Vestibular Migraine (VM) patients present with auditory symptoms such as aural pressure, tinnitus, and sudden sensorineural hearing loss. Half of Meniere’s Disease (MD) patients present with migrainous features, such as a headache with photophobia or positive family history of migraine. Moreover, about a quarter of VM and MD patients meet both diagnostic criteria. So far, the MD’s pathophysiology remains unknown. Nevertheless, depending on post-mortem temporal bone analyses, endolymphatic hydrops (EH) was noted as a potential MD marker. Current migraine treatment options have shown success in treating some of the patients with MD. In MD when medical treatment fails, the recommendation is to use a second-line treatment, such as the intratympanic injection of steroids. A third-line treatment could be either endolymphatic sac surgery or the intratympanic injection of gentamicin, which has a higher risk of hearing loss. The very last option is destructive surgical treatment labyrinthectomy, with or without cochlear implantation. Since VM and MD overlap, in a nitroglycerin-induced animal model of migraine, we may encounter endolymphatic hydrops experimentally and try to reverse the effect of NTG with migraine treatment. If our hypothesis is true; intractable Meniere’s disease’s treatment options would change and there would be no more destructive treatment methods like labyrinthectomy or intratympanic gentamicin injections and it could be treated conservatively. 

Hair cells are the cellular receptors for sound that reside in the inner ear. These cells are the epitome of cellular specialization to accomplish a specific biological task: mechanotransduction—the conversion of mechanical stimuli into an electrical response. These cells contain specific organelles on which hearing is dependent, including the stereocilia. The mechanosensitive hair bundle consists of a precise arrangement of actin-based stereocilia, which extend from the hair cell's apical surface. A systematic increase in stereociliary length results in a bevel-shaped hair bundle. Each cylindrical stereocilium is stiff, but its uniform girth tapers towards the base to allow for flexion. When sound enters the ear, it causes these tiny stereocilia to vibrate at high rates. Damage to the stereocilia is often the cause of hearing impairment. The damage can be caused by either loud noise or genetic mutations. In this grant, we will explore the self-healing capacity of the hair bundle and examine how it may be used for therapeutic approaches. 

Vibhuti Agrahari, Ph.D.

Cisplatin-Induced Ototoxicity (CIO) and associated hearing loss is irreversible and there are no treatments currently available to reverse CIO, therefore, prophylactic care is critical. However, to reduce CIO, there is a need to identify the appropriate route of drug administration, and selection of an optimal drug delivery strategy with enhanced therapeutic efficacy, and the product translation to clinical application. This project will investigate the development of novel targeted nanoformulations to provide a prophylactic cure of CIO not only in adults but also in pediatric patients. The bio-responsive nanoformulations (Nano-SensoGel) will be designed to provide a long-term therapeutic effect through enhanced bio-retention and inner ear targeted attributes of the delivery system. The outcomes of this study will be critical in addressing the clinical needs towards the development of inner ear targeted technologies for the prevention of CIO-induced hearing loss.

Project WHISPER will develop and evaluate a novel, web-based system to support widespread screening and prevention of hearing impairment. It will be the first system to combine: (1) remote speech recognition testing using an automated, language-independent speech-in-noise test, (2) assessment of the risk factors for developing hearing impairment via a language-independent, icon-based interface, and (3) modeling of the individual risk for developing hearing impairment and the associated cognitive decline using explainable artificial intelligence (AI). The project will help answer the need to increase access to screening and prevention (for older adults, for individuals in underserved areas, for minorities, and for those with low socioeconomic status). It will develop tools that are language-independent and natively designed to be delivered at a distance, e.g. via web or mobile app, and natively integrated with explainable AI to extract actionable knowledge from the measured data.

Currently gene therapy using adeno-associated viral vectors (AAV) has been successful in small mammals, but nearly 80% of all genes that are affected in genetic forms of hearing loss are too large to fit into AAV vectors found in humans. Thus, there is an unmet need for the development of alternative gene-delivery tools in the translational development of gene therapy for congenital hearing loss.  Successful completion of the aims in this proposal will provide a foundational understanding of Magnetic Nanoparticle (MNP) behavior in small animal models and accrue preclinical data to support the translational development of MNP technology for inner ear gene delivery. Leveraging this team’s experience in successfully bringing other inner ear therapeutics from the bench top to the bedside, we intend to similarly advance the translational development of MNPs into nonhuman primates and ultimately human clinical trials.

Mridula Sharma, Ph.D.

Macquarie University - Sydney, Australia 

Project Title:  "Effect of age and background noise on cortical EEG entrainment to natural conversation:  a preliminary study in adults with hearing loss"

This project addresses fundamental clinical and research needs in understanding how natural speech in a conversation is processed and perceived in complex listening situations and how this is affected by age in adults with hearing loss.  Therefore, the aims of this project are:
1. To assess and understand the mechanisms underlying speech perception in an innovative and more ecologically valid manner by using EEG and novel signal processing methods.
2. To delineate the effects of age on processing and understanding natural speech in noise.
3. To identify neural indices that could be used, in future clinical studies, as clinical measure of an individual’s ability to understand speech in the real world.
The outcomes will significantly advance knowledge in our understanding of the auditory processes that are required for older adults to understand natural speech. By including a clinical test population, the proposed project will provide the knowledge required for future development of clinical management protocols and strategies using speech tracking, thereby ensuring future clinical translation of the project outcomes.

The figure shows  EEG as recorded to the continuous speech and the continuous speech signal which is routed into the EEG amplifier. After the filtering and processing of the EEG and speech amplitude envelope, Temporal response function (TRF) is determined across all channels for the condition. Topographical maps of TRF at 100-150ms are also shown for the condition. 

The figure that shows the analysis from our pilot data

Soroush Sadeghi, M.D., Ph.D.

Center for Hearing and Deafness, State University of New York (SUNY) at Buffalo

Project Title: "Improving the vestibular nerve function by pharmacological manipulation of the inner ear"

The general aim of my research is to reach a better understanding of vestibular signaling and its modulation following compensation or adaptation and to find practical ways for enhancing vestibular compensation in humans.  This can be specifically useful for patients (e.g., after therapeutic vestibular neurectomy) or in conditions where unusual adaptation is required (e.g., space travel). 

Figure 1

Figure 1. Intra-labyrinthine injection and VsEP recordings.  (A)Method of injection through the oval window. Note the exit point made on the anterior canal.  (B) Mouse’s head is attached to a linear shaker for VsEP recordings. 

In recent years, the traditional notion that peripheral end organs (i.e., hair cells and afferent terminals) in the inner ear are mere sensors has been challenged due to the presence of feedback (via an efferent pathway) from central areas. It has been shown that efferent inputs can modulate the activity of hair cells and afferents in vitro. The funding from Capita Foundation will be used to study the effect of the GABAergic and cholinergic efferent pathways on the response properties of the vestibular pathway.  Using an in vivo mouse model, we will use a method developed in our lab for intralabyrinthine injection (Fig. 1A) of different agonists and antagonists of relevant receptors and ionic channels and evaluate their effect on the vestibular nerve response by measuring the vestibular sensory evoked potentials (VsEP) (Fig. 1B). To find the behavioral correlate of the observed neuronal changes, we will measure the effect of intralabyrinthine injections of these drugs on the vestibulo-ocular reflex (VOR) – a reflex that functions to stabilize the eyes during head movements (Fig. 2).

Figure 2

Figure 2. Recording the VOR response in mice.   Eye movements will be recorded with an infrared camera in a head-restrained mouse. The mouse is rotated in the horizontal plane at different frequencies and velocities in the dark.  Right panel traces shows example eye movements during VOR response to head rotation.  

Results of the above studies could provide the means for designing new therapeutic approaches through local application of drugs in the inner ear, which could result in fewer adverse effects compared to the current systemic (e.g., oral) use of similar drugs in patients.