2024

Franziska Auer, Ph.D.

Franziska Auer, Ph.D.

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.

Francisco Barros-Becker, Ph.D.

Francisco Barros-Becker, Ph.D.

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.

Divya Chari, M.D.

Divya Chari, M.D.

Mass Eye and Ear

Auditory and vestibular phenotype characterization of a Ménière’s disease model in humans and mice with X-linked hypophosphatemia

Our group has begun to segregate the pool of Ménière’s disease patients into distinct subtypes based upon specific clinical characteristics and morphologic features of the inner ear endolymphatic sac and vestibular aqueduct. One cohort—designated MDhp—demonstrated on histopathology and radiologic imaging an incompletely developed (hypoplastic) endolymphatic sac and vestibular aqueduct and had a high comorbid prevalence of X-linked hypophosphatemia. XLH is a genetic phosphate metabolism and bone growth disorder caused by a loss-of-function variant in the Phex gene. The high coincidence of XLH in the MDhp cohort led to the hypothesis that the two disorders may have etiologic similarities. Our preliminary studies suggest that the Phex gene-deficient XLH mouse also recapitulates clinical features of the MDhp cohort: hearing loss and balance dysfunction, endolymphatic hydrops, and hypoplasia of the endolymphatic sac and vestibular aqueduct. During this project we will determine whether the inner ear phenotype of humans with XLH generally resembles that of MDhp, and whether the XLH mouse model also exhibits an MDhp phenotype. Characterizing the MDhp phenotype within the context of patients with XLH and a Phex-deficient mouse model is a critical first step toward investigating the pathophysiology of MD and elucidating the genetic etiology of the MDhp subgroup. This research may demonstrate that the Phex gene-deficient mouse can be used as a reliable animal model of the MDhp subtype, which will pave the way for future studies of the role of the Phex gene mutation in MD patients and, more generally, the genetic basis of this complex disease. 

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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.

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Nicole Tin-Lok Jiam, M.D.

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Nicole Tin-Lok Jiam, M.D.

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.

Carolyn McClaskey, Ph.D.

Carolyn McClaskey, Ph.D.

Medical University of South Carolina

Age and hearing loss effects on subcortical envelope encoding

Generously funded by Royal Arch Research Assistance

Melissa McGovern, Ph.D.

Melissa McGovern, Ph.D.

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.

Sharlen Moore, Ph.D.

Sharlen Moore, Ph.D.

Johns Hopkins University

Modulation of neuro-glial cortical networks during tinnitus

My long term goals are to understand the complexity and temporal sequencing of tinnitus effectors with an integrative perspective, considering the interplay of the diverse cell types that might promote the development and maintenance of tinnitus to provide an updated interpretation of this disorder. Additionally, to use glial cells as a key therapeutic target to treat tinnitus.

Generously funded by the Les Paul Foundation

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Melissa Polonenko, Ph.D.

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Melissa Polonenko, Ph.D.

University of Minnesota–Twin Cities

Identifying hearing loss through neural responses to engaging stories

Spoken language acquisition in children with hearing loss relies on early identification of hearing loss followed by timely fitting of hearing devices to ensure they receive an adequate representation of the speech that they need to hear. Yet current tests for young children rely on non-speech stimuli, which are processed differently by hearing aids and do not fully capture the complexity of speech. This project will develop a new and efficient test - called multiband peaky speech - that uses engaging narrated stories and records responses from the surface of the head (EEG) to identify frequency-specific hearing loss. Computer modeling and EEG experiments in adults will determine the best combination of parameters and stories to speed up the testing for use in children, and evaluate the test’s ability to identify hearing loss. This work lays the necessary groundwork for extending this method to children and paves the way for clinics to use this test as a hearing screener for young children–and ultimately our ability to provide timely, enhanced information to support spoken language development.

The long-term goal is to develop an engaging, objective clinical test that uses stories to identify hearing loss in young children and evaluate changes to their responses to the same speech through hearing aids. This goal addresses two important needs identified by the U.S.’s Early Hearing Detection and Intervention (EHDI) program, and will positively impact the developmental trajectory of thousands of children who need monitoring of their hearing status and evaluation of outcomes with their hearing devices.

Generously funded by Royal Arch Research Assistance

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Robert Raphael, Ph.D.

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Robert Raphael, Ph.D.

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.

Wei Sun, Ph.D.

Wei Sun, Ph.D.

University at Buffalo

FOXG1 gene mutation-caused hyperacusis—a novel model to study hyperacusis

Hyperacusis is a common symptom in children with neurological disorders such as autism spectrum disorder, Williams syndrome, Rett syndrome, and FOXG1 syndrome (FS). The cause of hyperacusis in these neurological disorders has not been fully discovered. FOXG1 mutation is a recently defined, rare and devastating neurodevelopmental disorder. MRI studies show a spectrum of structural brain anomalies, including cortical atrophy, hypogenesis of the corpus callosum, and delayed myelination in children with FS. However, the impact of the FOXG1 mutation on the central auditory system and hyperacusis is largely unknown. Children with FS show signs of hyperacusis, including becoming startled, upset, and even experiencing seizures from loud sounds. The mouse model of FOXG1 mutation provides a novel model to study neurological dysfunction in the central auditory system resulting in hyperacusis. In this project, we will use a mouse model developed by colleagues at University at Buffalo that replicates gene mutations in FS children to study hyperacusis. In our preliminary studies, we found that the mutant mice showed a lack of habituation in the startle tests and an aversive reaction to loud sounds in the open field test. We also found that the cortical neurons showed reduced neural activities and prolonged responses to sound stimuli, suggesting hypoexcitability and a lack of adaptation to sound stimuli. The results point toward a novel neurological model of hyperacusis compared with the current “central gain” theory. Our findings will provide mechanistic insights into the role of the FOXG1 gene on hyperacusis and shed light on detecting potential therapeutic targets to alleviate hyperacusis caused by FS and other neurological disorders.

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