Project Summary This research program is motivated by two goals. First, we seek to understand the neural mechanisms by which the brain adapts to changes in vestibular (inner ear balance) input. Second, we seek to advance development of a vestibular prosthesis/implant, a highly innovative treatment approach with potential to improve quality of life for individuals disabled by disequilibrium and unsteady vision after loss of vestibular sensation. In the United States alone, approximately 150,000 adults suffer disabling vertigo and unsteadiness each year due to acute unilateral loss of vestibular function, while about 65,000 suffer chronic imbalance and unsteady vision typical of severe bilateral sensory loss that fails to resolve despite existing treatments. Sudden, permanent loss of vestibular nerve input causes disequilibrium, visual blurring due to disruption of the vestibulo-ocular reflex (VOR), and postural instability due to disruption of vestibulo-spinal reflexes. These symptoms are usually followed by impressive but incomplete recovery. During the previous funding period, we made excellent progress in defining the dynamics of compensation in these vital reflexes. In addition, we established how these pathways respond acutely to activation of a multichannel vestibular prosthesis (MVP), and have developed a primate model for single unit studies of MVP mediated restoration of gaze/postural control and gait stability. In the proposed research, we will build upon this solid foundation of progress through 3 synergistic aims. Experiments addressing Aim 1 will determine how central vestibular pathways encode motion-modulated MVP stimulation and establish whether the use of certain stimulation waveforms can enhance neural and resulting reflex responses. We predict that adaptation of vestibular nuclei neurons is detrimental to generating prosthesis-evoked responses, and that methods to desynchronize and increase afferent recruitment will improve functional outcomes. Aim 2 experiments will examine mechanisms underlying the context-specific integration of prosthetic and extravestibular information by investigating neural responses during gaze stabilizing & shifting behaviors. These experiments will extend our investigation beyond reflex pathways and provide both systems and neuronal-level insight into how the central nervous system (CNS) optimizes performance during complex behaviors typical of daily life. Experiments addressing Aim 3 will examine, in freely moving monkeys, the context-specific processing of prosthetic vestibular input at the single unit level during natural self-motion behaviors including postural control and gait. Combined, these studies will enhance our understanding of how the CNS adapts to changes in vestibular input; advance development of a potentially revolutionary treatment for loss of inner ear function; and clarify how neuronal mechanisms that underlie learning at a single cell level can be leveraged to optimize recovery o...