Search

The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as '(Chi/Alg)SPs', to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 μg of NT3 loaded per SP that weights ~50 μg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 μg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 μg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss. [Display omitted] • Supraparticles are a viable approach to deliver neurotrophin to the cochlea. • Neurotrophin was detected in the cochlea 8 weeks post-supraparticle implantation. • Variable drug distribution after round membrane implantation of supraparticles. • Coated supraparticles improve the longevity of drug elution in vitro , but not in vivo. [ABSTRACT FROM AUTHOR]

• Round window reinforcement impacts the inner ear mechanics with air and bone conduction stimulation differently. • For air conduction, the differential pressure, a measure closely related to the hearing sensation, decreases up to 11 dB after round window reinforcement. • For bone conduction, round window reinforcement on average causes only limited effects. • The effects of the round window reinforcement seen after cochlear implantation could explain part of the delayed loss of residual hearing. • With bone conduction largely unaffected by round window reinforcement, electro-vibrational stimulation might be preferred over electro-acoustic stimulation for people with a cochlear implant and ipsilateral residual hearing. The round window (RW) membrane plays an important role in normal inner ear mechanics. Occlusion or reinforcement of the RW has been described in the context of congenital anomalies or after cochlear implantation and is applied as a surgical treatment for hyperacusis. Multiple lumped and finite element models predict a low-frequency hearing loss with air conduction of up to 20 dB after RW reinforcement and limited to no effect on hearing with bone conduction stimulation. Experimental verification of these results, however, remains limited. Here, we present an experimental study measuring the impact of RW reinforcement on the middle and inner ear mechanics with air and bone conduction stimulation. In a within-specimen repeated measures design with human cadaveric specimens (n = 6), we compared the intracochlear pressures in scala vestibuli (P SV) and scala tympani (P ST) before and after RW reinforcement with soft tissue, cartilage, and bone cement. The differential pressure (P DIFF) across the basilar membrane – known to be closely related to the hearing sensation - was calculated as the complex difference between P SV and P ST. With air conduction stimulation, both P SV and P ST increased on average up to 22 dB at frequencies below 1500 Hz with larger effect sizes for P ST compared to P SV. The P DIFF , in contrast, decreased up to 11 dB at frequencies between 700 and 800 Hz after reinforcement with bone cement. With bone conduction, the average within-specimen effects were less than 5 dB for either P SV , P ST, or P DIFF. The inter-specimen variability with bone conduction, however, was considerably larger than with air conduction. This experimental study shows that RW reinforcement impacts air conduction stimulation at low frequencies. Bone conduction stimulation seems to be largely unaffected. From a clinical point of view, these results support the hypothesis that delayed loss of air conduction hearing after cochlear implantation could be partially explained by the impact of RW reinforcement. [ABSTRACT FROM AUTHOR]

• A finite element model of the human ear successfully predicted the occlusion effect. • Earplug use increased the ear canal pressure at frequencies below 500 Hz. • Nanoporous aerogel earplugs mitigated the occlusion effect better than foam earplugs. • The occlusion effect increased the stapes footplate and basilar membrane displacements. Poor utilization of earplugs among military personnel may be due to discomfort caused by the occlusion effect (OE). The OE occurs when an earplug occludes the ear canal, thereby changing bone conduction (BC) hearing and amplifying physiological noises from the wearer. There is a need to understand and reduce the OE in the human ear. A 3D finite element model of the human ear including a 3-chambered spiral cochlea was employed to simulate the OE caused by foam and aerogel earplugs. 90 dB sound pressure was applied at the ear canal entrance and BC sound was applied as vibration of the canal bony wall. The model reported the ear canal pressure and the displacements of the stapes footplate and cochlear basilar membrane with and without earplugs. Without BC stimulation, the foam earplug showed a greater pressure attenuation than the aerogel earplug. However, the foam earplug results were more affected by BC stimulation, with a maximum sound pressure increase of 34 dB, compared to the 21.0 dB increase with the aerogel earplug. The aerogel earplug's lower OE demonstrates its promise as an earplug material. Future work with this model will examine BC sound transmission in the cochlea. [ABSTRACT FROM AUTHOR]

In the mammalian auditory system, frequency discrimination depends on numerous morphological and physiological properties of the organ of Corti, which gradually change along the apex-to-base (tonotopic) axis of the organ. For example, the basilar membrane stiffness changes tonotopically, thus affecting the tuning properties of individual hair cells. At the molecular level, those frequency-specific characteristics are mirrored by gene expression gradients; however, the molecular mechanisms controlling tonotopic gene expression in the mouse cochlea remain elusive. Through analyzing single-cell RNA sequencing (scRNA-seq) data from E12.5 and E14.5 time points, we predicted that morphogens, rather than a cell division-associated mechanism, confer spatial identity in the extending cochlea. Subsequently, we reconstructed the developing cochlea in 3D space from scRNA-seq data to investigate the molecular pathways mediating positional information. The retinoic acid (RA) and hedgehog pathways were found to form opposing apex-to-base gradients, and functional interrogation using mouse cochlear explants suggested that both pathways jointly specify the longitudinal axis. [Display omitted] • 3D reconstruction of the developing cochlear duct from scRNA-seq data • Morphogens, not cell cycle exit, confer tonotopic information in the cochlea • Opposing RA and SHH gradients control apex-to-base gene expression in the cochlea Wang and Chakraborty et al. demonstrate that morphogens rather than a timing-related mechanism mediate positional information along the apex-to-base axis of the murine cochlea. Moreover, two morphogens, retinoic acid and sonic hedgehog, were identified to form opposing morphogen gradients, thereby controlling spatial gene expression along the apex-to-base axis. [ABSTRACT FROM AUTHOR]

• Within a cross-section of the organ of Corti complex, different regions experience cochlear activity differently. • Multi-tone stimuli are useful for identifying sub-BF activity. • Sub-BF activity is observed in the motion of the OHC-Deiters cells region but is not apparent in the lateral region of the organ of Corti or in the transverse motion of the reticular lamina. • At sub-BF frequencies, passive forces appear to dominate active forces over much of the organ of Corti complex. Auditory sensation is based in nanoscale vibration of the sensory tissue of the cochlea, the organ of Corti complex (OCC). Motion within the OCC is now observable due to optical coherence tomography. In a previous study (Cooper et al., 2018), the region that includes the electro-motile outer hair cells (OHC) and Deiters cells (DC) was observed to move with larger amplitude than the basilar membrane (BM) and surrounding regions and was termed the "hotspot." In addition to this quantitative distinction, the hotspot moved qualitatively differently than the BM, in that its motion scaled nonlinearly with stimulus level at all frequencies, evincing sub-BF activity. Sub-BF activity enhances non-BF motion; thus the frequency tuning of the OHC/DC region was reduced relative to the BM. In this work we further explore the motion of the gerbil basal OCC and find that regions that lack significant sub-BF activity include the BM, the medial and lateral OCC, and the reticular lamina (RL) region. The observation that the RL region does not move actively sub-BF (already observed in Cho and Puria 2022), suggests that hair cell stereocilia are not exposed to sub-BF activity in the cochlear base. The observation that the lateral and RL regions move approximately linearly sub-BF indicates that linear forces dominate non-linear OHC-based forces on these components at sub-BF frequencies. A complex difference analysis was performed to reveal the internal motion of the OHC/DC region and showed that amplitude structure and phase shifts in the directly measured OHC/DC motion emerge due to the internal OHC/DC motion destructively interfering with BM motion. [ABSTRACT FROM AUTHOR]

It can be observed from aminoglycoside-induced hair cell damage that the cochlea basal turn is more susceptible to trauma than the apex. Drug-induced hearing loss is closely related to oxidative damage. The basilar membrane directly exposed to these ototoxic drugs exhibits differences in damage, indicating that there is an inherent difference in the sensitivity to oxidative damage from the apex to the base of the cochlea. It has been reported that the morphology and characteristics of the cochlea vary from the apex to the base. Therefore, we investigated oxidative stress-related gene expression profiles in the apical, middle, and basal turns of the cochlea. The Oxidative Stress RT2 Profiler™ PCR Array revealed that three of the 84 genes (Mb, Mpo, and Ncf1) were upregulated in the middle turn compared to their level in the apical turn. Moreover, eight genes (Mb, Duox1, Ncf1, Ngb, Fmo2, Gpx3, Mpo, and Gstk1) were upregulated in the basal turn compared to their level in the apical turn. The qPCR verification data were similar to that of the PCR Array. We found that MPO was expressed in the rat cochlea and protected against gentamicin-induced hair cell death. This study summarized the data for the gradient of expression of oxidative stress-related genes in the cochlea and found potential candidate targets for prevention of ototoxic deafness, which may provide new insights for cochlear pathology. • We assessed changes in gene expression levels in different cochlear turns • Three genes were found to be upregulated in the middle turn of the cochlea • Eight genes were found to be upregulated in the basal turn of the cochlea • We explained the expression pattern of MPO in rat cochlea • We found that inhibition of MPO protected hair cells damage induced by gentamicin [ABSTRACT FROM AUTHOR]

Nonlinear responses to acoustic signals arise through active processes in the cochlea, which has an exquisite sensitivity and wide dynamic range that can be explained by critical nonlinear oscillations of outer hair cells. Here we ask how the interaction of critical nonlinearities with the basilar membrane and other organ of Corti components could determine tuning properties of the mammalian cochlea. We propose a canonical oscillator model that captures the dynamics of the interaction between the basilar membrane and organ of Corti, using a pair of coupled oscillators for each place along the cochlea. We analyze two models in which a linear oscillator, representing basilar membrane dynamics, is coupled to a nonlinear oscillator poised at a Hopf instability. The coupling in the first model is unidirectional, and that of the second is bidirectional. Parameters are determined by fitting 496 auditory-nerve (AN) tuning curves of macaque monkeys. We find that the unidirectionally and bidirectionally coupled models account equally well for threshold tuning. In addition, however, the bidirectionally coupled model exhibits low-amplitude, spontaneous oscillation in the absence of stimulation, predicting that phase locking will occur before a significant increase in firing frequency, in accordance with well known empirical observations. This leads us to a canonical oscillator cochlear model based on the fundamental principles of critical nonlinear oscillation and coupling dynamics. The model is more biologically realistic than widely used linear or nonlinear filter-based models, yet parsimoniously displays key features of nonlinear mechanistic models. It is efficient enough for computational studies of auditory perception and auditory physiology. • A canonical model of cochlear resonance and nonlinearities successfully recreates threshold auditory-nerve tuning curves. • The canonical model provides insight into the nature of auditory responses at many levels of description. • Canonical model links principles of nonlinear dynamics with perception and neurophysiology of pitch, music, and speech. • Analysis of model predicts spontaneous oscillation and gives exact solutions for tuning curves. • MATLAB implementation allows for inclusion in other models of perception and physiology as well as further validation. [ABSTRACT FROM AUTHOR]

Mechanical displacements of the basilar membrane (BM) and the electrophysiological responses of the auditory outer hair cells (OHCs) are key components of the frequency tuning and cochlear amplification in the mammalian cochlea. In the work presented here, we measured the responses of (1) the extracellular voltage generated by OHCs (V OHC) and (2) displacements within the organ of Corti complex (OCC) to a multi-tone stimulus, and to single tones. Using optical coherence tomography (OCT), we were able to measure displacements of different layers in the OCC simultaneously, in the base of the gerbil cochlea. We explored the effect of the two types of sound stimuli to the nonlinear behavior of voltage and displacement in two frequency regions: a frequency region below the BM nonlinearity (sub-BF region: f < ∼0.7 BF), and in the best frequency (BF) region. In the sub-BF region, BM motion (X BM) had linear growth for both stimulus types, and the motion in the OHC region (X OHC) was mildly nonlinear for single tones, and relatively strongly nonlinear for multi-tones. Sub-BF, the nonlinear character of V OHC was similar to that of X OHC. In the BF region X BM , V OHC and X OHC all possessed the now-classic nonlinearity of the BF peak. Coupling these observations with previous findings on phasing between OHC force and traveling wave motions, we propose the following framework for cochlear nonlinearity: The BF-region nonlinearity is an amplifying nonlinearity, in which OHC forces input power into the traveling wave, allowing it to travel further apical to the region where it peaks. The sub-BF nonlinearity is a non-amplifying nonlinearity; it represents OHC electromotility, and saturates due to OHC current saturation, but the OHC forces do not possess the proper phasing to feed power into the traveling wave. • Sub-BF, the OHC extracellular voltage is mildly/strongly nonlinear in response to single/multi-tones. • Sub-BF, the nonlinearity of the OHC region displacement is similar to that of the OHC extracellular voltage. • A phase shift in OHC extracellular voltage relative to displacement leads to cochlear amplification in the BF peak. [ABSTRACT FROM AUTHOR]

Abstract Transient-evoked otoacoustic emissions (TEOAEs) at high frequencies are a non-invasive physiological test of basilar membrane mechanics at the basal end, and have clinical potential to detect risk of hearing loss related to outer-hair-cell dysfunction. Using stimuli with constant incident pressure across frequency, TEOAEs were measured in experiment 1 at low frequencies (0.7–8 kHz) and high frequencies (7.1–14.7 kHz) in adults with normal hearing up to 8 kHz and varying hearing levels from 9 to 16 kHz. In combination with click stimuli, chirp stimuli were used with slow, medium and fast sweep rates for which the local frequency increased or decreased with time. Chirp TEOAEs were transformed into equivalent click TEOAEs by inverse filtering out chirp stimulus phase, and analyzed similarly to click TEOAEs. To improve detection above 8 kHz, TEOAEs were measured in experiment 2 with higher-level stimuli and longer averaging times. These changes increased the TEOAE signal-to-noise ratio (SNR) by 10 dB. Slower sweep rates were investigated but the elicited TEOAEs were detected in fewer ears compared to faster rates. Data were acquired in adults and children (age 11–17 y), including children with cystic fibrosis (CF) treated with ototoxic antibiotics. Test-retest measurements revealed satisfactory repeatability of high-frequency TEOAE SNR (median of 1.3 dB) and coherence synchrony measure, despite small test-retest differences related to changes in forward and reverse transmission in the ear canal. The results suggest the potential use of such tests to screen for sensorineural hearing loss, including ototoxic loss. Experiment 2 was a feasibility study to explore TEOAE test parameters that might be used in a full-scale study to screen CF patients for risk of ototoxic hearing loss. Highlights • Transient-evoked otoacoustic emissions non-invasively assess outer hair cell function upto 14.7 kHz. • First report of TEOAE measurements in children above 8 kHz. • Chirp stimuli elicit TEOAEs at higher sound exposure levels than possible with click stimuli. • Subset of clinically useful TEOAE measures do not require reflectance calibration for satisfactory repeatability. • High-frequency TEOAEs show promise to detect ototoxic hearing loss in children and adults. [ABSTRACT FROM AUTHOR]

The cochlea contains macrophages. These cells participate in inflammatory responses to cochlear pathogenesis. However, it is not clear how and when these cells populate the cochlea during postnatal development. The current study aims to determine the postnatal development of cochlear macrophages with the focus on macrophage development in the organ of Corti and the basilar membrane. Cochleae were collected from C57BL/6J mice at ages of postnatal day (P) 1 to P21, as well as from mature mice (1–4 months). Macrophages were identified based on their expression of F4/80 and Iba1, as well as their unique morphologies. Two sets of macrophages were identified in the regions of the organ of Corti and the basilar membrane. One set resides on the scala tympani side of the basilar membrane. These cells have a round shape at P1 and start to undergo site-specific differentiation at P4. Apical macrophages adopt a dendritic shape. Middle and basal macrophages take on an irregular shape with short projections. Basal macrophages further differentiate into an amoeboid shape. The other set of macrophages resides above the basilar membrane, either beneath the cells of the organ of Corti or along the spiral vessel of the basilar membrane. As the sensory epithelium matures, these cells undergo developmental death with the phenotypes of apoptosis. Macrophages are also identified in the spiral ligament, spiral limbus, and neural regions. Their numbers decrease during postnatal development. Together, these results suggest a dynamic rearrangement of the macrophage population during postnatal cochlear development. [ABSTRACT FROM AUTHOR]

Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure. [ABSTRACT FROM AUTHOR]

Hearing performance in cochlear implant (CI) users is variable. An objective measure which can allow a prediction of this performance is desirable. Spread of neural excitation (SoE) curves are an objective measure that can be obtained using the fitting software of cochlear implants and might be able to be used as a predictor. A novel method to interpret SoE curves is presented. Spread of excitation measurements for three recording sites were fitted using two exponential functions. An asymmetric width measure was developed, defined as the distance in mm to the point, where 25% or 50% of peak normalized amplitude was reached, for each half of the SoE separately. Also, a novel population of subjects with MED-EL CIs is used. Furthermore, speech perception (speech reception threshold, SRT) was evaluated using a matrix sentence test in a multi-source noise field. SoE width was narrowest for the basal recording site and widest for the apical recording site. Fitted SoE exponential functions were most asymmetric for the apical recording site. A significant positive correlation between sentence test SRT and SoE width at the apical recording site was found. The use of an asymmetric width measure correlated strongly and positively with speech perception for apical recording sites, unlike the symmetric width measure used in previous studies. Presumably, longer electrodes allow stimulation of a more apical part of the cochlear. At the apical part of the cochlea, dendrites from a large region of the basilar membrane map to a narrow portion on the spiral ganglion, which might explain the observed asymmetry. For subjects implanted with long electrode arrays, an asymmetric width measure correlates positively with apical SoE distance. However, due to lack of a sufficient amount of data, the results are currently less conclusive and need to be consolidated in a larger cohort of subjects. [Display omitted] • Exponential functions are a good match for spread of excitation (SoE) curves. • SoE measurements in long electrodes are highly asymmetric. • SoE width correlates with multi-noise sound field SRT for apical recording regions. [ABSTRACT FROM AUTHOR]

The stapes is held in the oval window by the stapedial annular ligament (SAL), which restricts total peak-to-peak displacement of the stapes. Previous studies have suggested that for moderate (<130 dB SPL) sound levels intracochlear pressure (P IC ), measured at the base of the cochlea far from the basilar membrane, increases directly proportionally with stapes displacement (D Stap ), thus a current model of impulse noise exposure (the Auditory Hazard Assessment Algorithm for Humans, or AHAAH) predicts that peak P IC will vary linearly with D Stap up to some saturation point. However, no direct tests of D Stap , or of the relationship with P IC during such motion, have been performed during acoustic stimulation of the human ear. In order to examine the relationship between D Stap and P IC to very high level sounds, measurements of D Stap and P IC were made in cadaveric human temporal bones. Specimens were prepared by mastoidectomy and extended facial recess to expose the ossicular chain. Measurements of P IC were made in scala vestibuli (P SV ) and scala tympani (P ST ), along with the SPL in the external auditory canal (P EAC ), concurrently with laser Doppler vibrometry (LDV) measurements of stapes velocity (V Stap ). Stimuli were moderate (∼100 dB SPL) to very high level (up to ∼170 dB SPL), low frequency tones (20–2560 Hz). Both D Stap and P SV increased proportionally with sound pressure level in the ear canal up to approximately ∼150 dB SPL, above which both D Stap and P SV showed a distinct deviation from proportionality with P EAC . Both D Stap and P SV approached saturation: D Stap at a value exceeding 150 μm, which is substantially higher than has been reported for small mammals, while P SV showed substantial frequency dependence in the saturation point. The relationship between P SV and D Stap remained constant, and cochlear input impedance did not vary across the levels tested, consistent with prior measurements at lower sound levels. These results suggest that P SV sound pressure holds constant relationship with D Stap , described by the cochlear input impedance, at these, but perhaps not higher, stimulation levels. Additionally, these results indicate that the AHAAH model, which was developed using results from small animals, underestimates the sound pressure levels in the cochlea in response to high level sound stimulation, and must be revised. [ABSTRACT FROM AUTHOR]

The frequency selectivity of a gerbil cochlea, unlike other mammals, does not depend on varying thickness and width of its basilar membrane from the basal to the apical end. We model the gerbil arched basilar membrane focusing on the radial tension, embedded fiber thickness, and the membrane arch, which replace the functionality of the variation in thickness and width. The model is verified with the previous gerbil cochlea model which estimated the equivalent basilar membrane thickness and is shown to be more accurate than the flat sandwiched basilar membrane model. The simple sinusoidal-shaped bending mode assumption in previous models is found to be valid in the present model with < 12 % error. Parametric study on the present model shows that fiber thickness contribution to the membrane stiffness is close to the 3 r d order, higher than the 1 s t order estimation of previous models. We found that the effective Young's modulus of the fiber bundle is at least 6 orders higher than the shear modulus of the soft-cells and the membrane radial bending stiffness is more sensitive to the membrane arch and the shear modulus of the soft-cells near the apical end. [ABSTRACT FROM AUTHOR]

Cochlear implant insertion should be as least traumatic as possible in order to reduce trauma to the cochlear sensory structures. The force applied to the cochlea during array insertion should be controlled to limit insertion-related damage. The relationship between insertion force and histological traumatism remains to be demonstrated. Twelve freshly frozen cadaveric temporal bones were implanted with a long straight electrodes array through an anterior extended round window insertion using a motorized insertion tool with real-time measurement of the insertion force. Anatomical parameters, measured on a pre-implantation cone beam CT scan, position of the array and force metrics were correlated with post-implantation scanning electron microscopy images and histological damage assessment. An atraumatic insertion occurred in six cochleae, a translocation in five cochleae and a basilar membrane rupture in one cochlea. The translocation always occurred in the 150- to 180-degree region. In the case of traumatic insertion, different force profiles were observed with a more irregular curve arising from the presence of an early peak force (30 ± 18.2 mN). This corresponded approximately to the first point of contact of the array with the lateral wall of the cochlea. Atraumatic and traumatic insertions had significantly different force values at the same depth of insertion (p < 0.001, two-way ANOVA), and significantly different regression lines (y = 1.34x + 0.7 for atraumatic and y = 3.37x + 0.84 for traumatic insertion, p < 0.001, ANCOVA). In the present study, the insertion force was correlated with the intracochlear trauma. The 150- to 180-degree region represented the area at risk for scalar translocation for this straight electrodes array. Insertion force curves with different sets of values were identified for traumatic and atraumatic insertions; these values should be considered during motorized insertion of an implant so as to be able to modify the insertion parameters (e.g axis of insertion) and facilitate preservation of endocochlear structures. [ABSTRACT FROM AUTHOR]

From our permanent collection of plastic-embedded flat preparations of chinchilla cochleae, 22 controls and 199 ears from noise-exposed animals were used to determine when, postexposure, hair cell (HC) and supporting cell (SC) degeneration were completed. The exposed ears were divided into four groups based on exposure parameters: 0.5- or 4-kHz octave band of noise at moderate (M) or high (H) intensities. Postexposure survival ranged from <1 h to 2.5 y. Ears fixed ≤ 0–12 h postexposure were called 'acute'. For 'chronic' ears, postexposure survival was ≥7 d for groups 0.5M and 4M, ≥ 1 mo for the 4H group and ≥7 mo for the 0.5H group. The time course of inner-ear degeneration after noise exposure was determined from data in the 0.5H and 4H groups because these groups contained ears with intermediate survival times. Outer hair cells (OHCs) began dying during the exposure. OHC loss slowed down beyond 1 mo but was still present. Conversely, much inner hair cell loss was delayed until 1–3 wk postexposure. Outer pillar and inner pillar losses were present at a low level in acute ears but increased exponentially thereafter. These results are the first to demonstrate quantitatively that hair cells (HCs) and supporting cells (SCs) may continue to degenerate for months postexposure. With short postexposure survivals, the remaining SCs often had pathological changes, including: buckled pillar bodies, shifted Deiters' cell (DC) nuclei, detachment of DCs from the basilar membrane and/or splitting of the reticular lamina. These pathological changes appeared to allow endolymph and perilymph to intermix in the fluid spaces of the organ of Corti, damaging additional HCs, SCs and nerve fibers. This mechanism may account for some postexposure degeneration. In ears exposed to moderate noise, some of these SC changes appeared to be reversible. In ears exposed to high-level noise, these changes appeared to indicate impending degeneration. [ABSTRACT FROM AUTHOR]

In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status. [ABSTRACT FROM AUTHOR]

• A 3D FE model was used to clarify the relationship between a promontory velocity and a BC hearing threshold. • The promontory velocity is not enough to show a whole head motion due to a rotational motion. • The promontory velocity is not proportional to one's hearing ability in BC hearing. • The intracochlear pressure can represent one's hearing ability in BC hearing. A whole head or temporal bone has been used in experiments to understand the mechanism of bone conduction (BC) hearing. In these experiments, two assumptions are generally accepted: (1) a promontory can be a representative point to show the motion of a specimen in BC hearing, and (2) the promontory velocity is proportional to a cochlear response so that the higher the promontory velocity, the better the BC hearing. To confirm the two assumptions, we investigated the velocities of various points corresponding to different BC input types and directions in the head. In this investigation, we used the three-dimensional finite element model of a human head, including an auditory periphery. Results showed that a single promontory was insufficient to be a representative point to show the motion of a specimen because the specimen could have rotational motion at frequencies below 0.5 kHz and the localized deformation at frequencies above 3 kHz. The promontory velocity had the same pattern as the basilar membrane velocity at low and high frequencies. However, at mid-frequencies between 0.5 and 3 kHz, the promontory did not exhibit the same pattern of velocity as the basilar membrane. Therefore, one's BC hearing ability must be carefully determined on the basis of promontory velocity. [ABSTRACT FROM AUTHOR]

• After cochlear implantation via cochleostomy, intracochlear fibrosis and neoossification appear at anatomical locations that could impact normal inner ear mechanics. • The round window is completely covered by fibro-osseous tissue in 85% of cases. • The cochlear aqueduct is obstructed in 100% of cases. • The basal end of the basilar membrane is abutted by the electrode or fibro-osseous tissue in all cases. • The apical region of the basilar membrane, tuned for frequencies < 500 Hz, appears normal in 89% of cases. Hearing preservation may be achieved initially in the majority of patients after cochlear implantation, however, a significant proportion of these patients experience delayed hearing loss months or years later. A prior histological report in a case of delayed hearing loss suggested a potential cochlear mechanical origin of this hearing loss due to tissue fibrosis, and older case series highlight the frequent findings of post-implantation fibrosis and neoosteogenesis though without a focus on the impact on residual hearing. Here we present the largest series (N = 20) of 3-dimensionally reconstructed cochleae based on digitally scanned histologic sections from patients who were implanted during their lifetime. All patients were implanted with multichannel electrodes via a cochleostomy or an extended round window insertion. A quantified analysis of intracochlear tissue formation was carried out via virtual re-sectioning orthogonal to the cochlear spiral. Intracochlear tissue formation was present in every case. On average 33% (SD 14%) of the total cochlear volume was occupied by new tissue formation, consisting of 26% (SD 12%) fibrous and 7% (SD 6%) bony tissue. The round window was completely covered by fibro-osseous tissue in 85% of cases and was associated with an obstruction of the cochlear aqueduct in 100%. The basal part of the basilar membrane was at least partially abutted by the electrode or new tissue formation in every case, while the apical region, corresponding with a characteristic frequency of < 500 Hz, appeared normal in 89%. This quantitative analysis shows that after cochlear implantation via extended round window or cochleostomy, intracochlear fibrosis and neoossification are present in all cases at anatomical locations that could impact normal inner ear mechanics. [ABSTRACT FROM AUTHOR]

This study describes a method based on temporal suppression of click-evoked otoacoustic emissions (CEOAEs) to estimate the time course and duration of human basilar membrane impulse responses (BM IRs). This was achieved by tracing the suppression of dominant peaks in the CEOAE spectrum as a function of the temporal separation between two equal-level stimulus clicks. The relationship between the suppression pattern and underlying BM IR duration near the generation site of the CEOAE frequency was established using model simulations. To relate BM IR duration estimates to cochlear filter tuning ( Q ERB ), a tuning ratio was derived from available BM IR measurements in animals. Results for 11 normal-hearing subjects yielded BM IR duration estimates of 37.4/ F ms at 65 dB peSPL and 36.4/ F ms at 71 dB peSPL, with F in kHz. Corresponding Q ERB estimates were 14.2 F [in kHz] 0.22 at 65 dB peSPL and 13.8 F [in kHz] 0.22 at 71 dB peSPL. Because the proposed temporal suppression method relies on cochlear nonlinearity, the method is applicable for stimulus levels above 30–40 dB SPL and complements existing OAE methods to assess human cochlear filter tuning. [ABSTRACT FROM AUTHOR]

The current impulse noise criteria for the protection against impulse noise injury do not incorporate an objective measure of hearing protection. A new biomechanically-based model has been developed based on improvement of the Auditory Hazard Assessment Algorithm for the Human (AHAAH) using the integrated cochlear energy (ICE) as the damage risk correlate (DRC). The model parameters have been corrected using the latest literature data. The anomalous dose–response inversion behavior of the AHAAH model was eliminated. The modeling results show that the annular ligament (AL) parameters are the dominant cause of the non-monotonic dose–response behavior of AHAAH. Based on parametric optimization analysis, a 40% reduction of the AL compliance from the AHAAH default value removed the dose–response inversion problem, and this value was found to be within the physiological range when compared with experimental data. The transfer functions from the new model are in good agreement with those of the human ear. A dose–response curve based on ICE was developed using the human walk-up temporary threshold shift (TTS) data. Furthermore, the ICE values calculated for the German rifle noise tests show excellent comparison with the injury outcomes, hence providing a significant independent validation of the improved model. The ICE was found to be the best DRC to both large weapons and small arms noise injury data, covering both protected and unprotected exposures, respectively. The new AHAAH model with ICE as the dose metric is adequate for use as a medical standard against impulse noise injury. [ABSTRACT FROM AUTHOR]

• A method for the localisation of cochlear implant electrodes from in vivo cone-beam computed tomography. • Segmentation of electrode contacts and intra-cochlear structures such as the modiolar wall, basilar membrane and Rosenthal's canal. • Validated in temporal bones using high-resolution synchrotron phase-contrast imaging. • The electrode-to-modiolus measurement shows mean error of approximately 0.11 mm. Positioning of the cochlear implant (CI) electrode in relation to the anatomical structures is a key factor for the hearing outcome and the preservation of residual hearing after cochlear implantation. Determining the exact electrode's location is therefore expected to play an important role in optimisation of the electrode design, the surgical techniques and the post-operative device fitting. The aim of this study is the development and validation of a robust and efficient computerised algorithm for three-dimensional (3D) localisation of the CI-electrode contacts with respect to the relevant cochlear structures, such as the basilar membrane and the modiolus, from modern clinical in vivo cone-beam computed tomography (CBCT). In the presented algorithm, the pre- and post-implantation CBCT are spatially aligned. To localise the anatomical structures, a cochlear microanatomical template derived from lab-based X-ray computed microtomography (µCT) measurements is warped to match the patient-specific cochlear shape acquired from pre-implantation CBCT. The electrode-contact locations, determined from the post-operative CBCT, are superimposed onto the cochlear fine-structure of the microanatomical template to localise the array. The accuracy of this method was validated in a temporal bone study by comparing the distance of the electrode contacts from the modiolar wall, as derived by the algorithm from CBCTs, with the distance determined from synchrotron-radiation (SR) µCT on the same specimens. Due to the achievable spatial resolution, good tissue contrast and limited presence of metallic artifacts, the SRµCT technique is considered to be a golden standard in the proposed approach. In contrast to other approaches, this validation method allowed for the evaluation of the final electrode-to-modiolus distance (EMD) error, and covers the error in co-alignment of the images, in the determination of the electrode contact location and in the localisation of the cochlear structures. The absolute mean error on the EMD parameter was determined at 0.11 mm (max = 0.29 mm, SD = 0.07 mm) across five samples, slightly lower than the voxel size of the CBCT-scans. In a retrospective study, the algorithm was applied to identify scalar translocations of the electrode from clinical in vivo CBCT datasets of 23 CI-recipients, which showed perfect (100%) agreement with the blinded opinion of two experienced neuroradiologists. [ABSTRACT FROM AUTHOR]

• A comprehensive finite-element human ear model can be used to quantitatively analyze the impact of noise-induced hearing loss. • Three-dimensional distribution of auditory risk units of the basilar membrane from frequency 0.2 to 10.0 kHz was demonstrated. • There is consistency between numerical simulation results and clinical data associated with occupational noise exposure. Noise is a common occupational and environmental hazard; however, little is known about the use of computational tools to quantitively analyze data on basilar membrane (BM) damage in noise-induced hearing loss (NIHL). Here, we established a comprehensive three-dimensional finite-element human ear model to quantify the impact of noise exposure on BM and perilymph fluid. We used auditory risk units (ARUs) to evaluate the BM damage for subjects (3 men and 5 women; mean age, 32.75 ± 8.86 years; age range, 24–44 years). A 90-dB sound pressure level (SPL) was normally applied at the external auditory canal (EAC) entrance to simulate sound transmission from the EAC to the cochlea at frequencies of 0.2–10.0 kHz. The pressure distribution of perilymph fluid is totally different on frequency responses under low and high sound-evoked (0.013–10.0 kHz). The highest ARUs were 18.479% at the distance of 1 mm from the base, and the second-highest to fourth-highest ARUs occurred at distances of 5–7 mm from the base, where their ARUs were 9.749%, 9.176%, and 11.231%. The total of the ARUs reached 81.956% at external frequencies' sounds of 3.2–5.0 kHz. Among these, the 3.8-kHz and 3.6-kHz frequencies yielded the highest and second-highest ARUs of 20.325% and 19.873%, respectively. This study would inform our understanding of NIHL associated with occupational noise exposure. We present a FE modelling and describe how it might provide a unique way to unravel mechanisms that drive NIHL due to loud noises. [ABSTRACT FROM AUTHOR]

Five different pathways are often suggested as important for bone conducted (BC) sound: (1) sound pressure in the ear canal, (2) inertia of the middle ear ossicles, (3) inertia of the inner ear fluid, (4) compression of the inner ear space, and (5) pressure transmission from the skull interior. The relative importance of these pathways was investigated with an acoustic-impedance model of the inner ear. The model incorporated data of BC generated ear canal sound pressure, middle ear ossicle motion, cochlear promontory vibration, and intracranial sound pressure. With BC stimulation at the mastoid, the inner ear inertia dominated the excitation of the cochlea but inner ear compression and middle ear inertia were within 10 dB for almost the entire frequency range of 0.1–10 kHz. Ear canal sound pressure gave little contribution at the low and high frequencies, but was around 15 dB below the total contribution at the mid frequencies. Intracranial sound pressure gave responses similar to the others at low frequencies, but decreased with frequency to a level of 55 dB below the total contribution at 10 kHz. When the BC inner ear model was evaluated against AC stimulation at threshold levels, the results were close up to approximately 4 kHz but deviated significantly at higher frequencies. [ABSTRACT FROM AUTHOR]

The present study investigated to what extent properties of local cochlear dispersion can be objectively assessed through auditory steady-state responses (ASSR). The hypothesis was that stimuli compensating for the phase response at a particular cochlear location generate a maximally modulated basilar membrane (BM) response at that BM position, due to the large “within-channel” synchrony of activity. This would lead, in turn, to a larger ASSR amplitude than other stimuli of corresponding intensity and bandwidth. Two stimulus types were chosen: 1] Harmonic tone complexes consisting of equal-amplitude tones with a starting phase following an algorithm developed by Schroeder [IEEE Trans. Inf. Theory 16, 85–89 (1970)] that have earlier been considered in behavioral studies to estimate human auditory filter phase responses; and 2] simulations of auditory-filter impulse responses (IR). In both cases, also the temporally reversed versions of the stimuli were considered. The ASSRs obtained with the Schroeder tone complexes were found to be dominated by “across-channel” synchrony and, thus, do not reflect local place-specific information. In the case of the more frequency-specific stimuli, no significant differences were found between the responses to the IR and its temporally reversed counterpart. Thus, whereas ASSRs to narrowband stimuli have been used as an objective indicator of frequency-specific hearing sensitivity, the method does not seem to be sensitive enough to reflect local cochlear dispersion. [ABSTRACT FROM AUTHOR]

• Aging outer hair cells (OHCs) show progressively lower Prestin levels that contribute to surface area reduction but maintain Prestin's density. • Voltage sensitivity of Prestin becomes less responsive to holding potential change manifested in reduced pre-pulse effect in aged OHCs. • Aged inner hair cells (IHCs) and OHCs both have reduced cell sizes, while elongated first row stereocilia only observed in aged IHCs but not in aged OHCs. • DPOAE group delays are prolonged in aged ear. • Acoustic lesions demarcate a shifted boundary and broader damage transition in aging cochleae, suggest a less effective frequency filter. Outer hair cells (OHC) are key to the mammalian cochlear amplifier, powered by the lateral membrane protein Prestin. In this study, we explored age-related OHC changes and how the changes affected hearing in mouse. OHC nonlinear membrane capacitance measurements revealed that, starting upon completion of postnatal auditory development, a continuous reduction of total Prestin in OHCs accompanied by a significant reduction in their cell surface area. Prestin's density is unaffected by Prestin level drop over the whole age range tested, suggesting that the OHC size reduction is Prestin-dependent. Stereocilia length in aged OHCs remained unchanged but the first row stereocilia on the aged inner hair cells (IHCs) were elongated. Distortion product otoacoustic emission (DPOAE) group delays became longer with aging, suggesting an apical shift in vibration on basilar membrane. Acoustic lesion experiments revealed an apical shift in damage place in old cochleae accompanied by a shallower progression in synaptic damage over a wider frequency range that was indicative of a broader frequency filter. Overall, these findings suggest that in aging cochlea, a shift in frequency place coding could occur due to the changes in cochlear active and passive mechanics. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam. [ABSTRACT FROM AUTHOR]

• Electrically evoked reticular lamina vibration in vivo includes a fast broadband component and a delayed sharply tuned component • Reticular lamina and basilar membrane vibrate in opposite directions at low frequencies and approximately in-phase at the best frequency • Reticular lamina vibration is physiologically vulnerable not only at the best frequency but also at low frequencies and high sound levels It is a common belief that the mammalian cochlea achieves its exquisite sensitivity, frequency selectivity, and dynamic range through an outer hair cell-based active process, or cochlear amplification. As a sound-induced traveling wave propagates from the cochlear base toward the apex, outer hair cells at a narrow region amplify the low level sound-induced vibration through a local feedback mechanism. This widely accepted theory has been tested by measuring sound-induced sub-nanometer vibrations within the organ of Corti in the sensitive living cochleae using heterodyne low-coherence interferometry and optical coherence tomography. The aim of this short review is to summarize experimental findings on the cochlear active process by the authors' group. Our data show that outer hair cells are able to generate substantial forces for driving the cochlear partition at all audible frequencies in vivo. The acoustically induced reticular lamina vibration is larger and more broadly tuned than the basilar membrane vibration. The reticular lamina and basilar membrane vibrate approximately in opposite directions at low frequencies and in the same direction at the best frequency. The group delay of the reticular lamina is larger than that of the basilar membrane. The magnitude and phase differences between the reticular lamina and basilar membrane vibration are physiologically vulnerable. These results contradict predictions based on the local feedback mechanism but suggest a global hydromechanical mechanism for cochlear amplification. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam. [ABSTRACT FROM AUTHOR]

• Soft high-frequency (HF) tones evoke an ∼1-μV AC receptor in basal OHCs; consequently, any mechanical amplification of HF tones would make them less audible. • A high K+ conductance in OHC does not boost HF receptor potentials. • OHC receptor currents display a substantial rectified (DC) component; sounds evoke large mechanical DC shifts in the organ of Corti, and these large baselineshifts occur both in the apex and the base of the cochlea. • Traveling waves can transport high-frequency energy of soft tones with minimal loss, but loud tones, if transported losslessly, would cause destructive displacement. • We propose that OHC motility serves to regulate local dissipation. In the cochlea, mechano-electrical transduction is preceded by dynamic range compression. Outer hair cells (OHCs) and their voltage dependent length changes, known as electromotility, play a central role in this compression process, but the exact mechanisms are poorly understood. Here we review old and new experimental findings and show that (1) just audible high-frequency tones evoke an ∼1-microvolt AC receptor potential in basal OHCs; (2) any mechanical amplification of soft high-frequency tones by OHC motility would have an adverse effect on their audibility; (3) having a higher basolateral K+ conductance, while increasing the OHC corner frequency, does not boost the magnitude of the high-frequency AC receptor potential; (4) OHC receptor currents display a substantial rectified (DC) component; (5) mechanical DC responses (baseline shifts) to acoustic stimuli, while insignificant on the basilar membrane, can be comparable in magnitude to AC responses when recorded in the organ of Corti, both in the apex and the base. In the basal turn, the DC component may even exceed the AC component, lending support to Dallos' suggestion that both apical and basal OHCs display a significant degree of rectification. We further show that (6) low-intensity cochlear traveling waves, by virtue of their abrupt transition from fast to slow propagation, are well suited to transport high-frequency energy with minimal losses (∼2-dB loss for 16-kHz tones in the gerbil); (7) a 90-dB, 16-kHz tone, if transmitted without loss to its tonotopic place, would evoke a destructive displacement amplitude of 564 nm. We interpret these findings in a framework in which local dissipation is regulated by OHC motility. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam. [ABSTRACT FROM AUTHOR]

• Both cubic and quadratic distortion can be detected on the reticular lamina. • While cubic distortion appears to decline with increasing frequency ratio, quadratic distortion is more wideband. • Low frequency reticular lamina mechanical properties may form the basis of an envelope extraction component of auditory processing. Cochlear distortions afford researchers and clinicians a glimpse into the conditions and properties of inner ear signal processing mechanisms. Until recently, our examination of these distortions has been limited to measuring the vibration of the basilar membrane or recording acoustic distortion output in the ear canal. Despite its importance, the generation mechanism of cochlear distortion remains a substantial task to understand. The ability to measure the vibration of the reticular lamina in rodent models is a recent experimental advance. Surprising mechanical properties have been revealed. These properties merit both discussion in context with our current understanding of distortion, and appraisal of the significance of new interpretations of cochlear mechanics. This review focusses on some of the recent data from our research groups and discusses the implications of these data on our understanding of vocalization processing in the periphery, and their influence upon future experimental directions. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam [ABSTRACT FROM AUTHOR]

• Salicylate applied to the cochlea caused temporary reductions in cochlear responses • Basilar membrane responses became approximately passive following salicylate • Organ of Corti responses retained wide-band nonlinearity following salicylate • Patterns of vibration shifted laterally and were relatively diffuse following salicylate • Following salicylate, responses recovered nearly completely over ∼ 3 hours Intra organ of Corti (OC) vibrations differ from those measured at the basilar membrane (BM), with higher amplitudes and a wide-band nonlinearity extending well below a region's best frequency. The vibrations are boosted by the cochlear amplifier, the active processes within the mammalian hearing organ, and are thus sensitive to metabolic or pharmacological manipulation. We introduced salicylate, a known blocker of outer hair cell (OHC) based electromotility, into the perilymphatic space by applying sodium salicylate onto the round window membrane. Vibration patterns of an area of the OC were mapped with phase sensitive optical coherence tomography before and after treatment; distortion product otoacoustic emissions (DPOAEs) were measured at similar times to assess the cochlear condition. Following treatment, all regions showed a loss of vibration amplitude and tuning while OHC-region vibrations retained their wide-band nonlinearity. OC vibrations, which had been relatively confined in a region including OHCs and extending to the BM at the outer pillar foot, became less confined with structures lateral to the OHCs sometimes exhibiting the highest amplitudes. Vibrations and DPOAEs could recover to baseline levels over approximately three hours post treatment. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam [ABSTRACT FROM AUTHOR]

• A 3D FE model of human head was developed to investigate BC hearing mechanism. • The head model included an auditory periphery composed of ME and cochlea. • BM velocities were calculated corresponding to BC stimulation on a head surface. • Intracochlear pressure at multi positions along the BM length was calculated. • Stimulation levels at hearing threshold for AC and BC were calculated. A three-dimensional finite-element (FE) model of a human head including the auditory periphery was developed to obtain a better understanding of bone-conducted (BC) hearing. The model was validated by comparison of cochlear and head responses in both air-conducted (AC) and BC hearing with experimental data. Specifically, the FE model provided the cochlear responses such as basilar membrane velocity and intracochlear pressure corresponding to BC stimulations applied to the mastoid or the conventional bone-anchored-hearing-aid (BAHA) positions. This is a strength of the model because it is difficult to obtain the cochlear responses from experiments corresponding to the BC stimulation applied at a specific position on the head surface. In addition, there have been few studies based on an FE model that can calculate the head and cochlear responses simultaneously from a BC stimulation. Moreover, in this study, the intracochlear sound pressure at multi-positions along the BM length was calculated and used to clarify the effect of stimulating force direction on the cochlear and promontory velocities in BC hearing. Also, the relationship between BC and AC stimulation and the basilar membrane velocity in the FE model was used to calculate the stimulation level at hearing thresholds which has been investigated only by psychoacoustical methods. [ABSTRACT FROM AUTHOR]

The immune response is an important component of the cochlear response to stress. As an important player in the cochlear immune system, the basilar membrane immune cells reside on the surface of the scala tympani side of the basilar membrane. At present, the immune cell properties in this region and their responses to stress are not well understood. Here, we investigated the functional role of these immune cells in the immune response to acoustic overstimulation. This study reveals that tissue macrophages are present in the entire length of the basilar membrane under steady-state conditions. Notably, these cells in the apical and the basal sections of the basilar membrane display distinct morphologies and immune protein expression patterns. Following acoustic trauma, monocytes infiltrate into the region of the basilar membrane, and the infiltrated cells transform into macrophages. While monocyte infiltration and transformation occur in both the apical and the basal sections of the basilar membrane, only the basal monocytes and macrophages display a marked increase in the expression of major histocompatibility complex (MHC) II and class II transactivator (CIITA), a MHC II production cofactor, suggesting the site-dependent activation of antigen-presenting function. Consistent with the increased expression of the antigen-presenting proteins, CD4 + T cells, the antigen-presenting partner, infiltrate into the region of the basilar membrane where antigen-presenting proteins are upregulated. Further pathological analyses revealed that the basal section of the cochlea displays a greater level of sensory cell damage, which is spatially correlated with the region of antigen-presenting activity. Together, these results suggest that the antigen-presenting function of the mononuclear phagocyte population is activated in response to acoustic trauma, which could bridge the innate immune response to adaptive immunity. [ABSTRACT FROM AUTHOR]

The basilar membrane velocity of gerbil cochlea showed discrepancy between theoretical model and experimental measurements. We hypothesize that the reasons of such discrepancies are due to the arch towards the scala tympani and radial tension present in the basilar membrane of the gerbil cochlea. The arch changes the bending stiffness in the basilar membrane, reduces the effective fluid force on the membrane and increases the basilar membrane's inertia. The existence of the radial tension also dampens the acoustic travelling wave. In this paper, the wave number functions along the gerbil basilar membrane are calculated from experimentally measured physical parameters with the theoretical model as well as extracted from experimentally measured basilar membrane velocity with the wave number inversion formula. The two wave number functions are compared and the effects of the tension and membrane arch on the wave number are studied based on various parameters of the model. We found that the bending stiffness across the gerbil basilar membrane varies (1–2 orders along the cochlea in the section 2.2 mm–3 mm from base) more than the calculated value in the flat basilar membrane model and the radial tension increases the damping of the travelling wave in gerbil cochlea significantly (5 times more than that without radial tension). These effects of arch and radial tension in the basilar membrane elucidate the discrepancy between previous theoretical model and experimental measurements in gerbil cochlea. [ABSTRACT FROM AUTHOR]

Previous investigations have shown that components of a tone burst-evoked otoacoustic emission (TBOAE) evoked by a 1 kHz tone burst (TB 1 ) can be suppressed by the simultaneous presence of a 2 kHz tone burst (TB 2 ) or a pair of tone bursts at 2 and 3 kHz (TB 2 and TB 3 respectively). No previous study has measured this “simultaneous suppression of TBOAEs” for both TB 2 alone and TB 2 and TB 3 from the same ears, so that the effect of the additional presence of TB 3 on suppression caused by TB 2 is not known. In simple terms, three outcomes are possible; suppression increases, suppression is reduced or suppression is not affected. Comparison of previously reported simultaneous suppression data suggests TB 3 causes a reduction in suppression, though it is not clear if this is a genuine effect or simply reflects methodological and ear differences between studies. This issue has implications for previously proposed mechanisms of simultaneous suppression of TBOAEs and the interpretation of clinical data, and is clarified by the present study. Simultaneous suppression of TBOAEs was measured for TB 1 and TB 2 as well as TB 1 , TB 2 and TB 3 at 50, 60 and 70 dB p.e. SPL from nine normal human ears. Results showed no significant difference between mean suppression obtained for the two and three-tone burst combinations, indicating the reduction of suppression inferred from comparison of previous data is likely a result of methodological and ear differences rather than a genuine effect. [ABSTRACT FROM AUTHOR]

Several multipolar current focussing strategies are examined in a computational model of the implanted human cochlea. The model includes a realistic spatial distribution of cell bodies of the auditory neurons throughout Rosenthal's canal. Simulations are performed of monopolar, (partial) tripolar and phased array stimulation. Excitation patterns, estimated thresholds, electrical dynamic range, excitation density and neural recruitment curves are determined and compared. The main findings are: (I) Current focussing requires electrical field interaction to induce spatially restricted excitation patterns. For perimodiolar electrodes the distance to the neurons is too small to have sufficient electrical field interaction, which results in neural excitation near non-centre contacts. (II) Current focussing only produces spatially restricted excitation patterns when there is little or no excitation occurring in the peripheral processes, either because of geometrical factors or due to neural degeneration. (III) The model predicts that neural recruitment with electrical stimulation is a three-dimensional process; regions of excitation not only expand in apical and basal directions, but also by penetrating deeper into the spiral ganglion. (IV) At equal loudness certain differences between the spatial excitation patterns of various multipoles cannot be simulated in a model containing linearly aligned neurons of identical morphology. Introducing a form of variability in the neurons, such as the spatial distribution of cell bodies in the spiral ganglion used in this study, is therefore essential in the modelling of spread of excitation. This article is part of a Special Issue entitled . [ABSTRACT FROM AUTHOR]

Tone burst-evoked otoacoustic emission (TBOAE) components measured in response to a 1 kHz tone burst (TB 1 ) are suppressed by the simultaneous presence of an additional tone burst (TB 2 ). This “simultaneous suppression of TBOAEs” has been explained in terms of a mechanism based on local nonlinear interactions between the basilar membrane (BM) travelling waves caused by TB 1 and TB 2 . A test of this local nonlinear interaction (LNI)-based mechanism, as a function of the frequency separation (Δ f , expressed in kHz) between TB 1 and TB 2 , has previously been reported by Killan et al. (2012) using a simple mathematical model [Killan et al., Hear. Res. 285, 58–64 (2012)]. The two experiments described in this paper add additional data on the extent to which the LNI-based mechanism can account for simultaneous suppression, by testing two further hypotheses derived from the model predictions. Experiment I tested the hypothesis that TBOAE suppression is directly linked to TBOAE amplitude nonlinearity where ears that exhibit a higher degree of amplitude nonlinearity yield greater suppression than more linear ears, and this relationship varies systematically as a function of Δ f . In order to test this hypothesis simultaneous suppression at a range of values of Δ f at 60 dB peak-equivalent sound pressure level (p.e. SPL) and TBOAE amplitude nonlinearity from normal human ears was measured. In Experiment II the hypothesis that suppression will also increase progressively as a function of increasing tone burst level was tested by measuring suppression for a range of Δ f and tone burst levels at 40, 50, 60 and 70 dB p.e. SPL. The majority of the findings from both experiments provide support for the LNI-based mechanism being primarily responsible for simultaneous suppression. However, some data were inconsistent with this view. Specifically, a breakdown in the relationship between suppression and TBOAE amplitude nonlinearity at Δ f = 1 (i.e. when TB 2 was reasonably well separated from, and had a higher frequency than TB 1 ) and unexpected level-dependence, most notably at Δ f = 1, but also where Δ f = −0.5, was observed. Either the LNI model is too simple or an alternative explanation, involving response components generated at basal regions of the basilar membrane, is required to account for these findings. [ABSTRACT FROM AUTHOR]

• The inner ear has intrinsic immune regulatory mechanisms involving resident macrophages. • Systemic immunity provides inner ear surveillance through its lymphatic drainage to cervical lymph nodes. • The inner ear is rapidly infiltrated by circulating immune cells in response to pathogens, foreign antigens and acoustic trauma. • The endolymphatic sac participates in immune activity; the specific actions are not yet defined. The inner ear, like all organs, interacts with the systemic immune system via lymphatic drainage and vascular circulation to protect itself from infections and stress such as acoustic trauma. The adult mammalian inner ear including the endolymphatic sac is populated with bone-marrow derived resident macrophages. Circulating macrophages continually renew the resident macrophage population. Cells within the endolymphatic sac participate in and affect inner ear immune responses, but specific mechanisms for the interactions are unknown. Resident macrophages are present within the cochlear modiolus, spiral ligament, stria vascularis, on the scala tympani surface of the basilar membrane and in the vestibular ganglia and connective tissue of the vestibular sensory epithelia. In general, the mammalian organ of Corti, on the other hand, does not contain resident macrophages. Although repair of the epithelium following hair cell death is performed by adjacent supporting cells, macrophages in the osseous spiral lamina have been seen to extend processes into the organ of Corti below the inner hair cells where they may assist in reducing synaptopathy. Systemic and middle ear bacterial infections, experimentally simulated by lipopolysaccharide (LPS) injections, cause circulating inflammatory cells to enter the inner ear from venules in the spiral ligament and modiolus. Presumably, this is a surveillance mechanism, and in the absence of cochlear infection, no action is taken, but if noise trauma or ototoxic drug exposure occurs simultaneously, a more aggressive immune response is mounted. Acoustic trauma alone induces influx of circulating immune cells. Vigorous immune responses to pathogens within the cochlea result in fibrotic tissue and osteoid formation within the fluid-filled inner ear spaces. Many of the signals for recruiting and activating immune cells have been identified, but little is known about exactly what the activated cells do, how they interact with resident macrophages and what signals terminate their activity. [ABSTRACT FROM AUTHOR]

The cochlear microphonic (CM) is an electrical signal generated inside the cochlea in response to sound. This electrical signal reflects mechanical activity in the cochlea and the excitation processes involved in its generation. However, the difficulty of obtaining this signal and the simplicity of obtaining other signals such as otoacoustic emissions have discouraged the use of the cochlear microphonic as a tool for studying cochlear functions. In this article, a model of the cochlea is presented which integrates both mechanical and electrical aspects, enabling the interaction between them to be investigated. The resulting model is then used to observe the effect of the cochlear amplifier on the CM. The results indicate that while the cochlear amplifier significantly amplifies the basilar membrane displacement, the effect on the CM is less significant. Both of these outcomes are consistent with previous physiological findings. Moreover, the close match between mechanical and electrical predictions of the model and experimental measurements validates the model, and suggests that further investigations using the model into various pathologies and anomalies are warranted. [ABSTRACT FROM AUTHOR]

Abstract: The effect of different stapes prostheses on the basilar membrane (BM) motion was determined. To that end, a three dimensional finite element (FE) model of the passive human cochlea was developed. Passive responses of the BM were found based on coupled fluid–structure interactions between the cochlear solid structures and the scala fluids. The passive BM vibrations in normal (healthy) cochlea were compared with vibrations in the cochlea in which a 0.4-mm piston or a proposed new type of prosthesis was implanted. The proposed chamber prosthesis was not experimentally implanted, but only numerically simulated. Design of the new chamber stapes prosthesis is presented for the first time in this paper. The simulation results showed 10–20 dB decrease in BM displacement amplitude in the case of the piston. In contrast, the BM responses in the cochlea with the new prosthesis are higher with respect to the healthy ear. The results obtained in this study are promising for further research to optimize the design of the new chamber stapes prosthesis. [Copyright &y& Elsevier]

We describe a method to use point-stiffness (PtSt) measurements, i.e., indentation measurements, to obtain elastic moduli of different organ of Corti (OC) tissues. A detailed finite element (FE) model of the OC is used to account for geometric effects in the indentation measurements. We also present a sensitivity analysis, performed within a Bayesian estimation framework, that can be used to improve experimental design. The sensitivity analysis shows that the basilar membrane (BM) PtSt is most sensitive to changes in the BM properties and to changes in the pillar cells (PC) properties. This result suggests that the BM and the PC dominate the macromechanics of the OC. The most likely values of the Young's modulus predicted for the middle turn for the BM arcuate, BM pectinate, and the PC are found to be 935 KPa (range 640-1360 KPa), 300 KPa (range 190-460 KPa), and 3 GPa (range 1-9 GPa), respec tively. [ABSTRACT FROM AUTHOR]

Narrow band CE-chirps® were developed to provide a better synchronization of neural response due to the compensation of the traveling wave delay in the basilar membrane. These stimuli combined with a detection method that includes higher response harmonics on the auditory steady-state response (ASSR) recording was studied in this research. Objective: (1) To establish air conduction thresholds for ASSR to narrow band CE-chirp® in normal hearing full-term neonates; (2) describe the test time needed for the above in one ear and (3) to compare the results in infants and normally hearing adults. Method: ASSR to air-conducted stimuli were obtained in 30 full-term neonates (14 girls and 16 boys) with an average age of 34.3h of life. All neonates were presented presence of transient-evoked otoacoustic emissions (TEOAE) and result “pass” in automatic ABR at 35dB nHL before ASSR test. ASSR thresholds of both ears of 10 normal hearing adults (5 girls and 5 boys) varied in age between 23 and 30 years and with hearing thresholds better than or equal to 15dB HL at all frequencies between 250 and 8000Hz were recorded to compare with the neonate data. Results: The neonate ASSR thresholds estimated from 50% using cumulative distributions were 24.5, 13.5, 7.5 and 10dB nHL at 500, 1000, 2000, and 4000Hz, respectively. For the same frequency order, ASSR thresholds estimated from 90% of the neonates were 34.5, 28, 12.5 and 15dB nHL. It required 21.2 (±5)min on average to obtain threshold in each ear in neonates, with a range of 12–29min. When ASSR thresholds recorded in full-term neonates and adults were directly compared, the differences between these groups were not significant for 1000Hz (p =0.500), 2000Hz (p =0.610) and 4000Hz (p =0.362). However, at 500Hz, ASSR thresholds in neonates tend to be greater than in adults (p =0.001). Conclusion: In this study ASSR thresholds estimated from 90% of the neonates were 34.5, 28, 12.5 and 15dB nHL. It required 21.2 (±5)min on average to obtain threshold in each ear and ASSR thresholds to narrow band CE-chirp® in neonates are not significant for adults ASSR thresholds, except at 500Hz, when the ASSR thresholds in neonates tend to be greater than in adults. [ABSTRACT FROM AUTHOR]

Highlights: [•] Contralateral noise variably suppresses stimulus-frequency otoacoustic emissions. [•] Tuning estimates based on otoacoustic delays are unchanged by contralateral noise. [•] The amount of contralateral suppression does not affect tuning estimates. [ABSTRACT FROM AUTHOR]

Summary: Bone conduction hearing inevitably involves vibration of the basilar membrane in response to a pressure gradient on either side of the membrane. The propagated wave that symbolizes this vibration of the basilar membrane can be triggered intentionally, when a bone vibrator is placed on the mastoid bone, or inadvertently when testing hearing of one ear by air conduction while disregarding transmission of the sound to the other side. When hearing is tested with a bone vibrator, the pathways leading to the basilar membrane can be divided into two main categories. The first type of pathway short-circuits the middle ear and comprises three distinct mechanisms: cochlear fluid inertia, compression of the cochlear walls, and pressure changes exerted via cerebrospinal fluid. In the second type of pathway, the stimulus reaches the basilar membrane via the middle ear, either directly or via the outer ear. Although it is difficult to precisely determine the contribution of each of these pathways to the basilar membrane, bone conduction remains the clinically most reliable way of directly testing cochlear function. [Copyright &y& Elsevier]

Abstract: In a previous study (Stenfelt and Håkansson, 2002) a loudness balance test between bone conducted (BC) sound and air conducted (AC) sound was performed at frequencies between 0.25 and 4 kHz and at levels corresponding to 30–80 dB HL. The main outcome of that study was that for maintaining equal loudness, the level increase of sound with BC stimulation was less than that of AC stimulation with a ratio between 0.8 and 0.93 dB/dB. However, because it was shown that AC and BC tone cancellation was independent of the stimulation level, the loudness level difference did not originate in differences in basilar membrane stimulation. Therefore, it was speculated that the result could be due to the loudness estimation procedure. To investigate this further, another loudness estimation method (adaptive categorical loudness scaling) was here employed in 20 normal-hearing subjects. The loudness of a low-frequency and a high-frequency noise burst was estimated using the adaptive categorical loudness scaling technique when the stimulation was bilaterally by AC or BC. The sounds where rated on an 11-point scale between inaudible and too loud. The total dynamic range for these sounds was over 80 dB when presented by AC (between inaudible and too loud) and the loudness functions were similar for the low and the high-frequency stimulation. When the stimulation was by BC the loudness functions were steeper and the ratios between the slopes of the AC and BC loudness functions were 0.88 for the low-frequency sound and 0.92 for the high-frequency sound. These results were almost equal to the previous published results using the equal loudness estimation procedure, and it was unlikely that the outcome stems from the loudness estimation procedure itself. One possible mechanism for the result was loudness integration of multi-sensory input. However, no conclusive evidence for such a mechanism could be given by the present study. This article is part of a Special Issue entitled “MEMRO 2012”. [Copyright &y& Elsevier]

Abstract: The effects of a superior-semicircular-canal (SSC) dehiscence (SSCD) on hearing sensitivity via the air-conduction (AC) and bone-conduction (BC) pathways were investigated using a three-dimensional finite-element (FE) model of a human middle ear coupled to the inner ear. Dehiscences were modeled by removing a section of the outer bony wall of the SSC and applying a zero-pressure condition to the fluid surface thus exposed. At each frequency, the basilar-membrane velocity, v BM, was separately calculated for AC and BC stimulation, under both pre- and post-dehiscence conditions. Hearing loss was calculated as the difference in the maximum magnitudes of v BM between the pre- and post-dehiscence conditions representing a change in hearing threshold. In this study, BC excitations were simulated by applying rigid-body vibrations to the model along the directions of the (arbitrarily defined) x, y, and z axes of the model. Simulation results are consistent with previous clinical measurements on patients with an SSCD and with results from earlier lumped-element electrical-circuit modeling studies, with the dehiscence decreasing the hearing threshold (i.e., increasing v BM) by about 35 dB for BC excitation at low frequencies, while for AC excitation the dehiscence increases the hearing threshold (i.e., decreases v BM) by about 15 dB. A new finding from this study is that the initial width (defined as the width of the edge of the dehiscence where the flow of the fluid-motion wave from the oval window meets it for the first time) on the vestibular side of the dehiscence has more of an effect on v BM than the area of the dehiscence. Analyses of dehiscence effects using the FE model further predict that changing the direction of the BC excitation should have an effect on v BM, with v BM being about 20 dB lower due to BC excitation parallel to the longitudinal direction of the BM in the hook region (the x direction) as compared to excitations in other directions (y and z). BC excitation in the x direction and with a ‘center’ dehiscence located midway along the length of the SSC causes a reduction in the anti-symmetric component of the fluid pressure across the BM, as compared to the other directions of BC excitation, which results in a decrease in v BM at high frequencies. This article is part of a Special Issue entitled “MEMRO 2012”. [Copyright &y& Elsevier]

Abstract: We have developed a high-frequency pulsed-wave Doppler ultrasound probe as a promising minimally-invasive technique for measuring intracochlear mechanics without damaging the cochlea. Using a custom high-frequency ultrasound system, we have measured dynamic motion of intracochlear structures by recording the pulsed-wave Doppler signal resulting from the vibration of the basilar and round window membranes. A 45 MHz needle-mounted Doppler probe was fabricated and placed against the round window membranes of eight different fresh human temporal bones. Pulsed-wave ultrasonic Doppler measurements were performed on the basilar membrane and round window membrane during the application of pure tones to the external ear canal. Doppler vibrational information for acoustic input frequencies ranging from 100–2000 Hz was collected and normalized to the sound pressure in the ear canal. The middle ear resonance, located at approximately 1000 Hz, could be characterized from the membrane velocities, which agreed well with literature values. The maximum normalized mean velocity of the round window and the basilar membrane were 180 μm/s/Pa and 27 μm/s/Pa at 800 Hz. The mean phase difference between the membrane displacements and the applied ear canal sound pressure showed a flat response almost up to 500 Hz where it began to accumulate. This is the first study that reports the application of high frequency pulsed wave Doppler ultrasound for measuring the vibration of basilar membrane through the round window. Since it is not required to open or damage the cochlea, this technique might be applicable for investigating cochlear dynamics, in vivo. [Copyright &y& Elsevier]

Abstract: This paper reviews the contributions of von Békésy to psychoacoustics, comparing his findings and interpretations to those that have emerged since his work. The areas covered include the perception of pitch for pure tones and complex tones, the effect of frequency on the apparent location of pure tones, estimation of the velocity of the traveling wave on the basilar membrane using judgments of lateralization, and the relative loudness of monaural and diotic sounds. While subsequent research has failed to replicate some of his findings, other findings have stood the test of time. There is no doubt that von Békésy made very substantial contributions to psychoacoustic research. [Copyright &y& Elsevier]

Abstract: Georg von Békésy was one of the first comparative auditory researchers. He not only studied basilar membrane (BM) movements in a range of mammals of widely different sizes, he also worked on the chicken basilar papilla and the frog middle ear. We show that, in mammals, at least, his data do not differ from those that could be collected using modern techniques but with the same, very loud sounds. There is in all cases a major difference to frequency maps collected using low-level sounds. In contrast, the same cannot be said of his chicken data, perhaps due to the different roles played by the BM in mammals and birds. In lizards, the BM is not tuned and it is perhaps good that Békésy did not begin with those species and get discouraged in his seminal comparative work. [Copyright &y& Elsevier]

Abstract: In the fifty years since Békésy was awarded the Nobel Prize, cochlear physiology has blossomed. Many topics that are now current are things Békésy could not have imagined. In this review we start by describing progress in understanding the origin of cochlear gross potentials, particularly the cochlear microphonic, an area in which Békésy had extensive experience. We then review progress in areas of cochlear physiology that were mostly unknown to Békésy, including: (1) stereocilia mechano-electrical transduction, force production, and response amplification, (2) outer hair cell (OHC) somatic motility and its molecular basis in prestin, (3) cochlear amplification and related micromechanics, including the evidence that prestin is the main motor for cochlear amplification, (4) the influence of the tectorial membrane, (5) cochlear micromechanics and the mechanical drives to inner hair cell stereocilia, (6) otoacoustic emissions, and (7) olivocochlear efferents and their influence on cochlear physiology. We then return to a subject that Békésy knew well: cochlear fluids and standing currents, as well as our present understanding of energy dependence on the lateral wall of the cochlea. Finally, we touch on cochlear pathologies including noise damage and aging, with an emphasis on where the field might go in the future. [Copyright &y& Elsevier]

Abstract: Recent studies indicate that the gap over outer hair cells (OHCs) between the reticular lamina (RL) and the tectorial membrane (TM) varies cyclically during low-frequency sounds. Variation in the RL-TM gap produces radial fluid flow in the gap that can drive inner hair cell (IHC) stereocilia. Analysis of RL-TM gap changes reveals three IHC drives in addition to classic SHEAR. For upward basilar-membrane (BM) motion, IHC stereocilia are deflected in the excitatory direction by SHEAR and OHC-MOTILITY, but in the inhibitory direction by TM-PUSH and CILIA-SLANT. Upward BM motion causes OHC somatic contraction which tilts the RL, compresses the RL-TM gap over IHCs and expands the RL-TM gap over OHCs, thereby producing an outward (away from the IHCs) radial fluid flow which is the OHC-MOTILITY drive. For upward BM motion, the force that moves the TM upward also compresses the RL-TM gap over OHCs causing inward radial flow past IHCs which is the TM-PUSH drive. Motions that produce large tilting of OHC stereocilia squeeze the supra-OHC RL-TM gap and caused inward radial flow past IHCs which is the CILIA-SLANT drive. Combinations of these drives explain: (1) the reversal at high sound levels of auditory nerve (AN) initial peak (ANIP) responses to clicks, and medial olivocochlear (MOC) inhibition of ANIP responses below, but not above, the ANIP reversal, (2) dips and phase reversals in AN responses to tones in cats and chinchillas, (3) hypersensitivity and phase reversals in tuning-curve tails after OHC ablation, and (4) MOC inhibition of tail-frequency AN responses. The OHC-MOTILITY drive provides another mechanism, in addition to BM motion amplification, that uses active processes to enhance the output of the cochlea. The ability of these IHC drives to explain previously anomalous data provides strong, although indirect, evidence that these drives are significant and presents a new view of how the cochlea works at frequencies below 3 kHz. [Copyright &y& Elsevier]