Outer Hair Cell Dysfunction Research Articles

Functional Role of GABAergic Innervation of the Cochlea: Phenotypic Analysis of Mice Lacking GABAAReceptor Subunits α1, α2, α5, α6, β2, β3, or δ

The olivocochlear efferent system is both cholinergic and GABAergic and innervates sensory cells and sensory neurons of the inner ear. Cholinergic effects on cochlear sensory cells are well characterized, bothin vivoandin vitro; however, the robust GABAergic innervation is poorly understood. To explore the functional roles of GABA in the inner ear, we characterized the cochlear phenotype of seven mouse lines with targeted deletion of a GABAAreceptor subunit (α1, α2, α5, α6, β2, β3, or δ). Four of the lines (α1, α2, α6, and δ) were normal: there was no cochlear histopathology, and cochlear responses suggested normal function of hair cells, afferent fibers, and efferent feedback. The other three lines (α5, β2, and β3) showed threshold elevations indicative of outer hair cell dysfunction. α5 and β2 lines also showed decreased effects of efferent bundle activation, associated with decreased density of efferent terminals on outer hair cells: although the onset of this degeneration was later in α5 (>6 weeks) than β2 (<6 weeks), both lines shows normal efferent development (up to 3 weeks). Two lines (β2 and β3) showed signs of neuropathy, either decreased density of afferent innervation (β3) or decreased neural responses without concomitant attenuation of hair cell responses (β2). One of the lines (β2) showed a clear sexual dimorphism in cochlear phenotype. Results suggest that the GABAergic component of the olivocochlear system contributes to the long-term maintenance of hair cells and neurons in the inner ear.

Effects of aspirin on distortion product otoacoustic emission suppression in human adults: A comparison with neonatal data

One of the distortion product otoacoustic emission (DPOAE) paradigms used to study cochlear function is DPOAE (2f1-f2) ipsilateral suppression. Newborns do not have adultlike DPOAE suppression. At 6000 Hz, infants show excessively narrow DPOAE suppression tuning and shallow growth of suppression for low-frequency suppressor tones. The source of this immaturity is not known but the outer hair cell (OHC) is one possible locus. In the present study, DPOAE suppression was measured at f2 = 1500 and 6000 Hz from two groups with impaired OHC function in an attempt to model the observed immaturity in neonates: adults with aspirin-induced OHC dysfunction and subjects with sensorineural hearing loss (SNHL). Their DPOAE suppression results were compared to those obtained from a group of term newborns to address whether infant DPOAE suppression resembles suppression from individuals with known OHC dysfunction. Results indicate that aspirin systematically alters DPOAE suppression in adults at f2 = 6000 Hz, but not 1500 Hz. However, neither aspirin-induced OHC dysfunction nor naturally occurring SNHL produces "neonatal-like" DPOAE suppression at either test frequency. This finding does not support the hypothesis that non-adultlike DPOAE suppression characterizing newborns can be explained by minor impairments or alterations of OHC function.

Apport des thérapies cognitives et comportementales dans la prise en charge des acouphènes: Implication de l’anxiété et de la dépression

Tinnitus is a common otologic symptom but, despite important advances in the evaluation and management of such symptom, ENTs often fail to address tinnitus properly. Some tinnitus patients report that tinnitus interferes with activities of daily living, such as reading, social interactions, sleep, concentrating on complex tasks. Anxiety and depression are current major disorders associated with tinnitus. Many theories exist regarding mechanisms of tinnitus origin. A number of publications favors the theory of discordant dysfunction of inner or outer hair cells of the organ of Corti. Nevertheless, some authors insist on the possible role of the central auditory pathways. Multiple functional connections between auditory system, limbic system, autonomic nervous system seem crucial in the development of tinnitus. The aim of this paper is to present a new approach in France of tinnitus treatment by cognitive-behavioral therapy (CBT).96 patients with chronic and intense tinnitus were included in the study (38 females, 36 males, mean age 48 years). A CBT was developed after a clinical evaluation based on standardized questionnaires.The two main results are: (i) the importance of anxiety and depression in this population, (ii) the amelioration of tinnitus perception in 750f the included patients.CBT shows promise as a treatment of tinnitus-related distress.

Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming alpha-subunit coexpressed with the auxiliary beta1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha-/-) and beta1-subunit (BKbeta1-/-) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta1-/- mice. During the first 4 postnatal weeks also, BKalpha-/- mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKalpha-/- mice only from approximately 8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations.

Perceptual consequences of normal and abnormal peripheral compression: Potential links between psychoacoustics and speech perception

Cochlear damage can lead to a reduction in the overall amount of peripheral auditory compression, presumably due to outer hair cell (OHC) loss or dysfunction. The perceptual consequences of functional OHC loss include loudness recruitment and reduced dynamic range, poorer frequency selectivity, and poorer effective temporal resolution. These in turn may lead to a reduced ability to make use of spectral and temporal fluctuations in background noise when listening to a target sound, such as speech. We tested the effect of OHC function on speech reception in hearing-impaired listeners by comparing psychoacoustic measures of cochlear compression and sentence recognition in a variety of noise backgrounds. In line with earlier studies, we found weak (nonsignificant) correlations between the psychoacoustic tasks and speech reception thresholds in quiet or in steady-state noise. However, when spectral and temporal fluctuations were introduced in the masker, speech reception improved to an extent that was well predicted by the psychoacoustic measures. Thus, our initial results suggest a strong relationship between measures of cochlear compression and the ability of listeners to take advantage of spectral and temporal masker fluctuations in recognizing speech. [Work supported by NIH Grants Nos. R01DC03909, T32DC00038, and R01DC00117.]

Cochlear nonlinearity between 500 and 8000 Hz in listeners with moderate cochlear hearing loss

For two listeners with flat hearing loss, temporal masking curves (TMCs) were measured for probe frequencies (Fp) of 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and masker frequencies of 0.5, 0.6, 0.7, 0.9, 1.0, 1.05, 1.1, and 1.2 Fp. From these, basilar membrane (BM) input/output (IO) functions and psychophysical tuning curves (PTCs) were derived and compared with corresponding data for normal-hearing listeners. Linear IO functions were observed for one ear only and for probe frequencies of 4 kHz and above. This result is consistent with the consequences of severe outer hair cell (OHC) damage on the BM response. Elsewhere, however, IO functions showed residual compression, with slopes in the compression region close to normal. This suggests that either the impairment relates mostly to inner hair cell (IHC) dysfunction, or that OHC dysfunction reduces the gain of the BM at low levels while maintaining the degree of maximum compression. The data suggest that the active and the passive BM mechanisms have different relative positions (in frequency) in the apical and the basal regions of the cochlea. Across probe frequencies, the slopes of the TMCs for off-frequency maskers are shallower for the impaired ears. It is considered that this possibly reflects IHC-related compression.

EOAE I/O curves in inner ear impairments

Input/output (I/O) curves of evoked otoacoustic emissions (EOAEs) reveal a saturation at 30 dB or thereabout above their detection threshold. It has been suggested that such I/O relation corresponds to that of the basilar membrane vibration related with an active electro-mechanical process of outer hair cells. EOAEs in response to 1–2 kHz short tone bursts were measured. EOAEs were examined in ears with idiopathic sudden hearing loss (HL), low tone type acute sensorineural HL, Ménière's disease and noise-induced HL. Three types of shift that were downward, horizontal and combined were observed in their I/O curves. The downward shift was seen mainly in the ears with high tone HL and the horizontal shift was in the ears with low tone HL. Three types of shift were observed in the ears of Ménière's disease, in which glycerol administration augmented EOAE amplitude beyond the normal saturation level of its cotralateral side. Measurements of EOAE I/O curves are useful for diagnosis of inner ear impairments related to outer hair cell dysfunction in ears with sensorineural HL.

Click-evoked otoacoustic emissions recorded from untreated congenital hypothyroid newborns

Thyroid hormone plays an important role in hearing development. Both a genetic or non-genetic hypothyroidism is often associated with congenital hearing loss. The exact incidence of hearing impairment in untreated congenital hypothyroid (CH) patients is unknown. This paper will present the results of measuring of the transient-evoked otoacoustic emissions (TEOAE) in a population of 29 newborns, who tested positive on a screening test for hypothyroidism (CH group) and in 68 well babies (control group) randomly chosen from all the newborns, classified as PASS, included in the Hearing Screening Program of the San Raffaele Hospital in Milan. TEOAE were recorded in all newborns within 1 month after birth and before beginning L-thyroxine treatment with conventional commercial instrumentation. Both temporal and time–frequency analyses of the emitted responses were conducted by means of a wavelet transform. The comparison of the characteristics of the temporal and frequency content of the responses of the two groups (CH and control) showed no statistically significant difference. No correlation was found between outer hair cell dysfunction and hypothyroidism.

Effects of age on the distortion product otoacoustic emission growth functions

Age-related hearing loss (presbycusis) is thought to result from age-related degeneration (aging) of the cochlea plus the cumulative effects of extrinsic damage (noise and other ototoxic agents) and intrinsic disorders (e.g. systemic diseases). Previous studies have implicated dysfunction of the hair cells (sensory presbycusis) as the principal mechanism of age-related hearing loss. However, recent evidence from quiet-reared gerbils suggests that cochlear aging results primarily from atrophy of the stria vascularis, which is associated with diminished endocochlear potential (EP), spiral ganglion atrophy, and a relatively flat audiometric loss, termed metabolic presbycusis. Because it is not currently possible to measure EP directly in the clinical setting, we wondered if cochlear metabolic dysfunction might be evidenced indirectly from existing clinical tests, specifically, the input–output (IO) growth function of the distortion product (DP) otoacoustic emissions in relation to behavioral hearing threshold levels (HTL). We anticipated finding discordance between the IO functions and HTL with either a greater decline with age in HTL than in IO functions if an age-related metabolic dysfunction of the cochlea was operant, or a greater loss of IO function than HTL if outer hair cell dysfunction was the dominant pathology. To address this supposition we analyzed existing auditory data from a large cohort of adults to determine the change with age in three aspects of the DP IO function: area under the curve, threshold, and slope. The analyses demonstrated a greater effect of age on HTL than on the DP IO measures. This effect supports the hypothesis that strial dysfunction is a substantive factor in cochlear aging. The etiology and mechanisms for this dysfunction are conjectural at present.

Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs.

The possible cochlear toxicity of systemically applied macrolides--erythromycin (ER), azithromycin (AZ) and clarithromycin(CL)--was investigated in guinea pigs by measuring transiently evoked otoacoustic emissions (TEOAEs). A single dose of 125 mg/kg intravenous (i.v.) ER caused no change in TEOAEs in guinea pigs (p>0.05), whereas AZ (45 mg/kg orally) and CL (75 mg/kg i.v.) reversibly reduced the emission response (p<0.05). The reversible reduction of TEOAE responses due to AZ and CL, which is in accordance with the clinical picture of AZ and CL ototoxicity, could likely be attributable to the transient dysfunction of outer hair cells. The present study reveals that at least one ototoxic effect of AZ and CL is on the inner ear. The results may also encourage planning clinical researches on TEOAE monitoring in patients receiving high doses of AZ or CL.

Psychophysical evaluation of cochlear hair cell damage due to the A3243G mitochondrial DNA mutation.

Mitochondrial dysfunction is an important cause of human deafness, implicated in genetic deafness, toxin and noise damage. We assessed the mechanism of cochlear dysfunction in a population of 11 subjects with a specific mitochondrial disorder caused by the A3243G mitochondrial DNA mutation. Psychophysical tests were carried out to assess the inner and outer hair cell functions in vivo. Inner hair cell function was assessed using a measure of hearing threshold in the presence of "threshold-equalizing noise" which can indicate "dead regions" where the transduction mechanism fails. Outer hair cell function was assessed by using the notched-noise method to measure auditory filter width, dependent on active mechanisms in the outer hair cell. The results support the conclusion that this mitochondrial disorder causes both inner and outer hair cell dysfunctions. Evidence of inner hair cell dysfunction was found mainly in basal (high frequency) regions of the cochlea and occurred even in some subjects with only mild hearing loss. Evidence of outer hair cell dysfunction was found in some instances where pure tone threshold was at or close to normal. The common occurrence of dead regions in the basal cochlea has treatment implication for this form of deafness; such people may not be helped by amplification of high frequencies.

Brief Report: The Cochlear Microphonic as an Indication of Outer Hair Cell Function

The extra-cellular cochlear microphonic is believed to be generated predominantly by outer hair cells and therefore it would seem reasonable to assume that the presence of a cochlear microphonic excludes outer hair cell dysfunction. Indeed, a diagnosis of auditory neuropathy might be, and has been, made on the basis of a cochlear microphonic present with an abnormal auditory brainstem response. Animal studies, however, have shown that the cochlear microphonic recorded from the round window is dominated by cellular generators located in the base of the cochlea. Primarily on this basis, it is argued that the presence of a cochlear microphonic does not exclude outer hair cell pathology and so outer hair cell integrity should not necessarily be inferred from the presence of the cochlear microphonic alone. In contrast, the absence of an otoacoustic emission in such cases is consistent with outer hair cell dysfunction.

Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2

Mutations in the human KCNQ4 gene were recently found by Kubisch et al. [Cell 96 (1999) 437–446] to cause a non-syndromic, autosomal dominant, progressive hearing loss, DFNA2. The mouse Kcnq4 orthologue was previously localized to the outer hair cells (OHCs) of the inner ear, suggesting the pathophysiological effects were due to dysfunctional OHCs. Yet, OHC dysfunction does not provide a plausible explanation for the progressive nature of the frequency specific hearing loss. We have re-examined and extended the expression analyses of KCNQ4 in the murine inner ear using RT-PCR and whole mount in situ hybridization. Our results confirmed that the rat KCNQ4 orthologue is expressed in both inner and outer hair cells. Reciprocal longitudinal gradients were found in inner hair cells (IHCs) and OHCs. The strongest expression of KCNQ4 in IHCc was in the base of the cochlea and in the apex for OHCs. Similar to the IHCs, a basal to apical gradient was present in the spiral sensory neurons. IHCs mediate hearing via their afferent sensory neurons, whereas OHCs function as active cochlear amplifiers. The complete absence of OHCs leads only to severe sensitivity reduction, but not complete hearing loss. Our data suggest that the primary defect leading to initial high frequency loss and subsequent progressive hearing loss for all frequencies may be due to spiral ganglion and/or IHC dysfunction, rather than an OHC aberration.

Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea

Cisplatin is well known to cause cochleotoxicity. In order to determine the underlying mechanisms of cisplatin-induced cell death in the cochlea, we investigated the apoptotic changes and the expression of bcl-2 family proteins controlling apoptosis. Mongolian gerbils were administered 4 mg/kg/day cisplatin consecutively for 5 days. The cisplatin-treated animals showed a significant deterioration in the responses of both distortion product otoacoustic emissions and the endocochlear potential as compared with those of the age-matched controls, suggesting outer hair cell and stria vascularis dysfunction. The presence of DNA fragmentation revealed by a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling method was recognized in the organ of Corti, the spiral ganglion, and the stria vascularis in the cisplatin-treated animals whereas almost negative results were obtained in the control animals. The nuclear morphology obtained by Hoechst 33342 staining revealed pyknotic and condensed nuclei, confirming the presence of the characteristic features of apoptosis. A significant increase and reduction in the number of bax- and bcl-2-positive cells, respectively, following cisplatin treatment was observed in the cells of the organ of Corti, the spiral ganglion, and the lateral wall. These findings suggest a critical role for bcl-2 family proteins in the regulation of apoptotic cell death induced by cisplatin. The underlying mechanisms of the cisplatin-induced cell death are discussed.

Drill-induced hearing loss in the nonoperated ear

The reversible hearing loss in the nonoperated ear noted by patients after ear surgery remains unexplained. This study proposes that this hearing loss is caused by drill noise conducted to the nonoperated ear by vibrations of the intact skull. This noise exposure results in dysfunction of the outer hair cells, which may produce a temporary hearing loss. Estimations of outer hair cell function in the nonoperated ear were made by recording the change in amplitude of the distortion-product otoacoustic emissions before and during ear surgery. Reversible drill-related outer hair cell dysfunction was seen in 2 of 12 cases. The changes in outer hair cell function and their clinical implications are discussed. (Otolaryngol Head Neck Surg 1997;117:555-8.)

Drill‐Induced Hearing Loss in the Nonoperated Ear

The reversible hearing loss in the nonoperated ear noted by patients after ear surgery remains unexplained. This study proposes that this hearing loss is caused by drill noise conducted to the nonoperated ear by vibrations of the intact skull. This noise exposure results in dysfunction of the outer hair cells, which may produce a temporary hearing loss. Estimations of outer hair cell function in the nonoperated ear were made by recording the change in amplitude of the distortion‐product otoacoustic emissions before and during ear surgery. Reversible drill‐related outer hair cell dysfunction was seen in 2 of 12 cases. The changes In outer hair cell function and their clinical implications are discussed.

Changes in evoked otoacoustic emissions in the guinea pig after pure-tone acoustic overstimulation.

To test if click-evoked otoacoustic emissions (CEOAEs) have frequency specificity, continuous changes in CEOAEs (especially frequency components of the CEOAE power spectrum) after pure-tone exposure in guinea pigs were examined. Pure-tone stimuli (0.5 kHz, 120 dB SPL; 2 kHz, 115 dB SPL; 4 kHz, 110 dB SPL) were given in a closed system for 3 min. After exposure, the frequency components in the CEOAE power spectrum decreased maximally at one-half octave or more above the overstimulation frequency. They partially recovered 2 h after exposure. The time course of compound action potential (CAP) thresholds after exposure was similar to that of the frequency components of the CEOAE power spectrum. It was concluded that some local damage caused by outer hair-cell dysfunction in the guinea pig cochlea can be detected by measuring shifts in frequency components in the CEOAE power spectrum.

The Effect of Quinine on Psychoacoustic Tuning Curves, Stapedius Reflexes and Evoked Otoacoustic Emissions in Healthy Volunteers

Quinine causes reversible hearing loss, closely related to the quinine plasma concentration. The effects of quinine on psychoacoustic tuning curves, stapedius reflex thresholds and evoked otoacoustic emissions were studied in healthy volunteers. The tuning curves became shallower, whereas reflex thresholds were unaffected. The shift in the emission thresholds paralleled that of the pure-tone thresholds. There were also qualitative changes in the emissions: 1) the exponent of the stimulus-response function changed from 0.34 to 0.56; 2) decay time shortened; 3) the power spectrum shifted towards lower frequencies. The results are discussed in relation to various aspects of cochlear performance and are suggested to depend on an outer hair cell dysfunction.

N1 latency prolongation in the guinea pig cochlea treated with nitrogen mustard-N-oxide studied by narrow band analysis.

The effect of nitrogen mustard-N-oxide (NMO) upon the click and tone burst-evoked N1 latency was examined in 14 albino guinea pigs. In all animals except one, the pseudothresholds of action potentials were elevated, especially in the high tone area. In addition to the amplitude reduction, the N1 latency was prolonged in 12 animals. The narrow band analysis of N1 revealed that the latency was equally prolonged in all frequency areas, although the amount of the amplitude reduction was much larger in the high frequency area. It was concluded that the prolongation of the N1 latency in NMO-treated animals was due to dysfunction of outer hair cells along the entire cochlear partition.

On the N1 latency prolongation in guinea pigs treated with nitrogen mustard-N-oxide with special reference to narrow-band analysis

The effect of nitrogen mustard-N-oxide (Nitromin®) upon the click evoked N1 latency was examined in 14 albino guinea pigs. Various dosage of NitrominR ranged from 5 to 30mg/kg were given intravenously and the cochlear potentials were recorded 3 to 7 days after the administration. The animals were histologically examined with a surface preparation technique after the measurements.In all animals except one, the thresholds of AP to the filtered tone burst were elevated especially in high frequency range. In addition to the amplitude reduction, the N1 latency evoked by a click was prolonged in 12 animals. Narrow-band analysis of the N1 revealed that the latency was equally prolonged in all frequencies, although the amount of the amplitude reduction was much larger in high frequency. The histological examination exhibited the various degrees of the outer hair cell damage and the results obtained in electrophysiological studies were correlated with these findings.It was concluded that the prolongation of the N1 latency in Nitromin® treated animals was due to the dysfunction of outer hair cells along the entire cochlear partition.