PI: SHERA, CHRISTOPHER A Title: Understanding Otoacoustic Emissions 

Received: 06/30/2018 Opportunity: PA-18-484 Council: 01/2019 

Clinical Trial:Not Allowed 

Competition ID: FORMS-E FOA Title: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) 

2R01DC003687-22A1 Dual: Accession Number: 4191818 

IPF: 7636101 Organization: 

Former Number: 

IRG/SRG: AUD 

Subtotal Direct Costs 

(excludes consortium F&A) 

Year 22: 

Department: Otolaryngology 

AIDS: N Expedited: N 

Animals: Y New Investigator: N 

Humans: Y Early Stage Investigator: N 

Clinical Trial: N 

Current HS Code: 30 

HESC: N 

Senior/Key Personnel: Organization: Role Category: 

Christopher Shera PD/PI 

Carolina Abdala Co-Investigator 

John Oghalai Co-Investigator 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

3. DATE RECEIVED BY STATE State Application Identifier 

4.a. Federal Identifier

DC003687

b. Agency Routing Number

c. Previous Grants.gov Tracking Number

Organizational 

Last Name*: Gonzales Suffix: 

Email: 

O: Private Institution of Higher Education

 Women Owned ❍ Socially and Economically Disadvantaged

If Revision, mark appropriate box(es). 

 A. Increase Award ❍ B. Decrease Award ❍ C. Increase Duration

 D. Decrease Duration ❍ E. Other (specify) :

No What other Agencies? 

10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER

TITLE:

13. CONGRESSIONAL DISTRICTS OF APPLICANT

 Page 1

 

 

APPLICATION FOR FEDERAL ASSISTANCE 

SF 424 (R&R) 

1. TYPE OF SUBMISSION*

❍ Pre-application ● Application ❍ Changed/Corrected

Application

2. DATE SUBMITTED Application Identifier 

2018-06-29 7632282

5. APPLICANT INFORMATION

Legal Name*:

Department:

Division:

Street1*:

County: 

State*: 

Province: 

Country*: USA: UNITED STATES

ZIP / Postal Code*: 

Person to be contacted on matters involving this application 

Prefix: First Name*: Rosemarie Middle Name: 

Position/Title: Contract and Grant Officer

Street1*: 

Province: 

Country*: USA: UNITED STATES

ZIP / Postal Code*: 

Phone Number* Fax Number: 

6. EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN)*

7. TYPE OF APPLICANT*

Other (Specify):

Small Business Organization Type ❍ 

8. TYPE OF APPLICATION*

❍ New ● Resubmission ❍ 

❍ Renewal ❍ Continuation ❍ Revision ❍ 

Is this application being submitted to other agencies?* ❍Yes ● 

9. NAME OF FEDERAL AGENCY*

National Institutes of Health

11. DESCRIPTIVE TITLE OF APPLICANT'S PROJECT*

Understanding Otoacoustic Emissions

12. PROPOSED PROJECT

Start Date* Ending Date* 

04/01/2019 03/31/2024

Tracking Number: GRANT12665698 

Page 1
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE Page 2 

14. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Dr. First Name*: Christopher Middle Name: Last Name*: Shera Suffix: 

Position/Title: Professor

Organization Name*:

Department: Otolaryngology

Division:

 Number: Email*: 

15. ESTIMATED PROJECT FUNDING

a. Total Federal Funds Requested*

16. IS APPLICATION SUBJECT TO REVIEW BY STATE

EXECUTIVE ORDER 12372 PROCESS?*

a. YES ❍ THIS PREAPPLICATION/APPLICATION WAS MADE

AVAILABLE TO THE STATE EXECUTIVE ORDER 12372 

PROCESS FOR REVIEW ON: 

DATE: 

b. NO ● PROGRAM IS NOT COVERED BY E.O. 12372; OR

❍ PROGRAM HAS NOT BEEN SELECTED BY STATE FOR

REVIEW

 By signing this application, I certify (1) to the statements contained in the list of certifications* and (2) that the statements herein 

are true, complete and accurate to the best of my knowledge. I also provide the required assurances * and agree to comply with 

any resulting terms if I accept an award. I am aware that any false, fictitious, or fraudulent statements or claims may subject me to 

criminal, civil, or administrative penalties. (U.S. Code, Title 18, Section 1001) 

● I agree*

* The list of certifications and assurances, or an Internet site where you may obtain this list, is contained in the announcement or agency specific instructions. 

18. SFLLL or OTHER EXPLANATORY DOCUMENTATION File Name: 

19. AUTHORIZED REPRESENTATIVE

First Name*: Rosemarie Middle Name: Last Name*: Gonzales Suffix: 

Position/Title*: Contract and Grant Officer

Organization Name*: 

Department: Div of Contracts and Grants

Division: Vice President For Research

Street1*: 

Province: 

Country*: USA: UNITED STATES

ZIP / Postal Code*: 

Fax Number: Email*: 

Signature of Authorized Representative* 

Rosemarie Gonzales

Date Signed* 

06/29/2018

20. PRE-APPLICATION File Name:

21. COVER LETTER ATTACHMENT File Name:Shera_Cover_Letter1012773856.pdf

Contact PD/PI: Shera, Christopher Page 2

 

 

Prefix: 

17. 

Prefix: 

Phone 
Contact PD/PI: Shera, Christopher Table of Contents 

424 R&R and PHS-398 Specific 

Table Of Contents 

SF 424 R&R Cover Page............................................................................................................1 

Table of Contents...................................................................................................................3 

Performance Sites.....................................................................................................................4 

Research & Related Other Project Information......................................................................5 

Project Summary/Abstract(Description)..............................................................................6 

Project Narrative....................................................................................................................7 

Facilities & Other Resources................................................................................................8 

Equipment.............................................................................................................................10 

Research & Related Senior/Key Person................................................................................12 

Research & Related Budget Year - 1......................................................................................29 

Research & Related Budget Year - 2......................................................................................32 

Research & Related Budget Year - 3......................................................................................35 

Research & Related Budget Year - 4......................................................................................38 

Research & Related Budget Year - 5......................................................................................41 

Budget Justification................................................................................................................44 

Research & Related Cumulative Budget...............................................................................46 

PHS398 Cover Page Supplement...........................................................................................47 

PHS 398 Research Plan...........................................................................................................49 

Introduction to Application.................................................................................................50 

Specific Aims........................................................................................................................51 

Research Strategy................................................................................................................52 

Progress Report Publication List.......................................................................................64 

PHS Human Subjects and Clinical Trials Information......................................................67 

Study 1: Understanding Otoacoustic Emissions..........................................................69 

Inclusion Enrollment Reports......................................................................................73 

Vertebrate Animals..............................................................................................................81 

Select Agent Research........................................................................................................82 

Bibliography & References Cited.......................................................................................83 

Letters of Support................................................................................................................89 

Resource Sharing Plan(s)...................................................................................................90 

Authentication of Key Biological and/or Chemical Resources.......................................91 

 Page 3
Contact PD/Pl: Shera, Christopher 0MB Number: 4040-0010 

Expiration Date: 10/31/2019 

Project/Performance Site Location(s) 

Project/Performance Site Primary Location O I am submitting an application as an individual, and not on behalf of 

a company, state, local or tribal government, academia, or other type of 

organization. 

Organization Name: 

Street2: 

City•:

-

Province: 

Country•: USA: UNITED STATES 

Z

P

i

r

p 

oj

/ 

ect/Perfo

Postal Code

rman

•

ce 

: 

Site Co

-

ngressional Districr: -

Additional Location(s) File Name: 

Page4 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA 18-484. Rece ved Date: 

2018-06 30T00:58:58.000-04:00 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484. Received Date: 

OMB Number: 4040-0001

Expiration Date: 10/31/2019

RESEARCH & RELATED Other Project Information

Are Human Subjects Involved?* ● Yes ❍ No

1.a. If YES to Human Subjects

Is the Project Exempt from Federal regulations? ❍ Yes ● No

If YES, check appropriate exemption number: 1 2 3 4 5 6 7 8 

If NO, is the IRB review Pending? ● Yes ❍ No

IRB Approval Date: 

Human Subject Assurance Number 00005906

Are Vertebrate Animals Used?* ● Yes ❍ No

2.a. If YES to Vertebrate Animals

Is the IACUC review Pending? ● Yes ❍ No 

IACUC Approval Date: 

Animal Welfare Assurance Number A3518-01

Is proprietary/privileged information included in the application?* ❍ Yes ● No

4.a. Does this project have an actual or potential impact - positive or negative - on the environment?* ❍ Yes ● No

4.b. If yes, please explain:

4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an

environmental assessment (EA) or environmental impact statement (EIS) been performed?

❍ Yes ❍ No

4.d. If yes, please explain:

Is the research performance site designated, or eligible to be designated, as a historic place?* ❍ Yes ● No

5.a. If yes, please explain:

Does this project involve activities outside the United States or partnership with international 

collaborators?* 

❍ Yes ● No

6.a. If yes, identify countries:

6.b. Optional Explanation:

Filename 

Project Summary/Abstract* Shera_Project_Abstract1012773832.pdf

Project Narrative* Shera_Project_Narrative21012773833.pdf

Bibliography & References Cited Shera_Literature_Cited1012773834.pdf

10.Facilities & Other Resources Shera_Facilities1012773835.pdf

11.Equipment Shera_Equipment1012773836.pdf

Contact PD/PI: Shera, Christopher

1. 

2. 

3. 

5. 

6. 

7. 

8. 

9. 

 Page 5 2018-06-30T00:58:58.000-04:00 
Project Summary 

Realizing the potential of otoacoustic emissions (OAEs) as noninvasive probes of cochlear function 

requires understanding the physical and physiological mechanisms that generate and shape these 

sounds. To address important unresolved issues of cochlear mechanics while improving our 

understanding of OAE generation, we propose three aims involving innovative theoretical modeling 

rigorously tested by experimental measurements. The first Aim studies the action of “suppressor” 

tones on OAE generation by testing the hypothesis that suppressors can both reduce the strength of 

existing OAE sources and create new sources of wave reflection within the cochlea. We determine 

whether suppressors can accurately map out the distribution of OAE generators in models where the 

distribution is known in advance and test whether eliminating sources created by the suppressor can 

improve the measurement of cochlear frequency selectivity using OAE suppression tuning curves. The 

second Aim studies the nature of the micromechanical irregularity believed necessary for the 

generation of reflection-source OAEs. We test whether efferent-induced changes in OAEs can be 

explained by the hypothesis that activation of medial olivocochlear (MOC) efferents alters the spatial 

pattern of irregularity. Using both measurements and models, we also explore the hypothesized but 

previously unrecognized role of irregularity on the generation of distortion-source OAEs and its 

modulation by contralateral acoustic stimulation. The third Aim explores the micromechanics of 

cochlear wave amplification and its consequences for OAE generation. Modeling work studies OAE 

generation in models incorporating forms of spatial feed-forward/backward amplification suggested by 

the oblique geometry of the outer hair cells. We also combine state-of-the-art measurements of organ 

of Corti vibration using optical coherence tomography (OCT) with theoretical inverse methods to study 

how the assumed coupling between the modes affects the generation and propagation of OAEs. 

Completion of these Aims will significantly enhance our understanding of OAE generation and its 

relationship to cochlear mechanics. The Aims are also directly relevant to improving the power of 

OAE-based diagnostics and other technological applications—such as hearing aids and 

preprocessors for speech-recognition devices—that benefit from knowledge of cochlear amplification, 

nonlinearity, and signal processing. 

Contact PD/PI: Shera, Christopher Project Summary/Abstract Page 6
Project Narrative 

Our experiments and models address the mechanisms by which healthy ears generate sound. Sounds 

from the ear, known as otoacoustic emissions (OAEs), are widely used for noninvasive tests of 

hearing function. By improving our understanding of how OAEs are produced within the cochlea, and 

how they can be used to probe aspects of cochlear function important for human communication, the 

proposed work will enhance the power of clinical hearing tests and help improve the design of auditory 

prosthetic devices. 

Contact PD/PI: Shera, Christopher Project Narrative Page 7
Contact PD/Pl: Shera, Christopher 

Facilities and Other Resources 

Laboratories: The -Department of Otolaryngology

Schooiot'Medicine provides a rich, mu 1 1sc1p inary environmen 

neuroscience that encourages and nurtures scientific discourse and collaboration. The growing

Department includes faculty with interests in basic science, translational science, biomedical 

engineering, and clinical practice. 

Dr. Shera and the members of the Auditory Physics Group have their primary research laboratory and 

office space in the Auditory Research Center (ARC) at the --School of Medicine. The 

laboratory features a vibration-isolated, electrically-shielded, andtemperature-controlled sound booths 

fully equipped for research studies on human subjects. All experimental hardware is controlled using

custom data-acquisition software written and maintained by the Pl and members of the group. In 

addition, the group has access to three full-time sound-attenuating research booths located in the 

Hearing Research Lab (HRL) on the --campus, a short walk from the Pl's office. Each site 

provides faxing, copying, computersupporr,-a front desk staff, and a waiting area for study

participants. These facilities also provide private space for obtaining informed consent and sharing 

personal health information. 

The Auditory Research Center also houses other research laboratories where human studies are 

performed Auditory researchers that require "wet lab" space 

are locate in e1 er Institute or in the adjacent Broad Center for 

Regenerative Medicine 

Finally, the -Fam1 y en er or I oo ommunica 10n a Jacen o e main nivers1 y ar 

Campus serves as home for research involving pediatric cochlear and brainstem implants -

Altogether, there are >50 faculty, staff, and trainees involved in auditory research within the -

-Department of Otolaryngology, and we interact and work together as a matter of routine.Ts

invigorating atmosphere provides ample opportunity for discussions, collaborations, and learning. The 

group is highly collaborative and diverse, allowing the skill sets of each investigator to be a resource 

for the other members. This is a practice promoted by the department and university and a philosophy 

shared by all. 

Animals: The vivarium is located in the basement of the ----Institute where ■ lab is located. The facility is AAALAC-approved w

with 24-hour care provided by the vivarium 

s a . is the head veterinarian and director of the 

Depa men o nima Resources (DAR). DAR and the staff of the vivarium ass1s acu y, s a , an 

students in carrying out animal-based research and teaching activities -- The vivarium also 

offers surgical and diagnostic laboratory services, assistance with ordering anesthetic drugs and 

supplies, assistance with rodent euthanasia, and animal orders and transfers and breeding. Training

programs in Animal Care and Use are also offered to principal investigators, staff, and students, as 

well as education programs for Laboratory Animal Technicians. Animals will be transferred from the 

animal facility to--laboratory for recordings. The laboratory features two vibration-isolated,

electrically-shielded, and Temperature-controlled sound booths and is equipped with a ventilation hood 

for the safe handling of animals during the course of the experiments. All experimental hardware is 

controlled using custom data-acquisition software written and maintained by his team. 

Computers and Data Acquisition Equipment: All research laboratories have multiple networked 

computers that are available for software development, data collection, analysis, and computational 

modeling of the mechanical data for the proposed research. Networked laser printers and scanners 

are available for lab and office use. Computer support is provided by USC Information Technology

Services. All research personnel have dedicated workstations linked via ethernet and secure wireless 

to the USC network and to a shared drive for data storage and backup. The network provides access 

to email and library services, including MEDLINE, PubMed, and a vast collection of eJournals. USC 

provides university-wide licenses for MATLAB and JMP statistical analysis tools, as well as software 

Page8

Facilties & Other Resources
for word processing, data analysis, and making figures. 

The experimental chambers at the ARC, where the human OAE experiments will take place, have 

RME Babyface Pro Audio Interfaces and a National Instruments PXI chassis housing an embedded 

dual-core computer controller and three NI PXI-4461 24-bit dual input-output boards for generating 

electrical signals to drive acoustic transducers and for recording analog responses. All experimental 

hardware is controlled using custom data-acquisition software written by the PI in LabVIEW and 

MATLAB. In addition to the data-acquisition equipment listed above, the sounds booths are equipped 

with miscellaneous acoustic drivers, transducer assemblies, filters, and OAE probes (i.e., Etymotic 

Research ER10X, ER10A, ER10B+, and ER10C probe systems). 

Office: The Department of Otolaryngology maintains office and workspace for the PI and coinvestigators (post-doctoral research fellows, graduate students) in the Auditory Research Center on 

the campus of the School of Medicine. Conference facilities are available on-site for lab 

meetings, and desks and carrels are provided for visitors and consultants. An administrative assistant 

is available as needed to help with research endeavors. 

Other resources: offers state of the art facilities in all major areas. fosters a collaborative 

spirit between schools and laboratories, facilitating interactions between laboratories and 

investigators. There are imaging (including light, TEM, and SEM setups), sequencing, bioinformatics, 

and biostatistics core labs in adjacent buildings that can be accessed on a fee basis. In addition, there 

are gene array and Next Gen sequencing facilities available. A machine shop is available on a fee-forservce basis. Translational research involving human patients is a strength of The otology clinics 

are set up to facilitate adult and pediatric research and many (if not most) hearing loss patients are 

enrolled in some type of research study. 

Contact PD/PI: Shera, Christopher Facilities & Other Resources Page 9

 

 

 

 
Major Equipment 

Auditory Physics Group (USC Auditory Research Center) 

 Double-walled, RF shielded sound booth for human subject testing 

 Soundcards (RME Babyface Pro and Lynx II) 

 Transducers for delivering stimuli to participants, including insert earphones (Etymotic 

Research ER2 and ER3A) 

 Portable oscilloscope (Tektronix) 

 Otoacoustic emission probe microphone systems (Etymotic Research ER10A, ER10B+, ER7, 

ER10C, and ER10X) 

 Desktop computers for data collection 

 Two GSI16 Audiometers, two GSI TympStar Immittance meters, two Interacoustic middle-ear 

analyzers, and two otoscopes. 

 Backsaver Zero-Gravity ergonomic chairs for adult OAE testing 

 Bruel & Kjaer digital sound level meter #2250, ear simulator #4127, and 1⁄4-inch microphone 

#4134 and amplifier for calibrating data-acquisition probes 

 National Instruments PXI chassis housing an embedded dual-core computer controller and 

three NI PXI-4461 24-bit dual input-output boards 

 Larsen-Davis microphone amplifier 

 Pistonphone for microphone calibrations 

Oghalai Lab (USC Zilkha Neurogenetics Institute) 

200 kHz Swept-Source VOCTV Imaging Suite 

 Double-walled, RF shielded sound booth 

 Custom-built, fiber based swept-source OCT system 

 Vibration isolation table 

 Surgical instruments 

 Temperature-regulated heating pad 

 Custom-machined animal head holder with ear bars 

 Zeiss dissecting microscope (Stemi-2000) with fiberoptic light source 

 National Instruments PCIe-6251 DAQ in one computer and another PXIe chassi with NI 

boards, including a computer controller, an ADC, and an FPGA. 

 Cochlear Monitoring Program (CMP) custom software developed in Python and C++ to present 

sound stimuli and record the responses 

 Power amplifier (Servo 600, Samson Technologies Corp., Syosset, NY) 

 Two high frequency speakers for generating sound stimuli for mouse auditory measurements 

 Probe tip microphone, calibrating microphone, and conditioning amplifier (microphone types 

8192 & 5939, NEXUS conditioning amplifier, Bruel and Kjar, Demark) 

 Bioamplifier (DP-311, Warner) to record electric field potentials 

 Oscilloscope (Tektronix) 

50 kHz Swept-Source VOCTV Imaging Suite 

 Double-walled, RF shielded sound booth 

 Custom-built, fiber based swept-source OCT system 

 Vibration isolation table 

 Surgical instruments 

 Temperature-regulated heating pad 

 Custom-machined animal head holder with ear bars 

 Zeiss dissecting microscope (Stemi-2000) with fiberoptic light source 

 National Instruments PCIe-6251 DAQ in one computer and another PXIe chassi with NI 

boards, including a computer controller, an ADC, and an FPGA. 

Contact PD/PI: Shera, Christopher Equipment Page 10
 Cochlear Monitoring Program (CMP) custom software developed in Python and C++ to present

sound stimuli and record the responses

 Power amplifier (Servo 600, Samson Technologies Corp., Syosset, NY)

 Two high frequency speakers for generating sound stimuli for mouse auditory measurements

 Probe tip microphone, calibrating microphone, and conditioning amplifier (microphone types

8192 & 5939, NEXUS conditioning amplifier, Bruel and Kjar, Demark)

 Bioamplifier (DP-311, Warner) to record electric field potentials

 Oscilloscope (Tektronix)

Spectral-Domain OCT Imaging Suite 

 Optical coherence tomography setup (spectral domain) custom built hardware and software

 Moveable objective microscope and all optical components designed for in vivo imaging

(MOM, Sutter)

 Optical components designed to carry the laser to the microscope, and target it in 3-D space

using galvometer-driven mirrors

 National Instruments PXIe chassis with a computer controller, I/O boards, and a FPGA.

 Custom Python and C++ software to drive the imaging equipment and present sound stimuli

 In vivo dissecting microscope on a boom stand (Zeiss)

 Vibration isolation table

 Surgical instruments

 Temperature-regulated heating pad

 Custom-machined animal head holder with ear bars

 Power amplifier (Servo 600, Samson Technologies Corp., Syosset, NY)

 Two high frequency speakers for generating sound stimuli for mouse auditory measurements

 Bioamplifier (DP-311, Warner) to record electric field potentials

 Oscilloscope (Tektronix)

 Laser doppler interferometer with digital displacement decoder (VDD-660, Polytech PI)

Contact PD/PI: Shera, Christopher Equipment Page 11

– 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED Senior/Key Person Profile (Expanded)

PROFILE - Project Director/Principal Investigator

Prefix: Dr. First Name*: Christopher Middle Name  Last Name*: Shera Suffix: 

Position/Title*: Professor

Organization Name*:

Department: Otolaryngology

Division:

Street2:

City*:

County:

State*:

Province:

Country*: USA: UNITED STATES

Zip / Postal Code*:

Phone Number*:  Fax Number: 

E-Mail*:

Credential, e

Project Role*:  PD/PI Other Project Role Category: 

Degree Type:  Ph.D Degree Year:  1992

Attach Biographical Sketch*:   File Name: Shera_NIH_Biosketch_2018051012773850.pdf

Attach Current & Pending Support:   File Name:

Contact PD/PI: Shera, Christopher Page 12 2018-06-30T00:58:58.000-04:00 
Attach Biographical Sketch*: File Name:

Attach Current & Pending Support: File Name:

PROFILE - Senior/Key Person

Prefix: Dr. First Name*: Carolina Middle Name  Last Name*: Abdala Suffix: 

Position/Title*: Professor of Research

Organization Name*:

Shera_Abdala_NIH_Biosketch1012773851.pdf

PROFILE - Senior/Key Person

Shera_Oghalai_NIH_Biosketch1012773855.pdf

Contact PD/PI: Shera, Christopher

Division:

+

Department: Otolaryngology

Phone Number*:  Fax Number: 

E-Mail*

Credential, e.g., agency login: 

Project Role*:  Co-Investigator Other Project Role Category: 

Degree Type:  Degree Year: 

Organization Name*:

City*:

Phone Number*:

Prefix:  First Name*: John Middle Name  Last Name*: Oghalai Suffix: 

Position/Title*:

Street2:

Province:

Country*: USA: UNITED STATES

Zip / Postal Code*:

Fax Number: 

E-Mail*

Credential, e.g., agency login: 

Project Role*:  Co-Investigator Other Project Role Category: 

Degree Type:  MD Degree Year:  1994

 Page 13

Attach Biographical Sketch*: File Name:

Attach Current & Pending Support: File Name:

Funding Opportunity Number: PA-18-484 . Received Date: Tracking Number: GRANT12665698 2018-06-30T00:58:58.000-04:00 
 Page 14

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Contact PD/PI: Shera, Christopher

OMB No. 0925-0001/0002 (Rev. 10/15 Approved Through 10/31/2018) 

BIOGRAPHICAL SKETCH 

NAME: Christopher A. Shera 

eRA COMMONS USER NAME: 

POSITION TITLE: Professor of Otolaryngology and Physics & Astronomy, University of Southern California 

EDUCATION/TRAINING: 

Haverford College, Haverford PA B.A. 05/1983 Physics 

California Institute of Technology, Pasadena CA Ph.D. 06/1992 Physics 

Massachusetts Institute of Technology, Cambridge MA Postdoctoral 11/1997 Neurophysiology 

A. Personal Statement

As head of USC’s Auditory Physics Group (apg.mechanicsofhearing.org) in the Caruso Department of

Otolaryngology, I have broad expertise in auditory physiology and mechanics, cochlear modeling, and

otoacoustic emissions (OAEs). Areas of special interest include cochlear nonlinearity (compression,

suppression) and the biophysical mechanisms of cochlear amplification, wave propagation, and OAE

generation. Work in my laboratory combines innovative measurements with the power of mathematical and

computational modeling. Together, we work towards the goal of understanding cochlear function and signal

processing while developing the power of OAEs as noninvasive probes of peripheral auditory function for

applications in both the research laboratory and the clinic. Historically, a key aspect of our work involves

collaborations with others in the field who have experimental or other facility beyond our reach. Past and

present collaborators include Carolina Abdala, Nigel Cooper, John Guinan, Philip Joris, and Andrew Oxenham.

With this application, I am excited to plant the seeds of a promising new collaboration with John Oghalai, who

has just joined the hearing research faculty at USC and brings with him deep expertise in cochlear imaging and

the measurement of organ of Corti vibrations using optical coherent tomography (OCT).

Shera CA. Laser amplification with a twist: Traveling-wave propagation and gain functions from 

throughout the cochlea. J Acoust Soc Am 122:2738–2758 (2007). 

Kalluri R, Shera CA. Measuring stimulus-frequency otoacoustic emissions using swept tones. J Acoust 

Soc Am 134:356–368 (2013). PMC3732205 

Verhulst S, Dau T, Shera CA. Nonlinear time-domain cochlear model for transient stimulation and 

human otoacoustic emission. J Acoust Soc Am 132:3842–3848 (2012). PMC3528681 

Charaziak KK, Shera CA. Compensating for ear-canal acoustics when measuring otoacoustic 

emissions. J Acoust Soc Am 141:515–531 (2017). PMC5848844 

B. Positions and Honors

Positions and Employment

1983–1994 Graduate Research Assistant, Los Alamos National Laboratory 

1992–1994 Research Associate, Signition Inc. 

1994–1997 Postdoctoral Research Fellow, Research Laboratory of Electronics, MIT 

1994–2016 Research Associate, Department of Otolaryngology, Massachusetts Eye & Ear Infirmary 

1997–1999 Instructor of Otology & Laryngology, Harvard Medical School 

1999–2004 Assistant Professor of Otology & Laryngology, Harvard Medical School 

1999–2005 HST Affiliated Faculty, Harvard–MIT Division of Health Sciences & Technology 

2004–2005 Associate Professor of Otology & Laryngology, Harvard Medical School 

2005–2013 Associate Professor of Otology & Laryngology and Health Sciences & Technology, HMS 

2013–2016 Professor of Otology & Laryngology, Harvard Medical School 

2016– Professor of Otolaryngology and Physics & Astronomy, University of Southern California 

Other Experience and Professional Memberships 

1985– Member, American Association for the Advancement of Science 

1989– Member, Acoustical Society of America (Fellow 2001) 

Biosketches
 Page 15

 

 

 

 

 

 

 

 

 

 

 

 

 

Contact PD/PI: Shera, Christopher

1989– Member, Association for Research in Otolaryngology 

2001– Member, American Physical Society 

2007– Member, American Auditory Society 

2007– Member, History of Science Society 

2005–2009 Member, NIH/NIDCD AUD Study Section 

2008–2014 Member, ASA Technical Committee for Psychological and Physiological Acoustics 

2010– Ad-Hoc Reviewer, Multiple NIH/NIDCD Special Emphasis Panels, Board of Scientific 

Counselors, and CDRC Study Section 

2011– Curator (with Elizabeth Olson), Mechanics of Hearing Digital Library 

2012– Associate Editor, Journal of the Acoustical Society of America 

2017– Member, ASA Technical Committee for Psychological and Physiological Acoustics 

2017– Co-Chair (with Carolina Abdala), ARO Scientific Program Committee 

Honors 

1979 U.S. Presidential Scholar 

1979 Geraldine R. Dodge Foundation Grant 

1982 Phi Beta Kappa Society 

1984–1987 National Science Foundation Graduate Fellow 

1994–1997 NRSA Postdoctoral Fellowship, NIH/NIDCD 

2001 Fellow, Acoustical Society of America 

2007 Irving M. London Teaching Award, Harvard Medical School / MIT 

C. Contributions to Science 

I. Mechanism-Based OAE Taxonomy 

To provide a foundation for understanding otoacoustic emissions (OAEs), we showed—contrary to the thencurrent consensus—that OAEs arise from at least two distinct mechanisms in the cochlea: linear reflection and 

nonlinear distortion [1]. Synthesizing diverse work in the field, we proposed an OAE taxonomy based on 

mechanisms of emission generation, rather than characteristics of the evoking stimulus. The recognition of 

multiple generation mechanisms allows one to make sense of previously anomalous or otherwise discrepant 

observations, such as different susceptibilities to ototoxic drugs and puzzling variation among species. The 

mechanism-based taxonomy now provides the standard framework for the interpretation of OAEs. 

In subsequent studies [2,4] we tested the dual-mechanism model for OAE generation and explored its potential 

for extending the power and precision of OAE-based clinical diagnostics. For example, we verified a major 

prediction of the OAE taxonomy—namely, that so-called distortion-product otoacoustic emissions (DPOAEs), 

previously thought to arise by nonlinear distortion operating at two different cochlear locations, actually 

comprise a mixture of OAEs produced by the two different source mechanisms. Source component “unmixing” 

is now widely used to improve the power of DPOAE measurements. 

In other evaluations of the framework [3], we tested key predictions of three competing models of spontaneous 

otoacoustic emission (SOAE) and demonstrated that mammalian SOAEs result from amplitude-stabilized, 

intracochlear standing waves caused by multiple internal reflection, rather than from the autonomous 

oscillation of hair-cell soma or their bundles. According to the analysis, spontaneous OAEs are emergent 

phenomena that result from the cochlea’s acting as a biological analog of a laser oscillator. 

[1] Shera CA, Guinan JJ. Evoked otoacoustic emissions arise by two fundamentally different 

mechanisms: A taxonomy for mammalian otoacoustic emissions. J Acoust Soc Am 105:782– 

798 (1999). 

[2] Kalluri R, Shera CA. Distortion-product source unmixing: A test of the two-mechanism model for 

DPOAE generation. J Acoust Soc Am 109:622–637 (2001). 

[3] Shera CA. Mammalian spontaneous otoacoustic emissions are amplitude-stabilized cochlear 

standing waves. J Acoust Soc Am 114:244–262 (2003). 

[4] Kalluri R, Shera CA. Near-equivalence of human click-evoked and stimulus-frequency otoacoustic 

emissions. J Acoust Soc Am 121:2097–2110 (2007). 

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Contact PD/PI: Shera, Christopher

II. Coherent Reflection Theory

[11] Shera CA, Tubis A, Talmadge CL. Do forward and backward-traveling waves occur within the

cochlea? Countering the critique of Nobili et al. J Assoc Res Otolaryngol 5:349–359 (2004). 

[10] Shera CA. Frequency glides in impulse responses of the basilar membrane and auditory nerve:

Their scaling behavior and origin in traveling-wave dispersion. J Acoust Soc Am 109:2023– 

2034 (2001). 

[9] Shera CA, Zweig G. A symmetry suppresses the cochlear catastrophe. J Acoust Soc Am

89:1276–1289 (1991). 

In other work [12], we combined theory and experiment to address a long-standing controversy in cochlear 

mechanics [11]: Whether otoacoustic emissions propagate within the cochlea as longitudinal sound waves in 

the fluid or via transverse surface waves involving the basilar membrane. Our results show convincingly that 

reverse propagation involves basilar-membrane traveling waves (see also [16]). 

Subsequent work [10] established the mechanisms responsible for the puzzling phenomenon known as “BM 

frequency glides,” changes over time in the instantaneous frequency of the basilar-membrane (BM) or 

auditory-nerve response to acoustic clicks. Although previous models for glides suggested that they arose 

through the differential build-up and decay of multiple micromechanical resonances local to each radial cross 

section of the organ of Corti, we identified the glide as the global consequence of the dispersive character of 

wave propagation in the cochlea. 

My approach typically involves theoretical analysis of experimental data to constrain models of cochlear 

function. For example, in early work we analyzed measurements of the cochlear input impedance to identify a 

new symmetry in cochlear mechanics (now called “tapering symmetry”) that requires that the width of the 

basilar membrane and the cross-sectional areas of the scalae taper in opposite directions [9]. We showed that 

violation of this symmetry would result in a dramatic decline in middle-ear efficiency at low frequencies. 

[8] Bergevin C, Shera CA. Coherent reflection without traveling waves: On the origin of long-latency

otoacoustic emissions in lizards. J Acoust Soc Am 127:2398–2409 (2010). PMC2865438 

[7] Shera CA, Tubis A, Talmadge CL. Testing coherent reflection in chinchilla: Auditory-nerve

responses predict stimulus-frequency otoacoustic emissions. J Acoust Soc Am 124:381–395 

(2008). PMC2677332 

[6] Shera CA, Tubis A, Talmadge CL. Coherent reflection in a 2-dimensional cochlea: Short-wave

versus long-wave scattering in the generation of reflection-source otoacoustic emissions. J 

Acoust Soc Am 118:287–313 (2005). 

[5] Zweig G, Shera CA. The origin of periodicity in the spectrum of evoked otoacoustic emissions. J

Acoust Soc Am 98:2018–2047 (1995). 

In addition, we successfully extended the coherent-reflection model to show how analogous mechanisms can 

account for stimulus-frequency emissions in animals, such as lizards, that have tuned mechanical responses 

but lack basilar-membrane traveling waves [8]. Coherent reflection thus provides a common framework for 

understanding otoacoustic emissions in a wide range of mammalian and non-mammalian species. 

We explained the physical mechanisms underlying the class

 are present—see [18].) 

the basal half of the cochlea. (In the apex, things are more 

 revealed by auditory-nerve responses accurately predict the measured 

coherent-reflection model in chinchilla [7] by showing that 

 of how OAEs are generated within the cochlea. 

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 of evoked otoacoustic emissions (OAEs) now

known as reflection-source OAEs [5]. The theory indicates that these OAEs arise through a process that we

dubbed “coherent reflection” and involving wave backscattering by densely distributed micromechanical

irregularities along the organ of Corti (e.g., spatial variations in the forces produced by outer hair cells). In

subsequent work [6], we extended the theory to account for the complicated geometry of fluid motion near the

peak of the traveling wave. Contrary to published theoretical arguments, we showed that these so-called shortwave effects significantly enhance, rather than suppress, the production of OAEs. The modeling framework we

introduced was subsequently extended by others to model distortion-source OAEs, and coherent-reflection

theory has since become the standard understanding

Among numerous subsequent studies, we tested the 

the characteristics of mechanical tuning

properties of reflection-source OAEs, at least in 

complicated and other emission components

III. Cochlear Mechanics and Wave Propagation

Biosketches
[12] Shera CA, Tubis A, Talmadge CL, de Boer E, Fahey PF, Guinan JJ. Allen–Fahey and related 

experiments support the predominance of cochlear slow-wave otoacoustic emissions. J 

Acoust Soc Am 121:1564–1575 (2007). 

Cochlear Nonlinearity and Amplification 

Perhaps my primary professional interest is the understanding of traveling-wave amplification and its control by 

nonlinearity and other feedback mechanisms operating within the cochlea. Work in this area has been varied. 

For example, by analyzing the fine-time structure of measurements of basilar-membrane and auditory-nerve 

responses to acoustic clicks, I showed that the cochlear amplifier operates primarily by modifying the effective 

resistance of the cochlear partition, rather than its stiffness [13]. This result ruled out many, if not most, 

contemporaneous cochlear models, in which outer-hair-cell forces produced significant changes in the 

reactance and the resonant frequencies of the system. Approximate intensity-invariance of the resonant 

frequencies of the cochlear filters is now recognized as a general principle of cochlear function; the feature is 

incorporated not only in most models but also in preprocessors used in machine hearing applications, such as 

sound indexing, music information retrieval, and speech recognition. 

other work [14], we performed simultaneous auditory-nerve and otoacoustic measurements to replicate, 

extend, and explain a major confounding result in cochlear physiology: Why the so-called “Allen-Fahey 

experiment,” a clever paradigm designed to measure the power gain of the cochlear amplifier using DPOAEs, 

showed no evidence of cochlear amplification. Although this classic null result was widely attributed to the 

effects of two-tone suppression, we showed that suppression actually increases the apparent gain measured 

the paradigm, heightening the contradiction. We then showed how the experimental findings can be 

understood as a consequence of phase cancellation among distributed DPOAE sources. Our analysis 

demonstrated that when generating DPOAEs the cochlea acts as a “distortion beamformer” in which the 

directionality of the distortion source, and thus the relative magnitudes of the reflection- and distortion-source 

components in the DPOAE, is tuned by the primary frequency ratio. 

In another major study of cochlear amplification [15], I analyzed published auditory-nerve-fiber responses to 

noise using a novel inverse method to derive functional properties of the cochlear traveling wave (“propagation 

and gain functions”), including its wavelength and power gain. The results established the existence and form 

of traveling-wave amplification throughout the cochlea, including the first (and still only) demonstration of power 

amplification in the apical half. Analysis of the propagation and gain functions showed that the cochlear 

amplifier has properties resembling those of an active optical medium, enabling the mammalian cochlea to 

operate as a wideband, hydromechanical laser analyzer. When the round-trip power gain is sufficiently high, 

multiple internal reflection can give rise to self-sustaining intracochlear standing waves, and the inner ear 

spontaneously emits sound (see also [3]). 

Most recently [16], we tested predictions of the internal reflection model by making simultaneous otoacoustic 

and basilar-membrane (BM) mechanical measurements. Our results showed that the rippling patterns often 

observed in BM frequency responses (and the waxing and waning seen in BM and auditory-nerve click 

responses) are strongly correlated with the acoustic interference pattern measured in ear-canal pressure, 

consistent with a common origin involving the generation and reflection of otoacoustic emissions. 

[13] Shera CA. Intensity invariance of fine time structure in basilar-membrane impulse responses: 

Implications for cochlear mechanics. J Acoust Soc Am 110:332–348 (2001). 

[14] Shera CA, Guinan JJ. Cochlear traveling-wave amplification, suppression, and beamforming 

probed using noninvasive calibration of intracochlear distortion sources. J Acoust Soc Am 

121:1003–1016 (2007). 

[15] Shera CA. Laser amplification with a twist: Traveling-wave propagation and gain functions from 

throughout the cochlea. J Acoust Soc Am 122:2738–2758 (2007). 

[16] Shera CA, Cooper NP. Basilar-membrane interference patterns from multiple internal reflection of 

cochlear traveling waves. J Acoust Soc Am 133:2224–2239 (2013). PMC4109360 

V. Cochlear Frequency Tuning and Tonotopy 

Last but not least, a major focus of my work has been to develop both new measurement and analysis tools 

and new applications for otoacoustic emissions whose purpose is to tells us things we do not already know 

about the cochlea and, indeed, about hearing. Much of this work is fundamentally comparative. For example, 

Contact PD/PI: Shera, Christopher Biosketches

 

 

 

 

IV. 

In 

by 

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Contact PD/PI: Shera, Christopher

by combining otoacoustic and psychophysical measurements we showed [17] that human cochlear tuning is 

both two-to-three times sharper, and has a different dependence on frequency, than was commonly believed 

based on the widespread presumption that auditory-nerve recordings in small laboratory animals could be 

applied directly to humans. Our results raised important questions about the mechanical, biophysical, and 

evolutionary origins of these prominent species differences in cochlear tuning and indicated that many models 

of human hearing function needed revision. 

As a test of the assumptions underlying our noninvasive methods for estimating cochlear tuning, we showed 

[18,19] that otoacoustic estimates of cochlear tuning in both chinchilla and macaque match direct measures 

obtained from the auditory nerve in these species. We identified a function—the “tuning ratio”—whose form is 

nearly invariant in cats, guinea pigs, chinchillas, macaques, and humans. In the process, we introduced the 

notion of the “apical-basal transition CF,” a location in the cochlea that divides the cochlea into regions of 

apical-like and basal-like behavior. Taking account of this transition, whose approximate location varies from 

species to species, is crucial for making interspecies comparisons of cochlear function. Although our results 

confirmed that human cochlear tuning is exceptionally sharp, we found the spatial spread of excitation along 

the human basilar membrane to be comparable to that in other common laboratory animals. Our results 

support the use of otoacoustic emissions as noninvasive probes of cochlear tuning. 

In related work [20], we predicted that mammalian cochlear frequency-position maps, although usually 

assumed to be smooth and continuous, actually manifest a staircase-like structure comprising plateaus of 

nearly constant characteristic frequency separated by abrupt discontinuities. The height and width of the stair 

steps are determined by parameters of cochlear frequency tuning and vary with location in the cochlea. We 

showed that stepwise tonotopy is an emergent property arising from wave reflection and interference within the 

cochlea (see also [16]), the same mechanisms responsible for the microstructure of the hearing threshold. As 

seeds for future experiments, we proposed possible functional and/or developmental relationships between the 

microstructure of the cochlear map and the tiered tonotopy observed in the inferior colliculus. 

[17] Shera CA, Guinan JJ, Oxenham AJ. Revised estimates of human cochlear tuning from

otoacoustic and behavioral measurements. Proc Natl Acad Sci (USA) 99:3318–3323 (2002). 

PMC122516 

[18] Shera CA, Guinan JJ, Oxenham AJ. Otoacoustic estimation of cochlear tuning: Validation in the

chinchilla. J Assoc Res Otolaryngol 11:343–365 (2010). PMC2914235 

[19] Joris PX, Bergevin C, Kalluri R, Mc Laughlin M, Michelet P, van der Heijden M, Shera CA.

Frequency selectivity in Old-World monkeys corroborates sharp cochlear tuning in humans. 

Proc Natl Acad Sci USA 108:17516–17520 (2011). PMC3198376 

[20] Shera CA. The spiral staircase: Tonotopic microstructure and cochlear tuning. J Neurosci

35:4683–4690 (2015). PMC4363394 

Complete List of Published Work 

In My Bibliography at NCBI: http://1.usa.gov/1JtJMZt 

At the Auditory Physics Group website: http://apg.mechanicsofhearing.org/#Publications 

D. Research Support

Ongoing 

R01 DC003687 Shera (PI) 1/1/99–12/31/18 

Understanding Otoacoustic Emissions 

Combined experimental and theoretical studies of the mechanisms of otoacoustic emission generation and 

related aspects of cochlear and middle-ear mechanics. 

Role: PI 

Completed During the Last 3 Years 

None 

Biosketches
OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) 

BIOGRAPHICAL SKETCH 

 the Senior/key personnel and other significant contributors. 

DO NOT EXCEED FIVE PAGES. 

 e.g., agency login):

Keck School of Medicine, University of Southern California 

DEGREE 

Completion 

Date 

MM/YYYY 

FIELD OF STUDY 

05/1983 Communicative Disorders 

06/1986 Hearing Science 

06/1993 Hearing Science 

 applied otoacoustic emissions (OAEs) to the study of human 

have conducted data collection in challenging subject populations such as day-old 

we have tested and developed innovative data collection 

unparalleled frequency resolution and rapid data 

separating the distortion-product OAE into its dual components with 

 each component independently and to disentangle the origin of our results; 

stimulus-frequency OAEs (SFOAE) in newborns and we 

 The consistent theme in my labs’ work is to push the 

populations, innovative data-collection systems, informative 

 applications. One such OAE application relevant to the 

contralateral acoustic stimulation (CAS) to activate the medial 

 amplitude and phase. There are many confounds in the 

 muscle reflex, poor SNR, DPOAE component-mixing), but 

techniques and analyses to address these issues. Over the 

newborns, school-aged children, young-adults and 

OAEs. Our studies of the auditory efferent system have 

confounds and describe changes in the efferent reflex 

Optimizing swept-tone protocols for recording distortion 

 in adults and newborns. J. Acoust. Soc. Am. 138(6): 3785-

(2014). “Aging of the medial olivocochlear reflex and 

 Acoust. Soc. Am. 135, 754. 

“Maturation of the medial olivocochlear reflex revisited,” 

“Maturation of medial efferent system function in humans,” 

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Contact PD/PI: Shera, Christopher

Provide the following information for 

Follow this format for each person. 

NAME: Carolina Abdala 

eRA COMMONS USER NAME (credential, 

POSITION TITLE: Professor of Otolaryngology, 

EDUCATION/TRAINING 

INSTITUTION AND LOCATION 

California State University, Fullerton B.A. 

University of California, Santa Barbara M.A.

University of Washington, Seattle WA Ph.D.

A. Personal Statement

For the last two decades, my laboratory has 

cochlear function. We 

newborns and those in their 8th decade of life; 

systems using sweeping stimulus tones (which allow for 

collection); we have analyzed DPOAEs by 

offline signal processing to study 

we have generated the only published report on the 

are currently studying SFOAEs to an aging population. 

boundaries of OAE research into challenging 

analysis schemes, and, eventually, to novel diagnostic 

current application includes the presentation of 

olivocochlear reflex (MOCR) while measuring OAE 

implementation of this paradigm (e.g., middle-ear 

we have extensive experience developing careful 

last decades, we have recorded reliable MOC reflexes in 

the elderly, using both reflection- and distortion-type 

allowed us to disentangle many of the potential 

throughout the arc of the human lifespan. 

1. Abdala, C., Luo, P., & Shera, C.A. (2015). 

product product otoacoustic emissions 

3799. 

2. Abdala, C., Dhar, S., Ahmadi, M., and Luo, P. 

associations with speech perception,” J. 

3. Abdala, C., Mishra, S., and Garinis, A. (2013). 

J. Acoust. Soc. Am. 133, 938-950.

4. Abdala, C., Ma, E., and Sininger, Y. (1999). 

J. Acoust. Soc. Am. 105, 2392-2402.

Biosketches
Graduate Research Asst., University of Washington, Infant Speech Perception 

Laboratory (Patricia Kuhl) and Electrophysiology Laboratory (Richard Folsom) 

 Institute, Los Angeles, CA 

 Angeles, CA 

 Northridge. Communicative Disorders 

 Angeles, CA 

 Division of Communication and Auditory Neuroscience 

Research Institute, Los Angeles, CA 

 Auditory Research & Evaluation Center 

 Program, University of Southern California 

 Keck School of Medicine, University of Southern California 

 Prize: Commencement Speaker; UC Santa Barbara, College of Letters & Science 

 Award, Virginia Merrill Bloedel Center for Hearing Research, 

 Seattle, WA 

 of the Acoustical Society of America 

 of Science, Association for Research in Otolaryngology, 

 of America, American Speech and Hearing Association 

 Am, J Assoc Res Otolaryngol, Hear Res, J Neurosci, 

 reviewer: National Institutes of Health, NIDCD R03, R21, R01 

Foundation, Cognitive Neuroscience 

National Institutes of Health, CSR AUD, (4-year term) 

Executive Committee: Hearing & Communication Neuroscience T32 Training Grant, 

 California, Otolaryngology Department + Neuroscience Graduate 

 Am, Physiological Acoustics Section 

Study Section Chair: National Institute of Health, CSR AUD (2-year term) 

 Research in Otolaryngology 

the Association for Research in Otolaryngology 

Human infants do not respond to auditory stimuli in 

(Auditory Brainstem Response, ABR) findings provide 

of this immaturity was not well understood just 20 years 

confirmed adult-newborn differences across frequency using the click-evoked 

 researcher I focused on 

function at birth, targeting the question of the origin of 

understand the mechanisms driving these age-related changes. 

and preneural window into the human cochlea. Over a 

in newborns using DPOAE ipsilateral suppression; 

medial efferent reflex, DPOAE input/output functions to 

to understand the dual-source nature of OAEs and 

work include: a) the basal half of the cochlea is adult-like in 

and adult-like tonotopy; and b) the apical half of the 

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Contact PD/PI: Shera, Christopher

B. Positions/Service and Honors 

Employment 

1987–1993 

1993–1995 Post-Doctoral Scientist, House Ear 

1995–1998 Scientist I, House Ear Institute, Los 

1998–2006 Lecturer, California State University, 

1999–2007 Scientist II, House Ear Institute, Los 

2007–2013 Scientist III, 

House 

Co-Director, Children’s 

2008– Faculty, Neuroscience Graduate 

2013– Professor of Otolaryngology, 

Honors 

1986 Dean’s 

2009 Visiting Scholar 

University of Washington, 

2013 Fellow 

Professional Memberships and Service 

Memberships: 

American Association for the Advancement 

American Auditory Society, Acoustical Society 

Service: 

1995– Manuscript Reviewer: J Acoust Soc 

Neurosci Letters, Ear Hear 

2000–2009 Ad hoc grant 

2004–2007 Grant reviewer: National Science 

2009–2012 Regular Study Section Member: 

2010– 

University of Southern 

Program 

2012– Associate Editor: J Acoust Soc. 

2012–2014 

2013–2017 Program Committee: Association for 

2017– Co-Chair of the Scientific Program for 

C. Contributions to Science 

I. The functional status of the human cochlea at birth: 

an adult-like way. Behavioral and electrophysiological 

evidence of immature responses at birth but the origin 

ago. Some of my earliest studies 

ABR recorded in notched-noise. As a postdoctoral 

developing targeted methods to assess human cochlear 

infant auditory immaturities. We also strove to 

Otoacoustic emissions (OAEs) offered a noninvasive 

decade and a half of work, we assessed cochlear tuning 

contralateral suppression of DPOAEs to measure the 

gauge cochlear compression, and DPOAE fine structure 

how it manifests at birth. The conclusions of this 

most ways, showing sharp tuning, robust nonlinearities, 

Biosketches
birth which may be related to the physical properties of the 

Residual immaturies in the apex are most concretely 

which are prolonged by almost one millisecond in the 

finding cannot be easily explained by conductive factors. 

low-frequency sound may indeed include a cochlear 

of frequency resolution in human adults and infants 

recorded with notched-noise masking. J. Acoust. Soc. Am., 98:921-930. 

 A developmental study of DPOAE (2f1-f2) suppression in humans. Hear. Res.121:125-

of DPOAE ipsilateral suppression and input/output characteristics 

114:3239-3250. 

breaking of cochlear scaling symmetry in human 

May; 129: 3104-3114. 

 immaturity. Although OAEs provide a preneural window 

 separate peripheral from neural contributions to immaturity), 

peripheral segments of the auditory system: the outer and 

months of life. Therefore, as a crucial step in defining 

had to account for and model the impact of developing 

 work was done with colleague, . 

to model the impact of an inefficient middle ear on 

 and the impact of reduced ear-canal area on reverse 

to estimate effects and correct for them in our efforts to 

In implementing these corrections, my lab essentially defined the outer 

 and how they influence OAE measurements. We found that the 

 the cochlea by ~15 dB (re: adult levels), and the reduced 

 OAE levels in neonates by 13-17 dB. These findings allowed 

and attribute many of the age effects on levelmiddle-ear factors, not cochlear immaturity. These 

 of a growing neonatal ear canal and middle ear on OAE-based 

 field with a model for how conductive immaturities impact 

Our careful consideration of newborn ear-canal and 

 in neonates as cochlear or conductive in nature. 

 A longitudinal study of DPOAE suppression tuning and acoustic 

 birth through six months of age. J. Acoust. Soc. Am. 121:3617-

of forward and reverse middle-ear transmission applied to 

Acoust. Soc. Am. 121:978-993. 

 immaturity on DPOAE suppression tuning in infant 

 otoacoustic emission suppression tuning in human 

 Soc. Am. 129:EL108-113. 

 conducted over the last two decades to understand 

 also contributed to the refinement of OAEs in their 

 example, we have characterized the normative DP-gram 

have described infant DPOAE fine structure, which 

hearing assessment; we have described optimal 

have implemented state-of-the-art OAE swept-tone 

 presentation); and we are the first lab to publish stimulus-

 were translational in nature, guiding the application of 

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Contact PD/PI: Shera, Christopher

human cochlea shows residual immaturities at 

basilar membrane and other gross cochlear structures. 

manifest in distortion OAE phase-gradient delays, 

newborn cochlea for frequencies below 1.5 kHz. This 

Infant immaturities in the behavioral response to 

component. 

1. Abdala, C. & Folsom, R. (1995). The development 

as revealed by the ABR 

2. Abdala, C. (1998). 

138. 

3. Abdala, C. (2003) A longitudinal Study 

in human neonates. J. Acoust. Soc. Am. 

4. Abdala, C., Dhar, S. & Mishra, S. (2011). The

newborns and adults. J. Acoust. Soc. Am. 

II. Disentangling outer/middle ear from cochlear 

into the human cochlea (and thus allowed me to 

OAEs are affected by the development of more 

middle ear, which develop most notably over the first six 

the maturational status of human cochlear function, we 

ear-canal and middle-ear acoustics on OAEs. Much of this 

Among other techniques, we used DPOAE I/O functions 

forward transmission of the evoking stimulus, 

transmission of the OAE in infants. We were able 

target cochlear mechanics in newborns. 

and middle ear transfer functions in newborns 

immature middle ear attenuates the stimulus driving 

area of the newborn ear canal effectively boosts 

us to disentangle cochlear from conductive immaturities 

dependent features of the OAE to ear-canal and 

experiments modeled and defined the impact 

metrics of cochlear mechanics and provided the 

otoacoustic emissions and the measurement of hearing. 

middle-ear acoustics allowed us to interpret OAE results 

1. Abdala, C., Keefe, D. & Oba, S. (2007). 

admittance in human infants from 

3627 

2. Keefe E. & Abdala, C. (2007). Theory 

otoacoustic emissions in infant and adult ears. J. 

3. Abdala, C. & Keefe, D. (2006). Effects of middle-ear 

ears. J. Acoust. Soc. Am. 120:3832-3842. 

4. Keefe, D.H. & Abdala, C. (2011). Distortion product 

infants using absorbed sound power. J. Acoust. 

III. Translational impact. Much of the work my lab has 

human cochlear mechanics during maturation has 

application to hearing diagnosis and screening. For 

(spectrum) from prematurity through six months of age; we 

impacts the effect of test frequency selection during 

parameters for DPOAE measurement in newborns; we 

methodology in newborns (versus discrete tone 

frequency OAEs measured in newborns. These studies 

OAEs to newborn hearing diagnosis and screening. 

Biosketches
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Contact PD/PI: Shera, Christopher

1. Abdala, C. & Dhar, S. (2010). Differences in distortion product otoacoustic emission phase recorded 

from human neonates using two popular probes. J. Acoust. Soc. Am. 128:EL49-55. 

2. Abdala, C. & Dhar, S. (2010). DPOAE phase and component analysis in human newborns. J. Acoust. 

Soc. Am. 127:316-325 

3. Abdala C., Oba, S. & Ramanathan, R. (2008). Changes in the DP-gram during the preterm and early 

postnatal period. Ear Hear. 29:512-523. 

4. Abdala, C. (1996). DPOAE (2f1 - f2) amplitude as a function of f2/f1 frequency ratio and primary tone level 

separation in human adults and neonates. J. Acoust. Soc. Am. 100:3726-3740. 

IV. The dual-source DPOAE in newborns and adults. In 1999, Shera and Guinan formalized and tested an 

updated taxonomy for OAEs, showing that reverse-traveling waves were initiated in the cochlea by two 

different mechanisms: nonlinear distortion and linear reflection. The DPOAE is a mixed emission, including 

both distortion and reflection energy, hence the term “dual-source DPOAE”. Any measurement of DPOAEs 

should take its dual-source nature into consideration, because each of the two components is differently 

affected by natural and experimental manipulations. In fact, they may also be differently sensitive to pathology 

(as we hypothesize in this grant project). The work from my laboratory helped confirm the independent effect 

of various factors (e.g., medial efferent activation, maturation, aging, stimulus level) on each OAE component 

and lent support to the dual-source model of OAE generation. We have conducted this work by applying 

swept-tone OAE methodology, non-FFT based analysis algorithms (least-squares fitting), and component 

separation techniques (inverse FFT) to estimate DPOAE reflection- and distortion-component amplitude and 

phase throughout the human lifespan. In defining how DPOAE components are impacted independently, we 

have accounted for spurious and confounding variables in the measurement and interpretation of OAEs and 

how they elucidate developmental trends in cochlear maturation. Our work has corrected an overly simplistic 

view of OAE measurement and confirmed that one must consider the complexity of cochlear generation 

mechanisms when applying OAEs for experimentation or clinical evaluation. 

1. Abdala, C., and Kalluri, R. (2017). “Towards a joint reflection-distortion otoacoustic emission profile: 

Results in normal and impaired ears,” J. Acoust. Soc. Am. 142, 812. 

2. Abdala, C. Guérit, F., Luo, P. & Shera C.A. (2014). Distortion-product otoacoustic emission reflectioncomponent delays and cochlear tuning: Estimates from across the human lifespan. J. Acoust. Soc. 

Am. 135:1950-1958. 

3. Abdala, C., Dhar, S. & Kalluri, R (2011). Level dependence of distortion product otoacoustic emission 

phase is attributed to component mixing. J. Acoust. Soc. Am. 129:3123-3133. 

4. Abdala, C. & Dhar, S. (2010). DPOAE phase and component analysis in human newborns. J. Acoust. 

Soc. Am. 127:316-325. 

V. A continuum of maturation and aging. My lab has embraced the notion that “maturity” is a moving target, 

which makes it difficult to define a homeostatic adult-like response with respect to cochlear function. For this 

reason, our most recent work defines changes in human cochlear function and the mechanisms driving these 

changes during a continuum of maturation and aging. We now study lifespan changes in cochlear function to 

better understand this arc of cochlear change throughout life. This model has allowed us to pinpoint 

mechanisms driving these changes and track the shifts throughout decades of life without a priori notions 

about when maturity is achieved or what the proper referent should be. We have begun to describe shifting 

features of the aging cochlea by considering both reflection and distortion OAEs separately. We have found 

that reflection OAEs are relatively preserved in the aging cochlea (compared to distortion OAEs), possibly due 

to increased mechanical irregularities in aging tissue (OHC loss, tissue degradation, etc.). We are in the 

process of modeling and further defining these aging-related shifts by studying both distortion OAEs and 

stimulus-frequency OAEs during senescence. 

1. Abdala, C., Luo, P. & Shera, C. (2017). Characterizing spontaneous otoacoustic emissions across the 

human lifespan. J. Acoust Soc, 141, 1874. 

2. Ortmann, A. & Abdala, C. (2016). Changes in the Compressive Nonlinearity of the Cochlea During 

Early Aging: Estimates From Distortion OAE Input/Output Functions. Ear Hear. 37, 306-314. 

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3. Abdala, C. Guérit, F., Luo, P. & Shera C.A. (2014). Distortion-product otoacoustic emission reflectioncomponent delays and cochlear tuning: Estimates from across the human lifespan. J. Acoust. Soc. 

Am. 135:1950-1958. 

4. Abdala, C. & Dhar, S. (2012). Maturation and aging of the human cochlea: A view through the DPOAE

looking glass. J. Assoc. Res. Otolaryngol.13:403-421. 

Complete list of published work in MyBibliography: 

http://www.ncbi.nlm.nih.gov/sites/myncbi/carolina.abdala.1/bibliography/40697758/public/?sort=date& 

direction=ascending. 

D. Other Support

Ongoing Research Support

R01 DC003552 Abdala (PI) 1998–2020

NIH/NIDCD

Human Cochlear Function: A Continuum of Maturation and Aging.

This project studies the timeline of changes in the human peripheral auditory system from the perinatal

period through senescence and the mechanisms driving these changes using reflection- and distortionsource otoacoustic emissions. Role: Principal Investigator

Completed Research Support

R01 DC003552-10 S1 Abdala (PI) 2009–2012

NIH/NIDCD

Administrative Supplement

Peripheral Auditory System Function in Humans: A Continuum of Maturation and Aging.

R01 DC003552-10 S1 Abdala (PI) 2009–2012

NIH/NIDCD

Equipment Supplement

Peripheral Auditory System Function in Humans: A Continuum of Maturation and Aging.

Biosketches
OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) 

BIOGRAPHICAL SKETCH 

for the Senior/key personnel and other significant contributors. 

DO NOT EXCEED FIVE PAGES. 

eRA COMMONS USER NAME (credential, e.g., agency login): 

POSITION TITLE: Tiber Alpert Professor and Department Chair 

(Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) 

DEGREE 

(if applicable) 

Completion 

Date 

MM/YYYY 

FIELD OF STUDY 

.S. 

M.D.

Internship 

Residency 

Post-doc (2 yrs) 

Fellowship 

05/1990 

05/1994 

06/1995 

06/2001 

06/1998 

06/2003 

Electrical Engineering 

Medicine 

General Surgery 

Otolaryngology 

Neuroscience Research 

Neurotology 

 a clinician-scientist and I work both in the lab and care for patients with otological disorders. My clinical 

practice is Neurotology, and I specialize in caring for patients with hearing and vestibular disorders. My 

research program is dedicated towards understanding mechanisms within the cochlea that underlie 

 and to translating these techniques to improve human hearing. It 

 arms. I have a rich experience with using advanced optical 

 auditory function from the cellular to systems level. 

 research studies involving human subjects with 

 in Neurotology/Skull Base Surgery, Dept. of Otolaryngology -

Head and Neck Surgery, University of California - San Francisco, San Francisco, CA. 

, Bobby R. Alford Department of Otolaryngology – Head and 

 College of Medicine, Houston, TX. 

 at Texas Children’s Hospital, Houston, TX. 

, Department of Bioengineering, Rice University, Houston, TX. 

Department of Neuroscience, Baylor College of Medicine, 

, Bobby R. Alford Department of Otolaryngology – Head and Neck 

College of Medicine, Houston, TX. 

Associate Professor, University Line with Tenure, Department of Otolaryngology – Head and 

Neck Surgery, Stanford University, Stanford, CA 

Director, Stanford Children’s Hearing Center, Stanford, CA 

Department of Otolaryngology – Head and Neck 

Professor and Chair, Tina and Rick Caruso Department of 

Head and Neck Surgery, University of Southern California, Los Angeles, CA 

Program faculty, Hearing and Communication Neuroscience Training Program, USC 

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Provide the following information 

Follow this format for each person. 

NAME: John S. Oghalai 

EDUCATION/TRAINING 

INSTITUTION AND LOCATION 

University of Wisconsin, Madison, WI B 

University of Wisconsin, Madison, WI 

Baylor College of Medicine, Houston, TX 

Baylor College of Medicine, Houston, TX 

Baylor College of Medicine, Houston, TX 

UCSF, San Francisco, CA 

A.Personal Statement

I am 

progressive sensorineural hearing loss 

includes basic, translational, and clinical 

techniques and electrophysiological measures to assess 

I also am experienced in running translational and clinical 

inner ear disorders. 

Positions and Honors 

Positions and Employment:

2001-2003 Clinical Instructor and Fellow 

2003-2009 Assistant Professor (Tenure Track) 

Neck Surgery, Baylor 

2004-2010 Clinic Chief, The Hearing Center 

2005-2015 Adjunct faculty member 

2008-2010 Secondary faculty appointment, 

Houston, TX 

2009-2010 Associate Professor (Tenured)

Surgery, Baylor 

2010-2015. 

2010-2017 

2015-2017 Professor, University Line with Tenure, 

Surgery, Stanford University, Stanford, CA 

2017-pres Leon J. Tiber and David S. Alpert

Otolaryngology – 

2017-pres 

Biosketches
Other Experience and Professional Memberships: 

Alpha Omega Alpha (1994-pres) 

The American Academy of Otolaryngology - Head and Neck Surgery (1995-pres.) 

• Co-chair of the Research Forum for the Annual Academy Meeting (2005-2010)

• Research Steering (CORE) Committee (2007-2012)

The Association for Research in Otolaryngology (1995-pres.)

• Member of the committee on patient advocacy group relations (2000-2002)

• JARO Publications Committee (2004-2007; 2012-2015)

• Animal Research Committee (2007-2010)

Otology and Neurotology, editorial board member (2005-pres.)

IEEE Journal of Translational Engineering in Health and Medicine, Associate Editor (2012-pres.)

Deafness Research Foundation Grant Reviewer (2010-11)

Chair, Research Committee – American Neurotology Society (2014-2017)

Executive Secretary, Research Committee – American Otological Society (2016-pres)

Laryngoscope, Associate Editor- Otology/Neurotology Section (2015-pres)

NIH/NIDCD Study Sections (CDRC full-time member: 7/2014-6/2018; CDRC 2/2014; AUD: 9/2009;

Special emphasis panels: 2/2006, 11/2006, 5/2010, 7/2010, 3/2011, 9/2011, 3/2012, 10/2012, 11/2012,

7/2014, 3/2014)

Honors and Awards: 

Stanford School of Medicine Faculty Fellow (2012) 

The Dawn and Brook Lenfest Grant in Auditory Science (2004) 

Neurotology Trainee Award from the American Neurotology Society (2002) 

Voted Administrative Chief Resident by the other residents (2000-2001) 

Resident Teaching Award (for peer and medical student teaching) (2000) 

Texas Association of Otolaryngology - Head and Neck Surgery Resident Paper Award (1998 & 1999) 

The J. Charles Dickson Award for Basic Science Research (1997, 1998, and 1999) 

ARO Midwinter Meeting Resident Travel Awards (1997, 1998, 1999, & 2001) 

The Evan and Marion Helfaer Scholarship (1993) 

The Youmans Award in Medical Physiology (1992) 

Contribution to Science 

We have sought to understand normal cochlear physiology by studying the non-linear biomechanical 

processes that underlie the high auditory sensitivity and sharp frequency selectivity of mammalian hearing. 

Our team has developed a non-invasive optical technique to measure vibrations within the cochlea. We 

have found that the tectorial membrane sustains traveling waves and demonstrates sharper frequency 

tuning than the basilar membrane. In addition, we discovered that low frequency hearing is not sharply 

tuned by cochlear amplification like it is for high frequency hearing. 

a) Lee HY, Raphael PD, Park J, Ellerbee AK, Applegate BE, Oghalai JS (2015) Noninvasive in vivo

imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the

mouse cochlea. Proc Natl Acad Sci 112: 3128–3133.

b) Lee HY, Raphael PD, Xia A, Kim J, Grillet N, Applegate BE, Bowden A, Oghalai JS. (2016) Twodimensional cochlear micromechanics measured in vivo demonstrate radial tuning within the mouse

organ of Corti. J Neurosci. 36:8160–8173.

c) Xia A, Liu X, Raphael PD, Applegate BE, Oghalai JS (2016) Mechanical hair cell properties do not

amplify the traveling wave within the chicken basilar papilla. Nat Commun. 7:13133.

d) Recio-Spinoso A, Oghalai JS (2017) Mechanical tuning and amplification within the apex of the guinea

pig cochlea. J Physiol. Apr 6; PMID: 28382742.

We have also sought to study mechanisms of hearing loss, with the ultimate goal of better treating our 

patients. We study the basis of cochlear pathology following noise and blast trauma. In particular, we 

examine how hair cells and auditory dendrites/neurons are lost. Furthermore, we study transgenic mice 

Contact PD/PI: Shera, Christopher Biosketches

 

 

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with targeted mutations in cellular biomechanics. This allows us to probe the roles of the different 

structures within the organ of Corti. As one example of the fruits of this research, we have discovered that 

blast-induced cochlear synaptopathy can be minimized by treating post-traumatic endolymphatic hydrops. 

a) Xia A, Gao SS, Yuan T, Osborn A, Bress A, Pfister M, Maricich SM, Pereira FA, Oghalai JS (2010)

Deficient forward transduction and enhanced reverse transduction in the alpha tectorin C1509G human

hearing loss mutation. Dis Model Mech 3: 209–223.

b) Song Y, Xia A, Lee HY, Wang R, Ricci AJ, Oghalai JS (2015) Activity-dependent regulation of prestin

expression in mouse outer hair cells. J Neurophysiol: jn.00869.2014.

c) Kim J, Xia A, Grillet N, Applegate BE, Oghalai JS (2018) Osmotic stabilization prevents cochlear

synaptopathy after blast trauma. Proc Natl Acad Sci U S A: in press

d) Dewey JB, Xia A, Mueller U, Belyantseva IA, Applegate BE, Oghalai JS. Mammalian auditory hair cell

bundle stiffness affects frequency tuning by increasing coupling along the length of the cochlea. Cell

Rep 2018; in press.

3. I also direct research to improve cochlear implant outcomes, which has more direct and immediate clinical

relevance. One representative project is to develop an evidence base for when children with both deafness

and developmental delays should undergo cochlear implantation. Another project is to develop the

translational technology for non-invasively measuring speech perception within the auditory cortex of

cochlear implant users. The ultimate goals of these efforts are to improve human health using carefullydesigned, hypothesis-driven, NIH-funded clinical and translational research studies.

a) Sevy ABG, Bortfeld H, Huppert TJ, Beauchamp MS, Tonini RE, Oghalai JS (2010) Neuroimaging with

near-infrared spectroscopy demonstrates speech-evoked activity in the auditory cortex of deaf children

following cochlear implantation. Hear Res 270: 39–47.

b) Oghalai JS, Caudle SE, Bentley B, Abaya H, Lin J, Baker D, Emery C, Bortfeld H, Winzelberg J (2012)

Cognitive outcomes and familial stress after cochlear implantation in deaf children with and without

developmental delays. Otol Neurotol 33: 947–956.

c) Pollonini L, Olds C, Abaya H, Bortfeld H, Beauchamp MS, Oghalai JS (2014) Auditory cortex activation

to natural speech and simulated cochlear implant speech measured with functional near-infrared

spectroscopy. Hear Res 309: 84–93.

d) Olds C, Pollonini L, Abaya H, Larky J, Loy M, Bortfeld H, Beauchamp MS, Oghalai JS (2015) Cortical

Activation Patterns Correlate With Speech Understanding After Cochlear Implantation. Ear Hear.

DOI:10.1097/AUD.0000000000000258.

Complete List of Published Work in MyBibliography (120 current publications in PubMed): 

https://www.ncbi.nlm.nih.gov/sites/myncbi/1R725cOelFEAq/bibliography/40679618/public/?sort=date&

direction=ascending 

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D. Research Support

Ongoing Research Support:

R01 DC013774-01A1 (PI: Oghalai) 4/10/2015-3/31/20 

NIH-NIDCD 

Optical coherence tomography for 3D measures of cochlear mechanics in vivo 

Mammals hear when the highly-organized organ of Corti vibrates in response to sound pressure waves 

and stimulates hair cells. Herein, we propose to develop the technology to image these vibrations noninvasively in 3D. We will then determine the impact of outer hair cell passive stiffness and active force 

generation on the vibratory patterns using transgenic mouse strains. 

R01 DC014450-01 (PI: Oghalai) 5/1/2015-4/30/20 

NIH-NIDCD 

Cochlear mechanics in the mouse 

Mammals hear when the highly-organized organ of Corti vibrates in response to sound pressure waves 

and stimulates hair cells. Herein, we propose image these vibrations non-invasively and understand how 

these structures work together to create high auditory sensitivity and sharp frequency tuning. This question 

remains unsolved and is clinically important because while hearing aids can compensate for the loss of 

sensitivity, we have no treatments for the loss of frequency tuning. 

R13 DC015965 (PI: Oghalai) 4/01/17-3/31/22 

NIH-NIDCD 

Conference on implantable auditory prostheses 

This supports the bi-annual auditory prosthesis conference that Bob Shannon has run for many years. Bob 

Shannon, PhD is listed as the co-PI, but it is really his grant and he runs the conference. I am only listed as 

the PI because Bob is retired and does not have PI status at USC any longer. 

Completed Research Support:

MR130316 (PI: Cheng; role: co-investigator) 9/30/2014-9/29/2017 

Department of Defense 

Regenerating the blast and noise damaged cochlea

This project applies Wnt signaling or reprogramming factors to regenerate the blast or noise damaged 

cochlea. I collaborate by developing and performing noise- and blast-exposure procedures, as well as with 

the assessment of cochlear function after the exposure. 

R21 HD08231901A1 (Bhutani; Role: co-investigator) 12/1/2015-11/30/2017 

NIH/NICHD 

Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants. 

This project evaluates two new innovative nanotechniques to quantify bilirubin load for the first time in the 

context of a clinical decision algorithm to identify those most at risk for any bilirubin-related neurotoxicity 

T32 DC015209 (PI: Oghalai) 7/1/2016-7/31/2017 

NIH-NIDCD – Grant was transferred to another PI when I moved from Stanford to USC. 

Clinician-Scientist Training Program in Otolaryngology 

This program aims to train otolaryngology residents and post-residency graduates to become physician 

scientists. It is designed to provide intense research experiences, a structured didactic program, and close 

mentorship and guidance in how to integrate clinical and research activities. Trainees will be ingrained with 

the philosophy that research is intrinsic to an academic surgeon’s career and that they should build their 

career by sustaining excellence in both research and clinical care. If our training program is successful, our 

graduates will become independent NIDCD-funded investigators in faculty positions in academic 

departments. The ultimate long-term goal, of course, is for them to improve human health by advancing our 

field via scientific discovery that is translated to clinical care. 

P30 DC010363 (PI: Heller; role: co-investigator) 9/18/09-7/31/17 

NIH/NIDCD 

Stanford OHNS Core Center 

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The Core Center at Stanford Otolaryngology - Head & Neck Surgery aims to support the research 

endeavors of a central group of 11 Principal Investigators working on topics related to auditory and 

vestibular neurobiology. It is meant to generate a central hub of knowledge, technology, and collaboration 

for R01- funded basic researchers as well as clinicians, thereby spawning new ideas and translational 

advances. I am the Director of the Physiology Core. 

R01 DC007910-05A1 (PI: Steele; role: co-investigator) 10/1/05-6/30/17 

NIH/NIDCD 

Three-dimensional and multi-scale organ of Corti biomechanics 

This proposal attempts to test the feed-forward feedback model of cochlear amplification by incorporating 

in vivo morphological data that assesses the tonotopic structural interaction of Dieter cells with outer hair 

cells as well as by incorporating realistic receptor potential parameters for outer hair cells. 

R01 DC010075 (PI: Oghalai) 9/18/09-8/31/16 (included a 2 yr no-cost extension) 

NIH-NIDCD 

Outcomes in Children with Developmental Delays and Deafness: A Randomized Trial 

We hypothesize that development and quality of life will improve more in deaf children with developmental 

delays when treated with a cochlear implant compared to those treated with hearing aids. We will perform 

a clinical trial to answer the question of which intervention provides more benefit to this population of 

children using validated, norm-referenced tests. This study will provide essential evidence to support 

clinical decision-making in this population. 

W81XWH-11-2-0004 (PI: Oghalai) 12/1/10-11/30/15 (includes a 2 yr no-cost extension) 

Department of Defense 

Diagnosis & Treatment of Blast-Induced Hearing Loss 

Blast-induced hearing loss is a common injury sustained by military personnel and produces a long-term 

disability that requires chronic management. We will develop improved techniques for imaging of the ear 

and correlate the findings with a detailed assessment of the tissue, cellular, and genetic changes that occur 

within the ear using a novel mouse model of blast injury. 

R56 DC010164 (PI: Oghalai) 8/1/10-7/31/12 

NIH-NIDCD 

Translation of near-infrared spectroscopy for use in clinical neuro-imaging of deaf children after cochlear 

implantation 

The goal of this proposal is to develop near-infrared spectroscopy neuroimaging into a valid and reliable 

clinical tool to aid the care of children who hear through a cochlear implant. This technique is expected to 

enhance the ability of a cochlear implant team to program a child’s device. 

K08 DC006671 (PI: Oghalai) 4/1/2004-3/31/2010 (includes a 1 yr no-cost extension) 

NIH-NIDCD 

Modulation of Cochlear Tuning 

We study the relationship between the passive and active tuning properties of the cochlear partition and to 

develop techniques that can be used to change the cochlear frequency map. 

R03 DC 05131 (PI: Oghalai) 8/1/2001-5/31/2004 

NIH-NIDCD 

Modulation of Cochlear Mechanics 

The objective of these studies is to understand how drugs modulate the cochlear amplifier, specifically 

those that affect outer hair cell biomechanics. 

Biosketches
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 2018-06-30T00:58:58.000-04:00 

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  1

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: 

Start Date*: 04-01-2019 End Date*: 03-31-2020 Budget Period: 1 

A. Senior/Key Person

Prefix First Name* Middle 

Name 

Last Name* Suffix Project Role* Base 

Salary ($) 

Calendar 

Months 

Academic 

Months 

Summer 

Months 

Requested 

Salary ($)* 

Fringe 

Benefits ($)* 

Funds Requested ($)* 

Christopher Shera PD/PI 0.00 7.8 

Total Funds Requested for all Senior Key Persons in the attached file 

Additional Senior Key Persons: File Name: Total Senior/Key Person 

B. Other Personnel

Number of 

Personnel* 

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)* 

3 Post Doctoral Associates 30 

Graduate Students 

Undergraduate Students 

Secretarial/Clerical 

1 Research Engineer 1.2 

4 Total Number Other Personnel Total Other Personnel 

RESEARCH & RELATED Budget {A-B} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 29

1 . Dr. 
RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 1 

03-31-2020 Budget Period: 1 

Funds Requested ($)* 

Total Equipment 

Funds Requested ($)* 

Total Travel Cost 

Funds Requested ($)* 

Total Participant Trainee Support Costs 

Contact PD/PI: Shera, Christopher Page 30

 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2019 End Date*: 

C. Equipment Description

List items and dollar amount for each item exceeding $5,000 

Equipment Item 

1 . two Dell Precision T7910 high-performance scientific workstation 

Total funds requested for all equipment listed in the attached file 

Additional Equipment: File Name: 

D. Travel

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions)

2. Foreign Travel Costs

E. Participant/Trainee Support Costs

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other:

Number of Participants/Trainees

RESEARCH & RELATED Budget {C-E} (Funds Requested) 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

Tracking Number: GRANT12665698 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 1 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2019 End Date*: 03-31-2020 Budget Period: 1 

F. Other Direct Costs Funds Requested ($)* 

1. Materials and Supplies

3. Consultant Services

4. ADP/Computer Services

5. Subawards/Consortium/Contractual Costs

6. Equipment or Facility Rental/User Fees

7. Alterations and Renovations

Subject Fees 

G. Direct Costs Funds Requested ($)* 

Total Direct Costs (A thru F) 

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)* 

On Campus Research 

Cognizant Federal Agency 

(Agency Name, POC Name, and POC Phone Number) 

DHHS, 

I. Total Direct and Indirect Costs Funds Requested ($)* 

Total Direct and Indirect Institutional Costs (G + H) 

J. Fee Funds Requested ($)* 

K. Total Costs and Fee Funds Requested ($)* 

L. Budget Justification* File Name: 

Shera_Budget_Justification_final_v21012774141.pdf 

(Only attach one file.) 

RESEARCH & RELATED Budget {F-K} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 31

 

8 . 

1 . 

2018-06-30T00:58:58.000-04:00 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 2018-06-30T00:58:58.000-04:00 

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  2

ORGANIZATIONAL DUNS*

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: 

Start Date*: 04-01-2020 End Date*: 03-31-2021 Budget Period: 2 

A. Senior/Key Person

Prefix First Name* Middle 

Name 

Last Name* Suffix Project Role* Base 

Salary ($) 

Calendar 

Months 

Academic 

Months 

Summer 

Months 

Requested 

Salary ($)* 

Fringe 

Benefits ($)* 

Funds Requested ($)* 

Christopher Shera PD/PI 0.00 7.8 

Total Funds Requested for all Senior Key Persons in the attached file 

Additional Senior Key Persons: File Name: Total Senior/Key Person 

B. Other Personnel

Number of 

Personnel* 

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)* 

3 Post Doctoral Associates 30 

Graduate Students 

Undergraduate Students 

Secretarial/Clerical 

1 Research Engineer 1.2 

RESEARCH & RELATED Budget {A-B} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 32

1 . Dr. 
RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 2 

03-31-2021 Budget Period: 2 

Funds Requested ($)* 

Total Equipment 

Funds Requested ($)* 

Total Travel Cost 

Funds Requested ($)* 

Total Participant Trainee Support Costs 

Contact PD/PI: Shera, Christopher Page 33

 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2020 End Date*: 

C. Equipment Description

List items and dollar amount for each item exceeding $5,000 

Equipment Item 

Total funds requested for all equipment listed in the attached file 

Additional Equipment: File Name: 

D. Travel

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions)

2. Foreign Travel Costs

E. Participant/Trainee Support Costs

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other:

Number of Participants/Trainees

RESEARCH & RELATED Budget {C-E} (Funds Requested) 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

Tracking Number: GRANT12665698 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 2 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2020 End Date*: 03-31-2021 Budget Period: 2 

F. Other Direct Costs Funds Requested ($)* 

1. Materials and Supplies

3. Consultant Services

4. ADP/Computer Services

5. Subawards/Consortium/Contractual Costs

6. Equipment or Facility Rental/User Fees

7. Alterations and Renovations

Subject Fees 

G. Direct Costs Funds Requested ($)* 

Total Direct Costs (A thru F) 

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)* 

On Campus Research 

Cognizant Federal Agency 

(Agency Name, POC Name, and POC Phone Number) 

DHHS, 

I. Total Direct and Indirect Costs Funds Requested ($)* 

Total Direct and Indirect Institutional Costs (G + H) 

J. Fee Funds Requested ($)* 

K. Total Costs and Fee Funds Requested ($)* 

L. Budget Justification* File Name: 

Shera_Budget_Justification_final_v21012774141.pdf 

(Only attach one file.) 

RESEARCH & RELATED Budget {F-K} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 34

 

8 . 

1 . 

2018-06-30T00:58:58.000-04:00 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 2018-06-30T00:58:58.000-04:00 

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  3

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: 

Start Date*: 04-01-2021 End Date*: 03-31-2022 Budget Period: 3 

A. Senior/Key Person

Prefix First Name* Middle 

Name 

Last Name* Suffix Project Role* Base 

Salary ($) 

Calendar 

Months 

Academic 

Months 

Summer 

Months 

Requested 

Salary ($)* 

Fringe 

Benefits ($)* 

Funds Requested ($)* 

Christopher Shera PD/PI 0.00 7.8 

Total Funds Requested for all Senior Key Persons in the attached file 

Additional Senior Key Persons: File Name: Total Senior/Key Person 

B. Other Personnel

Number of 

Personnel* 

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)* 

3 Post Doctoral Associates 30 

Graduate Students 

Undergraduate Students 

Secretarial/Clerical 

1 Research Engineer 1.2 

RESEARCH & RELATED Budget {A-B} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 35

1 . Dr. 
RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 3 

03-31-2022 Budget Period: 3 

Funds Requested ($)* 

Total Equipment 

Funds Requested ($)* 

Total Travel Cost 

Funds Requested ($)* 

Total Participant Trainee Support Costs 

Contact PD/PI: Shera, Christopher Page 36

 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2021 End Date*: 

C. Equipment Description

List items and dollar amount for each item exceeding $5,000 

Equipment Item 

Total funds requested for all equipment listed in the attached file 

Additional Equipment: File Name: 

D. Travel

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions)

2. Foreign Travel Costs

E. Participant/Trainee Support Costs

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other:

Number of Participants/Trainees

RESEARCH & RELATED Budget {C-E} (Funds Requested) 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

Tracking Number: GRANT12665698 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 3 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2021 End Date*: 03-31-2022 Budget Period: 3 

F. Other Direct Costs Funds Requested ($)* 

1. Materials and Supplies

3. Consultant Services

4. ADP/Computer Services

5. Subawards/Consortium/Contractual Costs

6. Equipment or Facility Rental/User Fees

7. Alterations and Renovations

Subject Fees 

G. Direct Costs Funds Requested ($)* 

Total Direct Costs (A thru F) 

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)* 

On Campus Research 

Total Indirect Costs 

Cognizant Federal Agency 

(Agency Name, POC Name, and POC Phone Number) 

DHHS, 

I. Total Direct and Indirect Costs Funds Requested ($)* 

Total Direct and Indirect Institutional Costs (G + H) 

J. Fee Funds Requested ($)* 

K. Total Costs and Fee Funds Requested ($)* 

L. Budget Justification* File Name: 

Shera_Budget_Justification_final_v21012774141.pdf 

(Only attach one file.) 

RESEARCH & RELATED Budget {F-K} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 37

 

 

8 . 

1 . 

2018-06-30T00:58:58.000-04:00 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 2018-06-30T00:58:58.000-04:00 

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  4

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: 

Start Date*: 04-01-2022 End Date*: 03-31-2023 Budget Period: 4 

A. Senior/Key Person

Prefix First Name* Middle 

Name 

Last Name* Suffix Project Role* Base 

Salary ($) 

Calendar 

Months 

Academic 

Months 

Summer 

Months 

Requested 

Salary ($)* 

Fringe 

Benefits ($)* 

Funds Requested ($)* 

Christopher Shera PD/PI 0.00 7.8 

Carolina Abdala Co-Investigator 0.6 

Total Funds Requested for all Senior Key Persons in the attached file 

Additional Senior Key Persons: File Name: Total Senior/Key Person 

B. Other Personnel

Number of 

Personnel* 

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)* 

3 Post Doctoral Associates 30 

Graduate Students 

Undergraduate Students 

Secretarial/Clerical 

1 Research Engineer 1.2 

RESEARCH & RELATED Budget {A-B} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 38

1 . Dr. 

2 . Dr. 
RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 4 

03-31-2023 Budget Period: 4 

Funds Requested ($)* 

Total Equipment 

Funds Requested ($)* 

Total Travel Cost 

Funds Requested ($)* 

Total Participant Trainee Support Costs 

Contact PD/PI: Shera, Christopher Page 39

 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2022 End Date*: 

C. Equipment Description

List items and dollar amount for each item exceeding $5,000 

Equipment Item 

Total funds requested for all equipment listed in the attached file 

Additional Equipment: File Name: 

D. Travel

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions)

2. Foreign Travel Costs

E. Participant/Trainee Support Costs

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other:

Number of Participants/Trainees

RESEARCH & RELATED Budget {C-E} (Funds Requested) 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

Tracking Number: GRANT12665698 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 4 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2022 End Date*: 03-31-2023 Budget Period: 4 

F. Other Direct Costs Funds Requested ($)* 

1. Materials and Supplies

3. Consultant Services

4. ADP/Computer Services

5. Subawards/Consortium/Contractual Costs

6. Equipment or Facility Rental/User Fees

7. Alterations and Renovations

Subject Fees 

G. Direct Costs Funds Requested ($)* 

Total Direct Costs (A thru F) 

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)* 

On Campus Research 

Total Indirect Costs 

Cognizant Federal Agency 

(Agency Name, POC Name, and POC Phone Number) 

DHHS, 

I. Total Direct and Indirect Costs Funds Requested ($)* 

Total Direct and Indirect Institutional Costs (G + H) 

J. Fee Funds Requested ($)* 

K. Total Costs and Fee Funds Requested ($)* 

L. Budget Justification* File Name: 

Shera_Budget_Justification_final_v21012774141.pdf 

(Only attach one file.) 

RESEARCH & RELATED Budget {F-K} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 40

 

8 . 

1 . 

2018-06-30T00:58:58.000-04:00 
OMB Number: 4040-0001 

Expiration Date: 10/31/2019 

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 2018-06-30T00:58:58.000-04:00 

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  5

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: 

Start Date*: 04-01-2023 End Date*: 03-31-2024 Budget Period: 5 

A. Senior/Key Person

Prefix First Name* Middle 

Name 

Last Name* Suffix Project Role* Base 

Salary ($) 

Calendar 

Months 

Academic 

Months 

Summer 

Months 

Requested 

Salary ($)* 

Fringe 

Benefits ($)* 

Funds Requested ($)* 

Christopher Shera PD/PI 0.00 7.8 

Total Funds Requested for all Senior Key Persons in the attached file 

Additional Senior Key Persons: File Name: Total Senior/Key Person 

B. Other Personnel

Number of 

Personnel* 

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)* 

3 Post Doctoral Associates 30 

Graduate Students 

Undergraduate Students 

Secretarial/Clerical 

1 Research Engineer 1.2 

4 Total Number Other Personnel Total Other Personnel 

RESEARCH & RELATED Budget {A-B} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 41

1 . Dr. 
RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 5 

03-31-2024 Budget Period: 5 

Funds Requested ($)* 

Total Equipment 

Funds Requested ($)* 

Total Travel Cost 

Funds Requested ($)* 

Total Participant Trainee Support Costs 

Contact PD/PI: Shera, Christopher Page 42

 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2023 End Date*: 

C. Equipment Description

List items and dollar amount for each item exceeding $5,000 

Equipment Item 

Total funds requested for all equipment listed in the attached file 

Additional Equipment: File Name: 

D. Travel

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions)

2. Foreign Travel Costs

E. Participant/Trainee Support Costs

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other:

Number of Participants/Trainees

RESEARCH & RELATED Budget {C-E} (Funds Requested) 

Funding Opportunity Number: PA-18-484 . Received Date: 

2018-06-30T00:58:58.000-04:00 

Tracking Number: GRANT12665698 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 5 

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: 

Start Date*: 04-01-2023 End Date*: 03-31-2024 Budget Period: 5 

F. Other Direct Costs Funds Requested ($)* 

1. Materials and Supplies

3. Consultant Services

4. ADP/Computer Services

5. Subawards/Consortium/Contractual Costs

6. Equipment or Facility Rental/User Fees

7. Alterations and Renovations

Subject Fees 

G. Direct Costs Funds Requested ($)* 

Total Direct Costs (A thru F) 

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)* 

On Campus Research 

Total Indirect Costs 

Cognizant Federal Agency 

(Agency Name, POC Name, and POC Phone Number) 

DHHS, 

I. Total Direct and Indirect Costs Funds Requested ($)* 

Total Direct and Indirect Institutional Costs (G + H) 

J. Fee Funds Requested ($)* 

K. Total Costs and Fee Funds Requested ($)* 

L. Budget Justification* File Name: 

Shera_Budget_Justification_final_v21012774141.pdf 

(Only attach one file.) 

RESEARCH & RELATED Budget {F-K} (Funds Requested) 

Contact PD/PI: Shera, Christopher Page 43

 

8 . 

1 . 

2018-06-30T00:58:58.000-04:00 
Budget Justification 

Personnel 

Christopher Shera, Ph.D. (Principal Investigator, 65% effort, 7.8 calendar months) The PI has responsibility for 

 aspects of this project, including theoretical and experimental design, software development, computational 

and mathematical modeling, data collection and analysis, and preparation of manuscripts. He will also be actively 

supervising and participating in the experimental and theoretical work of the postdoctoral fellows and any 

trainees who are recruited and supported by other means. This R01 is the PI’s principal daily focus. 

Carolina Abdala, Ph.D. (Co-Investigator, 5% effort, 0.6 calender month) Dr. Abdala is an expert in the 

measurement of MOC efferent effects in humans using OAEs. She will provide advice and assistance with the 

experimental design, data collection, and analysis for the OAE studies of Aim 2. 

John Oghalai, M.D. (Co-Investigator, 5% effort, 0.6 calendar month in years 1 and 2) Dr. Oghalai is an expert 

in the use of optical coherence tomography (OCT) to measure the sound-induced motions of the organ of Corti 

in intact cochleae. He will provide advice and assistance with the experimental design, data collection, and 

analysis for the experimental studies of Aim 3b. 

Karolina Charaziak, Ph.D. (Postdoctoral Fellow, 100% effort, 12 calendar months) Dr. Charaziak will be 

involved in all aspects of the work of Aim 1, including experimental design, data collection, theoretical and 

computational modeling, analysis, and writing and in the vibration measurements of Aim 3b including 

experimental design, data collection, and analysis. Dr. Charaziak is currently applying for a K99 award to pursue 

different project jointly mentored by Drs. Shera and Oghalai. Should that grant be awarded, we will recruit 

another postdoctoral fellow to complete the work described here, under the supervision of the PI. We do not 

anticipate any problems filling this position. 

Anders Christensen, Ph.D. (Postdoctoral Fellow, 75% effort, 9 calendar months) Dr. Christensen will be 

involved in the experimental work of Aim 2, including experimental design, data collection, analysis, and writing. 

When he finishes, sometime within the five-year grant period, we will recruit another research fellow or graduate 

student to complete the work described here, under the supervision of the PI. We do not anticipate any problems 

filling this trainee position. 

Alessandro Altoè, Ph.D. (Postdoctoral Fellow, 75% effort, 9 calendar months) Dr. Altoè will be involved in the 

theoretical and computational studies of Aim 3b, including model design and implementation, simulations, 

analysis, and writing. When he finishes, sometime within the five-year grant period, we will recruit another 

research fellow or graduate student to complete the work described here, under the supervision of the PI. We 

do not anticipate any problems filling this trainee position. 

Ping Luo, M.S.E.E. (Research Engineer, 10% effort, 1.2 calendar months) Mr. Luo will provide engineering and 

software support for the experiments of Aims 1, 2, and 3. Mr. Luo has over 15 years’ experience working in 

acoustics and electronics laboratories, where he was implemented and refined OAE measurement software, 

designed and calibrated acoustical and electronic hardware for data-collection systems, adapted data-analysis 

algorithms for studies on otoacoustic emissions and cochlear mechanics, and made precision acoustic 

measurements. 

we propose a 3% merit -based salary increase annually. 

Equipment (year 1 only) 

Scientific workstations for high-performance computing: Funds are requested to purchase two Dell Precision 

T7910 high-performance scientific workstations (dual 10-core processors, 128 GB memory, 1 TB SSD, and 21” 

flat-panel monitor at /workstation with discount) for the mathematical and computational modeling studies 

of Aims 1, 2, and 3. The scientific workstations currently used by the PI and postdoctoral fellows are more than 

five years old and need significantly improved processing speeds and additional memory to run the cochlear 

model simulations. 

Materials and Supplies (incremented by per year) 

Eartips and miscellaneous supplies: Funds are requested for disposable eartips for coupling probe 

assemblies to the subject’s ear and other miscellaneous supplies used in the experiments (e.g., batteries, gloves, 

Contact PD/PI: Shera, Christopher Budget Justification Attachment

 

 

all 

a 

 Page 44
surgical tape, laboratory notebooks and stationery supplies, printer supplies, acoustical tubing, electrical 

connectors and adapters, data storage media and services). 

Technical books: Funds are requested to purchase technical books necessary for the proposed 

research. 

Animals and surgical supplies: Funds yr in years 1 and 2) are requested for the purchase and housing 

of mice and for necessary surgical supplies. 

Travel 

Funds are requested for one trip per year for the PI and Postdoctoral Fellows to a scientific meeting (such as the 

ARO Midwinter Meeting) to present results from the projects funded by this R01 

Other Expenses 

Publication costs: Funds /yr) are requested to cover the cost of publishing papers in the Journal of the 

Acoustical Society of America (approx per article) and other relevant journals, the costs of publishing color 

figures per figure in JASA), and printing of posters for meetings such as the ARO Midwinter Meeting. The 

annual figure is based on the expected publication rate of three papers and two posters per year. 

Miscellaneous software licenses: Funds yr) are requested to cover the yearly cost of software usage 

licenses, maintenance, and upgrades for scientific computing and remote file-sharing software used by the PI 

and his trainees (Adobe Creative Suite , Mathematica Dropbox Logmein Pro 

Subject fees and expenses: Funds are requested for subject participation incentives and 

reimbursed public transportation or parking expenses 

Equipment maintenance and repair: Funds are requested to cover miscellaneous manufacturing, 

maintenance, repair, and/or replacement costs for transducers, amplifiers, filters, electronics, and other small 

equipment used in the experiments. 

Contact PD/PI: Shera, Christopher Budget Justification Attachment Page 45

 

 
- -

Contact PD/Pl: Shera, Christopher 

RESEARCH & RELATED BUDGET-Cumulative Budget 

Totals($) 

Section A, Senior/Key Person 

-

-

1. Domestic -

-

-

2. Foreign

Section E, Participant/Trainee Support 

Costs 

1. Tuition/Fees/Health Insurance 

2. Stipends

3. Travel

4. Subsistence 

5. Other

6. Number of Participants/Trainees

Sect

1. Mate

ion 

ri

F, 

als 

Other 

and S

D

u

irect 

pplies

Costs 

-

-

3. Consultant Services

-

4. ADP/Computer Services

5. Subawards/Consortium/Contractual

Costs

6. Equipment or Facility Rental/User

Fees

7

8

.

. Other 

Alterat

1

ions and Renovations

-

10. Other 3

(

Sect

A thru 

ion 

F

G

) 

, Direct Costs -

-

-

-

Page 46 

Track ng Number: GRANT12665698 Funding Opportunity Number: PA 18-484 . Received Date: 

2018 06 30T00 58:58.000 04:00 
PHS 398 Cover Page Supplement OMB Number: 0925-0001

Expiration Date: 03/31/2020

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 . Received Date: 

1. Vertebrate Animals Section

Are vertebrate animals euthanized? ● Yes ❍ No

If "Yes" to euthanasia

Is the method consistent with American Veterinary Medical Association (AVMA) guidelines?

● Yes ❍ No

If "No" to AVMA guidelines, describe method and provide scientific justification

2. *Program Income Section

*Is program income anticipated during the periods for which the grant support is requested?

❍ Yes ● No

If you checked "yes" above (indicating that program income is anticipated), then use the format below to reflect the amount and

source(s). Otherwise, leave this section blank.

*Budget Period *Anticipated Amount ($) *Source(s)

Contact PD/PI: Shera, Christopher

   

 Page 47 2018-06-30T00:58:58.000-04:00 
 Page 48 Contact PD/PI: Shera, Christopher

PHS 398 Cover Page Supplement

3. Human Embryonic Stem Cells Section

*Does the proposed project involve human embryonic stem cells? ❍ Yes ● No

If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the

following list: http://grants.nih.gov/stem_cells/registry/current.htm. Or, if a specific stem cell line cannot be referenced at this time,

check the box indicating that one from the registry will be used:

Specific stem cell line cannot be referenced at this time. One from the registry will be used.

Cell Line(s) (Example: 0004):

4. Inventions and Patents Section (Renewal applications)

*Inventions and Patents: ❍ Yes ● No

If the answer is "Yes" then please answer the following:

*Previously Reported: ❍ Yes ❍ No

5. Change of Investigator/Change of Institution Section

❏ Change of Project Director/Principal Investigator

Name of former Project Director/Principal Investigator

Prefix:

*First Name:

Middle Name:

*Last Name:

Suffix:

❏ Change of Grantee Institution

*Name of former institution:

Funding Opportunity Number: PA-18-484 . Received Date: Tracking Number: GRANT12665698 2018-06-30T00:58:58.000-04:00 
PHS 398 Research Plan OMB Number: 0925-0001

Expiration Date: 03/31/2020

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484. Received Date: 

Introduction

1. Introduction to Application

(for Resubmission and Revision applications) Shera_Introduction1012773854.pdf

Research Plan Section

2. Specific Aims Shera_Specific_Aims1012773838.pdf

3. Research Strategy* Shera_Research_Strategy1012773840.pdf

4. Progress Report Publication List Shera_Progress_Report_Publication_List1012773843.pdf

Other Research Plan Section

5. Vertebrate Animals Shera_Vertebrate_Animals1012773841.pdf

6. Select Agent Research Shera_Select_Agents1012773842.pdf

7. Multiple PD/PI Leadership Plan

8. Consortium/Contractual Arrangements

9. Letters of Support Shera_Oghalai_Letter_of_Collaboration1012773853.pdf

10. Resource Sharing Plan(s) Shera_Resource_Sharing1012773844.pdf

11. Authentication of Key Biological and/or

Chemical Resources Shera_Authentication_Plan1012773857.pdf

Appendix

12. Appendix

 Contact PD/PI: Shera, Christopher

 

 Page 49 2018-06-30T00:58:58.000-04:00 
Contact PD/Pl: Shera, Christopher 

INTRODUCTION 

We thank the reviewers for highlighting the strengths of the application and for their constructive criticism. 

Responses to the noted weaknesses of the proposal are summarized below. 

Uncertain significance of the fluid waveguide model. Aim 3 explores the micromechanics of cochlear wave amplification and its consequences for OAE generation. Unfortunately, reviewers were unconvinced that the previous 

focus of Aim 3a-van der Heijden's fluid-waveguide model and its controversial claim that passive "modeswapping" provides a viable basis for cochlear frequency selectivity1-was worthy of further pursuit. We have 

therefore refocused the modeling work of this sub-Aim on a topic more clearly related to the main thread of 

the application and its emphasis on addressing fundamental issues of cochlear mechanics relevant to OAE generation. The revised Aim 3a explores the implications for OAE generation of the oblique, Y-shaped geometry 

formed by the outer hair cells and phalangeal processes of the Deiter's cells. This striking anatomical feature 

of organ-of-Corti cytoarchitecture has been hypothesized to provide a key micromechanical component of the 

cochlear amplifier.2 Models that incorporate this concept predict that cochlear wave propagation is necessarily 

anisotropic (i.e., different for waves traveling in the two directions), a prediction with significant consequences 

for our understanding of OAE generation. 

Limited spatial resolution of OCT measurements. Although OCT measurements of the motions of the different parts 

of the organ of Corti are revolutionizing our understanding of cochlear mechanics, the ability to unambiguously 

resolve cellular or subcellular structures remains limited. Thus, when we use the term "reticular lamina" (RL) we 

mean that the measurements are from the center of the upper portion of the outer-hair-cell region, as determined 

visually by the experimenter. Typically, we can discern the tectorial membrane and the tunnel of Corti, so a 

measurement point is selected that is under the tectorial membrane and adjacent to the tunnel. Additionally, we 

use 2-D cross-sectional images with vibratory magnitudes and phases plotted in pseudocolor for every point 

in the image to further guide the selection of the measurement location. Depending on stimulus frequency 

and amplitude (and also on measurement angle), differences in response magnitude and/ or phase between 

regions can help to discriminate the structures. In practice, therefore, the resolution of OCT vibrometry is much 

better than suggested by the anatomical scans. Nevertheless, the finite spatial resolution of current vibration 

measurements is an important reason that we employ somewhat more abstracted phenomenological models 

involving coupled modes of motion rather than finite-element models designed to represent the microanatomy 

of the organ of Corti in realistic detail. 

Histology to visualize and quantify the irregularity. Unfortunately, modeling studies suggest that the micromechanical irregularities believed responsible for scattering traveling waves-and, as we hypothesize here, for introducing spatial variations in the operating point or other characteristics of the hair-bundle nonlinearity-are likely to 

be small and not necessarily discernible in the anatomy. This is especially true of the dynamical irregularity we 

hypothesize to be transiently induced by activation of MOC efferents. The introduction of controlled, artificial 

irregularities-for example, though the careful placement of heavy beads on the basilar membrane3 or via the 

targeted inactivation of specific outer hair cells4-may help circumvent this problem, and we are exploring the 

feasibility of these more invasive experiments for future projects. 

Subject numbers not determined by power analysis. The questions we pose here are not fundamentally statistical 

in character. Rather than looking for confirmation of hypothesized differences between groups, we seek robust 

relationships within individuals that reveal mechanisms or previously unrecognized patterns. Because our process of data collection and analysis is an iterative one, involving considerable back-and-forth with theoretical 

modeling, the most informative analysis metrics or procedures cannot be fully known in advance, and traditional power analysis is therefore not possible. Instead, our human and murine subject numbers are estimates 

based on 25 years of experience with the number of good data sets needed to achieve robust conclusions. 

Sex as a biological variable. Although small sex differences in OAE amplitudes have been reported in humansno doubt due in part to systematic differences in ear-canal and cochlear dimensions and/ or cumulative noise 

exposure-we have no reason to expect significant sex differences in the basic mechanisms of cochlear function 

or OAE generation explored here. Nevertheless, we will analyze all our data for possible sex effects. 

Page 50 

Introduction to Application 
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Contact PD/PI: Shera, Christopher

SPECIFIC AIMS 

Otoacoustic emissions (OAEs) constitute a powerful noninvasive window on the mechanics of the cochlea. 

OAEs provide both valuable assays of cochlear function and unique tools for exploring fundamental issues 

about how the cochlea works, especially in humans. Correct understanding and application of the information 

OAEs carry back to the ear canal requires a solid interpretive framework that describes inner-ear mechanics in 

general and emission generation in particular. To pursue the complementary goals of improving the diagnostic 

utility of OAE measurements while exploring basic, unresolved issues of cochlear mechanics, we propose three 

Aims that leverage the power of combining empirical and theoretical studies: 

Aim 1. Test the dual effect of suppressor tones on the distribution of OAE sources. Otoacoustic 

measurements often employ additional stimulus tones for the purpose of reducing or eliminating contributions 

from OAE sources located in particular regions of the cochlea (e.g., when assessing cochlear frequency selectivity by measuring OAE suppression tuning curves). However, our preliminary modeling studies suggest that 

“suppressor” tones have a dual effect: They can both reduce the strength of existing OAE sources and induce 

new sources that would not otherwise be present. Using measurements and models of stimulus-frequency and 

click-evoked OAEs, we test the hypothesis that suppressors can create new sources of wave refection within 

the cochlea. Preliminary modeling work predicts that the dominant effect of the suppressor tone depends systematically on stimulus parameters. Aim 1a tests these predictions experimentally in human ears while Aim 

1b explores their physical basis using OAE models. Aim 1c determines whether the results can be applied to 

improve the measurement of OAE suppression tuning curves. Unraveling the effects of suppressor tones has 

important implications for understanding and exploiting the frequency-specifcity of OAE measurements. 

Aim 2. Probe the nature of micromechanical irregularity and its role in OAE generation. Although models indicate that spatially irregular variations in cochlear micromechanics play an essential role in 

the wave scattering responsible for refection-source OAEs, the nature of this irregularity has yet to be understood. Micromechanical irregularity has conventionally been regarded as static and structural (e.g., arising from 

random, cell-to-cell variations in outer-hair-cell geometry). However, our preliminary results suggest that the 

irregularity involved in OAE generation can also have an important dynamical component whose action can 

alter the standard interpretation of OAE measurements. The modeling work of Aim 2a tests the hypothesis that 

reducing the gain of the cochlear amplifier by activating the medial-olivocochlear (MOC) efferents can actually 

increase refection-source OAEs by changing the spatial pattern of micromechanical irregularities. Motivated by 

our preliminary data, the experiments of Aim 2b test the intriguing idea that micromechanical irregularity can 

shape the properties of distortion- as well as refection-source OAEs. Combining nonlinear cochlear models and 

OAE measurements in humans, we test the hypothesis that irregularity, in addition to scattering traveling waves, 

can modulate the generation of nonlinear distortion, and that this modulation is enhanced by contralat-eral 

acoustic stimulation. Understanding micromechanical irregularity and its modifcation by MOC activation is 

crucial for interpreting, and perhaps improving, OAE-based tests of efferent function. 

Aim 3. Explore the micromechanics of cochlear wave amplifcation and its consequences for 

OAEs. Complex modes of motion in the organ of Corti—their existence long inferred from auditory-nerve 

recordings, from in-vitro studies of excised cochleae, and from computational models—have now been observed in direct measurements from the intact cochlea. The full import of these modes, and of the intricate 

cytoarchitecture that subserves them, remains unclear, but they may require signifcant revision to our understanding of cochlear amplifcation and OAEs. Aim 3a studies OAE generation in models incorporating forms 

of spatial feed-forward/backward amplifcation suggested by the oblique geometry of the outer hair cells. Although such models can match measured mechanical responses, published arguments suggest that they cannot 

produce realistic refection-source OAEs. We will test these arguments and determine how the existence and 

properties of OAEs constrain the micromechanics of cochlear wave amplifcation. Aim 3b combines multi-mode 

cochlear models and measurements of organ of Corti vibration to explore how assumptions about the modes 

of motion, their coupling with one another, and their interactions with the cochlear fuids affect (i) the form 

of the impedances determined by solving the cochlear “inverse problem” and (ii) the locus of OAE generation 

and the latency of reverse propagation to the ear canal. Model results will be calibrated against otoacoustic and 

mechanical measurements made using optical coherence tomography (OCT). 

Specific Aims
Contact PD/Pl: Shera, Christopher 

RESEARCH STRATEGY 

A. BACKGROUND AND SIGNIFICANCE 

Overall impact. Notwithstanding the wealth of information now available about the cellular, molecular, and 

genetic mechanisms of hearing, much remains unknown about the basic functional operation of the cochlea, 

including the mechanisms of OAE generation. For example, imaging techniques such as optical coherence 

tomography and vibrometry have recently revealed unexpected internal motions within the organ of Corti and 

along the tectorial membrane. Although the intricate structural architecture of the organ of Corti has always 

harbored the potential for supporting multiple v ibrational modes, parallel pathways of energy propagation, and 

non-local mechanisms of wave amplification, the implications of this newly revealed mechanical complexity 

remain unclear and controversial1, 9, 10 

Our long-term research strategy combines innovative theoretical and experimental studies to develop and 

apply quantitative models that address these and other fundamental issues. Historically, our approach has 

yielded novel insights into cochlear mechanics (e.g., the recent prediction that the cochlear frequency-position 

map has a staircase-like structure correlated with the critical band11), key concepts and theories about the 

generation and propagation of otoacoustic emissions (e.g., reflection, distortion, beamforming12 16), new ways 

of using OAEs to learn about hearing (e.g., estimating the bandwidths of human cochlear tuning using OAE 

delays1720), and powerful measurement and analysis paradigms (e.g., calibration of intracochlear distortion 

sources,16 swept stimulus-frequency OAEs,21 emitted pressure level

22). Thus, in addition to enhancing the 

clinical and scientific value of OAEs as noninvasive probes of hearing function, our approach has demonstrated 

that O AEs have much to teach us about basic issues of cochlear mechanics. 

Continuing this productive strategy while building upon substantial recent progress (see Progress Report), 

the research program pursued here explores essential but unresolved issues in cochlear mechanics and otoacoustic emissions. These include the nonlinear action of suppressor tones and the circumstances under which 

they reveal the sources producing otoacoustic emissions; the nature of the micromechanical irregularity believed 

to underlie the generation of click-evoked and stimulus-frequency OAEs; the implications of organ of Corti cytoarchitecture for cochlear amplification and OAE generation; and the functional significance of the multiple 

coupled modes of motion revealed by recent mechanical measurements. By studying the physical and physiological mechanisms responsible for generating and shaping OAEs, the proposed work promises to provide 

significant insight into the mechanisms underlying both otoacoustic emissions and the normal operation of the 

cochlea. Work of this sort addresses a nascent paradigm shift in cochlear mechanics while laying the essential 

foundation for developing new, more powerful probes of hearing. 

Aim 1. Two-tone suppression and OAEs 

The interpretation of OAE measurements often relies on a key but largely untested assumption derived from studies of two-tone suppression in auditorynerve and basilar-membrane responses: Namely, that so-called "suppressor" 

tones act to eliminate contributions from OAE sources located in particular regions of the cochlea. For example, the standard suppression method of measuring SFOAEs assumes that presentation of a second tone at a nearby frequency 

24 base -,ource,egion - apex reduces the amplitude of the emission evoked by the probe.23, Our previous Figure 1. Suppressor tones are often 

work has validated this assumption-for near-probe suppressors in the basal assumed to remove probe-frequency 

half of the cochlea-by comparing the SFOAEs derived using suppression with SFOAE generators at locations where the 

wave envelope overlaps with the probe. those obtained using methods that do not involve additional tones.25 However, 

the suppression assumption is often applied beyond its known region of validity. For example, by fixing the 

probe and varying the frequency of the second tone over a wide range (Fig. 1), multiple studies have applied the 

suppression assumption to map out the distribution of SFOAE generators within the cochlea.26-28 The results 

suggest that a significant fraction of the total SFOAE originates in the basal, tail-region of the traveling wave, 

contrary to the predictions of most OAE models.29 These studies, if valid, have significant implications for 

models of OAE generation and thus for the interpretation of OAE measurements. 

Our preliminary modeling results, however, call the basis of these mapping studies into question.30 In 

brief, we hypothesize that the effects of suppressor tones on OAEs are more complicated than their effects on 

Page 52 

Research Strategy 

Uns.uppressed 

generators 
Contact PD/Pl: Shera, Christopher 

either basilar-membrane motion or auditory-nerve responses. More specifically, our theoretical work, recently 

collaborated by others,31 indicates that the suppressor tone can act not only to reduce the strength of existing 

OAE sources but also to induce new (i.e., artifactual) sources that would not otherwise be present.30 The model 

predicts that the strength, latency, and net contribution of these induced sources depends on the frequency of 

the suppressor tone relative to the probe-although the induced sources contribute little when the suppressor 

is close to the probe, they can come to dominate the OAE when the suppressor is moved further away. 

By testing the validity of the suppression assumption for reflection-source OAEs, our results have significant 

potential to revise the interpretation of studies that employ suppressor tones to probe (or to manipulate) the 

locus of OAE generation. For example, the finding that "suppressors do not always suppress" would have 

major implications for understanding SFOAE suppression tuning curves (STCs) and for their interpretation as 

objective estimates of cochlear frequency selectivity.32-39 Indeed, measured SFOAE STCs often have apparently 

anomalous features (e.g., multiple lobes that vary somewhat idiosyncratically from ear to ear) whose origin is 

not yet well understood. Similar anomalies appear in the STCs of other OAE types, including both distortion41 2 product40, and spontaneous emissions.4 These anomalous features have lead to the conclusion that OAE 

suppression tuning curves, although useful at the group level, provide unreliable estimates of cochlear frequency selectivity in individual ears.36,

43 Our preliminary results suggest a promising new methodology for 

reducing the confounding effects of suppressor tones and improving the reliability of SFOAE STCs. 

Aim 2. Micromechanical irregularity and OAE generation 

Because the organ of Corti is a biological structure, its mechanical properties presumably vary somewhat irregularly with position. When introduced into cochlear models, small micromechanical irregularities have a remarkable effect-by disturbing the otherwise smooth forward flow of stimulus energy, they cause the model to emit 

sound (or its computational equivalent). As they propagate, traveling waves launched along the duct encounter 

44 the irregularities and are partially reflected back toward the stapes, producing reflection-source OAEs.12, (By 

"irregular" we do not mean necessarily "random" or "discontinuous;" we use the term to describe any variation that occurs on spatial scales that are short compared to the wavelength of the traveling wave at its peak.) 

Although it may be natural to suppose that the irregularity most relevant for generating OAEs occurs in parameters that influence the forces produced by hair cells (e.g., the geometry or mechanical characteristics of the 

hair bundle), the dominant biological source of irregularity remains unknown. 

Whatever its principal locus, the micromechanical irregularity involved in 

OAE generation has invariably been regarded as (i) static and structural- iii' 

because OAE spectra in healthy ears remain stable over months and even ] .../

years45-and (ii) unimportant for the production of distortion-source OAEs- c 

because the phase-vs-frequency functions of distortion-source OAEs indicate ::E

g, V -w th MOC (irregular gan reduct on} 

•··

· w th MOC (un form gan reduction} i i that their sources are wave- rather than place-fixed.

1 4 Recent results from 

1.5 2.0 2.5 3.0 

our lab and others, however, challenge both of these principles. For example, Frequency (kHz) 

our preliminary modeling work suggests that the ostensibly static pattern of 

micromechanical irregularities characteristic of a given ear may be reversibly Static baseline micro mechanical irregularity 

altered by activation of medial olivocochlear (MOC) efferents. Otoacoustic 

measurements from both human subjects46 and guinea pigs47 show that activation of the MOC system, which generally reduces the gain of the cochlear 

Figure 2. Although a spatially uniform de-­

amplifier, can both inhibit and enhance the magnitude of reflection-source crease in cochlear gain reduces SFOAE levOAEs (e.g., either SFOAEs or the reflection component of DPOAEs). Impor­ els from baseline (dotted line re black) a , more irregular gain decrease due to patchy tantly, enhancement can occur over wide frequency regions and is not lim­ efferent innervation (bottom) can both reited to intervals where out-of-phase components combine to produce spec­ duce and enhance SFOAEs (red re black).

tral notches. (Near notches, decreases in the level of either component can 

reduce the amount of destructive interference, producing the spurious impression that OAE levels have actually increased.) Our preliminary results (Fig. 2) suggest that this seemingly impossible combination reduced 

cochlear gain accompanied by increased reflection-source OAEs-can be explained by coherent reflection theory13 combined with the patchy innervation patterns of individual MOC efferent fibers revealed by anatomical 

studies.48,

49 We will test the hypothesis that by locally reducing the gain of innervated OHCs, efferent activation 

Page 53 

Research Strategy 
Contact PD/Pl: Shera, Christopher 

modifies the spatial pattern of micromechanical irregularities and thereby changes the effective strength of OAE 

reflection sources. Similar ideas-with permanent local irregularity due to aging substituting for the reversible 

changes induced by efferent activation-may account for the unexpected findings that elderly subjects often 

51 show relatively preserved reflection-source OAEs and surprisingly robust generation of SOAEs.50,

Preliminary results also question the common presumption that micromechanical irregularity plays no role 

in the generation of distortion-source OAEs. The principal nonlinearity in the cochlea is thought to reflect 

the shape and operating point of the OHC transducer function (i.e., the sigmoidal relation between bundle 

displacement and receptor potential). If the transducer function, and hence the effective strength of the cubic 

nonlinearity, were to vary somewhat irregularly along the cochlea, then the magnitude of the distortion-source 

( or "generator component") of the 2 Ji - h DPOAE would vary with frequency. Because DPOAEs are mixtures 

15 of both short-latency distortion- and long-latency reflection-source OAEs, 14, rapid or irregular variations in 

the distortion component can be difficult to distinguish from interference arising from component mixing (i.e., 

from DPOAE fine structure). Our preliminary studies suggest, however, that the two can be disentangled using time-frequency analysis. As a simple, illustrative example, suppose the short-latency distortion component 

D(f) has a sinusoidal amplitude modulation across frequency, D(f) =Do+ d cos(2nfI f..f), where d « Do and 

f..f is the modulation period. Then, because cos(2nf If..f) = 1⁄2 (e-i2nf /1).f + e+i2nf /1).f), time-frequency analysis 

of D (f) will reveal three components: A principal component of magnitude Do at zero delay, a component 

of magnitude d/2 with positive delay (r = 1/f..f), and a component (also of magnitude d/2) with apparently 

negative delay (-r). Our previous theoretical work indicates that energy 

in the time-frequency plot can be interpreted in terms of 5 I withCAS I 

sured in the same subject both with (right) and without (left) activation of tified subjects with negative-delay components, as pre- MOC efferents induced by contralateral acoustic stimulation (CAS) with 

reflection-source components. In this subject CAS greatly enhances

components can be enhanced by contralateral acoustic DPOAE components with nonzero "delays," both positive and negative. 

efferents modulates the form and/ or operating point of OHC transducer functions. The proposed experiments 

and modeling work will pursue these intriguing preliminary findings and test the hypothesis that reflectionand distortion-source OAEs are sensitive to different micromechanical sources of irregularity. 

Aim 3. Micromechanics of cochlear wave amplification and OAEs 

Aim 3a. OAE generation in models with spatial feed-forward/feed-backward (FF/FB) amplification. 

The oblique geometry of the organ of Corti seems likely to play an essential role in mammalian cochlear 

amplification. Some models incorporating this geometry suggest that the cochlear amplifier operates through 

mechanisms involving the spatial feed-forward and/ or feed-backward (FF /FB) of OHC somatic forces. In 

these models, OHCs sense stereociliary displacement at one location but produce forces and motion at another, 

their somatic forces being transmitted along the organ of Corti via the Y-shaped cytoarchitecture of the OHCs 

and phalangeal processes of the Deiter's cells (see Fig. 4).2,53

-58 Because of traveling-wave propagation, the 

longitudinal separation between the locations of OHC sensing and forcing introduces phase shifts that can yield 

a form of negative damping, amplifying traveling waves as they propagate. 

Although FF /FB amplification appears attractive for anatomical and engineering reasons,59 and models incorporating these principles appear capable of reproducing BM mechanical measurements,2,56,58 the viability 

Page 54 Emission Frequency (kHz)

the spatial distribution of the irregularities. I I 52 Our analy- I 

I 

I 

I 

4 I I

sis thus predicts that spectral modulation of the DPOAE I I

I I distortion component-arising from spatial irregularity I 

' 

I 

I I

3 I in the strength of cochlear nonlinearity-manifests itself I I 

as DPOAE time-frequency components with negative 2 delay. This signature negative delay-a convenient consequence of the analysis and not, of course, a true, physical delay-allows modulation of the distortion-source _20 _10 o 10 20 _20 _10 o 

Time "Delay" (ms) component to be "d1 entl "f" 1e d and stud"1ed. Interestmg • 1y, 

our preliminary analysis of human DPOAEs has iden- Figure 3. Time-frequency analysis of human swept-tone DPOAEs meadieted. Furthermore, the data suggest that the mag- wideband noise (60 dB SPL). Grayscales are identical in the two panels. Dashed lines delimit the time-frequency band expected for DPOAE nitude and spectral pattern of negative-delay DPOAE ,

5timulus parameters: {L1, L2} = {65 55} dBSPL h/fi = 1.22. , , stimulation (Fig. 3), suggesting that activation of MOC 

Research Strategy 
the mechanism as an explanation for in vivo cochlear amplifcation remains unclear. Heuristic arguments60, 61 

suggest that FF/FB amplifcation suffers from the very virtue that makes it so atFigure 4. Y-shaped geometry of the organ of Corti 

may underlie somatic amplifcation by OHCs.58 

tractive and stable from an engineering perspective: the amplifcation it provides depends 

the direction of wave propagation. The oblique geometry introduces a directionality to 

the amplifer—whereas forward-traveling waves are boosted, reverse-traveling waves are 

squelched. Unlike other forms of negative damping (e.g., time-delayed stiffness), spatial 

FF/FB amplifcation may therefore be effectively “one-way.” This anisotropy would not be 

problem—indeed, it might be an advantage for cochlear signal processing near threshold, where it would alleviate complications due to standing waves—were it not for the 

existence of otoacoustic emissions, which indicate that amplifed energy escapes from the 

cochlea via mechanisms involving reverse traveling waves. (Although the possible role of 

“fast waves” must be borne in mind, the accumulated evidence against a dominant role 

compressional waves in the reverse propagation of OAEs is compelling.3, 62–68). Thus, 

current models of FF/FB amplifcation might be signifcantly constrained by the existence 

and properties of OAEs. 

Since the arguments against FF/FB amplifcation remain heuristic, testing their validity becomes crucial 

understanding the contributions and possible limitations of FF/FB mechanisms to cochlear amplifcation.69 

Resolving the question is just as important, however, for understanding OAEs and their applications to research 

and the clinic. If the mammalian cochlea does, in fact, implement spatial FF/FB amplifcation, then current 

interpretations of OAEs in terms of cochlear mechanics—interpretations derived largely from studies of OAE 

generation in classical, point-impedance models—may require modifcation. 

Aim 3b. Organ of Corti vibrational modes and OAE generation 

Until recently, the common view of cochlear micromechanics regarded the organ of Corti as providing a leverlike proportional coupling of basilar-membrane (BM) motion to the reticular lamina (RL), whose shearing motion relative to the overlying tectorial membrane then defect the stereocilia of the inner hair cells.70 By pushing 

and pulling on the BM, the outer hair cells (OHCs) appear to amplify the traveling wave but do not, in this 

view, signifcantly modify the dominant pattern of simple, almost rigid-body motion. We now know from direct mechanical measurements in the intact cochlea that this view is incomplete, perhaps even fundamentally 

misleading—the motion of the organ of Corti revealed by imaging techniques such as optical coherence tomography (OCT) appears far more complex than previously supposed.6–8 For example, rather than moving together 

simple proportion, the basilar membrane and reticular lamina evidently vibrate with strikingly different amplitudes and phases. Furthermore, the frequency tuning of the compressive nonlinearity measured at these two 

locations within the organ of Corti (BM and RL) appears qualitatively different: Whereas compressive responses 

measured on the BM (and in the auditory nerve) are largely confned to the tip region of the traveling wave, 

the motion of the reticular lamina remains nonlinear at frequencies far into the tail region below CF. Although 

the potential relevance for cochlear function of multiple modes of vibration (“degrees of freedom”) in the organ 

Corti has long been recognized—whether from notches in rate-level functions and other telling responses 

the auditory-nerve,71–74 from the complex motions evoked by electrical stimulation in excised cochleae,75, 76 

from representations of cochlear micromechanics in computational models58, 77–79—none of these seminal 

studies envisioned the details now emerging. 

Whereas the complexities of cochlear motion are fnally coming into view, the functional and theoretical 

implications of these modes for the basic mechanical operation of the cochlea and for the generation of OAEs 

remain unclear. Current theoretical understanding of OAE generation derives almost entirely from models in 

which the motion of the organ of Corti couples to the cochlear fuids—and through the fuids outward to the 

middle ear and ear canal—via the basilar membrane. The recent discovery that reticular-lamina motion can be 

larger than that of the BM, and has a different dependence on stimulus level, raises important questions about 

the micromechanical basis of OAE generation. For example, do the properties and tuning of OAEs correlate 

better with the motion of the RL than they do with the BM?10 And, are the refections responsible for otoacoustic 

emissions a consequence of coupling between modes?80 

Seeking simple insights into the functional signifcance of the multiple coupled modes of motion revealed by 

Contact PD/PI: Shera, Christopher Research Strategy

of 

on 

a 

for 

for 

in 

of 

of 

or 

 Page 55
recent measurements, we propose a combination of theoretical models and mechanical measurements of BM and 

motion to address these interrelated questions. We will measure BM and RL motion (in collaboration with 

Dr. John Oghalai and his laboratory here at USC) and use the data to derive multi-mode cochlear models, with 

representations of both BM and RL motion, using the inverse method. (In the context of cochlear mechanics, 

the term “inverse method” refers to theoretical analysis procedures that combine experimental data and model 

assumptions about coupling to derive the empirical form of the complex wavenumber or effective mechanical 

impedances within the cochlear partition.) We will vary the model assumptions about fuid coupling to the 

organ of Corti—for example, whether the fuid couples primarily to the motion of the BM or the RL—and 

determine the impact on the OAEs predicted by the model. Comparison with OAEs measured in the same 

preparations will determine whether, and if so, how, current theories of OAE generation need revision. 

B. INNOVATION 

In the current application, this pioneering research program comes together with our continuing attention 

to the biophysics of cochlear wave propagation, nonlinearity, and amplifcation.16, 83–86 These threads unite 

here to address fundamental issues about otoacoustic emissions and their origins in cochlear mechanics. Aim 

1 combines empirical and theoretical studies to address the central but still unresolved question of whether 

“suppressors” always suppress. Understanding the answer to this question—so simple to ask but surprisingly 

diffcult to answer—is crucial for proper interpretation of OAE-based measurements of cochlear frequency selectivity and other applications that attempt to localize OAE generation within the cochlea by using additional 

stimuli to interfere with their production. Technical innovations made during the current grant period21, 22 facilitate the effcient measurement of SFOAEs over a wide frequency range. When combined with the synergy of 

concurrent modeling studies, these innovations allow us to address these long-standing issues using a powerful 

new experimental paradigm. Aim 2 is motivated by exciting new preliminary results that promise to provide a 

long-sought experimental handle on the nature of the “micromechanical irregularity” hypothesized to underlie 

the generation of refection-source OAEs. Our fndings suggest that irregularity has dynamical as well as static 

components and can be reversibly modulated via stimulation of MOC efferents. Furthermore, our discovery 

of distortion-source OAE components with “negative delay”—made possible by technical innovations in OAE 

measurement methodology and analysis—supports the novel hypothesis that micromechanical irregularities 

affect the OHC transducer nonlinearity and may therefore play a more substantial role in cochlear mechanics 

and OAE generation than previously recognized. Aim 3 probes the theoretical implications of the intricate 

micromechanical anatomy and complex internal motions now becoming evident in the in-vivo response of the 

organ of Corti. Models that simplify the complexities of cochlear micromechanics underlie much of what we 

think we know about cochlear mechanics, including the existence of traveling-wave power amplifcation and 

the physics of OAE generation. But are these models, despite their historical and conceptual successes, too 

simple to capture the essential operations of the cochlea? To address these questions, we combine innovative 

theoretical analysis and state-of-the-art techniques for measuring cochlear motions in vivo. The goal is explore 

whether basic insights gleaned from models derived using the inverse method need modifcation in light of 

recent mechanical data. These data raise intriguing (but not necessarily correct) alternatives to our classical 

conceptions of cochlear function (e.g., boosting the response by swapping energy between vibrational modes or 

generating OAEs by fuid coupling to the reticular lamina rather than the BM). 

C. APPROACH 

Aim 1. Two-tone suppression and OAEs 

Rationale. Preliminary modeling studies predict that “suppressor” tones can act not only to reduce the strength 

Contact PD/PI: Shera, Christopher Research Strategy

RL 

In the years since their discovery, OAEs have found widespread but diagnostically limited use in audiology clinics and research labs, where they serve primarily to detect (but not to describe) OHC-related hearing loss with 

roughly half-octave frequency resolution. Research has demonstrated, however, that OAEs have the potential 

for providing far more detailed and frequency-specifc information about normal hearing and its dysfunction. 

Beginning with the development of the coherent-refection model12, 81 and the mechanism-based classifcation 

scheme for OAEs,14, 82 our goal has been to discover and apply knowledge of OAE generation to develop the 

power of OAEs as noninvasive probes of hearing. 

 Page 56
Contact PD/Pl: Shera, Christopher 

of existing SFOAE sources but also to induce new sources that would not otherwise be present.3031 , Testing these 

predictions experimentally requires a paradigm that can distinguish whether changes observed when presenting 

the suppressor tone result from the creation of new sources or from the removal of old ones. Because individual 

sources can contribute to the total SFOAE with different phases (e.g., constructively or destructively), this task 

is not as easy as it might appear. A simple example illustrates the problem: If presenting an additional tone 

increases a measured SFOAE value from 2 - 3, one cannot legitimately conclude that the suppressor acts by 

creating a new source of value 1, although that is the apparent effect. If the original SFOAE (of value 2) is formed 

by adding two components with different magnitudes and opposite phases [e.g., 2 = 3 + ( -1) ], then the same 

net change (2 - 3) occurs if the additional tone acts as a suppressor and selectively eliminates the component 

with negative phase. (The tone might suppress only one of the two components because the components arise 

at different spatial locations.) 

Figure 5 shows preliminary data illustrating the effect of a suppressor tone on the generation of human 

SFOAEs. Trme-frequency analysis87 of high-resolution swept-tone SFOAEs reveals what can be difficult to appreciate from a conventional, discrete-tone emission spectrum: In addition to reducing the overall emission 

level (most of which occurs at a latency of 10-12 stimulus periods in the figure), the suppressor appears to 

induce additional short-latency components not present in the absence of the suppressor. In this example, the 

suppressor appears to create new short-latency components (e.g., those with delays ~2 periods and centered on 

the region marked with an x). We can determine whether the appearance of such short-latency components 

reflects an induction of new sources or a release from cancellation 

due to partial elimination of the old by measuring how the latency 

of the components at the probe frequency varies with the frequency of 

the suppressor: As the suppressor frequency increases relative to the 

probe, we expect that the latency of new (i.e., induced) components will 

decrease whereas the latency of pre-existing but now unmasked components will increase. To see this, note that if the suppressor induces new 

sources near the peak of its excitation pattern, then high-frequency 

suppressors-those that peak in the basal, tail region of the probe response where the probe phase varies slowly-will induce components 

with shorter latencies than will suppressors placed closer to the peak 

of the probe response, where the probe phase varies more rapidly. This 

qualitative pattern (i.e., higher frequency suppressors produce shorter 

latencies) is reversed if the suppressor removes existing sources that are 

otherwise in cancellation with sources at other locations. In this case, 

the measured delay of the short-latency component is determined not 

by phase slopes at the location of peak suppression but by phase slopes 

at the location of the sources that remain unsuppressed. For example, 

if high-frequency suppressors remove sources in the tail region of the 

probe response, where the phase gradients are shallow, then the surviving sources-the ones contributing to the measured emission-are 

located closer to the peak and have longer latencies. 

20 

12 

4 

vi' 2

-c -10 r­ • lD 0 <

.3- c..:

» C: 

20 m

12 "

C

7 - 4 

X 

0 

0.5 

Figure 5. Tune-frequency plots of human SFOAF.s 

measured both in the presence (bottom) and absence 

of (top) an additional suppressor tone placed ~0.22 

octave above the probe frequency. The suppressor 

both reduces overall emission levels and appeaxs to 

create new sources at short latencies (x). SFOAE 

latency is given in periods of the probe frequency; 22 SFOAE level in dB EPL Note the nonlinear latency

axis along the ordinate. Probe and suppressor levels 

were 40 and 59 dB FPL. respectively. 

Independent of the mechanisms by which they arise, the appearance of short-latency components due to presentation of the suppressor complicates the interpretation of SFOAE STCs as measures of cochlear frequency 

selectivity. Based on our preliminary data we conjecture that short-latency components induced by the suppressor are responsible for the multiple lobes and other anomalous features of these tuning curves. To test 

this hypothesis, we will compare SFOAE STCs measured using conventional suppression criteria, which are 

based on the magnitude of the total SFOAE, with the results of a new paradigm in which the short-latency 

components are first eliminated by time-frequency filtering. 

Methods. Although DPOAE studies employing high-frequency "suppressor" or "interference" tones also suggest the involvement of basal generators,41 we focus on SFOAEs because they are the simplest emission type to 

interpret theoretically. The interpretation of DPOAE studies is more complicated because of the possibility of 

Page 57 

Research Strategy 

0.75 1 1.5 

Emission Frequency (kHz) 
exciting multiple avenues of DP generation (e.g., via so-called “catalyst” or “harmonic” mechanisms88) due to 

the larger number of stimulus and combination tones simultaneously present in the cochlea. 

The experimental methods of Aim 1a will be similar to those used for the preliminary results; all are 

extensions of those developed and used routinely in our lab. The basic methodology generalizes our “ f1 -

primary mimicker” paradigm to swept tones. Using this paradigm, we will measure SFOAEs in normalhearing young adults using the interleaved suppression method at probe frequencies from 0.5–8 kHz. Past 

success with measurements of this kind suggests that data from ∼20 subjects will suffce. To map out the 

level dependence, we will use probe levels spanning the range 20–40 dB FPL in 5 dB steps. The near-probe 

suppressor ( fs) used to extract SFOAEs at the probe frequency will be fxed at Ls = 60 dB FPL and a frequency 

5% above the probe ( fs/ fp = 1.05). The additional “suppressor” tone whose effects we are studying (here called 

an “interference tone” (IT) to distinguish it from the near-probe suppressor) will be varied in frequency from 1 

to 2.5 times fs in tenth-octave steps. The effects of IT level will be determined using levels spanning the range 

50–65 dB FPL. To improve SNRs at low frequencies, where subject and microphone noise are greatest, we will 

use log or accelerated sweeps. Results obtained with SFOAEs will be compared with emissions evoked using 

clicks to test the hypothesis that suppressors have similar effects on all refection-source OAEs, independent of 

the evoking stimulus. Time-frequency analysis using continuous wavelet transforms (CWTs) 90 will be used 

to identify and separate short- and long-latency components of the emission. Unlike fltering performed using 

flter banks, CWT-based algorithms allow perfect reconstruction and reduce fltering artifacts. 

87 

89 

14 

15 21 

To compliment and inform these experimental studies, Aim 1b will pursue the same issues using our timedomain model of an active, nonlinear cochlea. We will test the validity of the suppression assumption computationally by simulating the experiment and using the method to map out the locations of SFOAE sources in 

models where the distribution of generators (e.g., roughness pattern) is known in advance. By using the model 

to probe the mechanisms by which suppressors modify OAEs, we aim to account for intriguing features of the 

data [e.g., the apparent variation with probe frequency in the magnitude of suppressor-related short-latency 

components (see Fig. 5)]. The methods used for the modeling work will extend those used for the preliminary 

results by employing our time-domain nonlinear model rather than relying on the so-called “quasilinear” 

approximation, an approximation whose assumptions are not always satisfed and which can therefore yield 

misleading results.92 

91 

91 

In broad outline, the SFOAE STCs of Aim 1c will be measured using the iso-response procedures of 

Charaziak et al. but with two principal modifcations: (i) We will construct STCs based on SFOAE residuals 

both before and after removing short-latency components using time-frequency fltering implemented using 

continuous wavelet transforms; and (ii) We will measure SFOAEs using swept rather than discrete tones,

focusing on probe frequencies ( fp) where short-latency components have been identifed in each subject (see 

Fig. 5). Together, these modifcations allow us to compare STCs based on the total emission residual with 

those based on residuals from which short-latency components created or revealed by the suppressor have been 

removed. Octave-wide sweeps centered on the frequency of interest will be employed to expedite the data collection. Rather than varying the suppressor level adaptively, we will construct iso-response STCs offine from 

sweeps measured at suppressor levels spanning the range 20–80 dB SL in 5 dB steps. STCs at higher resolution 

can be obtained by interpolation. Since multiple lobes and other anomalous features are more prevalent at 

lower residual levels, and at suppressor frequencies greater than the probe, we will use iso-response criteria of 

−6 and 0 dB EPL and vary the suppressor from 0.9 fp to 2.1 fp with a resolution of 15 points/octave. 

87 21 

36 

Expected results, potential problems, alternative strategies. Both our preliminary data for Aim 1a (see Fig. 

5) and the anomalies evident in SFOAE STCs suggest that the magnitude of short-latency components created 

and/or unmasked by the suppressor (interference) tone will be largest at low probe frequencies (<2 kHz) and 

for interference tones placed about one-quarter octave or more above the probe frequency. By contrast, we expect 

the interference tone to suppress long-latency components of the SFOAE under all conditions. Near-probe interference tones should result in near total suppression of the SFOAE, consistent with previous results. Based on 

preliminary modeling work, which indicates that high-frequency interference tones induce new SFOAE sources, 

we expect the group delays of the short-latency SFOAE components to decrease as the frequency of the interference tone increases. When necessary to improve the time-frequency resolution of the analysis, we will use 

25 

Contact PD/PI: Shera, Christopher Research Strategy Page 58
shorter, slower sweeps with fner probe and suppressor frequency resolution at frequencies where signifcant 

short-latency components appear. 

We expect the modeling studies to reveal that suppressor tones can act not only as suppressors (i.e., as magnitude reducers) but also in at least two attendant but unintended ways. First, suppressors may act via cochlear 

nonlinearities to induce additional SFOAE sources (e.g., wave-fxed mechanical perturbations that scatter the 

probe traveling wave). Second, suppressors may modify responses to the probe by shifting their phases (rather 

than, or in addition to, reducing their amplitudes). Both hypothesized effects should be largest for moderate 

to high-level suppressor levels, and both can severely compromise the ability to reconstruct the distribution 

of SFOAE sources via vector subtraction. Although we expect the general pattern of our results to depend 

on qualitative features of the model—such as the phase coherence or cancellation that arises from the spatial 

variation of traveling-wave amplitude and phase—rather than on specifc details of cochlear nonlinearities or 

amplifcation, we need to verify that our results are not somehow idiosyncratic to our particular model. We will 

establish the generality and potential limitations of our conclusions both by verifying our results using other 

models (e.g., that of Liu and Neely93, 94) and by adopting alternate forms of the nonlinearity. To facilitate the 

interpretation of our numerical results, as well as to identify possible discrepancies, we will compare our results 

with semi-analytic expressions and/or results obtained using the quasilinear method whenever possible. 

We expect our new protocol for measuring SFOAE STCs, in which suppression criteria are applied after fltering out short-latency emission components, to eliminate the anomalous features of STCs measured using conventional procedures in the same subjects. The experiments proposed here focus initially on the high-frequency 

fank of the STC, where confounding anomalies are most evident. However, if the new protocol seems likely 

to improve the reliability of STCs in individual subjects, we will extend the range of suppressor frequencies to 

capture the entire tip of the STC and test the method by comparing the results both to psychophysical tuning 

curves36, 95 and with tuning estimates obtained from SFOAE phase-gradient delays in the same subjects.17, 18 

Aim 2. Micromechanical irregularity and OAE sources 

Aim 2a. MOC-efferent activity and refection-source OAEs 

Rationale. Recent studies of the effects of MOC efferent stimulation on OAEs challenge our understanding 

not only of MOC efferent effects in the cochlea but also of the mechanisms of OAE generation and, more generally, the assumed relationship between OAE level changes and cochlear gain. Although activation of MOC 

efferents invariably appears to decrease the gain of the cochlear amplifer, the magnitudes of corresponding 

refection-source OAEs can be either reduced or enhanced over wide frequency intervals. To determine whether 

coherent-refection theory can explain these seemingly contradictory results—decreased cochlear gain accompanied by increased OAE levels—we will construct and evaluate a computational model of efferent action in 

the cochlea in which activation of MOC efferent fbers has two principal effects: It both reduces the gain of the 

cochlear amplifer in the vicinity of OHCs contacted by active fbers and, by doing so in a patchy or nonuniform 

fashion consistent with the anatomy, modifes the spatial pattern of micromechanical irregularities by altering 

the spatial profle of gain along the cochlea. 

96–98 

46, 47 

Methods. Cochlear responses and OAEs will be simulated at low sound levels using an active 2D transmissionline model of the cochlea that incorporates both short- and long-wave behavior. The reliability of the numerical simulations will be evaluated by comparing them to semi-analytic perturbative solutions obtained using the 

WKB approximation.

13 

Model parameters will be scaled to create simulations of both the guinea-pig and human cochlea. As in the preliminary results (see Fig. 2), refection-source OAEs will be produced by introducing 

micromechanical irregularities into the admittance of the organ of Corti. Activation of MOC efferents will be 

simulated by reducing the effective amplifer gain at cochlear locations corresponding to contacted OHCs. We 

will quantify the effects of variations in key variables, including: (i) the mean number of activated fbers; (ii) 

the mean number of OHCs contacted per fber and their spatial distribution; (iii) the amplitude of the local gain 

reduction at each contacted OHC. We will simulate the effects of different MOC innervation profles, including 

patterns that are spatially uniform, irregular or random, and quasi-realistic, the latter based on the statistics 

of measured anatomical distributions. We will compare the simulated SFOAEs with the measurements of 

Berezina-Greene and Guinan to determine whether the model can reproduce the major trends in the data, including the magnitudes and prevalence of SFOAE suppression and enhancement and the magnitude of cochlear 

47 

48, 49 

12, 99 

Contact PD/PI: Shera, Christopher Research Strategy Page 59
gain reduction, as assessed experimentally using compound-action-potential (CAP) threshold shifts. 

Aim 2b. Micromechanical irregularity and distortion-source OAEs 

Rationale. Preliminary data suggest that activation of MOC efferents in human subjects can signifcantly enhance DPOAE components with apparently “negative delay” (see time-frequency analysis in Fig. 3). We will 

use a combination of OAE measurements and computational modeling to explore the origin of these components. Using nonlinear cochlear models we will test the hypothesis that negative-delay DPOAE components can 

arise if activation of efferent fbers produces spatial variations in the form or strength of cochlear nonlinearity, 

thereby modulating the strength of OAE distortion sources irregularly with position. For example, the efferentinduced hyperpolarization and resulting elongation of OHC soma may alter the operating point of the hair 

bundle. We hypothesize that the putative efferent-induced mechanical irregularities also affect the generation 

of refection-source OAEs. We will test this hypothesis experimentally by quantifying and comparing the effects 

of contralateral acoustic stimulation (CAS) on both DPOAEs and SFOAEs in the same human subjects. 

Methods. We will measure distortion- and refection-source OAEs in ∼20 normal-hearing young adults from 

0.5–8 kHz using fast swept-tone paradigms now well developed in our lab.21, 100–102 DPOAEs and SFOAEs 

at standard primary levels and frequency ratios (i.e., {L1, L2} = {62, 62} dB FPL, f2/ f1 = 1.22 for DPOAEs 

and {Lp, Ls} = {37, 52} dB FPL, fs/ fp = 1.05 for SFOAEs) will be measured both with and without activation 

of MOC efferents using CAS. The spectral level of the contralateral elicitor—wideband noise, spectrally fattened to constant FPL—will be kept below the activation threshold for the middle-ear muscle refex (MEMR), 

assayed using ipsilateral wideband refectance. Time-frequency analysis of the OAE spectra using continuous wavelet transforms will be used to identify and separate short- and long-latency components of the 

total emission (at both positive and negative delays). The results will be used to estimate source distribution 

functions (i.e., the spatial pattern of irregularities contributing to the emission), using analysis methods previously described. When measuring DPOAEs we need to distinguish long-latency components that arise 

via distortion sources from those arising as refection-source OAEs. We will do this by selectively removing 

refection-source OAEs from the total DPOAE in two independent ways and comparing the results for consistency: (i) By using a third stimulus tone (L3 = 52 dB FPL) close to the distortion-product (DP) frequency 

(2 f 1 − f2) to suppress refection-source OAEs arising near the peak of the DP traveling wave; and (ii) By 

mathematically decomposing the results of the time-frequency (wavelet-transform) analysis into time-symmetric 

and time-asymmetric components. Preliminary modeling results (see Background and Signifcance) predict 

that long-latency contributions to the distortion component should be nearly symmetric in time (i.e., contribute 

equally at positive and negative delays). Our comparisons will test these predictions. 

108 

15, 106, 107 

52 

87 

103–105 

The theoretical studies will use the cochlear models employed in Aim 2a, extended to include representations 

of cochlear nonlinearity as in Aim 1. As shown previously, the model reproduces the cochlear compression 

measured in basilar-membrane growth functions. Efferent activation will be simulated as in Aim 2a and will 

be assumed to modify the effective operating point of the saturating nonlinearity. We hypothesize that this 

irregularity will produce correlated spatial modulations in the amplitudes and phases of both distortion and 

refection components. As a check on the integrity of our results, time-domain solutions will be compared 

with solutions obtained both perturbatively (i.e., assuming the distortion components are small relative to the 

primary tones) and iteratively, using the quasi-linear method.30, 31, 109 

91 

Expected results, potential problems, alternative strategies. Consistent with the preliminary results, we expect 

that the strength of negative-delay components will vary with frequency and from subject to subject, and we 

will quantify correlations with other relevant metrics (audiometric and MEM thresholds, DPOAE and SFOAE 

levels, etc) as clues for understanding the variation across frequency and between subjects. Although the 

initial plan is to use standard stimulus parameters, measurements at a broader range of levels and frequency 

ratios will be made in a subset of subjects showing strong effects. We expect that source distribution functions 

inferred from the DPOAE and SFOAE measurements will be correlated, but shifted in frequency (since a placefxed source at location x affects the distortion component when CF(x) =∼ f2 and the refection component 

w n CF he (x) =∼ fSFOAE, where CF is the local characteristic frequency). Artifactual components with apparently 

negative delay in the time-frequency representation can be created both by discontinuities at the low- and highfrequency ends of the measured emission spectrum and by subject and measurement noise. To avoid these 

Contact PD/PI: Shera, Christopher Research Strategy Page 60
artifacts we will extend the measurements one-half octave below and above the frequency range of interest, 

employ spectral tapers to eliminate sharp discontinuities in the frequency domain, utilize stringent online 

artifact-rejection criteria, and analyze repeated measurements to guarantee that the relevant time-frequency 

features are robust and reproducible. 

Aim 3. Micromechanics of cochlear wave amplifcation and OAE generation 

Aim 3a. OAE generation in models with spatial feed-forward/feed-backward (FF/FB) amplifcation 

Rationale. Our preliminary work provides the means to address the implications of spatial FF/FB amplifcation 

for OAE generation with rigorous modeling and analysis. The obvious strategy of comparing the OAEs (if any) 

produced by models utilizing FF/FB amplifcation with those produced by classical, point-impedance models 

fails if naively applied. The problem is that changing the underlying mechanics of the amplifer almost invariably modifes the basic macromechanical responses of the model (e.g., the magnitude and phase of BM velocity 

responses), and these secondary changes, although unintended, also modify the OAEs, confounding any clear 

interpretation of the results. (The problem is similar to that encountered in genetic experiments in which modifying or knocking out a gene, such as that for prestin, has unintended consequences that then frustrate defnitive 

conclusions.110 ) Thus, to understand how OAE properties depend on the mechanisms of amplifcation, per se, 

one needs to control for changes in the traveling wave. Ideally, one wants to vary the unknown mechanics of the 

amplifer while leaving the known and measured macromechanical responses (e.g., BM velocity) unchanged. 

In preliminary studies, we have solved this problem and shown how to derive an FF/FB model with the same 

BM velocity pattern as a given classical model. The method employs an inverse method, and builds on our 

solution to a similar problem encountered when studying the effects of fuid dimensionality on the mechanisms 

of coherent refection.13 

Methods. Using our inverse method we will derive “response-matched” FF/FB models whose BM velocity 

responses are matched to those of the classical models we employed in earlier studies of coherent refection.

The models will be supplemented with micromechanical irregularities (“roughness”) to generate reverse traveling waves and refection-source otoacoustic emissions.

13 

We will determine how the amplitude and phase 

characteristics (e.g., phase-gradient delay) of the simulated OAEs depend on the normalized strength of the 

FF/FB forces and the spatial feed-forward/backward distance. By averaging the results across multiple in-silico 

“subjects” (i.e., different roughness patterns), we will determine statistical reliability and expected variance. We 

will compare the results with those obtained from classical models with the same BM responses and roughness patterns. Model responses will be solved using fnite differences and methods previously described and 

validated. We will employ both 1D and 2D models to investigate the dependence on long- and short-wave 

behavior and the transition between the two that occurs basal to the peak of the traveling wave. 

13 

12, 81 

Expected results, potential problems, alternative strategies. We expect to fnd that OAE properties (both amplitude and delay) depend systematically on the parameters of the FF/FB amplifer. Comparing the pattern 

of results to the known characteristics of OAEs will enable us to assess the contributions and possible limitations of the FF/FB mechanism and understand whether the principles of coherent refection generalize to 

nonclassical forms of cochlear amplifcation. In its simplest form, our inverse method exploits the fact that the 

feed-forward/backward distances produced by the anatomical tilt are generally no more than a few hair cells 

in extent (e.g., 20–30 μm) and are therefore small compared to the wavelength of the traveling wave. To extend 

and check our results, we can relax this approximation. Should we encounter any problems, we will adopt an 

alternative method for solving the inverse problem in non-classical models developed by de Boer. As always, 

we will attempt to compare our numerical results with analytic approximations whenever possible. Obtaining 

analytic results for FF/FB models will require care, since many familiar tools (e.g., the WKB approximation) 

implicitly assume isotropic wave propagation. 

61 

Aim 3b. Organ of Corti vibrational modes and OAE generation 

Rationale. The unexpected vibrational modes now evident in organ-of-Corti micromechanics may have important implications for current understanding of OAE generation. In Aim 3b we (i) obtain mechanical data 

from intact cochleae; (ii) analyze it using inverse methods applied in dual-mode cochlear models that include 

representations of both BM and RL motion to derive effective impedances and wavenumbers; and (iii) use the 

Contact PD/PI: Shera, Christopher Research Strategy Page 61
C 10' 

Contact PD/Pl: Shera, Christopher 

results to simulate the generation of reflection-source OAEs. We will determine how the results depend on the 

assumed coupling between BM and RL motion and the cochlear fluids and test the recent hypothesis that OAEs 

are better correlated to the motion of the RL. (For comparison, standard cochlear models couple the fluid to 

the motion of the BM.) Model assumptions will be tested against independent measures of this coupling by 

comparing the simulated OAEs with emissions recorded concurrently with the mechanical measurements. 

10 

Methods. All measurements will be made in wild-type adult CBA mice using procedures well developed in the 

Oghalai lab, whose experience suggests that high-quality data from ~20 mice will 

suffice for the inverse analysis and comparisons proposed here. In the OCT measure7121,

111 

ments, the apical turn of the cochlea (CF~ 10 kHz) is imaged through the bone. Highreflectivity points corresponding to structures of interest are identified from depth scans 

(A-scans) targeting the RL and BM, which are identified in cross-sectional images (OCT 

B-scans) of the partition (Fig. 6A). Because v ibratory data are derived from the phase of

the interference signal, the motion resolution of the system is much better than its image

resolution. Vibrometry and OAE data will be collected simultaneously in response

to three principal sets of stimuli: (i) swept tones at a variety of fixed intensities to measure BM and RL describing functions (20-80 dB SPL) and SFOAEs; (ii) pseudo-random

noise at corresponding spectral levels to measure BM and RL transfer functions in response to linearizing stimuli appropriate for inverse analysis; and (iii) pairs of

tones (!1,/2) swept at fixed ratio (f 2/fi) and level difference (L 1 - L2) to monitor cochlear 

health using DPOAEs. 0 Our preliminary data demonstrate the ability of OCT vibrometry, usually applied to sinusoidal stimuli (e.g., tones or tone complexes), to measure

BM and RL responses to wideband stimuli, such as clicks and noise (see Fig. 6B,C).

1 1

86,l14-l17

112,

113 

The vibratory data will first be analyzed to test the analyticity constraints recently 

hypothesized to be universal features of mammalian cochlear responses. The 

principal modeling studies will employ inverse methods adapted to the dual-mode 

modeling framework recently developed by Liu and Neely, which provides 

convenient representations of both BM and RL motion and their coupling to cochlear 

macromechanics (e.g., fluid motion). In this model, the relative motions of the BM and 

RL define the transfer function HoHC, which can be determined from the measurements. 

Simple modifications to the model equations allow fluid motion to couple to either the 

BM or RL. BM motion is determined by HoHC and an admittance YBM, whose empirical form can be determined using equations that depend on the assumed coupling. 

Reflection-source OAEs will be simulated by adding micromechanical irregularity to the 

impedances representing the BM and/ or RL. 

93,121 

31,

93,94,121

118-1 02

Expected results, potential problems, alternative strategies. Recent studies have shown that non-fluid coupling 

along the organ of Corti (e.g., via the tectorial membrane ) plays an important role in cochlear mechanics, and 

perhaps also in OAE generation. Although our long-term goal is to put everything together by studying and 

incorporating these additional modes of longitudinal coupling, our strategy here is to approach the problem 

systematically. We therefore begin by focusing on what we tentatively assume to be the dominant interaction: 

coupling between vibrational modes within a given radial cross-section. We expect direct mechanical coupling 

along the organ of Corti or tectorial membrane to be less important because the wavelength of the traveling wave 

is long compared to the distance between coupled elements and partition displacements and their longitudinal 

derivatives are small at low sound levels. More generally, the models we employ involve significant but strategic 

simplifications--necessarily so with respect to the living cochlea but also compared to models that provide 

more realistic representations of the anatomy and material properties.

5

These different modeling 

approaches are complementary and mutually informative; indeed, as borne out by the history of the field, both 

are necessary for understanding complex systems such as the cochlea. 

58 8 9 ,7 ,7 ,1 1 3 22, 2

Sex as a biological variable. We have no reason to expect significant sex differences in the basic mechanisms of cochlear function or OAE generation explored here. Nevertheless, for both the human and the mouse 

experiments we will strive for gender balance in the subject pool and analyze the data for possible correlations. 

Page 62 

Research Strategy 

Figure 6. OCT image of the 

mouse cochlear partition obtained in the Oghalai lab.

Dashed lines mark the optical axes for the RL (red) and

BM (blue) locations. Panel

B shows vibratory resp0nses

to wideband acoustic clicks

recorded from the BM and

RL. Panel C compares BM

gain functions measured using clicks and tones at four

stimulus levels. 
Progress Report 

This report covers the period from 1 March 2013 to 1 June 2018. Progress on the prior Specifc Aims produced 27 

original publications (22 journal articles and 5 peer-reviewed conference papers) and three reviews/book chapters, for a total of 30 publications. An additional 14 published abstracts present work currently in preparation or 

submitted for publication. The last competitive renewal included three Aims with hypotheses targeting relationships between OAEs and the form and time course of the cochlear nonlinearities underlying compression and 

suppression (Aim 1), the mechanisms of cochlear wave amplifcation and refection (Aim 2), and apical/basal 

differences in cochlear mechanics (Aim 3). Space constraints allow only a brief summary of major highlights. 

Pub numbers refer to the list Publications Supported by This R01. 

Progress on the Aims includes signifcant advances in the methodology for measuring and extracting information from OAEs. These advances are both central to the experimental studies of Aims 1 and 3 and of broad 

beneft to the feld. For example, we developed and characterized a new method for measuring SFOAEs using 

swept tones [Pubs 1,22]. The technique yields much higher frequency resolution and roughly an order of magnitude improvement in measurement effciency compared to conventional, discrete-tone paradigms. The new 

method greatly enhances the utility of SFOAEs in laboratory and feld studies; when implemented in commercial instruments, the method will enable clinical applications to exploit the advantages of SFOAE-based hearing 

assessment. In addition to developing the power of swept-tone SFOAEs, we determined optimal measurement 

and analysis protocols for recording swept-tone DPOAEs [Pub 9]. We also explained—and developed methods 

to circumvent—the previously confounding artifact that OAEs appear to depend on the rate and direction of 

the frequency sweep [Pub 14]. Finally, we developed and validated a method—emitted pressure level (EPL)— 

that resolves a long-standing diffculty: The reproducibility and diagnostic power of OAE measurements can 

be seriously compromised by the acoustics of the ear canal and transducer. The new procedure yields OAE 

measurements largely free of contamination by ear-canal acoustics, including biases introduced by variations 

in probe insertion depth [Pubs 15,42]. The use of emitted pressure provides a powerful way to reduce the 

variability of OAE measurements and thereby improve their ability to detect and differentiate cochlear changes. 

Work on all three Aims produced important new fndings. Studies of two-tone interactions and the roundwindow cochlear microphonic (CM) [Pubs 17,23,40] lead to a promising new diagnostic tool. Using a combination of models and measurements, we showed that the “residual CM” (rCM)—the difference between the 

CM measured with and without a suppressor tone—originate near the cochlear place tuned to the suppressor frequency. Thus, the rCM can serve as a sensitive indicator of OHC-dependent nonlinearity and cochlear 

gain, overcoming the poor place-specifcity of conventional CM measurements. Our studies of OAEs and their 

relationship to the active mechanisms responsible for shaping the cochlea’s mechanical response to sound focused on phenomena unexplained by most cochlear models. We showed that the complex temporal modulation 

apparent in the envelope of BM responses to acoustic clicks can be well explained by a process of iterated internal refection within the cochlea [Pub 10]. The same mechanisms of wave refection and interference underlie 

our unexpected prediction that the mammalian cochlear frequency-position map—usually regarded as smooth 

and continuous—actually manifests an emergent staircase-like structure comprising plateaus of nearly constant 

characteristic frequency (CF) separated by abrupt discontinuities [Pub 7]. Signifcantly, a similar stepwise tonotopy occurs along the main axis of the central nucleus of the inferior colliculus (CNIC). As in the CNIC, the step 

height of the cochlear map is approximately equal to the bandwidth of the auditory flter (critical band). To 

study the temporal dynamics of nonlinear suppression and compression in the cochlea, we have combined clickevoked OAEs (CEOAEs) with measurements and models of BM motion [Pubs 19,26,35,36,43,46]. Our results 

to date reveal an intriguing dichotomy whose implications we are still pursuing: Although cochlear responses 

to narrowband stimuli (beating tones) appear to require only instantaneous nonlinear damping, responses to 

broadband stimuli (clicks) suggest the existence of adaptive (history-dependent) cochlear nonlinearities such as 

automatic gain control. Finally, we characterized differences between the base and apex of the cochlea in human 

subjects using high-resolution maps of OAE phase extending 1–2 octaves lower in frequency than previous reports [Pubs 24,44]. The measurements corroborate the break in scaling near the midpoint of the human cochlea 

but also provide tantalizing evidence for the emergence of a second scaling region about two octaves closer to 

the apex. 

Contact PD/PI: Shera, Christopher Research Strategy Page 63
Publications Supported By This R01 

All papers are freely available online at the Auditory Physics Group website (apg.mechanicsofhearing.org). 

Original Reports Supported by this R01 (3/1/13–6/1/18) 

1. Kalluri R, Shera CA (2013) Measuring stimulus-frequency otoacoustic emissions using swept tones. J 

Acoust Soc Am 134:356–368 (PMC3732205) 

2. Abdala C, Guérit F, Luo P, Shera CA (2014) Distortion-product otoacoustic emission refection-component 

delays and cochlear tuning: Estimates from across the human lifespan. J Acoust Soc Am 134:1950–1958 

(PMC4167749) 

3. Marshall L, Lapsley Miller JA, Guinan JJ, Shera CA, Reed CM, Perez ZD, Delhorne LA, Boege P (2014) 

Otoacoustic emission-based medial-olivocochlear refex assays for humans. J Acoust Soc Am 136:2697– 

2713 (PMC5392105) 

4. Shera CA (2014) On the method of lumens. J Acoust Soc Am 136:3126–3131 (PMC4281039) 

5. Knudson IM, Shera CA, Melcher JR (2014) Increased contralateral suppression of distortion-product otoacoustic emissions indicates hyper-responsiveness of the medial olivocochlear system in humans with 

chronic tinnitus and hyperacusis. J Neurophysiol 112:3197–3208 (PMC4269714) 

6. Sisto R, Moleti A, Shera CA (2015) On the spatial distribution of different latency components of refectionsource otoacoustic emissions. J Acoust Soc Am 137:768–776 (PMC4336253) 

7. Shera CA (2015) The spiral staircase: Tonotopic microstructure and cochlear tuning. J Neurosci 35:4683– 

4690 (PMC4363394) 

8. Verhulst S, Bharadwaj HM, Mehraei G, Shera CA, Shinn-Cunningham BG (2015) Functional modeling 

of the human auditory brainstem response to broadband stimulation. J Acoust Soc Am 138:1637–1659 

(PMC4592442) 

9. Abdala C, Luo P, Shera CA (2015) Optimizing swept-tone protocols for recording distortion-product otoacoustic emissions in adults and newborns. J Acoust Soc Am 138:3717–3722 (PMC4691260) 

10. Shera CA (2015) Iterated intracochlear refection shapes the envelopes of basilar-membrane click responses. J Acoust Soc Am 138:3785–3799 (PMC5392059) 

11. Verhulst S, Shera CA (2015) Relating the variability of tone-burst otoacoustic emission and auditory brainstem response latencies to the underlying cochlear mechanics. In: Karavitaki KD, Corey DP, eds. Mechanics 

of Hearing: Protein to Perception. Melville, NY: American Institute of Physics, 090003:1–6 (PMC4862599) 

12. Alkhairy SA, Shera CA (2015) Increasing computational effciency of cochlear models using boundary layers. In: Karavitaki KD, Corey DP, eds. Mechanics of Hearing: Protein to Perception. Melville, NY: American 

Institute of Physics, 070017:1–6 (PMC4862608) 

13. Berezina-Greene MA, Guinan JJ (2015) Stimulus-frequency otoacoustic emission delays and generating 

mechanisms in guinea pigs, chinchillas, and simulations. J Assoc Res Otolaryngol 16:679–694 (PMC4636597) 

14. Shera CA, Abdala C (2016) Frequency shifts in distortion-product otoacoustic emissions evoked by swept 

tones. J Acoust Soc Am 140:936–944 (PMC5392090) 

15. Charaziak KK, Shera CA (2017) Compensating for ear-canal acoustics when measuring otoacoustic emissions. J Acoust Soc Am 141:515–531 (PMC5848844) 

16. Abdala C, Luo P, Shera CA (2017) Characterizing spontaneous otoacoustic emissions across the human 

lifespan. J Acoust Soc Am 141:1874–1886 (PMC5848845) 

17. Charaziak KK, Shera CA, Siegel JK (2017) Using cochlear microphonic potentials to localize peripheral 

hearing loss. Front Neurosci 11:169 (PMC5378797) 

18. Berezina-Greene MA, Guinan JJ (2017) Electrically evoked medial olivocochlear efferent effects on stimulusfrequency otoacoustic emissions in guinea pigs. J Assoc Res Otolaryngol 18:153–163 (PMC5243264) 

19. Altoè A, Charaziak KK, Shera CA (2017) Dynamics of cochlear nonlinearity: Automatic gain control or 

instantaneous damping? J Acoust Soc Am 142:3510–3519 

20. Gruters KG, Murphy DLK, Jenson CD, Smith DW, Shera CA, Groh JM (2018) The eardrums move when 

the eyes move: A multisensory effect on the mechanics of hearing. Proc Nat Acad Sci USA E1309–1318 

(PMC5819440) 

Contact PD/PI: Shera, Christopher Progress Report Publication List Page 64
21. Sisto R, Shera CA, Moleti A (2018) Negative-delay sources in distortion-product otoacoustic emissions. 

Hear Res 360:25–30 

22. Abdala C, Guardia YC, Shera CA (2018) Swept-tone stimulus-frequency otoacoustic emissions: Normative 

data and methodological considerations. J Acoust Soc Am 143:181–192 

23. Charaziak KK, Siegel JH, Shera CA (2018) Spectral ripples in round-window cochlear microphonics: Evidence for multiple generation mechanisms. J Assoc Res Otolaryngol , in press 

24. Christensen AT, Abdala C, Shera CA (2018) Probing apical-basal differences in the human cochlea using 

DPOAE phase. In: Bergevin C, Puria S, eds To the Ear and Back Again: Advances in Auditory Biophysics. 

Melville, NY: American Institute of Physics, 090006:1–6 

25. Moleti A, Sisto R, Shera CA (2018) Introducing causality violation for improved DPOAE component 

unmixing. In: Bergevin C, Puria S, eds To the Ear and Back Again: Advances in Auditory Biophysics. 

Melville, NY: American Institute of Physics, 090008:1–5 

26. Charaziak KK, Dong W, Shera CA (2018) Temporal suppression of clicked-evoked otoacoustic emissions 

and basilar-membrane motion in gerbils. In: Bergevin C, Puria S, eds To the Ear and Back Again: Advances 

in Auditory Biophysics. Melville, NY: American Institute of Physics, 090001:1–9 

27. Abdala C, Ortmann AJ, Shera CA (2018) Refection- and distortion-source otoacoustic emissions: Evidence 

for increased irregularity in the human cochlea during aging. J Assoc Res Otolaryngol , in press 

Review Articles and Book Chapters Supported by this R01 

28. Shera CA (2015) Macromechanics of hearing: The unknown known. In: Karavitaki KD, Corey DP, eds. 

Mechanics of Hearing: Protein to Perception. Melville, NY: American Institute of Physics, 020002:1–2 

(PMC5019571) 

29. Abdala C, Winter M, Shera CA (2016) Otoacoustic emissions in infants and children: An updated approach. In: Tharpe AM, Seewald R, eds. Comprehensive Handbook of Pediatric Audiology, Second Edition. San Diego: Plural Publishing, 475–504 

30. Shera CA, Charaziak KK (2018) Cochlear frequency tuning and otoacoustic emissions. Cold Spring Harb 

Perspect Med, in press 

Dissertations Supported by this R01 

31. Alkhairy SA (2016) Development of cochlear models with high computational effciency by using spatial 

and parametric transformations. MS Dissertation, Department of Electrical Engineering and Computer 

Science, Massachusetts Institute of Technology 

32. Alkhairy SA (2017) An analytic model of the cochlea and its functional interpretations. PhD Dissertation, 

Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology 

Abstracts of Work Supported by this R01: Projects Pending Submission 

33. Sumner CJ, Wells TT, Bergevin C, Palmer AR, Oxenham AJ, Shera CA (2014) Comparing otoacoustic, 

auditory-nerve, and behavioral estimates of cochlear tuning in the ferret. Assoc Res Otolaryngol Abs 

37:PD017 

34. Alkhairy A, Shera CA (2015) Two forms of longitudinal coupling in the cochlea. Assoc Res Otolaryngol 

Abs 38:PS359 

35. Charaziak KK, Shera CA (2015) Measuring temporal suppression of clicked-evoked otoacoustic emissions 

at high frequencies. Assoc Res Otolaryngol Abs 38:PS481 

36. Charaziak KK, Shera CA (2016) Temporal suppression of click-evoked otoacoustic emissions measured 

over a wide frequency range. Assoc Res Otolaryngol Abs 39:PS666 

37. Abdala C, Luo P, Shera CA (2016) Comparison of methods for DPOAE component unmixing. Assoc Res 

Otolaryngol Abs 39:PS664 

38. Sisto R, Moleti A, Shera CA (2016) Basilar-membrane phase response in nonlinear transmission-line models. Assoc Res Otolaryngol Abs 39:PS136 

39. Berezina-Greene M, Shera CA (2016) Physiologically based simulation of MOC effects on SFOAEs. Assoc 

Res Otolaryngol Abs 39:PS866 

Contact PD/PI: Shera, Christopher Progress Report Publication List Page 65
40. Charaziak KK, Shera CA, Siegel JH (2016) Susceptibility of stimulus-frequency otoacoustic emissions and 

cochlear microphonics to acoustic trauma. Assoc Res Otolaryngol Abs 39:PS184 

41. Bharadwaj H, Varghese L, Mehraei G, Shera CA, Shinn-Cunningham BG (2016) Evidence of auditorynerve contribution to individual differences in suprathreshold brainstem temporal coding. Assoc Res Otolaryngol Abs 39:PS305 

42. Charaziak KK, Shera CA (2017) Effects of ear-canal acoustics on sound calibration and otoacousticemission measurements. Assoc Res Otolaryngol Abs 40:PS86 

43. Charaziak KK, Dong W, Altoè A, Shera CA (2018) Temporal interactions in basilar-membrane and otoacousticemission responses to pairs of clicks Assoc Res Otolaryngol Abs 41:PS465 

44. Christensen AT, Abdala C, Shera CA (2018) Phase characteristics of low-frequency distortion emissions in 

humans. Assoc Res Otolaryngol Abs 41:PS760 

45. Meenderink SWR, Shera CA, Valero MD, Liberman MC, Abdala C (2018) Neonatal morphology of the 

apical half of the human cochlea. Assoc Res Otolaryngol Abs 41:PS942 

46. Verhulst S, Altoè A, Raufer S, Charaziak KK, Shera CA (2018) Temporal dynamics of the generator of 

stimulated otoacoustic emissions. J Acoust Soc Am 143:1811 

Contact PD/PI: Shera, Christopher Progress Report Publication List Page 66
PHS Human Subjects and Clinical Trials Information OMB Number: 0925-0001 and 0925-0002

Expiration Date: 03/31/2020

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Are Human Subjects Involved ● Yes ❍ No

Is the Project Exempt from Federal regulations? ❍ Yes ● No

❏ 1 ❏ 2 ❏ 3 ❏ 4 ❏ 5 ❏ 6 ❏ 7 ❏ 8 Exemption Number 

Other Requested Information 

Contact PD/PI: Shera, Christopher Page 67
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Human Subject Studies 

Study# Study Title Clinical Trial? 

1 Understanding Otoacoustic Emissions No 

Contact PD/PI: Shera, Christopher Page 68
OMB Number: 0925-0001 and 0925-0002

Expiration Date: 03/31/2020

Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Section 1 - Basic Information (Study 1) 

1.1. Study Title * 

Understanding Otoacoustic Emissions 

1.2. Is this study exempt from Federal ❍ Yes ● No Regulations * 

1.3. Exemption Number ❏ 1 ❏ 2 ❏ 3 ❏ 4 ❏ 5 ❏ 6 ❏ 7 ❏ 8

1.4. Clinical Trial Questionnaire * 

1.4.a. Does the study involve human participants? ● Yes ❍ No

1.4.b. Are the participants prospectively assigned to an intervention? ❍ Yes ● No

1.4.c. Is the study designed to evaluate the effect of the intervention on the ❍ Yes ● No participants? 

1.4.d. Is the effect that will be evaluated a health-related biomedical or ❍ Yes ● No behavioral outcome? 

1.5. Provide the ClinicalTrials.gov Identifier (e.g. 

NCT87654321) for this trial, if applicable 

Contact PD/PI: Shera, Christopher Page 69
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Section 2 - Study Population Characteristics (Study 1) 

2.1. Conditions or Focus of Study

2.2. Eligibility Criteria

2.3. Age Limits Min Age: 18 Years Max Age: N/A (No limit)

2.4. Inclusion of Women, Minorities, and Children Shera_Inclusion_of_Women__Minotities_and_Children1012773848.pdf

2.5. Recruitment and Retention Plan Shera_Recruitment_Retention1012773858.pdf

2.6. Recruitment Status Recruiting

2.7. Study Timeline

2.8. Enrollment of First Subject 04/01/2019 Anticipated

Contact PD/PI: Shera, Christopher Page 70
Contact PD/Pl: Shera, Christopher 

Page 71 

Inclusion of Women, Minorities, and Children 

Inclusion of Women, Minorities, and Children 

We will use adults age 18 and older. The reason for excluding children under 18 is that our 

experiments require that subjects sit quietly and nearly motionless while the acoustic measurements 

are being made; too much noise and/or movement by the subject invalidates the measurement. Even 

certain adults have a difficult time remaining sufficiently still and relaxed. 

Targeted/planned distribution of subjects: Our targeted mix with regard to gender, ethnic,

and racial categories is based on the representation of these categories in the , 

area. Our Targeted Enrollment Table reflects the composition of the area based

on year 2010/2015 census statistics. 

Rationale for gender and racial/ethnic targets: Women have larger otoacoustic emissions than 

men and are therefore preferred on technical grounds. Despite this preference for women, we will 

strive to achieve a representative mix of genders. 

There is no known reason to expect differences in our results due to ethnic or racial categories. 

We will strive to achieve a representative mix with regard to ethnic and racial categories based 

on the representation of these categories 

Rationale for exclusions: We propose no exclusions. 

Proposed outreach programs: We generally have no trouble obtaining a good sampling 

of minorities. If we fall short in achieving representative samples in an ethnic or gender category, we 

will seek help in recruiting from the offices of minority affairs and recruit more subjects from 

the staff and hospital visitors. 
Inclusion Criteria: To provide useful data, our subjects must have normal hearing, good otoacoustic 

emissions, and be able to sit quietly for the duration of the measurements while following simple

directions (e.g., responding with appropriate button presses when sounds are presented). Criteria 

such as good otoacoustic emissions can only be assessed after the subject has consented and initial 

screening measurements performed. Subjects in this category would be officially enrolled in the study

but the otoacoustic data collected from them would be minimal and would not be used in subsequent

analyses.

Most adults below the age of 40 or so fit our criteria. Thus, there is a very large population from which 

we can draw for these tests. Normal hearing adult subjects will be recruited from student body 

and from nearby universities Recruitment is done by personal contacts, email,

and internet (e.g., via the lab website). Research staff will also invite participation through classroom 

visits. 

When not all tests can be completed within the allotted time (typically 1–2 hours), or when additional 

tests seem warranted, we will ask subjects at the conclusion of a session whether they are available

for additional measurement sessions. If we are unable to arrange additional sessions in person, we 

may contact a subject via email to ask if they are interested in volunteering for additional 

measurements. 

Exclusion Criteria: We exclude non-adult subjects or subjects with hearing loss. Subjects with

hearing loss usually have weak or unmeasurable OAEs. Subjects younger than 18 years of age often 

have difficulty sitting quietly during the session and are more difficult to measure. Although not 

technically excluded, subjects over ~40 often have otoacoustic emissions that are too weak and they 

are therefore less desirable for our study.

Withdrawal Criteria: Participants are free to withdraw from the study at any time. Most often,

sufficient data are obtained in a single measurement session. When additional data are desired,

subjects are invited to participate in additional sessions. Subjects who do not meet the criteria for 

providing useful data (e.g., good otoacoustic emissions, ability to sit still) are not invited back.

Contact PD/PI: Shera, Christopher Recruitment and Retention Plan Page 72
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Inclusion Enrollment Reports 

IER ID# Enrollment Location Type Enrollment Location

Study 1, IER 1 Domestic University of Southern California

Contact PD/PI: Shera, Christopher Page 73
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

Inclusion Enrollment Report 1 

Using an Existing Dataset or Resource* : ● Yes ❍ No

Enrollment Location Type* : ● Domestic ❍ Foreign

Enrollment Country(ies): USA: UNITED STATES

Enrollment Location(s): University of Southern California

Comments: As of 1 June 2018

Planned 

Racial Categories 

Ethnic Categories 

Not Hispanic or Latino 

Female Male 

Hispanic or Latino 

Female Male 

Total 

American Indian/ 

Alaska Native 0 0 0 0 0 

Asian 0 0 0 0 0 

Native Hawaiian or 

Other Pacific Islander 0 0 0 0 0 

Black or African 

American 0 0 0 0 0 

White 0 0 0 0 0 

More than One Race 0 0 0 0 0 

Total 0 0 0 0 0 

Cumulative (Actual) 

Racial Categories 

Ethnic Categories 

Not Hispanic or Latino 

Female Male 

Unknown/ 

Not 

Reported 

Hispanic or Latino 

Female Male 

Unknown/ 

Not 

Reported 

Unknown/Not 

Reported Ethnicity 

Female Male 

Unknown/ 

Not 

Reported 

Total 

American Indian/ 

Alaska Native 0 0 0 0 0 0 0 0 0 0 

Asian 8 8 0 0 0 0 0 0 0 16 

Native Hawaiian or 

Other Pacific Islander 0 0 0 0 0 0 0 0 0 0 

Black or African 

American 5 0 0 0 0 0 0 0 0 5 

White 13 8 2 4 1 0 0 0 0 28 

More than One Race 3 0 0 0 0 0 0 0 0 3 

Unknown or 

Not Reported 2 0 0 4 3 0 0 0 1 10 

Total 31 16 2 8 4 0 0 0 1 62 

Contact PD/PI: Shera, Christopher Page 74 2018-06-30T00:58:58.000-04:00 
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Section 3 - Protection and Monitoring Plans (Study 1) 

3.1. Protection of Human Subjects Shera_Human_Subjects1012773846.pdf

3.2. Is this a multi-site study that will use the same protocol to

conduct non-exempt human subjects research at more than one

domestic site?

❍ Yes ● No ❍ N/A

If yes, describe the single IRB plan 

3.3. Data and Safety Monitoring Plan Shera_Data_Safety_and_Monitoring1012773906.pdf

3.4. Will a Data and Safety Monitoring Board be appointed for

this study?

❍ Yes ● No

3.5. Overall structure of the study team

Contact PD/PI: Shera, Christopher Page 75
Protections for Human Subjects 

Risks to Human Subjects 

Human subjects involvement and characteristics: Human subjects will be involved in Aims 1 and 

2. All human subjects research will be performed in the Auditory Research Center on the

medical campus and/or on the adjacent campus; there are no collaborating sites. We will

use adult subjects in good general health with normal hearing. The work involves no special classes of

subjects.

We have no reason to expect differences in our results due to ethnic or racial categories, but women 

have larger otoacoustic emissions than men and are therefore preferred on technical grounds. Despite 

this preference, we will strive to achieve a representative mix of genders and ethnic backgrounds. 

Because of the general decline in hearing with age, and consequent difficulty in recording OAEs, we 

will prefer young adults in their 20’s and 30’s. However, since we wish to have a representative 

population, older subjects with measurable OAEs will also be included. 

We expect to use about 75–100 subjects total over the five years of the proposed work. This number 

is based on past experience and a basic comparison unit of 20–25 subjects for each experiment. 

Additional subjects (10–20) will be used to develop, test, and revise experimental paradigms. Most 

subjects participate in multiple measurement sessions. The majority of our subjects are students 

whose availability varies from one semester to the next. Although some subjects participate over 

several semesters, many cannot and we need to continually recruit new subjects. 

Our study involves only adult subjects with normal hearing thresholds (i.e., thresholds within 20 dB of 

normal and with no other known hearing pathology). Subjects with hearing thresholds outside of this 

range, or who do not have measurable OAEs, will be excluded. No other specific subpopulations will 

be excluded. 

Sources of materials: We will not obtain physical specimens from any subject. Neither will we obtain 

any part of their medical record. Subjects will be asked to fill out a questionnaire regarding (i) any past 

or present hearing issues; (ii) their handedness; and (iii) their age, ethnicity, and other information per 

NIH guidelines. 

Data collection involves measuring the subject's audiogram to determine hearing status and using 

insert earphones to record the subject's middle-ear reflectance and otoacoustic emissions (OAEs). 

The data are coded and subsequently identified only by subject number. The only connection 

between a subject’s name, birth date, or other identifying information is via a secured written file. 

Access to this file is available only to the PI and to any co-investigator (e.g., graduate student, 

postdoctoral fellow) who is actively working on the project. 

Potential risks: There are essentially no risks to the proposed measurements, all of which are very 

similar to standard clinical procedures. The proposed measurements involve listening to sounds 

presented by earphones held in the ear canal by foam or rubber plugs. The sounds presented will all 

be of low to moderate intensity, well within the guidelines of the Occupational Safety and Health 

Administration for acoustic stimuli. Subjects are reimbursed for their time, parking, and/or other 

transportation fares for their participation and incur no financial or legal risks. 

Adequacy of Protection Against Risks 

Recruitment and informed consent: Subjects will normally be recruited from personal contacts 

―principally employees of the School of Medicine and students Informed consent is 

obtained by the experimenter running the tests (i.e., by the PI, Research Associate, or Postdoctoral 

Fellows) when the subject comes to the laboratory. After prospective subjects read our informed 

consent form, we explain to them what the research is all about and what the measurements are like. 

We show them the sound booth and the chair that they will sit in, as well as the foam plug and inset 

earphone that will be put in their ear canal. We answer any questions they have. They then sign the 

informed consent form, the HIPPA form, the receipt of privacy notice, and they fill out our 

Contact PD/PI: Shera, Christopher Protection of Human Subjects Page 76

 

 
questionnaire. No wavers of any elements of the informed consent will be sought. 

Protection against risks: There are essentially no risks to our procedures and no special procedures 

are needed to prevent risk. The measurements employ only low to moderate sound intensities well 

within the range of sounds encountered in daily life and/or during clinical hearing tests. The equipment 

that drives the earphones has been electronically limited so that the highest possible output is 90–100 

dB SPL. Subject identity will be coded by giving each subject a number and having all records from a 

subject stored and referred to only by the subject number. These measures should be adequate to 

insure essentially zero risk for hearing damage and to guarantee subject confidentiality. None of the 

proposed research involves vulnerable populations. 

It is extremely unlikely that any harmful effects will result from this study. However, each subject will be 

given a copy of the consent form, which provides telephone numbers of the investigators and contact 

information for the local IRB. This information will allow subjects to report anything they feel has been 

a harmful effect of participating in the study. Should any substantial claim arise, the relevant 

committees will be informed. 

Potential Benefits of the Proposed Research to Human Subjects and Others 

Potential benefits: Although we anticipate no particular benefit to individual subjects, we expect both 

scientific and clinical benefits to society that accrue from providing a better understanding of OAEs 

and cochlear function. In addition to helping develop improved clinical hearing tests for the future, our 

work should aid in understanding and interpreting current OAE tests. Improved understanding of 

normal cochlear function should also benefit the design of preprocessors for speech-recognition 

systems and hearing aids. 

Risks in relation to benefits: The risks to subjects are minimal, and are certainly reasonable relative 

to the expected scientific and clinical value to society. 

Contact PD/PI: Shera, Christopher Protection of Human Subjects Page 77
Data Safety and Monitoring 

This study is not a clinical trial and therefore no formal data safety and monitoring plan is required. 

Although most of the issues addressed by such a plan are not pertinent to the application, a few are 

relevant to all studies involving human subjects. 

Data collection and management: Obtaining informed consent and all data collection are conducted 

in the Auditory Physics Group’s sound-attenuated booths at the Auditory Research Center and/or 

Medical Center. The data collected are in the form of acoustic measurements from the ear 

canal of each subject. Data are coded with a combination of letters and numbers unrelated to the 

subject’s name or other identifying information, such as the date the subject came in for testing. Once 

data are collected, they are no longer referred to or linked with any Private Health Information (PHI), 

such as the informed consent forms. Data are analyzed and managed using databases on passwordprotected computers and by written notation in lab notebooks. These notebooks and databases do not 

contain any patient identifiers, only the de-identified subject label. 

Data storage: Data are stored on password-protected computers, in lab notebooks, and on paper 

hard copies. Electronic de-identified data are transferred securely (e.g., via secure wireless 

connections or via password-protected portable flash drives) to a separate password-protected 

computer for analysis. Lab notebooks and paper hard copy files of the data are stored in a locked filing 

cabinet in the office of the Principal Investigator or study personnel. The subject key linking a subject’s 

PHI (informed consent) and the coded subject number is kept separate from the data in the locked 

files of the Principal Investigator (PI). Only the PI and study co-investigators have access to these 

files. 

Data monitoring: The PI and study co-investigators monitor the study for any safety concerns related 

to participants. The investigators regularly review overall assessment of data collection, the number of 

subjects tested, the number of sessions resulting in successful data collection, any issues with data 

collection, any problems with the equipment or software, and any comments or concerns voiced by 

study participants. Weekly lab meetings are held between all those involved in the project. The PI and 

co-investigators are responsible for reporting any adverse events to the IRB. 

Contact PD/PI: Shera, Christopher Data and Safety Monitoring Plan Page 78
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Section 4 - Protocol Synopsis (Study 1) 

4.1. Brief Summary

4.2. Study Design

4.2.a. Narrative Study Description

4.2.b. Primary Purpose

4.2.c. Interventions

Type Name Description 

4.2.d. Study Phase

Is this an NIH-defined Phase III Clinical Trial? ❍ Yes ❍ No

4.2.e. Intervention Model

4.2.f. Masking ❍ Yes ❍ No

❏ Participant ❏ Care Provider ❏ Investigator ❏ Outcomes Assessor

4.2.g. Allocation 

4.3. Outcome Measures

Type Name Time Frame Brief Description 

4.4. Statistical Design and Power

4.5. Subject Participation Duration

4.6. Will the study use an FDA-regulated intervention? ❍ Yes ❍ No

4.6.a. If yes, describe the availability of Investigational

Product (IP) and Investigational New Drug (IND)/

Investigational Device Exemption (IDE) status

4.7. Dissemination Plan 

Contact PD/PI: Shera, Christopher Page 79
Tracking Number: GRANT12665698 Funding Opportunity Number: PA-18-484 Received Date: 

2018-06-30T00:58:58.000-04:00 

Delayed Onset Studies 

Delayed Study Title Anticipated Clinical Justification 

Onset Trial? 

Study# 

The form does not have any delayed onset studies 

Contact PD/PI: Shera, Christopher Page 80
Vertebrate Animals 

Proposed use of animals: We will use mice to perform acute experiments for the research proposed in Aim 3. 

Most mice to be studied will be adults, ranging in age from (P28) through three months of age. We anticipate 

the use of ~30 mice total for this research. 

Justification: Animals are needed for these experiments because we seek basic knowledge that can only be 

obtained from a mammalian cochlea that is working normally and because we need to do invasive procedures 

(e.g., measuring the motions of the organ of Corti). Although we currently lack the basic knowledge necessary 

to construct comprehensive and realistic computer models of the auditory periphery, one of the long-term goals 

of our work is to make the measurements necessary to construct and test such a model. In addition, our work 

has a strong theoretical and modeling component that sharpens the experiments and helps reduce the number 

of animals required. There is ample evidence in the scientific literature demonstrating that mammalian 

cochleae cannot be maintained in good physiological condition using in vitro or ex vivo techniques. Cochlear 

amplification, which is characteristic of physiologically normal cochleae, has never been observed in vitro, for 

example. Since all of the main objectives in this proposal depend on the presence of cochlear amplification 

(i.e., of normal hearing), the only way to achieve the objectives is to perform experiments on living animals. In 

order to ensure that the answers obtained will be of direct relevance to human hearing, the animals have to be 

mammals. Because there is very little evidence that anesthesia has any direct effects on the cochlea, the 

experimental animals do not have to be either awake or behaving in order for us to study the processes of 

relevance to this project. This point is immensely fortuitous, as the only way to expose the cochlea for 

experimental studies without pain is to use surgical levels of anesthesia. All of the experiments to be performed 

in this project are to performed under deep surgical anesthesia, and none of them involve recovery from this 

anesthesia. We are using mice because their cochleae and hair cells use mechanisms that are similar to those 

found in humans. Thus, the results of this research will have general applicability to other mammalian species, 

including humans. In addition, mice offer the flexibility of using genetically identical as well as transgenic 

animals. 

We expect that roughly 75–90% of our experiments will involve animals with good hearing and yield data 

suitable for use in publications. (Poor hearing results mostly from surgical difficulties, especially cochlear 

damage incurred during surgery.) Animals with poor hearing are used for developing experimental techniques 

and paradigms. High quality data from 20 mice should prove sufficient to test the hypotheses set out 

elsewhere. Our hypotheses are not statistical in nature (e.g., we are not looking for differences between groups 

of animals) and do not require data sets from many animals. Thus, the number of animals to be used is based 

not on statistical criteria but on our estimate of the number of good experiments needed to establish the 

reliability and reproducibility of our findings. In addition, we sometimes have unexpected loss of animals during 

anesthesia or when housed in the animal facility. We have supplemented our estimates to account for these 

issues. 

Veterinary care: Animals are purchased and housed until the day of the experiment by the Center for 

Comparative Medicine. A mouse facility is located in the basement of our research building. The animal services 

facilities are accredited by the American Association for Accreditation of Animal Laboratory Care (AAALAC). The 

facilities comply with Federal Law (89-544, 91-579) and meet NIH guidelines for the humane and appropriate care 

of laboratory animals. 

Anesthesia and analgesia: All experiments are acute and the animal is kept fully anesthetized throughout the 

experiment. This regimen will include an IP injection of ketamine hydrochloride (80–100 mg/kg) and xylazine 

hydrochloride (5–10 mg/kg). No invasive procedures will be done until surgical anesthesia is reached. The 

depth of anesthesia will be assessed at 15 minute intervals with a paw pinch test. Supplemental doses of 

anesthetic will be administered at 1/4 the induction dose to maintain areflexia. The animal's body temperature 

will be maintained at 38–39°C using a rectal probe and an electric heating pad. Mice undergoing invasive 

surgical procedures will be euthanized following the procedure as described below. 

Euthanasia: At the end of an experiment, animals are killed humanely, without recovery from anesthesia, by 

cervical dislocation after the mouse has been anesthetized by ketamine/zylazine as described above. This 

method is painless, easy to perform, and IACUC approved. It is consistent with the recommendations of the 

Panel on Euthanasia of the American Veterinary Medical Association. 

Contact PD/PI: Shera, Christopher Vertebrate Animals Page 81
Select Agents 

Not applicable to this application. 

Contact PD/PI: Shera, Christopher Select Agent Research Page 82
Contact PD/Pl: Shera, Christopher 

Literature Cited 

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USA 111, 14548-14552 (2014). 

[2] Motallebzadeh, H., Soons, J., and Puria, S. Cochlear amplification and tuning depend on the cellular 

arrangement within the organ of Corti. Proc. Natl. Acad. Sci. USA, in press (2018). 

[3] Shera, C. A. and Cooper, N. P. Basilar-membrane interference patterns from multiple internal reflection 

of cochlear traveling waves. J Acoust Soc Am 133, 2224-2239 (2013). 

[4] Fisher, J. A., Nin, F., Reichenbach, T., Uthaiah, R. C., and Hudspeth, A. J. The spatial pattern of cochlear 

amplification. Neuron 76, 989-997 (2012). 

[5] Ghaffari, R., Aranyosi, A. J., and Freeman, D. M. Longitudinally propagating traveling waves of the 

mammalian tectorial membrane. Proc Natl Acad Sci USA 104, 16510-16515 (2007). 

[6] Chen, F., Zha, D., Fridberger, A., Zheng, J., Choudhury, N., Jacques, S. L., Wang, R. K., Shi, X., and Nuttall, 

A. L. A differentially amplified motion in the ear for near-threshold sound detection. Nat. Neurosci. 14, 

770-774 (2011). 

[7] Lee, H. Y., Raphael, P. D., Park, J., Ellerbee, A. K., Applegate, B. E., and Oghalai, J. S. Noninvasive in 

vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in 

the mouse cochlea. Proc Natl Acad Sci USA 112, 3128-3133 (2015). 

[8] Ren, T., He, W., and Kemp, D. T. Reticular lamina and basilar membrane vibrations in living mouse 

cochleae. Proc Natl Acad Sci USA 113, 9910-9915 (2016). 

[9] van der Heijden, M. and Versteegh, C. P. Energy flux in the cochlea: Evidence against power amplification 

of the traveling wave. J Assoc Res Otolaryngol 16, 581-597 (2015). 

[10] Siegel, J. H. Does reticular lamina active gain explain broad suppression tuning of SFOAEs? In To the 

Ear and Back Again: Advances in Auditory Biophysics, Bergevin, C. and Puria, S., editors, 140003:1-5. 

American Institute of Physics, Melville, NY (2018). 

[11] Shera, C. A. The spiral staircase: Tonotopic microstructure and cochlear tuning. J Neurosci 35, 4683-4690 

(2015). 

[12] Zweig, G. and Shera, C. A. The origin of periodicity in the spectrum of evoked otoacoustic emissions. J 

Acoust Soc Am 98, 2018-2047 (1995). 

[13] Shera, C. A., Tubis, A., and Talmadge, C. L. Coherent reflection in a two-dimensional cochlea: Short-wave 

versus long-wave scattering in the generation of reflection-source otoacoustic emissions. J Acoust Soc Am 

118, 287-313 (2005). 

[14] Shera, C. A. and Guinan, J. J. Evoked otoacoustic emissions arise by two fundamentally different mechanisms: A taxonomy for mammalian OAEs. J Acoust Soc Am 105, 782-798 (1999). 

[15] Kalluri, R. and Shera, C. A. Distortion-product source unmixing: A test of the two-mechanism model for 

DPOAE generation. J Acoust Soc Am 109, 622-637 (2001). 

[16] Shera, C. A. and Guinan, J. J. Cochlear traveling-wave amplification, suppression, and beamforming 

probed using noninvasive calibration of intracochlear distortion sources. J Acoust Soc Am 121, 1003-1016 

(2007). 

[17] Shera, C. A., Guinan, J. J., and Oxenham, A. J. Revised estimates of human cochlear tuning from otoacoustic and behavioral measurements. Proc Natl Acad Sci USA 99, 3318-3323 (2002). 

[18] Shera, C. A., Guinan, J. J., and Oxenham, A. J. Otoacoustic estimation of cochlear tuning: Validation in 

the chinchilla. J Assoc Res Otolaryngol 11, 343-365 (2010). 

[19] Joris, P. X., Bergevin, C., Kalluri, R., Mc Laughlin, M., Michelet, P., van der Heijden, M., and Shera, C. A. 

Frequency selectivity in Old-World monkeys corroborates sharp cochlear tuning in humans. Proc Natl 

Acad Sci USA 108, 17516-17520 (2011). 

Page 83 

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[20] Abdala, C., Guerit, F., Luo, P., and Shera, C. A. Distortion-product otoacoustic emission reflectioncomponent delays and cochlear tuning: Estimates from across the human lifespan. J Acoust Soc Am 134, 

1950-1958 (2014). 

[21] Kalluri, R. and Shera, C. A. Measuring stimulus-frequency otoacoustic emissions using swept tones. J 

Acoust Soc Am 134, 356-368 (2013). 

[22] Charaziak, K. K. and Shera, C. A. Compensating for ear-canal acoustics when measuring otoacoustic 

emissions. J Acoust Soc Am 141, 515-531 (2017). 

[23] Kemp, D. T. and Chum, R. A. Observations on the generator mechanism of stimulus frequency acoustic 

emissions - Two tone suppression. In Psychophysical Physiological and Behavioural Studies in Hearing, 

Brink, G. V. D. and Bilsen, F. A., editors, 34-42. Delft University Press, Delft (1980). 

[24] Guinan, J. J. Changes in stimulus frequency otoacoustic emissions produced by two-tone suppression and 

efferent stimulation in cats. In Mechanics and Biophysics of Hearing, Dallos, P., Geisler, C. D., Matthews, 

J. W., Ruggero, M. A., and Steele, C. R., editors, 170-177. Springer-Verlag, New York (1990). 

[25] Kalluri, R. and Shera, C. A. Comparing stimulus-frequency otoacoustic emissions measured by compression, suppression, and spectral smoothing. J Acoust Soc Am 122, 3562-3575 (2007). 

[26] Siegel, J. H., Temchin, A. N., and Ruggero, M. A. Empirical estimates of the spatial origin of stimulusfrequency otoacoustic emissions. Assoc Res Otolaryngol Abs 26, 679 (2003). 

[27] Siegel, J. H. Local and propagating components of stimulus frequency otoacoustic emissions. Assoc Res 

Otolaryngol Abs 29, 54 (2006). 

[28] Baiduc, R., Charaziak, K. K., and Siegel, J. H. Spatial distribution of stimulus-frequency otoacoustic 

emissions generators in humans. Assoc Res Otolaryngol Abs 35, 398 (2012). 

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Resource Sharing 

We will share the results of our work with the research community through peer-reviewed publications 

(approximately 3/yr) and presentations at international conferences, such as the meetings of the 

Association for Research in Otolaryngology, the Acoustical Society of America, and the Mechanics of 

Hearing Workshops (2/yr). Should journal space constraints preclude full descriptions of the 

experimental methods, the data analysis procedures, and/or the models and their parameters, we will 

make the necessary details and the corresponding computer software freely available on the lab 

website (apg.mechanicsofhearing.org) and/or via web-based software sharing and development 

platforms, such at GitHub. Data collected during the course of this project, de-identified to ensure the 

privacy of study participants, will also be made available (e.g., via the Auditory Physics Group 

Dataverse at the Harvard Dataverse Project). 

Contact PD/PI: Shera, Christopher Resource Sharing Plan(s) Page 90
Authentication of Key Biological and/or Chemical Resources 

Contact PD/PI: Shera, Christopher Authentication of Key Biological and/or Chemical Resources

Mice: This study involves the use of wild-type CBA but neither transgenic nor mutant mice. Animal 

husbandry adheres to USC IACUC policy. Breeding takes place within the mouse facility by trained 

personnel, and records of each mating are kept so that mouse lines can be accurately maintained. 

Although not relevant here, transgenic lines are genotyped by qPCR according to standard 

procedures to assure integrity of the transgenic strain. 

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