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Our Impact Invigorated: HHF Visits the NIDCD

By Timothy Higdon

In my role as CEO of Hearing Health Foundation (HHF), most of my time is spent liaising with the individuals who make our groundbreaking work possible—scientists, volunteers, Board members, and donors—from our New York City office. I was fortunate to recently step away from my typical routine to witness the excitement of hearing and balance science at the National Institutes of Health (NIH) on Wednesday, August 21. 

This educational visit was organized by the Friends of the Congressional Hearing Health Congressional (FCHHC), the coalition co-founded by HHF that supports the policy interests of the Congressional Hearing Health Caucus (CHHC), a bipartisan group to committed to increasing hearing health care.

We learned about the latest federally-funded advancements in hearing and balance disorders in a tour of the labs at NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD) Intramural Research Program at the Clinical Center in Bethesda, MD. The nation’s largest hospital devoted to clinical research, the center is one location where the NIDCD supports and conducts research on the normal and disordered processes of hearing, balance, taste, smell, voice, speech, and language with an annual budget of $474 million. 

Members of the FCHHC in the Clinical Center. Photo by Nichole Westin, American Cochlear Implant Alliance.

Members of the FCHHC in the Clinical Center. Photo by Nichole Westin, American Cochlear Implant Alliance.

NIDCD Scientific Director Andrew J. Griffith, M.D., Ph.D., and clinician-scientists Carmen Brewer, Ph.D., and Clint Allen, M.D., hosted a presentation and tour. Griffith noted the importance of animal models in his overview of the hearing and balance functions, a nod to our Hearing Restoration Project’s work with birds, fish, and mice to identify biological cures for hearing loss in humans.

I was very impressed by the state-of-the-art facilities, especially the vestibular testing booth that is used to evaluate hearing and balance patients. Eye movement is observed while the chair or walls of the booth spin rapidly, helping doctors to understand how conditions like vertigo or Ménière's disease are affecting the patient.

The support that is given to patients in clinical trials also inspired me immensely. Clinical trials recruitment can be challenging, but the NIH has a national reach with a database registry for interested patients. The NIH helps with relocation expenses for the patient to minimize disruption while necessary care is provided.

I am tremendously excited by the strong relationship HHF maintains with the NIDCD. The NIDCD’s newly appointed Director, Debara Tucci, M.D., is an alumnus of our Emerging Research Grants (ERG) program and Council of Scientific Trustees. Many of our ERG recipients subsequently qualify for funding from the NIDCD and other constituent institutes of the NIH at the rate of $91 for every $1 invested by HHF. My visit to the NIH was a meaningful reminder of the impact our scientists make at the federal level, while demonstrating that much more work must be done to better the millions who live with hearing and balance conditions. 

How wonderful it was to spend the day with so many individuals committed to hearing health. I look forward to continuing our relationships with the NIDCD and the FCHHC to advance our vision of a world in which people can live without hearing loss.

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A Newly Identified Neuron in a Brain Region Tied to Hearing

By Michael T. Roberts, Ph.D.

Most of our auditory experience requires extensive and precise computations in the brain. While the neural circuitry underlying these computations has become increasingly clear over the past several decades, there has remained a big gap in our understanding of the neural circuitry in an important brain region called the inferior colliculus (IC).

Located in the midbrain, the IC is the hub of the brain’s auditory pathway. Like an airport hub that processes travelers moving among farflung airports, the IC receives and processes most of the output of lower auditory centers and provides the major source of auditory input to higher brain centers.

Although the IC plays important roles in most auditory functions, including speech processing and sound localization, it has proven difficult to identify the types of neurons (nerve cells) that make up the IC. This has hampered progress because the ability to identify neuron types is a prerequisite for determining how specific neurons interconnect and function within the broader auditory circuitry.

Recently, my lab at the University of Michigan tackled this long-standing problem and successfully identified a novel neuron type called VIP neurons. VIP neurons make a small protein called vasoactive intestinal peptide. Despite its name, previous studies have shown that VIP is made by specific types of neurons in several other brain regions.

Sections of the inferior colliculus, the hub of the brain’s auditory pathway. A newly identified neuron type called VIP neurons, which make a small protein called vasoactive intestinal peptide, have been dyed magenta.

Sections of the inferior colliculus, the hub of the brain’s auditory pathway. A newly identified neuron type called VIP neurons, which make a small protein called vasoactive intestinal peptide, have been dyed magenta.

Our team, led by postdoctoral fellow David Goyer, Ph.D., hypothesized that VIP is a marker for a class of neurons in the IC. To test this hypothesis, we used a genetically engineered mouse to label VIP neurons with a red fluorescent protein. This made it possible to use fluorescence microscopy to target experiments to VIP neurons in the IC.

These experiments revealed that VIP neurons in the IC have internally consistent anatomical and physiological features, supporting the conclusion that IC VIP neurons constitute a distinct neuron type. Examination of the neuronal processes of VIP neurons further revealed that individual VIP neurons likely receive input from a range of sound frequencies. Work by collaborators in the Schofield Lab at Northeast Ohio Medical University showed that VIP neurons also send output to several brain regions, including to higher and lower auditory centers and to a brain region involved in visual processing.

In another set of experiments, we combined electrical recordings from VIP neurons with a technique called optogenetics, which allows scientists to stimulate specific populations of neurons using brief flashes of light. These experiments revealed that VIP neurons receive input from the dorsal cochlear nucleus, one of the first brain regions in the auditory pathway. The path from the cochlea to VIP neurons is therefore quite short, passing through only three synapses.

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This study, which combined both sets of experiments and was published in eLife on April 18, 2019, showed that VIP neurons are a distinct and readily identifiable class of IC neurons. Based on their features, we hypothesize that VIP neurons play a broadly influential role in sound processing. We and the Schofield lab are currently testing this hypothesis, with a particular emphasis on determining how VIP neurons contribute to speech processing in the IC. 

A 2017 Emerging Research Grants scientist, Michael T. Roberts, Ph.D., heads the Roberts Laboratory and is an assistant professor at the Kresge Hearing Research Institute, University of Michigan.

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Lasting Effects From Head and Brain Injury

By Elliott Kozin, M.D.

Traumatic brain injury (TBI) is a major public health issue and contributes to injury-related morbidity and mortality worldwide. The estimated economic cost of TBI is estimated to be in excess of $76 billion per year in the United States. Unfortunately, the health effects of TBI are profound. TBI can lead to chronic and debilitating physical and psychosocial symptoms, such as loss of cognitive, sensory, and psychological function. Auditory and vestibular dysfunction has long been recognized as a consequence of head injury, including TBI. 

In our research “Patient‐Reported Auditory Handicap Measures Following Mild Traumatic Brain Injury,” published in The Laryngoscope, we examined auditory complaints following traumatic brain injury, as well as changes that occur to the peripheral vestibular system in the postmortem setting. In patients with mild traumatic brain injury (mTBI), we used patient-reported outcome measures to assess auditory complaints. The team found that auditory symptoms and associated handicap were common in patients with non-blast mTBI. 

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For another paper in The Laryngoscope, “Peripheral Vestibular Organ Degeneration After Temporal Bone Fracture: A Human Otopathology Study,” we evaluated postmortem specimens from the National Temporal Bone Pathology Registry with head injury. In a cohort of patients with temporal bone fractures, there were distinct peripheral vestibular changes. Collectively, these findings have implications for the pathophysiology and management of symptoms in this patient population.

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Elliott Kozin, M.D., is a neurotology fellow at Eaton Peabody Laboratories, Massachusetts Eye and Ear/Harvard Medical School, and a 2018 Emerging Research Grants recipient generously funded by the General Grand Chapter Royal Arch Masons International.

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Making Sense of Sound

Rush College of Health Sciences

In most auditory testing, the emphasis is on accuracy in speech recognition, since speech is our primary means of communication. But myriad sounds beyond language are key to our understanding of the world around us.

“A car honking, a baby crying, a fire alarm — recognizing these sounds can be important to our safety,” explained Valeriy Shafiro, Ph.D. “And there are also lots of nonlinguistic environmental sounds we enjoy listening to: the sound of the ocean, the wind in the trees when we walk in the woods.” Shafiro, an associate professor of communication disorders and principal investigator in the Rush Auditory Research Laboratory, conducts research in hearing and speech perception that focuses on finding new ways to diagnose auditory deficits and improve communication abilities in adults. These new diagnostic techniques have the potential to improve the quality of life of a variety of audiology patients — even well beyond the groups Shafiro is currently studying.

Addressing a rehab deficit 

Much of Shafiro’s lab’s past work, which has been funded by the National Institutes of Health (NIH), the American Speech-Language-Hearing Foundation (ASHFoundation) and the Hearing Health Foundation, formerly known as the Deafness Research Foundation, has assessed the ability of people with cochlear implants to recognize a variety of nonspeech sounds — a particularly useful means of auditory assessment in a large, urban medical center that treats many non-English speakers.

A recent study tested listeners’ ability to recognize those sounds with or without the contextual clues present in everyday life. For example, an ambiguous sound can be perceived as a burning fuse when preceded by the sound of a match being struck and followed by the sound of an explosion, but it may be perceived as bacon frying when surrounded by other kitchen sounds.

Credit: Rush University

Credit: Rush University

“Compared with people with normal hearing, people with cochlear implants show some pretty clear deficits in identifying environmental sounds as well as speech,” Shafiro said. “Research from several labs, including ours, shows the possibility for cochlear implant users to improve if they work on it. But there are few readily available opportunities for these patients to obtain rehabilitation, for reasons including travel difficulties, health care reimbursements and scope of practice.”

Shafiro is now evaluating the usefulness of Internet-based environmental sound and speech training for people who rely on cochlear implants in daily life. “A Randomized Controlled Trial to Evaluate the Benefits of an Internet-Based Auditory Training Program for Cochlear Implant Patients,” a two-year grant from the ASHFoundation, aims to help fill the rehabilitation deficit for adults who receive cochlear implants.

“With Internet access now widely available, patients can do the auditory exercises online, at their own pace and without having to travel,” Shafiro said. When completed, the study will give him and his colleagues a deeper understanding of the benefits and challenges of computerized auditory training.

Hearing-dementia link

Measuring listeners’ recognition of nonlinguistic sounds was also a component of a recent study from the Rush Auditory Research Laboratory in collaboration with the Rush Alzheimer’s Disease Center.

“Hearing, Speech and Episodic Memory in Older African-American and White Adults,” funded with a grant from the NIH, examined a topic of wide current interest: the relationship between aging, hearing loss and cognitive deficits. As Baby Boomers age, research like this has major implications for the health and well-being of older adults. “Some recent research has reported that people with a greater rate of age-related hearing loss also have a greater rate of cognitive decline,” Shafiro explained.

“Typical tests of working memory are based on retaining words or numbers, but we wanted to explore this further by measuring both nonspeech and speech perception.” 

Using tests previously designed by Stanley Sheft, senior researcher at the Rush Auditory Research Laboratory and principal investigator on the study, the team measured the ability of a cohort of community-dwelling older adults without known dementia to discriminate brief nonlinguistic sound patterns.

The addition of nonlinguistic sounds produced somewhat different results than those yielded by previous research. Although other studies have associated speech perception with cognitive performance, the Rush study did not find this correlation when measuring hearing thresholds or the ability to recognize speech in noise.

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However, “We found a relationship between working memory and the ability to discriminate brief auditory patterns,” said Shafiro, who hopes to revisit the study cohort in the future to see whether the tests may be predictive of the trajectory of cognitive decline.

This article was repurposed with permission from Rush University Medical Center, and originally appeared in the Rush College of Health Sciences magazine Impact. Valeriy Shafiro, Ph.D., is a 2008 Emerging Research Grants recipient.

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Very High-Frequency Hearing Loss and Tinnitus: Is There a Link?

By Julia Campbell, Au.D., Ph.D.

Tinnitus is theorized to possibly arise from decreased central inhibition related to cochlear damage, or hearing loss. A reduction in inhibition function would allow signals that are normally suppressed to be perceived, resulting in tinnitus. However, many individuals with clinically typical hearing also present with tinnitus.

In our earlier study, results indicated that despite an apparently intact peripheral auditory system, inhibitory function was atypical and significantly related to tinnitus severity among a population reporting mild tinnitus. With central inhibition lowered, signals that are typically dampened are able to be perceived, potentially resulting in tinnitus. Our paper also showed the utility of measuring central inhibition through cortical auditory evoked potentials (CAEPs), which are electrical responses in the brain that reveal levels of central inhibition.

Given the prior study’s results, we thought it is possible that hearing loss within extended high-frequency thresholds (10, 12.5, and 16 kilohertz), which are not typically assessed in the clinic, may negatively impact inhibitory function and subsequent gating measures.

For our follow-up research, published in the American Journal of Audiology on April 22, 2019, we examined the role of both extended high-frequency thresholds and sensory gating dysfunction, a measure of central inhibition abnormality, in typical-hearing adults with and without tinnitus. Results suggest that extended high-frequency thresholds do not correlate with CAEP amplitude gating indices—in other words, high-frequency hearing loss was not associated with decreased central inhibition.

CAEP gating waveforms in A) a typical-hearing subject without tinnitus and B) a typical-hearing subject with tinnitus. The solid line represents the CAEP response to the first stimulus (S1) in a tonal pair, and the dashed the CAEP response to the second stimulus (S2) in a tonal pair. Typical gating is observed when CAEP S2 amplitude is lower compared with CAEP S1 amplitude (A). Atypical gating occurs when CAEP S2 amplitude is equal to or larger than CAEP S1 amplitude (B).

CAEP gating waveforms in A) a typical-hearing subject without tinnitus and B) a typical-hearing subject with tinnitus. The solid line represents the CAEP response to the first stimulus (S1) in a tonal pair, and the dashed the CAEP response to the second stimulus (S2) in a tonal pair. Typical gating is observed when CAEP S2 amplitude is lower compared with CAEP S1 amplitude (A). Atypical gating occurs when CAEP S2 amplitude is equal to or larger than CAEP S1 amplitude (B).

However, we found an unexpected relationship in the tinnitus group: Those with better (lower) thresholds also presented with worse tinnitus. We believe this finding may be due to typical-hearing adults with better high-frequency hearing to be more aware of internal auditory signals, and thus perceive tinnitus. However, further research is needed to investigate this hypothesis.

In addition, atypical gating performance was observed in adults with a Tinnitus Handicap Inventory score over 6, which may demonstrate that tinnitus severity must reach a certain point in order for central gating deficits to be observed, or vice versa. A hierarchical multiple regression showed both extended high-frequency thresholds and atypical gating function to account for a significant 49 percent of tinnitus severity.

Therefore, auditory gating appears to be a useful objective measure for tinnitus severity, at least in adults with clinically typical hearing. It also appears that the testing of extended high-frequency thresholds is warranted in this population, to be used in combination with CAEP amplitude gating indices. Our laboratory is now conducting studies investigating the utility of auditory gating as a clinical tool for the objective assessment of tinnitus severity in adults with hearing loss.

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2016 Emerging Research Grants scientist Julia Campbell, Au.D., Ph.D., CCC-A, FAAA, received the Les Paul Foundation Award for Tinnitus Research. She is an assistant professor in communication sciences and disorders in the Central Sensory Processes Laboratory at the University of Texas at Austin. If you are interested in participating in this research, email julia.campbell@austin.utexas.edu.

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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Developing Better Tests for Discovering “Hidden” Hearing Loss

By Hari Bharadwaj, Ph.D., with Inyong Choi, Ph.D.

Conventionally, hearing loss is thought to be a consequence of damage to delicate sensory hair cells in the inner ear (cochlea). However, over the past decade animal studies have shown that nerve endings in the cochlea are considerably more vulnerable to damage than the sensory hair cells, and that such nerve damage is likely to happen before conventionally recognized forms of hearing loss occur.

Emerging Research Grants (ERG) recipients Bharadwaj and Choi, and colleagues, systematically investigated the many sources of variability that obscure cochlear nerve damage (“synaptopathy”) to provide recommendations for how best to measure such nerve damage.

Emerging Research Grants (ERG) recipients Bharadwaj and Choi, and colleagues, systematically investigated the many sources of variability that obscure cochlear nerve damage (“synaptopathy”) to provide recommendations for how best to measure such nerve damage.

Unfortunately, damage to cochlear nerve endings cannot be detected by current clinical hearing tests. Yet, this “hidden” damage can hypothetically still affect hearing in everyday noisy environments such as crowded restaurants and busy streets. Therefore, it is important to develop tests to detect such damage in humans, and there is considerable interest among hearing scientists toward this enterprise.

In our paper published in Neuroscience on March 8, 2019, we considered noninvasive tests that can potentially reveal such nerve damage and systematically investigated other extraneous sources of variability that might reduce the sensitivity and specificity of these tests. This helped us come up with recommendations for how we can best apply these tests. Funding from Hearing Health Foundation’s Emerging Research Grants contributed to experiments that helped understand and articulate the role of two key variables: how variations in the anatomy of individuals (e.g., brain shape and size) affected our noninvasive tests; and how certain cognitive factors like attention may affect hearing independently of how well the inner ear is capturing the information in sounds.

Armed with the knowledge about these variables and other factors described in the paper, we anticipate that hearing scientists will be able to design more powerful experiments to understand the effects of damage to cochlear nerve endings, and build more powerful tests to detect such damage in the clinic. This work is crucial in enabling clinical translation of the basic science that has been uncovered over the past decade.

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A 2015 Emerging Research Grants (ERG) scientist, Hari Bharadwaj, Ph.D., is an assistant professor at Purdue University in Indiana with a joint appointment in speech, language, and hearing sciences, and biomedical engineering. Inyong Choi, Ph.D., is an assistant professor in the department of communication sciences and disorders at the University of Iowa. Choi’s 2017 ERG grant was generously funded by the General Grand Chapter Royal Arch Masons International.

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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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