Optimizing distortion product otoacoustic emission recordings in normal-hearing ears by adopting cochlear place-specific stimuli.

Distortion product otoacoustic emissions (DPOAEs) provide a window into active cochlear processes and have become a popular clinical and research tool. DPOAEs are commonly recorded using stimulus with fixed presentation levels and frequency ratio irrespective of the test frequency. However, this is inconsistent with the changing mechanical properties of the cochlear partition from the base to the apex that lend specific frequency-dependent spatial properties to the cochlear traveling wave. Therefore, the frequency and level characteristics between the stimulus tones should also need to be adjusted as a function of frequency to maintain optimal interaction between them. The goal of this investigation was to establish a frequency-specific measurement protocol guided by local cochlear mechanics. A broad stimulus parameter space extending up to 20 kHz was explored in a group of normal-hearing individuals. The stimulus frequency ratio yielding the largest 2f1-f2 DPOAE level changed as a function of frequency and stimulus level. Specifically, for a constant stimulus level, the frequency ratio producing the largest DPOAE level decreased with increasing frequency. Similarly, at a given f2 frequency, the stimulus frequency ratio producing the largest DPOAE level became wider as stimulus level increased. These results confirm and strengthen our current understanding of DPOAE generation in the normally functioning cochlea and expand our understanding to previously unexamined higher frequencies. These data support the use of frequency- and level-specific stimulus frequency ratios to maximize DPOAE generation.

Medial olivocochlear reflex effects on amplitude growth functions of long- and short-latency components of click-evoked otoacoustic emissions in humans.

Functional outcomes of medial olivocochlear reflex (MOCR) activation, such as improved hearing in background noise and protection from noise damage, involve moderate to high sound levels. Previous noninvasive measurements of MOCR in humans focused primarily on otoacoustic emissions (OAEs) evoked at low sound levels. Interpreting MOCR effects on OAEs at higher levels is complicated by the possibility of the middle-ear muscle reflex and by components of OAEs arising from different locations along the length of the cochlear spiral. We overcame these issues by presenting click stimuli at a very slow rate and by time-frequency windowing the resulting click-evoked (CE)OAEs into short-latency (SL) and long-latency (LL) components. We characterized the effects of MOCR on CEOAE components using multiple measures to more comprehensively assess these effects throughout much of the dynamic range of hearing. These measures included CEOAE amplitude attenuation, equivalent input attenuation, phase, and slope of growth functions. Results show that MOCR effects are smaller on SL components than LL components, consistent with SL components being generated slightly basal of the characteristic frequency region. Amplitude attenuation measures showed the largest effects at the lowest stimulus levels, but slope change and equivalent input attenuation measures did not decrease at higher stimulus levels. These latter measures are less commonly reported and may provide insight into the variability in listening performance and noise susceptibility seen across individuals.NEW & NOTEWORTHY The auditory efferent system, operating at moderate to high sound levels, may improve hearing in background noise and provide protection from noise damage. We used otoacoustic emissions to measure these efferent effects across a wide range of sound levels and identified level-dependent and independent effects. Previous reports have focused on level-dependent measures. The level-independent effects identified here may provide new insights into the functional relevance of auditory efferent activity in humans.

Click evoked middle ear muscle reflex: Spectral and temporal aspects.

This study describes a time series-based method of middle ear muscle reflex (MEMR) detection using bilateral clicks. Although many methods can detect changes in the otoacoustic emissions evoking stimulus to monitor the MEMR, they do not discriminate between true MEMR-mediated vs artifactual changes in the stimulus. We measured MEMR in 20 young clinically normal hearing individuals using 1-s-long click trains presented at six levels (65 to 95 dB peak-to-peak sound pressure level in 6 dB steps). Changes in the stimulus levels over the 1 s period were well-approximated by two-term exponential functions. The magnitude of ear canal pressure changes due to MEMR increased monotonically as a function of click level but non-monotonically with frequency when separated into 1/3 octave wide bands between 1 and 3.2 kHz. MEMR thresholds estimated using this method were lower than that obtained from a clinical tympanometer in ∼94% of the participants. A time series-based method, along with statistical tests, may provide additional confidence in detecting the MEMR. MEMR effects were smallest at 2 kHz, between 1 and 3.2 kHz, which may provide avenues for minimizing the MEMR influence while measuring other responses (e.g., the medial olivocochlear reflex).

The Spatial Origins of Cochlear Amplification Assessed by Stimulus-Frequency Otoacoustic Emissions.

Cochlear amplification of basilar membrane traveling waves is thought to occur between a tone's characteristic frequency (CF) place and within one octave basal of the CF. Evidence for this view comes only from the cochlear base. Stimulus-frequency otoacoustic emissions (SFOAEs) provide a noninvasive alternative to direct measurements of cochlear motion that can be measured across a wide range of CF regions. Coherent reflection theory indicates that SFOAEs arise mostly from the peak region of the traveling wave, but several studies using far-basal suppressor tones claimed that SFOAE components originate many octaves basal of CF. We measured SFOAEs while perfusing guinea pig cochleas from apex to base with salicylate or KCl solutions that reduced outer-hair-cell function and SFOAE amplification. Solution effects on inner hair cells reduced auditory nerve compound action potentials (CAPs) and provided reference times for when solutions reached the SFOAE-frequency CF region. As solution flowed from apex to base, SFOAE reductions generally occurred later than CAP reductions and showed that the effects of cochlear amplification usually peaked ∼1/2 octave basal of the CF region. For tones ≥2 kHz, cochlear amplification typically extended ∼1.5 octaves basal of CF, and the data are consistent with coherent reflection theory. SFOAE amplification did not extend to the basal end of the cochlea, even though reticular lamina motion is amplified in this region, which indicates that reticular lamina motion is not directly coupled to basilar membrane traveling waves. Previous reports of SFOAE-frequency residuals produced by suppressor frequencies far above the SFOAE frequency are most likely due to additional sources created by the suppressor. For some tones <2 kHz, SFOAE amplification extended two octaves apical of CF, which highlights that different vibratory motions produce SFOAEs and CAPs, and that the amplification region depends on the cochlear mode of motion considered. The concept that there is a single "cochlear amplification region" needs to be revised.

RNA Interference Prevents Autosomal-Dominant Hearing Loss.

Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

Within- and Across-Subject Variability of Repeated Measurements of Medial Olivocochlear-Induced Changes in Transient-Evoked Otoacoustic Emissions.

OBJECTIVES: Measurement of changes in transient-evoked otoacoustic emissions (TEOAEs) caused by activation of the medial olivocochlear reflex (MOCR) may have clinical applications, but the clinical utility is dependent in part on the amount of variability across repeated measurements. The purpose of this study was to investigate the within- and across-subject variability of these measurements in a research setting as a step toward determining the potential clinical feasibility of TEOAE-based MOCR measurements. DESIGN: In 24 normal-hearing young adults, TEOAEs were elicited with 35 dB SL clicks and the MOCR was activated by 35 dB SL broadband noise presented contralaterally. Across a 5-week span, changes in both TEOAE amplitude and phase evoked by MOCR activation (MOC shifts) were measured at four sessions, each consisting of four independent measurements. Efforts were undertaken to reduce the effect of potential confounds, including slow drifts in TEOAE amplitude across time, activation of the middle-ear muscle reflex, and changes in subjects' attentional states. MOC shifts were analyzed in seven 1/6-octave bands from 1 to 2 kHz. The variability of MOC shifts was analyzed at the frequency band yielding the largest and most stable MOC shift at the first session. Within-subject variability was quantified by the size of the standard deviations across all 16 measurements. Across-subject variability was quantified as the range of MOC shift values across subjects and was also described qualitatively through visual analyses of the data. RESULTS: A large majority of MOC shifts in subjects were statistically significant. Most subjects showed stable MOC shifts across time, as evidenced by small standard deviations and by visual clustering of their data. However, some subjects showed within- and across-session variability that could not be explained by changes in hearing status, middle ear status, or attentional state. Simulations indicated that four baseline measurements were sufficient to predict the expected variability of subsequent measurements. However, the measured variability of subsequent MOC shifts in subjects was often larger than expected (based on the variability present at baseline), indicating the presence of additional variability at subsequent sessions. CONCLUSIONS: Results indicated that a wide range of within- and across-subject variability of MOC shifts was present in a group of young normal-hearing individuals. In some cases, very large changes in MOC shifts (e.g., 1.5 to 2 dB) would need to occur before one could attribute the change to either an intervention or pathology, rather than to measurement variability. It appears that MOC shifts, as analyzed in the present study, may be too variable for clinical use, at least in some individuals. Further study is needed to determine the extent to which changes in MOC shifts can be reliably measured across time for clinical purposes.

Acoustic Hearing After Murine Cochlear Implantation: Effects of Trauma and Implant Type.

OBJECTIVES: To model the contribution of implant material and insertion trauma on loss of acoustic hearing after cochlear implantation in an appropriate animal model. METHODS: Sixty-five C57Bl/6J mice underwent unilateral implantation with implant grade materials: 2 implant grade silicones and a third uncoated platinum wire. A sham surgery group was included as a control. Serial auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were used to discern effects on hearing over 22 weeks. Histologic measurements of damage to the organ of Corti and spiral ganglion were correlated with degree of hearing loss and material type. RESULTS: Organ of Corti damage correlated with rate of hearing loss soon after implantation (0-2 weeks) but not subsequently (2-22 weeks). Organ of Corti damage did not depend on implant type and was present even in sham surgery subjects when hearing was severely damaged. Spiral ganglia appeared unaffected. There was no evidence of an inflammatory or toxic effect of the materials beyond the site of implant insertion. CONCLUSIONS: Hearing loss and cochlear damage appear to be related to insertion trauma, with minimal effect on delayed hearing loss caused by different materials. In the C57Bl/6J mouse model, the sensory epithelium appears to be the location of damage after cochlear implantation.

The effect on localization of frequency-specific gain reduction schemes when matched and mismatched across ears.

OBJECTIVE: To evaluate the impact of non-adaptive matched and mismatched gain reduction schemes on localization in spatially-separated noise. DESIGN: Inspired by the function of commercial noise reduction algorithms, five frequency-specific gain reduction filter schemes were created, three for a modulated babble-noise and two for an unmodulated speech-shaped noise. Applying these schemes as both matched and mismatched conditions across ears, localization of five everyday sounds in noise was measured in a virtual environment using insert earphones. The performance in the reference scheme (no gain reduction in either ear) was measured as well. STUDY SAMPLE: Twenty-four adult bilateral hearing-aid users were enrolled in this study. RESULTS: One of the two mismatched gain reduction schemes for the unmodulated noise had a small but negative impact on localization compared to the reference scheme. For that scheme more high-frequency reduction was noted than for the other schemes. Matching gain reduction across ears restored the deteriorated localization performance. No localization performance differences were observed in the modulated babble-noise regardless of whether the scheme was matched or mismatched across ears. CONCLUSIONS: The impact of noise-induced gain reduction on localization in noise was trivial in the study regardless of whether gain reduction schemes were matched or not across ears.

Human Olivocochlear Effects: A Statistical Detection Approach Applied to the Cochlear Microphonic Evoked by Swept Tones.

The human medial olivocochlear (MOC) reflex was assessed by observing the effects of contralateral acoustic stimulation (CAS) on the cochlear microphonic (CM) across a range of probe frequencies. A frequency-swept probe tone (125-4757 Hz, 90 dB SPL) was presented in two directions (up sweep and down sweep) to normal-hearing young adults. This study assessed MOC effects on the CM in individual participants using a statistical approach that calculated minimum detectable changes in magnitude and phase based on CM signal-to-noise ratio (SNR). Significant increases in CM magnitude, typically 1-2 dB in size, were observed for most participants from 354 to 1414 Hz, where the size and consistency of these effects depended on participant, probe frequency, sweep direction, and SNR. CAS-related phase lags were also observed, consistent with CM-based MOC studies in laboratory animals. Observed effects on CM magnitude and phase were in the opposite directions of reported effects on otoacoustic emissions (OAEs). OAEs are sensitive to changes in the motility of outer hair cells located near the peak region of the traveling wave, while the effects of CAS on the CM likely originate from MOC-related changes in the conductance of outer hair cells located in the basal tail of the traveling wave. Thus, MOC effects on the CM are complementary to those observed for OAEs.

The Origin Along the Cochlea of Otoacoustic Emissions Evoked by Mid-Frequency Tone Pips.

PURPOSE: Tone-pip-evoked otoacoustic emissions (PEOAEs) are transient-evoked otoacoustic emissions (OAEs) that are hypothesized to originate from reflection of energy near the best-frequency (BF) cochlear place of the stimulus frequency. However, individual PEOAEs have energy with a wide range of delays. We sought to determine whether some PEOAE energy is consistent with having been generated far from BF. METHODS: PEOAEs from 35 and 47 dB SPL tone pips were obtained by removing pip-stimulus energy by subtracting the ear-canal sound pressure from scaled-down 59 dB SPL tone pips (which evoke relatively small OAEs). PEOAE delays were measured at each peak in the PEOAE absolute-value waveforms. While measuring PEOAEs and auditory-nerve compound action potentials (CAPs), amplification was blocked sequentially from apex to base by cochlear salicylate perfusion. The perfusion time when a CAP was reduced identified when the perfusion reached the tone-pip BF place. The perfusion times when each PEOAE peak was reduced identified where along the cochlea it received cochlear amplification. PEOAEs and CAPs were measured simultaneously using one pip frequency in each ear (1.4 to 4 kHz across 16 ears). RESULTS: Most PEOAE peaks received amplification primarily between the BF place and 1-2 octaves basal of the BF place. PEOAE peaks with short delays received amplification basal of BF place. PEOAE peaks with longer delays sometimes received amplification apical of BF place, consistent with previous stimulus-frequency-OAE results. CONCLUSION: PEOAEs provide information about cochlear amplification primarily within ~ 1.5 octave of the tone-pip BF place, not about regions > 3 octaves basal of BF.

Short-latency transient-evoked otoacoustic emissions as predictors of hearing status and thresholds.

Estimating audiometric thresholds using objective measures can be clinically useful when reliable behavioral information cannot be obtained. Transient-evoked otoacoustic emissions (TEOAEs) are effective for determining hearing status (normal hearing vs hearing loss), but previous studies have found them less useful for predicting audiometric thresholds. Recent work has demonstrated the presence of short-latency TEOAE components in normal-hearing ears, which have typically been eliminated from the analyses used in previous studies. The current study investigated the ability of short-latency components to predict hearing status and thresholds from 1-4 kHz. TEOAEs were measured in 77 adult ears with thresholds ranging from normal hearing to moderate sensorineural hearing loss. Emissions were bandpass filtered at center frequencies from 1 to 4 kHz. TEOAE waveforms were analyzed within two time windows that contained either short- or long-latency components. Waveforms were quantified by root-mean-square amplitude. Long-latency components were better overall predictors of hearing status and thresholds, relative to short-latency components. There were no significant improvements in predictions when short-latency components were included with long-latency components in multivariate analyses. The results showed that short-latency TEOAE components, as analyzed in the current study, were less predictive of both hearing status and thresholds from 1-4 kHz than long-latency components.

Minimum Detectable Differences in Electrocochleography Measurements: Bayesian-Based Predictions.

Physiology of the cochlea and auditory nerve can be assessed with electrocochleography (ECochG), a technique that involves measuring auditory evoked potentials from an electrode placed near or within the cochlea. Research, clinical, and operating room applications of ECochG have in part centered on measuring the auditory nerve compound action potential (AP) amplitude, the summating potential (SP) amplitude, and the ratio of the two (SP/AP). Despite the common use of ECochG, the variability of repeated amplitude measurements for individuals and groups is not well understood. We analyzed ECochG measurements made with a tympanic membrane electrode in a group of younger normal-hearing participants to characterize the within-participant and group-level variability for the AP amplitude, SP amplitude, and SP/AP amplitude ratio. Results show that the measurements have substantial variability and that, especially with smaller sample sizes, significant reduction in variability can be obtained by averaging measurements across repeated electrode placements within subjects. Using a Bayesian-based model of the data, we generated simulated data to predict minimum detectable differences in AP and SP amplitudes for experiments with a given number of participants and repeated measurements. Our findings provide evidence-based recommendations for the design and sample size determination of future experiments using ECochG amplitude measurements, and the evaluation of previous publications in terms of sensitivity to detecting experimental effects on ECochG amplitude measurements. Accounting for the variability of ECochG measurements should result in more consistent results in the clinical and basic assessments of hearing and hearing loss, either hidden or overt.

Measurement of swept level distortion product otoacoustic emission growth functions at multiple frequencies simultaneously.

Otoacoustic emissions (OAEs) are low-level sounds generated by the inner ear that provide a non-invasive assessment of cochlear health. Advanced applications require recording OAEs across a wide range of frequencies and stimulus levels. Detailed here is a method for efficiently measuring distortion product otoacoustic emissions (DPOAEs) across an expansive stimulus space. Specifically, DPOAEs are recorded by sweeping the evoking stimuli in level across multiple frequencies simultaneously. This method generates DPOAE growth functions at multiple f2 frequencies in several minutes. Results indicate the swept level method yields DPOAEs equivalent to those measured in a traditional (discrete stimulus) paradigm, but with several advantages.

Further assessment of forward pressure level for in situ calibration.

Quantifying ear-canal sound level in forward pressure has been suggested as a more accurate and practical alternative to sound pressure level (SPL) calibrations used in clinical settings. The mathematical isolation of forward (and reverse) pressure requires defining the Thévenin-equivalent impedance and pressure of the sound source and characteristic impedance of the load; however, the extent to which inaccuracies in characterizing the source and/or load impact forward pressure level (FPL) calibrations has not been specifically evaluated. This study examined how commercially available probe tips and estimates of characteristic impedance impact the calculation of forward and reverse pressure in a number of test cavities with dimensions chosen to reflect human ear-canal dimensions. Results demonstrate that FPL calibration, which has already been shown to be more accurate than in situ SPL calibration, can be improved particularly around standing-wave null frequencies by refining estimates of characteristic impedance. Better estimates allow FPL to be accurately calculated at least through 10 kHz using a variety of probe tips in test cavities of different sizes, suggesting that FPL calibration can be performed in ear canals of all sizes. Additionally, FPL calibration appears a reasonable option when quantifying the levels of extended high-frequency (10-18 kHz) stimuli.

Detecting high-frequency hearing loss with click-evoked otoacoustic emissions.

In contrast to clinical click-evoked otoacoustic emission (CEOAE) tests that are inaccurate above 4-5 kHz, a research procedure measured CEOAEs up to 16 kHz in 446 ears and predicted the presence/absence of a sensorineural hearing loss. The behavioral threshold test that served as a reference to evaluate CEOAE test accuracy used a yes-no task in a maximum-likelihood adaptive procedure. This test was highly efficient between 0.5 and 12.7 kHz: Thresholds measured in 2 min per frequency had a median standard deviation (SD) of 1.2-1.5 dB across subjects. CEOAE test performance was assessed by the area under the receiver operating characteristic curve (AUC). The mean AUC from 1 to 10 kHz was 0.90 (SD=0.016). AUC decreased to 0.86 at 12.7 kHz and to 0.7 at 0.5 and 16 kHz, possibly due in part to insufficient stimulus levels. Between 1 and 12.7 kHz, the medians of the magnitude difference in CEOAEs and in behavioral thresholds were <4 dB. The improved CEOAE test performance above 4-5 kHz was due to retaining the portion of the CEOAE response with latencies as short as 0.3 ms. Results have potential clinical significance in predicting hearing status from at least 1 to 10 kHz using a single CEOAE response.

A Time-Course-Based Estimation of the Human Medial Olivocochlear Reflex Function Using Clicks.

The auditory efferent system, especially the medial olivocochlear reflex (MOCR), is implicated in both typical auditory processing and in auditory disorders in animal models. Despite the significant strides in both basic and translational research on the MOCR, its clinical applicability remains under-utilized in humans due to the lack of a recommended clinical method. Conventional tests employ broadband noise in one ear while monitoring change in otoacoustic emissions (OAEs) in the other ear to index efferent activity. These methods, (1) can only assay the contralateral MOCR pathway and (2) are unable to extract the kinetics of the reflexes. We have developed a method that re-purposes the same OAE-evoking click-train to also concurrently elicit bilateral MOCR activity. Data from click-train presentations at 80 dB peSPL at 62.5 Hz in 13 young normal-hearing adults demonstrate the feasibility of our method. Mean MOCR magnitude (1.7 dB) and activation time-constant (0.2 s) are consistent with prior MOCR reports. The data also suggest several advantages of this method including, (1) the ability to monitor MEMR, (2) obtain both magnitude and kinetics (time constants) of the MOCR, (3) visual and statistical confirmation of MOCR activation.

Measurements From Ears With Endolymphatic Hydrops and 2-Hydroxypropyl-Beta-Cyclodextrin Provide Evidence That Loudness Recruitment Can Have a Cochlear Origin.

Background: Loudness recruitment is commonly experienced by patients with putative endolymphatic hydrops. Loudness recruitment is abnormal loudness growth with high-level sounds being perceived as having normal loudness even though hearing thresholds are elevated. The traditional interpretation of recruitment is that cochlear amplification has been reduced. Since the cochlear amplifier acts primarily at low sound levels, an ear with elevated thresholds from reduced cochlear amplification can have normal processing at high sound levels. In humans, recruitment can be studied using perceptual loudness but in animals physiological measurements are used. Recruitment in animal auditory-nerve responses has never been unequivocally demonstrated because the animals used had damage to sensory and neural cells, not solely a reduction of cochlear amplification. Investigators have thus looked for, and found, evidence of recruitment in the auditory central nervous system (CNS). While studies on CNS recruitment are informative, they cannot rule out the traditional interpretation of recruitment originating in the cochlea. Design: We used techniques that could assess hearing function throughout entire frequency- and dynamic-range of hearing. Measurements were made from two animal models: guinea-pig ears with endolymphatic-sac-ablation surgery to produce endolymphatic hydrops, and naïve guinea-pig ears with cochlear perfusions of 13 mM 2-Hydroxypropyl-Beta-Cyclodextrin (HPBCD) in artificial perilymph. Endolymphatic sac ablation caused low-frequency loss. Animals treated with HPBCD had hearing loss at all frequencies. None of these animals had loss of hair cells or synapses on auditory nerve fibers. Results: In ears with endolymphatic hydrops and those perfused with HPBCD, auditory-nerve based measurements at low frequencies showed recruitment compared to controls. Recruitment was not found at high frequencies (> 4 kHz) where hearing thresholds were normal in ears with endolymphatic hydrops and elevated in ears treated with HPBCD. Conclusions: We found compelling evidence of recruitment in auditory-nerve data. Such clear evidence has never been shown before. Our findings suggest that, in patients suspected of having endolymphatic hydrops, loudness recruitment may be a good indication that the associated low-frequency hearing loss originates from a reduction of cochlear amplification, and that measurements of recruitment could be used in differential diagnosis and treatment monitoring of Ménière's disease.

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 µM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

Measurement of hearing aid internal noise.

Hearing aid equivalent input noise (EIN) measures assume the primary source of internal noise to be located prior to amplification and to be constant regardless of input level. EIN will underestimate internal noise in the case that noise is generated following amplification. The present study investigated the internal noise levels of six hearing aids (HAs). Concurrent with HA processing of a speech-like stimulus with both adaptive features (acoustic feedback cancellation, digital noise reduction, microphone directionality) enabled and disabled, internal noise was quantified for various stimulus levels as the variance across repeated trials. Changes in noise level as a function of stimulus level demonstrated that (1) generation of internal noise is not isolated to the microphone, (2) noise may be dependent on input level, and (3) certain adaptive features may contribute to internal noise. Quantifying internal noise as the variance of the output measures allows for noise to be measured under real-world processing conditions, accounts for all sources of noise, and is predictive of internal noise audibility.

Is cochlear synapse loss an origin of low-frequency hearing loss associated with endolymphatic hydrops?

There is a strong association between endolymphatic hydrops and low-frequency hearing loss, but the origin of the hearing loss remains unknown. A reduction in the number of cochlear afferent synapses between inner hair cells and auditory nerve fibres may be the origin of the low-frequency hearing loss, but this hypothesis has not been directly tested in humans or animals. In humans, measurements of hearing loss and postmortem temporal-bone based measurements of endolymphatic hydrops are generally separated by large amounts of time. In animals, there has not been a good objective, physiologic, and minimally invasive measurement of low-frequency hearing. We overcame this obstacle with the combined use of a reliable surgical approach to ablate the endolymphatic sac in guinea pigs and create endolymphatic hydrops, the Auditory Nerve Overlapped Waveform to measure low-frequency hearing loss (≤ 1 kHz), and immunohistofluorescence-based confocal microscopy to count cochlear synapses. Results showed low- and mid-(1-4 kHz) frequency hearing loss at all postoperative days, 1, 4, and 30. There was no statistically significant loss of cochlear synapses, and there was no correlation between synapse loss and hearing function. We conclude that cochlear afferent synaptic loss is not the origin of the low-frequency hearing loss in the early days following endolymphatic sac ablation. Understanding what is, and is not, the origin of a hearing loss can help guide preventative and therapeutic development.