Micheal Dent, Ph.D.

Micheal Dent, Ph.D.

University at Buffalo, the State University of New York
Noise-induced tinnitus in mice

Animal models of tinnitus have employed many different behavioral techniques, only one of which is not subject to motivational issues and changes in auditory acuity. Tinnitus has previously been induced in rats following a sodium salicylate injection. In the present proposal, this paradigm will be modified to investigate tinnitus in mice. These experiments as a whole aim to determine the time course of tinnitus and its recovery following nontraumatic noise exposures in mice. Until there is an objective measure that separates hearing loss from tinnitus, it is difficult to use mice to study tinnitus. This project seeks to define a way to measure and characterize tinnitus in the awake and behaving mouse model in order to compare this to humans with tinnitus.

James Dewey, Ph.D.

James Dewey, Ph.D.

University of Southern California
Filtering of otoacoustic emissions: a window onto cochlear frequency tuning

Healthy ears emit sounds that can be measured in the ear canal with a sensitive microphone. These otoacoustic emissions (OAEs) offer a noninvasive window onto the mechanical processes within the cochlea that confer typical hearing, and are commonly measured in the clinic to detect hearing loss. Nevertheless, their interpretation remains limited by uncertainties regarding how they are generated within the cochlea and how they propagate out of it. Through experiments in mice, this project will test theoretical relationships that suggest that OAEs are strongly shaped (or “filtered”) as they travel through the cochlea, and that this filtering is related to how well the ear can discriminate sounds at different frequencies. This may lead to novel, noninvasive tests of human cochlear function, and specifically frequency discrimination, which is important for understanding speech.

James W. Dias, Ph.D.

James W. Dias, Ph.D.

The Medical University of South Carolina
Neural determinants of age-related change in auditory-visual speech processing

Older adults typically have more difficulty than younger adults identifying the speech they hear, especially in noisy listening environments. However, some older adults demonstrate a preserved ability to identify speech that is both heard and seen. This preserved audiovisual speech perception by older adults is not explained by an improved ability to speechread (lipread), as speechreading also typically declines with age. Instead, older adults can exhibit an improved ability to integrate information available from across auditory and visual sources. This behavioral evidence is consistent with findings suggesting that the neural processing of audiovisual speech can improve with age. Despite the accumulating and intriguing evidence, the underlying changes in brain structure and function that support the preservation of audiovisual speech perception in older adults remains a critical knowledge gap. This project uses an innovative neural systems approach to determine how age-related changes in cortical structure and function, both within and between regions of the brain, can preserve audiovisual speech perception in older adults.

Oscar Diaz-Horta, Ph.D.

Oscar Diaz-Horta, Ph.D.

University of Miami
The role of FAM65B in the regulation of post-translational modifications of auditory hair cell proteins

Recent genetic studies have identified the FAM65B protein as an important molecule for hearing. In this study we will search for inner ear hair cell proteins interacting with FAM65B in order to further delineate FAM65B’s function. We will focus on FAM65B’s role in the modification of its partner proteins. These studies will help characterize molecular aspects of hearing and how hearing loss occurs when they are disrupted.

Andrew Dimitrijevic, Ph.D.

Andrew Dimitrijevic, Ph.D.

Cincinnati Children's Hospital Medical Center
Sensory and Cognitive Processing in Children with Auditory Processing Disorders: Behavior and Electrophysiology

Central Auditory Processing Disorder (CAPD) can be defined as having a listening difficulty despite having normal hearing. One theory of CAPD is that this bottom-up processing isn’t working properly, a bit like listening to a de-tuned radio or TV. However, when the sound code reaches the cortex, it is mixed with a variety of signals from other systems, including vision, memory and attention. A second theory of CAPD is that the problem occurs at this level of mixing. In this ‘top-down’ theory, inappropriate control signals from high-level thinking systems, especially memory and attention, are thought to lead to misunderstanding of the code produced in the auditory system. Unfortunately, these two theories are difficult to tease apart. For example, a typical statement by a parent of a child with CAPD is that (s)he seems unaware when being spoken to. This could indicate poor listening due to inattention, or due to an inability to process speech sounds in the auditory system. Understanding which theory is correct may be important for treatment of CAPD. This research aims to tease apart these two theories by examining how the brain processes sound. One aspect of this research will examine how the brain encodes pitch and level fluctuations in sound. Both of these sound qualities are the “building blocks” of speech. If there are deficits at this level of neural processing then perhaps a “bottom up” or sound encoding problem exists. Another aspect of this research will examine a more cognitive approach and examine how the brain deals with speech in noise. This will be indexed by use of brain oscillations which are thought to reflect neural networks across different parts of the brain. Therefore by approaching CAPD from these two directions, it may be possible to show whether their listening difficulties are due to bottom-up or top-down processing problems.

Elizabeth A. Dinces, M.D., M.S.

Elizabeth A. Dinces, M.D., M.S.

Albert Einstein College of Medicine
Effects of aging on selective attention in complex, multisource sound environments

Dinces’ basic science research focuses on understanding how the brain processes sounds into meaningful language and includes auditory scene analysis in the elderly, sound intensity processing in children, and development of auditory processing after cochlear implantation. The value of learning the role of attention and understanding the active and passive processes of stream segregation in aging populations will be to help develop therapeutic strategies to improve listening and understanding in noisy sound environments of aging adults.

Research area: fundamental auditory research

Long-term goal of research: to explain mechanisms of auditory scene analysis, which is how the auditory system processes sound into meaningful elements, that break down with aging.

Mishaela DiNino, Ph.D.

Mishaela DiNino, Ph.D.

Carnegie Mellon University
Neural mechanisms of speech sound encoding in older adults

Many older adults have trouble understanding speech in noisy environments, often to a greater extent than their hearing thresholds would predict. Age-related changes in the central auditory system, not just hearing loss, are thought to contribute to this perceptual impairment, but the exact mechanisms by which this would occur are not yet known. As individuals age, auditory neurons become less able to synchronize to the timing information in sound. This project will examine the relationship between reduced neural processing of fine timing information and older adults’ ability to encode the acoustic building blocks of speech sounds. Limited capacity to code and use these acoustic cues might impair speech perception, particularly in the presence of background noise, independent of hearing thresholds. The results of this study will provide a better understanding of how the neural mechanisms important for speech-in-noise recognition may be altered with age, laying the groundwork for development of novel treatments for older adults who experience difficulty perceiving speech in noise.

Noah R. Druckenbrod , Ph.D.

Noah R. Druckenbrod , Ph.D.

Harvard University
Identifying roles for contact-dependent signaling between neurons and glia during axon guidance and synaptic targeting

The mature cochlea is a spiraled hollow chamber of bone that contains all the necessary components to transmit sound information to the brain. This feat is accomplished by the precise arrangement of hair cells and spiral ganglion neurons (SGNs). This arrangement requires SGNs extend peripheral projections and establish precise synaptic connections with hair cells. What signals guide these axons through the three-dimensional terrain of the cochlea? Most studies focus on the roles of classically described axon guidance cues, which act over long distances to attract or repel axons. However, mounting evidence from recent studies and our own preliminary data lead us to hypothesize that contact-dependent signaling between SGNs and Schwann cells (SCs) are required for normal development of inner ear neural architecture and hearing. The precise role of contact-dependent interactions between SGN axons and SCs on auditory circuit formation remains unknown. This is due in part to the obstacles towards gathering high-resolution, time-lapsed information on the spatial relationships between SGNs and SCs in situ. Therefore, we will genetically label and characterize live cellular interactions between these cells in their normal, and then abnormal, physiological environment. We will measure the extent to which each of these cell types rely on each other for normal migration, differentiation, proliferation and survival. Because we have identified a mutant in which SGN-Schwann cell interaction appears disrupted, these studies will also provide insight to our understanding of Schwannoma formation. Schwannomas are Schwann cell tumors commonly found in the inner-ear and are thought to arise from a disruption in reciprocal signaling between spiral ganglion neurons (SGNs) and Schwann cells. As these tumors grow they compress afferent vestibular and auditory nerves, usually causing hearing loss, tinnitus, and dizziness. Therefore, these studies will not only contribute to our understanding of auditory circuit formation but also provide insight into what can go wrong when SGN-Schwann cell interaction is disrupted.

Brian R. Earl, Ph.D., CCCA, FAAA

Brian R. Earl, Ph.D., CCCA, FAAA

University of Cincinnati
Specifying the Integrity of Neurons in the Auditory Periphery (SiNAP)

Auditory nerve degeneration is thought to lead to difficulties with understanding speech, especially in noisy listening situations. Diagnosis of auditory nerve degeneration, however, may be missed by common hearing tests. This research examines the utility of a new technique to specify the extent and region of auditory nerve damage within the inner ear. Application of the technique in a clinical setting may help individualize hearing aids and cochlear implants, and in the future, guide delivery of therapeutic agents that can truly restore hearing to individuals with hearing loss.

Research area: Auditory physiology; Diagnostic audiology

Long-term goal of research: To develop tools for diagnosis of auditory nerve integrity that will improve the individualization of treatment options for individuals with hearing loss.

Vijayalakshmi Easwar, Ph.D.

Vijayalakshmi Easwar, Ph.D.

University of Wisconsin–Madison
Neural correlates of amplified speech in children with sensorineural hearing loss

About three of every 1,000 infants are born with permanent hearing loss. With the implementation of newborn hearing screening programs worldwide, infants born with hearing loss are now identified soon after birth and provided with hearing aids as early as 3 months of age. However, until infants are 8 to 10 months of age and can participate in clinical tests, the use of neural measures is the only feasible method to infer an infant’s hearing ability with hearing aids. This project will investigate the relationship between behavioral and neural measures of speech audibility in children ages 5 to 16 years old with congenital sensorineural hearing loss, who are capable of reliably indicating hearing sounds. Specifically, the project will use speech-elicited, envelope-following responses—a type of scalp-recorded measure that reflects neural activity to periodicity in speech. Study findings will reveal the accuracy of the chosen neural measure in confirming whether speech sounds are audible in children with congenital hearing loss when hearing aids are used. Results will inform future investigations and the clinical feasibility of using neural measures to assess hearing aid benefit in infants with hearing loss who are unable to confirm their detection of speech behaviorally.

Mark Eckert, M.D.

Mark Eckert, M.D.

Medical University of South Carolina

Neural changes underlying speech-perception training in the aging brain

Many older adults with hearing loss have difficulty understanding speech in noisy environments and some feel socially isolated. Although hearing aids can improve speech understanding, hearing aid benefit may be limited if the perception of certain speech sounds has changed. Speech training programs have been shown to improve the recognition of amplified speech by older adults by focusing on re-learning cues important for perception of specific sounds. The goal of our study is to examine how the brain changes during speech training programs designed to improve speech understanding in noise. To achieve this goal, we are using MRI to examine brain activation before and after speech training and relate this activation to improvements in speech recognition. Our long term goal is to enhance the effectiveness of speech training programs by understanding the brain systems that are important for learning to hear amplified speech.

This research award is funded by the Centurions of the Deafness Research Foundation. DRF partnered with CORE Grants Program of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) to offer a one-year Centurion Clinical Research Award (CCRA) for clinical research in hearing and balance sciences.

David Ehrlich, Ph.D

David Ehrlich, Ph.D

New York University School of Medicine
Neural computations for vestibular control of movement initiation

Loss of balance and falls are common in aging populations and associated with various neurological disorders. Balance is sensed using vestibular organs in the inner ear and processed in the brainstem. However, it remains unclear how the brainstem transforms sensations of instability into corrective movements that restore balance. The objective of this project is to define how cells in the brainstem act collectively to produce rapid responses to sensations of instability. In order to measure balance responses in populations of cells located deep within the brain, this project will apply cutting-edge microscopy techniques to the zebrafish. These fish swim to remain balanced, providing a model for balance control and brainstem function in general.

Richard A. Felix II, Ph.D.

Richard A. Felix II, Ph.D.

Washington State University Vancouver
Neural mechanisms underlying deficits encoding temporal sound features associated with central auditory processing disorder

A critical function of the auditory system is to extract meaning from complex sounds. When this basic function is impaired, quality of life can be greatly affected. This is particularly true for speech processing, where degrading temporal information significantly alters the ability to listen. Difficulty encoding temporal cues is a hallmark central auditory processing disorder (CAPD), which is also marked by problems understanding complex sounds despite normal function of the peripheral auditory system. The origin of deficits associated with CAPD has been localized to the brain, but the neural mechanisms underlying the encoding of temporal sound cues remain poorly understood.

The goal of this research is to examine the contributions of inhibitory connections to the midbrain, the first known site in the auditory pathway that exhibits abnormal function in those with CAPD. These midbrain inputs signal temporal sound features important in the emergence of CAP and might therefore play an important role in the generation of listening problems. The results of this project will be a key step in advancing our understanding of how the processing of temporal information at the level of brain circuits relate to deficits associated with CAPD.

Gregory I. Frolenkov, Ph.D.

Gregory I. Frolenkov, Ph.D.

University of Kentucky

Mechanoelectrical transduction without Myosin XVa

The long-term goal is to define the molecular and biophysical mechanisms shaping mechanosensitivity in cochlear hair cells. A common structural feature of hair cells in all vertebrates is the staircase arrangement of stereocilia, which is thought to be critical for mechanotransduction. This study will determine the distinguishing features of mechanotransduction in auditory hair cells of deaf shaker 2 mice that have abnormally short stereocilia due to a mutation in the motor domain of Myosin XVa.

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Amanda Griffin, Ph.D., Au.D.

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Amanda Griffin, Ph.D., Au.D.

Boston Children’s Hospital

Toward better assessment of pediatric unilateral hearing loss 

Although it is now more widely understood that children with unilateral hearing loss are at risk for challenges, many appear to adjust well without intervention. The range of options for audiological intervention for children with severe-to-profound hearing loss in only one ear (i.e., single-sided deafness, SSD) has increased markedly in recent years, from no intervention beyond classroom accommodations all the way to cochlear implant (CI) surgery. In the absence of clear data, current practice is based largely on the philosophy and convention at different institutions around the country. The work in our lab aims to improve assessment and management of pediatric unilateral hearing loss. This current project will evaluate the validity of an expanded audiological and neuropsychological test battery in school-aged children with SSD. Performance on test measures will be compared across different subject groups: typical hearing; unaided SSD; SSD with the use of a CROS (contralateral routing of signals) hearing aid; SSD with the use of a cochlear implant. This research will enhance our basic understanding of auditory and non-auditory function in children with untreated and treated SSD, and begin the work needed to translate experimental measures into viable clinical protocols.

Cynthia Grimsley-Myers, Ph.D.

Cynthia Grimsley-Myers, Ph.D.

Emory University
The essential role of URB, a novel secreted protein, in cochlear development and planar cell polarity signaling

Hearing depends on highly structured hair bundles in the cochlea properly oriented towards the lateral border of the cochlear duct. Abnormalities in this hair bundle structure or its orientation results in hearing loss, for example in the hereditary disorder Usher syndrome. However, the molecular mechanisms that build the polarized structure of individual hair cells remain poorly understood. Our research focuses on the role of a novel secreted protein, URB, in hair bundle morphogenesis and cochlear development. In particular, we are testing whether URB functions as part of a Planar Cell Polarity (PCP) signaling pathway, a highly conserved pathway of widespread biological interest. We are also investigating possible links between URB and the Usher syndrome network of proteins. We hope that defining these roles for URB in bundle morphogenesis will help in the design of rational therapies for the treatment of Usher syndrome and other forms of hereditary hearing loss in the future.

Andy K. Groves, Ph.D.

Andy K. Groves, Ph.D.

Baylor College of Medicine
Development of Biomarkers to Study Strial Development and Degeneration

The sensory hair cells of the cochlea are able to detect sound vibrations. Hair cells need a source of potassium that helps them to convert sound energy into electrical energy that is sent to the brain. Hair cells in our cochlea are bathed in a potassium-rich fluid called endolymph, and the potassium is constantly pumped into the endolymph by a specialized group of cells in the cochlea called the stria vascularis. As humans get older, the stria vascularis can degenerate, and so the “battery” that supplies potassium to the cochlea runs down, and we lose our hearing. The goal of this project is to understand how the stria vascularis develops, and to devise ways of looking at changes in this structure with age.

Research areas: the development and regeneration of the inner ear, stria vascularis development

Long-term goal of research: We hope this knowledge may allow us to repair or slow down damage to the cochlea and lessen the effects of age-dependent hearing loss.

Xiying Guan, Ph.D.

Xiying Guan, Ph.D.

Mass Eye and Ear, Harvard Medical School
Hyperacusis caused by abnormalities in auditory mechanics

Many hyperacusis patients have what is called “conductive hyperacusis,” due to mechanical abnormalities of the ear that result in a hypersensitivity to sounds/vibrations transmitted through their bodies. These include the sensation of one’s own voice (autophony), pulse, and body movements such as eye motion and footsteps, as well as sensing the vibrations of items such as vehicles. These symptoms are common among patients who have an opening in the bone encapsulating the inner ear (termed a superior canal dehiscence, a type of pathological third-window lesion).

Compared with hyperacusis stemming from neurosensory issues, conductive hyperacusis has the potential for treatment. Recently, surgical treatment for hyperacusis by changing the mechanics of surrounding structures of the inner ear show mixed results, with some patients experiencing worse symptoms after surgery.

Although these “experimental” surgical treatments in patients are increasing, the mechanisms of conductive hyperacusis are not well understood, and scientific research targeting this problem is lacking. This study aims to understand how mechanical changes in fresh cadaveric specimens with similar gross mechanics as the living can influence the cochlear input drive (an estimate of hearing), resulting in hyperacusis. Our novel intracochlear pressure measurement technique will allow the monitoring of the cochlear input drive as we manipulate the mechanics surrounding the inner ear.

Kristin Hamre, Ph.D.

Kristin Hamre, Ph.D.

University of Tennessee Health Science Center

Evaluation of Stereocilia Morphology in Genotypically Math 1-null Cells in Chimeric Mice

The current time period represents an exciting one in the field of auditory functioning with the advent of stem cells and the identification of molecules that control the formation of hair cells (HCs) holding the promise of creating new HCs. One such molecule is the transcription factor Math1 that has been shown to be critical for HC generation. We have examined environmental interactions in the development of HCs and emphasize its importance in hair cell generation by showing that cells that lack Math1 can form hair cells given the correct context. However, it remains unclear whether or not these cells fully differentiate or become functional. This grant is designed to address this issue by examining the morphology of the region of the hair cell that responds to sound, the stereocilia. Analysis will determine whether this region expresses its characteristic markers in a normal manner and whether they are organized correctly. This experiment will provide useful information for further studying how the mutant HCs develop and mature in the chimeric inner ear. The use of these animals creates a system to gain further understanding of the factors that affect hair cell differentiation, knowledge essential in any corrective therapies.

Michelle L. Hastings, Ph.D.

Michelle L. Hastings, Ph.D.

Rosalind Franklin University of Medicine and Science

Therapeutic correction of Ush1c splicing in a mouse model of usher syndrome

Usher syndrome is the leading genetic cause of combined hearing and vision loss. The long-term objective of this project is to develop therapeutics for the disease. Antisense oligonucleotides (ASOs) will be used in a mouse model of Usher syndrome to correct a specific genetic defect that causes the disease. This work will demonstrate the efficacy of ASOs as a therapeutic for Usher syndrome and will also provide insights about curing the disease.

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