Humans are able to hear in a variety of complicated acoustic environments. This feat begins in the peripheral auditory system, where the cochlea collects and transmits thousands of individual bits of sound data to the brain. Here, we introduce GSP Cochlea: a graph signal processing-based framework to investigate and visualize sound encoding. We show that a cochlea graph with a mesh topology provides a mechanism of denoising, efficient information transfer, and modular processing. We demonstrate an application to assess hearing loss as more than just a decibel loss at particular frequencies of sound but also a significant change to the cochlea graph architecture. GSP Cochlea is a generalized approach that provides new insight into the higher-level functional activity of the inner ear.

In the vestibular system, upon transduction of head motion, ionic currents from type I sensory hair cells alter [K+] and electrical potentials in an extended synaptic cleft formed by a calyx terminal of the associated afferent neuron. During excitatory stimuli, these changes in turn modulate post-synaptic currents across the calyx inner face to depolarize the afferent and initiate action potentials. Within the tightly packed columnar vestibular sensory epithelium, electrical currents from the hair cell and calyx must also traverse non-synaptic extracellular spaces and generate local extracellular potentials before dispersing into the perilymph beneath the basement membrane. Here we show that such dynamic electrical potentials enhance action potential generation by reducing outward K+ currents on both the inner and outer faces of the calyx. This effect also influences adjacent calyces and may explain the abundance of calyx terminals in amniotes where there is a need for rapid recognition of changes in head orientation and acceleration.

In the process of mechanotransduction, auditory and vestibular hair cells drain potassium ions (1() from the endolymph. The resupply of Kt to the endolymph requires significant energy expenditure and is accomplished by a layer of specialized epithelial cells m the cochlea (marginal cells) and vestibular system (dark cells). We constructed a biophysical model of ion transport across these epithelial layers by implementing mathematical expressions that describe the activity of known ion channels and transporters expressed m the marginal/dark cells. Using this model the net transepithelial potassium current (iK) can be studied as a function of parameters such as external potassium concentration and ATP levels which influence ion transporter activity and affect K.' homeostasis in the endolymph. The dependency of i K on external potassium concentrations is non-linear and can be used to study the stability of Kt transport and gain insight into how potassium resupply is altered as a result of energetic depletion and genetic mutations. A particularly interesting result is that increasing the IsK conductance expressed on the apical surface of marginal cells and dark cells causes the development of hypersensitive regions in the transport phase diagram that pm vide insight into the mechanism of noise-induced hearing loss.

We take a novel graph approach to study the complex cochlear mechanics during music encoding for patients with normal hearing and hearing loss. Audiograms from AudGenDB, a pediatric clinical database, are used in tandem with the UR Ear 2020b simulation of inner hair cell voltage responses to different musical stimuli. The stimuli that we use consist of single pitches, single timbres, pitch combinations (chords), timbre combinations, and song excerpts. Graph signal processing is used to model the inner hair cell responses of each patient as a new data structure that we term a "cochlea graph." By calculating various graph-theoretic properties, we show that these cochlea graphs carry distinguishing information based on a patient's hearing loss diagnosis. Our results are poised for application to improving cochlear implant signal processing of music, where these music-based cochlea graphs can be used to develop individualized solutions based on a user's underlying hearing health. Furthermore, the graph framework that we introduce here may be generalized to study other characteristics of auditory signal processing from a unique new lens.

Purpose: Best practices recommend promoting the use of the home language and allowing caregivers to choose the language(s) that they want to use with their child who is deaf or hard of hearing (DHH). We examined whether Spanish-speaking caregivers of children who are DHH receive professional recommendations on oral bilingualism that follow best practices. We also assessed whether professional recommendations, caregiver beliefs, and language practices had an impact on child language(s) proficiency. Method: Sixty caregivers completed a questionnaire on demographic questions, language(s) use and recommendations, beliefs on bilingualism, and child language proficiency measures in English, Spanish, and American Sign Language (ASL). Professional recommendations on oral bilingualism were reported descriptively, and linear regression was used to identify the predictors of child language(s) proficiency. Results: We found that only 23.3% of the caregivers were actively encouraged to raise their child orally bilingual. Language practices predicted child proficiency in each language (English, Spanish, and ASL), but professional recommendations and caregiver beliefs did not. Conclusions: Our results revealed that most caregivers received recommendations that do not follow current best practices. Professional training is still needed to promote bilingualism and increase cultural competence when providing services to caregivers who speak languages different from English. Supplemental Material: https://doi.org/10.23641/asha.21644846

Vestibular hair cells transmit information about head position and motion across synapses to primary afferent neurons. At some of these synapses, the afferent neuron envelopes the hair cell, forming an enlarged synaptic terminal called a calyx. The vestibular hair cell-calyx synapse supports a mysterious form of electrical transmission that does not involve gap junctions termed nonquantal transmission (NQT). The NQT mechanism is thought to involve the flow of ions from the pre-synaptic hair cell to the post-synaptic calyx through low-voltage-activated channels driven by changes in cleft [K + ] as K + exits the hair cell. However, this hypothesis has not been tested with a quantitative model and the possible role of an electrical potential in the cleft has remained speculative. Here we present a computational model that captures salient experimental observations of NQT and identifies overlooked features that corroborate the existence of an electrical potential ( ϕ ) in the synaptic cleft. We show that changes in cleft ϕ reduce transmission latency and illustrate the relative contributions of both cleft [K + ] and ϕ to the gain and phase of NQT. We further demonstrate that the magnitude and speed of NQT depend on calyx morphology and that increasing calyx height reduces action potential latency in the calyx afferent. These predictions are consistent with the idea that the calyx evolved to enhance NQT and speed up vestibular signals that drive neural circuits controlling gaze, balance, and orientation. Significance Statement The ability of the vestibular system to drive the fastest reflexes in the nervous system depends on rapid transmission of mechanosensory signals at vestibular hair cell synapses. In mammals and other amniotes, afferent neurons form unusually large calyx terminals on certain hair cells, and communication at these synapses includes nonquantal transmission (NQT), which avoids the synaptic delay of quantal transmission. We present a quantitative model that shows how NQT depends on the extent of the calyx covering the hair cell and attributes the short latency of NQT to changes in synaptic cleft electrical potential caused by current flowing through open potassium channels in the hair cell. This previously undescribed mechanism may act at other synapses.

This paper presents the biophysical modeling for neuronal stimulation caused by amplitude-modulated giga-hertz (GHz) electromagnetic (EM) waves. We model a 1D cable equation for electrical signal propagation in a vestibular ganglion neuronal fiber and use Hodgkin-Huxley formalism to model voltage-dependent channel conductances. We find out that for a given stimulation signal strength, the GHz waveform amplitude-modulated at a low frequency of Δf causes neuronal firing with the frequency of Δf whereas the continuous wave GHz did not elicit any neuronal firing. Moreover, the voltage-dependent channel gating dynamics of the Δf amplitude-modulated GHz stimulation matches that of a simple low frequency stimulation at Δf. Additionally, we find that the modulation depth controls the firing rate of the neurons. The significance of this property is that the amplitude modulation caused by the interference of two similar high frequency signals could be leveraged to focally excite neurons at depth without stimulating overlying cortical regions. These theoretical predictions based on the Hodgkin-Huxley model can later be tested experimentally.

Our sense of hearing and balance relies on mechanotransduction by auditory and vestibular hair cells that drain potassium from the endolymphatic fluid in the inner ear. We constructed a biophysical model of ion transport across epithelial layers that resupply potassium by implementing mathematical expressions for ion transporters expressed in marginal/dark cells, including the Na/K pump, NKCC, chloride channels and an IsK conductance composed of KCNQ/KCNE1 subunits. The transepithelial potassium current (IKte) can then be studied as a function of desired parameters of the system.

The electromechanical coupling exhibited by cochlear outer hair cells is a remarkable biophysical phenomenon. These specialized cells generate forces at acoustic frequencies and enable high-frequency hearing in mammals. While there has been significant progress since the discovery of electromotility - including the discovery of the motor protein prestin - we still do not have a clear picture of how electromotility works. A particularly vexing problem is how forces, generated by a membrane-based motor, are rapidly transmitted to the underlying cytoskeleton to enable force generation on the microsecond time scales required for amplification of acoustic signals. Here we approach the problem of electromotility from the perspective of soft matter physics in light of recent ultrastructural findings from 3D electron tomography studies on outer hair cells immobilized by high-pressure freezing. We then survey our understanding of prestin-membrane and prestin-cytoskeletal interactions in the context recently published cryoelectron microscopy (cryo-EM) structures of prestin. This will lead to the proposal of a new conceptual model of electromotility consistent with conformational states observed in the pillar proteins and actin filaments. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.

Mitochondria supply energy in the form of ATP to drive a plethora of cellular processes. In heart and liver cells, mitochondria occupy over 20% of the cellular volume and the major need for ATP is easily identifiable - i.e., to drive cross-bridge recycling in cardiac cells or biosynthetic machinery in liver cells. In vestibular and cochlear hair cells the overall cellular mitochondrial volume is much less, and mitochondria structure varies dramatically in different regions of the cell. The regional demands for ATP and cellular forces that govern mitochondrial structure and localization are not well understood. Below we review our current understanding of the heterogeneity of form and function in hair cell mitochondria. A particular focus of this review will be on regional specialization in vestibular hair cells, where large mitochondria are found beneath the cuticular plate in close association with the striated organelle. Recent findings on the role of mitochondria in hair cell death and aging are covered along with potential therapeutic approaches. Potential avenues for future research are discussed, including the need for integrated computational modeling of mitochondrial function in hair cells and the vestibular afferent calyx.

Sensory hair cells of the vestibular inner ear detect and relay information on head motion to afferent neurons, which in turn guide motor reflexes that maintain gaze, balance, and our sense of orientation. Afferent neurons form large cup-shaped synaptic terminals (calyces) on type I hair cells that transmit to calyces by both quantal (Q) release of glutamate from vesicles and non-quantal (NQ) flow of ions from the hair cell into the synaptic cleft and the postsynaptic calyx. The measurement of ion concentrations and electric potentials within the synaptic cleft is difficult and has been a barrier to understanding NQ transmission. We have developed a computational biophysical model of the vestibular hair cell-calyx (VHCC) synapse to overcome this limitation. To model the dynamic behavior of the system, the VHCC model uses expressions for K+ and Na+ electrodiffusion in the cleft, simplified Hodgkin-Huxley-style ion currents based on whole-cell recordings, and the cable equation. The input to the model is a step or sinusoidal deflection of the hair bundle, and the outputs include the spatio-temporal profile of K+ and Na+ within the synaptic cleft and the change in electrical potential within the synaptic cleft and the afferent neuron. Simulations reveal frequency independence of ephaptic coupling and low-pass behavior of K+ modulation at the synaptic cleft. Both processes mediate and hasten NQ transmission. Analysis of currents through the low voltage activated potassium conductance (gK,L) on the hair cell and currents through Kv7.4 and HCN channels on the calyx inner face suggest that gK,L and Kv7.4 are the foremost mediators of transmission during physiological operation. The VHCC model integrates a wealth of experimental data and advances our understanding of how channel expression and function enable NQ transmission.

Disability is an important and often overlooked component of diversity. Individuals with disabilities bring a rare perspective to science, technology, engineering, mathematics, and medicine (STEMM) because of their unique experiences approaching complex issues related to health and disability, navigating the healthcare system, creatively solving problems unfamiliar to many individuals without disabilities, managing time and resources that are limited by physical or mental constraints, and advocating for themselves and others in the disabled community. Yet, individuals with disabilities are underrepresented in STEMM. Professional organizations can address this underrepresentation by recruiting individuals with disabilities for leadership opportunities, easing financial burdens, providing equal access, fostering peer-mentor groups, and establishing a culture of equity and inclusion spanning all facets of diversity. We are a group of deaf and hard-of-hearing (D/HH) engineers, scientists, and clinicians, most of whom are active in clinical practice and/or auditory research. We have worked within our professional societies to improve access and inclusion for D/HH individuals and others with disabilities. We describe how different models of disability inform our understanding of disability as a form of diversity. We address heterogeneity within disabled communities, including intersectionality between disability and other forms of diversity. We highlight how the Association for Research in Otolaryngology has supported our efforts to reduce ableism and promote access and inclusion for D/HH individuals. We also discuss future directions and challenges. The tools and approaches discussed here can be applied by other professional organizations to include individuals with all forms of diversity in STEMM.

The maintenance of a high potassium concentration (∼150 mm) in the endolymphatic fluid in the inner ear is essential for hearing and balance. This is an energy intensive process carried out by specialized epithelial cells - marginal cells in the cochlear and vestibular dark cells in the vestibular labyrinth – that have extensive basolateral infoldings rich in mitochondria and s a high density of the Na+-K+-ATPase pump. The biophysics of marginal/dark cell ion transport is not fully understood. To advance this research, we extended a previously developed integrated mathematical model of ion transport across the marginal/dark cells (Qurashi, et al. Am. J. Phys. 2007) by implementing a 15-state Post-Albers model of the Na+-K+-ATPase that includes explicit affinities for Na+ and K+ on both sides of the membrane and voltage dependent dissociation constants. The model contains mathematical expressions for known ion transporters at the basal and apical faces of the marginal/dark cell. This extended model allows us to simulate the effects of energetic depletion by studying how potassium transport across the epithelium depends on ATP concentration. The results indicate that the current carried by the Na+-K+-ATPase, the K+ carried by the Na+-K+-Cl– cotransporter (NKCC1) and the net K+ current across the epithelium (iKte) all begin to decline when the ATP concentration on the basolateral side falls. Of particular physiological significance is that the model predicts that iKte reverses direction meaning that potassium will be transported out of the endolymph. The influences of extracellular K+ and Cl– on the transepithelial K+ current and the effects of genetic mutations in channels such as KCNQ1/KCNE1 that give rise to deafness and noise-induced hearing can also be simulated, advancing our understanding of the function and dysfunction of ion transport in the inner ear.

Outer Hair Cells (OHCs) in the mammalian cochlea display a unique type of voltage-induced mechanical movement termed electromotility, which amplifies auditory signals and contributes to the sensitivity and frequency selectivity of mammalian hearing. Electromotility occurs in the OHC lateral wall, but it is not fully understood how the supramolecular architecture of the lateral wall enables this unique form of cellular motility. Employing electron tomography of high-pressure frozen and freeze-substituted OHCs, we visualized the 3D structure and organization of the membrane and cytoskeletal components of the OHC lateral wall. The subsurface cisterna (SSC) is a highly prominent feature, and we report that the SSC membranes and lumen possess hexagonally ordered arrays of particles. We also find the SSC is tightly connected to adjacent actin filaments by short filamentous protein connections. Pillar proteins that join the plasma membrane to the cytoskeleton appear as variable structures considerably thinner than actin filaments and significantly more flexible than actin-SSC links. The structurally rich organization and rigidity of the SSC coupled with apparently weaker mechanical connections between the plasma membrane (PM) and cytoskeleton reveal that the membrane-cytoskeletal architecture of the OHC lateral wall is more complex than previously appreciated. These observations are important for our understanding of OHC mechanics and need to be considered in computational models of OHC electromotility that incorporate subcellular features.

We are a community of scientists who have personally experienced the barriers imposed by hearing loss described by G. Buckley et al. in their Letter “Building community for deaf scientists” (20 January, p. [255][1]). They propose an institutional hub for deaf and hard-of-hearing (D/HH) trainees

The motor protein prestin is a member of the SLC26 family of anion antiporters and is essential to the electromotility of cochlear outer hair cells and for hearing. The only direct inhibitor of electromotility and the associated charge transfer is salicylate, possibly through direct interaction with an anion-binding site on prestin. In a screen to identify other inhibitors of prestin activity, we explored the effect of the non-steroid anti-inflammatory drug diflunisal, which is a derivative of salicylate. We recorded prestin activity by whole-cell patch clamping HEK cells transiently expressing prestin and mouse outer hair cells. We monitored the impact of diflunisal on the prestin-dependent non-linear capacitance and electromotility. We found that diflunisal triggers two prestin-associated effects: a chloride independent increase in the surface area and the specific capacitance of the membrane, and a chloride dependent inhibition of the charge transfer and the electromotility in outer hair cells. We conclude that diflunisal affects the cell membrane organization and inhibits prestin-associated charge transfer and electromotility at physiological chloride concentrations. The inhibitory effects on hair cell function are noteworthy given the proposed use of diflunisal to treat neurodegenerative diseases.

The membrane protein prestin plays a central role in the mammalian auditory system by enabling outer hair cells in the cochlea to actively respond to electrical signals. Prestin belongs to the SLC26A family of membrane proteins, which all have a large cytosolic terminus containing a conserved region known as the STAS domain (Sulfate Transporters and Anti-Sigma factor antagonist), whose function remains unknown. We hypothesize that molecular interactions of the STAS domain are responsible for confining the lateral mobility of prestin. To test this hypothesis, we designed prestin constructs inserted with a Tobacco Etch Virus (TEV) protease recognition linker (tevS) into different sites, including the interface between the last transmembrane domain and the STAS domain, the disordered region from 563aa to 637aa, and after the STAS domain, and then tested for membrane expression and prestin function. We subsequently employed a PhyB-PIF6 dimerization system and a split-TEV strategy to regulate TEV protease activity via exposure to red and far red light. We found that the interface between the last transmembrane domain and cytoplasmic C-terminus is critical for molecular interactions and for prestin's functionality. We also inserted tevS between amino acids 596/597 and 620/621 in prestin; these modifications retained wild type membrane expression and function, and both constructs were successfully cleaved by the TEV protease. However, the 596/597 cleaved C-terminal tail localized near the membrane, whereas the 620/621 cleaved tail diffused into the cytosol, therefore suggesting the presence of a potential binding site between amino acids 597 and 620 in prestin. This work demonstrates the advantages of employing optogenetic approaches to dynamically study the role of the STAS domain in prestin's function and membrane organization.