Neuromuscular Specializations of the Human Soft Palate

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 DESCRIPTION (provided by applicant): The human soft palate is an extremely mobile structure that plays a critical role in breathing, swallowing, and speech. Disorders of its functio contribute to sleep apnea, dysphagia, and dysarthria. Soft palate collapse during sleep is commonly seen in patients with obstructive sleep apnea (OSA), a potentially life-threatening disorder affecting millions of Americans. The long-term goal of this research is to develop novel neuromodulation therapies to treat OSA. Over the last 20 years, we have focused on studying the specialized changes that have evolved in the human upper airway (tongue, larynx, and the pharynx). Findings from our work on the tongue and hypoglossal nerve have been directly applicable to the development of Inspire therapy for OSA, an FDA approved electrical "pacing" device for the tongue. Although effective for many patients, this stimulator has been found to be completely ineffective in those with soft palate collapse. These patients are among the most severe and are at high risk of heart attack and stroke. We believe that a pacing device can be developed for these patients. However, the use of electrical stimulation relies completely on a thorough knowledge of sensory and motor neuroanatomy. Unfortunately, neural control of the velopharyngeal mechanisms is poorly understood, as innervation of the soft palate has long been controversial. This research tests the hypothesis that the human soft palate has unique neuromuscular specializations presumably developed for human speech, swallowing, and upper airway respiratory function. As studying unique aspects of human anatomy can only be done with post mortem specimens, we have developed a combination of familiar and esoteric techniques for this purpose: Sihler's stain to visualize nerves in whole organ preparations, acetylcholinesterase and silver stain to visualize motor endplates, immunohistochemistry to study muscle fiber types, and others. Specific Aim 1 will determine the neural specializations of the human soft palate. A series of studies will be conducted to: (1) map out the entire nerve supply, define neuromuscular compartments, and quantify innervation densities; (2) localize motor zone within each muscle and analyze motor endplates; (3) determine the number and size of motor units in each muscle; and (4) quantify intraepithelial nerve fiber density and neuropeptide immunoreactive nerve fibers in the mucosa covering the soft palate and lateral pharyngeal walls. Specific Aim 2 will characterize the intrinsic properties of the human palatal muscles. Studies will be performed to: (1) measure the fiber type-specific activities of oxidative and glycolytic enzymes; and (2) analyze fiber type and myosin heavy chain composition in each muscle and compartment. Our well-established approach will demonstrate the neuromuscular specializations of the human soft palate and its extensions into the pharyngeal wall and tongue. The results from this research are expected to be directly transferable to the development of novel therapies to treat OSA.