Lina Reiss, Ph.D.

Lina Reiss, Ph.D.

Oregon Health & Science University
Changes in Residual Hearing in a Hearing-impaired Guinea Pig Model of Hybrid Cochlear Implants (CIs)

The goal of the current study is to understand mechanisms of hearing loss with “hybrid” or “electro-acoustic” cochlear implants (CIs), a new type of CI designed to preserve low-frequency hearing and allow combined acoustic-electric stimulation in the same ear. Hybrid CI users perform significantly better than standard CI users on musical melody recognition, voice recognition, and speech recognition in the presence of background talkers. However, approximately 10% of hybrid CI patients lose all residual hearing, and another 20% lose 20-30 dB after implantation. We hypothesize that in addition to surgical trauma, electrical stimulation through the hybrid CIs also damages cochlear cells, leading to the residual hearing loss (HL). Aim 1 is to determine the contribution of electrical stimulation to the residual HL in hybrid CI guinea pigs with noise-induced steeply-sloping high frequency hearing loss (NIHFHL). Aim 2 is to examine the effect of electrical stimulation on the cochlear pathology. The findings will guide the development of strategies to prevent hearing loss with electrical stimulation, and allow extension of the hybrid concept to all cochlear implant recipients with usable residual hearing.

Research area: Cochlear implants

Long term goal of research: To improve residual hearing preservation with “hybrid” or “electro-acoustic” cochlear implants (CIs), a new type of CI designed to preserve low-frequency hearing and allow combined acoustic-electric stimulation in the same ear.

Jennifer Resnik, Ph.D.

Jennifer Resnik, Ph.D.

Mass Eye and Ear, Harvard Medical School
Homeostatic modifications in cortical GABA circuits enable states of hyperexcitability and reduced sound level tolerance after auditory nerve degeneration

Sensorineural hearing loss due to noise exposure, aging, ototoxic drugs, or certain diseases reduce the neural activity transmitted from the cochlea to the central auditory system. These types of hearing loss often give rise to hyperacusis, an auditory hypersensitivity disorder in which low- to moderate-intensity sounds are perceived as intolerably loud or even painful. Previously thought as originating in the damaged ear, hyperacusis is emerging as a complex disorder. While it can be triggered by a peripheral injury, it develops from a maladaptation of the central auditory system to the peripheral dysfunction. My research will test the hypothesis that the recovery of sound detection and speech comprehension, may cause an overcompensation that leads to an increase in sound sensitivity and reduced tolerance of moderately loud sounds.

This hypothesis will be tested using a combination of chronic single-unit recordings, operant behavioral methods and optogenetic interrogation of specific sub-classes of cortical interneurons. By understanding how brain plasticity is modulated, we will gain deeper insight into the neuronal mechanism underlying aberrant sound processing and its potential reversal.

Christina Reuterskiöld, Ph.D.

Christina Reuterskiöld, Ph.D.

New York University
Rhyme Awareness in Children with Cochlear Implants: Investigating the Effect of a Degraded Auditory System on Auditory Processing, Language, and Literacy Development

Successful literacy is critical for a child’s development. Decoding written words is mostly dependent on the child’s processing of speech sounds, requiring a certain level of awareness of speech sounds and words in order to develop literacy skills. If the benefits of early cochlear implantation support the development of central auditory processing skills and phonological awareness, children with cochlear implants (CIs) would be expected to acquire phonological awareness skills comparable to children with typical hearing.

However, past research has generated conflicting results on this topic, which this project will attempt to remedy through investigating rhyme recognition skills and vocabulary acquisition in children who received CIs early in life. With co-principal investigator Katrien Vermeire, Ph.D., we will also shed light on the importance of central auditory processing during a child’s first years of life for developing strong literacy skills.

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.

Michael Roberts, Ph.D.

Michael Roberts, Ph.D.

University of Michigan
Cellular and synaptic basis of binaural gain control through the commissure of the inferior colliculus

Deficits in binaural hearing make it difficult for users of cochlear implants and hearing aids to localize sounds and follow speech in everyday situations. One of the most important sites for binaural computations is the inferior colliculus (IC). Located in the auditory midbrain, the IC is the hub of the central auditory system, receiving most of the ascending output of the auditory brainstem and much of the descending output of the auditory cortex. The left and right lobes of the IC communicate with each other through a massive connection called the commissure. Recent data from in vivo recordings show that commissural projections shape how IC neurons encode sound location. This suggests that important binaural interactions arise through the IC commissure, but the cellular and synaptic basis of these interactions are largely unknown. Understanding these interactions will provide foundational knowledge to guide future efforts to restore binaural hearing.

Susan M. Robey-Bond, Ph.D.

Susan M. Robey-Bond, Ph.D.

University of Vermont and State Agricultural College
The Role of a Mutation in Histidyl-tRNA Synthetase in Usher-like Syndrome Deafness

An Usher-like syndrome, comprising deafness, blindness, and fever-induced hallucinations was recently discovered, caused by recessive inheritance of a mutation in histidyl-tRNA synthetase (HARS). The HARS enzyme is required for protein production in cells: it attaches the amino acid histidine to a transfer ribonucleic acid (RNA) molecule which activates and transports the amino acid to the ribosome for protein synthesis. We will measure the effects of this mutation on the molecules required for protein synthesis. Preliminary results suggest HARS may be chemically modified by the cell, and that mutant HARS is modified differently, which is evidence HARS may have roles in the cell separate from its known function in protein synthesis. We additionally propose to determine the interactions of HARS and mutant HARS with other cellular proteins, specifically in cells derived from embryonic mouse inner ears, as a first step in elucidating a different role for HARS in hearing.

Research area: Usher and Usher-like syndrome deafness

Long-term goal of research: Our long term goal is to describe the specific role HARS, and the HARS mutation, plays in sensory cell development and maintenance. With a greater understanding of the proteome - the expressed proteins and protein interactions of a cell - during different stages of development of affected cells, we hope to discover more potential avenues for therapy to prevent or alleviate symptoms of Usher and Usher-like syndromes.

Sonia M. S. Rocha-Sanchez, Ph.D.

Sonia M. S. Rocha-Sanchez, Ph.D.

Creighton University

Role of central auditory neurons in pathogenic mechanism of progressive high frequency hearing loss (PHFHL)

The long-term objective of this study is to assess the relative contribution of Central Auditory Neurons (CANs) to high frequency hearing loss. The peripheral auditory system suggests that progressive hearing loss is resultant of SGNs and/or IHCs dysfunction. This study proposes to determine the effects of the mutations using genetically engineered mice with DN-KCNQ4 expression specific to CANs. Achieving these objectives will open doors to the formulation of therapeutic modalities and possible interventions to PHFHL treatment.

Adrian Rodriguez-Contreras, Ph.D.

Adrian Rodriguez-Contreras, Ph.D.

The City College of New York

Defining the role of olivo-cochlear feedback in the development of the auditory brainstem

During early brain development auditory neurons spontaneously generate highly patterned electrical activity in the absence of sound. In this project Rodriguez-Contreras will explore the role of cholinergic brainstem neurons in modulating the patterns of spontaneous activity. His work could provide clues to develop treatments that ameliorate hearing impairments such as tinnitus and deafness.

Merri J. Rosen, Ph.D.

Merri J. Rosen, Ph.D.

Northeast Ohio Medical University
Effects of developmental conductive hearing loss on communication processing: perceptual deficits and neural correlates in an animal model

Conductive hearing loss (CHL), which reduces the sound conducted to the inner ear, is often associated with chronic ear infections (otitis media). There is growing awareness that CHL in children is a risk factor for speech and language deficits. However, children often have intermittent bouts of hearing loss and receive varying treatments. My research uses an animal model in which the duration and extent of CHL can be effectively controlled. This research will identify parameters of natural vocalizations (such as slow or fast changes in pitch or loudness) that are poorly detected after early CHL. Neural responses from the auditory cortex will be recorded while animals behaviorally distinguish vocalizations that vary in specific ways. This will reveal the specific vocalization components that are perceptually impaired by developmental hearing loss. These components should be used as targets for intervention and remediation. Creating training paradigms for children that target these parameters should improve speech perception and comprehension.

Research area: Hearing Loss; Auditory Development; Auditory Physiology; Fundamental Auditory Research

Long-term goal of research: To identify neural mechanisms that impairs auditory perception of natural sounds as a result of hearing loss. This will show how the brain distinguishes sounds from different sources in complex environments. Neurophysiological, perceptual, and computational techniques to study animal models of hearing loss were applied. This multifaceted approach allowed the identification of neural impairments in more detail than if it was obtained when studying humans, yet is directly applicable to clarify human hearing problems and establish effective treatments.

Isabelle Roux, Ph.D.

Isabelle Roux, Ph.D.

Johns Hopkins University
Mechanisms involved in efferent synapse formation and maintenance in cochlear hair cells

This research aims at understanding the molecular mechanisms that underlie the formation and maintenance of the connections between the sensory hair cells and efferent nerve fibers that provide feedback from the brain to the ear. Such fibers are important modulators of inner ear activity. Our investigation includes different approaches (electrophysiology, confocal microscopy, and mouse genetics) in parallel.

Research area: synaptic transmission in the inner ear

Long-term goal of research: to understand the developmental machinery in the inner ear, which can lead to the ability to treat deficits in their function.

Soumen Roy, Ph.D.

Soumen Roy, Ph.D.

National Cancer Institute
High-dimensional analysis of cochlear immunity and cisplatin-induced inflammation

Cisplatin is a life-saving chemotherapy drug but has serious side effects, including causing hearing loss in 40 to 80 percent of cancer patients. Cisplatin enters the cochlea through systemic circulation and gains access to inner ear sensory hair cells after disrupting the protective blood-labyrinth-barrier (BLB). A damaged BLB also means a greater invasion of CD45(+) leukocytes (white blood cells), causing inflammation and, ultimately, hearing loss. We hypothesize that a defined subset of innate immune cells regulates hair cell death by controlling cisplatin-induced inflammatory pathways within the cochlea. Our preliminary data suggest that the cochlea has a different amount of defined leukocytes compared with blood-borne leukocytes. In addition, the data suggest that immune cells that regulate cochlear inflammation may play a role in overall ototoxicity. Understanding cochlear immunity and the interaction of immune cells with other sensory cells will shed light on ototoxicity research and its prevention.

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Regie Lyn P. Santos-Cortez, M.D., Ph.D.

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Regie Lyn P. Santos-Cortez, M.D., Ph.D.

Baylor College of Medicine
Identification of genes that predispose to chronic otitis media in an indigenous population

The study aims to identify genes predisposing to otitis media by studying gene variants that are identified from a complex pedigree within an indigenous population that has a high prevalence of chronic otitis media. The study population is ideal for gene mapping due to the limited number of founders and marriages only within the indigenous population. Next-generation sequencing will be performed in order to quickly and cost-effectively detect the causal genetic variants for otitis media that fall within the mapped genomic region. The discovery of gene variants predisposing to otitis media opens great possibilities towards increased knowledge of pathophysiology, prediction of the likelihood of otitis media through genetic diagnosis, and development of innovative treatments for otitis media.

Research areas: otitis media, genetics

Long-term goal of research: The discovery of genes predisposing to otitis media will lead to increased knowledge of the disease process behind otitis media and development of new diagnostic and treatment strategies for otitis media. The study findings are expected to benefit not only the indigenous population but also otitis media patients from other populations, as the genes that will be found can be followed up in other populations and as new therapies are developed through knowledge of genes predisposing to otitis media.

Regie-Lyn Santos-Cortez, M.D., Ph.D. graduated from the University of the Philippines Manila College of Medicine – Philippine General Hospital for both her medical education and residency in otorhinolaryngology. She studied genetic epidemiology in Erasmus Medical Centre Rotterdam, the Netherlands and did most of her PhD work on the genetics of non-syndromic hearing impairment at the Leal lab at Baylor College of Medicine, Houston, Texas, USA. She is now Assistant Professor at the Center for Statistical Genetics, Department of Molecular and Human Genetics at Baylor.

Takunori Satoh, Ph.D.

Takunori Satoh, Ph.D.

Purdue University

Gene discovery related to congenital deafness

Congenital deafness in humans occurs in approximately 1 in 1,000 live births, yet few of the responsible genes are known. This study aims to discover new genes important to the development of the auditory system using zebrafish to determine if they correspond to genes underlying congenital deafness in humans. Utilizing a new process, this study hopes to facilitate gene discovery then determine the involvement of the genes in the development of the auditory system.

Iris Schrijver, M.D.

Iris Schrijver, M.D.

Stanford University School of Medicine

The functional impact of single and dual expression of GJB2 missense variants V271 and E114G: An exploration of pathogenic effects on hearing

It is difficult to predict the consequences of DNA alterations that result in the replacement of one protein building block by another. Yet, an important aspect of genetic testing is to predict whether a DNA change is harmful or not. With this project, we will solve this dilemma for two relatively common variants in the connexin 26 gene. Interestingly, it appears that these two variants do not contribute to hearing loss when opposite of a disease causing change separately, but when they occur together opposite such a change, there is hearing loss as if these changes have an additive deleterious effect. By using techniques in which we are experienced, we plan to continue our research in hearing loss and directly observe whether and how these variants affect the connexin 26 protein functions within the cell. We will determine the effect on the amount of connexin 26 proteins, on localization and transport within the cell, and on function by establishing whether the essential communication channels between cells are still formed. This work will enable the correct clinical interpretation of these commonly observed changes, and can help begin to link DNA changes to protein effects and clinical symptoms in patients with hearing loss.

Rebecca Seal, Ph.D.

Rebecca Seal, Ph.D.

University of Pittsburgh
Role of outer hair cell glutamate release in cochlear function and dysfunction

Outer hair cells are vital for normal hearing. Although the cells are known to amplify the cochlear response to sound using an electromotile mechanism, they also signal to type II spiral ganglion neurons through the regulated release of glutamate. However, the function of this signaling remains unknown. Similar to inner hair cells, glutamate signaling by outer hair cells may influence sound transmission as well as the maintenance of spiral ganglion afferents. In the adult, cholinergic efferents play a critical role in maintaining outer hair cell viability and the innervation pattern of these fibers may also be influenced by the released glutamate. Thus, there are several potential mechanisms by which loss of glutamate signaling by outer hair cells could cause hearing loss. This proposal aims to address these possibilities.

Research area: fundamental auditory research

Long-term goal of research: To provide new information about the role of hair cell signaling in hearing and in disorders of the auditory system including hearing loss. These analyses will inform decisions on therapeutic strategies for the restoration of hearing and for other disorders that may be derived from aberrant cochlear function.

Rebecca Seal Ph.D. received her Ph.D. in Neuroscience from Oregon Health and Sciences University and completed her postdoctoral training in sensory circuits at the University of California, San Francisco. She is currently an Assistant Professor in the Department of Neurobiology at the University of Pittsburgh.

Armin Seidl, Ph.D.

Armin Seidl, Ph.D.

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

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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.

Valeriy Shafiro, Ph.D.

Valeriy Shafiro, Ph.D.

Rush University Medical Center

Perception of environmental sounds and speech in patients with cochlear implants

This project will assess the ability of patients with contemporary cochlear implants to perceive environmental sounds using a new test of environmental sound perception. It will further examine the relationships between perception of environmental sounds and speech. A close association between these abilities would open an exciting possibility of developing a language-independent instrument for estimating speech perception abilities based on environmental sound tests (e.g., when speech materials are not available for some languages for potential candidates). Such a test would have highly useful clinical applications in large urban clinics or in developing countries with fledgling implant programs.

Jun Shen, Ph.D.

Jun Shen, Ph.D.

Brigham and Women’s Hospital; Harvard Medical School
An integrated paradigm for efficient hearing loss gene discovery

Knowing the genetic cause of hearing loss allows early diagnosis before the onset of noticeable symptoms. It also informs the choice of optimal management plans, and predicts risks for relatives including future babies. We aim to identify novel hearing loss genes by studying three large families with hereditary hearing loss from an isolated population. We will integrate new High- Throughput (HTP) sequencing technology with family-based analyses and prior research findings concerning hearing into the Shared Harvard Inner Ear Laboratory Database (SHIELD). This integrated approach will enable efficient identification of one or more hearing loss genes in these families. The discovery of novel genes will increase our knowledge, enable early diagnosis, and ultimately lead to improved patient care.

Research area: Fundamental auditory research

Long-term goal of research: To translate genetic research findings into accurate and sensitive clinical molecular diagnostic tests to improve care for patients.

Yu-chi Shen, Ph.D.

Yu-chi Shen, Ph.D.

University of Michigan

The role of MIF in zebrafish inner ear development

We hypothesize that MIF plays a major role in otic development, specifically in neurite outgrowth and survival of the developing SAG neurons in the inner ear. We have found that MIF is expressed in the mammalian (mouse) inner ear, the chick inner ear and in the model system we have chosen to study, the zebrafish inner ear. Zebrafish auditory system development recapitulates many aspects of early mammalian inner ear development and neurogenesis. More importantly, the same molecules that are active in the mammal are active in the zebrafish and the zebrafish inner ear development is both easier to study and is extremely rapid. We will examine early survival and maturation factors for the SAG and use advanced imaging to trace SAG precursor cell movements from the otic vesicle to the ganglion. Preliminary studies using in situ hybridization demonstrated that MIF and MIF-like genes and their receptors are expressed in zebrafish SAG and developing inner ear. Our experiments will examine whether MIF and MIFlike gene loss-of-function using morpholino antisense oligonucleotides (MOs) affects SAG development and whether this loss of function can be "rescued" by introducing MIF RNA.

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