Journal of the Association for Research in Otolaryngology 2020-10-22

Human Vestibulo-Ocular Reflex Adaptation Reduces when Training Demand Variability Increases

Publicatie 22-10-2020


Abstract One component of vestibular rehabilitation in patients with vestibulo-ocular reflex (VOR) hypofunction is gaze-stabilizing exercises that seek to increase (adapt) the VOR response. These prescribed home-based exercises are performed by the patient and thus their use/training is inherently variable. We sought to determine whether this variability affected VOR adaptation in ten healthy controls (× 2 training only) and ten patients with unilateral vestibular hypofunction (× 1 and × 2 training). During × 1 training, patients actively (self-generated, predictable) move their head sinusoidally while viewing a stationary fixation target; for × 2 training, they moved their outstretched hand anti-phase with their head rotation while attempting to view a handheld target. We defined the latter as manual × 2 training because the subject manually controls the target. In this study, head rotation frequency during training incrementally increased 0.5–2 Hz over 20 min. Active and passive (imposed, unpredictable) sinusoidal (1.3-Hz rotations) and head impulse VOR gains were measured before and after training. We show that for controls, manual × 2 training resulted in significant sinusoidal and impulse VOR adaptation of ~ 6 % and ~ 3 %, respectively, though this was ~two-thirds lower than increases after computer-controlled × 2 training (non-variable) reported in a prior study. In contrast, for patients, there was an increase in impulse but not sinusoidal VOR response after a single session of manual × 2 training. Patients had more than double the variability in VOR demand during manual × 2 training compared to controls, which could explain why adaptation was not significant in patients. Our data suggest that the clinical × 1 gaze-stabilizing exercise is a weak stimulus for VOR adaptation.

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Effects of Kainic Acid-Induced Auditory Nerve Damage on Envelope-Following Responses in the Budgerigar ( Melopsittacus undulatus )

JL Wilson,KS Abrams,KS Henry

Publicatie 19-10-2020


Abstract Sensorineural hearing loss is a prevalent problem that adversely impacts quality of life by compromising interpersonal communication. While hair cell damage is readily detectable with the clinical audiogram, this traditional diagnostic tool appears inadequate to detect lost afferent connections between inner hair cells and auditory nerve (AN) fibers, known as cochlear synaptopathy. The envelope-following response (EFR) is a scalp-recorded response to amplitude modulation, a critical acoustic feature of speech. Because EFRs can have greater amplitude than wave I of the auditory brainstem response (ABR; i.e., the AN-generated component) in humans, the EFR may provide a more sensitive way to detect cochlear synaptopathy. We explored the effects of kainate- (kainic acid) induced excitotoxic AN injury on EFRs and ABRs in the budgerigar (Melopsittacus undulatus), a parakeet species used in studies of complex sound discrimination. Kainate reduced ABR wave I by 65–75 % across animals while leaving otoacoustic emissions unaffected or mildly enhanced, consistent with substantial and selective AN synaptic loss. Compared to wave I loss, EFRs showed similar or greater percent reduction following kainate for amplitude-modulation frequencies from 380 to 940 Hz and slightly less reduction from 80 to 120 Hz. In contrast, forebrain-generated middle latency responses showed no consistent change post-kainate, potentially due to elevated “central gain” in the time period following AN damage. EFR reduction in all modulation frequency ranges was highly correlated with wave I reduction, though within-animal effect sizes were greater for higher modulation frequencies. These results suggest that even low-frequency EFRs generated primarily by central auditory nuclei might provide a useful noninvasive tool for detecting synaptic injury clinically.

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Utricular Sensitivity during Hydrodynamic Displacements of the Macula

CJ Pastras,SP Stefani,IS Curthoys,AJ Camp,DJ Brown

Publicatie 01-10-2020


Abstract To explore the effects of cochlear hair cell displacement, researchers have previously monitored functional and mechanical responses during low-frequency (LF) acoustic stimulation of the cochlea. The induced changes are believed to result from modulation of the conductance of mechano-electrical transduction (MET) channels on cochlear hair cells, along with receptor potential modulation. It is less clear how, or if, vestibular hair cell displacement affects vestibular function. Here, we have used LF (<20 Hz) hydrodynamic modulation of the utricular macula position, whilst recording functional and mechanical responses, to investigate the effects of utricular macula displacement. Measured responses included the Utricular Microphonic (UM), the vestibular short-latency evoked potential (VsEP), and laser Doppler vibrometry recordings of macular position. Over 1 cycle of the LF bias, the UM amplitude and waveform were cyclically modulated, with Boltzmann analysis suggesting a cyclic modulation of the vestibular MET gating. The VsEP amplitude was cyclically modulated throughout the LF bias, demonstrating a relative increase (~20–50 %; re baseline) and decrease (~10–20 %; re baseline), which is believed to be related to the MET conductance and vestibular hair cell sensitivity. The relationship between macular displacement and changes in UM and VsEP responses was consistent within and across animals. These results suggest that the sensory structures underlying the VsEP, often thought to be a cranial jerk-sensitive response, are at least partially sensitive to LF (and possibly static) pressures or motion. Furthermore, these results highlight the possibility that some of the vestibular dysfunction related to endolymphatic hydrops may be due to altered vestibular transduction following mechanical (or morphological) changes in the labyrinth.

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Mechanical Properties of Baboon Tympanic Membrane from Young to Adult

J Liang,WG Engles,KD Smith,C Dai,RZ Gan

Publicatie 01-10-2020


Abstract Mechanical properties of the tympanic membrane (TM) play an important role in sound transmission through the middle ear. While numerous studies have investigated the mechanical properties of the adult human TM, the effects of age on the TM’s properties remain unclear because of the limited published data on the TM of young children. To address this deprivation, we used baboons in this study as an animal model for investigating the effect of age on the mechanical properties of the TM. Temporal bones were harvested from baboons (Papio anubis) of four different age groups: less than 1 year, 1–3 years, 3–5 years, and older than 5 years of age or adult. The TM specimens were harvested from baboon temporal bones and cut into rectangle strips along the inferior-superior direction, mainly capturing the influence of the circumferential direction fibers on the TM’s mechanical properties. The elasticity, ultimate tensile strength, and relaxation behavior of the baboon TM were measured in each of the four age groups with a mechanical analyzer. The average effective Young’s modulus of adult baboon TM was approximately 3.1 MPa, about two times higher than that of a human TM. The Young’s moduli of the TM samples demonstrated a 26 % decrease from newborn to adult (from 4.2 to 3.1 MPa). The average ultimate tensile strength of the TMs for all the age groups was ~ 2.5 MPa. There was no significant change in the ultimate tensile strength and relaxation behavior among age groups. The preliminary results reported in this study provide a first step towards understanding the effect of age on the TM mechanical properties from young to adult.

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Effects of Tonic Muscle Activation on Amplitude-Modulated Cervical Vestibular Evoked Myogenic Potentials (AMcVEMPs) in Young Females: Preliminary Findings

CG Clinard,AP Thorne,EG Piker

Publicatie 01-10-2020


Abstract Cervical vestibular evoked myogenic potentials (cVEMPs) are usually elicited by transient tonebursts, but when elicited by amplitude-modulated (AM) tones, they can provide new information about cVEMPs. Previous reports of cVEMPs elicited by AM tones, or AMcVEMPs, have not systematically examined the effects of tonic EMG activation on their response properties. Fourteen young, healthy female adults (ages 20–24) with clinically normal audiograms participated in this study. AMcVEMPs were elicited with bone-conducted 500 Hz tones amplitude modulated at a rate of 37 Hz and recorded for five different EMG targets ranging from 0 to 90 μV. Amplitude increased linearly as tonic EMG activation increased. Signal-to-noise ratio (SNR) was minimal at 0 μV, but robust and with equivalent values from 30 to 90 μV; phase coherence and EMG-corrected amplitude had findings similar to SNR across EMG target levels. Interaural asymmetry ratios for SNR and phase coherence were substantially lower than those for raw or corrected amplitude. AMcVEMP amplitude scaled with tonic EMG activation similar to transient cVEMPs. Signal-to-noise ratio, phase coherence, and EMG-corrected amplitude plateaued across a range of EMG values, suggesting that these properties of the response reach their maximum values at relatively low levels of EMG activation and that higher levels of EMG activation are not necessary to record robust AMcVEMPs.

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Correlating Cochlear Morphometrics from Parnell’s Mustached Bat ( Pteronotus parnellii ) with Hearing

CD Girdlestone,J Ng,M Kössl,A Caplot,RE Shadwick,M Morell

Publicatie 01-10-2020


Abstract Morphometric analysis of the inner ear of mammals can provide information for cochlear frequency mapping, a species-specific designation of locations in the cochlea at which different sound frequencies are encoded. Morphometric variation occurs in the hair cells of the organ of Corti along the cochlea, with the base encoding the highest frequency sounds and the apex encoding the lowest frequencies. Changes in cell shape and spacing can yield additional information about the biophysical basis of cochlear tuning mechanisms. Here, we investigate how morphometric analysis of hair cells in mammals can be used to predict the relationship between frequency and cochlear location. We used linear and geometric morphometrics to analyze scanning electron micrographs of the hair cells of the cochleae in Parnell’s mustached bat (Pteronotus parnellii) and Wistar rat (Rattus norvegicus) and determined a relationship between cochlear morphometrics and their frequency map. Sixteen of twenty-two of the morphometric parameters analyzed showed a significant change along the cochlea, including the distance between the rows of hair cells, outer hair cell width, and gap width between hair cells. A multiple linear regression model revealed that nine of these parameters are responsible for 86.9 % of the variation in these morphometric data. Determining the most biologically relevant measurements related to frequency detection can give us a greater understanding of the essential biomechanical characteristics for frequency selectivity during sound transduction in a diversity of animals.

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Does the “Reticular Lamina Nonlinearity” Contribute to the Basal DPOAE Source?

A Moleti,R Sisto

Publicatie 21-09-2020


Abstract The spatial extent of the cochlear region that actually contributes to the DPOAE signal measured in the ear canal may be evaluated experimentally using interference tones or computed numerically using nonlinear cochlear models. A nonlinear transmission-line cochlear model is used in this study to evaluate whether the recently reported nonlinear behavior of the reticular lamina (RL) over a wide basal region may be associated with generation of a significant distortion product otoacoustic emission (DPOAE) component. A two-degrees-of-freedom 1-D nonlinear model was used as discussed by Sisto et al. (2019), in which each local element consists of two coupled oscillators, roughly representing the basilar membrane (BM) and the RL. In this model, the RL shows a strongly nonlinear response over a wide region basal to the characteristic place, whereas the BM response is linear outside the narrow peak region. Such a model may be considered as that using the minimal number of degrees of freedom necessary to separately predict the motion of the BM and RL, while preserving important cochlear symmetries, such as the zero-crossing invariance of the impulse response. In the numerical simulations, the RL nonlinearity generates indeed a large intracochlear distortion product source, extended down to very basal cochlear regions. Nevertheless, due to the weak and indirect coupling between the RL motion and the differential fluid pressure in the basal part of the traveling wave path, no significant contribution from this mechanism is predicted by the model to the generation of the DPOAE signal that is eventually measured in the ear canal.

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Perceptual Weighting of Binaural Lateralization Cues across Frequency Bands

A Ahrens,SN Joshi,B Epp

Publicatie 11-09-2020


Abstract The auditory system uses interaural time and level differences (ITD and ILD) as cues to localize and lateralize sounds. The availability of ITDs and ILDs in the auditory system is limited by neural phase-locking and by the head size, respectively. Although the frequency-specific limitations are well known, the relative contribution of ITDs and ILDs in individual frequency bands in broadband stimuli is unknown. To determine these relative contributions, or spectral weights, listeners were asked to lateralize stimuli consisting of eleven simultaneously presented 1-ERB-wide noise bands centered between 442 and 5544 Hz and separated by 1-ERB-wide gaps. Either ITDs or ILDs were varied independently across each noise band, while fixing the other interaural disparity to either 0 dB or 0 μs. The weights were obtained using a multiple linear regression analysis. In a second experiment, the effect of auditory enhancement on the spectral weights was investigated. The enhancement of single noise bands was realized by presenting ten of the noise bands as preceding and following sounds (pre- and post-cursors, respectively). Listeners were asked to lateralize the stimuli as in the first experiment. Results show that in the absence of pre- and post-cursors, only the lowest or highest frequency band received highest weight for ITD and ILD, respectively. Auditory enhancement led to significantly enhanced weights given to the band without the pre- and post-cursor. The weight enhancement could only be observed at low frequencies, when determined with ITD cues and for low and high frequencies for ILDs. Hence, the auditory system seems to be able to change the spectral weighting of binaural information depending on the information content.

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Effect of the Relative Timing between Same-Polarity Pulses on Thresholds and Loudness in Cochlear Implant Users

F Guérit,J Marozeau,B Epp,RP Carlyon

Publicatie 24-08-2020


Abstract The effect of the relative timing between pairs of same-polarity monophasic pulses has been studied extensively in single-neuron animal studies and has revealed fundamental properties of the neurons. For human cochlear implant listeners, the requirement to use charge-balanced stimulation and the typical use of symmetric, biphasic pulses limits such measures, because currents of opposite polarities interact at the level of the neural membrane. Here, we propose a paradigm to study same-polarity summation of currents while keeping the stimulation charge-balanced within a short time window. We used pairs of mirrored pseudo-monophasic pulses (a long-low phase followed by a short-high phase for the first pulse and a short-high phase followed by a long-low phase for the second pulse). We assumed that most of the excitation would stem from the two adjacent short-high phases, which had the same polarity. The inter-pulse interval between the short-high phases was varied from 0 to 345 μs. The inter-pulse interval had a significant effect on the perceived loudness, and this effect was consistent with both passive (membrane-related) and active (ion-channel-related) neuronal mechanisms contributing to facilitation. Furthermore, the effect of interval interacted with the polarity of the pulse pairs. At threshold, there was an effect of polarity, but, surprisingly, no effect of interval nor an interaction between the two factors. We discuss possible peripheral origins of these results.

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Gap Detection Deficits in Chinchillas with Selective Carboplatin-Induced Inner Hair Cell Loss

E Lobarinas,R Salvi,D Ding

Publicatie 17-08-2020


Abstract Temporal resolution is essential for processing complex auditory information such as speech. In hearing impaired persons, temporal resolution, often assessed by detection of brief gaps in continuous sound stimuli, is typically poorer than in individuals with normal hearing. At low stimulus presentation levels, hearing impaired individuals perform poorly but the deficits are greatly reduced when the sensation level of the stimuli are adjusted to match their normal hearing peers. In the present study, we evaluated the effect of selective inner hair cell loss on gap detection in chinchillas treated with carboplatin, an anticancer drug that selectively damages inner hair cells and afferents in this species. Treatment with carboplatin-induced inner hair cell loss of ~ 70 % but had little effect on audiometric thresholds in quiet and produced no evidence of outer hair cell loss. In contrast, selective inner hair cell loss had a significant effect on gap detection ability across a wide range of presentation levels. These results suggest that gap detection tasks are more sensitive to inner hair cell pathology than audiometric thresholds.

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The Effect of Phantom Stimulation and Pseudomonophasic Pulse Shapes on Pitch Perception by Cochlear Implant Listeners

W Lamping,JM Deeks,J Marozeau,RP Carlyon

Publicatie 17-08-2020


Abstract It has been suggested that a specialized high-temporal-acuity brainstem pathway can be activated by stimulating more apically in the cochlea than is achieved by cochlear implants (CIs) when programmed with contemporary clinical settings. We performed multiple experiments to test the effect on pitch perception of phantom stimulation and asymmetric current pulses, both supposedly stimulating beyond the most apical electrode of a CI. The two stimulus types were generated using a bipolar electrode pair, composed of the most apical electrode of the array and a neighboring, more basal electrode. Experiment 1 used a pitch-ranking procedure where neural excitation was shifted apically or basally using so-called phantom stimulation. No benefit of apical phantom stimulation was found on the highest rate up to which pitch ranks increased (upper limit), nor on the slopes of the pitch-ranking function above 300 pulses per second (pps). Experiment 2 used the same procedure to study the effects of apical pseudomonophasic pulses, where the locus of excitation was manipulated by changing stimulus polarity. A benefit of apical stimulation was obtained for the slopes above 300 pps. Experiment 3 used an adaptive rate discrimination procedure and found a small but significant benefit of both types of apical stimulation. Overall, the results show some benefit for apical stimulation on temporal pitch processing at high pulse rates but reveal that the effect is smaller and more variable across listeners than suggested by previous research. The results also provide some indication that the benefit of apical stimulation may decline over time since implantation.

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Correction to: Speech Perception with Spectrally Non-overlapping Maskers as Measure of Spectral Resolution in Cochlear Implant Users

ER O'Neill,HA Kreft,AJ Oxenham

Publicatie 01-08-2020


An error in interpreting the statistical analysis output led to reporting errors in some of the effect sizes for the three-way repeated-measures ANOVAs in Experiment 1.

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The Genetics of Variation of the Wave 1 Amplitude of the Mouse Auditory Brainstem Response

EC Boussaty,D Gillard,J Lavinsky,P Salehi,J Wang,A Mendonça,H Allayee,U Manor,RA Friedman

Publicatie 01-08-2020


Abstract This is the first genome-wide association study with the Hybrid Mouse Diversity Panel (HDMP) to define the genetic landscape of the variation in the suprathreshold wave 1 amplitude of the auditory brainstem response (ABR) both pre- and post-noise exposure. This measure is correlated with the density of the auditory neurons (AN) and/or the compliment of synaptic ribbons within the inner hair cells of the mouse cochlea. We analyzed suprathreshold ABR for 635 mice from 102 HMDP strains pre- and post-noise exposure (108 dB 10 kHz octave band noise exposure for 2 h) using auditory brainstem response (ABR) wave 1 suprathreshold amplitudes as part of a large survey (Myint et al., Hear Res 332:113–120, 2016). Genome-wide significance levels for pre- and post-exposure wave 1 amplitude across the HMDP were performed using FaST-LMM. Synaptic ribbon counts (Ctbp2 and mGluR2) were analyzed for the extreme strains within the HMDP. ABR wave 1 amplitude varied across all strains of the HMDP with differences ranging between 2.42 and 3.82-fold pre-exposure and between 2.43 and 7.5-fold post-exposure with several tone burst stimuli (4 kHz, 8 kHz, 12 kHz, 16 kHz, 24 kHz, and 32 kHz). Immunolabeling of paired synaptic ribbons and glutamate receptors of strains with the highest and lowest wave 1 values pre- and post-exposure revealed significant differences in functional synaptic ribbon counts. Genome-wide association analysis identified genome-wide significant threshold associations on chromosome 3 (24 kHz; JAX00105429; p < 1.12E-06) and chromosome 16 (16 kHz; JAX00424604; p < 9.02E-07) prior to noise exposure and significant associations on chromosomes 2 (32 kHz; JAX00497967; p < 3.68E-08) and 13 (8 kHz; JAX00049416; 1.07E-06) after noise exposure. In order to prioritize candidate genes, we generated cis-eQTLs from microarray profiling of RNA isolated from whole cochleae in 64 of the tested strains. This is the first report of a genome-wide association analysis, controlled for population structure, to explore the genetic landscape of suprathreshold wave 1 amplitude measurements of the mouse ABR. We have defined two genomic regions associated with wave 1 amplitude variation prior to noise exposure and an additional two associated with variation after noise exposure.

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Age-Related Compensation Mechanism Revealed in the Cortical Representation of Degraded Speech

S Anderson,L Roque,CR Gaskins,S Gordon-Salant,MJ Goupell

Publicatie 01-08-2020


Abstract Older adults understand speech with comparative ease in quiet, but signal degradation can hinder speech understanding much more than it does in younger adults. This difficulty may result, in part, from temporal processing deficits related to the aging process and/or high-frequency hearing loss that can occur in listeners who have normal- or near-normal-hearing thresholds in the speech frequency range. Temporal processing deficits may manifest as degraded neural representation in peripheral and brainstem/midbrain structures that lead to compensation, or changes in response strength in auditory cortex. Little is understood about the process by which the neural representation of signals is improved or restored by age-related cortical compensation mechanisms. Therefore, we used vocoding to simulate spectral degradation to compare the behavioral and neural representation of words that contrast on a temporal dimension. Specifically, we used the closure duration of the silent interval between the vowel and the final affricate /t∫/ or fricative /ʃ/ of the words DITCH and DISH, respectively. We obtained perceptual identification functions and electrophysiological neural measures (frequency-following responses (FFR) and cortical auditory-evoked potentials (CAEPs)) to unprocessed and vocoded versions of these words in young normal-hearing (YNH), older normal- or near-normal-hearing (ONH), and older hearing-impaired (OHI) listeners. We found that vocoding significantly reduced the slope of the perceptual identification function in only the OHI listeners. In contrast to the limited effects of vocoding on perceptual performance, vocoding had robust effects on the FFRs across age groups, such that stimulus-to-response correlations and envelope magnitudes were significantly lower for vocoded vs. unprocessed conditions. Increases in the P1 peak amplitude for vocoded stimuli were found for both ONH and OHI listeners, but not for the YNH listeners. These results suggest that while vocoding substantially degrades early neural representation of speech stimuli in the midbrain, there may be cortical compensation in older listeners that is not seen in younger listeners.

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Using Spectral Blurring to Assess Effects of Channel Interaction on Speech-in-Noise Perception with Cochlear Implants

T Goehring,JG Arenberg,RP Carlyon

Publicatie 01-08-2020


Abstract Cochlear implant (CI) listeners struggle to understand speech in background noise. Interactions between electrode channels due to current spread increase the masking of speech by noise and lead to difficulties with speech perception. Strategies that reduce channel interaction therefore have the potential to improve speech-in-noise perception by CI listeners, but previous results have been mixed. We investigated the effects of channel interaction on speech-in-noise perception and its association with spectro-temporal acuity in a listening study with 12 experienced CI users. Instead of attempting to reduce channel interaction, we introduced spectral blurring to simulate some of the effects of channel interaction by adjusting the overlap between electrode channels at the input level of the analysis filters or at the output by using several simultaneously stimulated electrodes per channel. We measured speech reception thresholds in noise as a function of the amount of blurring applied to either all 15 electrode channels or to 5 evenly spaced channels. Performance remained roughly constant as the amount of blurring applied to all channels increased up to some knee point, above which it deteriorated. This knee point differed across listeners in a way that correlated with performance on a non-speech spectro-temporal task, and is proposed here as an individual measure of channel interaction. Surprisingly, even extreme amounts of blurring applied to 5 channels did not affect performance. The effects on speech perception in noise were similar for blurring at the input and at the output of the CI. The results are in line with the assumption that experienced CI users can make use of a limited number of effective channels of information and tolerate some deviations from their everyday settings when identifying speech in the presence of a masker. Furthermore, these findings may explain the mixed results by strategies that optimized or deactivated a small number of electrodes evenly distributed along the array by showing that blurring or deactivating one-third of the electrodes did not harm speech-in-noise performance.

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Vibration Measurements of the Gerbil Eardrum Under Quasi-static Pressure Steps

O Kose,WRJ Funnell,SJ Daniel

Publicatie 01-08-2020


Abstract Tympanometry is a relatively simple non-invasive test of the status of the middle ear. An important step towards understanding the mechanics of the middle ear during tympanometry is to make vibration measurements on the eardrum under tympanometric pressures. In this study, we measured in vivo vibration responses in 11 gerbils while varying the middle-ear pressure quasi-statically, with the ear canal at ambient pressure. Vibrations were recorded using a single-point laser Doppler vibrometer with five glass-coated reflective beads (diameter ~ 40 μm) as targets. The locations were the umbo, mid-manubrium, posterior pars tensa, anterior pars tensa and pars flaccida. As described in earlier studies, the unpressurized vibration magnitude was flat at low frequencies, increased until a resonance frequency at around 1.8–2.5 kHz, and became complex at higher frequencies. At both the umbo and mid-manubrium points, when the static pressure was decreased to the most negative middle-ear pressure (− 2500 Pa), the low-frequency vibration magnitude (measured at 1.0 kHz) showed a monotonic decrease, except for an unexpected dip at around − 500 to − 1000 Pa. This dip was not present for the pars-tensa and pars-flaccida points. The resonance frequency shifted to higher frequencies, to around 7–8 kHz at − 2500 Pa. For positive middle-ear pressures, the low-frequency vibration magnitude decreased monotonically, with no dip, and the resonance frequency shifted to around 5–6 kHz at + 2500 Pa. There was more inter-specimen variability on the positive-pressure side than on the negative-pressure side. The low-frequency vibration magnitudes on the negative-pressure side were higher for the pars-tensa points than for the umbo and mid-manubrium points, while the magnitudes were similar at all four locations on the positive-pressure side. Most gerbils showed repeatability within less than 10 dB for consecutive cycles. The results of this study provide insight into the mechanics of the gerbil middle ear under tympanometric pressures.

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Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents

BK Gersten,TS Fitzgerald,KA Fernandez,LL Cunningham

Publicatie 01-08-2020


Abstract Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.

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Relationships between Intrascalar Tissue, Neuron Survival, and Cochlear Implant Function

DL Swiderski,DJ Colesa,AP Hughes,Y Raphael,BE Pfingst

Publicatie 01-08-2020


Abstract Fibrous tissue and/or new bone are often found surrounding a cochlear implant in the cochlear scalae. This new intrascalar tissue could potentially limit cochlear implant function by increasing impedance and altering signaling pathways between the implant and the auditory nerve. In this study, we investigated the relationship between intrascalar tissue and 5 measures of implant function in guinea pigs. Variation in both spiral ganglion neuron (SGN) survival and intrascalar tissue was produced by implanting hearing ears, ears deafened with neomycin, and neomycin-deafened ears treated with a neurotrophin. We found significant effects of SGN density on 4 functional measures but adding intrascalar tissue level to the analysis did not explain more variation in any measure than was explained by SGN density alone. These results suggest that effects of intrascalar tissue on electrical hearing are relatively unimportant in comparison to degeneration of the auditory nerve, although additional studies in human implant recipients are still needed to assess the effects of this tissue on complex hearing tasks like speech perception. The results also suggest that efforts to minimize the trauma that aggravates both tissue development and SGN loss could be beneficial.

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Effects of Electrode Location on Estimates of Neural Health in Humans with Cochlear Implants

KC Schvartz-Leyzac,TA Holden,TA Zwolan,HA Arts,JB Firszt,CJ Buswinka,BE Pfingst

Publicatie 01-06-2020


Abstract There are a number of psychophysical and electrophysiological measures that are correlated with SGN density in animal models, and these same measures can be performed in humans with cochlear implants (CIs). Thus, these measures are potentially applicable in humans for estimating the condition of the neural population (so called “neural health” or “cochlear health”) at individual sites along the electrode array and possibly adjusting the stimulation strategy in the CI sound processor accordingly. Some measures used to estimate neural health in animals have included the electrically evoked compound potential (ECAP), psychophysical detection thresholds, and multipulse integration (MPI). With regard to ECAP measures, it has been shown that the change in the ECAP response as a function of increasing the stimulus interphase gap (“IPG Effect”) also reflects neural density in implanted animals. These animal studies have typically been conducted using preparations in which the electrode was in a fixed position with respect to the neural population, whereas in human cochlear implant users, the position of individual electrodes varies widely within an electrode array and also across subjects. The current study evaluated the effects of electrode location in the implanted cochlea (specifically medial-lateral location) on various electrophysiological and psychophysical measures in eleven human subjects. The results demonstrated that some measures of interest, specifically ECAP thresholds, psychophysical detection thresholds, and ECAP amplitude-growth function (AGF) linear slope, were significantly related to the distances between the electrode and mid-modiolar axis (MMA). These same measures were less strongly related or not significantly related to the electrode to medial wall (MW) distance. In contrast, neither the IPG Effect for the ECAP AGF slope or threshold, nor the MPI slopes were significantly related to MMA or MW distance from the electrodes. These results suggest that “within-channel” estimates of neural health such as the IPG Effect and MPI slope might be more suitable for estimating nerve condition in humans for clinical application since they appear to be relatively independent of electrode position.

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Effects of Gap Position on Perceptual Gap Detection Across Late Childhood and Adolescence

JD Gay,MJ Rosen,JJ Huyck

Publicatie 01-06-2020


Abstract The ability to detect a silent gap within a sound is critical for accurate speech perception, and gap detection has been shown to have an extended developmental trajectory. In certain conditions, the detectability of the gap decreases as the gap is placed closer to the beginning of the signal. Early in development, the detection of gaps shortly after signal onset may be especially difficult due to immaturities in the encoding and perception of rapidly changing sounds. The present study explored the development of gap detection from age 8 to 19 years, specifically when the temporal placement of the gap varied. Performance improved with age for all temporal placements of the gap, demonstrating a gradual maturation of gap detection abilities throughout adolescence. Younger adolescents did not benefit from increasing gap onset times, while older adolescents’ thresholds gradually improved as gap onset time lengthened. Regardless of age, listeners learned between the two testing days but did not improve within days. Younger adolescents had poorer thresholds for the last block of testing on the second day, returning to baseline performance despite learning between days. These data support earlier studies showing that gaps are harder to detect near stimulus onset and confirm that gap detection abilities continue to mature into adolescence. The data also suggest that younger adolescents do not receive the same benefit of increasing gap onset time and respond differently to repeated testing than older adolescents and young adults.

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