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Exposure to noise trauma, such as that from improvised explosive devices, can lead to sensorineural hearing loss and a reduced quality of life. In order to elucidate the mechanisms underlying noise-induced hearing loss, we have adapted optical coherence tomography (OCT) for real-time cochlear visualization in live mice after blast exposure. We demonstrated that endolymphatic hydrops develops following blast injury, and that this phenomenon may be associated with glutamate excitotoxicity and cochlear synaptopathy. Additionally, osmotic stabilization of endolymphatic hydrops partially rescues cochlear synapses after blast trauma. OCT is thus a valuable research tool for investigating the mechanisms underlying acoustic trauma and dynamic changes in endolymph volume. It may also help with the diagnosis and treatment of human hearing loss and/or vertigo in the near future.

Hearing consists of a delicate chain of events. Sound is first captured by an eardrum or similar organ which is set into vibrations, these vibrations must then be transmitted to sensory cells in a manner that opens mechanosensory channels generating an electrical signal. Studying this process is challenging. Auditory vibrations are in the nano- to picometer-scale and occur at fast temporal scales of milli to microseconds. Finally, most of this process occurs within the body of the animal where it is inaccessible to conventional measurement techniques. For instance, even in crickets, a century-old auditory model system, it is unclear how sound evoked vibrations are transmitted to sensory neurons. Here, we use optical coherence tomography (OCT) to measure how vibrations travel within the auditory organ of the western tree cricket (Oecanthus californicus). We also measure the reversal of this process as mechanosensory cells generate spontaneous oscillations and amplify sound-evoked vibrations. Most importantly, we found that while the mechanosensory neurons were not attached to the peripheral sound collecting structures, they were mechanically well-coupled through acoustic trachea. Thus, the acoustic trachea are not merely conduits for sound but also perform a mechanical function. Our results generate several insights into the similarities between insect and vertebrate hearing, and into the evolutionary history of auditory amplification.

Pigmented villonodular synovitis (PVNS) is a diffuse type tenosynovial giant cell tumor, which are benign but locally aggressive tumors presenting in joint, tendon sheath, and bursa synovium. This tumor most commonly occurs in the knee; it is rare in the head and neck region, where it most commonly arises in the temporomandibular joint (TMJ). We describe a case of PVNS occurring in the TMJ with extension into the external auditory canal and middle cranial fossa. The imaging characteristics, differential diagnosis, and treatment of PVNS is discussed.

After acoustic trauma, there can be loss of synaptic connections between inner hair cells and auditory neurons in the cochlea, which may lead to hearing abnormalities including speech-in-noise difficulties, tinnitus, and hyperacusis. We have previously studied mice with blast-induced cochlear synaptopathy and found that they also developed a build-up of endolymph, termed endolymphatic hydrops. In this study, we used optical coherence tomography to measure endolymph volume in live CBA/CaJ mice exposed to various noise intensities. We quantified the number of synaptic ribbons and postsynaptic densities under the inner hair cells 1 week after noise exposure to determine if they correlated with acute changes in endolymph volume measured in the hours after the noise exposure. After 2 h of noise at an intensity of 95 dB SPL or below, both endolymph volume and synaptic counts remained normal. After exposure to 2 h of 100 dB SPL noise, mice developed endolymphatic hydrops and had reduced synaptic counts in the basal and middle regions of the cochlea. Furthermore, round-window application of hypertonic saline reduced the degree of endolymphatic hydrops that developed after 100 dB SPL noise exposure and partially prevented the reduction in synaptic counts in the cochlear base. Taken together, these results indicate that endolymphatic hydrops correlates with noise-induced cochlear synaptopathy, suggesting that these two pathologic findings have a common mechanistic basis.

Mammalian hearing depends on an amplification process involving prestin, a voltage-sensitive motor protein that enables cochlear outer hair cells (OHCs) to change length and generate force. However, it has been questioned whether this prestin-based somatic electromotility can operate fast enough in vivo to amplify cochlear vibrations at the high frequencies that mammals hear. In this study, we measured sound-evoked vibrations from within the living mouse cochlea and found that the top and bottom of the OHCs move in opposite directions at frequencies exceeding 20 kHz, consistent with fast somatic length changes. These motions are physiologically vulnerable, depend on prestin, and dominate the cochlea's vibratory response to high-frequency sound. This dominance was observed despite mechanisms that clearly low-pass filter the in vivo electromotile response. Low-pass filtering therefore does not critically limit the OHC's ability to move the organ of Corti on a cycle-by-cycle basis. Our data argue that electromotility serves as the primary high-frequency amplifying mechanism within the mammalian cochlea.

Sensory hair cells, the mechanoreceptors of the auditory and vestibular systems, harbor two specialized elaborations of the apical surface, the hair bundle and the cuticular plate. In contrast to the extensively studied mechanosensory hair bundle, the cuticular plate is not as well understood. It is believed to provide a rigid foundation for stereocilia motion, but specifics about its function, especially the significance of its integrity for long-term maintenance of hair cell mechanotransduction, are not known. We discovered that a hair cell protein called LIM only protein 7 (LMO7) is specifically localized in the cuticular plate and the cell junction. Lmo7 KO mice suffer multiple cuticular plate deficiencies, including reduced filamentous actin density and abnormal stereociliar rootlets. In addition to the cuticular plate defects, older Lmo7 KO mice develop abnormalities in inner hair cell stereocilia. Together, these defects affect cochlear tuning and sensitivity and give rise to late-onset progressive hearing loss., In contrast to the extensively studied mechanosensory hair bundle, the cuticular plate is not as well understood. In this study, authors describe the discovery of a hair cell protein called LIM only protein 7, which is localized in the cuticular plate and the cell junction and may play a role in age-related deafness.

In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct. We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition. Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters' cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants. Vibratory responses to sound were measured in cochleae from live mice, revealing defects in the propagation and amplification of the traveling wave in Gas2 mutants. We propose that the microtubule bundling activity of GAS2 imparts supporting cells with mechanical properties for transmitting sound energy through the cochlea.

Mammalian hearing sensitivity and frequency selectivity depend on a mechanical amplification process mediated by outer hair cells (OHCs). OHCs are situated within the organ of Corti atop the basilar membrane (BM), which supports sound-evoked traveling waves. It is well established that OHCs generate force to selectively amplify BM traveling waves where they peak, and that amplification accumulates from one location to the next over this narrow cochlear region. However, recent measurements demonstrate that traveling waves along the apical surface of the organ of Corti, the reticular lamina (RL), are amplified over a much broader region. Whether OHC forces accumulate along the length of the RL traveling wave to provide a form of “global” cochlear amplification is unclear. Here we examined the spatial accumulation of RL amplification. In mice of either sex, we used tones to suppress amplification from different cochlear regions and examined the effect on RL vibrations near and far from the traveling-wave peak. We found that although OHC forces amplify the entire RL traveling wave, amplification only accumulates near the peak, over the same region where BM motion is amplified. This contradicts the notion that RL motion is involved in a global amplification mechanism and reveals that the mechanical properties of the BM and organ of Corti tune how OHC forces accumulate spatially. Restricting the spatial buildup of amplification enhances frequency selectivity by sharpening the peaks of cochlear traveling waves and constrains the number of OHCs responsible for mechanical sensitivity at each location.SIGNIFICANCE STATEMENTOuter hair cells generate force to amplify traveling waves within the mammalian cochlea. This force generation is critical to the ability to detect and discriminate sounds. Nevertheless, how these forces couple to the motions of the surrounding structures and integrate along the cochlear length remains poorly understood. Here we demonstrate that outer hair cell-generated forces amplify traveling-wave motion on the organ of Corti throughout the wave's extent, but that these forces only accumulate longitudinally over a region near the wave's peak. The longitudinal coupling of outer hair cell-generated forces is therefore spatially tuned, likely by the mechanical properties of the basilar membrane and organ of Corti. Our findings provide new insight into the mechanical processes that underlie sensitive hearing.

One of the tenets of mammalian auditory physiology is that the frequency selectivity at the cochlear base decreases as a function of stimulus level. Changes in frequency selectivity have been shown to be accompanied by changes in response phases as a function of stimulus level. The existence of such nonlinear properties has been revealed by the analysis of either direct or indirect recordings of mechanical vibrations of the cochlea. Direct measurements of cochlear mechanical vibrations, however, have been carried out with success primarily in cochlear regions that are tuned to frequencies >7 kHz, but not in regions sensitive to lower frequencies. In this paper we continue to analyze recently published data from measurements of sound-induced vibrations at four locations near the apex of the intact guinea pig cochlea, in a region encompassing approximately 25% of its total length. Analysis of the responses at all locations reveal level-dependent phase properties that are rather different from those usually reported at the base of the cochlea of laboratory animals such as the chinchilla. Cochlear group delays, for example, increase or remain constant with increasing stimulus. Similarly, frequency selectivity at all the regions increases as a function of stimulus level.

There is indirect evidence that the mammalian cochlea in the low-frequency apical and the more commonly studied high-frequency basal regions function in fundamentally different ways. Here, we directly tested this hypothesis by measuring sound-induced vibrations of the organ of Corti (OoC) at three turns of the gerbil cochlea using volumetric optical coherence tomography vibrometry (VOCTV), an approach that permits noninvasive imaging through the bone. In the apical turn, there was little frequency selectivity, and the displacement-vs.-frequency curves had low-pass filter characteristics with a corner frequency of ~0.5–0.9 kHz. The vibratory magnitudes increased compressively with increasing stimulus intensity at all frequencies. In the middle turn, responses were similar except for a slight peak in the response at ~2.5 kHz. The gain was ~50 dB at the peak and 30–40 dB at lower frequencies. In the basal turn, responses were sharply tuned and compressively nonlinear, consistent with observations in the literature. These data demonstrated that there is a transition of the mechanical response of the OoC along the length of the cochlea such that frequency tuning is sharper in the base than in the apex. Because the responses are fundamentally different, it is not appropriate to simply frequency shift vibratory data measured at one cochlear location to predict the cochlear responses at other locations. Furthermore, this means that the number of hair cells stimulated by sound is larger for low-frequency stimuli and smaller for high-frequency stimuli for the same intensity level. Thus the mechanisms of central processing of sounds must vary with frequency. NEW & NOTEWORTHY A volumetric optical coherence tomography and vibrometry system was used to probe cochlear mechanics within the intact gerbil cochlea. We found a gradual transition of the mechanical response of the organ of Corti along the length of the cochlea such that tuning at the base is dramatically sharper than that at the apex. These data help to explain discrepancies in the literature regarding how the cochlea processes low-frequency sounds.

SUMMARY The stereociliary bundles of cochlear hair cells convert mechanical vibrations into the electrical signals required for auditory sensation. While the stiffness of the bundles strongly influences mechanotransduction, its influence on the vibratory response of the cochlear partition is unclear. To assess this, we measured cochlear vibrations in mutant mice with reduced bundle stiffness or with a tectorial membrane (TM) that is detached from the sensory epithelium. We found that reducing bundle stiffness decreased the high-frequency extent and sharpened the tuning of vibratory responses obtained postmortem. Detaching the TM further reduced the high-frequency extent of the vibrations but also lowered the partition’s resonant frequency. Together, these results demonstrate that the bundle’s stiffness and attachment to the TM contribute to passive longitudinal coupling in the cochlea. We conclude that the stereociliary bundles and TM interact to facilitate passive wave propagation to more apical locations, possibly enhancing active wave amplification in vivo., In Brief The mechanical properties of the cochlear partition determine its vibratory response to sound. Dewey et al. demonstrate that the outer hair cell stereociliary bundles’ stiffness and attachment to the tectorial membrane influence the partition’s passive vibratory response. The stereociliary bundles facilitate the propagation of cochlear waves to more apical regions., Graphical Abstract

KEY POINTS A popular conception of mammalian cochlear physiology is that tuned mechanical vibration of the basilar membrane defines the frequency response of the innervating auditory nerve fibres However, the data supporting these concepts come from vibratory measurements at cochlear locations tuned to high frequencies (>7 kHz). Here, we measured the travelling wave in regions of the guinea pig cochlea that respond to low frequencies ( 7 kHz, not in regions sensitive to lower frequencies where human speech is encoded. Here, we overcame historical technical limitations and non-invasively measured sound-induced vibrations at four locations distributed over the apical two turns of the guinea pig cochlea. In turn 3, the responses demonstrated low-pass filter characteristics. In turn 2, the responses were low-pass-like, in that they occasionally did have a slight peak near the corner frequency. The corner frequencies of the responses were tonotopically tuned and ranged from 384 to 668 Hz. Non-linear gain, or amplification of the vibrations in response to low-intensity stimuli, was found both below and above the corner frequencies. Post mortem, cochlear gain disappeared. The non-linear gain was typically 10-30 dB and was broad-band rather than sharply tuned. However, the gain did reach nearly 50 dB in turn 2 for higher stimulus frequencies, nearly the amount of gain found in basal cochlear regions. Thus, our data prove that mechanical responses do not match neural responses and that cochlear amplification does not appreciably sharpen frequency tuning for cochlear regions that respond to frequencies

A principal tool for the visual inspection of the middle ear in the hearing clinic is the surgical stereo-microscope. We have developed a compact accessory for the surgical microscope that enables volumetric optical coherence tomography (OCT) imaging of the middle ear as well as functional vibratory imaging with subnanometer sensitivity. The sensitivity to vibration is achieved by careful engineering of the microscope attachment and frequency-domain processing. The microscope attachment integrates the entire OCT interferometer onto a custom aluminum base that mounts directly to the accessory area at the foot of most surgical microscopes. This approach is effective at removing high-frequency phase-noise, thus enabling near shot-noise limited sensitivity above ~2 kHz even though the OCT system is suspended above the patient by a boom arm. We analyze the vibratory response in the frequency domain, hence our ability to measure vibrations in the tympanic membrane and ossicles is near the shot-noise limit. As a demonstration of this system we have recorded in vivo volumetric images of a healthy human patient as well as the vibratory response at the tympanic membrane down to the hearing threshold. We also show that it is possible to use time averaging to drive the noise floor down below 2 pm which allowed us to make the first measure of distortion product otoacoustic emissions (DPOAE) using OCT. Finally, the system can easily be taken on and off of the surgical microscope and when in use does not impinge on the normal view through the surgical microscope.

We have developed a highly phase stable optical coherence tomography and vibrometry system that attaches directly to the accessory area of a surgical microscope common to both the otology clinic and operating room. Careful attention to minimizing sources of phase noise has enabled a system capable of measuring vibrations of the middle ear with a sensitivity of < 5 pm in an awake human patient. The system is shown to be capable of collecting a wide range of information on the morphology and function of the ear in live subjects, including frequency tuning curves below the hearing threshold, maps of tympanic membrane vibrational modes and thickness, and measures of distortion products due to the nonlinearities in the cochlear amplifier.

We describe an optical coherence tomography and vibrometry system designed for portable hand-held usage in the otology clinic on awake patients. The system provides clinically relevant point-of-care morphological imaging with 14-44 µm resolution and functional vibratory measures with sub-nanometer sensitivity. We evaluated various new approaches for extracting functional information including a multi-tone stimulus, a continuous chirp stimulus, and alternating air and bone stimulus. We also explored the vibratory response over an area of the tympanic membrane (TM) and generated TM thickness maps. Our results suggest that the system can provide real-time in vivo imaging and vibrometry of the ear and could prove useful for investigating otologic pathology in the clinic setting.

Neuroplastin (Nptn) is a member of the Ig superfamily and is expressed in two isoforms, Np55 and Np65. Np65 regulates synaptic transmission but the function of Np55 is unknown. In an N-ethyl-N-nitrosaurea mutagenesis screen, we have now generated a mouse line with an Nptn mutation that causes deafness. We show that Np55 is expressed in stereocilia of outer hair cells (OHCs) but not inner hair cells and affects interactions of stereocilia with the tectorial membrane. In vivo vibrometry demonstrates that cochlear amplification is absent in Nptn mutant mice, which is consistent with the failure of OHC stereocilia to maintain stable interactions with the tectorial membrane. Hair bundles show morphological defects as the mutant mice age and while mechanotransduction currents can be evoked in early postnatal hair cells, cochlea microphonics recordings indicate that mechanontransduction is affected as the mutant mice age. We thus conclude that differential splicing leads to functional diversification of Nptn, where Np55 is essential for OHC function, while Np65 is implicated in the regulation of synaptic function. SIGNIFICANCE STATEMENT Amplification of input sound signals, which is needed for the auditory sense organ to detect sounds over a wide intensity range, depends on mechanical coupling of outer hair cells to the tectorial membrane. The current study shows that neuroplastin, a member of the Ig superfamily, which has previously been linked to the regulation of synaptic plasticity, is critical to maintain a stable mechanical link of outer hair cells with the tectorial membrane. In vivo recordings demonstrate that neuroplastin is essential for sound amplification and that mutation in neuroplastin leads to auditory impairment in mice.

The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo . Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in TectaC1509G/C1509G mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification. SIGNIFICANCE STATEMENT Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Sensory hair cells, the mechanoreceptors of the auditory and vestibular system, harbor two specialized organelles, the hair bundle and the cuticular plate. Both subcellular structures have adapted to facilitate the remarkable sensitivity and speed of hair cell mechanotransduction. While the mechanosensory hair bundle is extensively studied, the molecules and mechanisms mediating the development and function of the cuticular plate are poorly understood. The cuticular plate is believed to provide a rigid foundation for stereociliar pivot movements, but specifics about its function, especially the significance of its integrity for long-term maintenance of hair cell mechanotransduction, are not known. In this study, we describe the discovery of a hair cell protein called LIM only protein 7 (LMO7). In the hair cell, LMO7 is specifically localized in the cuticular plate.Lmo7 KOmice suffer multiple deficiencies in the cuticular plate, including reduced filamentous actin density and abnormal length and distribution of stereociliar rootlets. In addition to the cuticular plate defects, olderLmo7 KOmice develop abnormalities in inner hair cell stereocilia. Together, these defects affect cochlear tuning and sensitivity and give rise to late-onset progressive hearing loss.

Traumatic noise causes hearing loss by damaging sensory hair cells and their auditory synapses. There are no treatments. Here, we investigated mice exposed to a blast wave approximating a roadside bomb. In vivo cochlear imaging revealed an increase in the volume of endolymph, the fluid within scala media, termed endolymphatic hydrops. Endolymphatic hydrops, hair cell loss, and cochlear synaptopathy were initiated by trauma to the mechanosensitive hair cell stereocilia and were K+-dependent. Increasing the osmolality of the adjacent perilymph treated endolymphatic hydrops and prevented synaptopathy, but did not prevent hair cell loss. Conversely, inducing endolymphatic hydrops in control mice by lowering perilymph osmolality caused cochlear synaptopathy that was glutamate-dependent, but did not cause hair cell loss. Thus, endolymphatic hydrops is a surrogate marker for synaptic bouton swelling after hair cells release excitotoxic levels of glutamate. Because osmotic stabilization prevents neural damage, it is a potential treatment to reduce hearing loss after noise exposure.

A highly-phase stable hand-held endoscopic system has been developed for optical coherence tomography and vibrometry. Designed to transit the ear canal to the middle ear space and peer through the round window, it is capable of imaging the vibratory function of the cochlear soft tissues with subnanometer scale sensitivity. A side-looking, 9 cm long rigid endoscope with a distal diameter of 1.2 mm, was able to fit within the round window niche and provide imaging access. The phase stability was achieved in part by fully integrating a Michelson interferometer into the hand-held device. Ex vivo imaging of a domestic pig demonstrated the system’s ability for functional vibratory imaging of the cochlea via the round window.

While most of human speech information is contained within frequencies < 3-4 kHz, only a few mechanical measurements have been made in cochlear regions responsive to such low frequencies. Furthermore, the data that do exist are difficult to interpret given the technical difficulties in performing the experiments and/or the artifacts that result from opening the otic capsule bone to visualize the organ of Corti. Here, we overcame historical technical limitations and non-invasively measured sound-induced vibrations within the apex of the guinea pig cochlea using volumetric optical coherence tomography vibrometry (VOCTV). We found that vibrations within apical cochlear regions, with neural tuning below 2 kHz, demonstrate low-pass filter characteristics. There was evidence of a low-level of broad-band cochlear amplification that did not sharpen frequency selectivity. We compared the vibratory responses we measured to previously-measured single-unit auditory nerve tuning curves in the same frequency range, and found that mechanical responses do not match neural responses. These data suggest that, for low frequency cochlear regions, inner hair cells not only transduce vibrations of the organ of Corti but also sharpen frequency tuning.While most of human speech information is contained within frequencies < 3-4 kHz, only a few mechanical measurements have been made in cochlear regions responsive to such low frequencies. Furthermore, the data that do exist are difficult to interpret given the technical difficulties in performing the experiments and/or the artifacts that result from opening the otic capsule bone to visualize the organ of Corti. Here, we overcame historical technical limitations and non-invasively measured sound-induced vibrations within the apex of the guinea pig cochlea using volumetric optical coherence tomography vibrometry (VOCTV). We found that vibrations within apical cochlear regions, with neural tuning below 2 kHz, demonstrate low-pass filter characteristics. There was evidence of a low-level of broad-band cochlear amplification that did not sharpen frequency selectivity. We compared the vibratory responses we measured to previously-measured single-unit auditory nerve tuning curves in the same frequency range, and...

Our understanding of cochlear amplification has been mainly informed by observations of the high-frequency basal region. Results from the few existing in vivo studies from the low-frequency apical region have suggested that cochlear amplification may be more broadly tuned and not as nonlinear as in the base. The current study explored micromechanics via sound evoked vibrations of the cochlear partition, including the organ of Corti (OoC), the basilar membrane (BM) and the tectorial membrane (TM), within the 2nd apical turn, corresponding to the 2.5 kHz best frequency region, of the gerbil cochlea using volumetric optical coherence tomography vibrometry (VOCTV), imaged non-invasively through the otic capsule bone in vivo. Sound induced radial displacements below 4 kHz showed similarities and differences to the well-established BM transverse responses at high-frequency basal region. Responses showed broader tuning, but similar gains at the best frequency and similar phase accumulation. The distinct difference found was the presence of compressive nonlinear growth with SPL below the best frequency down to 0.1 kHz observed at the outer hair cell (OHC) and reticular laminar (RL) locations but not in the BM or inner hair cell regions. These relative motions provide further insight on how OHC somatic forces are distributed within the cochlear partition.

We are developing endoscopic OCT to visualize the morphology and functional vibratory response of the human inner ear through the round window. Preliminary results show good image quality with 41±21 pm sensitivity on piezo element while hand-held.

Objectives/Hypothesis: To review the presentation and management of improper electrode array placement, and to help guide clinical decision-making. Study Design: Retrospective case series. Methods: Pediatric and adult cochlear implant patients managed from January 2001 to present whose electrode arrays were not placed properly within the cochlea or extended beyond the cochlea into the internal auditory canal or adjacent structures. Results: Four patients, three pediatric and one adult, were identified from over 824 cases (< 1%) managed over the study duration. All cases had normal cochlear anatomy. These cases were initially identified due to poor auditory skill development or absent behavioral responses following implantation, which prompted imaging. Two patients presented several years after surgery. Sites of improper placement included the eustachian tube, vestibule, internal carotid artery canal, and internal auditory canal (IAC). Intraoperative findings and management are reviewed. Conclusions: Electrode array malpositioning is a rare, but serious and correctable complication in cochlear implant surgery. A multidisciplinary approach, including prompt audiologic evaluation and imaging, is important, particularly when benefit from the implant is limited or absent. Management of electrode arrays in the IAC may be more challenging. Laryngoscope, 2013

Human hearing loss often occurs as a result of damage or malformations to the functional soft tissues within the cochlea, but these changes are not appreciable with current medical imaging modalities. We sought to determine whether optical coherence tomography (OCT) could assess the soft tissue structures relevant to hearing using mouse models. We imaged excised cochleae with an altered tectorial membrane and during normal development. The soft tissue structures and expected anatomical variations were visible using OCT, and quantitative measurements confirmed the ability to detect critical changes relevant to hearing.

A B S T R A C T Objective: To examine middle ear volume in patients with aural atresia and investigate the role of middle ear volume as an adjunct measure in determining surgical candidacy. Methods: We performed a retrospective review of children with aural atresia in a tertiary academic pediatric otolaryngology practice. High resolution multiplanar CT scans of the temporal bones were analyzed for middle ear volume and staged according to existing clinical grading scales. Atretic ears were compared to the nonatretic ears of the same patient as well as to ears of a control population. Results: The average age of patients at the time CT was performed was 4.7 years (range

The tectorial membrane (TM) connects to the stereociliary bundles of outer hair cells (OHCs). Humans with an autosomal dominant C1509G mutation in alpha-tectorin, a protein constituent of the TM, are born with a partial hearing loss that worsens over time. The Tecta(C1509/+) transgenic mouse with the same point mutation has partial hearing loss secondary to a shortened TM that only contacts the first row of OHCs. As well, Tecta(C1509G/+) mice have increased expression of the OHC electromotility protein, prestin. We sought to determine whether these changes impact OHC survival. Distortion product otoacoustic emission thresholds in a quiet environment did not change to 6 months of age. However, noise exposure produced acute threshold shifts that fully recovered in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice. While Tecta(+/+) mice lost OHCs primarily at the base and within all three rows, Tecta(C1509G/+) mice lost most of their OHCs in a more apical region of the cochlea and nearly completely within the first row. In order to estimate the impact of a shorter TM on the forces faced by the stereocilia within the first OHC row, both the wild type and the heterozygous conditions were simulated in a computational model. These analyses predicted that the shear force on the stereocilia is ~50% higher in the heterozygous condition. We then measured electrically induced movements of the reticular lamina in situ and found that while they decreased to the noise floor in prestin null mice, they were increased by 4.58 dB in Tecta(C1509G/+) mice compared to Tecta(+/+) mice. The increased movements were associated with a fourfold increase in OHC death as measured by vital dye staining. Together, these findings indicate that uncoupling the TM from some OHCs leads to partial hearing loss and places the remaining coupled OHCs at higher risk. Both the mechanics of the malformed TM and the increased prestin-related movements of the organ of Corti contribute to this higher risk profile.

The tectorial membrane (TM) is an extracellular matrix of the cochlea whose prominent role in hearing has been demonstrated through mutation studies. The C1509G mutation of the Tecta gene, which encodes for the α-tectorin protein, leads to hearing loss. The heterozygote TM only attaches to the first row of outer hair cells (OHCs), and the homozygote TM does not attach to any OHCs. Here we measured the morphology and mechanical properties of wild-type, heterozygous, and homozygous Tecta TMs. Morphological analyses conducted with second- and third-harmonic imaging, scanning electron microscopy, and immunolabeling revealed marked changes in the collagen architecture and stereocilin-labeling patterns of the mutant TMs. The mechanical properties of the mutant TM were measured by force spectroscopy. Whereas the axial Young's modulus of the low-frequency (apical) region of Tecta mutant TM samples was similar to that of wild-type TMs, it significantly decreased in the basal region to a value approaching that found at the apex. Modeling simulations suggest that a reduced TM Young's modulus is likely to reduce OHC stereociliary deflection. These findings argue that the heterozygote C1509G mutation results in a lack of attachment of the TM to the OHCs, which in turn reduces both the overall number of OHCs that are involved in mechanotransduction and the degree of mechanotransduction exhibited by the OHCs that remain attached to the TM.

Atoh1is a basic helix–loop–helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used theCre–loxPsystem and twoCre-driver lines (Egr2CreandHoxb1Cre) to deleteAtoh1from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). AdultAtoh1-conditional knock-out mice (Atoh1CKO) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition,Egr2; Atoh1CKOmice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

The measurement of mechanical vibrations within the living cochlea is critical to understanding the first nonlinear steps in auditory processing, hair cell stimulation, and cochlear amplification. However, it has proven to be a challenging endeavor. This chapter describes how optical coherence tomography (OCT) can be used to measure vibrations within the tissues of the organ of Corti. These experimental measurements can be performed within the unopened cochlea of living mice routinely and reliably.

Background Gene therapy may provide a way to restore cochlear function to deaf patients. The most successful techniques for cochlear gene therapy have been injection of early-generation adenoviral vectors into scala media in guinea pigs. However, it is important to be able to perform gene therapy research in mice because there is wide availability of transgenic strains with hereditary hearing loss. Purpose We demonstrate our technique for delivery of a third-generation adenoviral vector, helper-dependent adenovirus (HDAd), to the adult mouse cochlea. Methods Mice were injected with an HDAd that contained a reporter gene for either beta-galactosidase or green fluorescent protein into scala media. After 4 days, the cochleae were harvested for analyses. Auditory brainstem response monitoring of cochlear function was performed before making a cochleostomy, after making a cochleostomy, and before killing the animal. Results Beta-galactosidase was identified in the spiral ligament, the organ of Corti, and spiral ganglion cells by light microscopy. Green fluorescent protein epifluorescence was assessed in whole-mount organ of Corti preparations using confocal microscopy. This demonstrated transduction of inner hair cells, outer hair cells, and supporting cells. Paraffin-embedded cross sections similarly revealed gene transduction within the organ of Corti. Threshold shifts of 39.8 +/- 5.4 and 37.7 +/- 5.5 dB were observed in mice injected with HDAd or control buffer, respectively. Conclusion The technique of scala media HDAd injection reliably infects the adult mouse cochlea, including cells within the organ of Corti, although the procedure itself adversely affects hearing.

PURPOSE OF REVIEW The present review summarizes the current theories on arachnoid cyst formation, the common presentations of cysts surrounding or eroding the temporal bone from the middle and posterior cranial fossae, the diagnostic strategies and the management considerations and options. RECENT FINDINGS Arachnoid cysts are most common in the middle cranial fossa and rarely present in association with the petrous apex. They are frequently found incidentally on imaging studies performed in the workup for unrelated symptoms. When they do cause symptoms, these are usually nonspecific. Thus it is important to establish the relationship between the two. Peripetrosal arachnoid cysts may cause cranial nerve deficits in addition to symptoms related to intracranial hypertension. Small asymptomatic cysts are managed conservatively with serial imaging. Large symptomatic cysts are often managed surgically with shunting, open excision or open or neuroendoscopic fenestration or marsupialization. The management of large asymptomatic cysts depends on the patient and cyst characteristics. SUMMARY Peripetrosal arachnoid cysts are often incidental findings. Careful selection of surgical candidates is of utmost importance. Multiple surgical options with similar success rates are available. The rates and profile of their complications may differ. Overall, approximately 70% of patients experience improvement in their symptoms with surgery.

Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date.

Sensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells. We currently know little of the genetic networks which become active in supporting cells when hair cells die and that are activated in experimental models of hair cell regeneration.. Several studies have shown that neonatal mammalian cochlear supporting cells are able to trans-differentiate into hair cells when cultured in conditions in which the Notch signaling pathway is blocked. We now show that the ability of cochlear supporting cells to trans-differentiate declines precipitously after birth, such that supporting cells from six-day-old mouse cochlea are entirely unresponsive to a blockade of the Notch pathway. We show that this trend is seen regardless of whether the Notch pathway is blocked with gamma secretase inhibitors, or by antibodies against the Notch1 receptor, suggesting that the action of gamma secretase inhibitors on neonatal supporting cells is likely to be by inhibiting Notch receptor cleavage. The loss of responsiveness to inhibition of the Notch pathway in the first postnatal week is due in part to a down-regulation of Notch receptors and ligands, and we show that this down-regulation persists in the adult animal, even under conditions of noise damage. Our data suggest that the Notch pathway is used to establish the repeating pattern of hair cells and supporting cells in the organ of Corti, but is not required to maintain this cellular mosaic once the production of hair cells and supporting cells is completed. Our results have implications for the proposed used of Notch pathway inhibitors in hearing restoration therapies.

Objective Petrous apicitis and cranial base osteomyelitis are life-threatening conditions. A surgical management may be necessary in cases that progress, in conditions that fail to improve with medical treatment, or in cases with impending complications. In this study, we describe a technique to remove the maximum amount of infected temporal bone while preserving the integrity of the peripheral auditory pathway and facial nerve. Study design Retrospective study. Setting Tertiary referral hospital. Patients Five patients with impending complications, whose disease progressed or whose conditions failed to improve while on culture-directed antibiotics underwent circumferential petrosectomy. Interventions The circumferential petrosectomy removes most of the temporal bone around the external, middle, and inner ear. A combined retrolabyrinthine-apical petrosectomy is performed in conjunction with the fallopian bridge technique using a transmastoid and middle cranial fossa approach. A split temporalis muscle flap is used to bring vascularized tissue to the mastoid, jugular foramen, and petrous apex. Main outcome measures Disease resolution, change in hearing or facial nerve function, complications. Results Each of the five patients had modifications to the procedure tailored to their disease extent: three had disease primarily involving the petrous apex and two had disease adjacent to the jugular foramen. Additional cultures of the infected bone were obtained during surgery. A culture-directed antibiotic therapy (duration, 6-10 weeks) was administered after surgery, which resulted in the complete resolution of the disease and the associated symptoms in all five patients. No patient experienced hearing loss or facial nerve dysfunction as a result of the surgery within at least 1 year of follow-up in four of the five patients in this series. Conclusion The circumferential petrosectomy is a potential treatment option when medical treatment fails in patients with petrositis or cranial base osteomyelitis. It permits maximal temporal bone debridement while preserving hearing and facial nerve integrity in these life-threatening disease processes.

To define the presentation of patients with skull base chondrosarcoma, to elucidate surgical strategies, and to identify the role of postoperative radiotherapy.Retrospective review.Tertiary referral center.All patients (n = 33) with skull base chondrosarcoma managed at our institution. The average follow-up time was 7.7 years (range, 0-20 years).Tumor location, presenting symptoms, presence of residual or recurrent tumor, and mortality.The most common tumor location was the petroclival junction (n = 29). Common presenting symptoms were diplopia (48%) and headache (45%). Surgical approaches included retrosigmoid, transtemporal, transfacial, and frontotemporal craniotomies. Biopsy only was performed in four patients, subtotal resection in 19 patients, and total resection in nine patients. Most patients received postoperative radiotherapy (82%). Follow-up revealed residual, stable disease in 28% of patients and recurrent disease in 24% of patients. The mean time to recurrence was 3.0 +/- 2.8 years. The lack of postoperative radiation was significantly correlated with an increased risk of recurrence (odds ratio, 28; p = 0.007) but incomplete tumor resection was not (p = 0.6). Life-table analysis revealed that the 5-year survival rate was 85% and the 10-year survival rate was 77%. Five patients died; four of the deaths attributable to recurrent disease.The characteristic growth pattern of skull base chondrosarcoma is tumor eroding the petroclival junction. Current therapeutic strategy is resection through an extradural subtemporal craniotomy with removal of the petrous apex and clivus. Radical resection of uninvolved structures is often not necessary. Nonetheless, gross total removal is often achievable. Postoperative radiotherapy reduces the chance of tumor recurrence.

Intracochlear scarring is a well-described sequela of cochlear implantation. We developed a mathematical model of passive cochlear mechanics to predict the impact that this might have upon residual acoustical hearing after implantation. The cochlea was modeled using lumped impedance terms for scala vestibuli (SV), scala tympani (ST), and the cochlear partition (CP). The damping of ST and CP was increased in the basal one half of the cochlea to simulate the effect of scar tissue. We found that increasing the damping of the ST predominantly reduced basilar membrane vibrations in the apex of the cochlea while increasing the damping of the CP predominantly reduced basilar membrane vibrations in the base of the cochlea. As long as intracochlear scarring continues to occur with cochlear implantation, there will be limitations on hearing preservation. Newer surgical techniques and electrode technologies that do not result in as much scar tissue formation will permit improved hearing preservation.

Objective Although mastoid and middle ear obliteration provides the ultimate repair of an encephalocele, retained squamous epithelium may result in the occult recurrence of cholesteatoma. For most patients, a preferable technique is to perform a canal-wall-up mastoidectomy with middle fossa craniotomy. However, temporal lobe encephaloceles are occasionally found in patients with canal-wall-down cavities along with active cholesteatoma. We sought to describe our management strategy for this dilemma. Study design Retrospective review. Setting Tertiary referral center. Patients We reviewed all patients with encephaloceles treated by the primary surgeon. Patients without active cholesteatoma and a canal-wall-down cavity were excluded. Intervention Surgical management of the encephalocele and cholesteatoma. Main outcome measure Successful repair and a noninfected ear. Results Three patients met the inclusion criteria. All had previous canal-wall-down surgery for cholesteatoma by outside surgeons and presented with chronic otorrhea, large tegmen defects, and brain herniation into the mastoid cavity. All had incomplete removal of their posterior canal wall. Our management strategy involved completing the canal-wall-down mastoidectomy and repairing the temporal floor defect using a three-layer closure via a middle fossa craniotomy. This included suture repair of the dural defect with or without a graft, a temporalis muscle rotation flap, and a split-calvarial bone graft. All patients recovered from their surgery without evidence of further cerebrospinal fluid leak, encephalocele, or cholesteatoma with a minimum follow-up time of 6 months. Conclusions A temporal lobe encephalocele can be safely repaired while maintaining a mastoid bowl. This may be the safest treatment option for patients with active cholesteatoma.

Superior canal dehiscence syndrome is a recently described condition resulting in noise- or pressure-induced vertigo. We review the case of a 50-year-old woman who presented with debilitating pressure and noise-induced vertigo as well as a low-frequency conductive hearing loss. Imaging was consistent with superior semicircular canal dehiscence syndrome. An extradural middle fossa approach was used to approach the dehiscent superior canal. Intraoperatively, our patient was found to have extensive idiopathic skull base dehiscence of the temporal floor. Middle ear and mastoid mucosa was exposed with focal areas of dura prolapsed into the mastoid cavity. Because of these findings, temporalis fascia and bone pate were used to cover the dehiscent canal as well as a large area of the temporal floor. Additionally, a temporalis muscle flap was rotated between the dura and the dehiscent temporal floor to reconstruct the middle fossa skull base and prevent encephalocele.

Outer hair cell (OHC) electromotility provides mechanical positive feedback that functions as the cochlear amplifier. In isolated OHCs, chlorpromazine shifts the electromotility voltage-displacement transfer function in a depolarizing direction without affecting its magnitude. This study sought to measure the effects of chlorpromazine on cochlear function in vivo. Salicylate, a drug that greatly reduces the magnitude of electromotility, was used for comparison. Perilymphatic perfusion of the guinea pig cochlea with chlorpromazine or salicylate increased the compound action potential (CAP) threshold across the frequency spectrum (1-20 kHz). Both drugs also increased distortion product otoacoustic emission (DPOAE) thresholds in the higher frequencies (10-20 kHz). Complete reversibility of these effects occurred after washout. Both drugs demonstrated concentration-dependent reductions in cochlear function that followed sigmoidal curves with similar fits to previously reported results in isolated OHCs. The endolymphatic potential was not affected by either of these drugs. Thus, chlorpromazine inhibits cochlear function in a manner consistent with what would be expected from data in isolated OHCs. This suggests that shifting the electromotility transfer function correspondingly reduces the gain of the cochlear amplifier.

There have been many recent advancements in our understanding of cochlear function within the past ten years. In particular, several mechanisms that underlie the sensitivity and sharpness of mammalian tuning have been discovered. This review focuses on these issues.The cochlear amplifier is essentially a positive feedback loop within the cochlea that amplifies the traveling wave. Thus, vibrations within the organ of Corti are sensed and then force is generated in synchrony to increase the vibrations. Mechanisms that generate force within the cochlea include outer hair cell electromotility and stereociliary active bundle movements. These processes can be modulated by the intracellular ionic composition, the lipid constituents of the outer hair cell plasma membrane, and the structure of the outer hair cell cytoskeleton.A thorough understanding of the cochlear amplifier has tremendous implications to improve human hearing. Sensorineural hearing loss is a common clinical problem and a common site of initial pathology is the outer hair cell. Loss of outer hair cells causes loss of the cochlear amplifier, resulting in progressive sensorineural hearing loss.

Objective The objective of this study was to characterize the auditory dysfunction associated with chronic pachymeningitis (inflammation of the dura mater). Study design and setting We conducted a university-based retrospective review. Results Three patients were identified who were diagnosed with chronic pachymeningitis after being referred for asymmetric sensorineural hearing loss. All patients were found to have other neurologic symptoms and signs during careful neurotologic evaluation. Two varieties of chronic pachymeningitis exist: a hypertrophic mass lesion and a linear dural thickening. Although the hypertrophic variety could be easily detectable by noncontrast magnetic resonance imaging (MRI), the linear form is only visible with the use of gadolinium enhancement. Conclusion Chronic pachymeningitis is a rare form of sensorineural hearing loss that could portend an underlying disease of greater concern. Extensive evaluation is needed to exclude identifiable causes of chronic pachymeningitis, including infectious, neoplastic, and autoimmune diseases. Significance The clinician should be aware that the evaluation of a patient with asymmetric sensorineural hearing loss involves more than simply ruling out an acoustic neuroma. Fast-spin echo MRI techniques without the use of gadolinium contrast could miss a number of potentially treatable diseases such as chronic pachymeningitis. Patients with asymmetric sensorineural hearing loss should be carefully evaluated for other neurologic findings, and imaging with enhanced MRI is recommended.