers with dysphonia. SOVTE with increased vocal tract impedance leads to increased vocal efficiency and economy. Although there is a growing body of research on the physiological impact of SOVTE, and growing clinical sentiment about its therapeutic benefits, empirical data describing its potential efficacy in singers and nonsingers are lacking.

Quantifying vocal fold wound-healing biomechanical property changes.

Objectives: Development of novel vocal fold (VF) therapeutics is limited by a lack of standardized, meaningful outcomes. We hypothesize that automated microindentation-based VF biomechanical property mapping matched to histology permits quantitative assessment.

Study Design: Ex vivo.

Phosphorylation of the glucocorticoid receptor alters SMAD signaling in vocal fold fibroblasts.

Objectives/hypothesis: Direct glucocorticoid (GC) injection for vocal fold (VF) scarring has evolved as a therapeutic strategy, but the mechanisms underlying the antifibrotic effects remain unclear. GCs act via the glucocorticoid receptor (GR), which is phosphorylated at multiple serine residues in a hormone-dependent manner to affect bioactivity. We hypothesize that GCs regulate SMAD signaling via GR phosphorylation in vocal fold fibroblasts (VFFs).

The effects of cytosporone-B, a novel antifibrotic agent, on vocal fold fibroblasts.

Objectives/hypothesis: Our laboratory recently described NR4A1 as an endogenous inhibitor of TGF-β-induced vocal fold (VF) fibrosis. Our prior report described the temporal expression of NR4A1 during VF healing in vivo and the effects of NR4A1 knockdown on fibroplastic cell activities in vitro. Based on these findings, we hypothesized that cytosporone-B (Csn-B), an NR4A1 agonist, may hold significant therapeutic potential.

Supportive effect of interferential current stimulation on susceptibility of swallowing in guinea pigs.

Sensory-motor control of the pharyngeal swallow requires sensory afferent inputs from the pharynx and larynx evoked by introducing bolus into the pharynx. Patients with reduced sensitivity of the pharynx and larynx are likely to have a swallowing impairment, such as pre-swallow aspiration due to delayed swallow triggering. Interferential current stimulation applied to the neck is thought to improve the swallowing function of dysphagic patients, although the mechanism underlying the facilitatory effect of such stimulation remains unknown.

Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse.

The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV.

Role of the retrotrapezoid nucleus/parafacial respiratory group in coughing and swallowing in guinea pigs.

The retrotrapezoid/parafacial respiratory group (RTN/pFRG) located ventral to the facial nucleus plays a key role in regulating breathing, especially enhanced expiratory activity during hypercapnic conditions. To clarify the roles of the RTN/pFRG region in evoking coughing, during which reflexive enhanced expiration is produced, and in swallowing, during which the expiratory activity is consistently halted, we recorded extracellular activity from RTN/pFRG neurons during these fictive behaviors in decerebrate, paralyzed, and artificially ventilated guinea pigs. The activity of the majority of recorded respiratory neurons was changed in synchrony with coughing and swallowing.