Nirmal Kumar Srinivasan, Ph.D.

Nirmal Kumar Srinivasan, Ph.D.

Towson University
Understanding and decoding CAPD in adults

Understanding speech in complex listening environments involves both on top-down and bottom-up processes. Central auditory processing disorder (CAPD) refers to a reduction in the efficiency and effectiveness of how the central nervous system utilizes the presented auditory information. It is characterized by a diminished perception of speech and non-speech sounds that is not attributable to peripheral hearing loss or intellectual impairment. Hearing loss and CAPD can adversely affect everyday communication, learning, and physical well-being.

A substantial number of adults evaluated for CAPD complain about difficulties in resolving auditory events that are similar to that of individuals with hearing impairment. These individuals have audiograms that are similar to those of age-matched individuals. Since the audiogram is the primary tool used in the clinic to distinguish people with hearing loss, it is imperative to understand the fundamental differences observed in behavioral experiments for individuals with CAPD and individuals with hearing loss.

Olga Stakhovskaya, M.D., Ph.D.

Olga Stakhovskaya, M.D., Ph.D.

Click to download a PDF of Dr. Stakhovskaya’s Meet the Researcher profile.

Zlatka P. Stojanova, Ph.D.

Zlatka P. Stojanova, Ph.D.

House Research Institute
Epigenetic Regulation of the Atoh1 gene during development and regeneration of the mammalian organ of Corti

The Atoh1 gene is both necessary and sufficient for auditory hair cell formation during normal development. It is also one of the first genes to be upregulated during regeneration in non-mammalian vertebrates. The project is investigating novel mechanisms of Atoh1 gene regulation that involve epigenetic modifications (not due to changes in DNA sequence). During the 2nd year renewal we will analyze the mechanistic links between the discovered epigenetic state of the Atoh1 gene and the Atoh1 gene expression.

Research areas: hair cell regeneration, genetics

Long-term goal of research: To better understand how is Atoh1 gene regulated in order to reverse the failure of hearing regeneration in the mammalian organ of Corti.

Arminda Suli, Ph.D.

Arminda Suli, Ph.D.

University of Washington

Assessing functional recovery after mechanosensory hair cell regeneration in the zebrafish lateral line

Sensory hair cells located in the inner ear are responsible for converting sound into understandable signals for the brain. Damage of these cells from age-related factors, noise, and therapeutic drugs leads to hair cells loss, a process that is irreversible in humans and other mammals. In contrast, non-mammalians, such as zebrafish, are very effective in regenerating sensory hair cells; therefore, we use this organism to find mechanisms that lead to sensory hair cell regeneration. Since restoration of function depends on restoring the correct connections between hair cells and the brain, I am using a behavioral assay and molecular markers to determine how this process is accomplished during regeneration.

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.

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.

Chin-Tuan Tan, Ph.D.

Chin-Tuan Tan, Ph.D.

New York University School of Medicine

Measuring and predicting the quality of nonlinearly distorted music and speech as perceived by hearing-impaired people

Hearing aids and other communication devices, such as telephones, introduce significant nonlinear distortion which reduces sound quality and may interfere with speech perception. The goals of the proposed research are to characterize and model the perception of distorted speech and music by hearing-impaired listeners. The first objective of the proposed research is to conduct listening tests to determine how hearing-impaired listeners evaluate the perceived quality of distorted speech and music. The second objective of the proposed research is to develop a computational model for predicting perceived quality judgments made by hearing- impaired listener; in other words, to predict the data obtained in the first part of the project. The third objective of the proposed research is to test, and if necessary to refine, the developed models using recordings of speech and music replayed via existing assistive hearing devices.

Xiaodong Tan, Ph.D.

Xiaodong Tan, Ph.D.

Northwestern University
Oto-Protection of Honokiol Against Cisplatin-Induced Ototoxicity

Cisplatin is a common chemotherapy medication known to be ototoxic (damaging to hearing), but most proposed drugs to counteract this side effect compromise the antitumor effects of cisplatin. Honokiol is an antitumor agent derived from the magnolia plant that has been shown to have synergistic effects with cisplatin in cancer treatment because it activates an enzyme that protects healthy cells and suppresses tumor cells. As a result, honokiol may have a strong protective effect for cochlear hair cells. This study will investigate the hearing protective properties of honokiol using tissue cultures in the lab as well as through direct drug administration in an animal model.

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Pei-Ciao Tang, Ph.D.

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Pei-Ciao Tang, Ph.D.

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.

Wenxue Tang, M.D.

Wenxue Tang, M.D.

Emory University School of Medicine

The molecular diversity of gap junction channel systems in the cochlea

The long-term objective of this study is to understand how molecular mechanisms of different subtypes of connexins (Cxs) contribute to cochlear functions. Connexins (Cxs) are a family of proteins constituting the gap junctions (GJs). GJs allow direct intercellular exchanges of nutrients, inorganic ions, signaling molecules. The importance of Cxs in hearing functions has been revealed by large amount of genetic linkage studies showing that mutations in Cx genes are associated with about half of patients with childhood nonsyndromic hearing losses. Mutations in Cx26 are responsible for most of the cases. However, mutations in a myelinating Cx (Cx32) have also been linked to Charcot-Marie-Tooth syndrome that includes hearing defects in many cases. Despite their importance in hearing, we know very little about molecular mechanisms that GJs play in the cochlea.

Osama Tarabichi, M.D., MPH

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.

Zhengquan Tang, Ph.D.

Zhengquan Tang, Ph.D.

Oregon Health & Science University
Hyperexcitability dependent on Neuromodulatory state in the cochlear nucleus

Tinnitus affects approximately 50 million people in the USA, and millions more worldwide. However, the mechanisms underlying tinnitus are poorly understood. The dorsal cochlear nucleus (DCN), one of the first stations of the ascending auditory pathway, receives dense serotonergic input. Recent evidence indicates that the DCN may be a site of central tinnitus, and it is possible that serotonin might play a role in the generation or modulation of central tinnitus. Moreover, serotonin reuptake inhibitors (SSRIs) typically used as antidepressants in the treatment of depression and anxiety disorders, have been explored as a treatment for tinnitus. The goal of this research is to identify the cellular targets of serotonin and SSRIs in the DCN and understand their functional roles. The ultimate goals of this research are to understand how serotonin influences the output of the DCN, and whether serotonin may have a role in tinnitus.

Research area: Tinnitus

Long-term goal of research: To understand how different neuromodulators control the neural activity in the central auditory system and their role in pathological auditory processing.

Shikha Tarang, Ph.D.

Shikha Tarang, Ph.D.

Creighton University
Transient and Regulated Dominant-Negative RB1 Inhibition to Regenerate Hair Cells

Our ability to hear and communicate depends primarily on the sensory hair cells (HCs) and their associated spiral ganglion neurons (SGNs). Unfortunately, mammalian HCs and SGNs are not naturally replaceable, and their loss results in neurosensory hearing loss and balance impairment. To this date, any attempts to regenerate lost sensory HCs have been challenged by the early embryonic lethality of complete knockout mice or massive cell death after conditional deletion of targeted genes. In this light, we sought to design a new system that combines the inducible nature of an antibiotic-controlled system with the lysosomal fusion protease pre-procathepsinB (CB) to generate an inducible, temporal, and reversibly conditional mouse model. To build upon our laboratory’s expertise, we applied this technology to generate a mouse model carrying a transgenic version of the of the retinoblastoma (Rb1) gene. The Rb1 gene is a key component of cell cycle regulation. In addition to its role in cell proliferation, Rb1 expression in the inner ear also affects differentiation and survival of HCs and their associated supporting cells (SCs). Rb1 deletion leads to the production of supernumerary HCs and SCs. However, just like a number of other genes considered potential candidates for HC regeneration, complete and permanent elimination of Rb1 results in massive apoptosis, and as such, should be avoided at all costs. This study will allow us to characterize this newly generated model of transient and reversible gene ablation and gather information supporting pre-clinical studies on HC regeneration.

Joseph Toscano, Ph.D.

Joseph Toscano, Ph.D.

Villanova University
Cortical EEG measure of speech sound encoding for hearing assessment

Accurate speech recognition depends on fine-grained acoustic cues in the speech signal. Deficits in how these cues are processed may be informative for detecting hearing loss, and particularly for identifying auditory neuropathy, a problem with the way the brain processes sounds. Diagnosing auditory neuropathy in newborns and infants is particularly challenging, as it is often difficult to distinguish it from sensorineural hearing loss using current measurement approaches. Speech tests that measure cortical responses may allow us to overcome this problem. The current project uses electroencephalogram (EEG) techniques to measure brain responses to specific acoustic cues in speech (e.g., the difference between “d” and “t”). These data will be compared with listeners’ speech recognition accuracy, pure-tone audiograms, and self-reported hearing difficulty to determine how these responses vary as a function of hearing status and may be used to detect early stages of hearing loss.

Richard S. Tyler, Ph.D.

Richard S. Tyler, Ph.D.

University of Iowa
Literature review on hyperacusis, recruitment, misophonia, phonophobia, and mechanisms

The funded research will result in a thorough review of the literature, documenting causes, mechanisms, measurement and treatment. It is the intent that the review will provide a comprehensive document that clinicians and researchers will be able to use to understand hyperacusis and to improve current treatment approaches, and to suggest future treatment directions.

Research areas: cochlear implants, tinnitus

Long-term goal of research: The long-term goal is to provide a systematic, comprehensive review of the entire field of hyperacusis. By providing such a widespread and comprehensive review of hyperacusis, we should be able to provide the background necessary to direct research to find cures.

Lisa D. Urness, Ph.D.

Lisa D. Urness, Ph.D.

University of Utah

FGF-regulated hearing loss genes: fast-tracking to functional analysis

With the myriad roles of fibroblast growth factors (FGFs) in multiple stages of ear development, it is not surprising that some human hearing loss syndromes are caused by mutations affecting FGFs and their receptors. However, little is known about the genes that are controlled by FGFs. Because FGF signals are reused during later stages of otic innervation, morphogenesis, and sensory cell differentiation, the FGF target genes we identify during placodogenesis may also be targets of later FGF signaling events and could provide many new candidates for hearing and/or balance disorders, thereby impacting diagnosis. Importantly, elucidating the functions of these genes may suggest potential therapeutic interventions. FGFs are required to initiate otic development and are subsequently reused during morphogenesis and sensory development. Our long-term objective is to identify FGF effector genes and to determine their function and relevance to human deafness by analyzing mouse mutants. Specifically, we propose to isolate RNA from pre-otic ectoderm of control and FGF-deficient embryos and perform an expression profiling experiment utilizing a “gene-trap microarray.” This will identify embryonic stem cell lines that carry mutations in FGF target genes. Selected cell lines will be used to generate the corresponding mutant mouse strains for functional studies of hearing and balance.

Kenneth Vaden, Ph.D.

Kenneth Vaden, Ph.D.

Medical University of South Carolina
Adaptive control of auditory representations in listeners with central auditory processing disorder

Central Auditory Processing Disorder (CAPD) is typically defined as impairment in the ability to listen and use auditory information because of atypical function within the central auditory system. The current study uses neuroimaging to characterize CAPD in older adults whose impaired auditory processing abilities could be driven by cognitive and hearing-related declines, in addition to differences in central auditory nervous system function. Functional neuroimaging experiments will be used to test the hypothesis that older adults with CAPD fail to benefit from top-down enhancement of auditory cortex representations for speech. In particular, activation of the adaptive control system in cingulo-opercular cortex is predicted to enhance speech representations in auditory cortex for normal listeners, but not to the same extent for older adults with CAPD. This project aims to develop methods to assess the quality of speech representations based on brain activity and characterize top-down control systems that interact with auditory cortex. The results of this study will improve our understanding of a specific top-down control mechanism, and examine when and how adaptive control enhances speech recognition for people with CAPD.

Babak Vazifehkhahghaffari, Ph.D.

Babak Vazifehkhahghaffari, Ph.D.

Washington University in St. Louis
Enhancing cochlear implant performance through development of improved auditory nerve fiber biophysical models with a combined wet lab and dry lab approach

While the cochlear implant (CI) allows access to sound for those with severe hearing loss, perceiving pitch and music and understanding speech in the presence of reverberation, multiple speakers, or background noise remains very limited. To improve the CI, it is important to understand how it affects neuronal (nerve cell) behavior in the inner ear by uncovering the properties of neuronal excitability. Neuronal excitability mainly depends on the movement of different ions through the cell membrane and is affected by components such as ionic currents and ion channels. A more precise model of the auditory nerve combined with models of the CI electric field potential will help improve CI stimulation methods by understanding stimulus-response phenomena and their underlying biophysical mechanisms.

A. Catalina Vélez-Ortega, Ph.D.

A. Catalina Vélez-Ortega, Ph.D.

University of Kentucky
TRPA 1 activation in the cochlea as an intrinsic mechanism of protection against noise-induced hearing loss

TRPA1 is an ion channel mostly known for its role as an “irritant sensor” in pain-sensing neurons. Functional TRPA1 channels are also expressed in the inner ear. However, given that genetically modified mice lacking TRPA1 channels have typical hearing and balance, the role of these channels in the inner ear remains unknown. Noise exposure leads to the production of some of the cellular “irritants” that activate TRPA1 channels. Therefore, we hypothesized that TRPA1 channels are able to sense noise-induced damage in the cochlea. When we exposed adult mice to mild noise levels, we observed a temporary increase in hearing thresholds that lasted several days (making it harder to hear soft sounds). Mice lacking TRPA1 channels, however, recovered significantly faster than mice with typical TRPA1 expression. This project will explore whether, after noise exposure, TRPA1 activation contributes to the temporary shift in hearing thresholds to allow the cochlea enough time to repair or recover from the noise-induced tissue damage. This project will help us better understand the protective effects of TRPA1 activation after noise exposure, and the specific cell types within the inner ear that are involved in this process.

Philippe Vincent, Ph.D.

Philippe Vincent, Ph.D.

Johns Hopkins University
Investigating mechanisms of degeneration of ribbon synapses between auditory inner hair cells and type 1 afferent nerve fibers after noise trauma in mammals

Sensory hair cells in the inner ear pick up the sound signal and transmit it to auditory nerve fibers through chemical synapses by releasing the transmitter glutamate; auditory nerve fibers then transmit the sound-coding signal to the brain. Sound intensity is encoded by the amount of glutamate released by the hair cell, leading to glutamate receptor activation and then action potential firing in auditory nerve fibers. During noise exposure, auditory nerve fiber endings can be damaged short- or long-term, most likely due to an excessive influx of calcium. This phenomenon is called excitotoxicity, but the underlying mechanisms are not completely understood. This project will investigate molecular mechanisms of synaptic transmission between hair cells and auditory nerve fibers and how they are affected after noise trauma.

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