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The outer hair cells (OHCs) of the mammalian cochlea are the mediators of an active, nonlinear electromechanical process necessary for sensitive, frequency-specific hearing. The membrane protein prestin conveys to the OHC a piezoelectric-like behavior hypothesized to actuate a high frequency, cycle-by-cycle conversion of electrical to mechanical energy to boost cochlear responses to low-level sound. This hypothesis has been debated for decades, with two key remaining issues: the influence of the rate dependence of conformal changes in prestin and the OHC transmembrane impedance. In this paper, we mainly focus on the rate dependence of the conformal change in prestin. A theoretical electromechanical model of the OHC that explicitly includes rate dependence of conformal transitions, viscoelasticity, and piezoelectricity. Using this theory, we show the influence of rate dependence and viscoelasticity on electromechanical force generation and transmembrane impedance. Furthermore, we stress the importance of using the correct mechanical boundary conditions when estimating the transmembrane capacitance. Finally, a set of experiments is described to uniquely estimate the constitutive properties of the OHC from whole-cell measurements.

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Despite lacking ears, the nematode C. elegans senses airborne sound and engages in phonotaxis behavior, enabling it to locate and avoid sound sources.1 How worms sense sound, however, is not well understood. Here, we report an interesting observation that worms respond only to sounds emitted by small but not large speakers, indicating that they preferentially respond to localized sound sources. Notably, sounds emitted by small speakers form a sharp sound pressure gradient across the worm body, while sounds from large speakers do not, suggesting that worms sense sound pressure gradients rather than absolute sound pressure. Analysis of phonotaxis behavior, sound-evoked skin vibration, and sound-sensitive neuron activities further support this model. We suggest that the ability to sense sound pressure gradients provides a potential mechanism for worms to distinguish sounds generated by their predators, which are typically small animals, from those produced by large animals or background noise. As vertebrate cochlea and some insect ears can also detect sound pressure gradients, our results reveal that sensing of sound pressure gradients may represent a common mechanism in auditory sensation across animal phyla. VIDEO ABSTRACT.

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The outer hair cells (OHCs) of the mammalian cochlea are the mediators of an active, nonlinear electromechanical process necessary for sensitive, frequency specific hearing. The membrane protein prestin conveys to the OHC a piezoelectric-like behavior hypothesized to actuate a high frequency, cycle-by-cycle conversion of electrical to mechanical energy to boost cochlear responses to low-level sound. This hypothesis has been debated for decades, and we address two key remaining issues: the influence of the rate dependence of conformal changes in prestin and the OHC transmembrane impedance. We develop a theoretical electromechanical model of the OHC that explicitly includes rate dependence of conformal transitions, viscoelasticity, and piezoelectricity. Using this theory, we show the influence of rate dependence and viscoelasticity on electromechanical force generation. Further, we stress the importance of using the correct mechanical boundary conditions when estimating the transmembrane capacitance. Finally, a set of experiments is described to uniquely estimate the constitutive properties of the OHC from whole-cell measurements.

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For the last 20 years, researchers have developed accelerometers to function as ossicular vibration sensors in order to eliminate the external components of hearing aid and cochlear implant systems. To date, no accelerometer has met all of the stringent performance requirements necessary to function in this capacity. In this work, we present an accelerometer design with an equivalent noise floor less than 20 phon equal-loudness-level over a 0.1-8 kHz bandwidth in a package small enough to be implanted in the middle ear. Our approach uses a dual-bandwidth (two sensing elements) microelectromechanical systems piezoelectric accelerometer, sized using an area-minimization process based on an experimentally-validated analytical model of the sensor. The resulting bandwidth of the low-frequency sensing element is 0.1-1.25 kHz and that of the high-frequency sensing element is 1.25-8 kHz. These sensing elements fit within a silicon frame that is 795 µm × 778 µm, which can reasonably be housed along with a required integrated circuit in a 2.2 mm × 2.7 mm × 1 mm package. The estimated total mass of the packaged system is approximately 14 mg. This dual-bandwidth MEMS sensor fills a technological gap in current completely implantable auditory prosthesis research and development by enabling a device capable of meeting physical and performance specifications needed for use in the middle ear.

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Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL.

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Unlike olfaction, taste, touch, vision, and proprioception, which are widespread across animal phyla, hearing is found only in vertebrates and some arthropods. The vast majority of invertebrate species are thus considered insensitive to sound. Here, we challenge this conventional view by showing that the earless nematode C. elegans senses airborne sound at frequencies reaching the kHz range. Sound vibrates C. elegans skin, which acts as a pressure-to-displacement transducer similar to vertebrate eardrum, activates sound-sensitive FLP/PVD neurons attached to the skin, and evokes phonotaxis behavior. We identified two nAChRs that transduce sound signals independently of ACh, revealing an unexpected function of nAChRs in mechanosensation. Thus, the ability to sense airborne sound is not restricted to vertebrates and arthropods as previously thought, and might have evolved multiple times independently in the animal kingdom, suggesting convergent evolution. Our studies also demonstrate that animals without ears may not be presumed to be sound insensitive.

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[This corrects the article DOI: 10.1371/journal.pcbi.1008499.].

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Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans.

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The ubiquity of vibration sensors and accelerometers, as well as advances in microfabrication technologies, have led to the development of implantable devices for biomedical applications. This work describes a piezoelectric microelectromechanical systems accelerometer designed for potential use in auditory prostheses. The design includes an aluminum nitride bimorph beam with a silicon proof mass. Analytic models of the device sensitivity and noise are presented. These lead to a minimum detectable acceleration cost function for the sensor that can be used to optimize sensor designs more effectively than typical sensitivity maximizing or electrical noise minimizing approaches. A fabricated device with a 1 µm thick, 100 µm long, and 700 µm wide beam and a 400 µm thick, 63 µm long, and 740 µm wide proof mass is tested experimentally. Results indicate accurate modeling of the system sensitivity up to the first resonant frequency (1420 Hz). The low-frequency sensitivity of the device is 1.3 mV/g, and the input referred noise is 36.3 nV / Hz at 100 Hz and 11.8 nV / Hz at 1 kHz. The resulting minimum detectable acceleration at 100 Hz and 1 kHz is 28 µg / Hz and 9.1 µg / Hz , respectively. A brief explanation of the use of the validated cost function for sensor design is provided, as well as an example comparing the piezoelectric sensor design to another from the literature. It is concluded that a traditional single-resonance design cannot compete with the performance of acoustic sensors; therefore, novel device designs must be considered for implantable auditory prosthesis applications.

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Piezoelectric acoustic transducers consisting of a circular aluminum nitride and silicon nitride unimorph diaphragm and an encapsulated air-filled back cavity are reported. Analytical and finite element analysis models are used to design the transducer to achieve low minimum detectable pressure (MDP) within chosen size restrictions. A series of transducers with varying radii are fabricated using microelectromechanical systems (MEMS) techniques. Experimental results are reported for a transducer with a 175 µm radius on a 400 × 500 × 500 µm3 die exhibiting structural resonances at 552 kHz in air and 133 kHz in water. The low-frequency (10 Hz-50 kHz) sensitivity is 1.87 µV/Pa (-114.5 dB re 1 V/Pa) in both air and water. The sensor has an MDP of 43.7 mPa/ Hz (67 dB SPL) at 100 Hz and 10.9 mPa/ Hz (55 dB SPL) at 1 kHz. This work contributes a set of design rules for MEMS piezoelectric diaphragm transducers that focuses on decreasing the MDP of the sensor through size, material properties, and residual stress considerations.

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The mechanical and electrical responses of the mammalian cochlea to acoustic stimuli are nonlinear and highly tuned in frequency. This is due to the electromechanical properties of cochlear outer hair cells (OHCs). At each location along the cochlear spiral, the OHCs mediate an active process in which the sensory tissue motion is enhanced at frequencies close to the most sensitive frequency (called the characteristic frequency, CF). Previous experimental results showed an approximate 0.3 cycle phase shift in the OHC-generated extracellular voltage relative the basilar membrane displacement, which was initiated at a frequency approximately one-half octave lower than the CF. Findings in the present paper reinforce that result. This shift is significant because it brings the phase of the OHC-derived electromotile force near to that of the basilar membrane velocity at frequencies above the shift, thereby enabling the transfer of electrical to mechanical power at the basilar membrane. In order to seek a candidate physical mechanism for this phenomenon, we used a comprehensive electromechanical mathematical model of the cochlear response to sound. The model predicts the phase shift in the extracellular voltage referenced to the basilar membrane at a frequency approximately one-half octave below CF, in accordance with the experimental data. In the model, this feature arises from a minimum in the radial impedance of the tectorial membrane and its limbal attachment. These experimental and theoretical results are consistent with the hypothesis that a tectorial membrane resonance introduces the correct phasing between mechanical and electrical responses for power generation, effectively turning on the cochlear amplifier.

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The ability to create linear systems that manifest broadband nonreciprocal wave propagation would provide for exquisite control over acoustic signals for electronic filtering in communication and noise control. Acoustic nonreciprocity has predominately been achieved by approaches that introduce nonlinear interaction, mean-flow biasing, smart skins, and spatio-temporal parametric modulation into the system. Each approach suffers from at least one of the following drawbacks: the introduction of modulation tones, narrow band filtering, and the interruption of mean flow in fluid acoustics. We now show that an acoustic media that is non-local and active provides a new means to break reciprocity in a linear fashion without these deleterious effects. We realize this media using a distributed network of interlaced subwavelength sensor-actuator pairs with unidirectional signal transport. We exploit this new design space to create a stable metamaterial with non-even dispersion relations and electronically tunable nonreciprocal behavior over a broad range of frequencies.

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The spatial variations of the intricate cytoarchitecture, fluid scalae, and mechano-electric transduction in the mammalian cochlea have long been postulated to provide the organ with the ability to perform a real-time, time-frequency processing of sound. However, the precise manner by which this tripartite coupling enables the exquisite cochlear filtering has yet to be articulated in a base-to-apex mathematical model. Moreover, while sound-evoked tuning curves derived from mechanical gains are excellent surrogates for auditory nerve fiber thresholds at the base of the cochlea, this correlation fails at the apex. The key factors influencing the divergence of both mechanical and neural tuning at the apex, as well as the spatial variation of mechanical tuning, are incompletely understood. We develop a model that shows that the mechanical effects arising from the combination of the taper of the cochlear scalae and the spatial variation of the cytoarchitecture of the cochlea provide robust mechanisms that modulate the outer hair cell-mediated active response and provide the basis for the transition of the mechanical gain spectra along the cochlear spiral. Further, the model predicts that the neural tuning at the base is primarily governed by the mechanical filtering of the cochlear partition. At the apex, microscale fluid dynamics and nanoscale channel dynamics must also be invoked to describe the threshold neural tuning for low frequencies. Overall, the model delineates a physiological basis for the difference between basal and apical gain seen in experiments and provides a coherent description of high- and low-frequency cochlear tuning.

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The ability to measure the voltage readout from a sensor implanted inside the living cochlea enables continuous monitoring of intracochlear acoustic pressure locally, which could improve cochlear implants. We developed a piezoelectric intracochlear acoustic transducer (PIAT) designed to sense the acoustic pressure while fully implanted inside a living guinea pig cochlea. The PIAT, fabricated using micro-electro-mechanical systems (MEMS) techniques, consisted of an array of four piezoelectric cantilevers with varying lengths to enhance sensitivity across a wide frequency bandwidth. Prior to implantation, benchtop tests were conducted to characterize the device performance in air and in water. When implanted in the cochlea of an anesthetized guinea pig, the in vivo voltage response from the PIAT was measured in response to 80-95 dB sound pressure level 1-14 kHz sinusoidal acoustic excitation at the entrance of the guinea pig's ear canal. All sensed signals were above the noise floor and unaffected by crosstalk from the cochlear microphonic or external electrical interference. These results demonstrate that external acoustic stimulus can be sensed via the piezoelectric voltage response of the implanted MEMS transducer inside the living cochlea, providing key steps towards developing intracochlear acoustic sensors to replace external or subcutaneous microphones for auditory prosthetics.

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Acoustical excitation of the organ of Corti induces radial fluid flow in the subtectorial space (STS) that excites the hair bundles (HBs) of the sensory inner hair cell of the mammalian cochlea. The inner hair cell HBs are bathed in endolymphatic fluid filling a thin gap in the STS between the tectorial membrane and the reticular lamina. According to the fluctuation dissipation theorem, the fluid viscosity gives rise to mechanical fluctuations that are transduced into current noise. Conversely, the stochastic fluctuations of the mechanically gated channels of the HBs also induce dissipation. We develop an analytic model of the STS complex in a cross section of the gerbil organ of Corti. We predict that the dominant noise at the apex is due to the channel stochasticity whereas viscous effects dominate at the base. The net root mean square fluctuation of the HB motion is estimated to be at least 1.18 nm at the base and 2.72 nm at the apex. By varying the HB height for a fixed STS gap, we find that taller HBs are better sensors with lower thresholds. An integrated active HB model is shown to reduce the hydrodynamic resistance through a cycle-by-cycle power addition through adaptation, reducing the thresholds of hearing, hinting at one potential role for HB activity in mammalian hearing. We determine that a Couette flow approximation in the STS underestimates the dissipation and that modeling the entire STS complex is necessary to correctly predict the low-frequency dissipation in the cochlea. Finally, the difference in the noise budget at the base and the apex of the cochlea indicate that a sensing modality other than the shear motion of the TM that may be used to achieve low-noise acoustic sensing at the apex.

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Hearing relies on a series of coupled electrical, acoustical, and mechanical interactions inside the cochlea that enable sound processing. The local structural and electrical properties of the organ of Corti (OoC) and basilar membrane give rise to the global, coupled behavior of the cochlea. However, it is difficult to determine the root causes of important behavior, such as the mediator of active processes, in the fully coupled in vivo setting. An alternative experimental approach is to use an excised segment of the cochlea under controlled electrical and mechanical conditions. Using the excised cochlear segment experiment conducted by Chan and Hudspeth [Nat. Neurosci. 8, 149-155 (2005); Biophys. J. 89, 4382-4395 (2005)] as the model problem, a quasilinear computational model for studying the active in vitro response of the OoC to acoustical stimulation was developed. The model of the electrical, mechanical, and acoustical conditions of the experimental configuration is able to replicate some of the experiment results, such as the shape of the frequency response of the sensory epithelium and the variation of the resonance frequency with the added fluid mass. As in the experiment, the model predicts a phase accumulation along the segment. However, it was found that the contribution of this phase accumulation to the dynamics is insignificant. Taking advantage of the relative simplicity of the fluid loading, the three-dimensional fluid dynamics was reduced into an added mass loading on the OoC thereby reducing the overall complexity of the model.

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Passive control of low-frequency duct noise remains a technical challenge. Traditional noise control devices are either overly bulky or too narrowband. A broadband attenuation mechanism inspired by the mammalian cochlea is presented in this theoretical study. It consists of a parallel arrangement of an array of multiple beams or stretched strips backed by a cavity. The structure vibrates strongly in response to the broadband incident noise and hence creates substantial reflection. If both the media in the cavity and the duct are air, the mass-like load from the fluid in the cavity suppresses the response of the structure and thus lowers the transmission loss. If helium, or some other gas with lower density than air in the duct, fills the cavity, the mass-like reactance of the cavity is reduced and the silencing performance is improved. Then such a silencer can achieve a satisfactory attenuation performance at low frequency range. Multiple adjacent resonant peaks are found in the transmission loss curve and such a silencer has superiority in size and acoustic performance over expansion chamber and duct lining.

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In a sensitive cochlea, the basilar membrane response to transient excitation of any kind-normal acoustic or artificial intracochlear excitation-consists of not only a primary impulse but also a coda of delayed secondary responses with varying amplitudes but similar spectral content around the characteristic frequency of the measurement location. The coda, sometimes referred to as echoes or ringing, has been described as a form of local, short term memory which may influence the ability of the auditory system to detect gaps in an acoustic stimulus such as speech. Depending on the individual cochlea, the temporal gap between the primary impulse and the following coda ranges from once to thrice the group delay of the primary impulse (the group delay of the primary impulse is on the order of a few hundred microseconds). The coda is physiologically vulnerable, disappearing when the cochlea is compromised even slightly. The multicomponent sensitive response is not yet completely understood. We use a physiologically-based, mathematical model to investigate (i) the generation of the primary impulse response and the dependence of the group delay on the various stimulation methods, (ii) the effect of spatial perturbations in the properties of mechanically sensitive ion channels on the generation and separation of delayed secondary responses. The model suggests that the presence of the secondary responses depends on the wavenumber content of a perturbation and the activity level of the cochlea. In addition, the model shows that the varying temporal gaps between adjacent coda seen in experiments depend on the individual profiles of perturbations. Implications for non-invasive cochlear diagnosis are also discussed.

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The exceptional sensitivity of mammalian hearing organs is attributed to an active process, where force produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these fundamental precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. This shows that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex. A physiologically-based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity.

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The mechanical stimulation of the outer hair cell hair bundle (HB) is a key step in nonlinear cochlear amplification. We show how two-tone suppression (TTS), a hallmark of cochlear nonlinearity, can be used as an indirect measure of HB stimulation. Using two different nonlinear computational models of the cochlea, we investigate the effect of altering the mechanical load applied by the tectorial membrane (TM) on the outer hair cell HB. In the first model (TM-A model), the TM is attached to the spiral limbus (as in wild-type animals); in the second model (TM-D model), the TM is detached from the spiral limbus (mimicking the cochlea of Otoa(EGFP/EGFP) mutant mice). As in recent experiments, model simulations demonstrate that the absence of the TM attachment does not preclude cochlear amplification. However, detaching the TM alters the mechanical load applied by the TM on the HB at low frequencies and therefore affects TTS by low-frequency suppressors. For low-frequency suppressors, the suppression threshold obtained with the TM-A model corresponds to a constant suppressor displacement on the basilar membrane (as in experiments with wild-type animals), whereas it corresponds to a constant suppressor velocity with the TM-D model. The predictions with the TM-D model could be tested by measuring TTS on the basilar membrane of the Otoa(EGFP/EGFP) mice to improve our understanding of the fundamental workings of the cochlea.

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