ERG

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.

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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.

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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.

Empower groundbreaking research toward better treatments and cures for hearing loss and tinnitus. If you are able, please make a contribution today.

 
 
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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.

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.

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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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.

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).

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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.

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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.

 
 
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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.

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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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

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

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

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

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

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

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., 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.

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Detailing the Relationships Between Auditory Processing and Cognitive-Linguistic Abilities in Children

By Beula Magimairaj, Ph.D.

Children suspected to have or diagnosed with auditory processing disorder (APD) present with difficulty understanding speech despite typical-range peripheral hearing and typical intellectual abilities. Children with APD (also known as central auditory processing disorder, CAPD) may experience difficulties while listening in noise, discriminating speech and non-speech sounds, recognizing auditory patterns, identifying the location of a sound source, and processing time-related aspects of sound, such as rapid sound fluctuations or detecting short gaps between sounds. According to 2010 clinical practice guidelines by the American Academy of Audiology and a 2005 American Speech-Language-Hearing Association (ASHA) report, developmental APD is a unique clinical entity. According to ASHA, APD is not the result of cognitive or language deficits.

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In our July 2018 study in the journal Language Speech and Hearing Services in the Schools for its special issue on “working memory,” my coauthor and I present a novel framework for conceptualizing auditory processing abilities in school-age children. According to our framework, cognitive and linguistic factors are included along with auditory factors as potential sources of deficits that may contribute individually or in combination to cause listening difficulties in children.

We present empirical evidence from hearing, language, and cognitive science in explaining the relationships between children’s auditory processing abilities and cognitive abilities such as memory and attention. We also discuss studies that have identified auditory abilities that are unique and may benefit from assessment and intervention. Our unified framework is based on studies from typically developing children; those suspected to have APD, developmental language impairment, or attention deficit disorders; and models of attention and memory in children. In addition, the framework is based on what we know about the integrated functioning of the nervous system and evidence of multiple risk factors in developmental disorders. A schematic of this framework is shown here.

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In our publication, for example, we discuss how traditional APD diagnostic models show remarkable overlap with models of working memory (WM). WM refers to an active memory system that individuals use to hold and manipulate information in conscious awareness. Overlapping components among the models include verbal short-term memory capacity (auditory decoding and memory), integration of audiovisual information and information from long-term memory, and central executive functions such as attention and organization. Therefore, a deficit in the WM system can also potentially mimic the APD profile.

Similarly, auditory decoding (i.e., processing speech sounds), audiovisual integration, and organization abilities can influence language processing at various levels of complexity. For example, poor phonological (speech sound) processing abilities, such as those seen in some children with primary language impairment or dyslexia, could potentially lead to auditory processing profiles that correspond to APD. Auditory memory and auditory sequencing of spoken material are often challenging for children diagnosed with APD. These are the same integral functions attributed to the verbal short-term memory component of WM. Such observations are supported by the frequent co-occurrence of language impairment, APD, and attention deficit disorders.

Furthermore, it is important to note that cognitive-linguistic and auditory systems are highly interconnected in the nervous system. Therefore, heterogeneous profiles of children with listening difficulties may reflect a combination of deficits across these systems. This calls for a unified approach to model functional listening difficulties in children.

Given the overlap in developmental trajectories of auditory skills and WM abilities, the age at evaluation must be taken into account during assessment of auditory processing. The American Academy of Audiology does not recommend APD testing for children developmentally younger than age 7. Clinicians must therefore adhere to this recommendation to save time and resources for parents and children and to avoid misdiagnosis.

However, any significant listening difficulties noted in children at any age (especially at younger ages) must call for a speech-language evaluation, a peripheral hearing assessment, and cognitive assessment. This is because identification of deficits or areas of risk in language or cognitive processing triggers the consideration of cognitive-language enrichment opportunities for the children. Early enrichment of overall language knowledge and processing abilities (e.g., phonological/speech sound awareness, vocabulary) has the potential to improve children's functional communication abilities, especially when listening in complex auditory environments. 

Given the prominence of children's difficulty listening in complex auditory environments and emerging evidence suggesting a distinction of speech perception in noise and spatialized listening from other auditory and cognitive factors, listening training in spatialized noise appears to hold promise in terms of intervention. This needs to be systematically replicated across independent research studies. 

Other evidence-based implications discussed in our publication include improving auditory access using assistive listening devices (e.g., FM systems), using a hierarchical assessment model, or employing a multidisciplinary front-end screening of sensitive areas (with minimized overlap across audition, language, memory, and attention) prior to detailed assessments in needed areas.

Finally, we emphasize that prevention should be at the forefront. This calls for integrating auditory enrichment with meaningful activities such as musical experience, play, social interaction, and rich language experience beginning early in infancy while optimizing attention and memory load. While these approaches are not new, current research evidence on neuroplasticity makes a compelling case to promote auditory enrichment experiences in infants and young children.

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A 2015 Emerging Research Grants (ERG) scientist generously funded by the General Grand Chapter Royal Arch Masons International, Beula Magimairaj, Ph.D., is an assistant professor in the department of communication sciences and disorders at the University of Central Arkansas. Magimairaj’s related ERG research on working memory appears in the Journal of Communication Disorders, and she wrote about an earlier paper from her ERG grant in the Summer 2018 issue of Hearing Health.

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Accomplishments by ERG Alumni

By Elizabeth Crofts

Progress Investigating Potential Causes and Treatments of Ménière’s Disease

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Gail Ishiyama, M.D., a clinician-scientist who is a neurology associate professor at UCLA’s David Geffen School of Medicine, has been investigating balance disorders for nearly two decades and recently coauthored two studies on the topic. While not directly funded by HHF, Ishiyama is a 2016 Emerging Research Grants recipient and also received a Ménière’s Disease Grant in 2017.

Ishiyama and colleague’s December 2018 paper in the journal Brain Research investigated oxidative stress, which plays a large role in several inner ear diseases as well as in aging. Oxidative stress is an imbalance between the production of free radicals and antioxidant defenses. The gene responsible for reducing oxidative stress throughout the body is called nuclear factor (erythroid-derived 2)-like 2, or NRF2. Ishiyama’s study looked at the localization of NRF2 in the proteins in the cells of the human cochlea and vestibule. It was found that NRF2-immunoreactivity (IR) was localized in the organ of Corti of the cochlea. Additionally, it was observed that NRF2-IR decreases significantly in the cochlea of older individuals. The team postulates for future studies that modulation of NRF2 expression may protect from hearing loss that results from exposure to noise and ototoxic drugs.

In a January 2018 report in the journal Otology & Neurotology, Ishiyama and team researched endolymphatic hydrops (EH), a ballooning of the endolymphatic fluid system in the inner ear that is associated with Ménière’s disease. Symptoms include fluctuating hearing loss, as well as vertigo, tinnitus, and pressure in the ear.

For the study, patients with EH and vestibular schwannoma were tested to evaluate the clinical outcome of patients when EH is treated medically. Vestibular schwannoma, also known as acoustic neuroma, are benign tumors that grow in the vestibular system of the inner ear, which controls balance. Often when patients develop episodic vertigo spells and have a known diagnosis of vestibular schwannoma, surgeons recommend surgical intervention, as they attribute the symptoms to the vestibular schwannoma. However, a noninvasive treatment may hold promise. Through the use of high-resolution MRI scans, the researchers found that when EH coexists with vestibular schwannoma in a patient, and the patient also experiences vertigo spells, a medical treatment for EH—that is, the use of diuretics to relieve inner ear fluid buildup—may alleviate the vestibular symptoms.

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A 2016 ERG scientist funded by The Estate of Howard F. Schum, Gail Ishiyama, M.D., is an associate professor of neurology at UCLA’s David Geffen School of Medicine. She also received a 2017 Ménière’s Disease Grant.


New Insights Into Aging Effects on Speech Recognition

Age-related changes in perceptual organization have received less attention than other potential sources of decline in hearing ability. Perceptual organization is the process by which the auditory system interprets acoustic input from multiple sources, and creates an auditory scene. In daily life this is essential, because speech communication occurs in environments in which background sounds fluctuate and can mask the intended message.

Perceptual organization includes three interrelated auditory processes: glimpsing, speech segregation, and phonemic restoration. Glimpsing is the process of identifying recognizable fragments of speech and connecting them across gaps to create a coherent stream. Speech segregation refers to the process where the glimpses (speech fragments) are separated from background speech, to focus on a single target when the background includes multiple talkers. Phonemic restoration refers to the process of filling in missing information using prior knowledge of language, conversational context, and acoustic cues.

A July 2018 study in The Journal of the Acoustical Society of America by William J. Bologna, Au.D., Ph.D., Kenneth I. Vaden, Jr., Ph.D., Jayne B. Ahlstrom, M.S., and Judy R. Dubno, Ph.D., investigated these three components of perceptual organization to determine the extent to which their declines may be the source of increased difficulty in speech recognition with age. Younger and older adults with typical hearing listened to sentences interrupted with either silence or envelope-modulated noise, presented in quiet or with a competing talker.

As expected, older adults performed more poorly than younger adults across all speech conditions. The interaction between age and the duration of glimpses indicated that, compared with younger adults, older adults were less able to make efficient use of limited speech information to recognize keywords. There was an apparent decline in glimpsing, where interruptions in speech had a larger effect on the older adult group.

Older adults saw a greater improvement in speech recognition when envelope modulations were partially restored, leading to better continuity. This demonstrated that with age comes a poorer ability to resolve temporal distortions in the envelope. In speech segregation, the decline in performance with a competing talker was expected to be greater for older adults than younger adults, but this was not supported by the data.

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A 2015 Emerging Research Grants scientist, Kenneth I. Vaden, Jr., Ph.D., is a research assistant professor in the department of otolaryngology–head and neck surgery at the Medical University of South Carolina.

A 1986–88 ERG scientist, Judy R. Dubno, Ph.D., is a member of HHF’s Board of Directors. The study’s lead author, William Bologna, Au.D., Ph.D., is a postdoctoral research fellow at the National Center for Rehabilitative Auditory Research in Portland, Oregon.

A 2018 HHF intern, Author Elizabeth Crofts is a junior at Boston University studying biomedical engineering. For our continually updated list of published papers by ERG alumni, see hhf.org/erg-alumni.

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Meet the Researcher: A. Catalina Vélez-Ortega

By Yishane Lee

2018 Emerging Research Grants (ERG) awardee A. Catalina Vélez-Ortega received a master’s in biology from the University of Antioquia, Colombia, and a doctorate in physiology from the University of Kentucky, where she completed postdoctoral training and is now an assistant professor in the department of physiology.

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IN HER WORDS:

TRPA1 is an ion channel known for its role as an “irritant sensor” in pain-sensing neurons (nerve cells). Noise exposure leads to the production of some cellular “irritants” that activate TRPA1 channels in the inner ear. The role of TRPA1 channels has been a puzzling project, with most experiments leaving more questions to pursue. My current project seeks to uncover how TRPA1 activation modifies cochlear mechanics and hearing sensitivity, in order to find new therapeutic targets to prevent hearing loss or tinnitus.

My father, our town’s surgeon, fueled my desire to learn. When I asked him how the human heart works, he called the butcher, got a pig’s heart, and we dissected it together. I was about 5 when I learned how the heart’s chambers are connected and how valves work. He also set up an astronomy class at home with a flashlight, globe, and ball when I asked, “Why does the moon change shape?” My father’s excitement kept my curiosity from fading as I grew older. That eager-to-learn personality now drives my career in science and teaching.

My training in biomedical engineering guided my interest into hearing science. The field of inner ear research mixes physics and mechanics with molecular biology and genetics in a way I find extremely attractive. Analytics also intrigues me. People who work with me know how complex my calendar and spreadsheets can get. I absolutely love logging all kinds of data and looking for correlations. I also like to plan ahead—passport renewal 10 years from now? Already in my calendar!

I take dance lessons and participate in flash mobs and other dance performances. But I used to be extremely shy. As a child I simply could not look anyone in the eye when talking to them. I was also terrified of being onstage. It was only after college that I decided to finally correct the problem. Interestingly, taking sign language lessons was very helpful. Sign language forced me to stare at people to be able to communicate. It was terrifying at first, but it started to feel very natural after just a few months.

Vélez-Ortega’s 2018 ERG grant was generously funded by cochlear implant manufacturer Cochlear Americas.

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

 
 
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HHF 2019 Grant Applications Open

By Lauren McGrath

We are excited to inform you that the applications for Hearing Health Foundation (HHF)'s 2019 Emerging Research Grants (ERG) and Ménière's Disease Grants (MRG) programs are officially open as of September 1.

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HHF's ERG grants provide seed money to stimulate data collection that leads to a continuing, independently fundable line of research. According to a 2017 analysis, every $1 of funding that HHF awards to ERG grantees is matched by the NIH with $91.

ERG grant funding shall not exceed $30,000 for the one-year project period, and only research proposals in the following topic will be considered for the 2019 ERG cycle: General Hearing Health (GHH)*,  [Central] Auditory Processing Disorders, Hearing Loss in Children, Hyperacusis, Ménière’s Disease, Ototoxic Medications, Tinnitus, and Usher Syndrome.

More Information About ERG
Begin Your ERG Application

The highly competitive Ménière’s Disease Grants (MDG) program funds scientists to better our understanding of this complicated condition with an eye for better treatments and cures for those who suffer from Ménière’s disease.

MDG grant funding shall not exceed $125,000 for the two-year project period. Areas of interest for the 2019 MDG Cycle include: the mechanisms of endolymphatic hydrops; genetics of Ménière’s disease; development and validation of biomarkers, including imaging and/or electrophysiologic and behavioral measures for its diagnosis and measurement of therapeutic effectiveness; animal models of Ménière’s disease; and the development of novel therapeutics.

More Information About MDG
Begin Your MDG Application

Applications for both ERG and MDG will close Tuesday, January 15.

If you have any questions about the grant program and processes, contact us at grants@hhf.org.  
Please forward and share this information with your colleagues who may be interested.

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Understanding Individual Variances in Hearing Aid Outcomes in Quiet and Noisy Environments

By Elizabeth Crofts

Evelyn Davies-Venn, Au.D., Ph.D.

Evelyn Davies-Venn, Au.D., Ph.D.

More than 460 million people worldwide live with some form of hearing loss. For most, hearing aids are the primary rehabilitation tool, yet there is no one-size-fits-all approach. As a result, many hearing aid users are frustrated by their listening experiences, especially understanding speech in noise.

Evelyn Davies-Venn, Au.D., Ph.D., of the University of Minnesota is currently focusing on two projects, one of which is funded by Hearing Health Foundation (HHF) through its Emerging Research Grants (ERG) program, that will enhance the customization of hearing aids. She presented the two projects at the Hearing Loss Association of America (HLAA) convention in June.

Davies-Venn explains that some of the factors dictating individual variance in hearing aid listening outcomes in noisy environments include audibility, spectral resolution, and cognitive ability. Audibility changes—how much of the speech spectrum is available to the hearing aid user—is the biggest factor. “Speech must be audible before it is intelligible,” Davies-Venn says. Another primary factor is spectral resolution, or your ear’s ability to make use of the spectrum or frequency changes in sounds. This also directly affects listening outcomes.

Secondary factors include the user’s working memory and the volume of the amplified speech. These impact how well someone can handle making sense of distortions (from ambient noise as well as from signal processing) in an incoming speech signal. Working memory is needed to provide context in the event of missing speech fragments, for instance. Needless to say, it is a challenge for conventional hearing aid technology to address all of these complex variables.

Davies-Venn’s highlights two emerging projects that take an innovative approach to resolving this challenge. The first project aims to improve hearing aid success focuses on an emerging technology called the “cognitive control of a hearing aid,” or COCOHA. It is an improved hearing aid that will analyze multiple sounds, complete an acoustic scene analysis, and separate the sounds into individual streams, she says.

Then, based on the cognitive/electrophysiological recordings from the individual, the COCOHA will select the specific stream that the person is interested in listening to and amplify it—such as a particular speaker’s voice. The cognitive recording is captured with a noninvasive, far-field measure of electrical signals emitted from the brain in response to sound stimuli (similar to how an electroencephalogram, EEG, captures signals).

Davies-Venn’s ERG grant from HHF will support research on the use of electrophysiology, far-field or distant (i.e. recorded at the scalp) electrical signals from the brain, to design hearing aid algorithms that can control individual variances due to level-induced (i.e. high intensity) distortions from hearing aids.

The other project involves sensory substitution. This project explores the conversion of speech to another sense—for example, touch—through a mobile processing device or a “skin hearing aid.” For the device to function, a vibration is relayed to the brain for speech understanding. This technology seems cutting edge, but is believed to have been invented in the 1960s by Paul Bach-y-Rita, M.D., of the Smith-Kettlewell Institute of Visual Sciences in San Francisco. Even though it has not yet been incorporated into hearing aid technology intended for mass production, David Eagleman, Ph.D., of Stanford University and others are hoping to make this a reality.

Davies-Venn’s research motives are inspired by a personal connection to her work. “I have a conductive hearing loss myself,” she says. “I had persistent/chronic ear infections as a child that left me a bit delayed in developing speech, and still get ear infections as an adult and have ground accustomed to the low-frequency hearing loss that results until they resolve.” She also has family members with hearing loss and understands the importance of developing more advanced hearing assistance technology.

The projects are in the early stages, and it may take as long as a decade for them to reach the market from the concept. “The goal is to develop individualized hearing aid signal processing to improve treatment outcomes in noisy soundscapes,” Davies-Venn says. “We want to say, this is the most optimal treatment protocol, and it’s different from this person’s, even though you have the same hearing threshold.” Solving hearing aid variances in a precise, individual manner that accounts for variables such as age and cognitive ability will improve communication and quality of life for the millions with hearing loss who use hearing technology.

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

 
 
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