There is not yet a single unifying theory of cochlear amplification consistent with the organ of Corti cytoarchitecture, basilar membrane mechanics, and otoacoustic emissions (OAEs). Our central hypothesis is that the systematically organized Y-shaped structural elements between the reticular lamina and basilar membrane in the organ of Corti collectively form a mechanism for cochlear amplification in the best-frequency region of the basilar membrane, in which the angled outer hair cells (OHCs) provide an accumulating "feed- forward" force directed apically, and the oppositely angled phalangeal processes provide a "feed-backward" force directed basally. The feed-forward and feed-backward (FF/FB) amplification theory will be tested using anatomically realistic fluid-coupled 3D finite element computational models for the mouse and gerbil organs of Corti, constructed from two-photon and confocal microscopy images. After validation against previous physiological measurements and modeling results, the new models will be used to test the effects of FF/FB forces on cochlear amplification, as well as the effects of tectorial and basilar membrane mechanics. The hypothesis that the FF/FB amplifier concepts are compatible with theories and measurements of stimulus- frequency OAEs and distortion-product OAEs, and that selective modifications to the structure of the organ of Corti will produce predictable results, will be tested both in the model and experimentally using wild-type mice and alpha-tectorin protein mutated mice (TectaC1509G/+) that feature a shortened tectorial membrane. Cochlear models have typically assumed that the OHC force output is proportional to the stereociliary force input, with a gain ? assumed to be independent of cochlear location and frequency. We will improve upon this by creating a model for the OHC receptor potential that accounts for the basolateral conductances and cell wall capacitance, which we will then combine with an anatomically and physiologically realistic model for somatic motility in order to determine realistic values for ? as a function of location and frequency. The resulting ?(x,r,f) model will then be integrated into our FF/FB modeling frameworks as a further test of our central hypothesis. The scientific contributions stemming directly from this research are expected to be 1) a detailed 3D description of the Y- shaped elements in the organ of Corti across the different OHC rows, from base to apex;2) an incorporation of this information into computational models for testing the FF/FB amplifier theories with realistic anatomy;3) an improved understanding of how mechanisms of OAE generation and propagation relate to the FF/FB amplification theory;and 4) an enhanced understanding of the contributions of OHC basolateral conductances, receptor potential, and somatic motility to cochlear amplification. The resulting models will provide powerful new tools for future cochlear mechanics studies, including those involving normal, genetically modified, and regenerated mouse cochleae, and, due to homologs between humans and mice, the human cochlea as well.

Public Health Relevance

The proposed research will benefit public health by helping to address the needs of the millions of individuals with permanent sensorineural hearing loss who depend on acoustic hearing aids as the only form of treatment for their condition currently available. The results of the proposed research could provide critical information for improving the effectiveness of these hearing aids, leading to the design of better amplification algorithms, the incorporation of physiology-based loudness models, and improvements to the design of the computer chips that implement hearing-aid algorithms. The proposed anatomically accurate 3D cochlear models may also accelerate the development of future biological interventions centered around the regeneration of cochlear structures, by providing a computational framework within which various therapeutic strategies can be initially evaluated and compared.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007910-07
Application #
8685757
Study Section
Special Emphasis Panel (ZRG1-IFCN-Q (02))
Program Officer
Cyr, Janet
Project Start
2005-10-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
$561,480
Indirect Cost
$189,090
Name
Stanford University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Soons, Joris A M; Ricci, Anthony J; Steele, Charles R et al. (2015) Cytoarchitecture of the mouse organ of corti from base to apex, determined using in situ two-photon imaging. J Assoc Res Otolaryngol 16:47-66
Kim, Namkeun; Steele, Charles R; Puria, Sunil (2014) The importance of the hook region of the cochlea for bone-conduction hearing. Biophys J 107:233-41
Kim, Namkeun; Steele, Charles R; Puria, Sunil (2013) Superior-semicircular-canal dehiscence: effects of location, shape, and size on sound conduction. Hear Res 301:72-84
Liu, Christopher C; Gao, Simon S; Yuan, Tao et al. (2011) Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane. J Assoc Res Otolaryngol 12:577-94
Kim, Namkeun; Homma, Kenji; Puria, Sunil (2011) Inertial bone conduction: symmetric and anti-symmetric components. J Assoc Res Otolaryngol 12:261-79
Yoon, Yong-Jin; Steele, Charles R; Puria, Sunil (2011) Feed-forward and feed-backward amplification model from cochlear cytoarchitecture: an interspecies comparison. Biophys J 100:1-10
Yoon, Yongjin; Puria, Sunil; Steele, Charles R (2009) A COCHLEAR MODEL USING THE TIME-AVERAGED LAGRANGIAN AND THE PUSH-PULL MECHANISM IN THE ORGAN OF CORTI. J Mech Mater Struct 4:977-986
Steele, Charles R; Boutet de Monvel, Jacques; Puria, Sunil (2009) A MULTISCALE MODEL OF THE ORGAN OF CORTI. J Mech Mater Struct 4:755-778
Yoon, Yong-Jin; Puria, Sunil; Steele, Charles R (2007) Intracochlear pressure and derived quantities from a three-dimensional model. J Acoust Soc Am 122:952-66