This study examined the relationship between the difference limen for frequency (DLF) of pure tones and three commonly explored stimulus parameters of frequency, duration, and sensation level. Data from 12 published studies of pure-tone frequency discrimination (a total of 583 DLF measurements across 77 normal-hearing listeners) were analyzed using hierarchical (or “mixed-effects”) generalized linear models. Model parameters were estimated using two approaches (Bayesian and maximum likelihood). A model in which log-transformed DLFs were predicted using a sum of power-law functions plus a random subject- or group-specific term was found to explain a substantial proportion of the variability in the psychophysical data. The results confirmed earlier findings of an inverse-square-root relationship between log-transformed DLFs and duration, and of an inverse relationship between log(DLF) and sensation level. However, they did not confirm earlier suggestions that log(DLF) increases approximately linearly with the square-root of frequency; instead, the relationship between frequency and log(DLF) was best fitted using a power function of frequency with an exponent of about 0.8. These results, and the comprehensive quantitative analysis of pure-tone frequency discrimination on which they are based, provide a new reference for the quantitative evaluation of models of frequency (or pitch) discrimination.
frequency discrimination; difference limens; pure tones; pitch; models; Bayesian
Auditory hair cells in the amphibian papilla (APHCs) of the leopard frog, Rana pipiens pipiens, have a significantly higher permeability to water than that observed in mammalian hair cells. The insensitivity of water permeability in frog hair cells to extracellular mercury suggests that an amphibian homologue of the water channel aquaporin-4 (AQP4) may mediate water transport in these cells. Using immunocytochemistry, we show that an AQP4-like protein is found in APHCs. Rabbit anti-AQP4 antibody was used in multiple-immunohistochemical staining experiments along with AP hair cell and hair bundle markers in leopard frog and mouse tissue. AQP4-immunoreactivity was found in the basal and apical poles of the APHCs and shows uniform immunoreactivity. This study provides the first identification and localization of an AQP4-like protein in the amphibian inner ear. We also report a more direct measure of hyperosmotically-induced volume changes in APHCs that confirms previous findings. The presence of water channels in anuran APHCs constitutes a novel physiological difference between amphibian and mammalian hair cell structure and function.
amphibian papilla; aquaporin; AQP4; amphibian; Rana pipiens
Up to 7% of patients with severe-to-profound deafness do not benefit from cochlear implantation. Given the high surgical implantation and clinical management cost of cochlear implantation (> $1 million lifetime cost), prospective identification of the worst performers would reduce unnecessary procedures and healthcare costs. Because cochlear implants bypass the membranous labyrinth but rely on the spiral ganglion for functionality, we hypothesize that cochlear implant (CI) performance is dictated in part by the anatomic location of the cochlear pathology that underlies the hearing loss. As a corollary, we hypothesize that because genetic testing can identify sites of cochlear pathology, it may be useful in predicting CI performance.
29 adult CI recipients with idiopathic adult-onset severe-to-profound hearing loss were studied. DNA samples were subjected to solution-based sequence capture and massively parallel sequencing using the OtoSCOPE® platform. The cohort was divided into three CI performance groups (good, intermediate, poor) and genetic causes of deafness were correlated with audiometric data to determine whether there was a gene-specific impact on CI performance.
The genetic cause of deafness was determined in 3/29 (10%) individuals. The two poor performers segregated mutations in TMPRSS3, a gene expressed in the spiral ganglion, while the good performer segregated mutations in LOXHD1, a gene expressed in the membranous labyrinth. Comprehensive literature review identified other good performers with mutations in membranous labyrinth-expressed genes; poor performance was associated with spiral ganglion-expressed genes.
Our data support the underlying hypothesis that mutations in genes preferentially expressed in the spiral ganglion portend poor CI performance while mutations in genes expressed in the membranous labyrinth portend good CI performance. Although the low mutation rate in known deafness genes in this cohort likely relates to the ascertainment characteristics (postlingual hearing loss in adult CI recipients), these data suggest that genetic testing should be implemented as part of the CI evaluation to test this association prospectively.
Cochlear implant performance; spiral ganglion; hearing loss; genetic testing; massively parallel sequencing
Pitch experiments aimed at evaluating temporal pitch mechanism(s) often utilize complex sounds with only unresolved harmonic components, and a low-pass noise masker to eliminate the potential contribution of audible distortion products to the pitch percept. Herein we examine how: (i) masker induced reduction of neural distortion products (difference tone: DT; and cubic difference tone: CDT) alters the representation of pitch relevant information in the brainstem; and (ii) the pitch salience is altered when distortion products are reduced and/or eliminated. Scalp recorded brainstem frequency following responses (FFR) were recorded in normal hearing individuals using a complex tone with only unresolved harmonics presented in quiet, and in the presence of a low-pass masker at SNRs of +15, +5, and −5 dB. Difference limen for F0 discrimination (F0 DL) was obtained in quiet and in the presence of low-pass noise. Magnitude of DT components (with the exception of components at F0 and 2F0), and the CDT components decreased with increasing masker level. Neural pitch strength decreased with increasing masker level for both the envelope-related (FFRENV) and spectral-related (FFRSPEC) phase-locked activity. Finally, F0 DLs increased with decreasing SNRs suggesting poorer F0 discrimination with reduction of the distortion products. Collectively, these findings support the notion that both DT and CDT, as reflected in the FFRENV and FFRSPEC, respectively, influence both the brainstem representation of pitch relevant information and the pitch salience of the complex sounds.
Recent studies indicate that the gap over outer hair cells (OHCs) between the reticular lamina (RL) and the tectorial membrane (TM) varies cyclically during low-frequency sounds. Variation in the RL-TM gap produces radial fluid flow in the gap that can drive inner hair cell (IHC) stereocilia. Analysis of RL-TM gap changes reveals three IHC drives in addition to classic SHEAR. For upward basilar-membrane (BM) motion, IHC stereocilia are deflected in the excitatory direction by SHEAR and OHC-MOTILITY, but in the inhibitory direction by TM-PUSH and CILIA-SLANT. Upward BM motion causes OHC somatic contraction which tilts the RL, compresses the RL-TM gap over IHCs and expands the RL-TM gap over OHCs, thereby producing an outward (away from the IHCs) radial fluid flow which is the OHC-MOTILITY drive. For upward BM motion, the force that moves the TM upward also compresses the RL-TM gap over OHCs causing inward radial flow past IHCs which is the TM-PUSH drive. Motions that produce large tilting of OHC stereocilia squeeze the supra-OHC RL-TM gap and caused inward radial flow past IHCs which is the CILIA-SLANT drive. Combinations of these drives explain: (1) the reversal at high sound levels of auditory nerve (AN) initial peak (ANIP) responses to clicks, and medial olivocochlear (MOC) inhibition of ANIP responses below, but not above, the ANIP reversal, (2) dips and phase reversals in AN responses to tones in cats and chinchillas, (3) hypersensitivity and phase reversals in tuning-curve tails after OHC ablation, and (4) MOC inhibition of tail-frequency AN responses. The OHC-MOTILITY drive provides another mechanism, in addition to BM motion amplification, that uses active processes to enhance the output of the cochlea. The ability of these IHC drives to explain previously anomalous data provides strong, although indirect, evidence that these drives are significant and presents a new view of how the cochlea works at frequencies below 3 kHz.
cochlear mechanics; cochlear micromechanics; cochlear amplifier; BM motion amplifier; IHC drive amplifier
Implementation of the deep-etch technique enabled unprecedented definition of substructural elements of otoconia, including the fibrillar meshwork of the inner core with its globular attachments. Subsequently the effects of the principal soluble otoconial protein, otoconin 90, upon calcite crystal growth in vitro were determined, including an increased rate of nucleation, inhibition of growth kinetics and significant morphologic changes. The logical next step, ultrastructural localization of otoconin 90, by means of immunogold TEM in young mature mice, demonstrated a high density of gold particles in the inner core in spite of a relatively low level of mineralization. Here gold particles are typically arranged in oval patterns implying that otoconin 90 is attached to a scaffold consisting of the hexagonal fibrillar meshwork, characteristic of otolin. The level of mineralization is much higher in the outer cortex where mineralized fiber bundles are arranged parallel to the surface. Following decalcification, gold particles, as well as matrix fibrils, presumed to consist of a linear structural phenotype of otolin, are aligned in identical direction, suggesting that they serve as scaffold to guide mineralization mediated by otoconin 90. In the faceted tips, the level of mineralization is highest, even though the density of gold particles is relatively low, conceivably due to the displacement by the dense mineral phase. TEM shows that individual crystallites assemble into iso-oriented columns. Columns are arranged in parallel lamellae which convert into mineralized blocks for hierarchical assembly into the complex otoconial mosaic.
Another set of experiments based on immunogold TEM in young mice demonstrates that the fibrils interconnecting otoconia consist of the short chain collagen otolin. By two years of age the superficial layer of mouse otoconia (corresponding to mid-life human) has become demineralized resulting in weakening or loss of anchoring of the fibrils interconnecting otoconia. Consequently, otoconia detached from each other may be released into the endolymphatic space by minor mechanical disturbances. In humans, benign positional vertigo (BPV) is believed to result from translocation of otoconia from the endolymphatic space into the semi-circular canals rendering their receptors susceptible to stimulation by gravity causing severe attacks of vertigo. The combinations of these observations in humans, together with the presented animal experiments, provide a tentative pathogenetic basis of the early stage of BPV.
Almost all of the processing that occurs in the various lower auditory nuclei converges upon a common target in the central nucleus of the inferior colliculus (ICc) thus making the ICc the nexus of the auditory system. A variety of new response properties are formed in the ICc through the interactions among the excitatory and inhibitory inputs that converge upon it. Here we review studies that illustrate the dominant role inhibition plays in the ICc. We begin by reviewing studies of tuning curves and show how inhibition shapes the variety of tuning curves in the ICc through sideband inhibition. We then show how inhibition shapes selective response properties for complex signals, focusing on selectivity for the sweep direction of frequency modulations (FM). In the final section we consider results from in vivo whole-cell recordings that show how parameters of the incoming excitation and inhibition interact to shape directional selectivity. We show that post-synaptic potentials (PSPs) evoked by different signals can be similar but evoke markedly different spike-counts. In these cases, spike threshold acts as a non-linear amplifier that converts small differences in PSPs into large differences in spike output. Such differences between the inputs to a cell compared to the outputs from the same cell suggest that highly selective discharge properties can be created by only minor adjustments in the synaptic strengths evoked by one or both signals. These findings also suggest that plasticity of response features may be achieved with far less modifications in circuitry than previously supposed.
Human listeners sensitivity to interaural time differences (ITD) was assessed for 1000 Hz tone bursts (500 ms duration) preceded by trains of 500-ms “adapter” tone bursts (7 s total adapter duration, frequencies of 200, 665, 1000, or 1400 Hz) carrying random ITD, or by an equal-duration period of silence. Presentation of the adapter burst train reduced ITD sensitivity in a frequency-specific manner. The observed effect differs from previously described forms of location-specific psychophysical adaptation, as it was produced using a binaurally diffuse sequence of tone bursts (i.e., a location-nonspecific adapter stimulus). Results are discussed in the context of pre-binaural adaptation.
Sound localization; binaural sensitivity; psychophysical adaptation; ITD discrimination
Phantom electrode (PE) stimulation consists of out-of-phase stimulation of two electrodes. When presented at the apex of the electrode array, phantom stimulation is known to produce a lower pitch sensation than monopolar (MP) stimulation on the most apical electrode. The ratio of the current between the primary electrode (PEL) and the compensating electrode (CEL) is represented by the coefficient σ, which ranges from 0 (monopolar) to 1 (full bipolar). The exact mechanism by which PE stimulation produces a lower pitch sensation is unclear. In the present study, unmasked and masked thresholds were obtained using a forward masking paradigm to estimate the spread of current for MP and PE stimulation. Masked thresholds were measured for two phantom electrode configurations (1) PEL = 4, CEL = 5 (lower pitch phantom) and (2) PEL = 4, CEL = 3 (higher pitch phantom). The unmasked thresholds were subtracted from the masked thresholds to obtain masking patterns which were normalized to their peak. The masking patterns reveal (1) differences in the spread of excitation that are consistent with the direction of pitch shift produced by PE stimulation, and (2) narrower spread of electrical excitation for PE stimulation relative to MP stimulation.
The marmoset (Callithrix jacchus) is a valuable non-human primate model for studying behavioral and neural mechanisms related to vocal communication. It is also well suited for investigating neural mechanisms related to cochlear implants. The purpose of this study was to characterize marmoset temporal bone anatomy and investigate the feasibility of implanting a multi-channel intracochlear electrode into the marmoset scala tympani. Micro computed tomography (microCT) was used to create high-resolution images of marmoset temporal bones. Cochlear fluid spaces, middle ear ossicles, semicircular canals and the surrounding temporal bone were reconstructed in three-dimensional space. Our results show that the marmoset cochlea is ~16.5 mm in length and has ~2.8 turns. The cross-sectional area of the scala tympani is greatest (~0.8 mm2) at ~1.75 mm from the base of the scala, reduces to ~0.4 mm2 at 5 mm from the base, and decreases at a constant rate for the remaining length. Interestingly, this length-area profile, when scaled 2.5 times, is similar to the scala tympani of the human cochlea. Given these dimensions, a compatible multi-channel implant electrode was identified. In a cadaveric specimen, this electrode was inserted ¾ turn into the scala tympani through a cochleostomy at ~1 mm apical to the round window. The depth of the most apical electrode band was ~8 mm. Our study provides detailed structural anatomy data for the middle and inner ear of the marmoset, and suggests the potential of the marmoset as a new non-human primate model for cochlear implant research.
cochlear implant; marmoset; cochlear scalae; temporal bone anatomy
Deiters cells extend from the basilar membrane to the reticular lamina and, together with pillar cells and outer hair cells, structurally define the micro-architecture of the organ of Corti. Studying vibrotome sections of the mouse organ of Corti with confocal and scanning electron microscopy we found that the basal pole of every Deiters cell, independently of their position in the organ of Corti and along the cochlear spiral, attached to the basilar membrane within a 15.1±0.3 µm-wide stripe running the length of the cochlear spiral adjacent to the row of outer pillar cells. All Deiters cells’ basal poles had similar diameter and general morphology, and distributed on the stripe in a precise arrangement with a center-to-center distance of 7.1±0.3 µm between neighbor cells of the same row and 5.9±0.4 µm for neighbor cells in adjacent rows. Complete detachment of Deiters cells revealed an elliptical imprint on the top surface of the basilar membrane consisting of a smaller central structure with a very smooth surface surrounded by a rougher area, suggesting the presence of two different anchoring junctions. These previously unidentified morphological features of Deiters cells could be critical for the mechanical response of the organ of Corti.
Deiters cells; pillar cells; basilar membrane; cochlear micromechanics; organ of Corti; cochlea
This study focused on mechanisms underlying azimuth selectivity in the primary auditory cortex (A1) of pallid bats. The pallid bat listens to prey-generated noise (5–35 kHz) to localize and hunt terrestrial prey. The region of A1 tuned between 5–35 kHz consists of two clusters of neurons distinguished by interaural intensity difference (IID) selectivity: binaurally inhibited (EI) and peaked. The first aim of this study was to use sequential dichotic/free-field stimulation to test the hypothesis that IID is the primary cue underlying azimuth selectivity in neurons tuned in the prey-generated noise frequency band. IID selectivity and ear directionality at the neuron’s characteristic frequency (CF) were used to predict azimuth selectivity functions. The predicted azimuth selectivity was compared with the actual azimuth selectivity from the same neurons. Prediction accuracy was similarly high for EI neurons and peaked neurons with low CF, whereas predictions were increasingly inaccurate with increasing CF among the peaked neurons. The second aim of this study was to compare azimuth selectivity obtained with noise and CF tones to determine the extent to which stimulus bandwidth influences azimuth selectivity in neurons with different binaural properties. The azimuth selectivity functions were similar for the two stimuli in the majority of EI neurons. A greater percentage of peaked neurons showed differences in their azimuth selectivity for noise and tones. This included neurons with multiple peaks when tested with tones and a single peak when tested with noise. Taken together, data from the two aims suggest that azimuth tuning of EI neurons is primarily dictated by IID sensitivity at CF. Peaked neurons, particularly those with high CF, may integrate IID sensitivity across frequency to generate azimuth selectivity for broadband sound. The data are consistent with those found in cat and ferret A1 in that binaurally facilitated neurons depend to a greater extent (compared to EI neurons) on spectral integration of binaural properties to generate azimuth selectivity for broadband stimuli.
sound localization; binaural properties; azimuth tuning; auditory cortex; pallid bat
Some forms of tinnitus are likely to be perceptual consequences of altered neural activity in the central auditory system triggered by damage to the auditory periphery. Animal studies report changes in the evoked responses after noise exposure or ototoxic drugs in inferior colliculus and auditory cortex. However, human electrophysiological evidence is rather equivocal: increased, reduced or no difference in N1/N1m evoked amplitudes and latencies in tinnitus participants have been reported.
The present study used magnetoencephalography to seek evidence for altered evoked responses in people with tinnitus compared to controls (hearing loss matched and normal hearing) in four different stimulus categories (a control tone, a tone corresponding to the audiometric edge, to the dominant tinnitus pitch and a tone within the area of hearing loss). Results revealed that amplitudes of the evoked responses differed depending on the tone category. N1m amplitude to the dominant tinnitus pitch and the frequency within the area of hearing loss were reduced compared to the other two categories. Given that tinnitus pitch is typically within the area of hearing loss, the differences in the evoked responses pattern in tinnitus participants seem to be related more to the hearing loss than to the presence of tinnitus.
•We use MEG to compare evoked responses in participants with tinnitus and controls.•We compare N1m responses to control, edge, tinnitus and hearing loss tone.•N1m amplitudes to the tinnitus and hearing loss tones are reduced.•Differences in N1m amplitudes are related to hearing loss rather than tinnitus.•There are no tinnitus-specific changes in the pattern of N1m responses.
ABR, auditory brainstem responses; ANOVA, analysis of variance; EEG, electroencephalography; HL, hearing loss; MEG, magnetoencephalography; PTA, pure tone average; SL, sensation level; TI, tinnitus; THI, Tinnitus Handicap Inventory
The electrically-evoked compound action potential (ECAP) is the synchronous whole auditory nerve activity in response to an electrical stimulus, and can be recorded in situ on cochlear implant (CI) electrodes. A novel procedure (ECAP-ICA) to isolate the ECAP from the stimulation artifact, based on independent component analysis (ICA), is described here. ECAPs with artifact (raw-ECAPs) were sequentially recorded for the same stimulus on 9 different intracochlear recording electrodes. The raw-ECAPs were fed to ICA, which separated them into independent sources. Restricting the ICA projection to 4 independent components did not induce under-fitting and was found to explain most of the raw-data variance. The sources were identified and only the source corresponding to the neural response was retained for artifact-free ECAP reconstruction. The validity of the ECAP-ICA procedure was supported as follows: N1 and P1 peaks occurred at usual latencies; and ECAP-ICA and artifact amplitude-growth functions (AGFs) had different slopes. Concatenation of raw-ECAPs from multiple stimulus currents, including some below the ECAP-ICA threshold, improved the source separation process. The main advantage of ECAP-ICA is that use of maskers or alternating polarity stimulation are not needed.
•Novel technique to cancel artifact in electrically-evoked compound action potentials.•No maskers or alternate polarity are required.•ECAPs output from the procedure are compared to forward-masking technique.
AN, auditory nerve; CI, cochlear implant; CI24RE, Cochlear® Nucleus Freedom™ cochlear implant – 22 active electrodes and 2 ground electrodes; ECAP, electrically-evoked compound action potential; ECAP-FM, ECAP obtained with the forward-masking technique; ECAP-ICA, ECAP obtained with the ICA artifact rejection technique; ICA, independent component analysis; IC, independent component (or source); JADE-R, joint approximate diagonalisation of the cross-cumulants eigenmatrices (computational implementation of ICA); MP1, extracochlear ground electrode; MP2, ground electrode placed on the case of the cochlear implant; N1P1, peak-to-peak voltage difference measurement of ECAP amplitude; RMS, root mean square; SNR, signal to noise ratio
The aims of this paper are to (i) provide a brief history of cochlear implants; (ii) present a status report on the current state of implant engineering and the levels of speech understanding enabled by that engineering; (iii) describe limitations of current signal processing strategies and (iv) suggest new directions for research. With current technology the “average” implant patient, when listening to predictable conversations in quiet, is able to communicate with relative ease. However, in an environment typical of a workplace the average patient has a great deal of difficulty. Patients who are “above average” in terms of speech understanding, can achieve 100% correct scores on the most difficult tests of speech understanding in quiet but also have significant difficulty when signals are presented in noise. The major factors in these outcomes appear to be (i) a loss of low-frequency, fine structure information possibly due to the envelope extraction algorithms common to cochlear implant signal processing; (ii) a limitation in the number of effective channels of stimulation due to overlap in electric fields from electrodes, and (iii) central processing deficits, especially for patients with poor speech understanding. Two recent developments, bilateral implants and combined electric and acoustic stimulation, have promise to remediate some of the difficulties experienced by patients in noise and to reinstate low-frequency fine structure information. If other possibilities are realized, e.g., electrodes that emit drugs to inhibit cell death following trauma and to induce the growth of neurites toward electrodes, then the future is very bright indeed.
Auditory prosthesis; Cochlear implant; Cortical plasticity; Deafness; Electrical stimulation; Hearing; Neural prosthesis; Speech perception
Perceptual weights were estimated in a pitch-comparison experiment to assess the relative influences of individual partial tones on listeners’ pitch judgments. The stimuli were harmonic sounds (F0 = 200 Hz) with partials up to the 12th. Low-numbered partials were removed step-by-step, so that the remaining higher-numbered partials would have a better chance of showing any effect. The individual frequencies of the partials were perturbed randomly on each stimulus presentation, and weights were estimated as the correlation coefficients between the frequency perturbations and the listeners’ responses. When the harmonic sounds contained all twelve partials, the listeners depended mostly on the low-numbered, resolved partials within the well-established dominance region. As the low-numbered partials were taken out of the dominance region, the listeners began to focus on only the lowest and highest partials at the spectral edges. For one listener, such an edge-listening strategy took the form of relying on nonlinear combination tones. Overall, there was no indication of any influence on pitch from unresolved partials, thus no evidence of contribution to pitch from temporal cues carried by this group of partials. The estimated patterns of weights were well described by the predictions of Goldstein’s optimal-processor model. The predicted weights were inversely proportional to the amount of error for estimating the individual frequencies of the partials. The agreement between the predicted and measured weights suggests that, for harmonic sounds, partials whose frequencies are perceived with the best precision will likely have the greatest influence on perceived pitch.
harmonic pitch; resolved and unresolved partials; place and temporal cues; perceptual weights; correlation analysis
This report introduces a system for the objective physiological classification of single-unit activity in the anteroventral cochlear nucleus (AVCN) of anesthetized CBA/129 and CBA/CaJ mice. As in previous studies, the decision criteria are based on the temporal properties of responses to short tone bursts that are visualized in the form of peri-stimulus time histograms (PSTHs). Individual unit types are defined by the statistical distribution of quantifiable metrics that relate to the onset latency, regularity, and adaptation of sound-driven discharge rates. Variations of these properties reflect the unique synaptic organizations and intrinsic membrane properties that dictate the selective tuning of sound coding in the AVCN. When these metrics are applied to the mouse AVCN, responses to best frequency (BF) tones reproduce the major PSTH patterns that have been previously demonstrated in other mammalian species. The consistency of response types in two genetically diverse strains of laboratory mice suggests that the present classification system is appropriate for additional strains with normal peripheral function. The general agreement of present findings to established classifications validates laboratory mice as an adequate model for general principles of mammalian sound coding. Nevertheless, important differences are noted for the reliability of specialized endbulb transmission within the AVCN, suggesting less secure temporal coding in this high-frequency species.
peri-stimulus time histograms; onset latency; regularity analysis; prepotential; rate adaptation
Brief tones of 1.0 and 8.0 kHz were used to evoke auditory brainstem responses (ABRs), and the differences between the wave-V latencies for those two frequencies were used as a proxy for cochlear length. The tone bursts (8 ms in duration including 2-ms rise/fall times, and 82 dB in level) were, or were not, accompanied by a continuous, moderately intense noise band, highpass filtered immediately above the tone. The proxy values for length were compared with various measures of otoacoustic emissions (OAEs) obtained from the same ears. All the correlations were low, suggesting that cochlear length, as measured by this proxy at least, is not strongly related to the various group and individual differences that exist in OAEs. Female latencies did not differ across the menstrual cycle, and the proxy length measure exhibited no sex difference (either for menses females vs. males or midluteal females vs. males) when the highpass noises were used. However, when the subjects were partitioned into Whites and Non-Whites, a substantial sex difference in cochlear length did emerge for the White group, although the correlations with OAEs remained low. Head size was not highly correlated with any of the ABR measures.
auditory brainstem response (ABR); otoacoustic emission (OAE); cochlear length; sex difference; race difference; menstrual difference
Loss of hair cells in humans leads to irreversible hearing deficits, since auditory hair cells are not replaced. In contrast, hair cells are regenerated in the auditory epithelium of mature birds after damage by non-sensory supporting cells that transdifferentiate into hair cells by mitotic and/or non-mitotic mechanisms. Factors controlling these processes are poorly understood. The basic helix-loop-helix transcription factor ATOH1 is both necessary and sufficient for developmental hair cell differentiation, but it is unclear if it plays the same role in the mitotic and non-mitotic pathways in hair cell regeneration. We examined Atoh1 expression and function during hair cell regeneration in chickens. Atoh1 transcripts were increased in many supporting cells in the damaged auditory epithelium shortly after ototoxin administration and later became restricted to differentiating hair cells. Fate-mapping in vitro using an Atoh1 enhancer reporter demonstrated that only 56% of the supporting cells that spontaneously upregulate Atoh1 enhancer activity after damage acquired the hair cell fate. Inhibition of notch signaling using a gamma secretase antagonist stimulated an increase in Atoh1 reporter activity and induced a higher proportion of supporting cells with Atoh1 activity (73%) to differentiate as hair cells. Forced overexpression of Atoh1 in supporting cells triggered 66% of them to acquire the hair cell fate and nearly tripled their likelihood of cell cycle entry. These findings demonstrate that Atoh1 is broadly upregulated in supporting cells after damage, but a substantial proportion of supporting cells with Atoh1 activation fails to acquire hair cell features, in part due to gamma secretase-dependent activities.
Auditory brainstem responses (ABRs), and envelope and frequency following responses (EFRs and FFRs) are widely used to study aberrant auditory processing in conditions such as aging. We have previously reported age-related deficits in auditory processing for rapid amplitude modulation (AM) frequencies using EFRs recorded from a single channel. However sensitive testing of EFRs along a wide range of modulation frequencies is required to gain a more complete understanding of the auditory processing deficits. In this study, ABRs and EFRs were recorded simultaneously from two electrode configurations in young and old Fischer-344 rats, a common auditory aging model. Analysis shows that the two channels respond most sensitively to complementary AM frequencies. Channel 1, recorded from Fz to mastoid, responds better to faster AM frequencies in the 100–700 Hz range of frequencies, while Channel 2, recorded from the inter-aural line to the mastoid, responds better to slower AM frequencies in the 16–100 Hz range. Simultaneous recording of channels 1 and 2 using AM stimuli with varying sound levels and modulation depths show that age related deficits in temporal processing are not present at slower AM frequencies but only at more rapid ones, which would not have been apparent recording from either channel alone. Comparison of EFRs between unanesthetized and isoflurane anesthetized recordings in young animals, as well as comparison with previously published ABR waveforms, suggests that the generators of Channel 1 may emphasize more caudal brainstem structures while those of Channel 2 may emphasize more rostral auditory nuclei including the inferior colliculus and the forebrain, with the boundary of separation potentially along the cochlear nucleus/superior olivary complex. Simultaneous two channel recording of EFRs help to give a more complete understanding of the properties of auditory temporal processing over a wide range of modulation frequencies which is useful in understanding neural representations of sound stimuli in normal, developmental or pathological conditions
Envelope following response; FFR; ABR; Isoflurane; brainstem; inferior colliculus; evoked potentials
The avian basilar papilla (BP) is a likely homolog of the auditory sensory epithelium of the mammalian cochlea, the organ of Corti. During mammalian development Fibroblast growth factor receptor-3 (Fgfr3) is known to regulate the differentiation of auditory mechanosensory hair cells (HCs) and supporting cells (SCs), both of which are required for sound detection. Fgfr3 is expressed in developing progenitor cells (PCs) and SCs of both the BP and the organ of Corti; however its role in BP development is unknown. Here we utilized an in vitro whole organ embryonic culture system to examine the role of Fgf signaling in the developing avian cochlea. SU5402 (an antagonist of Fgf signaling) was applied to developing BP cultures at different stages to assay the role of Fgf signaling during HC formation. Similar to the observed effects of inhibition of Fgfr3 in the mammalian cochlea, Fgfr inhibition in the developing BP increased the number of HCs that formed. This increase was not associated with increased proliferation, suggesting that inhibition of the Fgf pathway leads to the direct conversion of PCs or supporting cells into HCs, a process known as transdifferentiation. This also implies that Fgf signaling is required to prevent the conversion of PCs and SCs into HCs. The ability of Fgf signaling to inhibit transdifferentiation suggests that its down-regulation may be essential for the initial steps of HC formation, as well as for the maintenance of SC phenotypes.
Fgf; transdifferentiation; hair cell; basilar papilla; supporting cell; SU5402
Early experience of structured inputs and complex sound features generate lasting changes in tonotopy and receptive field properties of primary auditory cortex (A1). In this study we tested whether these changes are severe enough to alter neural representations and behavioral discrimination of speech. We exposed two groups of rat pups during the critical period of auditory development to pulsed noise or speech. Both groups of rats were trained to discriminate speech sounds when they were young adults, and anesthetized neural responses were recorded from A1. The representation of speech in A1 and behavioral discrimination of speech remained robust to altered spectral and temporal characteristics of A1 neurons after pulsed-noise exposure. Exposure to passive speech during early development provided no added advantage in speech sound processing. Speech training increased A1 neuronal firing rate for speech stimuli in naïve rats, but did not increase responses in rats that experienced early exposure to pulsed noise or speech. Our results suggest that speech sound processing is resistant to changes in simple neural response properties caused by manipulating early acoustic environment.
pulsed-noise; early acoustic experience; primary auditory cortex; speech discrimination; plasticity; critical period
A wideband (WB) aural acoustical test battery of middle-ear status, including acoustic-reflex thresholds (ARTs) and acoustic-transfer functions (ATFs, i.e., absorbance and admittance) was hypothesized to be more accurate than 1-kHz tympanometry in classifying ears that pass or refer on a newborn hearing screening (NHS) protocol based on otoacoustic emissions. Assessment of middle-ear status may improve NHS programs by identifying conductive dysfunction and cases in which auditory neuropathy exists. Ipsilateral ARTs were assessed with a stimulus including four broadband-noise or tonal activator pulses alternating with five clicks presented before, between and after the pulses. The reflex shift was defined as the difference between final and initial click responses. ARTs were measured using maximum likelihood both at low frequencies (0.8–2.8 kHz) and high (2.8–8 kHz). The median low-frequency ART was elevated by 24 dB in NHS refers compared to passes. An optimal combination of ATF and ART tests performed better than either test alone in predicting NHS outcomes, and WB tests performed better than 1-kHz tympanometry. Medial olivocochlear efferent shifts in cochlear function may influence ARs, but their presence would also be consistent with normal conductive function. Baseline clinical and WB ARTs were also compared in ipsilateral and contralateral measurements in adults.
acoustic reflex; middle-ear muscle; medial olivocochlear efferent; newborn hearing screening
Transtympanic administration of gentamicin is a widely accepted and effective approach for treating patients with intractable vertigo. Previous studies have demonstrated the uptake, distribution and effects of gentamicin in peripheral vestibular and cochlear structures after transtympanic injection. However, little is known about whether transtympanically administered gentamicin is trafficked into more central auditory and vestibular structures and its effect on these structures. In this study, we used immunofluorescence to determine the distribution of gentamicin within the auditory and vestibular brainstem. We observed gentamicin immunolabeling bilaterally in the vestibular efferent neurons, and in the superior olivary complex, and ipsilaterally in the cochlear nucleus 24 h after transtympanic administration of gentamicin, and that the drug could still be detected in these locations 30 days after injection. In contrast, no gentamicin labeling was detected in the vestibular nuclear complex. In the vestibular efferent neurons and superior olivary complex, gentamicin labeling was detected in the cytoplasm and cell processes, while in the cochlear nucleus gentamicin is mainly localized outside and adjacent to the cell bodies of neurons. Nerve fibers in cochlear nucleus, root of eighth nerve, as well as descending pathways from the superior olivary complex, are also immunolabeled with gentamicin continuously. Based on these data, we hypothesize that retrograde axonal transport of gentamicin is responsible for the distribution of gentamicin in these efferent nuclei including vestibular efferent neurons and superior olivary complex and anterograde axonal transport into the ipsilateral cochlear nucleus.
The objective of this study was to develop reliable pediatric psychophysical methodologies in order to address the limits of frequency and electrode discrimination in children with cochlear implants. Discrimination was measured with a two-alternative, adaptive, forced choice design using a video game graphical user interface. Implanted children were compared to normal-hearing children in the same age ranges. Twenty-nine implanted children and 68 children with normal-hearing performed frequency discrimination studies at varying frequencies. Electrode discrimination was assessed in thirty-four implanted children at varying electrode locations and stimulation intensities. Older children had better frequency discrimination than younger children, both for implanted and hearing subjects. Implanted children had worse frequency discrimination overall and exhibited learning effects at older ages than hearing children. Frequency discrimination Weber fractions were smallest in low frequencies. Electrode discrimination improved with stimulus intensity level for older but not younger children at all electrode locations. These results support the premise that developmental changes in signal processing contribute to discrimination of simple acoustic stimuli. For implanted children, auditory discrimination improved at lower frequencies and with electrodes at higher intensity. These findings imply that spatial separation may not be the key determinant in creating discriminable electrical stimuli for this population.