Perception of sound with cochlear implants (CIs) is currently accomplished, in most cases, by stimulating spiral ganglion neuron (SGN) bodies in Rosenthal's canal, since cochleae without hair cells typically lack auditory nerve fibers in the basilar membrane area (BMA). If auditory nerve fibers could be induced to regenerate back into the BMA, stimulation of such fibers could potentially lower the amount of current required for stimulus detection, increase dynamic range, improve temporal response properties and decrease channel interaction, thereby enhancing the perception of CI stimulation. Using recently developed methods, we generated preliminary data demonstrating the feasibility for long-term over-expression of a neurotrophin which targeted to the BMA of deaf ears, leading to robust regrowth of auditory nerve fibers into this tissue. This nerve regeneration was accomplished using non-toxic long-acting adeno- associated viral vectors that delivered into the cochlea using clinically feasible routes. Our proposed experiments will test the global hypothesis that presence of neurotrophins secreted by cells in and around the auditory epithelium will attract and maintain auditory nerve fibers, leading to improvement in measurable parameters of the functional (psychophysical and electrophysiological) responses to CI stimulation. Experiments in Aim 1 will compare the efficiency of BDNF versus NTF3 in attracting neurons to the deaf BMA and characterize the source of the neurons and their position in the tissue. Work in Aim 2 will compare detection threshold levels, dynamic ranges, temporal integration properties, spatial selectivity, and amplitude growth functions using established animal psychophysics procedures and electrically-induced auditory brainstem responses (EABR) in deaf reinnervated cochleae and deaf non-reinnervated cochleae.
Aim 3 will determine if auditory nerve fiber regeneration into the BMA improves SGN survival and central connections.
Aim 4 will determine how the combined effects of long-term chronic electrical stimulation and neurotrophin over-expression influence SGN cell bodies and projections. These experiments will set the groundwork for clinical methods to induce nerve regeneration that could enhance the outcome of cochlear implant procedures in patients with severe or profound sensorineural hearing loss.

Public Health Relevance

The need to develop methods for inducing, directing and maintaining auditory nerve regeneration has been a critical barrier to the field. Our recent break-through in the application of gene transfer now provides the ability to target cells in the deaf inner ear, and insert genes into these cells for secreting a protein of choice (neurotrophin) leading to stable, long-term nerve regeneration in these ears. Auditory nerve fibers will grow into an area where they will be in close proximity to the cochlear implant electrode. Our proposed studies can, for the first time, test the long-term influence of auditory nerve regeneration on the psychophysical responses to electrical stimulation provided by the cochlear implant. We will further correlate these responses with survival and condition of the neurons and their peripheral and central processes. The outcome of the proposed work may improve communication for thousands of people who have severe or profound hearing impairments and use cochlear implants.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Auditory System Study Section (AUD)
Program Officer
Miller, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Devare, Jenna; Gubbels, Samuel; Raphael, Yehoash (2018) Outlook and future of inner ear therapy. Hear Res 368:127-135
Carlson, Krystin; Schacht, Jochen; Neitzel, Richard L (2018) Assessing ototoxicity due to chronic lead and cadmium intake with and without noise exposure in the mature mouse. J Toxicol Environ Health A 81:1041-1057
Wang, Guo-Peng; Basu, Ishani; Beyer, Lisa A et al. (2017) Severe streptomycin ototoxicity in the mouse utricle leads to a flat epithelium but the peripheral neural degeneration is delayed. Hear Res 355:33-41
Pfingst, Bryan E; Colesa, Deborah J; Swiderski, Donald L et al. (2017) Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures. J Assoc Res Otolaryngol 18:731-750
Choo, Daniel I; Tawfik, Kareem O; Martin, Donna M et al. (2017) Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures. Am J Med Genet C Semin Med Genet 175:439-449
Klimpel, Katarina E M; Lee, Min Young; King, W. Michael et al. (2017) Vestibular dysfunction in the adult CBA/CaJ mouse after lead and cadmium treatment. Environ Toxicol 32:869-876
Lee, Min Young; Hackelberg, Sandra; Green, Kari L et al. (2017) Survival of human embryonic stem cells implanted in the guinea pig auditory epithelium. Sci Rep 7:46058
Lee, Min Young; Kurioka, Takaomi; Nelson, Megan M et al. (2016) Viral-mediated Ntf3 overexpression disrupts innervation and hearing in nondeafened guinea pig cochleae. Mol Ther Methods Clin Dev 3:16052
Kurioka, Takaomi; Lee, Min Young; Heeringa, Amarins N et al. (2016) Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus. Neuroscience 332:242-57
Budenz, Cameron L; Wong, Hiu Tung; Swiderski, Donald L et al. (2015) Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear. Sci Rep 5:8619

Showing the most recent 10 out of 28 publications