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1.  Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss 
Exogenous tumor necrosis factor-alpha (TNF-α) plays a role in auditory hair cell death by altering the expression of apoptosis-related genes in response to noxious stimuli. Little is known, however, about the function of TNF-α in normal hair cell physiology. We, therefore, investigated the cochlear morphology and auditory function of TNF-α-deficient mice. Auditory evoked brainstem response showed significantly higher thresholds, especially at higher frequencies, in 1-month-old TNF-α−/− mice as compared to TNF-α+/− and wild type (WT); hearing loss did not progress further from 1 to 4 months of age. There was no difference in the gross morphology of the organ of Corti, lateral wall, and spiral ganglion cells in TNF-α−/− mice compared to WT mice at 4 months of age, nor were there differences in the anatomy of the auditory ossicles. Outer hair cells were completely intact in surface preparations of the organ of Corti of TNF-α−/− mice, and synaptic ribbon counts of TNF-α−/− and WT mice at 4 months of age were similar. Reduced amplitudes of distortion product otoacoustic emissions, however, indicated dysfunction of outer hair cells in TNF-α−/− mice. Scanning electron microscopy revealed that stereocilia were sporadically absent in the basal turn and distorted in the middle turn. In summary, our results demonstrate that TNF-α-mutant mice exhibit early hearing loss, especially at higher frequencies, and that loss or malformation of the stereocilia of outer hair cells appears to be a contributing factor.
doi:10.1007/s10162-013-0410-3
PMCID: PMC3825018  PMID: 23996384
TNF-alpha-deficient mice; higher frequency hearing loss; malformation of the stereocilia of outer hair cells
2.  Medial Olivocochlear-Induced Transient-Evoked Otoacoustic Emission Amplitude Shifts in Individual Subjects 
ABSTRACT
Activation of the medial olivocochlear reflex (MOCR) can be assessed indirectly using transient-evoked otoacoustic emissions (TEOAEs). The change in TEOAE amplitudes when the MOCR is activated (medial olivocochlear (MOC) shift) has most often been quantified as the mean value in groups of subjects. The usefulness of MOC shift measurements may be increased by the ability to quantify significant shifts in individuals. This study used statistical resampling to quantify significant MOC shifts in 16 subjects. TEOAEs were obtained using transient stimuli containing energy from 1 to 10 kHz. A nonlinear paradigm was used to extract TEOAEs. Transient stimuli were presented at 30 dB sensation level (SL) with suppressor stimuli presented 12 dB higher. Contralateral white noise, used to activate the MOCR, was presented at 30 dB SL and was interleaved on and off in 30-s intervals during a 7-min recording period. Confounding factors of middle ear muscle reflex and slow amplitude drifts were accounted for. TEOAEs were analyzed in 11 1/3-octave frequency bands. The statistical significance of each individual MOC shift was determined using a bootstrap procedure. The minimum detectable MOC shifts ranged from 0.10 to 3.25 dB and were highly dependent on signal-to-noise ratio at each frequency. Subjects exhibited a wide range of magnitudes of significant MOC shifts in the 1.0–3.2-kHz region (median = 1.94 dB, range = 0.34–6.51 dB). There was considerable overlap between the magnitudes of significant and nonsignificant shifts. While most subjects had significant MOC shifts in one or more frequency bands below 4 kHz, few had significant shifts in all of these bands. Above 4 kHz, few significant shifts were seen, but this may have been due to lower signal-to-noise ratios. The specific frequency bands containing significant shifts were variable across individuals. Further work is needed to determine the clinical usefulness of examining MOC shifts in individuals.
doi:10.1007/s10162-013-0409-9
PMCID: PMC3825019  PMID: 23982894
MOC; efferent; contralateral suppression; TEOAE; statistical validity; prevalence
3.  A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2 
Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P < 10−4 and 12 imputed SNPs with P < 10−4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P = 1.30 × 10−5) on chromosome 2 in the independent otitis media population (P = 4.7 × 10−5; meta-analysis P = 1.52 × 10−8). Three additional SNPs had replication P values < 0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P = 3.4 ×10−7) in KIF7 intron 7 (P = 0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P = 0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P = 0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.
doi:10.1007/s10162-013-0411-2
PMCID: PMC3825021  PMID: 23974705
otitis media; genetics; genome; susceptibility; locus
4.  Predicting Perception in Noise Using Cortical Auditory Evoked Potentials 
Speech perception in background noise is a common challenge across individuals and health conditions (e.g., hearing impairment, aging, etc.). Both behavioral and physiological measures have been used to understand the important factors that contribute to perception-in-noise abilities. The addition of a physiological measure provides additional information about signal-in-noise encoding in the auditory system and may be useful in clarifying some of the variability in perception-in-noise abilities across individuals. Fifteen young normal-hearing individuals were tested using both electrophysiology and behavioral methods as a means to determine (1) the effects of signal-to-noise ratio (SNR) and signal level and (2) how well cortical auditory evoked potentials (CAEPs) can predict perception in noise. Three correlation/regression approaches were used to determine how well CAEPs predicted behavior. Main effects of SNR were found for both electrophysiology and speech perception measures, while signal level effects were found generally only for speech testing. These results demonstrate that when signals are presented in noise, sensitivity to SNR cues obscures any encoding of signal level cues. Electrophysiology and behavioral measures were strongly correlated. The best physiological predictors (e.g., latency, amplitude, and area of CAEP waves) of behavior (SNR at which 50 % of the sentence is understood) were N1 latency and N1 amplitude measures. In addition, behavior was best predicted by the 70-dB signal/5-dB SNR CAEP condition. It will be important in future studies to determine the relationship of electrophysiology and behavior in populations who experience difficulty understanding speech in noise such as those with hearing impairment or age-related deficits.
doi:10.1007/s10162-013-0415-y
PMCID: PMC3825022  PMID: 24030818
cortical auditory evoked potentials (CAEPs); event-related potentials (ERPs); signals in noise; signal-to-noise ratio (SNR); background noise; N1
5.  Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae 
Balance disorders caused by hair cell loss in the sensory organs of the vestibular system pose a significant health problem worldwide, particularly in the elderly. Currently, this hair cell loss is permanent as there is no effective treatment. This is in stark contrast to nonmammalian vertebrates who robustly regenerate hair cells after damage. This disparity in regenerative potential highlights the need for further manipulation in order to stimulate more robust hair cell regeneration in mammals. In the utricle, Notch signaling is required for maintaining the striolar support cell phenotype into the second postnatal week. Notch signaling has further been implicated in hair cell regeneration after damage in the mature utricle. Here, we investigate the role of Notch signaling in the mature mammalian cristae in order to characterize the Notch-mediated regenerative potential of these sensory organs. For these studies, we used the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), in conjunction with a method we developed to culture cristae in vitro. In postnatal and adult cristae, we found that 5 days of DAPT treatment resulted in a downregulation of the Notch effectors Hes1 and Hes5 and also an increase in the total number of Gfi1+ hair cells. Hes5, as reported by Hes5-GFP, was downregulated specifically in peripheral support cells. Using lineage tracing with proteolipid protein (PLP)/CreER;mTmG mice, we found that these hair cells arose through transdifferentiation of support cells in cristae explanted from mice up to 10 weeks of age. These transdifferentiated cells arose without proliferation and were capable of taking on a hair cell morphology, migrating to the correct cell layer, and assembling what appears to be a stereocilia bundle with a long kinocilium. Overall, these data show that Notch signaling is active in the mature cristae and suggest that it may be important in maintaining the support cell fate in a subset of peripheral support cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s10162-013-0414-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s10162-013-0414-z
PMCID: PMC3825023  PMID: 23989618
inner ear; regeneration; vestibular; DAPT
6.  Directional Plasticity Rapidly Improves 3D Vestibulo-Ocular Reflex Alignment in Monkeys Using a Multichannel Vestibular Prosthesis 
Bilateral loss of vestibular sensation can be disabling. We have shown that a multichannel vestibular prosthesis (MVP) can partly restore vestibular sensation as evidenced by improvements in the 3-dimensional angular vestibulo-ocular reflex (3D VOR). However, a key challenge is to minimize misalignment between the axes of eye and head rotation, which is apparently caused by current spread beyond each electrode’s targeted nerve branch. We recently reported that rodents wearing a MVP markedly improve 3D VOR alignment during the first week after MVP activation, probably through the same central nervous system adaptive mechanisms that mediate cross-axis adaptation over time in normal individuals wearing prisms that cause visual scene movement about an axis different than the axis of head rotation. We hypothesized that rhesus monkeys would exhibit similar improvements with continuous prosthetic stimulation over time. We created bilateral vestibular deficiency in four rhesus monkeys via intratympanic injection of gentamicin. A MVP was mounted to the cranium, and eye movements in response to whole-body passive rotation in darkness were measured repeatedly over 1 week of continuous head motion-modulated prosthetic electrical stimulation. 3D VOR responses to whole-body rotations about each semicircular canal axis were measured on days 1, 3, and 7 of chronic stimulation. Horizontal VOR gain during 1 Hz, 50 °/s peak whole-body rotations before the prosthesis was turned on was <0.1, which is profoundly below normal (0.94 ± 0.12). On stimulation day 1, VOR gain was 0.4–0.8, but the axis of observed eye movements aligned poorly with head rotation (misalignment range ∼30–40 °). Substantial improvement of axis misalignment was observed after 7 days of continuous motion-modulated prosthetic stimulation under normal diurnal lighting. Similar improvements were noted for all animals, all three axes of rotation tested, for all sinusoidal frequencies tested (0.05–5 Hz), and for high-acceleration transient rotations. VOR asymmetry changes did not reach statistical significance, although they did trend toward slight improvement over time. Prior studies had already shown that directional plasticity reduces misalignment when a subject with normal labyrinths views abnormal visual scene movement. Our results show that the converse is also true: individuals receiving misoriented vestibular sensation under normal viewing conditions rapidly adapt to restore a well-aligned 3D VOR. Considering the similarity of VOR physiology across primate species, similar effects are likely to occur in humans using a MVP to treat bilateral vestibular deficiency.
doi:10.1007/s10162-013-0413-0
PMCID: PMC3825024  PMID: 24013822
vestibular nerve; vestibular prosthesis; vestibular implant; vestibulo-ocular reflex; VOR; labyrinth; bilateral vestibular deficiency; adaptation; electrical stimulation
7.  Stimulus-Frequency Otoacoustic Emission Suppression Tuning in Humans: Comparison to Behavioral Tuning 
As shown by the work of Kemp and Chum in 1980, stimulus-frequency otoacoustic emission suppression tuning curves (SFOAE STCs) have potential to objectively estimate behaviorally measured tuning curves. To date, this potential has not been tested. This study aims to do so by comparing SFOAE STCs and behavioral measures of tuning (simultaneous masking psychophysical tuning curves, PTCs) in 10 normal-hearing listeners for frequency ranges centered around 1,000 and 4,000 Hz at low probe levels. Additionally, SFOAE STCs were collected for varying conditions (probe level and suppression criterion) to identify the optimal parameters for comparison with behavioral data and to evaluate how these conditions affect the features of SFOAE STCs. SFOAE STCs qualitatively resembled PTCs: they demonstrated band-pass characteristics and asymmetric shapes with steeper high-frequency sides than low, but unlike PTCs they were consistently tuned to frequencies just above the probe frequency. When averaged across subjects the shapes of SFOAE STCs and PTCs showed agreement for most recording conditions, suggesting that PTCs are predominantly shaped by the frequency-selective filtering and suppressive effects of the cochlea. Individual SFOAE STCs often demonstrated irregular shapes (e.g., “double-tips”), particularly for the 1,000-Hz probe, which were not observed for the same subject’s PTC. These results show the limited utility of SFOAE STCs to assess tuning in an individual. The irregularly shaped SFOAE STCs may be attributed to contributions from SFOAE sources distributed over a region of the basilar membrane extending beyond the probe characteristic place, as suggested by a repeatable pattern of SFOAE residual phase shifts observed in individual data.
doi:10.1007/s10162-013-0412-1
PMCID: PMC3825025  PMID: 24013802
frequency selectivity; normal hearing; psychophysical tuning curve
8.  Clinical Testing of Otolith Function: Perceptual Thresholds and Myogenic Potentials 
Cervical and ocular vestibular-evoked myogenic potential (cVEMP/oVEMP) tests are widely used clinical tests of otolith function. However, VEMP testing may not be the ideal measure of otolith function given the significant inter-individual variability in responses and given that the stimuli used to elicit VEMPs are not physiological. We therefore evaluated linear motion perceptual threshold testing compared with cVEMP and oVEMP testing as measures of saccular and utricular function, respectively. A multi-axis motion platform was used to measure horizontal (along the inter-aural and naso-occipital axes) and vertical motion perceptual thresholds. These findings were compared with the vibration-evoked oVEMP as a measure of utricular function and sound-evoked cVEMP as a measure of saccular function. We also considered how perceptual threshold and cVEMP/oVEMP testing are each associated with Dizziness Handicap Inventory (DHI) scores. We enrolled 33 patients with bilateral vestibulopathy of different severities and 42 controls to have sufficient variability in otolith function. Subjects with abnormal oVEMP amplitudes had significantly higher (poorer) perceptual thresholds in the inter-aural and naso-occipital axes in age-adjusted analyses; no significant associations were observed for vertical perceptual thresholds and cVEMP amplitudes. Both oVEMP amplitudes and naso-occipital axis perceptual thresholds were significantly associated with DHI scores. These data suggest that horizontal perceptual thresholds and oVEMPs may estimate the same underlying physiological construct: utricular function.
doi:10.1007/s10162-013-0416-x
PMCID: PMC3825026  PMID: 24077672
DHI score; motion perception threshold testing; otolith function; vestibular-evoked myogenic potential
9.  Threshold Levels of Dual Electrode Stimulation in Cochlear Implants 
Simultaneous stimulation on two contacts (current steering) creates intermediate pitches between the physical contacts in cochlear implants. All recent studies on current steering have focused on Most Comfortable Loudness levels and not at low stimulation levels. This study investigates the efficacy of dual electrode stimulation at lower levels, thereby focusing on the requirements to correct for threshold variations. With a current steered signal, threshold levels were determined on 4 different electrode pairs for 7 different current steering coefficients (α). This was done psychophysically in twelve postlingually deafened cochlear implant (HiRes90K, HiFocus1J) users and, in a computer model, which made use of three different neural morphologies. The analysis on the psychophysical data taking all subjects into account showed that in all conditions there was no significant difference between the threshold level of the physical contacts and the intermediate created percepts, eliminating the need for current corrections at these very low levels. The model data showed unexpected drops in threshold in the middle of the two physical contacts (both contacts equal current). Results consistent with this prediction were obtained for a subset of 5 subjects for the apical pair with wider spacing (2.2 mm). Further analysis showed that this decrease was only observed in subjects with a long duration of deafness. For current steering on adjacent contacts, the results from the psychophysical experiments were in line with the results from computational modelling. However, the dip in the threshold profile could only be replicated in the computational model with surviving peripheral processes without an unmyelinated terminal. On the basis of this result, we put forward that the majority of the surviving spiral ganglion cells in the cochlea in humans with a long duration of deafness still retain peripheral processes, but have lost their unmyelinated terminals.
doi:10.1007/s10162-013-0395-y
PMCID: PMC3767869  PMID: 23695303
current steering; computational model; peripheral processes; unmyelinated terminal
10.  Dopamine Modulates Auditory Responses in the Inferior Colliculus in a Heterogeneous Manner 
Perception of complex sounds such as speech is affected by a variety of factors, including attention, expectation of reward, physiological state, and/or disorders, yet the mechanisms underlying this modulation are not well understood. Although dopamine is commonly studied for its role in reward-based learning and in disorders, multiple lines of evidence suggest that dopamine is also involved in modulating auditory processing. In this study, we examined the effects of dopamine application on neuronal response properties in the inferior colliculus (IC) of awake mice. Because the IC contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase, we predicted that dopamine would modulate auditory responses in the IC. We recorded single-unit responses before, during, and after the iontophoretic application of dopamine using piggyback electrodes. We examined the effects of dopamine on firing rate, timing, and probability of bursting. We found that application of dopamine affected neural responses in a heterogeneous manner. In more than 80 % of the neurons, dopamine either increased (32 %) or decreased (50 %) firing rate, and the effects were similar on spontaneous and sound-evoked activity. Dopamine also either increased or decreased first spike latency and jitter in almost half of the neurons. In 3/28 neurons (11 %), dopamine significantly altered the probability of bursting. The heterogeneous effects of dopamine observed in the IC of awake mice were similar to effects observed in other brain areas. Our findings indicate that dopamine differentially modulates neural activity in the IC and thus may play an important role in auditory processing.
doi:10.1007/s10162-013-0405-0
PMCID: PMC3767870  PMID: 23835945
mouse; iontophoresis; midbrain; D2 receptors
11.  Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss 
Several nitriles, including allylnitrile and cis-crotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2-dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement.
doi:10.1007/s10162-013-0399-7
PMCID: PMC3767873  PMID: 23749193
ototoxicity; vestibular toxicity; allylnitrile; cis-crotononitrile; mouse; hair cell ablation
12.  Classifying Human Audiometric Phenotypes of Age-Related Hearing Loss from Animal Models 
Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations (“audiometric phenotypes”). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for “exemplars” (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans.
doi:10.1007/s10162-013-0396-x
PMCID: PMC3767874  PMID: 23740184
metabolic presbyacusis; sensory presbyacusis; endocochlear potential; animal models; audiogram classification; supervised machine learning classifiers
13.  Identification of Inputs to Olivocochlear Neurons Using Transneuronal Labeling with Pseudorabies Virus (PRV) 
Olivocochlear (OC) neurons respond to sound and provide descending input that controls processing in the cochlea. The identities of neurons in the pathways providing inputs to OC neurons are incompletely understood. To explore these pathways, the retrograde transneuronal tracer pseudorabies virus (Bartha strain, expressing green fluorescent protein) was used to label OC neurons and their inputs in guinea pigs. Labeling of OC neurons began 1 day after injection into the cochlea. On day 2 (and for longer survival times), transneuronal labeling spread to the cochlear nucleus, inferior colliculus, and other brainstem areas. There was a correlation between the numbers of these transneuronally labeled neurons and the number of labeled medial (M) OC neurons, suggesting that the spread of labeling proceeds mainly via synapses on MOC neurons. In the cochlear nucleus, the transneuronally labeled neurons were multipolar cells including the subtype known as planar cells. In the central nucleus of the inferior colliculus, transneuronally labeled neurons were of two principal types: neurons with disc-shaped dendritic fields and neurons with dendrites in a stellate pattern. Transneuronal labeling was also observed in pyramidal cells in the auditory cortex and in centers not typically associated with the auditory pathway such as the pontine reticular formation, subcoerulean nucleus, and the pontine dorsal raphe. These data provide information on the identity of neurons providing input to OC neurons, which are located in auditory as well as non-auditory centers.
doi:10.1007/s10162-013-0400-5
PMCID: PMC3767876  PMID: 23728891
superior olive; cochlear nucleus; inferior colliculus; reflex pathway; reticular formation
14.  An Analysis of the Acoustic Input Impedance of the Ear 
Ear canal acoustics was examined using a one-dimensional lossy transmission line with a distributed load impedance to model the ear. The acoustic input impedance of the ear was derived from sound pressure measurements in the ear canal of healthy human ears. A nonlinear least squares fit of the model to data generated estimates for ear canal radius, ear canal length, and quantified the resistance that would produce transmission losses. Derivation of ear canal radius has application to quantifying the impedance mismatch at the eardrum between the ear canal and the middle ear. The length of the ear canal was found, in general, to be longer than the length derived from the one-quarter wavelength standing wave frequency, consistent with the middle ear being mass-controlled at the standing wave frequency. Viscothermal losses in the ear canal, in some cases, may exceed that attributable to a smooth rigid wall. Resistance in the middle ear was found to contribute significantly to the total resistance. In effect, this analysis “reverse engineers” physical parameters of the ear from sound pressure measurements in the ear canal.
doi:10.1007/s10162-013-0407-y
PMCID: PMC3767877  PMID: 23917695
ear canal acoustics; input impedance
15.  The Effect of Flying and Low Humidity on the Admittance of the Tympanic Membrane and Middle Ear System 
ABSTRACT
Many passengers experience discomfort during flight because of the effect of low humidity on the skin, eyes, throat, and nose. In this physiological study, we have investigated whether flight and low humidity also affect the tympanic membrane. From previous studies, a decrease in admittance of the tympanic membrane through drying might be expected to affect the buffering capacity of the middle ear and to disrupt automatic pressure regulation. This investigation involved an observational study onboard an aircraft combined with experiments in an environmental chamber, where the humidity could be controlled but could not be made to be as low as during flight. For the flight study, there was a linear relationship between the peak compensated static admittance of the tympanic membrane and relative humidity with a constant of proportionality of 0.00315 mmho/% relative humidity. The low humidity at cruise altitude (minimum 22.7 %) was associated with a mean decrease in admittance of about 20 % compared with measures in the airport. From the chamber study, we further found that a mean decrease in relative humidity of 23.4 % led to a significant decrease in mean admittance by 0.11 mmho [F(1,8) = 18.95, P = 0.002], a decrease of 9.4 %. The order of magnitude for the effect of humidity was similar for the flight and environmental chamber studies. We conclude that admittance changes during flight were likely to have been caused by the low humidity in the aircraft cabin and that these changes may affect the automatic pressure regulation of the middle ear during descent.
doi:10.1007/s10162-013-0408-x
PMCID: PMC3767878  PMID: 23887775
air travel; tympanic membrane; relative humidity; admittance; otic barotrauma; pressure regulation
16.  Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line 
Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.
doi:10.1007/s10162-013-0404-1
PMCID: PMC3767879  PMID: 23821348
aminoglycoside; ototoxicity; neuromast; hearing loss; Danio rerio
17.  On the Controversy About the Sharpness of Human Cochlear Tuning 
In signal processing terms, the operation of the mammalian cochlea in the inner ear may be likened to a bank of filters. Based on otoacoustic emission evidence, it has been recently claimed that cochlear tuning is sharper for human than for other mammals. The claim was corroborated with a behavioral method that involves the masking of pure tones with forward notched noises (NN). Using this method, it has been further claimed that human cochlear tuning is sharper than suggested by earlier behavioral studies. These claims are controversial. Here, we contribute to the controversy by theoretically assessing the accuracy of the NN method at inferring the bandwidth (BW) of nonlinear cochlear filters. Behavioral forward masking was mimicked using a computer model of the squared basilar membrane response followed by a temporal integrator. Isoresponse and isolevel versions of the forward masking NN method were applied to infer the already known BW of the cochlear filter used in the model. We show that isolevel methods were overall more accurate than isoresponse methods. We also show that BWs for NNs and sinusoids equate only for isolevel methods and when the levels of the two stimuli are appropriately scaled. Lastly, we show that the inferred BW depends on the method version (isolevel BW was twice as broad as isoresponse BW at 40 dB SPL) and on the stimulus level (isoresponse and isolevel BW decreased and increased, respectively, with increasing level over the level range where cochlear responses went from linear to compressive). We suggest that the latter may contribute to explaining the reported differences in cochlear tuning across behavioral studies and species. We further suggest that given the well-established nonlinear nature of cochlear responses, even greater care must be exercised when using a single BW value to describe and compare cochlear tuning.
doi:10.1007/s10162-013-0397-9
PMCID: PMC3767880  PMID: 23690279
frequency selectivity; cochlear nonlinearity; forward masking; notched noise; auditory model
18.  Gaze Shifts to Auditory and Visual Stimuli in Cats 
While much is known about the metrics and kinematics of gaze shifts to visual targets in cats, little is known about gaze shifts to auditory targets. Here, cats were trained to localize auditory and visual targets via gaze shifts. Five properties of gaze shifts to sounds were observed. First, gaze shifts were accomplished primarily by large head movements. Unlike primates, the head movement in cats often preceded eye movement though the relative timing of eye in head and head latencies depended upon the target modality and gaze shift magnitude. Second, gaze shift latencies to auditory targets tended to be shorter than equivalent shifts to visual targets for some conditions. Third, the main sequences relating gaze amplitude to maximum gaze velocity for auditory and visual targets were comparable. However, head movements to auditory and visual targets were less consistent than gaze shifts and tended to undershoot the targets by 30 % for both modalities. Fourth, at the end of gaze movement, the proportion of the gaze shift accomplished by the eye-in-head movement was greater to visual than auditory targets. On the other hand, at the end of head movement, the proportion of the gaze shift accomplished by the head was greater to auditory than visual targets. Finally, gaze shifts to long-duration auditory targets were accurate and precise and were similar to accuracy of gaze shifts to long-duration visual targets. Because the metrics of gaze shifts to visual and auditory targets are nearly equivalent, as well as their accuracy, we conclude that both sensorimotor tasks use primarily the same neural substrates for the execution of movement.
doi:10.1007/s10162-013-0401-4
PMCID: PMC3767881  PMID: 23749194
sound localization; saccade; gaze shift; cat
20.  Experimental Study of Vibrations of Gerbil Tympanic Membrane with Closed Middle Ear Cavity 
The purpose of the present work is to investigate the spatial vibration pattern of the gerbil tympanic membrane (TM) as a function of frequency. In vivo vibration measurements were done at several locations on the pars flaccida and pars tensa, and along the manubrium, on surgically exposed gerbil TMs with closed middle ear cavities. A laser Doppler vibrometer was used to measure motions in response to audio frequency sine sweeps in the ear canal. Data are presented for two different pars flaccida conditions: naturally flat and retracted into the middle ear cavity. Resonance of the flat pars flaccida causes a minimum and a shallow maximum in the displacement magnitude of the manubrium and pars tensa at low frequencies. Compared with a flat pars flaccida, a retracted pars flaccida has much lower displacement magnitudes at low frequencies and does not affect the responses of the other points. All manubrial and pars tensa points show a broad resonance in the range of 1.6 to 2 kHz. Above this resonance, the displacement magnitudes of manubrial points, including the umbo, roll off with substantial irregularities. The manubrial points show an increasing displacement magnitude from the lateral process toward the umbo. Above 5 kHz, phase differences between points along the manubrium start to become more evident, which may indicate flexing of the tip of the manubrium or a change in the vibration mode of the malleus. At low frequencies, points on the posterior side of the pars tensa tend to show larger displacements than those on the anterior side. The simple low-frequency vibration pattern of the pars tensa becomes more complex at higher frequencies, with the breakup occurring at between 1.8 and 2.8 kHz. These observations will be important for the development and validation of middle ear finite-element models for the gerbil.
doi:10.1007/s10162-013-0389-9
PMCID: PMC3705090  PMID: 23624883
middle ear; pars tensa; pars flaccida; manubrium; vibration pattern; laser Doppler vibrometry
21.  Early Development of Hearing in Zebrafish 
The zebrafish (Danio rerio) has become a valuable vertebrate model for human hearing and balance disorders because it combines powerful genetics, excellent embryology, and exceptional in vivo visualization in one organism. In this study, we investigated auditory function of zebrafish at early developmental stages using the microphonic potential method. This is the first study to report ontogeny of response of hair cells in any fish during the first week post fertilization. The right ear of each zebrafish embedded in agarose was linearly stimulated with a glass probe that was driven by a calibrated piezoelectric actuator. Using beveled micropipettes filled with standard fish saline, extracellular microphonic potentials were recorded from hair cells in the inner ear of zebrafish embryos or larvae in response to 20, 50, 100, and 200-Hz stimulation. Saccular hair cells expressing green fluorescent protein of the transgenic zebrafish from 2 to 7 days post fertilization (dpf) were visualized and quantified using confocal microscopy. The otic vesicles’ areas, otoliths’ areas, and saccular hair cell count and density increased linearly with age and standard body length. Microphonic responses increased monotonically with stimulus intensity, stimulus frequency, and age of zebrafish. Microphonic threshold at 200 Hz gradually decreased with zebrafish age. The increases in microphonic response and sensitivity correlate with the increases in number and density of hair cells in the saccule. These results enhance our knowledge of early development of auditory function in zebrafish and provide the control data that can be used to evaluate hearing of young zebrafish morphants or mutants.
doi:10.1007/s10162-013-0386-z
PMCID: PMC3705082  PMID: 23575600
hair cell; inner ear; otic vesicle; otolith organ; saccule; utricle
22.  Full-Field Thickness Distribution of Human Tympanic Membrane Obtained with Optical Coherence Tomography 
The full-field thickness distribution, three-dimensional surface model and general morphological data of six human tympanic membranes are presented. Cross-sectional images were taken perpendicular through the membranes using a high-resolution optical coherence tomography setup. Five normal membranes and one membrane containing a pathological site are included in this study. The thickness varies strongly across each membrane, and a great deal of inter-specimen variability can be seen in the measurement results, though all membranes show similar features in their respective relative thickness distributions. Mean thickness values across the pars tensa ranged between 79 and 97 μm; all membranes were thinnest in the central region between umbo and annular ring (50–70 μm), and thickness increased steeply over a small distance to approximately 100–120 μm when moving from the central region either towards the peripheral rim of the pars tensa or towards the manubrium. Furthermore, a local thickening was noticed in the antero–inferior quadrant of the membranes, and a strong linear correlation was observed between inferior–posterior length and mean thickness of the membrane. These features were combined into a single three-dimensional model to form an averaged representation of the human tympanic membrane. 3D reconstruction of the pathological tympanic membrane shows a structural atrophy with retraction pocket in the inferior portion of the pars tensa. The change of form at the pathological site of the membrane corresponds well with the decreased thickness values that can be measured there.
doi:10.1007/s10162-013-0394-z
PMCID: PMC3705083  PMID: 23673509
eardrum; OCT; finite element modeling; pars tensa; 3D model
23.  Detection of Tones and Their Modification by Noise in Nonhuman Primates 
A fundamental function of the auditory system is to detect important sounds in the presence of other competing environmental sounds. This paper describes behavioral performance in a tone detection task by nonhuman primates (Macaca mulatta) and the modification of the performance by continuous background noise and by sinusoidally amplitude modulating signals or noise. Two monkeys were trained to report detection of tones in a reaction time Go/No-Go task using the method of constant stimuli. The tones spanned a wide range of frequencies and sound levels, and were presented alone or in continuous broadband noise (40 kHz bandwidth). Signal detection theoretic analysis revealed that thresholds to tones were lowest between 8 and 16 kHz, and were higher outside this range. At each frequency, reaction times decreased with increases in tone sound pressure level. The slope of this relationship was higher at frequencies below 1 kHz and was lower for higher frequencies. In continuous broadband noise, tone thresholds increased at the rate of 1 dB/dB of noise for frequencies above 1 kHz. Noise did not change either the reaction times for a given tone sound pressure level or the slopes of the reaction time vs. tone level relationship. Amplitude modulation of tones resulted in reduced threshold for nearly all the frequencies tested. Amplitude modulation of the tone caused thresholds for detection in continuous broadband noise to be changed by smaller amounts relative to the detection of steady-state tones in noise. Amplitude modulation of background noise resulted in reduction of detection thresholds of steady-state tones by an average of 11 dB relative to thresholds in steady-state noise of equivalent mean amplitude. In all cases, the slopes of the reaction time vs. sound level relationship were not modified. These results show that macaques have hearing functions similar to those measured in humans. These studies form the basis for ongoing studies of neural mechanisms of hearing in noisy backgrounds.
doi:10.1007/s10162-013-0384-1
PMCID: PMC3705086  PMID: 23515749
threshold; reaction time slope; amplitude modulation
24.  Conductive Hearing Loss Induced by Experimental Middle-Ear Effusion in a Chinchilla Model Reveals Impaired Tympanic Membrane-Coupled Ossicular Chain Movement 
Otitis media with effusion (OME) occurs when fluid collects in the middle-ear space behind the tympanic membrane (TM). As a result of this effusion, sounds can become attenuated by as much as 30–40 dB, causing a conductive hearing loss (CHL). However, the exact mechanical cause of the hearing loss remains unclear. Possible causes can include altered compliance of the TM, inefficient movement of the ossicular chain, decreased compliance of the oval window-stapes footplate complex, or altered input to the oval and round window due to conduction of sound energy through middle-ear fluid. Here, we studied the contribution of TM motion and umbo velocity to a CHL caused by middle-ear effusion. Using the chinchilla as an animal model, umbo velocity (VU) and cochlear microphonic (CM) responses were measured simultaneously using sinusoidal tone pip stimuli (125 Hz–12 kHz) before and after filling the middle ear with different volumes (0.5–2.0 mL) of silicone oil (viscosity, 3.5 Poise). Concurrent increases in CM thresholds and decreases in umbo velocity were noted after the middle ear was filled with 1.0 mL or more of fluid. Across animals, completely filling the middle ear with fluid caused 20–40-dB increases in CM thresholds and 15–35-dB attenuations in umbo velocity. Clinic-standard 226-Hz tympanometry was insensitive to fluid-associated changes in CM thresholds until virtually the entire middle-ear cavity had been filled (approximately >1.5 mL). The changes in umbo velocity, CM thresholds, and tympanometry due to experimentally induced OME suggest CHL arises primarily as a result of impaired TM mobility and TM-coupled umbo motion plus additional mechanisms within the middle ear.
doi:10.1007/s10162-013-0388-x
PMCID: PMC3705087  PMID: 23615802
conductive hearing loss; tympanometry; umbo velocity; middle-ear effusion; cochlear microphonic
25.  Perception of Across-Frequency Asynchrony by Listeners with Cochlear Hearing Loss 
Cochlear hearing loss is often associated with broader tuning of the cochlear filters. Cochlear response latencies are dependent on the filter bandwidths, so hearing loss may affect the relationship between latencies across different characteristic frequencies. This prediction was tested by investigating the perception of synchrony between two tones exciting different regions of the cochlea in listeners with hearing loss. Subjective judgments of synchrony were compared with thresholds for asynchrony discrimination in a three-alternative forced-choice task. In contrast to earlier data from normal-hearing (NH) listeners, the synchronous-response functions obtained from the hearing-impaired (HI) listeners differed in patterns of symmetry and often had a very low peak (i.e., maximum proportion of “synchronous” responses). Also in contrast to data from NH listeners, the quantitative and qualitative correspondence between the data from the subjective and the forced-choice tasks was often poor. The results do not provide strong evidence for the influence of changes in cochlear mechanics on the perception of synchrony in HI listeners, and it remains possible that age, independent of hearing loss, plays an important role in temporal synchrony and asynchrony perception.
doi:10.1007/s10162-013-0387-y
PMCID: PMC3705088  PMID: 23612740
synchrony perception; cochlear delays; asynchrony detection; asynchrony discrimination; hearing loss

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