Hideko Heidi Nakajima - US grants

DESCRIPTION (provided by applicant): This grant seeks to address important clinical and scientific questions regarding human hearing diseases and their treatment. To do so, we make simultaneous pressure measurements on each side of the cochlear partition in human cadaveric temporal bones. This new and powerful technique enables direct determination of the differential pressure across the cochlear partition, the stimulus that excites the cochlear partition and initiates the cochlear traveling wave. Thus, this intracochlear differential pressure measurement in cadaveric temporal bones allows for a representation of what a live human with normal sensory function would hear, enabling us to investigate human hearing under controlled circumstances and to answer questions which could not be previously addressed, as outlined in the following 3 aims: Aim 1) Determine if a useful level of hearing is possible when the oval window is blocked and the cochlea is stimulated via the round window (RW). The experiments under this aim will establish whether or not RW stimulation can effectively treat stapes fixation in patients where stapedectomy is contraindicated. Furthermore, they will test the degree to which the cochlea can be approximated as a rigid bone containing incompressible fluid with only two flexible windows (oval and round windows) responsible for the pressure difference across the cochlear partition. Aim 2) Understand how pathologic third-window lesions of the inner ear can result in hearing loss. Superior semicircular canal dehiscence (SCD) is a prototypical third window lesion, and it is unknown why some individuals with SCD have hearing loss while others do not. By studying the impact of controlled dehiscences on differential pressure and other measurements, we will test two hypotheses: 1. Pathologic third windows shunt fluid flow away from the cochlea, resulting in decreased pressure difference across the cochlear partition, leading to hearing loss;2. The size of the dehiscence is a major factor in the determination of the hearing loss. This study will aid in understanding when and how third-window lesions produce hearing loss and determine whether size of the dehiscence is an important variable. The present treatment for SCD is highly invasive and is reserved for debilitating vestibular symptoms only. A novel alternative treatment for SCD-induced hearing loss is addressed as part of Aim 3. Aim 3) Investigate the application of RW stimulation to treat various diseases of the middle and inner ear, including: 1. semicircular canal dehiscence;2. discontinuity of the ossicular chain;3. non-aerated middle ear;and 4. stapes fixation (as in Aim 1). By measuring the trans-cochlear differential pressure evoked by RW stimulation in the controlled setting of cadaveric preparations, while simulating various diseased states, we will investigate whether RW stimulation is a feasible and efficacious treatment for various middle- and inner-ear disorders. It is anticipated that the results of the investigations under these three aims will answer fundamental questions regarding human hearing, and yield advances in the clinical diagnosis and treatment of hearing diseases. PUBLIC HEALTH RELEVANCE: This grant addresses mechanisms and treatments of middle- and inner-ear diseases that are common causes of hearing loss. A new measurement technique based on fiberoptic micro- pressure transducers will be employed in human cadaveric specimens to obtain previously unavailable knowledge and test new treatments.

Project Summary/Abstract Many patients suffer from conductive hearing loss (CHL) that is intractable to treatment, although their neurosensory system is intact. Round-window (RW) and bone-conduction (BC) stimulation have been proven to provide improved hearing for CHL that have failed various treatments. However these alternative stimulation methods have limited success. Their application is hindered both by a lack of knowledge of the unique mechanisms by which sound is transmitted to the cochlear partition by these stimulus methods, and limitations in the manner in which they are applied. Fresh human cadaveric preparations allow for controlled invasive experiments to elucidate these mechanisms, simulate various conductive diseases and evaluate and improve devices and treatments. With our new technique of intracochlear pressure measurement, we can better understand the mechanisms of these alternative sound stimulus pathways that differ substantially from normal air-conducted sound stimulation. Furthermore, the determination of the differential pressure stimulus, DP, allows monitoring of the input to the cochlea during normal and alternative stimulation and in disease conditions where the inner-ear impedances are changed, such as superior semicircular canal dehiscence (SCD). We employ this technique to answer questions that could not be previously addressed: Aim 1) Evaluate and improve methods for stimulating the RW. RW stimulation with crudely-modified middle-ear implants has aided numerous patients with CHL that were not helped by other means. However, hearing results have varied. We will develop a coupling system for RW stimulation that is specific for the unique anatomy and mechanical properties of the RW. This system will provide safer, more efficient and consistent RW stimulation. By measuring DP in the controlled environment of human cadaveric preparations, the performance of our coupling system will be compared quantitatively to other RW stimulation coupling methods, and critical features for safety, efficiency, consistency and ease of surgical implementation will be ascertained. Furthermore, the mechanical specifications required to optimize performance of a RW actuator will be determined. Aim 2) Elucidate the mechanisms involved in BC stimulation of the ear and determine how BC is affected by different pathologies. BC stimulation is used to diagnose sensory-neural hearing loss and to treat conductive and mixed hearing loss, yet the mechanisms of BC stimulation are not well understood. We will advance the understanding of BC and its effects by measuring intracochlear differential pressure, DP, evoked by BC stimulation in human cadaveric preparations. The study will: 1) Determine the contributions to BC of the inertial effects of ossicular motion and cochlear fluids and the compression effect of surrounding bone; 2) Determine the effects of the direction of BC stimulation; and 3) Determine the effect of SCD on BC. The measurements of BC-evoked DP will elucidate BC mechanisms and improve applications of BC for diagnosis and treatment.

DESCRIPTION (provided by applicant): The goal of our work is to understand sound transmission in normal, diseased and reconstructed middle ears so as to develop better diagnostic tests and surgical procedures for patients with middle-ear disease. Middle ear diseases, such as chronic otitis media and otosclerosis, which affect over 30 million people in the U.S., are common causes of significant conductive hearing loss that range in severity up to 60 dB. Hearing losses of 30-60 dB have significant adverse effects on patients' lives and their ability to communicate. Many aspects of middle ear sound transmission are not well understood. Additionally, hearing results after certain types of middle-ear surgical procedures (especially for chronic otitis media) are often unsatisfactory, because the structural factors that are important for good hearing results are not all that clear. Over the past 10 years, we have utilized a unique and powerful combination of methods to study middle-ear mechanics including in-vivo measurements using laser Doppler vibrometry, in-vitro measurements in cadaveric human temporal bones, and physics-based, quantitative modeling. Our work has a) provided insight into mechanisms of conductive hearing loss caused by a variety of pathologies affecting the middle- and inner- ears, b) resulted in new diagnostic concepts, and c) provided specific surgical recommendations to optimize postoperative hearing results in certain types of middle-ear surgical procedures. Over the next five years, we aim to exploit these methods and use new tools such as external-ear acoustic reflectance and laser holography of motion of the tympanic membrane in order to: a) investigate correlations between ear canal reflectance and umbo velocity in normal and pathologic ears, b) define critical structural features that determine postoperative hearing results in aerated ears after ossicular reconstructions, and c) investigate use of a novel implant to improve post-surgical hearing results in non-aerated ears. We anticipate that our work will lead to better understanding of structure-function relationships in normal and pathological middle ears, improved differential diagnosis of conductive hearing loss, and optimization of surgical techniques and hearing results.

PROJECT SUMMARY Although the inner workings of the cochlea are responsible for the most fundamental aspects of hearing, including hearing sensitivity and frequency tuning, our direct knowledge of human cochlear mechanics is limited. This lack of information has forced researchers to rely on animal experiments to make inferences about cochlear behavior in humans, under the assumption that the motions of the cochlear partition (CP), including the basilar membrane (BM) and the organ of Corti (OoC), are similar between humans and laboratory animals. However, we have recently found surprising differences in human CP anatomy and motion as compared to laboratory animals. The BM in animals is attached to a narrow fixed bony structure, the osseous spiral lamina (OSL), and accounts for almost all of the CP motion. In contrast, the OSL in humans is much wider, is mobile, and connects to the BM via a newly identified soft-tissue structure that we have named the CP ?bridge?. The bridge, which is non-existent in laboratory animals, is as wide as and vibrates as much as the BM. Combined with the fact that the OSL itself is mobile, the BM therefore only accounts for a fraction of total CP motion in humans. These newly discovered aspects of human CP anatomy and motion challenge the long-held assumption that cochlear mechanics can be regarded as similar across mammals. Because CP structures such as the OSL, bridge, and location where the tectorial membrane (TM) attaches to the limbus are all mobile in humans but not in laboratory animals, we hypothesize that the motions of the OoC structures, including the reticular lamina and TM, are different in humans, thereby altering the input driving the transduction process at the hair bundles of the inner and outer hair cells. To test this, Optical Coherence Tomography (OCT) will allow us to determine the anatomy and relative motion of various CP structures in situ in very fresh human cadaveric specimens. We will also investigate and elucidate the relationships between mechanics and anatomy in the human CP using a variety of techniques to characterize the morphometry, structural architecture, and material composition of the CP. We will further test our hypothesis by developing finite-element models of the human cochlea that incorporate the measured anatomy and CP mechanics. As our measurements are from postmortem ears, they cannot reveal the effects of active processes. However, our models can approximate active behavior based on live-animal results, which are predicted to be functionally similar to human given the similar anatomies of these structures. The resulting models will be tested and validated against known human tuning capabilities from psychoacoustic data, opening the door to future applications in which human cochlear pathologies, manipulations, and treatments can be simulated with unprecedented fidelity. This research will greatly advance our understanding of how the structures of the human CP work together to define the inputs to the transducers formed by the hair cells. It will also enable us to better understand the applicability and limitations of animal experiments in the study of human hearing, and to better utilize animal models for scientific inquiry. Moreover, the proposed computational models will be valuable both for scientific investigation of hearing phenomena and for future improvements in the understanding, diagnosis and treatment of hearing disease.

Project Summary We are developing implantable microphones for assistive hearing devices, which are essential for enabling prosthetic hearing devices such as cochlear implants (CI) and middle-ear implants to become fully implantable. Fully-implanted systems offer significant advantages over conventional devices with external microphones: access to hearing 24/7 (such as when sleeping), which can benefit children's brain development and prevent limitations on activities and lifestyles for all ages; benefit from the external ear's acoustic enhancement to improve hearing in noisy environments; ease of use (less challenges in dexterity); cosmetic appeal. We have successfully developed proof-of-concept prototypes for each microphone design and have demonstrated ease of implantation and high-fidelity responses in fresh human cadaveric ears. In this application we focus on two basic microphone designs, with the goal that at the end of the project they will be ready for large-animal experimentation and/or clinical trials. One is an intracochlear microphone embedded within a cochlear implant that senses inner-ear pressure. The other is a motion-sensing device that attaches to the distal end of the malleus, the umbo, within the middle-ear cavity. The devices are based on polyvinylidene fluoride (PVDF), a piezoelectric polymer. The fabrication of the devices starts with a PVDF film, which is metalized to form electrical contacts to transmit the piezoelectric signal. They are then encapsulated and electrically shielded. The devices, already operating at a useful level, will be modeled, evaluated and refined to perform at a level comparable to hearing aid microphones, with high sensitivity, low noise and flat response over a wide bandwidth.