Representation of the vowel /epsilon/ in normal and impaired auditory nerve fibers: model predictions of responses in cats.

The temporal response of auditory-nerve (AN) fibers to a steady-state vowel is investigated using a computational auditory-periphery model. The model predictions are validated against a wide range of physiological data for both normal and impaired fibers in cats. The model incorporates two parallel filter paths, component 1 (C1) and component 2 (C2), which correspond to the active and passive modes of basilar membrane vibration, respectively, in the cochlea. The outputs of the two filters are subsequently transduced by two separate functions, added together, and then low-pass filtered by the inner hair cell (IHC) membrane, which is followed by the IHC-AN synapse and discharge generator. The C1 response dominates at low and moderate levels and is responsible for synchrony capture and multiformant responses seen in the vowel responses. The C2 response dominates at high levels and contributes to the loss of synchrony capture observed in normal and impaired fibers. The interaction between C1 and C2 responses explains the behavior of AN fibers in the transition region, which is characterized by two important observations in the vowel responses: First, all components of the vowel undergo the C1/C2 transition simultaneously, and second, the responses to the nonformant components of the vowel become substantial.

The role of deferoxamine in the prevention of gentamicin ototoxicity: a histological and audiological study in guinea pigs.

CONCLUSION: The addition of deferoxamine to gentamicin seems to confer partial functional and histological protection to the cochlea. OBJECTIVE: Aminoglycosides are known ototoxic agents. The toxicity occurs via an activation process involving the formation of an iron-gentamicin complex with free radical production. Iron chelation will supposedly limit this toxic effect. This study aimed to determine the possible cochleoprotective role of deferoxamine on the ototoxic effect of gentamicin. MATERIALS AND METHODS: Sixty healthy active guinea pigs, weighing 400-600 g, with an average age of 6 months were used. They were divided into three groups. Group 1 received intramuscular gentamicin 8 mg/kg/day, group 2 received gentamicin 8 mg/kg/day and deferoxamine 150 mg/kg twice daily for 19 days and group 3 served as a control. All animals had a baseline measurement of distortion product oto-acoustic emissions. At the end of 33 days they were submitted to another measurement and then the animals were sacrificed and their cochleas were examined histologically by light and transmission electron microscopy. RESULTS: In group 1 the mean amplitude post-injection ranged from 5.83 dB at 1001 Hz to 22.33 dB at 6348 Hz. In the deferoxamine + gentamicin group the mean amplitude post-injection ranged from 5.10 dB at 1001 Hz, to 24.45 dB at 6348 Hz. This was statistically significant. At 4004, 5042 and 6348 Hz group 2 showed less histological damage than group 1.

Electrophysiological correlates of progressive sensorineural pathology in carboplatin-treated chinchillas.

Carboplatin produces progressive damage to auditory nerve fibers, spiral ganglion neurons (SGNs) and inner hair cells (IHC) in the chinchilla cochlea but leaves outer hair cells intact. Within 1 h after injection, many afferent terminals beneath IHCs and myelin lamellae surrounding SGN processes are vacuolated. One day after injection, approximately half of the nerve fibers are missing. IHCs are intact at 2 days, but 20-30% are missing at 3 days. We studied the electrophysiological correlates of this progressive morphological damage by recording cochlear microphonics (CM), distortion product otoacoustic emissions (DPOAE), summating potentials (SP), compound action potentials (CAP) and midbrain evoked potentials (IC-EVP) before and 1 h, 12 h, 1 days, 3 days, 5 days, 7 days and 14 days after carboplatin injection (75 mg/kg IP) in four chinchillas. CM and DPOAEs tended to be unchanged or enhanced. CAP and SP showed little change until Day 3, when amplitudes were reduced in all animals and CAP thresholds were elevated by 9 dB; amplitudes declined further between Days 3 and 5 but not thereafter. IC-EVP amplitudes decreased on Days 3 or 5 but thresholds were relatively unchanged. All animals showed some recovery of IC-EVP between Days 7 and 14, including one with 70% enhancement on Day 14. The results indicate that threshold and amplitude measures fail to detect peripheral pathology until some relatively high threshold level of damage has been exceeded. This has important implications for monitoring peripheral damage and interpreting electrophysiological test results in animals and humans.

High-frequency tinnitus without hearing loss does not mean absence of deafferentation.

A broad consensus within the neuroscience of tinnitus holds that this audiologic condition is triggered by central deafferentation, mostly due to cochlear damage. The absence of audiometrically detectable hearing loss however poses a challenge to this rather generalizing assumption. The aim of this study was therefore to scrutinize cochlear functioning in a sample of tinnitus subjects audiometrically matched to a normal hearing control group. Two tests were applied: the Threshold Equalizing Noise (TEN) test and a pitch scaling task. To perform well on both tasks relatively normal functioning of inner hair cells is a requirement. In the TEN test the tinnitus group revealed a circumscribed increment of thresholds partially overlapping with the tinnitus spectrum. Abnormal slopes were observed in the pitch scaling task which indicated that tinnitus subjects, when presented with a high-frequency stimulus, relied heavily on input derived from lower-frequency inner hair cells (off-frequency listening). In total both results argue for the presence of a deafferentation also in tinnitus subjects with audiometrically normal thresholds and therefore favour the deafferentation assumption posed by most neuroscientific theories.

Low-dose, long-term caroverine administration attenuates impulse noise-induced hearing loss in the rat.

CONCLUSION: Physiological and morphological assessments indicated that low-dose and long-term caroverine delivery might be a new approach to protect against impulse noise-induced hearing loss. BACKGROUND: Although the exact mechanisms by which impulse noise causes hearing loss are still unclear, there is accumulating evidence that increased reactive oxygen species (ROS) production and excessive glutamate released from the inner hair cells lead to hair cell loss and consequently hearing loss. Caroverine is an antagonist of two glutamate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the inner ear, as well as an antioxidant. MATERIALS AND METHODS: In this study, caroverine was delivered subcutaneously using an osmotic pump. This kind of delivery has the advantage, via continuous, long-term and low dose drug administration, of avoiding systemic side effects. RESULTS: It was shown that caroverine could significantly protect the cochlea against impulse noise trauma.

[Diagnosis and therapy of auditory synaptopathy/neuropathy]. / Diagnostik und Therapie der auditorischen Synaptopathie/Neuropathie.

Pathological auditory brainstem responses (lack of responses, elevated thresholds and perturbed waveforms) in combination with present otoacoustic emissions are typical audiometric findings in patients with a hearing impairment that particularly affects speech comprehension or complete deafness. This heterogenous group of disorders first described as "auditory neuropathy" includes dysfunction of peripheral synaptic coding of sound by inner hair cells (synaptopathy) and/or of the generation and propagation of action potentials in the auditory nerve (neuropathy). This joint statement provides prevailing background information as well as recommendations on diagnosis and treatment. The statement focuses on the handling in the german language area but also refers to current international statements.

A model of peripherally developing hearing loss and tinnitus based on the role of hypoxia and ischemia.

The incidence of sensorineural hearing loss often caused by direct damage to the cochlear hair cells is by far more frequent and more serious than disorders affecting the external ear or the middle ear. Mechanisms that are discussed to be relevant for the genesis of tinnitus and acquired hearing impairment are hair cell loss, signal transduction disturbances in the region of the outer and inner hair cells and the spiral ganglion, impairment of cochlear blood flow, mechanical disturbance, and hypoxia and ischemia. The present model surveys the possible cellular and molecular biological causes of peripherally developing hearing loss and tinnitus. In particular, the paper discusses the roles of hypoxia and ischemia in the cochlea and in the etiology of the neurosensory types of tinnitus. Peripheral origins of hearing disturbances and tinnitus may be: (a) damage to the stereocilia and the tip links, (b) dysfunction of potassium channels or (c) modification of the glutamate release. Moreover, the hypoxia inducible factor-1 may have an important role to play as a key transcription factor in the cells' adaptation to hypoxia and ischemia. An impairment of the cochlear blood flow may be induced by the expression of target genes like nitrogen monoxide synthase and endothelin-1 resulting in tinnitus. The paper discusses consequences resulting from the present model for the medical treatment of peripherally developing tinnitus and hearing loss.

Dead regions and noisiness of pure tones.

Some hearing-impaired subjects report pure tones as sounding highly distorted and noise-like. We assessed whether such reports indicate that the tone frequency falls inside a dead region (DR). Nine hearing-impaired and four normally hearing subjects rated pure tones on a scale from 1 to 7, where 1 indicates clear tone and 7 indicates noise. A white noise was presented as a reference for a sound that should be rated as 7. Stimuli covered the whole audible range of frequencies and levels. The noisiness ratings were, on average, higher for hearing-impaired subjects than for normally hearing subjects. For the former, the ratings were not markedly different for tones with frequencies just outside or inside a DR. However, ratings always exceeded 3 for tones falling more than 1.5 octaves inside a DR. The results indicate that judgement of a tone as sounding noise-like does not reliably indicate that the tone frequency falls in a DR. Both normally hearing and hearing-impaired subjects rated 0.125 kHz and 12 kHz tones as somewhat noise-like, independently of the existence of a DR.

Hypothesis: could Meniere's disease be a channelopathy?

Meniere's disease is a clinical syndrome of uncertain aetiology but it is a widespread belief that it is related to endolymphatic hydrops. Clinically, it is a paroxysmal disorder with vertigo and subsequent deafness. It is responsive to acetazolamide and sensitive to the sodium content in the diet, many of the features of the channelopathies. The present paper explores the possibility that it may be related to a channelopathy.

Neural stem cells suppress the hearing threshold shift caused by cochlear ischemia.

Neural stem cells are multipotent progenitor cells that show self-renewal activity. In this study, we assessed the use of neural stem cells for ameliorating ischemia-reperfusion injury of the gerbil cochlea. Neural stem cells were injected into one inner ear through the round window 1 day after ischemic insult. Immunostaining for nestin showed that the distribution of neural stem cells was concentrated within the organ of Corti. Seven days after ischemia, the injury-induced auditory brainstem response threshold shift and progressive inner hair cell damage were markedly less on the neural stem cell-transplanted side. These results suggest that the transplantation of neural stem cells is therapeutically useful for preventing damage to hair cells that occurs after transient ischemia of the cochlea.

Cochlear compression in listeners with moderate sensorineural hearing loss.

Psychophysical estimates of basilar membrane (BM) responses suggest that normal-hearing (NH) listeners exhibit constant compression for tones at the characteristic frequency (CF) across the CF range from 250 to 8000 Hz. The frequency region over which compression occurs is broadest for low CFs. This study investigates the extent that these results differ for three hearing-impaired (HI) listeners with sensorineural hearing loss. Temporal masking curves (TMCs) were measured over a wide range of probe (500-8000 Hz) and masker frequencies (0.5-1.2 times the probe frequency). From these, estimated BM response functions were derived and compared with corresponding functions for NH listeners. Compressive responses for tones both at and below CF occur for the three HI ears across the CF range tested. The maximum amount of compression was uncorrelated with absolute threshold. It was close to normal for two of the three HI ears, but was either slightly (at CFs < or =1000 Hz) or considerably (at CFs > or =4000 Hz) reduced for the third ear. Results are interpreted in terms of the relative damage to inner and outer hair cells affecting each of the HI ears. Alternative interpretations for the results are also discussed, some of which cast doubts on the assumptions of the TMC-based method and other behavioral methods for estimating human BM compression.

Sensitivity of distortion product otoacoustic emissions in noise-exposed chinchillas.

The present study investigates the effect of small amounts of outer hair cell (OHC) loss on distortion product otoacoustic emission (DPOAE) levels and evoked potential permanent threshold shifts (PTS) in a population of 12 noise-exposed chinchillas. The group mean DPOAE level, which decreased by up to approximately 15 dB in the presence of less than 8 dB PTS and 15% OHC loss, indicates that DPOAEs can detect an underlying cochlear pathology (i,e., OHC damage/loss) despite the presence of normal to near normal thresholds. The sensitivity of DPOAEs in detecting OHC loss makes this test measure suited for diagnosing sensorineural hearing impairment, particularly when abnormal auditory symptoms (i.e., speech discrimination problems) are associated with a normal audiogram in the clinical setting and as part of a hearing conservation program.

Application of the TEN test to hearing-impaired teenagers with severe-to-profound hearing loss.

Hearing impairment is often associated with damage to the hair cells of the cochlea. An area of the cochlea with complete loss of function of inner hair cells is known as a 'dead region'. Dead regions can be identified by measuring detection thresholds for pure tones in quiet and in threshold-equalizing noise (TEN). So far, the TEN test has only been used to identify dead regions in adults with moderate-to-severe hearing impairment. The aim of this study was to assess problems in applying the TEN test to teenagers with longstanding severe-to-profound sensorineural hearing impairment, and to assess the prevalence of dead regions in this population. The subjects had a mean age of 14 years, and there were 13 females and 20 males. The stimuli for the TEN test were derived from a CD, whose output was routed via a GSI-16 audiometer and an amplifier to Sennheiser HD580 earphones. For each ear of each subject, both absolute thresholds and masked thresholds in the TEN were measured. For the majority of ears, the results were in-conclusive at some frequencies, due to the maximum output of the audiometer being reached when measuring the absolute or masked threshold. In almost all cases, the diagnosis was uncertain at some frequencies because the TEN could not be made sufficiently intense to produce significant masking. However, for 23 (70%) subjects, the criteria for a dead region at medium or high frequencies were met in at least one ear. For eight (35%) of these subjects, the criteria were only just met. Sixteen of the 24 subjects with a congenital hearing impairment, and four of the five subjects with an acquired impairment, met the criteria for a dead region. The results suggest that dead regions are relatively common among teenagers with a longstanding hearing impairment.

Dead regions in the cochlea: implications for speech recognition and applicability of articulation index theory.

Dead regions in the cochlea have been suggested to be responsible for failure by hearing aid users to benefit from apparently increased audibility in terms of speech intelligibility. As an alternative to the more cumbersome psychoacoustic tuning curve measurement, threshold-equalizing noise (TEN) has been reported to enable diagnosis of dead regions. The purpose of the present study was first to assess the feasibility of the TEN test protocol, and second, to assess the ability of the procedure to reveal related functional impairment. The latter was done by a test for the recognition of low-pass-filtered speech items. Data were collected from 22 hearing-impaired subjects with moderate-to-profound sensorineural hearing losses. The results showed that 11 subjects exhibited abnormal psychoacoustic behaviour in the TEN test, indicative of a possible dead region. Estimates of audibility were used to assess the possible connection between dead-region candidacy and ability to recognize low-pass-filtered speech. Large variability was observed with regard to the ability of audibility to predict recognition scores for both dead-region and no-dead-region subjects. Furthermore, the results indicate that dead-region subjects might be better than no-dead-region subjects at recognizing speech of marginal audibility.

Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse.

We identified two novel mouse mutants with abnormal head-shaking behavior and neural tube defects during the course of independent ENU mutagenesis experiments. The heterozygous and homozygous mutants exhibit defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. The homozygous mutants exhibit severe neural tube defects as a result of failure to initiate neural tube closure. We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1]. Celsr1 is one of three mammalian homologs of Drosophila flamingo/starry night, which is essential for the planar cell polarity pathway in Drosophila together with frizzled, dishevelled, prickle, strabismus/van gogh, and rhoA. The identification of mouse mutants of Celsr1 provides the first evidence for the function of the Celsr family in planar cell polarity in mammals and further supports the involvement of a planar cell polarity pathway in vertebrate neurulation.

The effects of the amplitude distribution of equal energy exposures on noise-induced hearing loss: the kurtosis metric.

Seventeen groups of chinchillas with 11 to 16 animals/group (sigmaN = 207) were exposed for 5 days to either a Gaussian (G) noise or 1 of 16 different non-Gaussian (non-G) noises at 100 dB(A) SPL. All exposures had the same total energy and approximately the same flat spectrum but their statistical properties were varied to yield a series of exposure conditions that varied across a continuum from G through various non-G conditions to pure impact noise exposures. The non-G character of the noise was produced by inserting high level transients (impacts or noise bursts) into the otherwise G noise. The peak SPL of the transients, their bandwidth, and the intertransient intervals were varied, as was the rms level of the G noise. The statistical metric, kurtosis (beta), computed on the unfiltered noise beta(t), was varied 3 < or = beta(t) < or = 105. Brainstem auditory evoked responses were used to estimate hearing thresholds and surface preparation histology was used to determine sensory cell loss. Trauma, as measured by asymptotic and permanent threshold shifts (ATS, PTS) and by sensory cell loss, was greater for all of the non-G exposure conditions. Permanent effects of the exposures increased as beta(t) increased and reached an asymptote at beta(t) approximately 40. For beta(t) > 40 varying the interval or peak histograms did not alter the level of trauma, suggesting that, in the chinchilla model, for beta(t) > 40 an energy metric may be effective in evaluating the potential of non-G noise environments to produce hearing loss. Reducing the probability of a transient occurring could reduce the permanent effects of the non-G exposures. These results lend support to those standards documents that use an energy metric for gauging the hazard of exposure but only after applying a "correction factor" when high level transients are present. Computing beta on the filtered noise signal [beta(f)] provides a frequency specific metric for the non-G noises that is correlated with the additional frequency specific outer hair cell loss produced by the non-G noise. The data from the abundant and varied exposure conditions show that the kurtosis of the amplitude distribution of a noise environment is an important variable in determining the hazards to hearing posed by non-Gaussian noise environments.

[The effects of auditory research on clinical practice]. / Auswirkungen der Hörforschung auf die klinische Arbeit.

Recent research has shown that only the inner hair cells pass information on to the brain while the outer hair cells serve as an active amplifier and thus stimulate the inner cells. The electromotility of the outer hair cells is very vulnerable. If it is lacking, sensorineuronal hearing loss occurs. Substances, that compete for the chloride combining site of the motor protein prestin, such as salicylate, might have a blocking effect on the regulation of electromotility. On the other hand, the control of the intracellular Ca(2+) level and the intracellular combination of ions in the outer hair cells might protect their electromotile properties against damage caused by harmful substances (ototoxic drugs) or mechanisms (exposition to noise), which would otherwise lead to irreversible sensorineuronal hearing loss. This is because an increase in the intracellular Ca(2+) level activates phosphorylating enzymes. Thus the stiffness of the outer hair cells is reduced, causing an increase in electromotility.

Differential responses to acoustic damage and furosemide in auditory brainstem and otoacoustic emission measures.

Characteristics of distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs) were measured in Mongolian gerbil before and after the introduction of two different auditory dysfunctions: (1) acoustic damage with a high-intensity tone, or (2) furosemide intoxication. The goal was to find emission parameters and measures that best differentiated between the two dysfunctions, e.g., at a given ABR threshold elevation. Emission input-output or "growth" functions were used (frequencies f1 and f2, f2/f1 = 1.21) with equal levels, L1 = L2, and unequal levels, with L1 = L2 + 20 dB. The best parametric choice was found to be unequal stimulus levels, and the best measure was found to be the change in the emission threshold level, delta x. The emission threshold was defined as the stimulus level required to reach a criterion emission amplitude, in this case -10 dB SPL. (The next best measure was the change in emission amplitude at high stimulus levels, specifically that measured at L1 x L2 = 90 x 70 dB SPL.) For an ABR threshold shift of 20 dB or more, there was essentially no overlap in the emission threshold measures for the two conditions, sound damage or furosemide. The dividing line between the two distributions increased slowly with the change in ABR threshold, delta ABR, and was given by delta x(t) = 0.6 delta ABR + 8 dB. For a given delta ABR, if the shift in emission threshold was more than the calculated dividing line value, delta x(t), the auditory dysfunction was due to acoustic damage, if less, it was due to furosemide.

Cochlear toughening, protection, and potentiation of noise-induced trauma by non-Gaussian noise.

An interrupted noise exposure of sufficient intensity, presented on a daily repeating cycle, produces a threshold shift (TS) following the first day of exposure. TSs measured on subsequent days of the exposure sequence have been shown to decrease relative to the initial TS. This reduction of TS, despite the continuing daily exposure regime, has been called a cochlear toughening effect and the exposures referred to as toughening exposures. Four groups of chinchillas were exposed to one of four different noises presented on an interrupted (6 h/day for 20 days) or noninterrupted (24 h/day for 5 days) schedule. The exposures had equivalent total energy, an overall level of 100 dB(A) SPL, and approximately the same flat, broadband long-term spectrum. The noises differed primarily in their temporal structures; two were Gaussian and two were non-Gausssian, nonstationary. Brainstem auditory evoked potentials were used to estimate hearing thresholds and surface preparation histology was used to determine sensory cell loss. The experimental results presented here show that: (1) Exposures to interrupted high-level, non-Gaussian signals produce a toughening effect comparable to that produced by an equivalent interrupted Gaussian noise. (2) Toughening, whether produced by Gaussian or non-Gaussian noise, results in reduced trauma compared to the equivalent uninterrupted noise, and (3) that both continuous and interrupted non-Gaussian exposures produce more trauma than do energy and spectrally equivalent Gaussian noises. Over the course of the 20-day exposure, the pattern of TS following each day's exposure could exhibit a variety of configurations. These results do not support the equal energy hypothesis as a unifying principal for estimating the potential of a noise exposure to produce hearing loss.

An auditory-periphery model of the effects of acoustic trauma on auditory nerve responses.

Acoustic trauma degrades the auditory nerve's tonotopic representation of acoustic stimuli. Recent physiological studies have quantified the degradation in responses to the vowel /E/ and have investigated amplification schemes designed to restore a more correct tonotopic representation than is achieved with conventional hearing aids. However, it is difficult from the data to quantify how much different aspects of the cochlear pathology contribute to the impaired responses. Furthermore, extensive experimental testing of potential hearing aids is infeasible. Here, both of these concerns are addressed by developing models of the normal and impaired auditory peripheries that are tested against a wide range of physiological data. The effects of both outer and inner hair cell status on model predictions of the vowel data were investigated. The modeling results indicate that impairment of both outer and inner hair cells contribute to degradation in the tonotopic representation of the formant frequencies in the auditory nerve. Additionally, the model is able to predict the effects of frequency-shaping amplification on auditory nerve responses, indicating the model's potential suitability for more rapid development and testing of hearing aid schemes.