2019

Dunia Abdul-Aziz, M.D.

Dunia Abdul-Aziz, M.D.

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.

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Pierre Apostolides, Ph.D.

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Pierre Apostolides, Ph.D.

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.

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.

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.

Kristi Hendrickson, Ph.D., CCC-SLP

Kristi Hendrickson, Ph.D., CCC-SLP

University of Iowa
Neural correlates of semantic structure in children who are hard of hearing

Mild to severe hearing loss places children at risk for delays in language development. One aspect of language that is affected is vocabulary development; children who are hard of hearing tend to know less about word meanings than their typical hearing peers. This gap in vocabulary skills is crucial because vocabulary is one of the strongest predictors of academic achievement. Therefore, it is essential to examine factors that are both: 1) amenable to change through intervention, and 2) influence vocabulary knowledge, in order to help close the vocabulary gap. One such factor is semantic memory structure (i.e., how the brain groups concepts with common properties). In essence, semantic structure determines how individuals understand and interact with the social and physical world. Yet, very little is known about how children with hearing loss structure semantic information in the brain. This project addresses a critical need by characterizing semantic structure in the brains of children who are hard of hearing, and results will inform vocabulary interventions. Given the predictive validity of vocabulary knowledge for academic achievement, improving vocabulary understanding in children with hearing loss has the potential to impact all aspects of language (form, content, and use).

Kristy J. Lawton, Ph.D.

Kristy J. Lawton, Ph.D.

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.

Anat Lubetzky, Ph.D.

Anat Lubetzky, Ph.D.

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.

Hao Luo, M.D., Ph.D.

Hao Luo, M.D., Ph.D.

Wayne State University
Cochlear electrical stimulation-induced tinnitus suppression and related neural activity change in the rat inferior colliculus

Tinnitus is a prevalent public health problem that affects millions of people and imposes a significant economic burden on society. Cochlear electrical stimulation (CES) is one promising treatment for managing tinnitus. However, little is known about the underlying mechanisms of CES-induced tinnitus suppression. In addition, electrode insertion during surgery can cause acute tissue trauma and cell losses, initiating programmed cell death within the damaged tissue of the cochlea. Recently, we demonstrated that cochlear stimulation suppressed tinnitus-like behaviors in rats, which is accompanied with tinnitus-related neural activity changes. We therefore suggest that CES-induced tinnitus suppression would be more robust when hearing is protected from implant trauma by intra-cochlear application of AM-111, a novel enzyme inhibitor.

David Martinelli, Ph.D.

David Martinelli, Ph.D.

University of Connecticut Health Center
Creation and validation of a novel, genetically induced animal model for hyperacusis

Hyperacusis is a condition in which a person experiences pain at much lower sound levels than listeners with typical hearing. While the presence of outer hair cell afferent neurons is known, it is not known what information the outer hair cells communicate to the brain through these afferents. This project’s hypothesis is that the function of these mysterious afferents is to communicate to the brain when sounds are intense enough to be painful and/or damaging, and that this circuitry is distinct from the cochlea-to-brain circuitry that provides general hearing. The hypothesis will be tested using a novel animal model in which a certain protein that is essential for the proposed “pain” circuit is missing. The absence of this protein is predicted to cause a lessening of the perception of auditory pain when high intensity sounds are presented. If true, this research has implications for those suffering from hyperacusis.

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Jameson Mattingly, M.D.

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Jameson Mattingly, M.D.

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).

Vijaya Prakash Krishnan Muthaiah, Ph.D.

Vijaya Prakash Krishnan Muthaiah, Ph.D.

University at Buffalo, the State University of New York
Potential of inhibition of poly ADP-ribose polymerase as a therapeutic approach in blast-induced cochlear and brain injury

Many potential drugs in the preclinical phase for treating different types of noise-induced hearing loss (from blast and non-blast noise) revolve around targeting oxidative stress or interfering in the cell death cascade. Though noise-induced oxidative stress and cell death is well studied in the auditory periphery, the effects of noise exposure on the central auditory system remains understudied, especially in blast noise exposure where both auditory and non-auditory structures in the brain are affected. Impulsive noise (blast wave)-induced hearing loss is different from continuous noise exposure as it is more likely to be accompanied by accelerated cognitive deficits, depression, anxiety, dementia, and brain atrophy. It is well established that poly ADP-ribose polymerase (PARP) is a key mediator of cell death and it is overactivated by oxidative stress. Thus this project will explore the potential of PARP inhibition as a potential therapeutic approach for blast-induced cochlear and brain injury. The dampening of PARP overactivation by its inhibitor 3-aminobenzamide is expected to both mitigate blast noise-induced oxidative stress and to interfere with the cell death cascade, thereby reducing cell death in both the peripheral and central auditory system.

William “Jason” Riggs, Au.D.

William “Jason” Riggs, Au.D.

The Ohio State University
Electrophysiological characteristics in children with auditory neuropathy spectrum disorder

This project will focus on understanding different sites of lesion (impairment) in children with auditory neuropathy spectrum disorder (ANSD). ANSD is a unique form of hearing loss that is thought to occur in approximately 10 to 20 percent of all children with severe to profound sensorineural hearing loss and results in abnormal auditory perception. Neural encoding processes of the auditory nerve in children using electrophysiologic techniques (acoustically and electrically evoked) will be investigated in order to provide objective evidence of peripheral auditory function. Results can then be used to optimize and impact care from the very beginning of cochlear implant use in children with this impairment.

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Gail M. Seigel, Ph.D.

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Gail M. Seigel, Ph.D.

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.

Ian Swinburne, Ph.D.

Ian Swinburne, Ph.D.

Harvard Medical School
Development and Physiology of the Endolymphatic Duct and Sac in Zebrafish

Abnormalities in our sense of hearing and balance are incapacitating in the extreme, and, when subtle, cause psychological distress. Meniere’s disease is an inner ear disease with unclear causes that is inferred from episodes of vertigo, hearing loss, tinnitus, and the sensation of fullness in the ear that can last two to four hours. An unstable inner ear environment is believed to underlie Meniere’s disease. Recently, Swinburne has developed methods to image the live development and physiology of the portion of the Zebrafish ear conserved in humans and believed to be dysfunctional in Meniere’s disease: the endolymphatic duct and sac. With these methods, Ian hopes to gain basic understanding of how the inner ear’s environment is normally maintained and how a defect can lead to a disease.

Classifying the endolymphatic duct and sac cell types and their gene sets using high-throughput single-cell transcriptomics

To understand how the inner ear endolymphatic duct and sac stabilize the inner ear’s environment and to identify ways to restore or elevate this function to mitigate or cure Ménière's disease. The endolymphatic duct and sac play important roles in stabilizing a fluid composition necessary for sensing sound and balance. The recurrent vertigo in Ménière's is likely caused by a malfunction of the endolymphatic sac, causing volume or pressure changes in the inner ear.

Swinburne recently found that the typical-functioning endolymphatic sac periodically inflates and deflates like a balloon, and that specialized cell structures in the sac appear to transiently open, causing the deflation of the endolymphatic sac. The sac, then, appears to act as a relief valve to maintain a consistent volume and pressure within the inner ear. This project will generate a list of endolymphatic sac cell types and the genes governing their function, which will aid in Ménière's diagnosis (which can be delayed due to the range of fluctuating symptoms) and the development of a targeted drug or gene therapy.

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.

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