Hearing Research

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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ERG Grantees' Advancements in OAE Hearing Tests, Speech-in-Noise Listening

By Yishane Lee and Inyong Choi, Ph.D.

Support for a Theory Explaining Otoacoustic Emissions: Fangyi Chen, Ph.D.

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It’s a remarkable feature of the ear that it not only hears sound but also generates it. These sounds, called otoacoustic emissions (OAEs), were discovered in 1978. Thanks in part to ERG research in outer hair cell motility, measuring OAEs has become a common, noninvasive hearing test, especially among infants too young to respond to sound prompts..

There are two theories about how the ear produces its own sound emanating from the interior of the cochlea out toward its base. The traditional one is the backward traveling wave theory, in which sound emissions travel slowly as a transverse wave along the basilar membrane, which divides the cochlea into two fluid-filled cavities. In a transverse wave, the wave particles move perpendicular to the wave direction. But this theory does not explain some anomalies, leading to a second hypothesis: The fast compression wave theory holds that the emissions travel as a longitudinal wave via lymph fluids around the basilar membrane. In a longitudinal wave, the wave particles travel in the same direction as the wave motion.

Figuring out how the emissions are created will promote greater accuracy of the OAE hearing test and a better understanding of cochlear mechanics. Fangyi Chen, Ph.D., a 2010 Emerging Research Grants (ERG) recipient, started investigating the issue at Oregon Health & Science University and is now at China’s Southern University of Science and Technology. His team’s paper, published in the journal Neural Plasticity in July 2018, for the first time experimentally validates the backward traveling wave theory.

Chen and his coauthors—including Allyn Hubbard, Ph.D., and Alfred Nuttall, Ph.D., who are each 1989–90 ERG recipients—directly measured the basilar membrane vibration in order to determine the wave propagation mechanism of the emissions. The team stimulated the membrane at a specific location, allowing for the vibration source that initiates the backward wave to be pinpointed. Then the resulting vibrations along the membrane were measured at multiple locations in vivo (in guinea pigs), showing a consistent lag as distance increased from the vibration source. The researchers also measured the waves at speeds in the order of tens of meters per second, much slower than would be the speed of a compression wave in water. The results were confirmed using a computer simulation. In addition to the wave propagation study, a mathematical model of the cochlea based on an acoustic electrical analogy was created and simulated. This was used to interpret why no peak frequency-to-place map was observed in the backward traveling wave, explaining some of the previous anomalies associated with this OAE theory.

Speech-in-Noise Understanding Relies on How Well You Combine Information Across Multiple Frequencies: Inyong Choi, Ph.D.

Understanding speech in noisy environments is a crucial ability for communications, although many individuals with or without hearing loss suffer from dysfunctions in that ability. Our study in Hearing Research, published in September 2018, finds that how well you combine information across multiple frequencies, tested by a pitch-fusion task in "hybrid" cochlear implant users who receive both low-frequency acoustic and high-frequency electric stimulation within the same ear, is a critical factor for good speech-in-noise understanding.

In the pitch-fusion task, subjects heard either a tone consisting of many frequencies in a simple mathematical relationship or a tone with more irregular spacing between frequencies. Subjects had to say whether the tone sounded "natural" or "unnatural" to them, given the fact that a tone consisting of frequencies in a simple mathematical relationship sounds much more natural to us. My team and I are now studying how we can improve the sensitivity to this "naturalness" in listeners with hearing loss, expecting to provide individualized therapeutic options to address the difficulties in speech-in-noise understanding.

2017 ERG recipient Inyong Choi, Ph.D., is an assistant professor in the department of communication sciences and disorders at the University of Iowa in Iowa City.

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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Hearing Loss Film “Hearing Hope” Captures Personal Strength, Scientific Vision

Hearing Health Foundation (HHF) has created a new short film, “Hearing Hope,” to expand awareness of hearing health through the voices of those who benefit from and those who carry out the foundation’s life-changing work.

 "It took me longer to talk than most kids. Because I couldn't understand what they were saying so I couldn't copy it," explains Emmy, 7.

"It took me longer to talk than most kids. Because I couldn't understand what they were saying so I couldn't copy it," explains Emmy, 7.

The third most prevalent chronic physical condition in the U.S., hearing loss can affect anyone—from first-grader Emmy to retired U.S. Army Colonel John—but its reach is often underestimated. “It’s one of the most common sensory deficits in humans,” explains cochlear implant surgeon Dr. Anil Lalwani. “I think we have to go from it being hidden to being visible.”

Both a hearing aid user and cochlear implant recipient, seventh-grader Alex is doing his part to make hearing loss less hidden. Smiling, he says he wants people to know that hearing with his devices makes him happy. John wishes to be an advocate for veterans and all who live with hearing loss and tinnitus.

 When she received her hearing loss diagnosis at 17, NASA engineer Renee never thought she'd be living her dream.

When she received her hearing loss diagnosis at 17, NASA engineer Renee never thought she'd be living her dream.

The film also highlights resilience in response to the challenges associated with hearing conditions. Video participant Renee saw her dream of becoming an astronaut halted at 17 when her hearing loss was detected. Now she helps send people to space as an engineer at NASA.

Sophia describes the “low, low rock bottom” she hit when she was diagnosed with Usher Syndrome, the leading cause of deafblindness. Yet she feels special knowing her disability shapes her and sets her apart.

Jason recounts having no resources for hearing loss in children when his son, Ethan, failed his newborn hearing screening. Today he’s grateful for Ethan’s aptitude for language, made possible through his early hearing loss intervention.

With the support of HHF, more progress is made each year. “I’m glad that the doctors are trying to figure out how fish and birds can restore their hearing,” says Emmy.

For the past 60 years, HHF has funded promising hearing science and in 2011 established the Hearing Restoration Project (HRP), an international consortium dedicated to finding biological cures for hearing loss using fish, bird, and mouse models to replicate the phenomenon of hearing loss reversal in humans.

“If [the HRP] can achieve that goal of hearing restoration...that would be a marvelous thing for hearing loss,” reiterates Dr. Robert Dobie.

Through “Hearing Hope,” HHF would like to share its mission and message of hope to as many individuals as possible and reassure those with hearing loss and their loved ones they are not alone. As an organization that channels all efforts into research and education, HHF would greatly appreciate any assistance or suggestions to increase visibility of the film.

Watch the full film at www.hhf.org/video. Closed captioning is available.

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Understanding a Pressure Relief Valve in the Inner Ear

By Ian Swinburne, Ph.D.

The inner ear senses sound to order to hear as well as sensing head movements in order to balance. Sounds or body movements create waves in the fluid within the ear. Specialized cells called hair cells, because of their thin hairlike projections, are submerged within this fluid. Hair cells bend in response to these waves, with channels that open in response to the bending. The makeup of the ear’s internal fluid is critical because as it flows through these channels its contents encode the information that becomes a biochemical and then a neural signal. The endolymphatic sac of the inner ear is thought to have important roles in stabilizing this fluid that is necessary for sensing sound and balance.

  This study helps unravel how a valve in the inner ear's endolymphatic sac acts to relieve fluid pressure, one key to understanding disorders affected by pressure abnormalities such as Ménière’s disease.

This study helps unravel how a valve in the inner ear's endolymphatic sac acts to relieve fluid pressure, one key to understanding disorders affected by pressure abnormalities such as Ménière’s disease.

While imaging transparent zebrafish, my team and I found a pressure-sensitive relief valve in the endolymphatic sac that periodically opens to release excess fluid, thus preventing the tearing of tissue. In our paper published in the journal eLife June 19, 2018, we describe how the relief valve is composed of physical barriers that open in response to pressure. The barriers consist of cells adhering to one another and thin overlapping cell projections that are continuously remodeling and periodically separating in response to pressure.

The unexpected discovery of a physical relief valve in the ear emphasizes the need for further study into how organs control fluid pressure, volume, flow, and ion homeostasis (balance of ions) in development and disease. It suggests a new mechanism underlying several hearing and balance disorders characterized by pressure abnormalities, including Ménière’s disease.

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Here is a time-lapse video of the endolymphatic sac, with the sac labeled “pressure relief valve” at 0:40.

2017 Ménière’s Disease Grants scientist Ian A. Swinburne, Ph.D., is conducting research at Harvard Medical School. He was also a 2013 Emerging Research Grants recipient.

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Uncovering a Signaling Molecule That Modulates Avian Hair Cell Regeneration

By Rebecca M. Lewis, Au.D., Ph.D., and Jennifer Stone, Ph.D.

Mammals including humans cannot regenerate hair cells, but other species such as birds and fish readily regenerate hair cells after damage to restore auditory function. The gene ATOH1 produces a protein that pushes supporting cells—cells that neighbor hair cells—to either directly convert into a hair cell or to divide and form a new hair cell. However, ATOH1 expression (when the gene is turned on) does not guarantee that hair cells develop in birds or mammals, which suggests that there are factors that prevent supporting cells from changing into hair cells. Identifying these factors in birds may help us better understand the lack of hair cell regeneration in mammals.

  This schematic depicts our current ideas for how BMP4 regulates ATOH1 expression and therefore hair cell regeneration in the avian hearing organ. It shows (from left) typical hair cells, hair cell damage, and hair cell regeneration. Typical hair cells secrete BMP4. When hair cells die, BMP4 signaling is reduced, which allows ATOH1 to be expressed in supporting cells and pushes supporting cells to turn into hair cells. The newly regenerated hair cells secrete BMP4, suppressing ATOH1 in supporting cells and restoring the normal condition.

This schematic depicts our current ideas for how BMP4 regulates ATOH1 expression and therefore hair cell regeneration in the avian hearing organ. It shows (from left) typical hair cells, hair cell damage, and hair cell regeneration. Typical hair cells secrete BMP4. When hair cells die, BMP4 signaling is reduced, which allows ATOH1 to be expressed in supporting cells and pushes supporting cells to turn into hair cells. The newly regenerated hair cells secrete BMP4, suppressing ATOH1 in supporting cells and restoring the normal condition.

We examined the avian auditory system to characterize a potential inhibitor to ATOH1 during hair cell regeneration: bone morphogenetic protein 4 (BMP4). Bone morphogenetic proteins are secreted signaling molecules that regulate cellular processes in many regions of the body, including the nervous system. We found that BMP4 localizes to hair cells of the mature avian hearing organ and disappears when hair cells die or sustain damage. From this, we hypothesized that BMP4 may prevent ATOH1 expression in supporting cells and loss of BMP4 when hair cells die may enable ATOH1 to be expressed in supporting cells, driving them to convert into hair cells.

When we exposed avian auditory organs to BMP4 after selectively killing hair cells, this prevented ATOH1 expression and hair cell regeneration. When we antagonized BMP4 using an inhibitor, we found a generally opposite result: an increase in the number of regenerated hair cells.

We conclude that BMP4 is a potent inhibitor of ATOH1 and therefore suppresses hair cell regeneration. We recommend that BMP4 be explored further in studies of mammalian hair cell regeneration.

Published in Hearing Research on May 2, 2018, this study detailing BMP4’s negative effect on ATOH1 expands our knowledge of signaling molecules that suppress hair cell regeneration in birds and may also modulate hair cell regeneration in humans.

Rebecca M. Lewis, Au.D., Ph.D., is a clinical audiologist and auditory neuroscientist at Massachusetts Eye and Ear/Harvard Medical School in Boston. HRP researcher Jennifer Stone, Ph.D., is the director of research in the department of otolaryngology–head and neck surgery at the Virginia Merrill Bloedel Hearing Research Center at the University of Washington.

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

 
 
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Researchers Fighting the Effects of Noise

By Yishane Lee

The cornerstone of Hearing Health Foundation, ever since its founding in 1958 as the Deafness Research Foundation, has been funding early-career researchers who bring innovative thinking to hearing and balance research. HHF’s Emerging Research Grants (ERG) are awarded to the most promising scientists in the field, with many going on to earn prestigious National Institutes of Health backing.

HHF is always proud to see ERG grantees thrive in their careers and research. Most recently, two ERG scientists funded in the mid-1990s have made headlines, each for treatments for noise-induced hearing loss (NIHL).

1996 and 1997 ERG scientist John Oghalai, M.D., of the University of Southern California, coauthored a study showing promise for preventing NIHL. Published May 7, 2018, in the Proceedings of the National Academy of Sciences, Oghalai and team used miniature optics to examine the mouse cochlea after exposure to extremely loud noise, and found that in addition to immediate hair cell death, a fluid buildup in the inner ear over several hours eventually led to nerve cell loss. The fluid buildup, or endolymph hydrops, contributes to synaptopathy, or damage to the auditory nerve cell synapse. In a USC News press release, Oghalai described the excess fluid as a feeling of fullness and ringing in the ear that a person may experience after attending a loud concert.

Because the extra fluid showed a high concentration of potassium, the team saw a method to re-balance the fluids that naturally occur in the inner ear by injecting a salt (sodium) and sugar solution into the middle ear three hours after exposure. Nerve cell loss was reduced by 45 to 64 percent, which may help preserve hearing. The researchers see applications for this treatment for military service members who experience blast trauma as well as for people who have Ménière’s disease, the hearing and balance condition that is associated with inner ear fluid buildup.

  Images from the cochleae of guinea pigs show the presence of more hair cells in animals treated with a short interfering RNA that interrupts a gene upregulated after damage (right; control on left). Inner and outer hair cells (IHC and OHC) are labeled in green, stereocilia in yellow, and nuclei in blue. Arrowheads indicate ectopic hair cells. Credit:    The Scientist    via    Molecular Therapy   .

Images from the cochleae of guinea pigs show the presence of more hair cells in animals treated with a short interfering RNA that interrupts a gene upregulated after damage (right; control on left). Inner and outer hair cells (IHC and OHC) are labeled in green, stereocilia in yellow, and nuclei in blue. Arrowheads indicate ectopic hair cells. Credit: The Scientist via Molecular Therapy.

1996 ERG scientist Richard Kopke, M.D., FACS, of the Hough Ear Institute in Oklahoma, spent more than 20 years serving with the U.S. Army, becoming well aware of the dangers of NIHL for service members. In a paper in Molecular Therapy, published online in March 2018, Kopke and colleagues used “small interfering RNAs” (siRNAs) to block the activity of the Notch signaling pathway gene Hes1 that itself blocks hair cell differentiation in developing supporting cells and may contribute to the failure of hair cells to regenerate after injury.

These siRNAs were delivered using nanoparticles directly injected to the cochleae of live, adult guinea pigs. Kopke’s team had previously shown using siRNAs to block Hes1 to be effective in regenerating hair cells in cultured mouse cochlea. In the current study, the 24-hour, sustained-release of siRNAs through nanoparticles three days after deafening resulted in the recovery of some hearing ability, measured using auditory brainstem responses, at three weeks and continuing to nine weeks, when the study ended. Compared with the control mice, the RNA-injected mice showed less overall hair cell loss and early signs of immature hair cell development, which the authors say may signal hair cell regeneration. Hearing loss caused by noise, chemotherapy drugs, or aging that damages or kills hair cells are all targets for this potential treatment.

In an article in The Scientist, HHF’s Hearing Restoration Project consortium member Jennifer Stone, Ph.D., who was not involved in the paper, echoed the study authors in saying further research should work to determine which cells are turning into hair cells, and whether the observed hair cell development is truly new hair cells and not the repair of damaged hair cells. Kopke and team plan to test the treatment using longer periods between deafening and injection, while also modifying dose and delivery.

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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Stenting to Relieve One Specific Cause of Pulsatile Tinnitus

By Jayne Wallace for the Weill Cornell Medicine Brain and Spine Center

The Centers for Disease Control and Prevention estimates that 15 percent of the U.S. population, or 48 million people, have some type of tinnitus, hearing a ringing or buzzing in the absence of an external sound source.

Pulsatile tinnitus, in contrast, usually has a sound source. In these cases, affecting fewer than 10 percent of tinnitus patients, sounds are caused by turbulence in the blood flow around the ear. And among these cases, intracranial hypertension comprises about 8 percent of cases. This is when narrowing in one of the large veins in the brain causes a disturbance in the blood flow, leading to the pulsatile tinnitus.

  Dural arteriovenous fistula, MRA showed only subtle alterations as a result of atypical flows in the right transverse sinus (arrow). Photo courtesy of Deutsches Ärzteblatt International.

Dural arteriovenous fistula, MRA showed only subtle alterations as a result of atypical flows in the right transverse sinus (arrow). Photo courtesy of Deutsches Ärzteblatt International.

“Traditionally there has been no good treatment for many of these patients who are told to learn to live with it,” says Athos Patsalides, M.D., an interventional neuroradiologist at New York City’s Weill Cornell Medicine Brain and Spine Center, where he also serves as an associate professor of radiology in neurological surgery.

Till now, available treatments—medication or more complicated surgery—were either ineffective or produced side effects and other problems just as bad or worse. “That’s why we started the clinical trials for venous sinus stenting, a minimally invasive procedure that is very effective in alleviating the narrowing in the vein,” says Patsalides, who pioneered the use of VSS to treat patients with idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri because the symptoms tend to mirror those of a brain tumor.

“Many IIH patients suffer from vision loss, headaches, and pulsatile tinnitus, and I saw a pattern with patients experiencing resolution of the pulsatile tinnitus immediately after VSS,” Patsalides says.

This led to the possibility of using VSS for selected patients with pulsatile tinnitus. After the Food and Drug Administration approved the clinical trial, it began in May 2016 and has an estimated completion date of January 2021.

“In the stenting procedure, with the patient under general anesthesia, we insert a tiny, soft catheter into a vein located in the upper part of the leg and thread it up to the affected vein in the brain,” Patsalides says.

A self-expanding stent is deployed into the narrowed segment of the vein, relieving the stenosis, restoring normal blood flow, and reducing or eliminating the pulsatile tinnitus. “Happily, the patient is typically discharged from the hospital within 24 to 48 hours,” he says.

To learn more, see weillcornellbrainandspine.org. Hearing Health Foundation notes that the trial is ongoing, and that the procedure is potentially able to address only one specific cause of pulsatile tinnitus and should not be taken as a solution for other forms of tinnitus, which often has no known cause.

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A Clinical Trial for a New Drug to Protect Hearing

By Yishane Lee

The U.S. Food and Drug Administration (FDA) has approved a novel drug to protect against ototoxicity (harmfulness to hearing) due to the use of aminoglycoside antibiotics to treat severe infections. The FDA approval paves the way for a Phase I clinical trial to test whether the drug, found to be significantly protective in animals, is safe for humans.

  Mature lateral line hair cells from larval zebrafish (shown with the neuromast sensory organ enlarged) serve as a platform for studying drugs and genes that modulate hair cell susceptibility to ototoxic agents.  

Mature lateral line hair cells from larval zebrafish (shown with the neuromast sensory organ enlarged) serve as a platform for studying drugs and genes that modulate hair cell susceptibility to ototoxic agents.  

The drug, ORC-13661, was developed by University of Washington professors Edwin Rubel, Ph.D., and David Raible, Ph.D., who are members of Hearing Health Foundation’s Scientific Advisory Board and Hearing Restoration Project, respectively, and Fred Hutchinson Cancer Research Center scientist Julian Simons, Ph.D. “While this program was not directly funded by HHF, both David and I have definitely been supported by HHF for a long time,” Rubel says. “This is a drug to prevent hearing loss that we've developed over the past 15-plus years.”

Rubel points out the drug’s two main features: “It is a brand new drug with a composition of matter patent, not one that is used for other medical purposes and being repurposed; and it is the first drug that was developed, from the get-go, to protect hair cells from ototoxic injury.”

After screening libraries of potential chemicals to see which stopped hair cell death in zebrafish lateral line system, Rubel, Raible, and team identified the best candidate and then boosted its effectiveness by tweaking its chemical structure; results were published in the Journal of Medicinal Chemistry in January 2018.

Rubel adds, “Toxicity studies in zebrafish, rats, and dogs required by the FDA show superior safety and nearly 100 percent hearing protection at all frequencies.” If the Phase I trial shows the drug is safe for humans, the next step is to test its efficacy among patients using aminoglycosides.

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