Mass Eye and Ear, Harvard Medical School
Targeting epigenetics to restore hair cells

Most commonly, deafness is due to loss of cochlear sensory hair cells, which can occur because of genetic diseases, loud noise, certain drugs, or aging, and it can also result in the development of sometimes disabling ringing in the ear (tinnitus) and sound sensitivity (hyperacusis). Balance disorders similarly arise from loss of respective sensory hair cells in the inner ear vestibular organ. Treatments aimed at reversing hearing loss by stimulating the recovery of hair cells are greatly needed. The death of these hair cells in the ear is permanent because the inner ear loses its ability to replenish lost cells once it has matured, which occurs shortly after birth in mice and in the fetus in humans. To reestablish this potential and to recover lost hair cells, this project uses a novel technology to reprogram stem cells from the inner ear to turn into hair cells. This has pointed to a new candidate drug target, lysine-specific demethylase 1 (Lsd1), an epigenetic regulator that appears to be at least partly responsible for this loss of regenerative capacity. By targeting Lsd1, this project will study its role in the formation of hair cells and investigate its potential as a drug target for treatment of hearing loss.

University of Michigan
Novel mechanisms of cortical neuromodulation

Although there is currently no cure for tinnitus, recent experimental studies propose vagus nerve stimulation (VNS) may be a potential treatment to mitigate the condition because VNS releases natural chemicals (neuromodulators) that increase the brain’s ability to change. This is interesting because VNS has previously received Food and Drug Administration approval for treating drug-resistant epilepsy and treatment-resistant major depressive disorder. Despite considerable interest, how neuromodulators released by VNS could be therapeutically useful for tinnitus is unknown. This project will employ cutting-edge techniques to test a novel hypothesis: A major mechanism of action for neuromodulators is that they affect the function of dendrites, the long cable-like structures upon which neurons receive and integrate electrical signals. By identifying how neuromodulators impact the function of dendrites, these experiments may uncover novel targets for developing new treatments for tinnitus.

New York University

Defining myelin’s role in developing vestibular circuits

The vestibular system serves a vital purpose, to stabilize posture and gaze by producing corrective head and body movements. Vestibular circuits are myelinated early in life, suggesting a crucial role in proper balance development. In addition, balance, posture, and gait deficits are common symptoms for patients affected by diseases where myelin breaks down. Myelination alters conduction velocity thus it is crucial for circuit function. Recent studies have shown that the formation of novel myelin plays an essential role in memory formation and learning. The overall goal of this project is to define a role for myelin in vestibular circuit development and postural behaviors. We will investigate the consequences of loss of vestibular myelin on postural development. The work will also establish and validate transformative new tools to selectively disrupt the myelination of genetically defined subsets of neurons. I will test the role of myelin in different circuits for postural behavior, locomotion, and coordination in order to understand myelin’s contributions to circuit function. These novel tools will also permit future investigations into the role of myelin in auditory circuits and the consequences for hearing health.

University of Washington

Aminoglycoside compartmentalization and its role in hair cell death

The goals for this project are to develop new tools that will help the scientific community to deepen our understanding of the vesicular network in hair cells, both during stress and normal conditions. We will develop novel fluorescent probes to mark the different compartments in the vesicular network. This will allow for visualization of the drug as it transitions through various levels within the vesicular network. In order to better analyze these structures, we will pair these images with custom-made image analysis algorithms that will allow us to study vesicles in a deeper way. Overall, these tools will allow us to open new research avenues that will help to further understand how aminoglycosides, and other drugs with ototoxic effects, like cisplatin, a cancer chemotherapy drug, are killing hair cells. Our results could help direct new research and lead to novel therapeutic treatments to avoid further hearing loss in patients undergoing these treatments.

Oregon Health & Science University

Apical cochlear mechanics after cochlear implantation

The long-term research goal is to establish, treat, and prevent cochlear implantation-induced hearing loss. This mechanics project is the first time the vibration of the inner ear has been measured in the presence of a cochlear implant, and there is much to discover—such as measuring the efficacy of drugs that help to suppress scarring, as well as testing different electrode designs, and even extending to other diseases of the inner ear such as Ménière’s disease. I believe that optical coherence tomography has a big role to play in the future of both basic hearing science and hearing restoration.

University of California, Los Angeles
Leveraging automatic speech recognition algorithms to understand how the home listening environment impacts spoken language development among infants with cochlear implants

To develop spoken language, infants must rapidly process thousands of words spoken by caregivers around them each day. This is a daunting task, even for typical hearing infants. It is even harder for infants with cochlear implants as electrical hearing compromises many critical cues for speech perception and language development. The challenges that infants with cochlear implants face have long-term consequences: Starting in early childhood, cochlear implant users perform 1-2 standard deviations below peers with typical hearing on nearly every measure of speech, language, and literacy. My lab investigates how children with hearing loss develop spoken language despite the degraded speech signal that they hear and learn language from. This project addresses the urgent need to identify predictors of speech-language development for pediatric cochlear implant users in infancy.

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.

Mass Eye and Ear

Age-specific cochlear implant programming for optimal hearing performance

Cochlear implants (CI) offer life-altering hearing restoration for deafened individuals who no longer benefit from hearing aid technologies. Despite advances in CI technology, recipients struggle to process complex sounds in real-world environments, such as speech-in-noise and music. Poor performance results from artifacts of the implants (e.g., adjacent channel interaction, distorted signal input) and age-specific biological differences (e.g., neuronal health, auditory plasticity). Our group determined that children with CIs require a better signal input than adults with CIs to achieve the same level of performance. Additional evidence demonstrates that auditory signal blurring in adults is less impactful on performance outcomes. These findings imply that age should be considered when programming a CI. However, the current clinical practice largely adopts a one-size-fits-all approach toward CI management and uses programming parameters defined by adult CI users. Our project’s main objective is to understand how to better program CIs in children to improve complex sound processing by taking into context the listening environment (e.g., complex sound processing in a crowded room), differences between age groups, and variations in needs or anatomy between individuals.

Purdue University
Influence of individual pathophysiology and cognitive profiles on noise tolerance and noise reduction outcomes

Listening to speech in noisy environments can be significantly challenging for people with hearing loss, even with help from hearing aids. Current digital hearing aids are commonly equipped with noise-reduction algorithms; however, noise-reduction processing introduces inevitable distortions of speech cues while attenuating noise. It is known that hearing-impaired listeners with similar audiograms react very differently to background noise and noise-reduction processing in hearing aids, but the biological mechanisms contributing to that variability is particularly understudied.

This project is focused on combining an array of physiological and psychophysical measures to obtain comprehensive hearing and cognitive profiles for listeners. We hope this approach will allow us to explain individual noise tolerance and sensitivity to speech-cue distortions induced by noise-reduction processing in hearing aids. With these distinct biological profiles, we will have a deeper understanding of individual differences in listeners and how those profiles affect communication outcomes across patients who are clinically classified with the same hearing status. This study’s results will assist in the development of objective diagnostics for hearing interventions tailored to individual needs.

Washington State University Vancouver
Characterizing noise-induced synaptic loss in the zebrafish lateral line

Recent findings indicate that noise levels thought to be safe for auditory sensory hair cells may actually damage hearing at the level of peripheral auditory synapses. Little is known about this type of damage, which is usually not detectable using traditional audiograms and so has been dubbed “hidden hearing loss.” This project will study noise-induced hearing loss using zebrafish, where the auditory sensory cells are easily accessible and highly similar to those in humans, in order to uncover mechanisms of synaptic damage due to noise exposure. It will use a combination of techniques including immunohistochemistry and calcium imaging to directly examine the timing and extent of noise damage on peripheral auditory synapses.

New York University
A balancing act in hearing and vestibular loss: assessing auditory contribution to multisensory integration for postural control in an immersive virtual environment

Humans are surrounded by sensory information and need to select the most reliable ones in order to maintain balance and disregard input that might make us fall. This is called “weighting” and “reweighting” of sensory inputs. This project uses a virtual reality, head-mounted display (HMD) application to test balance with varying sensory cues, including visual, somatosensory, and auditory. With this application, an individual’s ability to weight and reweight visual and auditory information based on their head and eye movement and their postural sway can be identified. This method has been successfully used in prior studies to test responses to visual changes. The novelty of this project includes: the addition of auditory cues scaled to well-established visual cues; the measurement of head movement via the HMD; and the portability, simplicity, and affordability of the HMD system, which increases the likelihood of future clinical translation of this assessment. In this current pilot study, 12 individuals with unilateral sensorineural hearing loss will be compared with 12 individuals with unilateral peripheral vestibular hypofunction and with 24 healthy controls. Wearing the HMD, they will go through a series of postural tasks with several combinations of visual and auditory cues of two intensity levels while standing on either a stable floor (all somatosensory cues available) or a compliant foam (to reduce somatosensory input). Their postural sway and head movement responses to the stimuli will be calculated, and gaze patterns among the groups will be compared, along with exploring whether changes in eye position can explain changes in head movement.

University of Florida
Contributions of auditory and somatosensory feedback to speech motor control in congenitally deaf 9- to-10-year-olds and adults

Cochlear implants have led to stunning advances in prospects for children with congenital hearing loss to acquire spoken language in a typical manner, but problems persist. In particular, children with CIs show much larger deficits in acquiring sensitivity to the individual speech sounds of language (phonological structure) than in acquiring vocabulary and syntax. This project will test the hypothesis that the acquisition of detailed phonological representations would be facilitated by a stronger emphasis on the speech motor control associated with producing those representations. This approach is novel because most interventions for children with CIs focus strongly on listening to spoken language, which may be overlooking the importance of practice in producing language, an idea we will examine. To achieve that objective, we will observe speech motor control directly in speakers with congenital hearing loss and CIs, with and without sensory feedback.

The Ohio State University
Differentiating Ménière's disease and vestibular migraine using audiometry and vestibular threshold measurements

Patients presenting with recurrent episodic vertigo (dizziness), such as Ménière's disease (MD) and vestibular migraine (VM), can present a diagnostic challenge as they can both produce recurrent vertigo, tinnitus, motion intolerance, and hearing loss. Further complicating this issue is that the diagnosis of each is based upon patient history with little contribution from an objective measure. Previous attempts to better differentiate MD and VM have included a variety of auditory and vestibular tests, but these evaluations have demonstrated limitations or not shown the appropriate sensitivity and specificity to be used in the clinical setting. Recently, vestibular perceptual threshold testing has shown the potential to better differentiate MD and VM by demonstrating different and opposite trends with testing, and these evaluations are ongoing. In addition to vestibular evaluations, audiometry (hearing testing) is a mainstay of testing in those with vestibular symptoms, especially with any concern of MD, and is thus commonly available. Standard hearing testing, however, is not sensitive or specific enough alone to differentiate MD and VM, but this project’s hypothesis is that combining audiograms with vestibular perceptual threshold testing will result in a diagnostic power greater than that possible with either option used individually. The population of patients with MD and VM is an ideal setting to examine similarities and differences, as MD is classically an otologic disease and VM, in theory, has little to do with auditory function. Additionally, this same principal can be applied to any disease process that affects both vestibular and auditory function (such as tumors, ototoxicity).

University of Pittsburgh

Hair cell regeneration in the mature cochlea: investigating new models to reprogram cochlear epithelial cells into hair cells 

Sensory hair cells in the inner ear detect mechanical auditory stimulation and convert it into a signal that the brain can interpret. Hair cells are susceptible to damage from loud noises and some medications. Our lab investigates the ability of nonsensory cells in our inner ears to be able to regenerate lost hair cells. We regenerate cells in the ear by converting nonsensory cells into sensory cells through genetic reprogramming. Key hair cell-inducing program genes are expressed in non-hair cells and partially convert them into hair cells. There are multiple types of nonsensory cells in the inner ear and they are all important for different reasons. In addition, they are in different locations relative to the sensory hair cells. In order to better understand the ability of different groups of cells to restore hearing, we need to be able to isolate different populations of cells. The funded project will allow us to create a new model to target specific nonsensory cells within the inner ear to better understand how these cells can be converted into hair cells. By using this new model, we can specifically investigate cells near the sensory hair cells and understand how they can be reprogrammed. Our lab is also very interested in how the partial loss of genes in the inner ear can affect cellular identities. In addition to targeting specific cells in the ear, we will investigate whether the partial loss of a protein in nonsensory cells may improve their ability to be converted into sensory cells. This information will allow us to further explore possible therapeutic targets for hearing restoration.

University of Tennessee

Auditory neuroplasticity following experience with cochlear implants

Cochlear implants provide several benefits to older adults, though the amount of benefit varies across people. The greatest improvements in speech understanding abilities usually happen within the first 6 months after implantation. It is generally accepted that these gains in performance are a result of neural changes in the auditory system, but while there is strong evidence of neural changes following cochlear implantation in children, there is limited evidence in adults with hearing loss in both ears. This study will examine how neural responses change as a function of the amount of cochlear implant use, when compared to longstanding hearing aid use. Listeners who are candidates for a cochlear implant (who either decide to pursue implantation or to keep wearing hearing aids) will be tested at several time points, from pre-implantation and up to 6 months after implantation. The results of this project will improve our understanding of the impact of cochlear implant use on neural responses in older adults, and their relationship with the ability to understand speech.

Rice University
Understanding the biophysics and protein biomarkers of Ménière’s disease via optical coherence tomography imaging

Our sense of hearing and balance depends on maintaining proper fluid balance in a specialized fluid in the inner ear called the endolymph. Ménière’s disease is an inner ear disorder associated with increased fluid pressure in the endolymph that involves dizziness, hearing loss, and tinnitus. Ménière’s disease is difficult to diagnose and treat clinically, which is a source of frustration for both physicians and patients. Part of the barrier to diagnosing and treating Ménière’s disease is the lack of imaging tools to study the inner ear and a poor understanding of the underlying causes. The goal of this research is to develop an approach to noninvasively image the inner ear and study the internal structures in the vestibular system in typical and disease states. We will utilize optical coherence tomography (OCT), a technique capable of imaging through bone, and observe changes in the fluid compartments in the inner ear. The expected outcome of this research will be the establishment of a powerful non-invasive imaging platform of the inner ear that will enable us to test hypotheses, in living animals, on how ion transport regulates the endolymph, how disorders of ion transport cause disruption of endolymphatic fluid, and how the expression of different biomarkers lead to disorders of ion transport.

University at Buffalo, the State University of New York
Targeting microglial activation in hyperacusis

Hyperacusis is a hearing condition in which moderate-level noise becomes intolerable. The Centers for Disease Control estimates that nearly 6 percent of the U.S. population experiences some form of hyperacusis, ranging from mild discomfort to severe medical disability, with a diminished quality of life. There is currently no cure for hyperacusis. Therefore, there is a pressing medical need for targeted treatment approaches for the permanent relief of hyperacusis. This study will focus on the involvement of inflammation in the sound processing centers of the brain following noise exposure by using anti-inflammatory drugs to attempt to reduce inflammation and prevent hyperacusis after noise exposure. Results from this study will test the feasibility of anti-inflammatory drugs as a potential therapy for hyperacusis and hearing loss caused by excessive noise exposure.

University of Miami Miller School of Medicine
Elucidating the development of the otic lineage using stem cell-derived organoid systems

One of the main causes of hearing loss is the damage to and/or loss of specialized, cochlear hair cells and neurons, which are ultimately responsible for our sense of hearing. Stem cell–derived 3D inner ear organoids (lab-grown, simplified mini-organs) provide an opportunity to study hair cells and sensory neurons in a dish. However, the system is in its infancy, and hair cell–containing organoids are difficult to produce and maintain. This project will use a stem cell–derived 3D inner ear organoid system as a model to study mammalian inner ear development. The developmental knowledge gained will then be used to optimize the efficacy of the organoid system. As such, the results will progress our understanding of how the inner ear forms and functions, with the improved organoid system then allowing us directly to elucidate the factors causing the congenital hearing loss.

University of Iowa

The role of inner ear lymphatics in the foreign body response to cochlear implantation

To develop spoken language, infants must rapidly process thousands of words spoken by caregivers around them each day. This is a daunting task, even for typical hearing infants. It is even harder for infants with cochlear implants as electrical hearing compromises many critical cues for speech perception and language development. The challenges that infants with cochlear implants face have long-term consequences: Starting in early childhood, cochlear implant users perform 1-2 standard deviations below peers with typical hearing on nearly every measure of speech, language, and literacy. My lab investigates how children with hearing loss develop spoken language despite the degraded speech signal that they hear and learn language from. This project addresses the urgent need to identify predictors of speech-language development for pediatric cochlear implant users in infancy.

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.

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.