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The prevailing theory of cochlear function states that outer hair cells amplify sound-induced vibration to improve hearing sensitivity and frequency specificity. Recent micromechanical measurements in the basal turn of gerbil cochleae through the round window have demonstrated that the reticular lamina vibration lags the basilar membrane vibration, and it is physiologically vulnerable not only at the best frequency but also at the low frequencies. These results suggest that outer hair cells from a broad cochlear region enhance hearing sensitivity through a global hydromechanical mechanism. However, the time difference between the reticular lamina and basilar membrane vibration has been thought to result from a systematic measurement error caused by the optical axis non-perpendicular to the cochlear partition. To address this concern, we measured the reticular lamina and basilar membrane vibrations in the transverse direction through an opening in the cochlear lateral wall in this study. Present results show that the phase difference between the reticular lamina and basilar membrane vibration decreases with frequency by ~ 180 degrees from low frequencies to the best frequency, consistent with those measured through the round window. Together with the round-window measurement, the low-coherence interferometry through the cochlear lateral wall demonstrates that the time difference between the reticular lamina and basilar membrane vibration results from the cochlear active processing rather than a measurement error.

In cochlear implant surgery, insertion of perimodiolar electrode arrays into the scala tympani can be complicated by trauma or even accidental translocation of the electrode array within the cochlea. In patients with partial hearing loss, cochlear trauma can not only negatively affect implant performance, but also reduce residual hearing function. These events have been related to suboptimal positioning of the cochlear implant electrode array with respect to critical cochlear walls of the scala tympani (modiolar wall, osseous spiral lamina and basilar membrane). Currently, the position of the electrode array in relation to these walls cannot be assessed during the insertion and the surgeon depends on tactile feedback, which is unreliable and often comes too late. This study presents an image-guided cochlear implant device with an integrated, fiber-optic imaging probe that provides real-time feedback using optical coherence tomography during insertion into the human cochlea. This novel device enables the surgeon to accurately detect and identify the cochlear walls ahead and to adjust the insertion trajectory, avoiding collision and trauma. The functionality of this prototype has been demonstrated in a series of insertion experiments, conducted by experienced cochlear implant surgeons on fresh-frozen human cadaveric cochleae. ispartof: SCIENTIFIC REPORTS vol:12 issue:1 ispartof: location:England status: published

Within the cochlea, the basilar membrane (BM) is coupled to the reticular lamina (RL) through three rows of piezo-like outer hair cells (OHCs) and supporting cells that endow mammals with sensitive hearing. Anatomical differences across OHC rows suggest differences in their motion. Using optical coherence tomography, we measured in vivo and postmortem displacements through the gerbil round-window membrane from approximately the 40–47 kHz best-frequency (BF) regions. Our high spatial resolution allowed measurements across the RL surface at the tops of the three rows of individual OHCs and their bottoms, and across the BM. RL motion varied radially; the third-row gain was more than 3 times greater than that of the first row near BF, whereas the OHC-bottom motions remained similar. This implies that the RL mosaic, comprised of OHC and phalangeal-process tops joined together by adhesion molecules, is much more flexible than the Deiters’ cells connected to the OHCs at their bottom surfaces. Postmortem, the measured points moved together approximately in phase. These imply that in vivo, the RL does not move as a stiff plate hinging around the pillar-cell heads near the first row as has been assumed, but that its mosaic-like structure may instead bend and/or stretch.

The human cochlea transforms sound waves into electrical signals in the acoustic nerve fibers with high acuity. This transformation occurs via vibrating anisotropic membranes (basilar and tectorial membranes) and frequency-specific hair cell receptors. Frequency-positions can be mapped within the cochlea to create a tonotopic chart which fits an almost-exponential function with lowest frequencies positioned apically and highest frequencies positioned at the cochlear base (Bekesy 1960, Greenwood 1961). To date, models of frequency positions have been based on a two-dimensional analysis with inaccurate representations of the cochlear hook region. In the present study, the first three-dimensional frequency analysis of the cochlea using dendritic mapping to obtain accurate tonotopic maps of the human basilar membrane/organ of Corti and the spiral ganglion was performed. A novel imaging technique, synchrotron radiation phase-contrast imaging, was used and a spiral ganglion frequency function was estimated by nonlinear least squares fitting a Greenwood-like function (F = A (10ax − K)) to the data. The three-dimensional tonotopic data presented herein has large implications for validating electrode position and creating customized frequency maps for cochlear implant recipients.

The basilar membrane (BM) of the mammalian cochlea constitutes a spiraling acellular ribbon that is intimately attached to the organ of Corti. Its graded stiffness, increasing from apex to the base of the cochlea provides the mechanical basis for sound frequency analysis. Despite its central role in auditory signal transduction, virtually nothing is known about the BM’s structural development. Using polarized light microscopy, the present study characterized the architectural transformations of freshly dissected BM at time points during postnatal development and maturation. The results indicate that the BM structural elements increase progressively in size, becoming radially aligned and more tightly packed with maturation and reach the adult structural signature by postnatal day 20 (P20). The findings provide insight into structural details and developmental changes of the mammalian BM, suggesting that BM is a dynamic structure that changes throughout the life of an animal.

While separating sounds into frequency components and subsequently converting them into patterns of neural firing, the mammalian cochlea processes signal components in ways that depend strongly on frequency. Indeed, both the temporal structure of the response to transient stimuli and the sharpness of frequency tuning differ dramatically between the apical and basal (i.e., the low- and high-frequency) regions of the cochlea. Although the mechanisms that give rise to these pronounced differences remain incompletely understood, they are generally attributed to tonotopic variations in the constituent hair cells or cytoarchitecture of the organ of Corti. As counterpoint to this view, we present a general acoustic treatment of the horn-like geometry of the cochlea, accompanied by a simple 3-D model to elucidate the theoretical predictions. We show that the main apical/basal functional differences can be accounted for by the known spatial gradients of cochlear dimensions, without the need to invoke mechanical specializations of the sensory tissue. Furthermore, our analysis demonstrates that through its functional resemblance to an ear horn (aka ear trumpet), the geometry of the cochlear duct manifests tapering symmetry, a felicitous design principle that may have evolved not only to aid the analysis of natural sounds but to enhance the sensitivity of hearing.

To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3−/−) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100–500 µs. No auditory responses to acoustic stimuli could be evoked in any of these animals. INS could not evoke auditory brainstem responses in Atoh1 CKO mice but could in Neurog1 KI and Vglut3−/− mice. X-ray micro-computed tomography of the cochleae showed that responses correlated with the presence of SGNs and hair cells. Results in Neurog1 KI mice do not support a mechanical stimulation through the vibration of the basilar membrane, but cannot rule out the direct activation of the inner hair cells. Results in Vglut3−/− mice, which have no synaptic transmission between inner hair cells and SGNs, suggested that hair cells are not required.

The mammalian basilar membrane (BM) consists of two collagen-fiber layers responsible for the frequency-to-place tonotopic mapping in the cochlea, which together form a flat beam over at least part of the BM width. The mechanics of hearing in rodents such as gerbil pose a challenge to our understanding of the cochlea, however, because for gerbil the two layers separate to form a pronounced arch over the remaining BM width. Moreover, the thickness and total width normally thought to determine the local stiffness, and tonotopic mapping in turn, change little along the cochlear length. A nonlinear analysis of a newly developed model, incorporating flat upper and arched lower fiber layers connected by ground substance, explains the initial plateau and subsequent quadratic increase found in measured stiffness vs. deflection curves under point loading, while for pressure loading the model accurately predicts the tonotopic mapping. The model also has applicability to understanding cochlear development and to interpreting evolutionary changes in mammalian hearing.

When two sound tones are delivered to the cochlea simultaneously, they interact with each other in a suppressive way, a phenomenon referred to as two-tone suppression (2TS). This nonlinear response is ascribed to the saturation of the outer hair cell’s mechano-transduction. Thus, 2TS can be used as a non-invasive probe to investigate the fundamental properties of cochlear mechano-transduction. We developed a nonlinear cochlear model in the time domain to interpret 2TS data. The multi-scale model incorporates cochlear fluid dynamics, organ of Corti (OoC) mechanics and outer hair cell electrophysiology. The model simulations of 2TS show that the threshold amplitudes and rates of low-side suppression are dependent on mechano-transduction properties. By comparing model responses to existing 2TS measurement data, we estimate intrinsic characteristics of mechano-transduction such as sensitivity and adaptation. For mechano-transduction sensitivity at the basal location (characteristic frequency of 17 kHz) at 0.06 nm−1, the simulation results agree with 2TS measurements of basilar membrane responses. This estimate is an order of magnitude higher than the values observed in experiments on isolated outer hair cells. The model also demonstrates how the outer hair cell’s adaptation alters the temporal pattern of 2TS by modulating mechano-electrical gain and phase.

The sharp frequency tuning and exquisite sensitivity of the mammalian cochlea is due to active forces delivered by outer hair cells (OHCs) to the cochlear partition. Force transmission is mediated and modulated by specialized cells, including Deiters’ cells (DCs) and pillar cells (PCs), coupled by gap-junctions composed of connexin 26 (Cx26) and Cx30. We created a mouse with conditional Cx26 knock-out (Cx26 cKO) in DCs and PCs that did not influence sensory transduction, receptor-current-driving-voltage, low-mid-frequency distortion-product-otoacoustic-emissions (DPOAEs), and passive basilar membrane (BM) responses. However, the Cx26 cKO desensitizes mid-high-frequency DPOAEs and active BM responses and sensitizes low-mid-frequency neural excitation. This functional segregation may indicate that the flexible, apical turn cochlear partition facilitates transfer of OHC displacements (isotonic forces) for cochlear amplification and neural excitation. DC and PC Cx26 expression is essential for cochlear amplification in the stiff basal turn, possibly through maintaining cochlear partition mechanical impedance, thereby ensuring effective transfer of OHC isometric forces.

Optical stimulation of the cochlea with laser light has been suggested as an alternative to conventional treatment of sensorineural hearing loss with cochlear implants. The underlying mechanisms are controversially discussed: The stimulation can either be based on a direct excitation of neurons, or it is a result of an optoacoustic pressure wave acting on the basilar membrane. Animal studies comparing the intra-cochlear optical stimulation of hearing and deafened guinea pigs have indicated that the stimulation requires intact hair cells. Therefore, optoacoustic stimulation seems to be the underlying mechanism. The present study investigates optoacoustic characteristics using pulsed laser stimulation for in vivo experiments on hearing guinea pigs and pressure measurements in water. As a result, in vivo as well as pressure measurements showed corresponding signal shapes. The amplitude of the signal for both measurements depended on the absorption coefficient and on the maximum of the first time-derivative of laser pulse power (velocity of heat deposition). In conclusion, the pressure measurements directly demonstrated that laser light generates acoustic waves, with amplitudes suitable for stimulating the (partially) intact cochlea. These findings corroborate optoacoustic as the basic mechanism of optical intra-cochlear stimulation.

Since the discovery of otoacoustic emissions and outer hair cell (OHC) motility, the fundamental question of whether the cochlea produces mechanical power remains controversial. In the present work, direct calculations are performed on power loss due to fluid viscosity and power generated by the OHCs. A three-dimensional box model of the mouse cochlea is used with a feed-forward/feed-backward approximation representing the organ of Corti cytoarchitecture. The model is fit to in vivo basilar membrane motion with one free parameter for the OHCs. The calculations predict that the total power output from the three rows of OHCs can be over three orders of magnitude greater than the acoustic input power at 10 dB sound pressure level (SPL). While previous work shows that the power gain, or the negative damping, diminishes with intensity, we show explicitly based on our model that OHC power output increases and saturates with SPL. The total OHC power output is about 2 pW at 80 dB SPL, with a maximum of about 10 fW per OHC.

Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.

Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

The exceptional sensitivity of mammalian hearing organs is attributed to an active process, where force produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these fundamental precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. This shows that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex. A physiologically-based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity. Funding Agencies|NIH [DC-004554, DC-004084]; Swedish Research Council [K2011-63X-14061-11-39]; Research Council for Health, Working Life and Welfare [2006-1526]; Horselskadades Riksforbund; Tysta skolan foundation

To understand how the inner ear-generated sound, i.e., otoacoustic emission, exits the cochlea, we created a sound source electrically in the second turn and measured basilar membrane vibrations at two longitudinal locations in the first turn in living gerbil cochleae using a laser interferometer. For a given longitudinal location, electrically evoked basilar membrane vibrations showed the same tuning and phase lag as those induced by sounds. For a given frequency, the phase measured at a basal location led that at a more apical location, indicating that either an electrical or an acoustical stimulus evoked a forward travelling wave. Under postmortem conditions, the electrically evoked emissions showed no significant change while the basilar membrane vibration nearly disappeared. The current data indicate that basilar membrane vibration was not involved in the backward propagation of otoacoustic emissions and that sounds exit the cochlea probably through alternative media, such as cochlear fluids.

The estimation of scalar electrode position is a central point of quality control during the cochlear implant procedure. Ionic radiation is a disadvantage of commonly used radiologic estimation of electrode position. Recent developments in the field of cochlear implant magnets, implant receiver magnet position, and MRI sequence usage allow the postoperative evaluation of inner ear changes after cochlear implantation. The aim of the present study was to evaluate the position of lateral wall and modiolar cochlear implant electrodes using 3 T MRI scanning. In a prospective study, we evaluated 20 patients (10× Med-El Flex 28; 5× HFMS AB and 5× SlimJ AB) with a 3 T MRI and a T2 2D Drive MS sequence (voxel size: 0.3 × 0.3 × 0.9 mm) for the estimation of the intracochlear position of the cochlear implant electrode. In all cases, MRI allowed a determination of the electrode position in relation to the basilar membrane. This observation made the estimation of 19 scala tympani electrode positions and a single case of electrode translocation possible. 3 T MRI scanning allows the estimation of lateral wall and modiolar electrode intracochlear scalar positions.