Middle ear instillation of gentamicin and streptomycin in chinchillas: electrophysiological appraisal of selective ototoxicity.

The purpose of this study was to investigate selective vestibular ototoxicity of gentamicin and streptomycin in the chinchilla model. In total, 10 chinchillas underwent left middle ear instillation of one of three agents: gentamicin, streptomycin and saline. Electrophysiological data (otoacoustic emissions (OAEs), auditory brainstem evoked response (ABRs), and ice-water electronystagmography were recorded before and after instillation. Animals were sacrificed for temporal bone studies using scanning electron microscopy. Morphological changes in the cochlear and vestibular neuroepithelia were correlated with electrophysiological changes. Widespread ipsilateral cochlear and vestibular neuroepithelial injuries were observed and correlated with loss of OAEs, ABRs and ice-water caloric response. This study provides no evidence of selective vestibular ototoxicity of gentamicin or streptomycin. Morphological damage correlates with, but precedes loss of electrophysiological parameters. Chinchillas, like other small mammals, may not be an ideal model for the study of human ototoxicity.

Contralateral suppression of DPOAE measured in real time.

The aim of this study was to measure contralateral suppression of distortion product otoacoustic emissions (DPOAE) in real time. A total of 10 human subjects were studied with a novel device to record DPOAE without signal time averaging, using digital narrow band pass filtering. Real time DPOAE levels were recorded at 2f1-f2 using primary tone settings of f2/f1 = 1.22 and L1 = 70 dB SPL, L2 = 65 dB SPL, at five values of f2 between 2.2 and 7.7 kHz. An acoustic stimulus was applied intermittently to the contralateral ear to cause DPOAE suppression. Characteristic features of contralateral suppression were identified and distinguished from small spontaneous variations in the real time DPOAE signal. Magnitude of suppression increased with contralateral stimulus intensity. Onset latency of suppression was around 43 ms (31-95 ms). Potential clinical applications are discussed in the light of these findings, including a role in improving the specificity of neonatal hearing screening.

Arterial blood supply to the auditory cortex of the chinchilla.

Utilizing optical imaging we identified and named the arteries that supply the primary auditory cortex in the chinchilla (Chinchilla laniger). The primary auditory cortex is located 2-3 mm caudal to the medial cerebral artery and is supplied by it. Using corrosion casts and scanning electron microscopy we visualized the capillary networks in the auditory cortex and found regional variations in the densities of the capillary bed. We hypothesize that the uneven capillary densities observed in the auditory cortex correspond to neurologically more active areas.

Assessment of vocabulary development in children after cochlear implantation.

OBJECTIVES: To assess vocabulary development in children following cochlear implantation and to evaluate the effect of age at implantation on performance. DESIGN: Retrospective study (mean follow-up, 3(1/2) years). SETTING: Tertiary center. PATIENTS: Children with prelingual deafness provided with a cochlear implant between 1988 and 1999, who serially performed the Peabody Picture Vocabulary Test-Revised (60 patients) and the Expressive One-Word Picture Vocabulary Test-Revised (52 patients). The children were subgrouped into those receiving implants at younger than 5 years and at 5 years or older. OUTCOME MEASURES: Age-equivalent vocabulary test score and gap index (chronological age minus the age-equivalent score, divided by the chronological age at the time of testing) were calculated. For each test, the following were performed: calculation of rate of change for age-equivalent score; comparison of earliest and latest gap indices means (the cohort and intergroup and intragroup comparison); and multiple regression analysis demonstrating the effect of age at implantation, sex, communication mode, etiology of deafness, and residual hearing on the rate of vocabulary development. RESULTS: Expressive and receptive vocabulary development rates were 0.93 and 0.71 (age-equivalent scores per year), respectively. Subgrouped by age at implantation, the children's rates (for both vocabularies) were not statistically different (Peabody Picture Vocabulary Test-Revised, P =.90; Expressive One-Word Picture Vocabulary Test-Revised, P =.23). The global latest gap indices were significantly less than the earliest (Peabody Picture Vocabulary Test-Revised, P =.048; Expressive One-Word Picture Vocabulary Test-Revised, P<.001), indicating an improvement in age-appropriate vocabulary development over time. The age subgroups demonstrated similar results, except for the younger group's receptive gap index. On multiple regression analysis, the significant predictive variables were residual hearing (Expressive One-Word Picture Vocabulary Test-Revised) and male sex and oral communication mode (Peabody Picture Vocabulary Test-Revised). CONCLUSIONS: Children with cochlear implants developed their vocabularies at rates that were sufficient to prevent an increase in their gap indices as related to ideal scores at testing. A late age at implantation does not singularly preclude beneficial development of vocabulary.

The effects of age of cochlear implantation on speech perception outcomes in prelingually deaf children.

We have made a retrospective analysis on 70 prelingually deaf children (78% congenital; age range 2-15 years) followed for up to 5 years post-implant during which both closed set speech perception tests (TAC, WIPI) and open set tasks (PBK, GASP) were administered. We used a binary partitioning algorithm to optimally divide our dataset on the basis of age at implantation This technique achieves an optimal split when the heterogeneity of the data is most reduced (maximal drop in deviance). For the closed set speech perception tests (TAC and WIPI) partitioning best divided-out data at age 4.4 years. For the open set tests optimal division was at a higher age of implantation (GASP word, 5.6 years; PBK word, 8.4 years). Using these partitioning values, we have found statistically significant differences between rate of improvement of scores in the younger implanted children compared with those implanted later.

Vocabulary acquisition rate after pediatric cochlear implantation and the impact of age at implantation.

OBJECTIVE: studies of early vocabulary development after pediatric cochlear implantation show growth rates that approach normality. Do these growth rates continue to rise over time and, therefore, allow a 'catch up' with ideal scores for age, or do they decline after an initial peak. Could age at implantation be a decisive factor in that process? DESIGN: retrospective study (mean follow-up 4 years). PATIENTS: pre-lingually deaf children implanted between 1988 and1999, who serially performed Peabody Picture Vocabulary Test-Revised (PPVT), (37 patients) and Expressive One-word Picture Vocabulary Test-Revised (EOWPVT), (35 patients). OUTCOME MEASURES: the mean rates of age equivalent scores were determined for the whole follow-up period and analyzed further for two post-implant periods (the two halves of follow-up duration of individual patients). After sub-grouping by age at implantation (younger or older than 5 years old), the same analysis was executed for each subgroup. RESULTS: the mean EOWPVT rate of the earlier period was higher than that of the later period (1.33 vs. 0.67, P<0.01) and the mean PPVT rate of the earlier period was higher than that of the later period (0.72 vs. 0.5). The latter difference was not statistically significant (P>0.05). Within subgroups by age at implantation, the PPVT mean rates were stable for younger implanted patients (0.56 for both periods) and dropped for the older implanted sub-group (0.87-0.43, P>0.05). The EOWPVT mean rates declined significantly for the older patients group (1.72-0.55, P<0.01) but insignificantly for the younger patients (0.99-0.77, P>0.05). CONCLUSIONS: vocabulary acquisition rates decline in the post-implantation period. This is more pronounced with older implanted children and the EOWPVT rates. This information on the time course development of vocabulary after implantation would be valuable in counseling and planning habilitation in addition to candidate selection.

Differential vulnerability of inner and outer hair cell systems to chronic mild hypoxia and glutamate ototoxicity: insights into the cause of auditory neuropathy.

OBJECTIVE: To describe the effects of long-term mild hypoxia and of glutamate poisoning on the functional properties of the cochlea. METHODS: Outer hair cell activity was monitored using otoacoustic emissions and cochlear microphonics, and inner hair cell/cochlear afferent function was measured using neural responses (cochlear action potentials or auditory brainstem responses [ABRs]). RESULTS: In contrast to the effects of acute anoxia, in which all aspects of cochlear function are simultaneously lost, mild, long-term hypoxia results in a clear differential effect on outer versus inner hair cell systems. During a 2-hour period of mild hypoxia, ABR amplitude and threshold deteriorate significantly, whereas outer hair cell function, as reflected by otoacoustic emissions, shows little or no change. A similar dissociation between inner and outer hair cell function is observed during instillation of glutamate (1-10 mM), where the cochlear microphonic and the otoacoustic emissions are unchanged, whereas cochlear action potential amplitudes are reduced. CONCLUSION: These studies demonstrate a difference in vulnerability of inner and outer hair cell systems. The inner hair cell/cochlear afferent system is vulnerable to long-term, mild hypoxia; this may be an etiologic factor in hearing loss of cochlear origin, particularly in high-risk birth infants with auditory neuropathy.

Tonotopic mapping in auditory cortex of the adult chinchilla with amikacin-induced cochlear lesions.

We have found a reorganization of tonotopic maps (based on neuron response thresholds) in primary auditory cortex of the adult chinchilla after amikacin-induced basal cochlear lesions. We find an over-representation of a frequency that corresponds to the border area of the cochlear lesion. The reorganization observed is similar in extent to that previously seen in a developmental model. The properties of neurons within the over-represented area were investigated in order to determine whether their responses originated from a common input (an indication of true plasticity) or represented only the result of truncating the activity of the sensory epithelium ("pseudo-plasticity"). Some aspects of our data fit with a true plasticity model and indicate the potential for the deafferented cortex of the mature cortex to regain connections with the surviving sensory epithelium.

Three distinct auditory areas of cortex (AI, AII, and AAF) defined by optical imaging of intrinsic signals.

Using pure-tone sound stimulation, three separate auditory areas are revealed by optical imaging of intrinsic signals in the temporal cortex of the chinchilla (Chinchilla laniger). These areas correlate with primary auditory cortex (AI) and two secondary areas, AII and the anterior auditory field (AAF). We have distinguished AI on the basis of concurrent single-unit electrophysiological recording; neurons within the AI intrinsic signal region have short (<15 ms) onset-response latencies compared with neurons recorded in AII and the AAF. Within AI, AII, and AAF we have been able to define cochleotopic or tonotopic organization from the differences in intrinsic signal areas evoked by pure tones at octave-spaced frequencies from 500 Hz to 16 kHz. The maps in AI and AII are arranged orthogonal to each other.

Local haemodynamic changes associated with neural activity in auditory cortex.

We used an optical technique to study haemodynamic changes associated with acoustically driven activity in auditory cortex of the chinchilla. Such changes are first detectable c. 0.5 s after stimulation, peak at 2-3 s, and decay within a further 3-6 s. This intrinsic signal imaging reveals activity in separate cortical areas, including primary auditory cortex (AI), secondary auditory cortex (AII) and an anterior auditory field (AAF). We have measured the timing of haemodynamics associated with each area, and find that AI has a different time course from AII and AAF; its haemodynamic change recovers more rapidly. We also show that within AI and AII, place specific activity related to acoustic stimulus frequency can be resolved by this optical imaging method. Our results show the close association between blood flow change and the local metabolic demands of neural activity. The data provide information about the potential of other functional imaging methods (e.g. PET, fMRI) which rely on activity related haemodynamic events.

Middle ear instillation of gentamicin and streptomycin in chinchillas: morphologic appraisal of selective ototoxicity.

OBJECTIVE: To determine selective cochlear and vestibular ototoxicity of two aminoglycoside antibiotics (gentamicin and streptomycin) in the chinchilla model. Middle ear application of these agents mirrors the clinical practice of chemical vestibular ablation used in Meniere's disease. BACKGROUND: Middle ear instillation of gentamicin or streptomycin has become a popular form of vestibular ablative treatment for disabling Meniere's disease. The vestibular selectivity of these two drugs applied in this fashion has clinical support but is not fully established in humans. Our understanding in this regard has largely been limited to animal models exposed to systemic infusion of aminoglycosides. METHOD: Ten chinchillas underwent left middle ear instillation of one of three agents using variable dosing schedules: gentamicin (n = 6), streptomycin (n = 2), and saline (n = 2) as control. Animals were sacrificed for temporal bone studies using scanning electron microscopy. Morphologic changes in the cochlear and vestibular neuroepithelia were identified. RESULTS: Widespread cochlear and vestibular neuroepithelial injuries were observed with both gentamicin and streptomycin. Contralateral ototoxicity was variable and not related to the total dose of drug delivered. The effect of these two aminoglycosides on the dark cells of the vestibular system appeared negligible. CONCLUSION: We were unable to confirm the selective damage of vestibular end-organ in the chinchilla by either gentamicin or streptomycin, a phenomenon that is generally perceived to occur in humans. Chinchillas, like other small mammals, may not be an ideal model for the study of human ototoxicity.

Increased otoacoustic-emission amplitude secondary to cochlear lesions.

OBJECTIVE: The measurements of transient evoked otoacoustic emissions and distortion-product otoacoustic emissions are being used increasingly, both as an objective hearing test clinically, and as a research tool to investigate the micromechanical aspects of cochlear function. We hypothesized that localized damage in the apical or middle cochlear turns may have an influence on the micromechanics and the function of adjacent, apparently normal cochlea. For that purpose, we used an animal model of localized apical and middle-turn cochlear lesions. METHOD: Extent of damage was assessed by scanning electron microscopy and the function of the damaged cochlea by change in the otoacoustic emission (OAE) levels. RESULTS: We found that localized damage to the apical or middle turn may be accompanied by an increase in OAE measured from adjacent apparently normal cochlea. CONCLUSION: Explanations to this phenomenon are suggested, and possible clinical associations such as to Meniere's disease and to sudden hearing loss are reviewed.

Plasticity of tonotopic maps in auditory midbrain following partial cochlear damage in the developing chinchilla.

There is substantial reorganization of the midbrain (inferior colliculus) tonotopic map following neonatally induced partial cochlear lesions in the chinchilla. The most obvious feature of this remapping is a large "iso-frequency" region in the ventral sector of the central nucleus of inferior colliculus (ICC). Neurons in this region exhibit similar threshold and tuning properties, with a common characteristic frequency which corresponds to the high-frequency audiometric cutoff. This overrepresented frequency range also corresponds to the high-frequency border of the cochlear lesion. Alterations to the tonotopic map corresponding to lower frequencies, in more dorsal regions of ICC, depend on the extent and degree of the cochlear lesion. When there is minimal damage to apical (low-frequency) cochlear areas, the dorsal ICC has relatively normal frequency representations. With more extensive apical cochlear lesions there is a corresponding disruption of ICC tonotopic representation of the low frequencies. We conclude that the tonotopic map within the ICC can become (re)organized postnatally according to the abnormal pattern of neural activity from the auditory periphery. Similar reorganization can be expected to occur in human infants with a partial cochlear hearing loss from birth.

Comparison of distortion-product and transient evoked otoacoustic emissions with ABR threshold shift in chinchillas with ototoxic damage.

In this study we compare distortion product otoacoustic emissions (DPOAEs), transient evoked otoacoustic emissions (TEOAEs) and ABR threshold shifts in an animal model (chinchilla) of cochlear hearing loss. Subjects were treated with an aminoglycoside (amikacin) to produce basal cochlear lesions of various degree. DPOAE and TEOAE were measured throughout the treatment period and until hearing thresholds stabilized. ABR thresholds to tone pip stimuli were determined. Cytocochleograms of cochleas were prepared using scanning microscopy. DPOAEs (2f1-f2) were compared to fast Fourier transform (FFT)-analyzed TEOAEs components in the 1-, 2-, and 4-kHz frequency regions. Both types of emission were compared with corresponding ABR thresholds. There was no significant linear correlation between these different measures of cochlear function. Moreover, the amplitudes of DPOAEs reflected smaller regions of cochlear outer hair cell (OHC) damage better than TEOAEs. These results suggest that DPOAEs can be used to more accurately monitor hair cell function at specific hearing locations than TEOAEs.

Basal cochlear lesions result in increased amplitude of otoacoustic emissions.

We have measured the changes in transient otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) during and after ototoxic amikacin treatment in an animal (chinchilla) model. TEOAE and DPOAE were recorded from 6 adult chinchillas over a 6-week time course starting just before a 5-day or 7-day treatment period with amikacin sulphate (400 mg/kg/day, i.m.). After final recordings, cochlear morphology was assessed by scanning electron microscopy. Generally, both DPOAE and TEOAE amplitudes change during and after treatment in a systematic fashion. High-frequency components change first, followed by lower-frequency components. We note that there is often a long latency to the onset of changes in otoacoustic emissions (OAE), and that these changes can continue for weeks after treatment. Most importantly we report that when the basal region of the cochlea is damaged in the frequency region above the OAE recording bandwidth (0.6-6 kHz for TEOAE; 1-6.7 kHz for DPOAE), we often find an increase in OAE amplitudes. More specifically, we note that as a cochlear lesion progresses apically, there is often a transient increase in a frequency-specific OAE before it reduces or is lost. Our results suggest that the increase in OAE amplitudes precedes the expression of detectable cochlear pathology.

Degeneration of spiral ganglion cells in the chinchilla after inner hair cell loss induced by carboplatin.

The anticancer drug carboplatin has been used to generate inner hair cell (IHC) lesions in the cochlea of chinchillas. This has provided a valuable model for the study of the relative roles of IHCs and outer hair cells (OHCs). In the present study, we examined the pathological and temporal relationships between the degeneration of the cochlear IHCs and type I spiral ganglion cells (SGCs). A single intravenous dose of 200 mg/m2 carboplatin produced extensive IHC loss with no apparent effect on the OHCs. The auditory brainstem response threshold was significantly elevated by 2 weeks following treatment and remained stable through 12 weeks. Elevated thresholds were well correlated with morphological lesions. On the other hand, the SGC population progressively decreased from 2 to 12 weeks after treatment, to about half of the control density values. A positive correlation existed between the density of SGC and the number of surviving IHCs. These results indicate that selective damage to IHCs causes a distinct loss of SGCs.

Optical imaging of intrinsic signals in chinchilla auditory cortex.

We have assessed sound frequency and intensity responses in primary auditory cortex of the (ketamine) anesthetized chinchilla using optical imaging of intrinsic signals. Temporal cortex was exposed via a 10-mm craniotomy and a windowed chamber was mounted. A 4-second period of gated tones (10 ms rise/fall; 50 ms plateau; 10/s) was presented to the contralateral ear at levels between 0 and 80 dB SPL. The cortical surface was illuminated with 540 nm light and video images captured in 0.5-second bins for 7.5 s (Imager 2001; Optical Imaging). Intrinsic signals were first apparent 0.5-1 s after stimulus onset, and were maximal after 3-4 s; they decayed over several seconds. The cortical area in which intrinsic activity was detected corresponded closely with electrophysiologically defined AI cortex. Intrinsic signals can reliably be detected to stimuli at 30-40 dB SPL, and in general, the area of intrinsic signal activity tends to expand with increasing stimulation level. Using stimulation levels of 80 dB SPL, we show that low-frequency stimuli (0.5-1 kHz) evoke intrinsic signals in anterior areas whilst posterior areas are activated by high-frequency stimuli (e.g. 16 kHz). Thus a low- to high-frequency tonotopic organization is seen along this axis.

The effects of anesthesia on otoacoustic emissions.

We have measured transient-evoked and distortion-product otoacoustic emissions (OAEs) in the chinchilla and compared them in the awake and anesthetized animal (using either ketamine or barbiturate agents). We report a significant increase in OAE amplitudes during anesthesia, particularly using ketamine. These effects are most evident for transient-evoked otoacoustic emissions (TEOAEs) as measured in the non-linear mode. Our data support the hypothesis that tonic activity levels in cochlear efferents may be reduced by anesthetic effects, either directly or indirectly (e.g., by general reductions in descending pathway activity), and that reduced cochlear efferent activity will result in the observed increase of OAE amplitudes.

The effects of crossed olivocochlear bundle section on transient evoked otoacoustic emissions.

The purpose of this study was to investigate the effect of sectioning the crossed olivocochlear bundle (COCB) on transient evoked otoacoustic emissions (TEOAEs) in anesthetized adult chinchillas. Of particular interest is the role of cochlear efferents to the outer haircells (OHCs) and how they control mechanisms responsible for otoacoustic emissions. Specifically the experiment addressed whether a tonic level of inhibitory control is reduced by COCB section. The nonlinear component of TEOAEs was measured before and after COCB section. Analysis was made of the 1, 2, 3, 4, and 5 kHz frequency components and of the total emission, as quantified by fast Fourier transform (FFT) of the raw (time domain) response. After COCB section, the amplitude of the total response and of the 2, 3, 4, and 5 kHz components increased whereas the amplitude of the 1 kHz component decreased. The results indicate that COCB section reduces inhibitory control of the OHC mechanisms responsible for nonlinear TEOAE generation. It is not clear whether the nerve section eliminates a spontaneous level of activity in COCB efferents, or whether it results in the interruption of a stimulus-evoked feedback loop.

Total ablation of cochlear haircells by perilymphatic perfusion with water.

Inner and outer haircells are destroyed within one day following perfusion of the perilymphatic spaces with water, otherwise the structural integrity of the cochlea and the organ of Corti are preserved. This technique is a reliable method to create an acute unilateral deafness model for investigations of auditory function.