Joseph Toscano, Ph.D.

Joseph Toscano, Ph.D.

Villanova University
Cortical EEG measure of speech sound encoding for hearing assessment

Accurate speech recognition depends on fine-grained acoustic cues in the speech signal. Deficits in how these cues are processed may be informative for detecting hearing loss, and particularly for identifying auditory neuropathy, a problem with the way the brain processes sounds. Diagnosing auditory neuropathy in newborns and infants is particularly challenging, as it is often difficult to distinguish it from sensorineural hearing loss using current measurement approaches. Speech tests that measure cortical responses may allow us to overcome this problem. The current project uses electroencephalogram (EEG) techniques to measure brain responses to specific acoustic cues in speech (e.g., the difference between “d” and “t”). These data will be compared with listeners’ speech recognition accuracy, pure-tone audiograms, and self-reported hearing difficulty to determine how these responses vary as a function of hearing status and may be used to detect early stages of hearing loss.

Richard S. Tyler, Ph.D.

Richard S. Tyler, Ph.D.

University of Iowa
Literature review on hyperacusis, recruitment, misophonia, phonophobia, and mechanisms

The funded research will result in a thorough review of the literature, documenting causes, mechanisms, measurement and treatment. It is the intent that the review will provide a comprehensive document that clinicians and researchers will be able to use to understand hyperacusis and to improve current treatment approaches, and to suggest future treatment directions.

Research areas: cochlear implants, tinnitus

Long-term goal of research: The long-term goal is to provide a systematic, comprehensive review of the entire field of hyperacusis. By providing such a widespread and comprehensive review of hyperacusis, we should be able to provide the background necessary to direct research to find cures.

Lisa D. Urness, Ph.D.

Lisa D. Urness, Ph.D.

University of Utah

FGF-regulated hearing loss genes: fast-tracking to functional analysis

With the myriad roles of fibroblast growth factors (FGFs) in multiple stages of ear development, it is not surprising that some human hearing loss syndromes are caused by mutations affecting FGFs and their receptors. However, little is known about the genes that are controlled by FGFs. Because FGF signals are reused during later stages of otic innervation, morphogenesis, and sensory cell differentiation, the FGF target genes we identify during placodogenesis may also be targets of later FGF signaling events and could provide many new candidates for hearing and/or balance disorders, thereby impacting diagnosis. Importantly, elucidating the functions of these genes may suggest potential therapeutic interventions. FGFs are required to initiate otic development and are subsequently reused during morphogenesis and sensory development. Our long-term objective is to identify FGF effector genes and to determine their function and relevance to human deafness by analyzing mouse mutants. Specifically, we propose to isolate RNA from pre-otic ectoderm of control and FGF-deficient embryos and perform an expression profiling experiment utilizing a “gene-trap microarray.” This will identify embryonic stem cell lines that carry mutations in FGF target genes. Selected cell lines will be used to generate the corresponding mutant mouse strains for functional studies of hearing and balance.

Kenneth Vaden, Ph.D.

Kenneth Vaden, Ph.D.

Medical University of South Carolina
Adaptive control of auditory representations in listeners with central auditory processing disorder

Central Auditory Processing Disorder (CAPD) is typically defined as impairment in the ability to listen and use auditory information because of atypical function within the central auditory system. The current study uses neuroimaging to characterize CAPD in older adults whose impaired auditory processing abilities could be driven by cognitive and hearing-related declines, in addition to differences in central auditory nervous system function. Functional neuroimaging experiments will be used to test the hypothesis that older adults with CAPD fail to benefit from top-down enhancement of auditory cortex representations for speech. In particular, activation of the adaptive control system in cingulo-opercular cortex is predicted to enhance speech representations in auditory cortex for normal listeners, but not to the same extent for older adults with CAPD. This project aims to develop methods to assess the quality of speech representations based on brain activity and characterize top-down control systems that interact with auditory cortex. The results of this study will improve our understanding of a specific top-down control mechanism, and examine when and how adaptive control enhances speech recognition for people with CAPD.

Babak Vazifehkhahghaffari, Ph.D.

Babak Vazifehkhahghaffari, Ph.D.

Washington University in St. Louis
Enhancing cochlear implant performance through development of improved auditory nerve fiber biophysical models with a combined wet lab and dry lab approach

While the cochlear implant (CI) allows access to sound for those with severe hearing loss, perceiving pitch and music and understanding speech in the presence of reverberation, multiple speakers, or background noise remains very limited. To improve the CI, it is important to understand how it affects neuronal (nerve cell) behavior in the inner ear by uncovering the properties of neuronal excitability. Neuronal excitability mainly depends on the movement of different ions through the cell membrane and is affected by components such as ionic currents and ion channels. A more precise model of the auditory nerve combined with models of the CI electric field potential will help improve CI stimulation methods by understanding stimulus-response phenomena and their underlying biophysical mechanisms.

A. Catalina Vélez-Ortega, Ph.D.

A. Catalina Vélez-Ortega, Ph.D.

University of Kentucky
TRPA 1 activation in the cochlea as an intrinsic mechanism of protection against noise-induced hearing loss

TRPA1 is an ion channel mostly known for its role as an “irritant sensor” in pain-sensing neurons. Functional TRPA1 channels are also expressed in the inner ear. However, given that genetically modified mice lacking TRPA1 channels have typical hearing and balance, the role of these channels in the inner ear remains unknown. Noise exposure leads to the production of some of the cellular “irritants” that activate TRPA1 channels. Therefore, we hypothesized that TRPA1 channels are able to sense noise-induced damage in the cochlea. When we exposed adult mice to mild noise levels, we observed a temporary increase in hearing thresholds that lasted several days (making it harder to hear soft sounds). Mice lacking TRPA1 channels, however, recovered significantly faster than mice with typical TRPA1 expression. This project will explore whether, after noise exposure, TRPA1 activation contributes to the temporary shift in hearing thresholds to allow the cochlea enough time to repair or recover from the noise-induced tissue damage. This project will help us better understand the protective effects of TRPA1 activation after noise exposure, and the specific cell types within the inner ear that are involved in this process.

Philippe Vincent, Ph.D.

Philippe Vincent, Ph.D.

Johns Hopkins University
Investigating mechanisms of degeneration of ribbon synapses between auditory inner hair cells and type 1 afferent nerve fibers after noise trauma in mammals

Sensory hair cells in the inner ear pick up the sound signal and transmit it to auditory nerve fibers through chemical synapses by releasing the transmitter glutamate; auditory nerve fibers then transmit the sound-coding signal to the brain. Sound intensity is encoded by the amount of glutamate released by the hair cell, leading to glutamate receptor activation and then action potential firing in auditory nerve fibers. During noise exposure, auditory nerve fiber endings can be damaged short- or long-term, most likely due to an excessive influx of calcium. This phenomenon is called excitotoxicity, but the underlying mechanisms are not completely understood. This project will investigate molecular mechanisms of synaptic transmission between hair cells and auditory nerve fibers and how they are affected after noise trauma.

Bradley J. Walters, Ph.D.

Bradley J. Walters, Ph.D.

St. Jude Children's Research Hospital
Potential regeneration of auditory hair cells in the opossum, Monodelphis domestica

Millions of Americans suffer from sensorineural hearing loss: a disability that is permanent and on the rise as the iPod generation ages. For those who would seek to regain hearing, one potential solution may be offered by the regeneration of sensory hair cells within the inner ear. However, this is, as yet, unachievable in humans. Despite this, many non-mammalian vertebrates, like fish, amphibians, reptiles, and birds, naturally regenerate their sensory cells and regain their ability to hear, suggesting that humans lost this regenerative potential at some point during their evolution. It is hoped that discovering the critical differences between the hearing organs of these non-mammals and humans will allow us to manipulate the human ear to behave more like a bird’s or a reptile’s, and allow for human auditory cells to be regenerated. However, there are many differences between the ear of a human and that of a chicken, and narrowing down the search for the most important differences represents a daunting task. Marsupials, like the gray short-tailed opossum, represent an intermediate group, sharing many similarities with both humans and with non-mammals. Of particular interest, supporting cells in the opossum inner ear retain the ability to proliferate well after birth, an indication that these marsupials may possess some regenerative ability. This project aims to determine whether or not opossums are capable of hair cell regeneration or recovery of hearing and to characterize the extent of supporting cell proliferation that occurs both during development and after hearing loss. From this, comparisons will be able to be made between the various model species (e.g. chickens, opossums, humans) to gain a better understanding of which differences between the various hearing organs are essential for regeneration, and which differences are detrimental or unrelated.

Research area: hair cell regeneration

Long-term goal of research: The long term goal of the proposed research is to apply what we learn from proliferative and potentially regenerative processes in opossums and incorporate these discoveries into a comparative approach where we may discover key differences that either allow for regeneration to occur in the mammalian cochlea, or, conversely, prevent it. Once these differences are identified, we can begin to develop drugs and/or gene therapies for pre-clinical testing.

Brandon Walters, Ph.D.

Brandon Walters, Ph.D.

St. Jude Children's Research Hospital
Conditional Reprogramming of Otic Stem Cells: Development of a Novel In-Vitro Hair Cell Line

One of the major limitations in studies of hearing loss is the inability to study the phenomenon of hearing in a petri dish (in-vitro), thereby limiting the use of tools that are essential for understanding the causes of, and treatments for, hearing loss. In addition to this obvious limitation, the use of in-vitro studies is hindered primarily by technical limitations related to the low abundance of hair cells that are responsible for our sense of hearing. Researchers have attempted to overcome the issue of insufficient cell numbers by creating cell lines that mimic the properties of human hair cells, but success of these approaches have been limited. The goal of the proposed experiments is to utilize approaches from other fields to create a cell line that will allow for infinite proliferation of low abundance cells that can be turned into hair cells when needed, thus providing a limitless supply of hair cells for the study of hearing loss.

Research area: Hair Cells; Hearing Loss

Long-term goal of research: To identify drugs that can modulate the differentiation of hair cells, focusing primarily on compounds that promote hair cell formation, which we believe, will be of therapeutic benefit to people with hearing loss. To this end, we plan to utilize high throughput screening to test hundreds of thousands of compounds for potential effects on hair cell formation. We plan to combine the hair cell line that we create with various tools for tracking the developmental state of the cell to aid our evaluation of drugs that increase the number of all viable hair cells and to potentially extend our investigation to specific subtypes of hair cells that play distinct roles in hearing loss.

Ilse Wambacq, Ph.D.

Ilse Wambacq, Ph.D.

Montclair State University

Neurophysiological and psychoacoustic indices of binaural processing in adults

The overall goal of the proposed research is to investigate neurophysiological and psychoacoustic indices of binaural processing in adults with normal and impaired hearing. In order to develop and implement effective remediation for individuals with sensorineural hearing loss, it is essential to determine a straightforward means to identify binaural processing problems. It is particularly important to ascertain the relationship between neurophysiological and psychoacoustic measures because there are many individuals for whom it is difficult to obtain behavioral responses. In the proposed study we will evaluate the effect of sensorineural hearing loss on processing of interaural intensity differences (IIDs) and determine the relationship between neurophysiological and behavioral measures of sensitivity to IIDs. Results will provide the information necessary to assess binaural processing of IIDs and to develop remediation strategies for individuals with sensorineural hearing loss.

Guoqiang Wan, Ph.D.

Guoqiang Wan, Ph.D.

University of Michigan
Functions of supporting cell-derived neurotrophin-3 in noise-induced hearing loss

Emerging evidence shows that “benign” noise levels, initially thought to only result in temporary hearing impairment, can cause irreversible damage to the connections between hair cells the auditory neurons, and the synapses, which can lead to a permanent hearing decrease later in life. Currently, we have a limited understanding of how these synapses are maintained in the healthy cochlea and how they can be regenerated after noise overexposure. The overall goal of this study is to examine the potential of the neurotrophic factor, neurotrophin-3 (NT-3), to assist in preserving or regenerating these synaptic connections in cochlea after noise overexposure. We have generated genetic mouse models that allow us to remove or overproduce NT-3 from the supporting cells, which are the cells surrounding the sensory hair cells. We have found that NT-3 produced from the supporting cells is critical for regulation of hearing sensitivity and synaptic density in the cochlea. Based on this finding, we propose that NT-3 may present a novel therapeutic agent for NIHL. In this proposal, we will use these mouse models to address the following questions: does removing NT-3 exacerbate the damage to the loss of synapses and hearing sensitivity after noise overexposure? Does overproducing NT-3 prevent or promote recovery from noise-induced loss of synapses and hearing? These experiments will provide us with a better understanding of the pathophysiology of NIHL and the potential of neurotrophin-based therapeutics for treating hearing loss.

Bryan Ward, M.D.

Bryan Ward, M.D.

Johns Hopkins University School of Medicine
The effect of fluid volume on vestibular function and adaptation in patients with Ménière’s disease

Individuals with Ménière’s disease experience spontaneous attacks of spinning vertigo, ear fullness, tinnitus, and hearing loss. We do not know the pathophysiology of Ménière’s disease. On some tests of the inner ear, individuals with Ménière’s have responses indicating inner ear balance is not functioning well (absent caloric responses), but other tests suggesting it is (head impulse testing). The reason for this is debated. Strong magnetic resonance imaging (MRI) scanners cause dizziness and nystagmus (back-and-forth beating of the eyes from inner ear stimulation) in all healthy humans due to magnetic vestibular stimulation (MVS). The combination of MVS and MRI imaging provides a unique opportunity to better understand the physiology of patients with Ménière’s disease. This project will assess nystagmus in strong MRI machines in individuals with Ménière’s and compare this to tests of vestibular function and to imaging of the inner ear.

Patricia A. White, Ph.D.

Patricia A. White, Ph.D.

House Ear Institute

“Forkhead box o” transcription factors and mammalian cochlear regeneration

To restore hearing to the deaf will require an understanding of the genes that regulate proliferation of adult supporting cells. While tumor suppressors, such as Cdkn1b, have well described functions in the cochlea, upstream regulators of such genes are not understood. White’s research will characterize the expression and function of Foxo3 (Forkhead box O3), a candidate regulator of Cdkn1b, in supporting cells.

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Ross Williamson, Ph.D.

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Ross Williamson, Ph.D.

University of Pittsburgh
Characterizing tinnitus-induced changes in auditory corticofugal networks

The irrepressible perception of sounds without an external sound source is a symptom that is present in a number of different auditory dysfunctions. It is the primary complaint of tinnitus sufferers, who report significant “ringing” in the ears, and it is one of the primary sensory symptoms present in schizophrenia sufferers who “hear voices.” Tinnitus is thought to reflect a disorder in gain: A loss of input at the periphery shifts the balance of excitation and inhibition throughout the auditory hierarchy leading to excess hyperexcitability, which then leads to the perception of phantom sounds. This project aims to quantify how such “phantom sound” signals are routed and broadcast across the entire brain, and to understand how these signals impact our ability to perceive sound. Identifying improper regulation of brain-wide neural circuits in this way will provide a foundation for the development of new treatments for tinnitus and other hearing disorders.

Daniel Winkowski, Ph.D.

Daniel Winkowski, Ph.D.

University of Maryland
Noise trauma induced reorganization of the auditory cortex

Tinnitus (‘ringing in the ears’) is a debilitating condition that is experienced by millions of people worldwide. Tinnitus is frequently seen after noise trauma to the ear. One of the core hypotheses of the etiology of tinnitus is that the percept of ‘ringing in the ears’ is generated by changes in patterns of neural activity in brain circuits at many levels of the auditory pathway. One brain area thought to be at least partly responsible for the tinnitus percept is the primary auditory cortex (A1). However, the precise changes in neural activity within local neuron populations have not been investigated directly. The goal of the proposed project is to probe how noise trauma affects both large- and local-scale organization of A1 brain circuits with unprecedented spatial and cellular resolution in an animal model of tinnitus. Proposed experiments will use state-of-the-art optical imaging approaches to investigate how entire auditory cortical areas (large-scale) and auditory cortical microcircuits (local-scale) are disrupted by noise trauma. A multi-level understanding of circuit dynamics underlying tinnitus (from single neurons to complete representations) will enhance our understanding of precisely how cortical circuits remodel after noise trauma and, in turn, develop and identify strategies by which this debilitating condition can be repaired.

Victor Wong, Ph.D.

Victor Wong, Ph.D.

Burke Neurological Institute, Weill Cornell Medicine
Targeting tubulin acetylation in spiral ganglion neurons for the treatment of hearing loss

Both the success of cochlear implants and of future therapeutic approaches critically depend on the integrity of spiral ganglion neurons and the availability of functional neurites (axons) for direct stimulation. Since very little is known about how to promote spiral ganglion neuron neurite growth, there is a critical need to understand how to reinforce these peripheral neurites to regenerate. Many of the molecular players that facilitate regeneration have been characterized in both the peripheral and central nervous systems. Among these are microtubules, which are a major mediator of the overall extension, consolidation, and navigation of the growing axon. In addition to providing structural support for the growth and targeting of axons, microtubules make up the major molecular “tracks” for transporting cargoes necessary for proper neurite function and growth. α-Tubulin, a major component of these tracks, can undergo a number of post-translational modifications which alter stability, intracellular transport, and axonal growth. α-Tubulin acetylation is an attractive target in particular since α-tubulin acetylation-promoting drugs have been found to increase neurite growth in injured neurons and to promote movement of intracellular cargoes such as mitochondria and mRNA. This project will examine how enhancing α-tubulin acetylation can alter the course of functional repair and regeneration of the molecular tracks after age-related and noise-induced hearing loss, thereby restoring auditory function.

Megan Beers Wood, Ph.D.

Megan Beers Wood, Ph.D.

Johns Hopkins University School of Medicine
Type II auditory nerve fibers as instigators of the cochlear immune response after acoustic trauma

A subset of patients with hyperacusis experience pain in the presence of typically tolerated sound. Little is known about the origin of this pain. One hypothesis is that the type II auditory nerve fibers (type II neurons) of the inner ear may act as pain receptors after exposure to damaging levels of noise (acoustic damage). Our lab has shown that type II neurons share key characteristics with pain neurons: They respond to tissue damage; they are hyperactive after acoustic damage; and they express genes similar to pain neurons, such as the gene for CGRP-alpha. However, type II neurons are not the only cell types that respond to acoustic damage. The immune system responds quickly after damaging noise exposure. In other systems of the body such as the skin, CGRP-alpha can affect immune cell function. This project looks at the expression of CGRP-alpha in type II neurons after noise exposure. CGRP-alpha will be blocked during noise exposure to see if this affects the immune response to tissue damage.

Julian R A Wooltorton, Ph.D.

Julian R A Wooltorton, Ph.D.

University of Pennsylvania

Probing the inner hair cell bundle displacement-quantal synaptic response transfer function

How do submicron displacements of hair bundles on inner hair cells lead to a neural code perceived as sound? This proposal investigates the critical relationship (or transfer function) between hair bundle displacements and afferent fiber bouton responses in the gerbil cochlea. Understanding how we encode the acoustic wave into sound is vital to hearing research. By investigating the relationship between the response to acoustic waves of sensory cells in the cochlea and the resulting postsynaptic neuronal response, we will provide vital information on how the first synapse in the auditory pathway works. This is the basic step carried out by cochlear prostheses. Further insight into the biological details of this encoding step promise new insight into how to improve the design and performance of cochlear prostheses, and help to further ameliorate hearing loss and deafness. Mechanical energy of an acoustic wave enters the ear en route to the cochlea where it is translated into the electrical signals of the auditory nerve. This process involves numerous steps dependent upon the unique architecture of the mammalian ear and various specialized cellular processes to maintain fidelity in reporting frequency, amplitude, timing, and range of auditory stimuli. The inner hair cell processes acoustic waves in the cochlea. A hair bundle atop this cell senses acoustic stimulus and allows current to flow into the hair cell. This ultimately results in neurotransmitter release onto an afferent fiber bouton and subsequent sound perception. One of the true wonders of the biological world is the ability of the auditory system to detect the nearly molecular scale displacements of the hair bundle that result from acoustic wave stimulation. How these tiny displacements lead to a neural code that we perceive as sound is poorly understood. In this application, we propose to define the quantitative relationship (transfer function) between inner hair cell bundle displacement and the quantal response in the afferent fiber bouton.

Calvin Wu, Ph.D.

Calvin Wu, Ph.D.

University of Michigan
Development and transmission of the tinnitus neural code

Noise overexposure is a common risk factor of tinnitus, and is thus used as a common tinnitus inducer in animal research. However, noise exposure does not always cause tinnitus, and researchers would rely on behavioral testing to infer an animal’s subjective pathology. However, behavioral tests only work under the assumption that tinnitus is unchanging during the long testing period, which does not reflect the dynamic nature of tinnitus as well as ignoring variability. This inability to measure tinnitus within a short time window impedes our understanding of its emergence and progression. The project addresses these limitations through bypassing behavioral testing and directly identifying and locating an objective code for tinnitus in real-time spiking neurons. Using a novel data-driven approach, we can pinpoint exactly when/where tinnitus emerges and examine how noise trauma triggers and transmits the tinnitus signal throughout the auditory pathway.

Hsiao-Huei (Juli) Wu, Ph.D.

Hsiao-Huei (Juli) Wu, Ph.D.

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