James O. Phillips - US grants

This application seeks support for a basic research symposium designed to stimulate a thorough discussion of areas of controversy in the field of vestibular physiology and related movement control. Over the course of 2 and 1/2 days, there will be six workshops concerning active research areas. We will bring together scientists interested in psychophysics, systems level neuroscience, and cellular and molecular mechanisms to facilitate discussions that incorporate a broad perspective. This format will provide basic information to the field at large, help resolve issues by direct confrontation of scientists with disparate views and inform younger investigators about the important issues in the field that they are entering. Indeed, the principal objective of this grant is to generate funds so that junior investigators and women and minority participants who are making exciting contributions to the field but who have limited travel funds may attend the meeting. An airing of the issues raised in this symposium will ultimately guide the clinical application of our knowledge in persons with balance and orientation problems, as well as a variety of motion-induced visual disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Currently there are limited treatment options for patients with pathological vestibular function. Loss of vestibular sensation from the inner ear results in imbalance and oscillopsia. Partial loss results in disequilibrium. Fluctuating loss in conditions such as Meniere's disease, results in intermittent vertigo and nausea. Our project was to develop an implantable vestibular prosthesis to replace lost vestibular function or correct abnormal vestibular function in patients suffering from these conditions. Specifically, we developed a modification of cochlear implant technology to provide the implantable portion of our device, and then developed new software and external hardware to drive individual semicircular canal nerves with electrical stimuli appropriate to produce reflexive eye movement responses in rhesus monkeys. We then recorded from individual vestibular neurons to determine the central processing that takes place during stimulation to produce the observed behavior. We are now using transtympanic injections of gentamicin to eliminate vestibular input and then using electrical stimulation to compensate for the loss.

This project will provide research and development of methods for electrically stimulating the vestibular nerve following loss of function from the vestibular end organs. The objective of this research is to develop methods of electrically stimulating the vestibular nerve, which can provide patient benefit during transient attacks of irregular activity leading to dizziness and/or act as a component of a balance prosthesis. This contract is directed towards animal studies with close ties to clinical applications in human patients in the near future.

PROJECT SUMMARY (See instructions): Hearing loss is the most frequent sensory defect in humans. Congenital, perinatal or eariy onset hearing loss occurs in approximately 7 out of 1000 neonates in the United States. In approximately half of the children born with severe hearing impairment, a genetic contribution is suspected. The powerful molecular and genetic techniques available in zebrafish and mouse combined with the functional similarities between mouse and human audition make these organism useful model systems for studying deafness. Core D supports users of genetic models to study genes affecting auditory, vestibular and olfactory system function. We provide technical support in the form of expert mouse husbandry (receiving, setting up crosses, weaning, fostering, background transfers, etc), genotyping, and notification/delivery of requested mice to the users. Core D also supports several facilities for behavioral and physiological analyses of mutants including auditory brainstem responses (ABR), simple motor tests, rotarod testing, and vestibulo-ocular reflex (VOR) analysis. Other services include access to lentiviral transfection technologies and resources for genomic and proteomic data analysis. Advice and training is available to all users from a knowledgeable and helpful Core staff. The Genetics Core will provide greater efficiency for researchers and promote new collaborations between investigators. Quarteriy user meetings provide information on Core resources, discussion of protocols, and talks by Core users on their own research projects currently being pursued. Our goal is to facilitate the use of genetic models to broaden our knowledge of communicafive disorders toward improving human health.

Implantable vestibular prosthetic devices, based on cochlear implants, are an emerging technology currently in limited clinical trials. These devices have significant technical constraints and may have limited ability to restore reflexive eye movements with head motion, and appear promising for improving function in some patients with bilateral vestibular deficits. To date, all available devices only stimulate semicircular canal afferents to restore sensitivity to angular acceleration. The other half of the vestibular system, that responding to linear acceleration, is not addressed by these prostheses. Our hypothesis is that restoration of semicircular canal function can improve a patients? sense of balance by working with residual otolith function. If true, our findings may help select the candidates for vestibular implantation who would be most likely to benefit from this technology. Our methodology is to examine eye movements and perform single unit recordings from macaques with vestibular implants during combined linear acceleration and prosthetic semicircular canal stimulation. Our project has two specific aims. In the first, we will examine if prosthetic canal stimulation, like natural canal stimulation, can enable discrimination between linear acceleration from gravity from acceleration due to translation. The ability to discriminate tilt from translation is a fundamental role of the semicircular canal system and critical to spatial orientation. This first aim will use the differences in eye movements elicited during tilt and translation to discern whether prosthetic canal signals can facilitate discrimination of reorientation due to gravity from translation. In the second aim, we will record single unit vestibular nucleus neuronal activity to compare the interactions of prosthetic semicircular canal signals with natural otolith signals to interactions of natural semicircular canal and otolith signals. These experiments will be the first looking at how prosthetic vestibular signals and natural signals interact in the brain. These experiments should provide insight into how the brain process signals from currently used vestibular prostheses and may lead to improvements in approaches to treatment of vestibular problems.