University of Michigan
Ototoxicity of a common drug delivery tool and FDA Orphan Drug, 2-hydroxypropyl-beta-cyclodextrin

Cyclodextrins are a class of molecules that can dissolve cholesterol and other lipids in the body. They are commonly found in household cleaning products, and they are being studied in the treatment of Niemann-Pick disease. Unfortunately, cyclodextrins cause hearing loss and damage to the cochlea at high doses. This project will study the effects of 2-hydroxypropyl-betacyclodextrin (HPBCD) on hearing in a mouse model by injecting this drug under the skin and into the brain. This research will quantify the level of hearing loss and cochlear damage caused by this medication. In addition, the mechanisms of hearing loss and ototoxicity through a variety of techniques will be studied. This novel approach to studying HPBCD may have powerful impacts for patients with Niemann-Pick disease as well as advance our understanding of drug related ototoxicity.

Research area: Hearing loss; Ototoxicity

Long term goal of research: To develop novel tools for both the prevention and treatment of hearing loss. Cyclodextrins are powerful drugs that can be used to deliver a variety of drugs into the eye, brain, and even the ear. They can also be used to treat lysosomal storage disorders such as Niemann-Pick disease. Unfortunately, at high doses they cause hearing loss and damage the cochlea. The long-term objective is to understand the mechanisms of cyclodextrin induced hearing loss. Hopefully this will lead to novel strategies to ameliorate cyclodextrin damage while retaining its drug-delivery and therapeutic advantages. In addition, new therapeutic uses for HPBCD to treat inner ear disorders will be developed.

University of Minnesota
Behavioral and neural correlates of amplification outcome

Understanding individual factors, beyond hearing thresholds, that account for the high variability in success in the use of hearing aids is an important question with immediate clinical implications. This project aims to evaluate how fundamental aspects of auditory processing interact with high-intensity sounds and influence hearing aid amplification outcomes. Behavioral and speech and non-speech measures will be used to determine how spectral auditory processing interacts with high intensity sounds and influences amplification. This will help us determine factors that contribute to diminished speech perception in noisy environments for individuals with hearing loss and how their perception of amplified speech can be enhanced in noisy environments.

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.

Harvard University
Identifying roles for contact-dependent signaling between neurons and glia during axon guidance and synaptic targeting

The mature cochlea is a spiraled hollow chamber of bone that contains all the necessary components to transmit sound information to the brain. This feat is accomplished by the precise arrangement of hair cells and spiral ganglion neurons (SGNs). This arrangement requires SGNs extend peripheral projections and establish precise synaptic connections with hair cells. What signals guide these axons through the three-dimensional terrain of the cochlea? Most studies focus on the roles of classically described axon guidance cues, which act over long distances to attract or repel axons. However, mounting evidence from recent studies and our own preliminary data lead us to hypothesize that contact-dependent signaling between SGNs and Schwann cells (SCs) are required for normal development of inner ear neural architecture and hearing. The precise role of contact-dependent interactions between SGN axons and SCs on auditory circuit formation remains unknown. This is due in part to the obstacles towards gathering high-resolution, time-lapsed information on the spatial relationships between SGNs and SCs in situ. Therefore, we will genetically label and characterize live cellular interactions between these cells in their normal, and then abnormal, physiological environment. We will measure the extent to which each of these cell types rely on each other for normal migration, differentiation, proliferation and survival. Because we have identified a mutant in which SGN-Schwann cell interaction appears disrupted, these studies will also provide insight to our understanding of Schwannoma formation. Schwannomas are Schwann cell tumors commonly found in the inner-ear and are thought to arise from a disruption in reciprocal signaling between spiral ganglion neurons (SGNs) and Schwann cells. As these tumors grow they compress afferent vestibular and auditory nerves, usually causing hearing loss, tinnitus, and dizziness. Therefore, these studies will not only contribute to our understanding of auditory circuit formation but also provide insight into what can go wrong when SGN-Schwann cell interaction is disrupted.

University of Cincinnati
Specifying the Integrity of Neurons in the Auditory Periphery (SiNAP)

Auditory nerve degeneration is thought to lead to difficulties with understanding speech, especially in noisy listening situations. Diagnosis of auditory nerve degeneration, however, may be missed by common hearing tests. This research examines the utility of a new technique to specify the extent and region of auditory nerve damage within the inner ear. Application of the technique in a clinical setting may help individualize hearing aids and cochlear implants, and in the future, guide delivery of therapeutic agents that can truly restore hearing to individuals with hearing loss.

Research area: Auditory physiology; Diagnostic audiology

Long-term goal of research: To develop tools for diagnosis of auditory nerve integrity that will improve the individualization of treatment options for individuals with hearing loss.

New York University School of Medicine
Neural computations for vestibular control of movement initiation

Loss of balance and falls are common in aging populations and associated with various neurological disorders. Balance is sensed using vestibular organs in the inner ear and processed in the brainstem. However, it remains unclear how the brainstem transforms sensations of instability into corrective movements that restore balance. The objective of this project is to define how cells in the brainstem act collectively to produce rapid responses to sensations of instability. In order to measure balance responses in populations of cells located deep within the brain, this project will apply cutting-edge microscopy techniques to the zebrafish. These fish swim to remain balanced, providing a model for balance control and brainstem function in general.

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.

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.

Baylor College of Medicine
Development of Biomarkers to Study Strial Development and Degeneration

The sensory hair cells of the cochlea are able to detect sound vibrations. Hair cells need a source of potassium that helps them to convert sound energy into electrical energy that is sent to the brain. Hair cells in our cochlea are bathed in a potassium-rich fluid called endolymph, and the potassium is constantly pumped into the endolymph by a specialized group of cells in the cochlea called the stria vascularis. As humans get older, the stria vascularis can degenerate, and so the “battery” that supplies potassium to the cochlea runs down, and we lose our hearing. The goal of this project is to understand how the stria vascularis develops, and to devise ways of looking at changes in this structure with age.

Research areas: the development and regeneration of the inner ear, stria vascularis development

Long-term goal of research: We hope this knowledge may allow us to repair or slow down damage to the cochlea and lessen the effects of age-dependent hearing loss.