This application uses a multidisciplinary approach to ontoneurology in which clinical and basic scientists interact to achieve a better understanding of vestibular disorders. Three interrelated projects are proposed. Subproject 1, Pathophysiology of Vestibular Disorders, is directed toward acquisition of fundamental clinical information. A unique feature is the study of post-mortem material from patients whose performance has been documented by a battery of laboratory tests enabling clinical pathological correlations by classical and molecular methods. Patients suffering from familial vestibular disorders will be studied to identify genetic defects. The hope is that new insights into cause of such common disorders as migraine, Meniere's syndrome and dysequilibrium of aging will be obtained. Subproject 2, New approaches to Vestibular Testing, involves quantitative assessment of vestibular performance during routine daily activities. Such natural stimuli include high frequency angular and linear accelerations in all six degrees of freedom, interacting with visual stimuli. The subproject will develop tests of vestibular function during natural activities such as ambulation, as well as specific controlled tests of multidimensional angular and linear vestibulo-ocular reflexes, visual vestibular interaction, and dynamic visual acuity. The investigators will measure and theoretically model human gaze stability and eye-hear kinematics in normal and vistibulopathic subjects. Data will be correlated with pathophysiologic studies in Subproject 1. Subproject 3, Studies on Vestibular Hair Cell Regeneration, seeks to understand the reparative mechanisms that ameliorate the disorders investigated in humans. Experiments will document morphological and functional aspects of vestibular hair cell recovery in chinchillas after ototoxic treatment. Several histological methods will be used to investigate mechanisms of repair and of hair cell reinnervation. The effect of brain derived neurotropic factor (BDNF) to the recovery process will be examined. Physiological tests are proposed to evaluate concomitant changes in vestibulo-visual-ocular, vestibulocollic and vestibulo-spinal reflexes. Results of these experiments have potential theoretical and practical value for the management of patients suffering from dizziness and dysequilibrium due to inner ear lesions as well as sensorineural disorders.
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