Kathleen E. Cullen - US grants

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, about 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 toward defining the dynamics of compensation in pathways that mediate these vital reflexes. In addition, we established how these pathways respond acutely to activation of a multichannel vestibular prosthesis (MVP). In the proposed research program, we will build upon this solid foundation of progress through 3 synergistic aims. Experiments addressing Aim 1 will determine how central vestibular neurons adapt to the onset of constant prosthetic stimulation, to subsequent cessation of stimulation, and to motion-modulated stimulation. We predict that adaptation predominantly involves changes in one of two parallel paths, and that reduction of afferent discharge synchrony and/or addition of congruent extra-vestibular self-motion cues will further improve responses. Aim 2 experiments will examine how central neurons process prosthetic vestibular input during natural behaviors such as vergence, active gaze shifts and VOR suppression, which all require context-specific integration of neuronal signals encoding non-vestibular senses and efferent commands. 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 characterize central vestibular neuron adaptation to natural and prosthetic stimulation during a novel training paradigm designed to reduce VOR asymmetry. Combined, these studies in alert nonhuman primates will enhance 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 cellular level can be leveraged to optimize recovery of individuals disabled by loss of vestibular sensation.

Project Summary: This research program is motivated by three goals. First, we will establish the neural mechanisms that underlie the brain's ability to estimate and cancel self-generated vestibular (inner ear balance) input during active movement. Second, we will determine how the vestibular cerebellum learns to adapt to changes in the relationship between expected and actual sensory input to maintain stabile perception and accurate behavior. Third, we will assess how reward-motivation signals influence circuit performance. The brain's ability to distinguish sensory stimuli that are the result of self-generated (i.e., active) versus unexpected or externally generated (i.e., passive) stimulation is vital to ensuring perceptual stability and accurate motor control. Notably, in the vestibular system, the same central neurons that receive afferent input also send direct projections to motor centers to control balance and posture via the vestibular-spinal reflex. This reflex is essential for providing robust postural responses to unexpected vestibular stimuli, yet is counter- productive when the goal is to make active head movements. Accordingly, it is advantageous to suppress this pathway during active self-motion. Over the past two decades, we have made excellent progress toward identifying where brain makes the distinction between reafferent (i.e., active) and exafferent (i.e., passive) vestibular signals. Specifically, while the responses of vestibular afferents remain robust (and equivalent) regardless of whether stimulation is active or passive, neurons at the next stage of processing in the vestibular nuclei are significantly less responsive to active self-motion. In addition, we have shown that this suppression only occurs when sensory feedback matches that expected based on the motor command (e.g., during normal active movements). In the proposed research, we will address several fundamental questions that remain open regarding the computations that the brain performs to ensure stable perception and accurate motor control during self-motion. First, experiments in Aim 1 will investigate how the brain computes the vestibular cancellation signal that eliminates actively generated signals from early sensory processing. We predict that the cerebellar cortex plays an essential role in computing the mismatch between expected and actual vestibular input to compute a cancellation signal. Aim 2 will determine how the cerebellum learns to interpret active motion as self-generated when the relationship between the actual and expected sensory feedback is altered. These experiments will provide insight into the error-based mechanisms that ensure calibration of the vestibular reafference suppression mechanism is maintained. Finally, in Aim 3 we will determine whether and how motivation modulates cerebellum-mediated vestibular reafference suppression. Combined, these studies will (1) determine the source of the vestibular reafference cancellation signal, (2) advance our understanding of the cerebellum adapts to changes in vestibular input, and (3) clarify how neuronal mechanisms underlying reafference suppression can be leveraged by motivational influences to optimize performance.