Howard Francis - US grants

A study of the electrophysiology of the cochlear nucleus in deafness is being proposed as part of an overall career development plan for funding by a Mentored Clinical Scientist Development Award. The candidate proposes a combination of didactic learning and research experience in the Center for Hearing Science and the department of Otolaryngology at Johns Hopkins University under the sponsorship of Paul Manis, Ph.D. The candidate is a neurotologist with a special interest in disorders of the auditory system. A research study is proposed to characterize the functional consequences and cellular mechanisms of central adaptation to deafness. A career plan has been organized to provide the biophysical and mathematical skills needed to fulfill his research objectives and long-term goals, which include the use of in vitro data to characterize and model central auditory mechanisms in deafness. This research effort may provide insights with clinical implications in the rehabilitation of hearing loss. The electrophysiological effects of bilateral cochlear ablation will be studied in rat. In experiments of the first aim morphologically identified VCN neurons will undergo intracellular current-clamp recordings in brainstem slices to test the hypothesis that cochlear ablation alters the electrical properties and discharge characteristics of these neurons. Preliminary studies show significant changes in the electrical properties of deafferented VCN neurons including the slowing of action potential repolarization in type 1 (stellate) cells, and a decrease in resting membrane potential and increase in current-voltage rectification in type II (bushy) cells. Experiments of the second aim will evaluate how the altered electrical properties of differentiate stellate and bushy cells affect their encoding properties, by studying their response to trains of brief current pulses that mimic the response of auditory nerve fibers to acoustic stimuli. Preliminary studies suggest that the representation of acoustic amplitude modulation by stellate cells, and phase locking by bushy cells are impaired following cochlear ablation. Experiments of the third aim will test the hypothesis that changes in the electrical and encoding properties of deafferented VCN neurons are associated with alterations in sodium and potassium conductance as measured by tight-seal whole-cell voltage-clamp recordings performed in both brainstem slice and acutely isolated cell preparations.

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of my research is to understand fundamental structure-function relationships in the cochlea of terrestrial mammals. Hair cell loss and stereocilia pathology can be found in cochlear regions where hearing is impaired, but not always. Afferent terminals on inner hair cells (IHC), however, undergo acute structural changes in response to noise, but the long-term effects on innervation density and synaptic morphology, and their implications for hearing are unknown. This study will first establish a frequency-place map for the C57BL/6J mouse cochlea, which will enable us to make structure-function correlations in the subsequent experiments. At present there is no conclusive map for any mouse strain. Using retrograde tracer injections into defined frequency regions of the cochlear nucleus, we will plot auditory nerve afferent projections into the organ of Corti. Once a frequency map is available, we will characterize the morphology, density, and organization of nerve terminals on IHCs at specific frequency locations (e.g. 16kHz) using electron microscopic analyses of serial sections. We will combine this analysis with an unbiased stereological protocol developed to use only a fraction of the sections for accurate and efficient study of synaptic morphology in several animals. Lastly, we will test the hypothesis that noise damage has a detrimental long term effect on the structure of afferent terminals and their synapses with IHCs, and that these changes are associated with permanent hearing loss. This aim will study the effects of noise on structure of the IHC-afferent interface at frequency locations corresponding to permanent threshold shift, using stereological techniques developed in the 2nd aim. The mouse is a useful model for auditory neuroanatomy because its small size makes for efficient microscopic analysis, and its genome is indispensable for transgenic and mutant creations. A better understanding of normal and abnormal synaptic structure at IHCs may provide new insights into the mechanisms of hearing loss and will increase opportunities for discovery and for the development of new therapies.

At present, otologic surgeons are unable to perform surgical procedures on the inner ear without rendering irreversible injury to cochlear and vestibular function. This limitation fundamentally constrains our ability to understand, diagnose, and treat inner ear disorders such as hearing loss and vertigo.
This exploratory research program seeks to develop and test a "proof of concept" real-time cochlear imaging system that will provide navigation for the precise and atraumatic placement of micro-needles into compartments of the inner ear using robotic assistance. The system will consist of a robotic end-effector combining a 70 MHz focused-beam ultrasonic transducer with a 110 micron diameter micro-needle. The end-effector will be actuated in two degrees-of-freedom and mounted on a robotic arm to acquire both 2-D planar and 3-D volumetric ultrasonic images, and to insert and retract the micro-needle.
Intellectual Merit: The proposed robotic device will be the first system capable of (a) performing real-time ultrasonic imaging of the cochlea and (b) employing these images for image-guided needle placement into the compartments of the cochlea. The proposed system will enable in vivo otologic research presently considered impossible. The proposed SGER will enable us to do the basic research necessary to develop a working real-time robotic image guided intervention system.
Broader Impact: The ability to perform real-time in vivo imaging of the intracochlear membranes and to place precisely tools and sensors within the cochlea with minimal trauma would open new avenues for the diagnosis and treatment of inner ear disorders. The intracochlear placement of sensors for example, would allow real-time spectrographic assessment of metabolic changes inside the cochlea, enabling new lines of research into cochlear pathophysiology. In the future, the placement of needles within the inner ear would permit the direct delivery of therapeutic compounds to treat cochlear disease, including medications, gene therapy vectors and stem cell therapy

? DESCRIPTION (provided by applicant): The goals of this application are to: 1) determine what level of involvement by the primary care practitioner (PCP) is required to inform and encourage adults age 65-75 to follow through with routine hearing screening; 2) develop a model of effective adult hearing screening, based on resource utilization and screening compliance in each intervention group, that maximizes identification of hearing loss in affected patients and minimizes burden to the PCP and patient; 3) determine what factors are important to adults 65-75 in making decisions about hearing screening and interventions and develop strategies to optimize appropriate intervention; and 4) provide data on the ability of patients, audiologists and primary care providers to identify significant medical conditions that should be evaluated by an ear specialist prior to hearing aid procurement. This latter goal could help to inform FDA policy which currently requires either medical evaluation and clearance or a waiver to forego medical evaluation prior to hearing aid fitting. The current recommendation by the FDA is not evidence-based, and has been interpreted by some as prohibitive of less resource-intensive care delivery models such as remote hearing aid sales or over the counter (OTC) procurement. In the proposed research, we will compare implementation of three PCP-based hearing screening strategies (total N=660) that include progressive levels of PCP time and guidance to complete telephone-based hearing screening. Those who fail screening (estimate: N=100) go on to a medical referral study and receive (1) diagnostic audiological testing and (2) determination of the reliability and validity of identification of conditions that should require medical referral pior to hearing aid provision. The N in the medical referral study from the PCP-based screening is complemented by a sample of 500 patients from the NIH-funded CHEER network seen for ear related problems. A successful implementation of the study will help us understand: 1) the most effective and cost-efficient strategy for hearing screening implementation in this population; 2) the factors that are important to patients in their decisions regarding hearing healthcare; 3) the level of medical care required to insure that hearing aid fitting is safe, and whether the 'medical model' of hearing aid procurement is warranted. Our team of collaborators includes providers and academics of diverse backgrounds, to provide wide expertise and perspective. The study will utilize both PCP practices from the Primary Care Research Consortium in the Duke Health System, and the NIH-supported CHEER practice-based network, to ensure diversity of patient enrollment and generalizability to community practice. Our research will serve as the basis for future efforts to meaningfully influence health care approaches to hearing loss and health care policy related to hearing health care delivery, including FDA policy on hearing aid care delivery. Our ultimate goal is to provide information to inform changes in health care policy to facilitate accessible and affordable hearing health care.