SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communication ) Release Date: 10/23/2018 

Revised Date: 

Application Number: 2 R01 DC003687-22A1 

Principal Investigator 

SHERA, CHRISTOPHER A 

Applicant Organization: 

Review Group: AUD 

Auditory System Study Section 

Meeting Date: 10/11/2018 

Council: JAN 2019 

Requested Start: 04/01/2019 

Project Title: Understanding Otoacoustic Emissions 

SRG Action: Impact Score:20 Percentile:3 

RFAIPA: PA18-484 

PCC: HRS0 

Next Steps: Visit https://grants.nih.gov/grants/next_steps.htm 

Human Subjects: 30-Human subjects involved - Certified, no SRG concerns

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted

Gender: 1A-Both genders, scientifically acceptable 

Minority: 1A-Minorities and non-minorities, scientifically acceptable 

Children: 3A-No children included, scientifically acceptable 

Project 

Year 

22 

23 

24 

25 

26 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

BUDGET MODIFICATIONS 

SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communication ) Release Date: 10/23/2018 

Revised Date: 

Application Number: 2 R01 DC003687-22A1 

Principal Investigator 

SHERA, CHRISTOPHER A 

Applicant Organization: 

Review Group: AUD 

Auditory System Study Section 

Meeting Date: 10/11/2018 

Council: JAN 2019 

Requested Start: 04/01/2019 

Project Title: Understanding Otoacoustic Emissions 

SRG Action: Impact Score:20 Percentile:3 

RFAIPA: PA18-484 

PCC: HRS0 

Next Steps: Visit https://grants.nih.gov/grants/next_steps.htm 

Human Subjects: 30-Human subjects involved - Certified, no SRG concerns

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted

Gender: 1A-Both genders, scientifically acceptable 

Minority: 1A-Minorities and non-minorities, scientifically acceptable 

Children: 3A-No children included, scientifically acceptable 

Project 

Year 

22 

23 

24 

25 

26 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

BUDGET MODIFICATIONS 

SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communication ) Release Date: 10/23/2018 

Revised Date: 

Application Number: 2 R01 DC003687-22A1 

Principal Investigator 

SHERA, CHRISTOPHER A 

Applicant Organization: 

Review Group: AUD 

Auditory System Study Section 

Meeting Date: 10/11/2018 

Council: JAN 2019 

Requested Start: 04/01/2019 

Project Title: Understanding Otoacoustic Emissions 

SRG Action: Impact Score:20 Percentile:3 

RFAIPA: PA18-484 

PCC: HRS0 

Next Steps: Visit https://grants.nih.gov/grants/next_steps.htm 

Human Subjects: 30-Human subjects involved - Certified, no SRG concerns

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted

Gender: 1A-Both genders, scientifically acceptable 

Minority: 1A-Minorities and non-minorities, scientifically acceptable 

Children: 3A-No children included, scientifically acceptable 

Project 

Year 

22 

23 

24 

25 

26 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

BUDGET MODIFICATIONS 

SUMMARY STATEMENT 

( Privileged Communication) Release Date: 10/23/2018 

Revised Date: 

Application Number: 2 R01 DC003687-22A1 

Principal Investigator 

SHERA, CHRISTOPHER A 

Applicant Organization: 

Review Group: AUD 

Auditory System Study Section 

Meeting Date: 10/11/2018 

Council: JAN 2019 

Requested Start: 04/01/2019 

Project Title: Understanding Otoacoustic Emissions 

SRG Action: Impact Score:20 Percentile:3 

RFAIPA: PA18-484 

PCC: HRSO 

Next Steps: Visit https://grants.nih.gov/grants/next steps. htm 

Human Subjects: 30-Human subjects involved - Certified, no SRG concerns 

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted 

Gender: 1A-Both genders, scientifically acceptable 

Minority: 1A-Minorities and non-minorities, scientifically acceptable 

Children: 3A-No children included, scientifically acceptable 

Project 

Year 

22 

23 

24 

25 

26 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers . If an award is p lanned, the costs will be calculated by 

Institute grants management staff based on the recommendations outli ned below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

BUDGET MODIFICATIONS 
2 R01 DC003687-22A1 2 AUD

SHERA, C 

2R01DC003687-22A1 SHERA, CHRISTOPHER

COMMITTEE BUDGET RECOMMENDATIONS

RESUME AND SUMMARY OF DISCUSSION: This well-written resubmitted renewal R01 application 

from an established investigator aims to address important unresolved issues in cochlear mechanics 

and further develop the theoretical underpinning to help with interpretation of experimental otoacoustic 

emissions (OAEs) data. The scientific significance of the proposed research is very high, and the use of 

the combination of experimental and modeling approaches was viewed positively by the reviewers. The 

approach to the OAE acquisition protocol to decrease the testing time could be clinically applicable, 

particularly for pediatric populations. The principal investigator (PI) is a leader in the field of OAEs, well 

positioned to carry out the work. He was extremely productive in the previous grant cycles, adding to 

the strength of this competing renewal. The research team has considerable experience in obtaining 

OAEs in humans, and the collaboration with to study the mechanics in the mouse cochlea 

further instills confidence of success. This resubmission was largely responsive to the prior critiques by 

modifying one of the aims. However, the response to the lack of description of statistical approach is 

unsatisfactory, slightly diminishing the enthusiasm for some reviewers. Nevertheless, the panel 

concluded that this strong application will likely have long-term high impact in enhancing our basic 

understanding of cochlear mechanics with potential translational application to improve OAE measures 

in clinical settings. 

DESCRIPTION (provided by applicant): 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 feedforward/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.

PUBLIC HEALTH RELEVANCE: 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 

2 RO 1 DC003687-22A1 

SHERA,C 

2R01 DC003687-22A1 SHERA, CHRISTOPHER 

COMMITTEE BUDGET RECOMMENDATIONS 

2 AUD 

RESUME AND SUMMARY OF DISCUSSION: This well-written resubmitted renewal R01 application 

from an established investigator aims to address important unresolved issues in cochlear mechanics 

and further develop the theoretical underpinning to help with interpretation of experimental otoacoustic 

emissions (OAEs) data. The scientific significance of the proposed research is very high, and the use of 

the combination of experimental and modeling approaches was viewed positively by the reviewers. The 

approach to the OAE acquisition protocol to decrease the testing time could be clinically applicable, 

particularly for pediatric populations. The principal investigator (Pl) is a leader in the field of OAEs, well 

positioned to carry out the work. He was extremely productive in the previous grant cycles, adding to 

the strength of this competing renewal. The research team has considerable experience in obtaining 

OAEs in humans, and the collaboration with to study the mechanics in the mouse cochlea 

further instills confidence of success. This resubmission was largely responsive to the prior critiques by 

modifying one of the aims. However, the response to the lack of description of statistical approach is 

unsatisfactory, slightly diminishing the enthusiasm for some reviewers. Nevertheless, the panel 

concluded that this strong application will likely have long-term high impact in enhancing our basic 

understanding of cochlear mechanics with potential translational application to improve OAE measures 

in clinical settings. 

DESCRIPTION (provided by applicant): 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 feedforward/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. 

PUBLIC HEALTH RELEVANCE: 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 
2 R01 DC003687-22A1 3 AUD

SHERA, C 

for human communication, the proposed work will enhance the power of clinical hearing tests and help 

improve the design of auditory prosthetic devices.

CRITIQUE 1:

Significance: 2

Investigator(s): 1

Innovation: 3

Approach: 4

Environment: 2

Overall Impact: This is an excellent proposal from a productive PI whose techniques and strategies 

have driven the OAE field for many years. Overall, the project seeks to enrich our understanding of 

OAEs by (1) carefully studying the nonlinear interactions that occur during SFOAEs under different 

suppression paradigms especially those that speed acquisition (2) study the possibility that “irregularity” 

(and this could be from outer hair cells (soma, HB), material parameters, or other sources) could give 

rise to time varying (dynamic) effects (3) study the possible influence of new concepts in mathematical 

modelling of the cochlea ((a) spatial feedforward of gain – feedback of elastic properties) and (b) 

multimodal structure-fluid waves (coupled to the BM and TM)) on the interpretation of OAEs (do these 

new findings upset any of the tenets used in analyzing the data). 

Collaborations with experts in VOCTV will be used to inform the model and provide state-of-the-art 

interpretations of OAEs. They seek to address a key new question – do OAEs correlate more with RL 

motion than BM motion.

A strength of the application is to combine an excellent team for measurements of OAEs in humans 

and mice with nonlinear analytic modeling for interpretation of the data. This is especially important 

when interpreting different protocols for SFOAE analysis, the model will inform the community as to 

approach with a known dynamical. This research will develop a theoretical framework to better 

understand OAEs and better clinical procedures (faster and reliable).

The application is focusing on new mechanisms and model correlations. Hence potential sex 

differences and statistical power are not as critical as they would be for comparisons between 

interventions, for instance, which are not being made. Further, we expect the basic mechanics of, say, 

multimodal behavior, to be the same in males and females. Statistical rigor for measurements is still a 

weakness. The application would be improved if a better (brief) discussion of statistics of the number of 

subjects needed to get reliable (within variance) results. Both sexes used and will be examined for 

differences (not statistically powered). However, in humans females are preferred because of higher 

OAEs.

1. Significance

Strengths 

 The scientific premise of this work is strong – understanding how to interpret otoacoustic 

emissions is important because of its noninvasive and quantitative nature. However, the source 

of the emissions, causes for variability, and interpretation of the data (delays, amplitudes) are 

still open issues as is the need for the development of clinically efficient techniques (with regard 

to time and repeatability of the measurements). The premise of Aim 1 is strong.

 Two-tone suppression and interaction require a more complete understanding, especially as 

applied to OAEs. SFOAEs are complex (protocols) – the question of do suppressors always 

suppress will be addressed.

2 RO 1 DC003687-22A1 

SHERA,C 

3 AUD 

for human communication, the proposed work will enhance the power of clinical hearing tests and help 

improve the design of auditory prosthetic devices. 

CRITIQUE 1: 

Significance: 2 

lnvestigator(s): 1 

Innovation: 3 

Approach: 4 

Environment: 2 

Overall Impact: This is an excellent proposal from a productive Pl whose techniques and strategies 

have driven the OAE field for many years. Overall, the project seeks to enrich our understanding of 

OAEs by (1) carefully studying the nonlinear interactions that occur during SFOAEs under different 

suppression paradigms especially those that speed acquisition (2) study the possibility that "irregularity" 

(and this could be from outer hair cells (soma, HB), material parameters, or other sources) could give 

rise to time varying (dynamic) effects (3) study the possible influence of new concepts in mathematical 

modelling of the cochlea ((a) spatial feedforward of gain - feedback of elastic properties) and (b) 

multimodal structure-fluid waves (coupled to the BM and TM)) on the interpretation of OAEs (do these 

new findings upset any of the tenets used in analyzing the data). 

Collaborations with experts in VOCTV will be used to inform the model and provide state-of-the-art 

interpretations of OAEs. They seek to address a key new question - do OAEs correlate more with RL 

motion than BM motion. 

A strength of the application is to combine an excellent team for measurements of OAEs in humans 

and mice with nonlinear analytic modeling for interpretation of the data. This is especially important 

when interpreting different protocols for SFOAE analysis, the model will inform the community as to 

approach with a known dynamical. This research will develop a theoretical framework to better 

understand OAEs and better clinical procedures (faster and reliable). 

The application is focusing on new mechanisms and model correlations. Hence potential sex 

differences and statistical power are not as critical as they would be for comparisons between 

interventions, for instance, which are not being made. Further, we expect the basic mechanics of, say, 

multimodal behavior, to be the same in males and females. Statistical rigor for measurements is still a 

weakness. The application would be improved if a better (brief) discussion of statistics of the number of 

subjects needed to get reliable (within variance) results. Both sexes used and will be examined for 

differences (not statistically powered). However, in humans females are preferred because of higher 

OAEs. 

1. Significance 

Strengths 

• The scientific premise of this work is strong - understanding how to interpret otoacoustic 

emissions is important because of its noninvasive and quantitative nature. However, the source 

of the emissions, causes for variability, and interpretation of the data (delays, amplitudes) are 

still open issues as is the need for the development of clinically efficient techniques (with regard 

to time and repeatability of the measurements). The premise of Aim 1 is strong. 

• Two-tone suppression and interaction require a more complete understanding, especially as 

applied to OAEs. SFOAEs are complex (protocols) - the question of do suppressors always 

suppress will be addressed. 
2 R01 DC003687-22A1 4 AUD

SHERA, C 

 Aim 3a is added/altered to address critiques to not only look at other aspects of micromechanics 

that may give rise to 

 Aim 3b has been changed in name (still essentially testing the hypothesis of van der Heijden) 

but it still is mainly looking at this idea of the correlating of structures other than the BM with 

OAE. The collaboration with Oghalai enables the PI makes this possible. They seek to address 

the question of correlation of OAEs with RL motion rather than BM motion. This is important to 

do as the BM-only view of the cochlear mechanics is now disrupted and we are coming closer to 

understanding the mechanics by which the ANF tuning curves and other physiologically 

important measures (as well as OAEs) may differ from BM motion. 

 The notion of a “dynamic” component of irregularity is interesting and could lead to an 

understanding of the source of irregularities causing scattering. (Aim 2)

 If this work is successful, the connection between OAEs and sensorineural hearing loss and 

noninvasive tuning measures will be more secure.

 This work should be done to move this field forward from a theoretical, clinical, and 

methodological standpoint.

Weaknesses

 Using MOC and MOC irregularity to probe irregularity will present confounding result (both are 

posited to be irregular).

 Aim 2 is weakened because there is no mechanistic hypothesis for the dynamical nature of the 

irregularity (is it HB related/OHC somatic related) and a discussion of how it might be 

determined is missing.

2. Investigator(s)

Strengths 

 Shera is a leader in the analysis (analytic and via signal processing) of OAEs. His methods 

have influenced interpretation of this important clinical tool worldwide.

 The team is outstanding and very complementary with all important areas (OAE measurements 

in the clinic; OCT measurements; MOC stimulation) covered.

Weaknesses

 Very little discussion of an interaction plan justifying all parties’ involvement (the work is there to 

do - but some discussion of the interaction plan is missing).

3. Innovation

Strengths

 Studying wave anisotropy in models due to feedforward/feedback mechanisms while relating 

them to OAEs is innovative (with the hypothesis that such mechanisms may not be consistent 

with OAEs).

 Irregularities having a “dynamic” component (that might be indicative of placement of the 

irregularities in the HB or OHC soma).

 Including VOCTV measurements to analyze the correlate of mechanics of different structures to 

OAEs and compare latencies in OAEs to putative intracochlear generators.

 Using MOC to see if reducing the effectiveness of OHCs can increase the emission is 

innovative.

Weaknesses

2 RO 1 DC003687-22A1 

SHERA,C 

4 AUD 

• Aim 3a is added/altered to address critiques to not only look at other aspects of micromechanics 

that may give rise to 

• Aim 3b has been changed in name (still essentially testing the hypothesis of van der Heijden) 

but it still is mainly looking at this idea of the correlating of structures other than the BM with 

OAE. The collaboration with Oghalai enables the Pl makes this possible. They seek to address 

the question of correlation of OAEs with RL motion rather than BM motion. This is important to 

do as the BM-only view of the cochlear mechanics is now disrupted and we are coming closer to 

understanding the mechanics by which the ANF tuning curves and other physiologically 

important measures (as well as OAEs) may differ from BM motion. 

• The notion of a "dynamic" component of irregularity is interesting and could lead to an 

understanding of the source of irregularities causing scattering. (Aim 2) 

• If this work is successful, the connection between OAEs and sensorineural hearing loss and 

noninvasive tuning measures will be more secure. 

• This work should be done to move this field forward from a theoretical, clinical, and 

methodological standpoint. 

Weaknesses 

• Using MOC and MOC irregularity to probe irregularity will present confounding result (both are 

posited to be irregular). 

• Aim 2 is weakened because there is no mechanistic hypothesis for the dynamical nature of the 

irregularity (is it HB related/OHC somatic related) and a discussion of how it might be 

determined is missing. 

2. lnvestigator(s) 

Strengths 

• Shera is a leader in the analysis (analytic and via signal processing) of OAEs. His methods 

have influenced interpretation of this important clinical tool worldwide. 

• The team is outstanding and very complementary with all important areas (OAE measurements 

in the clinic; OCT measurements; MOC stimulation) covered. 

Weaknesses 

• Very little discussion of an interaction plan justifying all parties' involvement (the work is there to 

do - but some discussion of the interaction plan is missing). 

3. Innovation 

Strengths 

• Studying wave anisotropy in models due to feedforward/feedback mechanisms while relating 

them to OAEs is innovative (with the hypothesis that such mechanisms may not be consistent 

with OAEs). 

• Irregularities having a "dynamic" component (that might be indicative of placement of the 

irregularities in the HB or OHC soma). 

• Including VOCTV measurements to analyze the correlate of mechanics of different structures to 

OAEs and compare latencies in OAEs to putative intracochlear generators. 

• Using MOC to see if reducing the effectiveness of OHCs can increase the emission is 

innovative. 

Weaknesses 
2 R01 DC003687-22A1 5 AUD

SHERA, C 

 None noted. 

4. Approach 

Strengths

 The use of complementary models (Shera versus Liu and Neely models) is a strength (needed 

to study 3b) and the use of simplified (phenomenological) models like this is important for all 

aims. This is especially true for Aim 1, where these models can provide a relatively simple 

platform to test algorithms (swept protocols) for experiments. These models are important 

because they show potentially important wave phenomena that can be linked to mechanism for 

each effect.

 The CWT approach put forth in Bergevin and Shera uses advanced and efficient signal 

processing as well as the recognition (often not mentioned) that reflections will confound the 

delay measurements and must be taken into account – great that this is proposed.

 Relatively simple model allows for rapid and controllable variation of the model and for nonlinear 

simulations in the time domain to be used.

 Sex as a biological variable is addressed – but downplayed.

Weaknesses

 Modeling details not spelled out – making them hard to evaluate. “Strategic simplifications” 

(otherwise known as either modeling assumptions or hypotheses about the central structures 

necessary for modeling) are mentioned but not specified. Elastic coupling by the TM is 

mentioned not to be important – but it has already been shown important (models and 

experiments – Russell ... Richardson (2007)) – especially around the best place – so some of 

the model concepts still need to be settled for the multicomponent model (aim 3b) to test OCT 

measured RL responses.

 The irregularity hypothesis testing is still troublesome because it is difficult to validate 

physiologically (although it is supported now by several models) – the notion that spotty 

(irregular) MOC activation plus static irregularity could predict increased OAE under MOC stim 

(which should reduce the OAE because of reduced OHC activity) seems to compound two 

uncertain (and difficult to verify experimentally) contributors. I’m concerned that this may be 

unproductive because of the confounding nature.

 For two-tone interaction (suppression) there are interactions at the level of the suppressor 

interacting with the probe tone more than just at each tone’s primary frequency (i.e., there are 

distortion products). The effect of this nonlinearity is not discussed – even though it will be 

present in their model.

 Statistics of obtaining reliable experimental data are not clearly described – while mentioned it’s 

not very clear. They plan to utilize sufficient animals until significance is attained (with initial 

estimates based on past experience). 

5. Environment:

Strengths

 For all components; an excellent environment is in place to perform these experiments.

Weaknesses

 None noted. 

Protections for Human Subjects:

2 RO 1 DC003687-22A1 

SHERA,C 

• None noted. 

4. Approach 

Strengths 

5 AUD 

• The use of complementary models (Shera versus Liu and Neely models) is a strength (needed 

to study 3b) and the use of simplified (phenomenological) models like this is important for all 

aims. This is especially true for Aim 1, where these models can provide a relatively simple 

platform to test algorithms (swept protocols) for experiments. These models are important 

because they show potentially important wave phenomena that can be linked to mechanism for 

each effect. 

• The CWT approach put forth in Bergevin and Shera uses advanced and efficient signal 

processing as well as the recognition (often not mentioned) that reflections will confound the 

delay measurements and must be taken into account - great that this is proposed. 

• Relatively simple model allows for rapid and controllable variation of the model and for nonlinear 

simulations in the time domain to be used. 

• Sex as a biological variable is addressed - but downplayed. 

Weaknesses 

• Modeling details not spelled out - making them hard to evaluate. "Strategic simplifications" 

(otherwise known as either modeling assumptions or hypotheses about the central structures 

necessary for modeling) are mentioned but not specified. Elastic coupling by the TM is 

mentioned not to be important - but it has already been shown important (models and 

experiments - Russell ... Richardson (2007)) - especially around the best place - so some of 

the model concepts still need to be settled for the multicomponent model (aim 3b) to test OCT 

measured RL responses. 

• The irregularity hypothesis testing is still troublesome because it is difficult to validate 

physiologically (although it is supported now by several models) - the notion that spotty 

(irregular) MOC activation plus static irregularity could predict increased OAE under MOC stim 

(which should reduce the OAE because of reduced OHC activity) seems to compound two 

uncertain (and difficult to verify experimentally) contributors. I'm concerned that this may be 

unproductive because of the confounding nature. 

• For two-tone interaction (suppression) there are interactions at the level of the suppressor 

interacting with the probe tone more than just at each tone's primary frequency (i.e., there are 

distortion products). The effect of this nonlinearity is not discussed - even though it will be 

present in their model. 

• Statistics of obtaining reliable experimental data are not clearly described - while mentioned it's 

not very clear. They plan to utilize sufficient animals until significance is attained (with initial 

estimates based on past experience). 

5. Environment: 

Strengths 

• For all components; an excellent environment is in place to perform these experiments. 

Weaknesses 

• None noted. 

Protections for Human Subjects: 
2 R01 DC003687-22A1 6 AUD

SHERA, C 

Acceptable Risks and/or Adequate Protections

Inclusion of Women, Minorities and Children:

 Sex/Gender: Distribution justified scientifically

 Race/Ethnicity: Distribution justified scientifically

 Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically

Vertebrate Animals:

YES, all criteria addressed

Biohazards:

Not Applicable (No Biohazards)

Resubmission:

 Generally, addresses previous critique.

Resource Sharing Plans:

Acceptable

Budget and Period of Support:

Budget Modifications Recommended (in amount/time)

Recommended budget modifications or possible overlap identified:

 The budget seems high - work could be done with one fewer post-doc.

CRITIQUE 2:

Significance: 2

Investigator(s): 1

Innovation: 2

Approach: 2

Environment: 1

Overall Impact: 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. For example, 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. A more thorough understanding of inner-ear mechanics and emission generation 

may allow for more widespread clinical applicability of OAEs. Thus, there is high potential significance 

of the work. The foundational premise of the work is strong and based on prior literature and 

preliminary data. Additional strengths included the fantastic PI and assembled team, superb progress 

during the prior grant period, good conceptual innovation, a logical and feasible approach and a strong 

environment. Weaknesses were few and negligible but did include a general lack of description of 

2 RO 1 DC003687-22A1 

SHERA,C 

Acceptable Risks and/or Adequate Protections 

Inclusion of Women, Minorities and Children: 

6 

• Sex/Gender: Distribution justified scientifically 

• Race/Ethnicity: Distribution justified scientifically 

• Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically 

Vertebrate Animals: 

YES, all criteria addressed 

Biohazards: 

Not Applicable (No Biohazards) 

Resubmission: 

• Generally, addresses previous critique. 

Resource Sharing Plans: 

Acceptable 

Budget and Period of Support: 

Budget Modifications Recommended (in amount/time) 

Recommended budget modifications or possible overlap identified: 

• The budget seems high - work could be done with one fewer post-doc. 

CRITIQUE 2: 

Significance: 2 

lnvestigator(s): 1 

Innovation: 2 

Approach: 2 

Environment: 1 

AUD 

Overall Impact: 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. For example, 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. A more thorough understanding of inner-ear mechanics and emission generation 

may allow for more widespread clinical applicability of OAEs. Thus, there is high potential significance 

of the work. The foundational premise of the work is strong and based on prior literature and 

preliminary data. Additional strengths included the fantastic Pl and assembled team, superb progress 

during the prior grant period, good conceptual innovation, a logical and feasible approach and a strong 

environment. Weaknesses were few and negligible but did include a general lack of description of 
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SHERA, C 

statistical treatment of the data and sample sizes. The weaknesses did not detract from enthusiasm for 

this proposal.

1. Significance

Strengths 

 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. For example, 

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. A more thorough understanding of inner-ear 

mechanics and emission generation may allow for more widespread clinical applicability of 

OAEs.

 The premise of the work is that there are several key areas of OAE generation that are likely not 

correct and could lead to inaccuracies in interpretation of the results – e.g., the role and 

mechanism of suppressor tones necessary to measure cochlear frequency selectivity. The 

premise is based on literature and preliminary data including modeling.

Weaknesses

 None noted. 

2. Investigator(s)

Strengths 

 The PI, Dr Chris Shera, is a leader and pioneer in the study of OAEs. The PI is more than 

capable of conducting the proposed work.

 Progress during the prior grant period was phenomenal, with at least 27 peer reviewed 

publications and several review chapters.

 The PI has assembled a stellar team 

to assist with novel measurement using optical coherence tomography (OCT).

Weaknesses

 None noted. 

3. Innovation

Strengths

 The combination of experiment and modeling, while commonplace in many proposals, is 

innovative here due to how tightly the models and experiments are woven together.

 There are several conceptual innovations including focus on OAE components that were once 

likely thought to be simply sources of noise, including the role of suppressor tones, the role of 

micromechanical irregularities, and new ideas of how OAEs are modulated by efferent 

innervation

Weaknesses

 None noted. 

4. Approach 

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SHERA,C 

7 AUD 

statistical treatment of the data and sample sizes. The weaknesses did not detract from enthusiasm for 

this proposal. 

1. Significance 

Strengths 

• 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. For example, 

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. A more thorough understanding of inner-ear 

mechanics and emission generation may allow for more widespread clinical applicability of 

OAEs. 

• The premise of the work is that there are several key areas of OAE generation that are likely not 

correct and could lead to inaccuracies in interpretation of the results - e.g., the role and 

mechanism of suppressor tones necessary to measure cochlear frequency selectivity. The 

premise is based on literature and preliminary data including modeling. 

Weaknesses 

• None noted. 

2. lnvestigator(s) 

Strengths 

• The Pl, Dr Chris Shera, is a leader and pioneer in the study of OAEs. The Pl is more than 

capable of conducting the proposed work. 

• Progress during the prior grant period was phenomenal, with at least 27 peer reviewed 

publications and several review chapters. 

• 

-to 

The Pl has assembled a stellar team 

assist with novel measurement using optical coherence tomography ( 

Weaknesses 

• None noted. 

3. Innovation 

Strengths 

• The combination of experiment and modeling, while commonplace in many proposals, is 

innovative here due to how tightly the models and experiments are woven together. 

• There are several conceptual innovations including focus on OAE components that were once 

likely thought to be simply sources of noise, including the role of suppressor tones, the role of 

micromechanical irregularities, and new ideas of how OAEs are modulated by efferent 

innervation 

Weaknesses 

• None noted. 

4. Approach 
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SHERA, C 

Strengths

 As stated by the PI, most of the methodology uses the already innovative and powerful 

acquisition and analysis techniques that the PI and collaborators have developed over the past 

several years. The experiments leverage these vetted methodologies to explore new ideas 

regarding OAE generation.

 There were good preliminary data for most of the more difficult experiments lending confidence 

that the experiments will bear solid data necessary to test core hypotheses

 In Aim 1 the method proposed to eliminate sources of suppressor tone effects on frequency 

selectivity estimates by filtering out the short latency components is neat

 The identification and use of a negative delay component in Aim 2 and its use to study biological 

sources of small micromolecular irregularities is also neat

 Use of OCT to measure displacements of the basilar membrane and reticular lamina and 

correlate those results with obtained OAEs to study sources of vibrational modes of the organ of 

corti that might be OAE generators is strong

 Sex as a biological variable was addressed adequately 

Weaknesses

 There still remains no power analysis nor statistical methods to rigorously examine the results. 

The PI suggests that animal and human numbers are based on past experience in the lab. With 

increased emphasis on methods to bolster rigor and reproducibility this is no longer sufficient.

5. Environment:

Strengths

 The scientific and intellectual environment is world class.

 The PI and team have all of the necessary equipment and facilities to conduct the proposed 

work.

Weaknesses

 None noted. 

Protections for Human Subjects:

Acceptable Risks and/or Adequate Protections

 The proposed use of human subjects is acceptable and necessary for the research. Adequate 

provisions are in place to protect human subjects from anticipated risks.

Inclusion of Women, Minorities and Children:

 Sex/Gender: Distribution justified scientifically

 Race/Ethnicity: Distribution justified scientifically 

 Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically

 Equal numbers of males and females will be recruited. The study achieves a representative mix 

with regard to ethnic and racial categories based on the representation of these categories 

 Children under 18 are justifiably excluded based on task difficulty.

Vertebrate Animals:

2 RO 1 DC003687-22A1 

SHERA,C 

Strengths 

8 AUD 

• As stated by the Pl, most of the methodology uses the already innovative and powerful 

acquisition and analysis techniques that the Pl and collaborators have developed over the past 

several years. The experiments leverage these vetted methodologies to explore new ideas 

regarding OAE generation. 

• There were good preliminary data for most of the more difficult experiments lending confidence 

that the experiments will bear solid data necessary to test core hypotheses 

• In Aim 1 the method proposed to eliminate sources of suppressor tone effects on frequency 

selectivity estimates by filtering out the short latency components is neat 

• The identification and use of a negative delay component in Aim 2 and its use to study biological 

sources of small micromolecular irregularities is also neat 

• Use of OCT to measure displacements of the basilar membrane and reticular lamina and 

correlate those results with obtained OAEs to study sources of vibrational modes of the organ of 

corti that might be OAE generators is strong 

• Sex as a biological variable was addressed adequately 

Weaknesses 

• There still remains no power analysis nor statistical methods to rigorously examine the results. 

The Pl suggests that animal and human numbers are based on past experience in the lab. With 

increased emphasis on methods to bolster rigor and reproducibility this is no longer sufficient. 

5. Environment: 

Strengths 

• The scientific and intellectual environment- is world class. 

• The Pl and team have all of the necessary equipment and facilities to conduct the proposed 

work. 

Weaknesses 

• None noted. 

Protections for Human Subjects: 

Acceptable Risks and/or Adequate Protections 

• The proposed use of human subjects is acceptable and necessary for the research. Adequate 

provisions are in place to protect human subjects from anticipated risks. 

Inclusion of Women, Minorities and Children: 

• Sex/Gender: Distribution justified scientifically 

• Race/Ethnicity: Distribution justified scientifically 

• Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically 

• Equal numbers of males and females will be recruited. The study achieves a representative mix 

-

and racial categories based on the representation of these categories I Children under 18 are justifiably excluded based on task difficulty. 

Vertebrate Animals: 
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SHERA, C 

YES, all criteria addressed

 Species, strain, sex, age and numbers of animals needed are adequately indicated. 

Experiments are well justified. Appropriate care is indicated as are procedures to minimize pain 

and discomfort. Appropriate methods for euthanasia are indicated.

Biohazards:

Not Applicable (No Biohazards)

Budget and Period of Support:

Recommend as Requested

CRITIQUE 3:

Significance: 2

Investigator(s): 2

Innovation: 3

Approach: 3

Environment: 2

Overall Impact: This is a well-written application proposing experiments to better understand the 

generation of OAEs through a combination of human data and modelling. The first aim tests the idea 

that suppressor tones can themselves introduce reflections and offers a procedure for removing these 

effects. The second aim evaluates possible contributions of dynamic, MOC related changes to the 

irregularities associated with reflections. And the third aim evaluates the possible role of feedforward/backward amplification in OAE generation. Experiments address important and fundamental 

questions about cochlear function. This work is likely to result in concrete tools and procedures for 

interpreting OAE data, with applications for both clinical and research endeavors. Importantly, results 

are expected to lead to a re-interpretation of published data (e.g., SFOAE suppression tuning curves). 

The PI is highly qualified to carry out this work, and the credentials of his Co-investigators further 

bolster confidence. Progress in the previous funding period was excellent, and response to prior 

reviews for this resubmission was strong. 

The scientific premise is supported by published and pilot data. Rigor is demonstrated via careful 

consideration of alternative explanations for patterns of data observed, stringent artifact rejection, 

repeated measurements, comparison of models from other groups, and converging evidence across 

modeling, behavioral and imaging.

No sex effects are expected, but analyses will be performed to look for them.

Protections for Human Subjects:

Acceptable Risks and/or Adequate Protections

 Risks are minimal and well controlled.

Inclusion of Women, Minorities and Children:

 Sex/Gender: Distribution justified scientifically

 Race/Ethnicity: Distribution justified scientifically 

 Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically

2 RO 1 DC003687-22A1 

SHERA,C 

YES, all criteria addressed 

9 

• Species, strain, sex, age and numbers of animals needed are adequately indicated. 

AUD 

Experiments are well justified. Appropriate care is indicated as are procedures to minimize pain 

and discomfort. Appropriate methods for euthanasia are indicated. 

Biohazards: 

Not Applicable (No Biohazards) 

Budget and Period of Support: 

Recommend as Requested 

CRITIQUE 3: 

Significance: 2 

lnvestigator(s): 2 

Innovation: 3 

Approach: 3 

Environment: 2 

Overall Impact: This is a well-written application proposing experiments to better understand the 

generation of OAEs through a combination of human data and modelling. The first aim tests the idea 

that suppressor tones can themselves introduce reflections and offers a procedure for removing these 

effects. The second aim evaluates possible contributions of dynamic, MOC related changes to the 

irregularities associated with reflections. And the third aim evaluates the possible role of feedforward/backward amplification in OAE generation. Experiments address important and fundamental 

questions about cochlear function. This work is likely to result in concrete tools and procedures for 

interpreting OAE data, with applications for both clinical and research endeavors. Importantly, results 

are expected to lead to a re-interpretation of published data (e.g., SFOAE suppression tuning curves). 

The Pl is highly qualified to carry out this work, and the credentials of his Co-investigators further 

bolster confidence. Progress in the previous funding period was excellent, and response to prior 

reviews for this resubmission was strong. 

The scientific premise is supported by published and pilot data. Rigor is demonstrated via careful 

consideration of alternative explanations for patterns of data observed, stringent artifact rejection, 

repeated measurements, comparison of models from other groups, and converging evidence across 

modeling, behavioral and imaging. 

No sex effects are expected, but analyses will be performed to look for them. 

Protections for Human Subjects: 

Acceptable Risks and/or Adequate Protections 

• Risks are minimal and well controlled. 

Inclusion of Women, Minorities and Children: 

• Sex/Gender: Distribution justified scientifically 

• Race/Ethnicity: Distribution justified scientifically 

• Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically 
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 The recruitment plan calls for running equal numbers of males and females, and for a

racial/ethnic demographic that reflects the local population. Children are omitted due to the task

demands.

Vertebrate Animals:

Not Applicable (No Vertebrate Animals)

Biohazards:

Not Applicable (No Biohazards)

Budget and Period of Support:

Budget Modifications Recommended 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS’ 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES:

PROTECTION OF HUMAN SUBJECTS: ACCEPTABLE

INCLUSION OF WOMEN PLAN: ACCEPTABLE

INCLUSION OF MINORITIES PLAN: ACCEPTABLE

INCLUSION OF CHILDREN PLAN: ACCEPTABLE

VERTEBRATE ANIMALS: ACCEPTABLE

COMMITTEE BUDGET RECOMMENDATIONS: After discussion, the panel recommended the 

elimination of one postdoc position.

Footnotes for 2 R01 DC003687-22A1; PI Name: SHERA, CHRISTOPHER A

NIH has modified its policy regarding the receipt of resubmissions (amended applications). 

See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOTOD-14-074.html. The impact/priority score is calculated after discussion of an application by

averaging the overall scores (1-9) given by all voting reviewers on the committee and

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual

reviewers assigned to an application, and are not discussed specifically at the review meeting

or calculated into the overall impact score. Some applications also receive a percentile

ranking. For details on the review process, see

http://grants.nih.gov/grants/peer_review_process.htm#scoring.

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SHERA,C 

10 AUD 

• The recruitment plan calls for running equal numbers of males and females, and for a 

racial/ethnic demographic that reflects the local population. Children are omitted due to the task 

demands. 

Vertebrate Animals: 

Not Applicable (No Vertebrate Animals) 

Biohazards: 

Not Applicable (No Biohazards) 

Budget and Period of Support: 

Budget Modifications Recommended 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: 

PROTECTION OF HUMAN SUBJECTS: ACCEPTABLE 

INCLUSION OF WOMEN PLAN: ACCEPTABLE 

INCLUSION OF MINORITIES PLAN: ACCEPTABLE 

INCLUSION OF CHILDREN PLAN: ACCEPTABLE 

VERTEBRATE ANIMALS: ACCEPTABLE 

COMMITTEE BUDGET RECOMMENDATIONS: After discussion, the panel recommended the 

elimination of one postdoc position. 

Footnotes for 2 R01 DC003687-22A1; Pl Name: SHERA, CHRISTOPHER A 

NIH has modified its policy regarding the receipt of resubmissions (amended applications). 

See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOTOD-14-074.html. The impact/priority score is calculated after discussion of an application by 

averaging the overall scores (1-9) given by all voting reviewers on the committee and 

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual 

reviewers assigned to an application, and are not discussed specifically at the review meeting 

or calculated into the overall impact score. Some applications also receive a percentile 

ranking. For details on the review process, see 

http://grants.nih.gov/grants/peer review process.htm#scoring.