Improved TMC1 Gene Therapy Restores Hearing and Balance in Mice

By Christopher Geissler, Ph.D.

Half of all inner ear disorders, which have a negative impact on hearing and/or balance, are caused by genetic mutations. A study published in January 2019 in Nature Communications demonstrates the effectiveness of a gene therapy targeting one specific gene mutation, TMC1 (transmembrane channel-like 1). The research was conducted by Carl A. Nist-Lund in the Harvard Medical School lab of Gwenaëlle S. Géléoc, Ph.D., and Jeffrey R. Holt, Ph.D., with contributions from colleagues including 2017 Emerging Research Grants (ERG) recipient Jennifer Resnik, Ph.D., and her ERG co-principal investigator Daniel B. Polley, Ph.D., both also of Harvard Medical School.

So far, 35 TMC1 mutations have been identified in humans, including several that are responsible for moderate to severe hearing loss, representing between 3 to 8 percent of cases of genetic hearing loss. This TMC1 gene therapy has had an encouraging level of success in mice and may prove capable of addressing similar genetic mutations in humans in the future.

Previous studies targeting this gene were only moderately successful in restoring function in inner hair cells, with little or no success in outer hair cells. Both types of hair cell are necessary for hearing.

The team decided to look at improving the mechanism that encodes TCM1 in affected mice, using a synthetic delivery vehicle they hoped would be more effective than the conventional one used in previous studies. In mice with this TCM1 mutation, hair cells begin to die when the mouse reaches 4 weeks of age. The treated mice in this study showed improved rates of survival in both inner and outer hair cells.

Most importantly, the improvement in hearing in the mice that received this intervention occurred primarily in the lower frequencies. Human speech is at the low to mid frequency range of the auditory spectrum, so if future human trials are able to replicate the success of this study, speech perception may improve.

The study additionally provided evidence of improved responses in the brain of the treated mice. This indicates that treatment of the cochlea by injection had knock-on effects in the auditory cortex, the part of the brain that plays an important role in hearing.

Finally, the team recorded improved balance function in the mice that received the gene therapy. While only very young mice experienced better hearing, even older mice showed improvement in balance. The team writes that this improvement in balance function in mature mice may contribute to eventually developing a way to treat balance disorders in humans.

Jennifer Resnik, Ph.D., is a postdoctoral fellow in the Polley Lab, part of the Eaton Peabody Laboratories, Massachusetts Eye and Ear/Harvard Medical School. Her 2017 Emerging Research Grant was generously funded by Hyperacusis Research Ltd. Christopher Geissler, Ph.D., is HHF’s director of program and research support.

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Single-Cell RNA Sequencing Reveals More Clues for Hair Cell Regeneration

By Mark E. Lush, Ph.D., and Daniel C. Diaz

Sensorineural hearing loss in mammals can often be attributed to damage or destruction of the delicate hair cells located within the inner ear. The microscopic hairlike projections on the surface of these cells are the key structure responsible for converting sound waves to electrical signals that travel to the brain through the auditory nerve. Unlike mammals, other vertebrates such as fish, birds, and reptiles routinely regenerate sensory hair cells during homeostasis and following injury. By studying the genetic program of hair cell regeneration in nonmammalian vertebrate organisms, researchers may discover therapeutic targets for treating hearing loss in humans.

The lateral line is a sensory system that allows aquatic vertebrates to orient themselves by detecting water motion. The lateral line organs (neuromasts), distributed on the head and along the body, contain approximately 60 cells, composed of central sensory hair cells surrounded by support cells and an outer ring of mantle cells. Using single-cell RNA sequencing, we combined some of the less well-defined clusters and identified major neuromast cell types, shown in this illustration, ranging from support cells to mature sensory hair cells. Credit: The lab of Tatiana Piotrowski, Ph.D., Stowers Institute for Medical Research, Kansas City

One such organism, the zebrafish, has emerged as a powerful model for studying sensory hair cell regeneration. Like other fish, zebrafish contain a network of sensory hair cells throughout their body to detect changes in water movement. The hair cells are located in small organs in the skin called neuromasts, which also contains cell types that are remarkably similar to those found in the mammalian inner ear. To study the genetic program of hair cell regeneration in zebrafish, we sequenced the RNA of individual cells within neuromasts, allowing us to classify cell types based on their gene expression signature. This included cells transitioning from support cells to fully mature sensory hair cells, thereby identifying new genes that are expressed during hair cell development. In addition, we characterized the role of the growth factor fgf3, and found that it acts to inhibit hair cell progenitor proliferation. Our results were published in the journal eLife on Jan. 25, 2019. Future work will examine the function of these genes in sensory hair cell regeneration.

Mark E. Lush, Ph.D., and Daniel C. Diaz both work in the lab of Tatjana Piotrowski, Ph.D., at Stowers Institute for Medical Research in Kansas City. Piotrowski is a member of the Hearing Restoration Project, which helped fund this study.

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Hearing Restoration Project Scientific Director to Lead University’s Research Enterprise

By Tamara Hargens-Bradley, OHSU News

OHSU/Kristyna Wentz-Graff

Peter Barr-Gillespie, Ph.D., will be Oregon Health & Science University’s (OHSU) first chief research officer and executive vice president, effective Jan. 1, 2019. Barr-Gillespie has served as interim senior vice president for research at OHSU since 2017.

In his new role, Barr-Gillespie will be principal adviser to OHSU President Danny Jacobs, M.D., FACS, on research strategy and research resource allocation. He will lead and manage OHSU’s research enterprise—comprising dozens of internationally and nationally acclaimed basic, translational, clinical, and public health research programs—and serve on the president’s executive leadership team.

“Dr. Barr-Gillespie has done a tremendous job leading the OHSU research mission on an interim basis. I’m delighted to appoint him to a new, permanent position that reflects his contributions and capabilities as well as the vital role of research at OHSU,” Jacobs says.

Barr-Gillespie also will collaborate with external academic, industrial and community research partners, and the various funding, regulatory and accrediting bodies. Moreover, he will represent OHSU in research collaborations with other universities in Oregon and the northwest region.

“I am excited to support Dr. Jacobs in developing OHSU’s 2025 strategic plan for research,” Barr-Gillespie says. “To be among the top-ranked research universities for NIH funding in the country and maintain our national reputation for cutting-edge research, we need to empower our researchers to do their best science by smartly investing in people, core resources, and space, and enhancing our graduate programs.”

OHSU/Kristyna Wentz-Graff

Barr-Gillespie is an internationally recognized scholar, biomedical researcher and visionary academic leader who has been on faculty at OHSU since 1999. He currently holds faculty appointments in the departments of Otolaryngology/Head and Neck Surgery, Biochemistry and Molecular Biology, and Cell and Developmental Biology in OHSU’s School of Medicine and Oregon Hearing Research Center. He also is a senior scientist in the OHSU Vollum Institute.

An NIH-funded investigator, Barr-Gillespie’s research focus, his passion, is understanding the molecular mechanisms that enable our sense of hearing. Specifically, the Barr-Gillespie lab endeavors to determine how sensory cells in the inner ear called hair cells allow humans to perceive sound. Barr-Gillespie will maintain his active research program while serving as chief research officer.

Barr-Gillespie is also the scientific director of the Hearing Restoration Project (HRP), an international consortium of 14 investigators funded by Hearing Health Foundation. The HRP’s goal is to develop a biological therapy for hearing loss arising from destruction of hair cells, which are not regenerated after damage from noise, ototoxic drugs, or aging.

Barr-Gillespie earned his bachelor’s degree in chemistry from Reed College in 1981, carrying out his senior undergraduate thesis at OHSU after a summer fellowship in OHSU’s biochemistry department. He received his doctorate in pharmacology at the University of Washington in 1988, and completed a postdoctoral fellowship in physiology, cell biology and neuroscience with Jim Hudspeth, M.D., Ph.D., at the University of California San Francisco and the University of Texas Southwestern Medical Center in 1993.

Following his fellowship, he accepted a faculty position in physiology at Johns Hopkins and remained there until accepting the position of scientist at the OHSU Vollum Institute and associate professor of otolaryngology/head and neck surgery in the OHSU School of Medicine in 1999. In 2014, Barr-Gillespie was appointed associate vice president for basic research at OHSU.

As a young investigator, Barr-Gillespie was named a Pew Scholar in Biomedical Sciences, a program that funds research “that shows outstanding promise in science relevant to the advancement of human health.” During his tenure at OHSU, he has been honored with the Faculty Excellence in Education Award and the John A. Resko Faculty Research Achievement and Mentoring Award.

Over his distinguished career, he has published more than 115 scholarly articles, chapters, and reviews, and has been an invited lecturer at dozens of research universities, academic conferences, and scientific events.

Barr-Gillespie and his wife, Ann Barr-Gillespie, D.P.T., Ph.D., live in Portland. She is the vice provost and executive dean of the College of Health Professions at the Pacific University Hillsboro campus. Their children are Aidan Gillespie, 17, and Katie Gillespie, 24, whom Peter and Ann share with their mother, Susan Gillespie. In their spare time, Peter and Ann enjoy cycling and hiking.

This is republished with permission from OHSU News.

First Study to Examine Cognitive Development in Deaf Babies Finds Differences Begin in Infancy

By The Ohio State University Wexner Medical Center

Deaf children face unique communication challenges, but a new study shows that the effects of hearing impairment extend far beyond language skills to basic cognitive functions, and the differences in development begin surprisingly early in life. Researchers at The Ohio State University Wexner Medical Center are the first to study how deaf infants process visual stimuli compared to hearing infants and found they took significantly longer to become familiar with new objects.

 “This is somewhat counterintuitive because a lot of people assume that deaf children compensate for their lack of hearing by being better at processing visual things, but the findings of the study show the opposite,” said Claire Monroy, post doctorate otolaryngology fellow at The Ohio State University Wexner Medical Center and co-author of the study.

Macey Kinney plays with her 10-month-old son Zealand, who was born deaf. A new study shows that developmental differences in deaf babies extend beyond language and hearing, and begin surprisingly early in life. Credit: Ohio State University Wexner Medical Center

To test their visual processing skills, researchers showed infants different objects on a screen. When a baby has successfully encoded the object, they will lose interest and look away. This familiarization is what researchers call habituation. “Deaf infants took longer to habituate to the objects and looked away from them less than hearing infants,” said Derek Houston, associate professor of otolaryngology at Ohio State. “These results were surprising because you wouldn’t expect there to be such profound differences in a test that really has nothing to do with hearing.”

However, researchers say the results don’t necessarily mean that deaf children are learning at a slower pace. “Because they use vision to process the world around them, they may pay closer attention to visual objects,” said Houston. “They might actually be processing more about each object.”

Future research will examine why these differences in visual learning exist so that each child is taught in a way that works best for them and leads to healthy development. “Understanding the source of these differences can really help us tailor interventions specifically for these children,” said Monroy. “And the earlier that happens, the better.”

This article was republished with permission from the Ohio State University Wexner Medical Center. See the original press release here.

Shared Knowledge Is Power

By Lauren McGrath

Each February, thousands of hearing and balance scientists join their colleagues from around the world at the Association for Research in Otolaryngology (ARO) Mid-Winter Meeting. It is one of the premier international conferences for those in the field. I was fortunate to attend this year’s 42nd meeting, held in Baltimore, on behalf of Hearing Health Foundation (HHF), along with Emerging Research Grants (ERG) awardees past and present, Hearing Restoration Project (HRP) consortium scientists, and HHF scientific committee members—all of whom are integral to our mission to advance the prevention, treatment, and cures of hearing and balance conditions.

ARO provides auditory and vestibular researchers opportunities present their latest findings and engage in meaningful conversations with one another. If one scientist presents an idea to an audience of 100 scientists, she’s just created the possibility for 100 new ideas will form. Even one novel suggestion following a presentation at ARO can be invaluable to science.

Tenzin Ngodup, Ph.D., represents his HHF-funded tinnitus project at ARO.

One forum through which scientists share their knowledge at ARO is in the poster hall. ERG grantees including Tenzin Ngodup, Ph.D., and Samira Anderson, Au.D. Ph.D., stood proudly alongside large poster board displays ready to answer questions about their respective projects. Ngodup, who is currently funded by HHF and based at Oregon Health and Science University, used his poster to visually explain his progress investigating neuronal activity in the ventral cochlear nucleus (VCN) in order to prevent and treat tinnitus. “It was previously thought that there were a few hundred inhibitory glycinergic cells called D-stellate cells in the VCN, but we found a surprisingly large population of glycinergic cells— approximately 2,700—that are physiologically and morphologically distinct from D-stellate cells,” Ngodup says. By quantifying inhibitory neurons in the VCN he aims to examine inhibition in typical vs. tinnitus models, especially after noise exposure.

University of Maryland’s Anderson, a 2014 ERG grantee, represented an impressive half dozen informational poster boards with her colleagues. The titles included: “Aging Effects on the Auditory Evoked Cortical Potentials in Cochlear Implant Users”; “Mutual Information Analysis of Neural Representations of Speech in Noise in the Aging Midbrain”; and “Age-Related Degradation Is More Evident for Speech Stimuli With Longer Than With Shorter Consonant Transitions.” A clinician who transitioned to research, Anderson graciously thanked HHF for funding her first-ever scientific grant, and was thrilled to tell me her work had just been cited by the Wall Street Journal in an article called “Better Hearing Can Lead to Better Thinking,” published February 6, 2019, about the importance of hearing loss treatment in older adults.

Outside of the poster sessions in lecture halls, ARO attendees conduct topic-specific seminars to seated audiences. Elizabeth McCullagh, Ph.D., of University of Colorado Denver, a 2016 ERG grantee, led a symposium called “Mechanisms of Auditory Hypersensitivity in Fragile X Syndrome” in which she and other speakers, including Kelly Radziwon, Ph.D. (2017 ERG), and Khaleel Razak, Ph.D. (2018 ERG), presented their novel findings related to Fragile X syndrome: a genetic model for autism, difficulties in sound localization, and overstimulation by sound in mouse models.

2018 ERG grantees Joseph Toscano, Ph.D., A. Catalina Vélez-Ortega, Ph.D., and David Jung, M.D., Ph.D.

Achim Klug, Ph.D., a volunteer ERG grant reviewer, remarked during the Council of Scientific Trustees (CST) reception—a gathering to formally honor our ERG 2018 grantees—how critical McCullagh’s ERG grant has been to her work as an early-career scientist. With seed funding from HHF, McCullagh was able to investigate and publish information about a previously underfunded topic and deepen understanding within the hearing research field, he said. Allen Ryan, Ph.D., another member of the CST, added the program is “immensely valuable for helping young scientists advance to receive a Research Project Grant [R01] from the National Institutes of Health.” Every dollar invested in ERG grantees yields $91 from the NIH.

The HRP consortium also convened at ARO to deliver updates on five active projects following their most recent Seattle meeting. Bioinformatics and epigenetics were major focal points with Ronna Hertzano, M.D., Ph.D., showcasing updates to the gEAR database that she created (“Gene Expression Analysis Resource”) and Neil Segil, Ph.D., reporting on gene changes in the mouse inner ear, a project he works on with fellow HRP scientists Michael Lovett, Ph.D., David Raible, Ph.D., and Jennifer Stone, Ph.D.

Stefan Heller, Ph.D., who spoke about his Stanford lab’s work on transcriptome changes in single chick cells, noted: "The investments in the HRP are truly paying off, especially in the last one to two years. HRP investigators had major papers published and obtained National Institutes of Health support with the help of funding for the HRP consortium. Regarding my laboratory’s work, HRP support has given us the chance to focus on getting the highest possible quality of data—in my mind, the most important foundation for future work."

HHF looks forward to work to come from Ngodup, Anderson, McCullagh, and other ERG grantees, as well as the collaborative efforts of the HRP to advance a biological cure for hearing loss. We sincerely thank our generous donors and supporters who make this life-changing work possible.

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New Insights into the Development of the Hair Cell Bundle

By Yishane Lee

Recent genetic studies have identified that the protein Ripor2 (formerly known as Fam65b) is an important molecule for hearing. It localizes to the stereocilia of auditory hair cells and causes deafness when mutations disrupt its function.

In a study published in the Journal of Molecular Medicine in November 2018, Oscar Diaz-Horta, Ph.D., a 2017 Emerging Research Grants (ERG) scientist, and colleagues further show the role the protein plays by demonstrating how it interacts with other proteins during the development of the hair cell bundle. The team found that the absence of Ripor2 changes the orientation of the hair cell bundle, which in turn affects hearing ability.

Ripor2 interacts with Myh9, a protein encoded by a known deafness gene, and Myh9 is expressed in the hair cell bundle stereocilia as well as its kinocilia (apices). The team found that the absence of Ripor2 means that Myh9 is low in abundance. In the study, Ripor2-deficient mice developed hair cell bundles with atypically localized kinocilia and reduced abundance of a phosphorylated form of Myh9. (Phosphorylation is a cellular process critical for protein function.)

Another specific kinociliary protein, acetylated alpha tubulin, helps stabilize cell structures. The researchers found it is also reduced in the absence of Ripor2.

The study concludes that Ripor2 deficiency affects the abundance and/or role of proteins in stereocilia and kinocilia, which negatively affects the structure and function of the auditory hair cell bundle. These newly detailed molecular aspects of hearing will help to better understand how, when these molecular actions are disrupted, hearing loss occurs.

A 2017 ERG scientist funded by the Children’s Hearing Institute (CHI), Oscar Diaz-Horta, Ph.D., was an assistant scientist in the department of human genetics at the University of Miami. He passed away suddenly in August 2018, while this paper was in production. HHF and CHI both send our deepest condolences to Diaz-Horta’s family and colleagues.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

Disrupted Nerve Cell Function and Tinnitus

By Xiping Zhan, Ph.D.

Tinnitus is a condition in which one hears a ringing and/or buzzing sound in the ear without an external sound source, and as a chronic condition it can be associated with depression, anxiety, and stress. Tinnitus has been linked to hearing loss, with the majority of tinnitus cases occurring in the presence of hearing loss. For military service members and individuals who are constantly in an environment where loud noise is generated, it is a major health issue.

This figure shows the quinine effect on the physiology of dopaminergic neurons in the substantia nigra, a structure in the midbrain.

During this phantom ringing/buzzing sensation, neurons in the auditory cortex continue to fire in the absence of a sound source, or even after deafferentation following the loss of auditory hair cells. The underlying mechanisms of tinnitus are not yet known.

In our paper published in the journal Neurotoxicity Research in July 2018, my team and I examined chemical-induced tinnitus as a side effect of medication. Tinnitus patients who have chemical-induced tinnitus comprise a significant portion of all tinnitus sufferers, and approaching this type of tinnitus can help us to understand tinnitus in general.

We focused on quinine, an antimalarial drug that also causes hearing loss and tinnitus. We theorized this is due to the disruption of dopamine neurons rather than cochlear hair cells through the blockade of neuronal ion channels in the auditory system. We found that dopamine neurons are more sensitive than the hair cells or ganglion neurons in the auditory system. To a lesser extent, quinine also causes muscle reactions such as tremors and spasms (dystonia) and the loss of control over body movements (ataxia).

As dopaminergic neurons (nerve cells that produce the neurotransmitter dopamine) are implicated in playing a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic neurons derived from human pluripotent stem cells and isolated dopaminergic neurons from the mouse brain.

We found that quinine can affect the basic physiological function of dopamine neurons in humans and mice. Specifically, we found it can target and disturb the hyperpolarization-dependent ion channels in dopamine neurons. This toxicity of quinine may underlie the movement disorders and depression seen in quinine overdoses (cinchonism), and understanding this mechanism will help to learn how dopamine plays a role in tinnitus modulation.

A 2015 ERG scientist, Xiping Zhan, Ph.D., received the Les Paul Foundation Award for Tinnitus Research. He is an assistant professor of physiology and biophysics at Howard University in Washington, D.C. One figure from the paper appeared on the cover of the July 2018 issue of Neurotoxicity Research.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

Headlines in Hearing Restoration

By Yishane Lee

The cornerstone of Hearing Health Foundation for six decades has been funding early-career hearing and balance researchers through its Emerging Research Grants (ERG) program. Many ERG scientists have gone on to obtain prestigious National Institutes of Health (NIH) funding to continue their HHF-funded research; since 1958, each dollar awarded to ERG scientists by HHF has been matched by NIH investments of more than $90. Within the scientific community, ERG is a competitive grant awarded to the most promising investigators, and we’re always especially pleased when our ERG alumni who are now also members of or affiliated with our Hearing Restoration Project consortium make headlines in the mainstream news for their scientific breakthroughs.

Hair cells in the mouse cochlea courtesy of the lab of Hearing Restoration Project (HRP) member Andy Groves, Ph.D., Baylor College of Medicine.

Ronna Hertzano, M.D., Ph.D. (2009–10): Hearing Restoration Project consortium member Hertzano, an associate professor at the University of Maryland School of Medicine, and colleagues identified a gene, Ikzf2, that acts as a key regulator for outer hair cells whose loss is a major cause of age-related hearing loss. The Ikzf2 gene encodes helios, a transcription factor (a protein that controls the expression of other genes). The mutation of the gene in mice impairs the activity of helios in the mice, leading to an outer hair cell deficit.

Reporting in the Nov. 21, 2018, issue of Nature, the team tested whether the opposite effect could be created—if an abundance of helios could boost the population of outer hair cells. They introduced a virus engineered to overexpress helios into the inner ear hair cells of newborn mice, and found that some mature inner hair cells became more like outer hair cells by exhibiting electromotility, a property limited to outer hair cells. The finding that helios can drive inner hair cells to adopt critical outer hair cell characteristics holds promise for future treatments of age-related hearing loss.

Patricia White, Ph.D. (2009, 2011), with Hearing Restoration Project member Albert Edge, Ph.D.: White, a research associate professor at the University of Rochester Medical Center, Edge, a professor of otolaryngology at Massachusetts Eye and Ear and Harvard Medical School, and team have been able to regrow the sensory hair cells found in the mouse cochlea. The study, published in the European Journal of Neuroscience on Sep. 30, 2018, builds on White’s prior research that identified a family of receptors called epidermal growth factor (EGF) that is responsible for activating supporting cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. In mice, EGF receptors are expressed but do not drive regeneration of hair cells, so it could be that as mammals evolved, the signaling pathway was altered.

The new study aimed to unblock the regeneration of hair cells and also integrate them with nerve cells, so they are functional, by switching the EGF signaling pathway to act as it does in birds. The team focused on a specific receptor called ERBB2, found in supporting cells. They used a number of methods to activate the EGF signaling pathway: a virus targeting ERBB2 receptors; mice genetically altered to overexpress activated ERBB2; and two drugs developed to stimulate stem cell activity in the eye and pancreas that are already known to activate ERBB2 signaling. The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events: Supporting cells began to proliferate and started the process of activating other neighboring stem cells to lead to “apparent supernumerary hair cell formation,” and these hair cells’ integration with the network of neurons was also supported.

This was prepared using press materials from the University of Maryland and the University of Rochester. For more, see hhf.org/hrp.

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Recording Electrical Responses to Improve the Diagnosis of Hearing Conditions

By Yishane Lee

Electrocochleography (ECochG) is a method to record electrical responses from the inner ear and the auditory nerve in the first 5 milliseconds after a sound stimulus, such as a click or tone burst. These stimuli can be adjusted for repetition rate and polarity, and recordings can also be taken from either the ear canal, eardrum, or through the eardrum. The main components of ECochG response are the summating potential (SP), from the sensory hair cells in the cochlea, and the action potential (AP) of auditory nerve fibers. In an October 2018 paper in the journal Canadian Audiologist, 2015 ERG scientist Wafaa Kaf, Ph.D., reviews the diagnostic applications for using ECochG for Ménière’s disease and cochlear synaptopathy, two conditions that can be difficult to pinpoint, especially early in the disease, and suggests how to improve the use of ECochG as a clinical tool.

Shutterstock

Endolymphatic hydrops, or abnormal fluctuations in inner ear fluid, is believed to be the underlying cause of Ménière’s disease and its associated hearing and balance disorder. ECochG collects information about the SP/AP amplitude and area ratios that can be used to confirm a Ménière’s diagnosis, without relying solely on clinical symptoms.

Since the SP/AP amplitude ratio can vary among known Ménière’s patients, Kaf suggests including data about the SP/AP area ratio as well can help with diagnosing the disease. To further distinguish Ménière’s, Kaf suggests using ECochG AP latencies, and, building on her prior research, the effect of fast click rates on the auditory nerve latency and amplitude. Using the continuous loop averaging deconvolution technique, various properties of the SP and AP waveforms are easier to identify and parse. Results suggest that the functions of the cochlear nerve and/or cochlear synapses are damaged in Ménière’s. Earlier research that shows an abnormal acoustic reflex decay in about a quarter of Ménière’s patients, and a reduced number of synapses between inner hair cells and auditory nerve fibers, underscores the presence of nerve damage in Ménière’s.

Cochlear synaptopathy is a noise-induced or age-related dysfunction that is also causing reduced synapses between inner ear hair cells and auditory nerve fibers, resulting in tinnitus, hyperacusis, and difficulty hearing in noise despite normal hearing sensitivity. ECochG may help with its diagnosis, especially given that traditional audiograms and hearing tests have been found to miss this “hidden hearing loss.” The use of both the SP/AP amplitude and area ratios and specific auditory brainstem responses can help confirm this condition and distinguish it from Ménière’s disease.

ECochG can also be used to help confirm the diagnosis of auditory neuropathy spectrum disorder, a problem with the way sound is transmitted between the inner ear and the brain, and other inner ear disorders. The technique can also be used to monitor ear responses, real-time, during surgeries such as a stapedectomy, endolymphatic shunt, and cochlear implantation, additional instances demonstrating how ECochG holds promise for expanded use in the clinic.

A 2015 ERG scientist funded by The Estate of Howard F. Schum, Wafaa Kaf, Ph.D., is a professor of audiology at Missouri State University.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

The People Behind the Science

By Yishane Lee

Eight years ago we introduced a column called “Meet the Researcher.” Placed on the last page of the magazine (prime editorial real estate!), the MTR column was designed as a way to give our Emerging Research Grants (ERG) scientists a place to talk about their ERG project in more detail—and in lay terms for our readers—including its genesis, planned execution, and future goals.

Credit: Jane G. Photography

“Meet the Researcher” also is an opportunity for us to glimpse the person behind the science, with the researchers sharing how they became interested in their field and whether they have any personal connection to hearing conditions. Perhaps not surprisingly, many researchers do become interested in hearing and balance science as a result of their own experience with hearing loss. For instance, 2010 ERG scientist Judith Kempfle, M.D., told us she received an artificial eardrum at age 13, after many ear infections that her brother also got when they were kids growing up in Germany. With her ERG funded by the Royal Arch Masons General Grand Chapter International, Kempfle has gone on to work on many papers with Hearing Restoration Project member Albert Edge, Ph.D. (including a recent one about the effort to deliver drugs directly to the inner ear).

Ed Bartlett, Ph.D., Purdue University

Also a Royal Arch Masons grantee, 2011 ERG scientist Ed Bartlett, Ph.D., who published research on the lasting effects of blast shock waves on auditory processing, remembers asking his teacher whether we actually hear thoughts or if it something else. “So, I guess I was destined for auditory neuroscience,” says Bartlett, who also earned ERG funding in 2003, 2004, and 2009.

2011 and 2012 ERG scientist Regie Santos-Cortez, M.D., Ph.D., who earned the Collette Ramsey Baker Award named after HHF’s founder, spoke about the challenges of getting access to genetic information for her study that eventually pinpointed a gene mutation linked to a predisposition for ear infections. 2012 ERG scientist Bradley J. Walters, Ph.D., says he started out studying evolutionary biology, switched to studying regenerating damaged brain tissue, and then switched to hearing research. “I realized a lot of the ideas I had been working on in the brain could be applied to the ear,” he says. A 2017 paper he coauthored described successfully using gene therapy to regenerate hair cells in adult mice.

Alan Kan, Ph.D., University of Wisconsin, Madison

An early love of logic puzzles for 2013 ERG scientist Alan Kan, Ph.D., a Royal Arch Masons grantee, turned into studying audio engineering and his 2018 paper looking at how to improve speech understanding among people who use bilateral cochlear implants. Fellow 2013 Royal Arch Masons recipient Ross Maddox, Ph.D., remembers varying how he cupped his hands over his ears to get different sounds, leading to an interest in auditory processes and, eventually, research on how auditory and visual input is synthesized to understand sound.

After 26 years as a clinical audiologist, Royal Arch Masons 2014 ERG scientist Samira Anderson, Ph.D., switched to research. “Part of my motivation came from working with patients who struggled with their hearing aids,” she says. “I was frustrated that I was unable to predict who would benefit from hearing aids based on the results of audiological evaluations.” She produced three papers on the topic, bringing us closer to improving fit for and increasing the use of hearing aids.

Likewise, fellow Royal Arch Masons grantee Srikanta Mishra, Ph.D., produced two papers, one in 2017 and one in 2018, on children’s hearing that stemmed from his 2014 ERG grant—work that also led to a prestigious National Institutes on Deafness and Other Communication Disorders grant. And we liked the backstory for 2014 ERG scientist Brad Buran, Ph.D., so much that we put him on the cover of our magazine. Buran, who wears cochlear implants, multitasks during happy hour with his colleagues. “In an environment where it’s hard to hear,” he says, “within an hour they have all the information they need to use Cued Speech,” which uses visual representations of phonemes.

Beula Magimairaj, Ph.D., University of Central Arkansas

In 2015, we expanded our coverage of ERG recipients, so that every grantee is profiled in a “Meet the Researcher” column, all available online. Three papers resulted from the Royal Arch Masons grant received by 2015 ERG scientist Beula Magimairaj, Ph.D., and her research into children’s speech perception in noise and auditory processing (the third paper is in press). Funded by Hyperacusis Research Ltd., 2015 ERG scientist Kelly Radziwon, Ph.D., has managed to create a reliable animal model for loudness hyperacusis (essentially, inducing loudness intolerance in a rat and making sure it reacts to gradually increasing sound intensities) as well as finding a potential link between neuroinflammation and hyperacusis. 2015 and 2016 ERG scientist Wafaa Kaf, Ph.D.—who has 18 other family members (and counting!) who work in science—has been investigating Ménière’s disease, publishing on improving its diagnosis as it can be mistaken for other conditions, and the use of electrocochleography (ECochG) for diagnosing and monitoring the hearing and balance disorder.

Elizabeth McCullagh, Ph.D., University of Colorado

A karaoke fan who admits he “cannot resist Celine Dion,” Royal Arch Masons 2016 ERG scientist Richard Felix II, Ph.D. published on the greater-than-expected role of lower-level brain regions on speech processing. Fellow Royal Arch Masons grantee, 2016 ERG scientist Elizabeth McCullagh, Ph.D., makes her own cheese and beer in between uncovering new clues to sound localization problems in the genetic condition known as Fragile X syndrome, which can lead to autism.

Rahul Mittal, Ph.D., University of Miami Miller School of Medicine

2016 ERG scientist Harrison Lin, Ph.D., funded by The Barbara Epstein Foundation Inc., credits his older brother, also an otolaryngologist, for developing in him a love for science. He coauthored a January 2018 JAMA Otolaryngology–Head & Neck Surgery paper that detailed the gap between hearing loss diagnoses and treatments. 2016 ERG scientist Rahul Mital, Ph.D., who says he’d write fiction if not doing research, published an overview of hair cell regeneration, and Julia Campbell, Au.D., Ph.D., whose 2016 grant was funded by the Les Paul Foundation, understands firsthand what is feels like to have tinnitus, a topic she recently published a paper that investigated mild tinnitus in young patients with typical hearing. Hyperacusis Research-funded 2016 ERG scientist Xiying Guan, Ph.D., whose parents grew up doing manual labor in China, published a paper evaluating a treatment for conductive hyperacusis.

Some of our 2017 ERG scientists are already publishing. Royal Arch Masons grantee Inyong Choi, Ph.D., produced research on hybrid cochlear implants, which make use of residual hearing to produce more natural hearing. Oscar Diaz-Horta, Ph.D., whose 2017 ERG grant was funded by the Children’s Hearing Institute, investigated hair cell bundle structure and orientation. Very regretfully, Diaz-Horta died unexpectedly just as this paper was published.

Ian Swinburne, Ph.D., Harvard Medical School

Ian Swinburne, Ph.D., one of our Ménière’s Disease Grants scientists during its inaugural year in 2017, published a paper detailing one possible cause of Ménière’s disease. Swinburne and team discovered a structure in the inner ear’s endolymphatic sac acts a pressure-sensitive relief valve. Its failure may account for problems with inner ear fluid pressure and volume that may lead to hearing and balance disorders, including Ménière’s. “One activity I loved as a child was waterworks: building canals and aqueducts out of sand or dirt and then pouring water through them just to watch it flow,” he says. “Now I recognize an echo of that play in my study of water pressure and flow within the ear.”

We very much look forward to published research from all of our ERG scientists, including our latest crop of 2018 ERG scientists, whose ranks include a former college mascot, a violinist, a horse rider (of a horse named Gandalf), a Tibetan neuroscientist (and cookbook writer), a cricket player, a nonprofit cook who has prepared meals for 50,000 people, a dancer (including in flash mobs), and a builder of airplane scale models. Our ERG scientists deliver surprises of all sorts, from their backgrounds and how they got to where they are to the ground-breaking science they are spearheading in the lab.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.