Timothy E. Hullar, M.D. - US grants

DESCRIPTION (provided by applicant): The vestibular system is responsible for collecting information about the head's position and movement in space. This information is used to maintain posture through the actions of the vestibulospinal reflexes and to stabilize gaze by means of the vestibulo-ocular reflex (VOR). Dysfunction of these reflexes due to disruption of vestibular input to the brainstem can lead to pathologies such as Meniere's disease and aminoglycoside toxicity and may bring about disabling vertigo and disequilibrium. In mammals, three types of vestibular-nerve afferent neurons carry these signals from the vestibular periphery to the brainstem, but the purpose for these separate classes is not known. Based on their sensitivity and baseline discharge patterns, they have been termed "regularly discharging," "irregularly discharging," and "low-gain irregularly discharging." Indirect evidence suggests that these afferent types may be differentially affected by various pathologic processes. The studies proposed here aim to define the contribution of irregular afferents to the VOR by reversibly stimulating or inhibiting their contribution to the vestibulo-ocular reflex during high-frequency sinusoidal rotations as well as short transient motions of the head. The dynamics of irregular afferents suggest that their contribution to the VOR may be particularly important under these previously untested conditions. Techniques of signal theory will be used, based on the responses of individual afferents to sharp movements, to determine the relative information carrying capacity of neurons over the short latencies (< 10 ms) allowed by the VOR. A model of vestibular-nerve afferents that predicts neural responses to high-frequency and transient head motion will be developed from the data collected. Findings from this study will allow better understanding of pathologies of the peripheral vestibular system.

Multiple sensory cues are generated by discrete events and while they do not reach the cerebrum simultaneously, the brain can synthesize them if they are interpreted as corresponding to a single event. This is critical because the central representation of an event or action is improved if two or more relevant cues are integrated but conversely is degraded if unrelated inputs are mistakenly synthesized. Little research has focused on temporal binding of vestibular and non-vestibular cues even though the vestibular system operates in an inherently multimodal environment, and virtually nothing is known about abnormalities in temporal binding that occur with peripheral or central vestibular disorders. Temporal binding is often quantified with two values derived from psychophysical tests, the point of subjective simultaneity (PSS) and the temporal binding window (TBW). We will use these perceptual measures to test a series of hypotheses about the physiology and pathophysiology of vestibular temporal binding. Two sets of specific aims will be investigated: Aim 1 will investigate the mechanisms used by the brain to bind vestibular and non-vestibular signals in time. Aim 1A examines how the precision of the vestibular signal affects its binding with non-vestibular cues. Precision (1/variability) of the spatial and temporal characteristics of vestibular afferents and their relationship to temporal binding will be studied in normal subjects, and we predict that the two precision measures will be correlated with each other and with the TBW. We will also manipulate vestibular precision using patients with combined vestibular (VI) and cochlear (CI) implants in the same ear and predict that additional noise will widen the TBW and increase the PSS. Aim 1B uses the prosthetic signals that are available in the VI-CI patients to examine how adaptation driven by habitual exposure to timing cues affects temporal binding. Since the brain is naïve to these stimulus pairs and the patients have longstanding absence of cochlear and vestibular function in both ears, we can study how the brain binds signals in time when it has no prior exposure to the cues, and predict that the PSS will reflect the relative time for the signals to reach the cerebrum, the TBW will be wide, and both will be abnormally amenable to adaptation. Aim 2 investigates how temporal binding contributes to the pathophysiology of peripheral and central vestibular disorders. Aim 2A examines the effects of acute loss of peripheral vestibular function and the subsequent process of compensation on temporal binding. We predict that both passive and active processes will contribute to recalibration of the PSS and TBW, that patient outcome will correlate with the changes in these values, and that adaptation of the PSS and TBW will improve clinical outcome. Aim 2B examines how temporal binding contributes to central vestibular dysfunction, focusing on motion sickness and migraine. We predict that subjects with more severe motion sickness will have wider TBWs and that adaptation that narrows the TBW will reduce susceptibility to motion sickness.