Elizabeth S. Olson - US grants

The proposed project explores the mechanics of the cochlea and middle ear via measurements of sound pressure in the cochlea, the ear canal and the middle ear cavity. The experiments and interpretation are direct, basic probes of auditory mechanics. The majority of the research effort will be spent on the cochlear study; the middle ear work is a related, smaller study. The cochlea is selective to individual frequencies of sound pressure, as sensitive as physical limits allow, and instantaneously adaptive to a wide range of stimulus levels. At the heart of cochlear operation is a fluid/tissue -and- pressure/motion wave which transports sound energy down the cochlea to frequency-dependent locations on the organ of Corti. Many questions about cochlear mechanics remain. These questions concern fundamental unknowns, such as the physical basis for frequency mapping and tuning, as well as more refined issues, such as the basis for nonlinearity. The proposed experiments examine both the tissue and fluid components of the cochlear traveling wave by using pressure maps to simultaneously measure the wave's pressure and motion components. Pressure will be mapped in the fluid close to the basilar membrane while stimulating the cochlea with sound delivered to the ear canal, or with electric current (at levels which activate the cochlea's natural electro-mechanical transduction). The results will be used to quantify and explore elements central to tuning, frequency mapping and nonlinearity: the wave's effective fluid mass and the mechanical impedance of the organ of Corti, mode changes in the motion of the basilar membrane and energy injection into the traveling wave. Understanding the mechanics of the cochlea is a vital and elusive goal. The progress of many researchers, and technical and computing innovations are bringing this goal within reach. Better understanding the cochlea's mechanical operation will impact on deafness prevention and treatment, especially the design of digital hearing aids and cochlear implants. Accumulating evidence indicates that sound is transmitted through the middle ear as a traveling wave. For example, the phase-vs- frequency behavior of the sound pressure inside the cochlea at the stapes (the output of the middle ear), relative to that in the ear canal (the input to the middle ear) is delay-like between 2 and 40 kHz. The gain (cochlear pressure/ear canal pressure) is nearly flat over these frequencies. Thus, both the temporal and the frequency information in sound is transmitted by the middle ear to the cochlea with high fidelity. How does the middle ear do it? To address this question, sound will be delivered to the ear canal and pressure measurements will be made in the ear canal, the cochlea's scala vestibuli, and the middle ear space. These pressures, and their changes following reversible and irreversible manipulations to the ear will be analyzed to understand how the tympanic membrane and ossicles deliver sound to the cochlea. These results will impact on the treatment of the middle ear and the design of middle ear prostheses.

[unreadable] DESCRIPTION (provided by applicant): The proposed project explores the mechanics of the cochlea and middle ear via measurements of sound pressure in the cochlea, the ear canal and the middle ear cavity. The experiments and interpretation are direct, basic probes of auditory mechanics. The majority of the research effort will be spent on the cochlear study; the middle ear work is a related, smaller study. The cochlea is selective to individual frequencies of sound pressure, as sensitive as physical limits allow, and instantaneously adaptive to a wide range of stimulus levels. At the heart of cochlear operation is a fluid/tissue -and- pressure/motion wave that transports sound energy down the cochlea to frequency-dependent locations on the organ of Corti. Many questions about cochlear mechanics remain. These questions concern fundamental unknowns, such as the physical basis for frequency mapping and tuning, as well as more refined issues, such as the basis for nonlinearity. The proposed experiments examine both the tissue and fluid components of the cochlear traveling wave by using pressure maps to simultaneously measure the wave's pressure and motion components. Pressure will be mapped in the fluid close to the basilar membrane while stimulating the cochlea with sound delivered to the ear canal, or with electric current (at levels which activate the cochlea's natural electro-mechanical transduction). The results will be used to quantify and explore elements central to tuning, frequency mapping and nonlinearity: the wave's effective fluid mass and the mechanical impedance of the organ of Corti, mode changes in the motion of the basilar membrane and energy injection into the traveling wave. [unreadable] [unreadable] Understanding the mechanics of the cochlea is a vital and elusive goal. The progress of many researchers, and technical and computing innovations are bringing this goal within reach. Better understanding the cochlea's mechanical operation will impact on deafness prevention and treatment, especially the design of digital hearing aids and cochlear implants. [unreadable] [unreadable] Accumulating evidence indicates that sound is transmitted through the middle ear as a traveling wave. For example, the phase-vs-frequency behavior of the sound pressure inside the cochlea at the stapes (the output of the middle ear), relative to that in the ear canal (the input to the middle ear) is delay-like between 2 and 40 kHz. The gain (cochlear pressure/ear canal pressure) is nearly flat over these fi'equencies. Thus, both the temporal and the frequency information in sound are transmitted by the middle ear to the cochlea with high fidelity. How does the middle ear do it? To address this question, sound will be delivered to the ear canal and pressure measurements will be made in the ear canal, the cochlea's scala vestibuli, and the middle ear space. These pressures, and their changes following reversible and irreversible manipulations to the ear will be analyzed to understand how the tympanic membrane and ossicles deliver sound to the cochlea. These results will impact on the treatment of the middle ear and the design of middle ear prostheses. [unreadable] [unreadable] This supplement adds in-vivo measurements of basilar membrane and ossicular motion. The additional measurements tie in directly with the aims of the original proposal. The b.m. motion measurements add to the studies of mode changes in b.m. motion and the mechanical impedance of the organ of Corti. The ossicular motion measurements enhance the study of transmission through the middle ear. [unreadable] [unreadable]

The primary objective of this research is to further our understanding of the mechanics of the healthy cochlea. A secondary objective is to understand how sound is transmitted through the healthy middle ear. To attain these objectives we use two powerful experimental techniques: intracochlear pressure measurements and interferometric measurements of intracochlear and middle ear motion. Specific experiments measure sound transmission within the cochlea to explore the interaction between the cochlea's active mechanics and the cochlear traveling wave, and sound transmission between the cochlea and the ear canal to determine how the middle ear filters cochlear emissions. Other experiments will measure detailed motion of the cochlea's basilar membrane;subtle spatial variations could reveal the operation of the cell- based forces that shape cochlear tuning. In order to understand the passive substrate for cochlear tuning, upon which the interesting "active" cell-based forces must build, one experiment will measure the stiffness and resistance of the cochlea's basilar membrane and organ of Corti in situ, another will measure tuning in cochleae in which the organ of Corti was ototoxically damaged. Finally, one experiment will trace the source of the observed middle ear transmission delay. The measurements are aimed at understanding the mechanics of the normal cochlea and middle ear. Nevertheless, they are significant to the treatment of the hearing impaired. While cochlear implants have been breathtakingly successful, a divide remains between the functional hearing available with an implant and the natural auditory experience of music, language, and nature. To decrease this divide, cochlear implants and hearing aids continue to be improved and a better understanding of the natural processing of the cochlea will benefit this work. Beyond implants and aids, the promise of repairing the organ of Corti through therapies that regenerate or repair cochlear hair cells is very exciting, and the understanding of the normal mechanics will help guide these advances. In the case of the middle ear, surgical therapies are available but are not always successful. Better understanding the transmission of sound through the middle ear is one of the goals of this proposal, and gaining that knowledge could influence its surgical repair.

DESCRIPTION (provided by applicant): Two fundamental facts of mammalian auditory processing are: (1) the frequency selectivity that exists in the auditory nerve is due to mechanical preprocessing in the cochlea and (2) the mechanics of the cochlea are highly nonlinear. Cochlear nonlinearity works to boost the mechanical response at low sound pressure levels at frequencies close to the location's best frequency. Thus, cochlear nonlinearity is central to the cochlea's frequency selectivity. In ears in which the mechanics are damaged (through overstimulation, some chemotherapies, and simply aging) nonlinearity is reduced or eliminated, leading to severe loss of hearing acuity. Much remains to be learned about the micromechanical actions and interactions that produce cochlear nonlinearity, termed the "cochlear amplifier." Mouse models in which cellular and acellular cochlear components are altered through genetic engineering have been developed and are already being used to advance our understanding of cochlear mechanics. However, historically mice were not used for cochlear mechanics and robust normative data is lacking. We propose to measure normal intracochlear pressures and motions in mice upon acoustic stimulation. These are the basic responses to normal stimulation. We will also measure pressures and motions upon electrical current stimulation, which is similar and in some ways complementary to acoustic stimulation, and has been used already in modified mouse studies with interesting results. Upon establishing robust normative results we plan to go on, in future projects, to study mice with genetically modified cochlear components. PUBLIC HEALTH RELEVANCE: Healthy hearing relies upon mechanical boosting of the response within the inner ear (cochlea). In ears in which cochlear mechanics are damaged due to overstimulation, chemotherapies or simply aging the boosting is reduced or eliminated, leading to hearing loss. With the advent of genetic engineering, mouse models are being developed in which specific components of the cochlea are modified. This leads to many possibilities to explore the workings of the healthy cochlea and the ways to repair a damaged cochlea. In this project, the foundation for such advances is laid by measuring the mechanical responses of the cochleae of normal mice.

? DESCRIPTION (provided by applicant): Sound input to the inner ear (cochlea) causes a frequency-segregated wave-pattern of sensory tissue motion that conveys sound information to the auditory neurons, leading to hearing. A currently untreatable aspect of hearing impairment is the deterioration of the cochlea's ability to sharply segregate sound by frequency. The cochlea's healthy frequency tuning is largely provided by the cochlear amplifier, an outer-hair-cell-driven, place-frequency-localized electromechanical engine that is both powerful and fragile. This project's aims 1-3 explore the cell/structure basis of cochlear amplification. The studies use intracochlear micro-sensors that have been developed, enhanced and used in our laboratory over the past 20 years, along with a cutting-edge imaging technology, spectral- domain optical-coherence-tomography. With these tools, localized measurements of mechanical and electrical responses at and within the cochlea's sensory tissue will be made before and after treatment by auditory-active substances. These substances are cochlear-perfused Tributyltin, which increases intracellular Cl- and thus alters prestin-based OHC activity, and systemically-injected Furosemide, a loop diuretic that reduces endocochlear potential. The analysis of simultaneously measured responses (endocochlear potential, pressure at and motion of the sensory tissue, outer-hair-cell- derived extracellular voltage) will inform our understanding of the workings of th cochlear amplifier, and the ways in which it fails. These intracochlear experiments form the primary overarching theme of the project. The second theme of the project explores the transmission of sound to the cochlea by the middle ear, a mechanical process that remains unexplained. In particular, while the mechanical response of the middle ear's tympanic membrane appears to be a poor representation of the incoming sound, the middle ear is nevertheless able to transmit sound to the inner ear with high fidelity. This ability has been the subject of physics-based theories and we will test those theories by investigating the transmission of an impulse sound stimulus in motion measurements from the tympanic membrane's outer edge to the ossicular malleus.

Project Summary / Abstract: Auditory Mechanics and Cochlear Amplification Sound input to the inner ear (cochlea) causes a frequency-segregated wave-pattern of sensory tissue motion that conveys sound information to the auditory neurons, leading to hearing. A currently untreatable aspect of hearing impairment is the deterioration of the cochlea's ability to sharply segregate sound by frequency. The cochlea's healthy frequency tuning is largely provided by the cochlear amplifier, an outer-hair-cell-driven, place-frequency-localized electromechanical engine that is both powerful and fragile. This project's aims 1-3 explore the cell/structure basis of cochlear amplification. The studies use intracochlear micro-sensors that have been developed, enhanced and used in our laboratory over the past 20 years, along with a cutting-edge imaging technology, spectral- domain optical-coherence-tomography. With these tools, localized measurements of mechanical and electrical responses at and within the cochlea's sensory tissue will be made before and after treatment by auditory-active substances. These substances are cochlear-perfused Tributyltin, which increases intracellular Cl- and thus alters prestin-based OHC activity, and systemically-injected Furosemide, a loop diuretic that reduces endocochlear potential. The analysis of simultaneously measured responses (endocochlear potential, pressure at and motion of the sensory tissue, outer-hair-cell- derived extracellular voltage) will inform our understanding of the workings of the cochlear amplifier, and the ways in which it fails. These intracochlear experiments form the primary overarching theme of the project. The second theme of the project explores the transmission of sound to the cochlea by the middle ear, a mechanical process that remains unexplained. In particular, while the mechanical response of the middle ear's tympanic membrane appears to be a poor representation of the incoming sound, the middle ear is nevertheless able to transmit sound to the inner ear with high fidelity. This ability has been the subject of physics-based theories and we will test those theories by investigating the transmission of an impulse sound stimulus in motion measurements from the tympanic membrane's outer edge to the ossicular malleus.

Project Summary / Abstract: Auditory Mechanics and Cochlear Amplification 2020 Sound input to the cochlea causes a frequency-sorted wave-pattern of sensory tissue motion that conveys sound information to the auditory neurons, leading to hearing. A currently untreatable aspect of hearing impairment is the deterioration of the cochlea's ability to sharply separate sound by frequency. The cochlea's healthy frequency tuning is largely provided by the cochlear amplifier, an outer-hair-cell-driven, place-frequency-localized electromechanical feedback mechanism that is both powerful and fragile. This project's aims 1-3 explore the cell/structure basis of cochlear amplification. The studies use intracochlear sensors and a cutting-edge imaging and vibrometry technology, spectral-domain optical-coherence-tomography (SD-OCT). Localized measurements of mechanical and electrical responses at and within the cochlea's sensory tissue will be made both in healthy normal and in modified cochleae. Gerbils and guinea pigs are used and critical aspects of cochlear amplification are compared in the two species in aim 2. In aim 1, measurements are made in cochleae before and after intracochlear injection of substances that will modify tectorial membrane (TM) mechanics. Because it governs transduction in hair cells, the TM plays a profound role in cochlear amplification; our studies test hypotheses that are based on cochlear models and measurements in isolated TMs and in TM-mutant mice. Aim 3 makes use of SD-OCT's penetrating abilities to test previously untestable fluid-mechanical properties of the organ of Corti. Aim 4 explores the transmission of sound to the cochlea by the middle ear, and how this transmission is modified by feedback from the middle ear muscle, tensor tympani. In preliminary work, tensor tympani modified transmission in a subtle, frequency-dependent manner that could be involved in focusing on particular sound sources, for example during communication. Experiments in which tensor tympani is tensed with voltage pulses will determine how the muscle affects the transmitted sound signal.