2027

Bshara Awwad, Ph.D.

Bshara Awwad, Ph.D.

Mass Eye and Ear

Auditory-limbic circuit dynamics as therapeutic targets in hyperacusis

Our research addresses a critical gap in understanding the neural basis of hyperacusis by focusing on the emotional dimensions of sound hypersensitivity. Previous work has established that cochlear damage leads to hyperexcitability throughout the central auditory pathway, but our approach uniquely focuses on the circuit-specific mechanisms that link auditory processing to emotional responses.

Specifically, we investigate how noise-induced hearing loss affects two parallel pathways to the lateral amygdala: the cortico-amygdalar (CAmy) and thalamo-amygdalar (TAmy) projections. This pathway- specific investigation represents a novel approach to understanding hyperacusis, as it targets the precise neural circuits that may mediate both the perceptual and emotional components of this disorder.

Brad Buran, Ph.D.

Brad Buran, Ph.D.

Oregon Health & Science University

Drug-mediated cochlear synapse regeneration: reversing central gain and hyperacusis in a gerbil model

Loud noise exposure in the workplace and everyday environments is one of the leading causes of hidden inner ear damage. While traditional hearing tests measure the quietest sounds a person can detect, they frequently miss a critical form of injury: the damage to the nerve connections (synapses) that carry sound signals from the inner ear to the brain. Because standard hearing tests only evaluate basic sound detection, individuals with this nerve loss can still register “normal” hearing thresholds on standard audiograms. However, behind this apparent typical hearing, the brain is not receiving normal auditory information from the ear.

To compensate for this reduced input, the central auditory system turns up its internal “volume knob.” This adaptive brain response, known as “central gain,” is an attempt to amplify faint signals. Unfortunately, when the volume remains turned up too high, it can cause decreased sound tolerance where some sounds become uncomfortably loud. Decreased sound tolerance can impact daily function and affects up to 15 percent of older adults, yet there are currently no approved medications available to repair auditory nerve damage.

To address this critical therapeutic gap, this project evaluates a promising strategy: repurposing an extensively tested, FDA-approved drug. Utilizing a medication with an already established human safety profile dramatically accelerates the timeline for bringing a tangible treatment to patients. This specific drug acts on key biological pathways that actively stimulate the repair and regeneration of damaged auditory nerve connections.

Our research will test two clinically practical delivery routes to determine the most effective approach: an oral pill that works systemically, and a targeted gel placed directly into the ear to deliver the medication locally. Using preclinical models of noise-induced damage, we will examine the direct relationship between rebuilding ear-to-brain nerve connections, turning down central gain in the brain, and restoring normal loudness perception.

Patrick Cody, Ph.D.

Patrick Cody, Ph.D.

University of Pittsburgh

Comprehensive hearing recovery evaluation of novel targeting sequences for cell-type–specific gene therapy for hearing loss

Gene replacement therapy has the potential to restore natural hearing in individuals with congenital deafness, potentially overcoming the limitations of cochlear implants. While cochlear implants provide substantial benefits, they rely on artificial signals to bypass affected inner ear structures that are essential for accurate speech perception in noisy environments. In contrast, gene therapy treats congenital hearing loss by delivering a functional copy of affected genes to restore natural mechanisms of the inner ear. However, evaluations of current therapies fail to capture hearing recovery in complex listening situations and hearing restoration is limited due to imprecise targeting of the affected inner ear cell types. There are over 100 forms of congenital deafness that impact specific inner ear cell types making treatments challenging to scale.

This project addresses these limitations through two innovations. First, using an established animal model of congenital deafness, we introduce a comprehensive approach to gene therapy evaluation that tracks how the auditory pathway adapts to complex sound environments and recovers over time. We will explore whether improved cell-type targeting of gene delivery can improve how the brain recovers and adapts to sound. Second, we apply a model-based platform to design gene regulatory elements that target gene therapy to specific inner ear cell types. This generalizable approach can be tailored to target various cell types for delivery at specific ages and thus can accelerate the development of therapies for other forms of gene linked deafness.

Douglas Epstein, Ph.D.

Douglas Epstein, Ph.D.

University of Pennsylvania, Perelman School of Medicine

Defining the role of EYA4 risk variants in the pathogenesis of Ménière’s disease.

Ménière’s disease is a disabling inner-ear condition that can cause sudden episodes of spinning dizziness, changing hearing loss, ringing in the ears, and a feeling of pressure or fullness. Although these symptoms can be severe and unpredictable, we still do not understand why most people develop the disease.

Our recent large genetic study—comparing nearly 9,000 people with Ménière’s disease with more than 1.9 million people without it— identified several DNA regions associated with disease risk. Two of the strongest signals lie near a gene called EYA4, which is active in the inner ear and is already known to be important for hearing. The DNA differences associated with Ménière’s disease are likely not changing the EYA4 protein itself. Instead, they may act like altered “dimmer switches,” changing when, where, or how strongly EYA4 is turned on in the cells that support hearing and balance.

This project will determine which of these DNA differences are most likely to cause increased disease risk and test how they affect EYA4 activity in the inner ear. We will use advanced genetic analyses to narrow the list of possible causal variants, then test human DNA regulatory sequences in mice to see whether risk-associated versions behave differently from non-risk versions in the living inner ear.

We will also investigate what happens when EYA4 is disrupted in specific inner-ear cell types in adult mice. By measuring balance behavior, hearing, inner-ear function, and tissue changes, we will test whether loss of EYA4 produces key features of Ménière’s disease, including vertigo, progressive hearing loss, and abnormal fluid buildup in the inner ear.

Together, these studies will convert newly discovered genetic clues into a clearer explanation of disease biology. The work may identify the molecular changes that make some people more susceptible to Ménière’s disease and establish experimental models needed to develop better risk prediction, prevention strategies, and ultimately more precise treatments.

Jenelle Feather, Ph.D.

Jenelle Feather, Ph.D.

Carnegie Mellon University

Models and mechanisms for auditory event categorization

Our auditory input is often a cacophony of sounds composing an auditory scene. When speaking to a friend in a crowded city park, one can simultaneously hear the music of buskers nearby, the water flowing in a nearby fountain, the chirping of birds in nearby trees, and cars honking at the intersection. However, an individual with hearing impairment may have difficulty recognizing these everyday auditory events. Although there has been immense progress to optimize hearing aids and cochlear implants to improve speech recognition, there has been relatively little work on understanding how these devices, and the listeners using them, process broad categories of non-speech sounds. Unlike deficits in speech understanding, which have immediate social consequences, deficits in audio event perception often go unnoticed and untested clinically, yet these can be detrimental to listener well-being. While much of the field focuses on narrow acoustic domains (like speech or pitch) or the detection of sounds in complex mixtures, this project will systematically evaluate how we recognize broad categories of natural sounds.

In recent years, rapid advancements in artificial intelligence have led to the development of deep neural networks (DNNs) that are top-performing models for both engineering purposes and in capturing properties of human hearing. These computational models can be harnessed to design technology that augments sensory input for devices like hearing aids or cochlear implants, provided that the models process sound the way the brain does. We will develop a sound dataset and novel behavioral testing paradigm to characterize human and model auditory sound categorization, and will use this task to compare artificial neural networks and human observers on both natural stimuli and hearing-aid–processed stimuli. We will additionally develop machine learning models with more perceptual alignment to humans, and test human listeners on synthetic sounds designed to highlight potential differences between models and humans. By taking steps towards a perceptually aligned “digital twin” of the auditory system, this work provides the foundational framework required to optimize hearing devices for real-world listening.

Paul Gratias, Ph.D.

Paul Gratias, Ph.D.

Mass Eye and Ear

Efferent function and noise vulnerability in otoferlin-deficient and gene-therapy-treated cochlea

Some children are born deaf because they carry a disease-causing variant in both copies of a single gene, OTOF, which encodes the protein otoferlin. Without functional otoferlin, the sensory hair cells of their inner ear still detect sound. But they cannot release the chemical messenger that carries the signal across the synapse toward the brain.

Using gene therapy, a healthy copy of the OTOF gene can be delivered into the inner ear to restore this release. Children born deaf can then begin to hear and to develop speech. This is the first form of genetic deafness to be treated with gene therapy.

But by the time children receive the treatment, their ears have already been developing in silence for years. Sound is not only what the ear detects. During development, the activity it drives also shapes the connections between ear and brain. The synapses that the therapy relies on are normally refined by the activity that flows through them, first spontaneous, then driven by sound. In mice lacking otoferlin, this activity is missing. There are fewer of these synapses, and they look abnormal. These connections are now asked to carry sound for a lifetime, in a world that is frequently loud.

In response to loud sound, a healthy ear reduces its own amplification. Activity traveling up to the brain triggers a reflex back to the ear (the medial olivocochlear reflex) that turns this amplification down. This protects the hair cells and these same synapses from damage. The reflex is set in motion by sound, so an ear deaf from birth has never used it. We do not know whether it was ever formed, or whether it can still be engaged when the first sound reaches the brain later in life.

Gene therapy switches the sound signal on for the first time in the ear's life. Working in mice that, like these children, lack functional otoferlin, we will measure this reflex before and after treatment. We will also examine the synapses as they begin to function, and determine how a treated ear withstands a controlled period of loud sound. Together, these experiments will show whether an ear that hears for the first time following gene therapy is also built to last, both robust enough to withstand noise and able to protect itself from it.

Jia Guo, Ph.D.

Jia Guo, Ph.D.

Columbia University

Enhanced cochlear endolymphatic hydrops imaging for Ménière’s disease with intracochlear MRI contrast delivery via microneedle

Ménière’s disease is a chronic inner ear disorder that causes episodes of vertigo, hearing loss, tinnitus, and aural fullness. These symptoms are thought to arise from endolymphatic hydrops (EH)—a buildup of fluid in the inner ear. Current MRI methods can visualize EH but are limited by long wait times, high contrast doses, and inconsistent image quality. This project introduces a new microneedle-based technique that delivers MRI contrast agents directly into the cochlea through a minimally invasive injection. By bypassing systemic delivery, this method allows faster, more reliable imaging with smaller doses of contrast. The project also integrates advanced 3D image segmentation powered by artificial intelligence (AI) to automatically and accurately measure EH. Through safety testing in animal models and development of an automated 3D segmentation pipeline, this research will establish a foundation for clinical translation. The ultimate aim is to create a precise, safe, and efficient imaging approach for early diagnosis and monitoring of Meniere’s disease, improving treatment decisions and patient outcomes.

Hui Hong, Ph.D.

Hui Hong, Ph.D.

Creighton University

Peripheral auditory input regulates lateral cochlear efferent system

When we think about hearing, we often picture sound traveling from the ear to the brain—a one-direction sensory pathway. However, hearing also involves a lesser-known feedback system called the auditory efferent system, which sends signals from the brain back to the ear. This system helps regulate how we hear in different sound environments and plays a protective role for the inner ear. Hearing loss is a prevalent health issue in modern society and is closely associated with other auditory disorders. Most research on hearing loss has focused on the sensory pathway. In contrast, much less is known about how the efferent system contributes to these conditions.

This project focuses on the lateral olivocochlear (LOC) neurons, the most abundant auditory efferent neurons, to understand how their function changes after noise-induced hearing loss. These changes include both the neurons’ own activity and the inputs that regulate that activity. A key question is whether the observed changes are driven directly by noise exposure or by the resulting hearing loss. To address this, we will compare LOC function following noise- induced hearing loss with that following non-noise-induced hearing loss, the latter produced by targeted ear lesions. Our approach combines whole-cell patch-clamp electrophysiology, a classic technique for recording the activity of individual neurons, with state-of-the-art optogenetics, which allows precise control and study of neuronal inputs. This research will deepen our understanding of how hearing loss impacts the auditory efferent system and help resolve inconsistencies observed in clinical studies on efferent involvement in conditions such as central auditory processing disorder, hyperacusis, and tinnitus. Ultimately, these insights will guide clinicians in refining therapeutic interventions by pinpointing dysfunctions within the brain and suggesting strategies for functional recovery. They will also help tailor treatments based on the underlying cause of hearing loss.

Marina Kabirova, Ph.D.

Marina Kabirova, Ph.D.

The University of Chicago

Age-related disruption of calcium homeostasis in vestibular sensory cells

Falls are a major health concern for older adults, and problems with balance are one of the main reasons they occur. Our sense of balance relies on sensory cells in the inner ear, called vestibular hair cells, that detect head movements and communicate this information to the brain. As we age, some of these cells are lost, but their function may begin to change long before that. We want to understand what happens during this earlier stage, when it may still be possible to protect hair cells' function.

Our project focuses on calcium, which plays an essential role in how vestibular hair cells work. These cells need calcium to sense movement and communicate with the brain, but they also need to carefully control how much calcium is present and where it goes. We think that this control may become less effective with age, gradually interfering with the cells’ ability to provide accurate information about head movement.

To study this, we will compare young and old mice at several levels. First, we will study individual vestibular hair cells to understand how their calcium signals and electrical activity change with age. We will then use specialized imaging methods to directly observe calcium activity in many hair cells at the same time. This will allow us to see how strongly the cells respond to a given mechanical stimulus and how well their responses are synchronized across the population. Finally, we will use behavioral tests of balance to examine whether changes in hair cell function are associated with impaired vestibular function in older mice.

By finding out what starts to go wrong in vestibular hair cells as they age, we hope to better understand why balance declines in older adults. In the long term, this knowledge could help identify ways to protect the inner ear and prevent or reduce age-related balance problems.

Jacie R. McHaney, Ph.D.

Jacie R. McHaney, Ph.D.

The University of Texas at Austin

Neural and cognitive mechanisms of hearing aid signal processing

Millions of adults with hearing loss rely on hearing aids, yet many still struggle to follow conversations, especially in noisy, everyday settings. Even when a hearing aid makes sounds loud enough to hear, understanding speech clearly is a different challenge. This often means extra mental effort just to keep up, along with sound that doesn't feel quite right. Current methods for testing hearing aid fit and satisfaction mostly ask, “Can you hear this?” or “Can you repeat this word?” These methods do not show what is happening in the brain as it processes speech through a hearing aid’s processing. This research project aims to close that gap. We will study how a hearing aid’s internal processing affects the brain’s ability to recognize individual speech sounds (i.e., phonemes) in real time. We will use electroencephalography (EEG) to track brain responses while people listen to naturalistic speech through different hearing aid processing parameters. Additionally, we will measure pupil sizes during listening, which subtly changes based on how hard someone has to focus on listening, providing a window into listening effort. Participants will also report how well they understood the speech and their perceived quality of the speech. By testing different hearing aid processing settings in a controlled environment, we can examine which processing parameters help the brain encode speech clearly, which ones ease listening effort, and which do both. The findings from this study could reveal specific, measurable brain and effort signals that explain why some hearing aid settings work better than others, rather than solely depending on yes-or-no hearing tests. These insights could guide the design of “smarter” hearing aids that don’t just make sound louder, but also make listening easier and communication clearer for millions of people.

Jane Mondul, Au.D., Ph.D., CCC-A

Jane Mondul, Au.D., Ph.D., CCC-A

Purdue University

Sound-induced plasticity of the lateral olivocochlear efferent system

Loud sounds can damage the auditory system and cause hearing loss. But not all sound is bad – safe sound exposure can actually help the brain fine-tune how we hear, especially in noisy places. A part of the auditory system called the lateral olivocochlear (LOC) pathway may help with this. The LOC system’s chemical signals change after sound exposure, suggesting a form of “plasticity” (adaptability), but scientists don’t yet know exactly how it works. Our project will study how the LOC system changes after safe sound exposure, how this LOC plasticity affects hearing, and whether it still occurs when the ear is damaged. We will test this in mice by measuring their ability to hear sounds in noise and by looking closely at cells in the ear and brain. What we learn could guide new sound-based or drug-based therapies to protect hearing and improve communication in noisy settings.

Patrick D. Parker, Ph.D.

Patrick D. Parker, Ph.D.

Johns Hopkins University School of Medicine

Emergence of tonotopically organized spontaneous activity in the brain after genetic disruption of MET channel

Secondary disorders develop alongside hearing loss, such as the perception of phantom sounds (tinnitus) and a hypersensitivity to sound (hyperacusis). These disorders have no curative treatment, in part due to our poor understanding of the underlying neurobiology. Using experimental models of hearing loss, I recently discovered that sound-independent (SI) patterns of neural activity emerge in the brain’s auditory centers that resemble those elicited by sound in hearing mice. This finding indicates that the brain can self- generate neural patterns that resemble sound processing, independent of the inner ear. To understand the relevance of SI activity to human disorders like tinnitus, I’ll expand these findings to more translationally relevant models of hearing loss (loud noise exposure and age-related hearing loss), as well as determine the area of the brain that generates these patterns. The results of these studies may help to develop new approaches to treat tinnitus, hyperacusis, and related disorders.

Lina Reiss, Ph.D.

Lina Reiss, Ph.D.

Oregon Health & Science University

Role of abnormal binaural fusion in central auditory processing disorder

Central auditory processing disorder (CAPD) is a condition in which people with typical hearing have greater than normal difficulty with understanding speech in background noise. One possible mechanism is excessive binaural fusion, the process of combining sounds from both ears into a single, unified percept. In people with hearing loss, excessive binaural fusion was recently shown to be a strong predictor for the ability to understand a target voice in the presence of competing voices—and may also be the mechanism underlying difficulties in people with CAPD. Binaural fusion may also be possible to measure using electrophysiology (EEG), without requiring behavioral responses. This project will 1) investigate whether excessive binaural fusion is the mechanism underlying difficulties in people with CAPD, by comparison of binaural fusion with controls; and 2) develop an EEG measure of binaural fusion, which will allow for diagnosis in young children without requiring behavioral responses.

Mark A. Rutherford, Ph.D.

Mark A. Rutherford, Ph.D.

Washington University in St. Louis

Preventing or mitigating hyperacusis with blockade of calcium-permeable AMPA receptors

Pain hyperacusis is an abnormal sound level tolerance associated with increased activity in the central auditory system. It can be caused by damage to the inner ear that is not detected on a typical hearing test. This type of damage is associated with permanent loss of cochlear nerve fibers. Paradoxically, in some patients this decrease in cochlear function leads to an increase in the brain’s sensititivity to sound. We have developed a therapy in mice to prevent loss of nerve fibers during noise trauma by inhibiting the synaptic communication between the cochlea and the auditory nerve. Importantly, animals can still hear during the protection because the communication is not blocked entirely. However, it is not known if preventing cochlear nerve loss would prevent the development of hyperacusis. We call our therapy “chemical earmuffs.”

The brain also has synapses that are inhibited by our chemical earmuffs. However, it is not known if inhibiting those could mitigate hyperacusis after it has emerged. If loss of input to the brain is responsible for the increase in activity in the central auditory system, then preventing this loss could prevent hyperacusis in the first place. If overactivity in the brain depends partly on activation of synapses inhibited by chemical earmuffs, then blocking them could mitigate active hyperacusis. Our small molecule therapy works when given systemically because it enters the inner ear and the brain from the blood. In this proposal, we hypothesize that (1) Preventing loss of cochlear nerve fibers will eliminate the development of hyperacusis, and (2) Giving our therapy to animals with hyperacusis will mitigate hyperacusis-associated phenotypes.

Marina Silveira, Ph.D.

Marina Silveira, Ph.D.

University of Texas at San Antonio

Age-related changes in neuromodulatory signaling in the auditory midbrain

Age-related hearing loss is the most common form of hearing loss in older adults. Age-related hearing loss causes difficulty understanding speech in noisy environments. Consequently, hearing loss has a major negative impact on quality of life and leads to social isolation, loneliness, and is a significant risk factor for dementia and Alzheimer’s. It is well known that age-related hearing loss shifts the excitatory-inhibitory balance in the inferior colliculus to favor excitability. This enhancement in excitability can contribute to pathological conditions such as tinnitus and poor temporal processing. However, the mechanisms that regulate this enhanced excitability in the inferior colliculus are unclear. A major neuromodulator called serotonin has been shown to regulate the excitatory-inhibitory balance in other brain regions. In preliminary studies for this proposal, we found that serotonin strongly influences the activity of a class of inhibitory neurons in the inferior colliculus that express neuropeptide Y. Here, we will test the hypothesis that dysfunction in serotonergic and neuropeptide Y signaling underlies enhanced excitability in the inferior colliculus in age-related hearing loss. Because the serotonergic system is a common target for pharmaceuticals, our results will also provide foundational insights that might guide future pharmacological interventions for age-related hearing loss.

Kirupa Suthakar, Ph.D.

Kirupa Suthakar, Ph.D.

The University of Texas at Dallas

Serotonin signaling of auditory efferent neurons in noise-induced hyperacusis and tinnitus (NIHT)

A single exposure to loud noise can cause lasting changes in hearing. Tinnitus (the phantom perception of sounds such as ringing or buzzing) and hyperacusis (an increased sensitivity to everyday sounds resulting in discomfort or pain) can develop following exposure to loud sounds. Both conditions can have a profound impact on quality of life, affecting communication, concentration, sleep, mood and social interactions. Depression and other mood disorders also occur at unusually high rates in people with tinnitus and/or hyperacusis, suggesting that hearing and mental health may be biologically connected.

Serotonin is a chemical messenger in the brain best known for its role in mood, but it also regulates the activity of nerve cells throughout the brain, including those involved in hearing. Altered serotonin signaling is associated with depression and is targeted by antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs). SSRIs increase serotonin signaling by blocking the serotonin transporter (SERT), a protein that normally removes serotonin from the spaces between neurons, known as synapses. By blocking SERT, SSRIs increase the amount of serotonin available to signal nerve cells.

A specialized group of nerve cells called medial olivocochlear (MOC) efferent neurons act as a volume control for the auditory system. When activated, MOC neurons reduce the ear’s sensitivity to sound, helping protect the auditory system from the effects of intense noise. Our previous work has shown that serotonin can increase MOC activity. However, it is not yet known if differences in serotonin signaling change an individual’s vulnerability to noise-related hearing problems.

We propose that altered serotonin signaling provides a mechanistic link between mood and auditory disorders. We hypothesize that serotonin influences the ear’s protective mechanisms, and, consequently, vulnerability to tinnitus and hyperacusis following exposure to loud sounds. Using mice with genetically altered SERT function, we will directly test this possibility. We will determine whether long- term disruption of serotonin signaling during development alters MOC activity, vulnerability to noise-induced hyperacusis and tinnitus, and measures of depression-like behaviors. By manipulating both serotonin signaling and noise exposure, we can test whether serotonin plays a causal role rather than simply being associated with hearing or mood disorders.

This research offers a new approach for understanding the neurobiological connection between auditory and mental health disorders. Our findings could help explain why some individuals are particularly vulnerable to noise-induced hearing problems, identify an underexplored protective pathway in the auditory system, and provide a foundation for investigating whether medications that alter serotonin signaling, including SSRIs, could eventually have utility in preventing or treating these disabling conditions.

Ross S. Williamson, Ph.D.

Ross S. Williamson, Ph.D.

University of Pittsburgh

Active corticofugal control of sound localization in noise

Locating sounds in a noisy environment is essential for everyday communication, and it is a task we accomplish with our bodies as much as with our ears. Listeners naturally turn their heads and orient toward a sound source, and these movements change the signal arriving at each ear from moment to moment, giving the brain additional information about where the sound originated. Exposure to loud noise permanently damages the connections between the inner ear and the auditory nerve, degrading the fine detail required to separate competing sound sources. The result is that many people report considerable difficulty following a conversation in a crowded room despite a normal audiogram, a core complaint in central auditory processing disorder. Almost everything known about how the brain computes sound location, however, comes from experiments in which the head is held still, eliminating the very movements listeners rely on in natural settings.

This project asks how noise-induced hearing loss disrupts active listening, and which neural circuit is responsible. We have developed a task in which mice move freely around an arena surrounded by speakers, searching for a target sound while a competing distractor sound plays simultaneously. Video tracking allows us to measure the strategies they use: pausing to scan the head from side to side, correcting an initial trajectory with a sharp turn, or spiraling gradually toward the target. Comparing these strategies before and after noise exposure will reveal whether noise damage degrades not only what an animal hears, but how it searches. We will then examine the descending pathway connecting auditory cortex, which identifies the features of a sound, to the superior colliculus, a midbrain structure containing a map of space that issues commands to orient the head and body. We hypothesize that this pathway converts sound features into a direction to turn, and that noise damage dysregulates it. We will record from the pathway during behavior, suppress it in normal-hearing mice to determine whether this reproduces the deficit, and activate it in noise-exposed mice to determine whether the deficit can be reversed.

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