Hover over the dots to see research funded by American Hearing.
“Investigation of Salivary Calcitonin Gene-Related Peptide (CGRP) in Vestibular Migraine”
Summary: About 7% of adults will experience vertigo at some point in their lives. While we know much about a few specific ear disorders that cause vertigo (e.g., benign positional vertigo, Meniere’s disease, superior canal dehiscence syndrome), the majority of patients with vertigo do not fall into these tidy categories. Recent studies suggest that migraine is frequently found in patients with recurrent vertigo, but how migraine might cause vertigo is still unclear, and many doctors question the association.
Our research focuses on one aspect of migraine that is emerging as an important explanation of some of the symptoms in migraine. Our own sensory nerves in the head and neck can release inflammatory chemicals (peptides, or small pieces of protein) that can cause blood vessels to swell, leak plasma, throb and hurt. Calcitonin gene-related peptide (CGRP) is one of the best studied examples. Some migraine specialists think that this may be a cause of head and neck pain in migraine. We are exploring whether these inflammatory peptides might also cause vertigo when released onto the blood vessels in the head and neck, including the fine vessels going to the inner ear. Specifically, we collect saliva from patients with migraine headaches and from patients with recurrent vertigo and examine it for CGRP, and we compare the results to those from individuals without headaches or vertigo. Our preliminary results show that patients with recurrent vertigo do have elevated levels of CGRP; we are now trying to see if there is a correlation in time with the vertigo attacks. The findings could better establish the role of migraine as a common cause of vertigo, help lead the way to a convenient clinical test, and open new targets for treatment of vertigo. Finally, if we find that inflammatory peptides affect inner ear balance function, it will motivate further studies on the effects on hearing and tinnitus.
Monita Chatterjee, PhD
Director, Auditory Prostheses & Perception Laboratory
Boys Town National Research Hospital, Omaha, Nebraska
Monita Chatterjee (right) and fellow investigator Aditya M Kulkarni
“Modulation Interference in Listeners With Cochlear Implants”
Summary: A cochlear implant (CI) is a neural prosthesis that partially restores speech recognition to patients with severe hearing loss. CIs work by electrically activating auditory nerve neurons located at different sites within the inner ear. Speech sounds streaming into the CI microphone are first processed by a miniaturized speech processor worn outside the ear. Next, information about energy within individual audio frequency bands is sent to an internally-implanted system through radio frequency waves. The internal system generates tiny electrical charges that excite specific neurons in the inner ear. The activity of these neurons is transmitted via action potentials to the higher auditory centers of the brain, and heard and interpreted by patients as speech.
Since their inception a few decades ago, CIs have achieved strong success in restoring speech communication to hundreds of thousands of patients worldwide. However, listening in noise remains a significant challenge for many patients. To understand why CI users still struggle to communicate well in background noise, we need to consider fundamental limitations of the device that need improvement. An important aspect of the signal is its frequency resolution: if signals from neurons excited by sounds with different pitches/frequencies cannot be distinguished by the brain, the sound image received has poor resolution (like looking at a very pixellated version of a painting). A major limitation of today’s CI technology is that this resolution is very poor. In background noise, the challenge escalates. Another key aspect of the CI signal is that it emphasizes slow changes (up to a couple of hundred Hz) in energy within individual frequency bands. We refer to these slow changes as the “temporal envelope” of the signal. Given their poor frequency resolution, CI patients rely more on these temporal envelopes to access speech than listeners with normal hearing.
Our project aims to deepen our scientific understanding of the impact of background noise on cochlear implant patients’ hearing of these temporal envelopes. We hypothesize that a substantial portion of the interference is due to a form of masking by the background noise that occurs in the temporal envelope domain (modulation interference). We propose to quantify modulation interference in CI patients in conditions in different adverse listening conditions, and to relate such interference to their speech recognition in background noise. This work is expected to contribute strongly to both our understanding of speech recognition in noise and to future development of cochlear implant processing strategies.
Allison Coffin, PhD
Assistant Professor, Neuroscience
Department of Neuroscience
Washington State University Vancouver
“High-throughput drug discovery for prevention of noise‐induced hair cell loss”
Summary: Millions of people in the U.S. suffer from hearing loss caused by permanent damage to sensory cells of the inner ear. Sensory cell damage often results from exposure to excessive sound in occupational or recreational settings such as industrial work or listening to loud music. Use of hearing protection such as earplugs is often the best way to prevent noise-induced hearing loss, but earplugs are not practical in some work environments, and often are not used in recreational situations such as concerts or sporting events. Our research will identify and develop new drug candidates to prevent hearing loss due to loud noise.
Our research is unique because we study noise damage in the lateral line of small zebrafish. The lateral line is a sensory system that fish use to sense nearby water movement, and cells in the lateral line are very similar to cells in the ears of all vertebrates, including humans. Because zebrafish are small and breed readily in the lab, we can use these fish to quickly test hundreds of potential drug candidates in order to identify the most effective drugs. In the future, we will test our most promising drug candidates in rodents as a precursor to possible clinical trials.
“Investigation of gender differences in noise-induced cochlear synaptopathy”
Summary: The funded research is to investigate whether female sex hormones have protective effects against noise trauma to synaptic connections between auditory sensory cells (“hair cells”) and auditory nerve cells (“spiral ganglion neurons” or “SGNs”) in the cochlea, and whether the variability in susceptibility to this trauma in female subjects is due to the estrous cycle and underlying fluctuation of circulating female hormones.
Sound is initially detected by hair cells in the cochlea. The hair cells convert the sound vibrations into synaptic activity. The synaptic activity, in turn, activates SGNs that convey the auditor information from the cochlea to the brain. Exceptional or repetitive loud noise can permanently damage or kill hair cells and cause tinnitus and hearing loss. Research in the past ten years has revealed an additional insidious effect of noise. Noise, even at sound levels too low to kill hair cells, can damage or destroy the synapses between hair cells and SGNs because of pathologically high levels of synaptic excitation (“excitotoxicity”). This is termed “noise-induced cochlear synaptopathy (NICS)” and NICS occurs at noise levels that may be commonly encountered in the workplace or during recreational activities. Thus, it is an increasingly significant cause of hearing impairment.
Our studies have shown a sex difference, with female mice significantly less susceptible to NICS than males. Interestingly, there is greater variability in susceptibility among females than among males, leading to the hypothesis that susceptibility varies with stage of the estrous cycle and hormone levels. This research will test that hypothesis and define the relationship between female hormones and NICS. First, by comparing NICS among male mice, female mice with ovaries surgically removed, and control females to confirm that lower susceptibility to NICS in female mice is indeed due to female hormones. Second, by correlating stage of the estrous cycle and hormone levels in blood samples with the measures of NICS, we can establish whether the variability in susceptibility to NICS observed in females is due to female hormone level and identify the hormone(s) that confer protection against NICS. The results will provide information for individuals to better protect themselves against noise trauma as well as identify new pharmacological strategies for prevention and therapy of noise damage.
Timothy Hullar (2nd from left) and team
“Audition and Balance”
Summary: Just as sight provides visual spatial landmarks, hearing provides auditory spatial landmarks that may serve as important reference points for maintaining posture and performing navigation. Recent work suggests that the brain is likely to integrate all sensory cues possible—including those derived from the auditory system—in order to maintain balance. Our current research focuses on understanding how auditory information contributes to postural stability and global balance, especially balancing during normal daily activities such as walking.
Dr. Hullar is a Professor and Director of the Division of Otology, Neurotology, and Skull Base Surgery at Oregon Health and Science University. His research interests include better understanding how ear surgery may impact the balance system, and how hearing (including through hearing aids and cochlear implants) may function to improve balance. Dr. Hullar and his team are excited to partner with the American Hearing Research Foundation to answer questions regarding how the brain processes information related to balance- questions that are especially relevant to those with hearing and balance impairment.
Elliot D. Kozin, MD
Investigator, Massachusetts Eye and Ear Infirmary
Aaron K. Remenschneider, MD, MPH
Investigator, Massachusetts Eye and Ear Infirmary
Daniel J. Lee, MD
Associate Professor of Otology and Laryngology
Massachusetts Eye and Ear Infirmary
Harvard Medical School, Boston, Massachusetts
Pictured, left to right: Daniel Lee, Elliot Kozin, Aaron Remenschneider & Elliot D. Kozin, MD
“Application of diffusion tensor imaging to evaluate central auditory pathways in patients with congenital deafness”
Summary: Pediatric patients with hearing loss face challenges in academic performance, quality of life, and financial independence. Hearing devices, such as the cochlear implant (CI), have revolutionized the treatment of profound hearing loss, offering not only hearing rehabilitation but also improved quality of life. Many patients undergoing CI will obtain excellent hearing outcomes; unfortunately, a subset of patients experience variable results. Success following CI is challenging to predict as many factors can affect CI performance, including the etiology and duration of hearing loss, as well as anatomic factors related to the inner ear. Imaging tests, such computed tomography (CT) and magnetic resonance imaging (MRI), are commonly performed in the preoperative assessment of children with congenital hearing loss, especially when considering an auditory implant. Although CT and MRI can provide macro-level data about the structure of the inner ear and brain, they are unable to provide detailed information about the organization of critical auditory neuronal networks along the auditory pathway.
Diffusion Tensor Imaging (DTI) is a relatively new and exciting radiologic approach that can map neuronal networks (also called ‘fiber tracks’). Today, neuronal networks of the central nervous system are being heavily investigated by researchers in neurology, psychology, and neurosurgery. Unfortunately, few studies have applied this groundbreaking technology to study the auditory system. Differences in DTI parameters between pediatric patients with hearing loss may allow better prediction of performance following cochlear implantation. The study, supported by the American Hearing Research Foundation, may lead to major breakthroughs in our understanding of the pediatric auditory pathway, as well as directly impact the evaluation and treatment of pediatric patients with hearing loss.
Katherine Rennie, PhD (Co-investigator)
Associate Professor of Otolaryngology, Resident Research Director
Departments of Otolaryngology and Physiology & Biophysics
University of Colorado, Denver
“Identification and Modulation of Na+ Currents in Vestibular Afferent Terminals”
Summary: Sensory hair cells of the vestibular system detect the direction and speed of head movement and then send this information to the primary afferent nerve endings that contact them. Information about head position and movement is transmitted along primary afferent neurons in the form of action potentials which are relayed to vestibular nuclei in the brainstem. A subset of primary afferent neurons form unusual cup-shaped synaptic endings called calyx terminals that almost completely surround one or more type I vestibular sensory hair cells. I am interested in how action potentials are generated and propagated in calyx afferents.
The process involves entry of sodium (Na+) ions and exit of potassium (K+) ions through voltage gated ion channels present on the inner and outer faces of calyx terminals. Na+ currents play a crucial role in the physiological coding of information but their role in the generation and propagation of action potentials within inner ear afferents is not well understood. There are nine known pore-forming subunits that form voltage-gated Na+ channels. The goals of this proposal are: (1) to use patch clamp and immunohistochemistry techniques to identify variations in Na+ channel subtypes in calyces supplying central and peripheral regions of vestibular sensory neuroepithelia, (2) to determine the role of Na+ conductances in generating and shaping action potentials and (3) to elucidate the contribution of Na+ channel subtypes to regular and irregular action potential firing patterns.
Disruption of events at this poorly understood early step of vestibular processing could cause vestibular disorders. Establishing the identities of Na+ channel subtypes in calyx afferents and understanding their roles in driving action potential firing could lead to therapies targeting Na+ channels to alleviate vestibular symptoms.
Jason Rudman, MD
3rd Year Resident
Department of Otolaryngology-Head and Neck Surgery
University of Miami Miller School of Medicine
“A sequential screening strategy for genetic hearing loss in a native black South African population”
Summary: Genetic deafness remains a common problem worldwide. Finding a specific mutation can be a challenge, but can lead to more accurate diagnosis, better treatment, and the opportunity to counsel for future inheritance patterns. One gene in particular – GJB2 – is the most common cause of genetic deafness in many diverse populations, including Caucasians, Asians, and Ashkenazi Jews. Interestingly, GJB2 almost never causes deafness in populations of African descent, yet these populations still suffer from genetic hearing loss. In fact, the specific cause of genetic deafness in these populations largely remains a mystery. This begs the question: which mutated genes are responsible for deafness in populations of African descent?
In our project, we hope to answer exactly that question. Collaborating with a South African researcher, we have obtained DNA samples from 182 native African patients from the Limpopo Province of South Africa. After confirming the absence of GJB2 and other common genes, each of these samples underwent screening with the 180-gene MiamiOtoGenes Panel using Next Generation Sequencing, a new technology that allows for rapid screening of many genes simultaneously to identify if any of the world’s known deafness mutations are present. If a mutation is still not found, we then proceed to sequencing all or most of the entire DNA strand to find new mutations. In this manner, we can save time and resources by efficiently screening for common mutations first and progressing to the more costly process of finding rare mutations.
We have obtained promising early results with preliminary identification of several deafness-causing mutations in this native African population, pending confirmation studies. We hope to apply these findings to other populations of African descent in the future as there is a large opportunity for discovery in this previously underserved population.
“Activity-dependent plasticity in the cochlear hair cell stereocilia cytoskeleton and its effect on mechanotransduction”
Summary: Stereocilia – the sensory organelles of the inner ear hair cells – have a remarkably stable morphology. We recently found that this stability depends on the ability of stereocilia to detect sound-induced vibrations via the activation of mechano-sensitive channels. Our preliminary results indicate that stereocilia shorten in response to a decrease in “mechano-sensation”, and later regrow upon the recovery of their mechano-sensitivity. This project will explore the changes in stereocilia morphology (in live cells and at nanoscale resolution) and their impact on the mechanical sensitivity of the hair cells.
The results of this study will provide insight into the mechanisms controlling stereocilia maintenance and the mechanical tuning of the hair cells. In addition, these results may provide a deeper understanding of the mechanisms involved in certain types of pathological stereocilia degeneration (for example, after noise exposure or in certain types of congenital deafness).