Effects of the relative timing of opposite-polarity pulses on loudness for cochlear implant listeners.

The symmetric biphasic pulses used in contemporary cochlear implants (CIs) consist of both cathodic and anodic currents, which may stimulate different sites on spiral ganglion neurons and, potentially, interact with each other. The effect on the order of anodic and cathodic stimulation on loudness at short inter-pulse intervals (IPIs; 0-800 µs) is investigated. Pairs of opposite-polarity pseudomonophasic (PS) pulses were used and the amplitude of each pulse was manipulated independently. In experiment 1 the two PS pulses differed in their current level in order to elicit the same loudness when presented separately. Six users of the Advanced Bionics CI (Valencia, CA) loudness-ranked trains of the pulse pairs using a midpoint-comparison procedure. Stimuli with anodic-leading polarity were louder than those with cathodic-leading polarity for IPIs shorter than 400 µs. This effect was small-about 0.3 dB-but consistent across listeners. When the same procedure was repeated with both PS pulses having the same current level (experiment 2), anodic-leading stimuli were still louder than cathodic-leading stimuli at very short intervals. However, when using symmetric biphasic pulses (experiment 3) the effect disappeared at short intervals and reversed at long intervals. Possible peripheral sources of such polarity interactions are discussed.

In Vivo Electrocochleography in Hybrid Cochlear Implant Users Implicates TMPRSS3 in Spiral Ganglion Function.

Cochlear implantation, a surgical method to bypass cochlear hair cells and directly stimulate the spiral ganglion, is the standard treatment for severe-to-profound hearing loss. Changes in cochlear implant electrode array design and surgical approach now allow for preservation of acoustic hearing in the implanted ear. Electrocochleography (ECochG) was performed in eight hearing preservation subjects to assess hair cell and neural function and elucidate underlying genetic hearing loss. Three subjects had pathogenic variants in TMPRSS3 and five had pathogenic variants in genes known to affect the cochlear sensory partition. The mechanism by which variants in TMPRSS3 cause genetic hearing loss is unknown. We used a 500-Hz tone burst to record ECochG responses from an intracochlear electrode. Responses consist of a cochlear microphonic (hair cell) and an auditory nerve neurophonic. Cochlear microphonics did not differ between groups. Auditory nerve neurophonics were smaller, on average, in subjects with TMPRSS3 deafness. Results of this proof-of-concept study provide evidence that pathogenic variants in TMPRSS3 may impact function of the spiral ganglion. While ECochG as a clinical and research tool has been around for decades, this study illustrates a new application of ECochG in the study of genetic hearing and deafness in vivo.

Cochlear implant simulator with independent representation of the full spiral ganglion.

In cochlear implant simulation with vocoders, narrow-band carriers deliver the envelopes from each analysis band to the cochlear positions of the simulated electrodes. However, this approach does not faithfully represent the continuous nature of the spiral ganglion. The proposed "SPIRAL" vocoder simulates current spread by mixing all envelopes across many tonal carriers. SPIRAL demonstrated that the classic finding of reduced speech-intelligibility benefit with additional electrodes could be due to current spread. SPIRAL produced lower speech reception thresholds than an equivalent noise vocoder. These thresholds are stable for between 20 and 160 carriers.

Evaluation of focused multipolar stimulation for cochlear implants in long-term deafened cats.

OBJECTIVE: Focused multipolar (FMP) stimulation has been shown to produce restricted neural activation using intracochlear stimulation in animals with a normal population of spiral ganglion neurons (SGNs). However, in a clinical setting, the widespread loss of SGNs and peripheral fibres following deafness is expected to influence the effectiveness of FMP. APPROACH: We compared the efficacy of FMP stimulation to both monopolar (MP) and tripolar (TP) stimulation in long-term deafened cat cochleae (n = 8). Unlike our previous study, these cochleae contained <10% of the normal SGN population adjacent to the electrode array. We also evaluated the effect of electrode position on stimulation modes by using either modiolar facing or lateral wall facing half-band electrodes. The spread of neural activity across the inferior colliculus, a major nucleus within the central auditory pathway, was used as a measure of spatial selectivity. MAIN RESULTS: In cochleae with significant SGN degeneration, we observed that FMP and TP stimulation resulted in greater spatial selectivity than MP stimulation (p < 0.001). However, thresholds were significantly higher for FMP and TP stimulation compared to MP stimulation (p < 0.001). No difference between FMP and TP stimulation was found in any measures. The high threshold levels for FMP stimulation was significantly reduced without compromising spatial selectivity by varying the degree of current focusing (referred as 'partial-FMP' stimulation). Spatial selectivity of all stimulation modes was unaffected by the electrode position. Finally, spatial selectivity in long-term deafened cochleae was significantly less than that of cochleae with normal SGN population (George S S et al 2014 J. Neural Eng. 11 065003). SIGNIFICANCE: The present results indicate that the greater spatial selectivity of FMP and TP stimulation over MP stimulation is maintained in cochleae with significant neural degeneration and is not adversely affected by electrode position. The greater spatial selectivity of FMP and TP stimulation would be expected to result in improved clinical performance.

Factors influencing electrical place pitch perception in bimodal listeners.

Factors that might affect perceptual pitch match between acoustic and electric stimulation were examined in 25 bimodal listeners using magnitude estimation. Pre-operative acoustic thresholds in both ears, and duration of severe-profound loss, were first examined as correlates with degree of match between the measured pitch and that predicted by the spiral ganglion frequency-position model. The degree of match was examined with respect to (1) the ratio between the measured and predicted pitch percept on the most apical electrode and (2) the ratio between the slope of the measured and predicted pitch function. Second, effect of listening experience was examined to assess whether adaptation occurred over time to match the frequency assignment to electrodes. Pre-experience pitch estimates on the apical electrode were within the predicted range in only 28% of subjects, and the slope of the electrical pitch function was lower than predicted in all except one subject. Subjects with poorer hearing tended to have a lower pitch and a shallower electrical pitch function than predicted by the model. Pre-operative hearing thresholds in the contralateral ear and hearing loss duration were not correlated with the degree of pitch match, and there was no significant group effect of listening experience.

Optogenetic stimulation of the auditory pathway.

Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics.

Abnormal pitch perception produced by cochlear implant stimulation.

Contemporary cochlear implants with multiple electrode stimulation can produce good speech perception but poor music perception. Hindered by the lack of a gold standard to quantify electric pitch, relatively little is known about the nature and extent of the electric pitch abnormalities and their impact on cochlear implant performance. Here we overcame this obstacle by comparing acoustic and electric pitch perception in 3 unilateral cochlear-implant subjects who had functionally usable acoustic hearing throughout the audiometric frequency range in the non-implant ear. First, to establish a baseline, we measured and found slightly impaired pure tone frequency discrimination and nearly perfect melody recognition in all 3 subjects' acoustic ear. Second, using pure tones in the acoustic ear to match electric pitch induced by an intra-cochlear electrode, we found that the frequency-electrode function was not only 1-2 octaves lower, but also 2 times more compressed in frequency range than the normal cochlear frequency-place function. Third, we derived frequency difference limens in electric pitch and found that the equivalent electric frequency discrimination was 24 times worse than normal-hearing controls. These 3 abnormalities are likely a result of a combination of broad electric field, distant intra-cochlear electrode placement, and non-uniform spiral ganglion cell distribution and survival, all of which are inherent to the electrode-nerve interface in contemporary cochlear implants. Previous studies emphasized on the "mean" shape of the frequency-electrode function, but the present study indicates that the large "variance" of this function, reflecting poor electric pitch discriminability, is the main factor limiting contemporary cochlear implant performance.

Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis.

BACKGROUND: Up to 7% of patients with severe-to-profound deafness do not benefit from cochlear implantation. Given the high surgical implantation and clinical management cost of cochlear implantation (>$1 million lifetime cost), prospective identification of the worst performers would reduce unnecessary procedures and healthcare costs. Because cochlear implants bypass the membranous labyrinth but rely on the spiral ganglion for functionality, we hypothesize that cochlear implant (CI) performance is dictated in part by the anatomic location of the cochlear pathology that underlies the hearing loss. As a corollary, we hypothesize that because genetic testing can identify sites of cochlear pathology, it may be useful in predicting CI performance. METHODS: 29 adult CI recipients with idiopathic adult-onset severe-to-profound hearing loss were studied. DNA samples were subjected to solution-based sequence capture and massively parallel sequencing using the OtoSCOPE(®) platform. The cohort was divided into three CI performance groups (good, intermediate, poor) and genetic causes of deafness were correlated with audiometric data to determine whether there was a gene-specific impact on CI performance. RESULTS: The genetic cause of deafness was determined in 3/29 (10%) individuals. The two poor performers segregated mutations in TMPRSS3, a gene expressed in the spiral ganglion, while the good performer segregated mutations in LOXHD1, a gene expressed in the membranous labyrinth. Comprehensive literature review identified other good performers with mutations in membranous labyrinth-expressed genes; poor performance was associated with spiral ganglion-expressed genes. CONCLUSIONS: Our data support the underlying hypothesis that mutations in genes preferentially expressed in the spiral ganglion portend poor CI performance while mutations in genes expressed in the membranous labyrinth portend good CI performance. Although the low mutation rate in known deafness genes in this cohort likely relates to the ascertainment characteristics (postlingual hearing loss in adult CI recipients), these data suggest that genetic testing should be implemented as part of the CI evaluation to test this association prospectively.

Effect of early postnatal air-conduction auditory deprivation on the development and function of the rat spiral ganglion.

OBJECTIVE: To evaluate the effect of early postnatal air-conduction auditory deprivation on the development and function of the rat spiral ganglion. STUDY DESIGN: Randomised animal study. METHODS: Sixty neonatal Sprague-Dawley rats were randomly divided into two groups: controls (n = 30) given regular chow and water ad libitum; and study animals (n = 30) fed within a soundproof chamber. Auditory brainstem response testing was conducted in both groups on postnatal day 42. RESULTS: Auditory deprivation between postnatal days 12 and 42 resulted in an increased hearing threshold and reduced auditory brainstem response amplitudes, together with degeneration of type I spiral ganglion neurons and the presence of apoptotic cells. CONCLUSION: Non-invasive auditory deprivation during a critical developmental period resulted in numerous changes in rat cochlear function and morphology.

Oxidative stress in spiral ganglion cells of pigmented and albino guinea pigs exposed to impulse noise.

CONCLUSIONS: The results suggest that melanin inhibits formation of reactive oxygen species (ROS) and prevents apoptosis in spiral ganglion cells (SGCs) of pigmented guinea pigs following impulse noise. OBJECTIVE: The stria vascularis of pigmented guinea pig cochlea contains melanocytes that produce melanin, which has a protective effect on noise-induced hair cell damage through its antioxidant property. ROS are involved in cochlear damage induced by impulse noise trauma. The purpose of the present study was to investigate the oxidative stress in SGCs of pigmented and albino guinea pigs after exposure to impulse noise. METHODS: Pigmented and albino guinea pigs were exposed to impulse noise. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) before impulse noise exposure and 72 h after impulse noise exposure. 4-Hydroxynonenal (HNE) was used as a histochemical marker of ROS formation, and active-caspase-3 (cas-3) served as a marker for apoptosis. 4-HNE and cas-3 were determined immunohistochemically. Hair cell damage was analyzed by scanning electron microscopy. RESULTS: The rates of 4-HNE-positive and cas-3-positive SGCs in pigmented guinea pigs were much less than those for albino guinea pigs. Correspondingly, there was less hair cell damage and reduced ABR threshold shifts in pigmented guinea pigs.

Migraine, vertigo and migrainous vertigo: Links between vestibular and pain mechanisms.

This review develops the hypothesis that co-morbid balance disorders and migraine can be understood as additive effects of processing afferent vestibular and pain information in pre-parabrachial and pre-thalamic pathways, that have consequences on cortical mechanisms influencing perception, interoception and affect. There are remarkable parallel neurochemical phenotypes for inner ear and trigeminal ganglion cells and these afferent channels appear to converge in shared central pathways for vestibular and nociceptive information processing. These pathways share expression of receptors targeted by anti-migraine drugs. New evidence is also presented regarding the distribution of serotonin receptors in the planum semilunatum of the primate cristae ampullaris, which may indicate involvement of inner ear ionic homeostatic mechanisms in audiovestibular symptoms that can accompany migraine.

Examining the auditory nerve fiber response to high rate cochlear implant stimulation: chronic sensorineural hearing loss and facilitation.

Neural prostheses, such as cochlear and retinal implants, induce perceptual responses by electrically stimulating sensory nerves. These devices restore sensory system function by using patterned electrical stimuli to evoke neural responses. An understanding of their function requires knowledge of the nerves responses to relevant electrical stimuli as well as the likely effects of pathology on nerve function. We describe how sensorineural hearing loss (SNHL) affects the response properties of single auditory nerve fibers (ANFs) to electrical stimuli relevant to cochlear implants. The response of 188 individual ANFs were recorded in response to trains of stimuli presented at 200, 1,000, 2,000, and 5,000 pulse/s in acutely and chronically deafened guinea pigs. The effects of stimulation rate and SNHL on ANF responses during the 0-2 ms period following stimulus onset were examined to minimize the influence of ANF adaptation. As stimulation rate increased to 5,000 pulse/s, threshold decreased, dynamic range increased and first spike latency decreased. Similar effects of stimulation rate were observed following chronic SNHL, although onset threshold and first spike latency were reduced and onset dynamic range increased compared with acutely deafened animals. Facilitation, defined as an increased nerve excitability caused by subthreshold stimulation, was observed in both acute and chronic SNHL groups, although the magnitude of its effect was diminished in the latter. These results indicate that facilitation, demonstrated here using stimuli similar to those used in cochlear implants, influences the ANF response to pulsatile electrical stimulation and may have important implications for cochlear implant signal processing strategies.

Chronic electrical stimulation does not prevent spiral ganglion cell degeneration in deafened guinea pigs.

Several studies have demonstrated that treatment with intracochlear chronic electrical stimulation (CES) protects spiral ganglion cells (SGCs) from degeneration in deafened animals. Other studies could not confirm this effect of CES. The present study examined whether CES in a mode as presented in cochlear implant users (amplitude modulated, high pulse rate) affects survival, morphology and functionality of SGCs in deafened guinea pigs. Eleven guinea pigs were implanted in the right cochlea with an electrode array to monitor the electrically evoked auditory brainstem responses (eABRs). The guinea pigs were deafened four weeks later. Two days after deafening, monopolar CES was started in five animals through three electrodes in the basal cochlear turn. CES lasted 4 hours per day, five days per week, for six weeks. SGC packing densities, perikaryal area, cell circularity, amplitudes of suprathreshold eABRs and eABR thresholds were not affected by CES. SGCs of all implanted cochleae were larger and more circular than SGCs in unimplanted cochleae, but this did not depend on CES treatment. Interestingly, an increase in eABR latencies observed after deafening, occurred faster in CES-treated than in untreated animals. In conclusion, amplitude-modulated chronic electrical stimulation with a high pulse rate does not affect survival, morphology and functionality of spiral ganglion cells with the exception of eABR latencies.

beta-Bungarotoxin application to the round window: an in vivo deafferentation model of the inner ear.

Hearing impairment can be caused by a primary lesion to the spiral ganglion neurons (SGNs) with the hair cells kept intact, for example via tumours, trauma or auditory neuropathy. To mimic these conditions in animal models various methods of inflicting damage to the inner ear have been used. However, only a few methods have a selective effect on the SGNs, which is of importance since it might be clinically more relevant to study hearing impairment with the hair cells undamaged. beta-Bungarotoxin is a venom of the Taiwan banded krait, which in vitro has been shown to induce apoptosis in neurons, leaving remaining cochlear cells intact. We wanted to create an in vivo rat model of selective damage to primary auditory neurons. Under deep anaesthesia, 41 rats received beta-Bungarotoxin or saline to the round window niche. At postoperative intervals between days 3 and 21 auditory brainstem response (ABR) measurement, immunohistochemistry, SGN quantification and cochlear surface preparation were performed. The results in the beta-Bungarotoxin-treated ears, as compared with sham-operated ears, show significantly increased ABR thresholds at all postoperative intervals, illustrating a severe to profound hearing loss at all tested frequencies (3.5, 7, 16 and 28 kHz). Quantification of the SGNs showed no obvious reduction in neuronal numbers until 14 days postoperatively. Between days 14 and 21 a significant reduction in SGN numbers was observed. Cochlear surface preparation and immunohistochemistry showed that the hair cells were intact. Our results illustrate that in vivo application of beta-Bungarotoxin to the round window niche is a feasible way of deafening rats by SGN reduction while the hair cells are kept intact.

Auditory development in progressive motor neuronopathy mouse mutants.

The present study was performed to elucidate the hearing development in the progressive motor neuronopathy (pmn) mouse mutant. This mouse has been used as a model for human motoneuron disease. A missense mutation in the tubulin-specific chaperon E (Tbce) gene on mouse chromosome 13 was localized as the underlying genetic defect. The protein encoded by the Tbce gene is essential for the formation of primary tubulin complexes. Studies on motoneurons show disorganization in microtubules and disturbed axonal transport, followed by retrograde degeneration of the motoneurons. A similar pathomechanism is also possible for hearing disorders where disrupted microtubules could cause functional deficits in spiral ganglion neurons or in cochlear hair cells. Click auditory brainstem response (ABR) audiometry in homozygous pmn mutants showed a normal onset of hearing, but an increasing hearing threshold from postnatal day 26 (P26) on to death, compared to heterozygous mutants and wild-type mice. Histological sections of the cochlea at different ages showed a regular morphology. Additionally, spiral ganglion explants from mutant and wild-type mice were cultured. The neurite length from pmn mutants was shorter than in wild-type mice, and the neurite number/explant was significantly decreased in pmn mutants. We show that the pmn mouse mutant is a model for a progressive rapid hearing loss from P26 on, after initially normal hearing development. Heterozygous mice are not affected by this defect. With the knowledge of the well-known pathomechanism of this defect in motoneurons, a dysfunction of cellular mechanisms regulating tubulin assembling suggests that tubulin assembling plays an essential role in hearing function and maintenance.

Prospective electrophysiologic findings of round window stimulation in a model of experimentally induced stapes fixation.

HYPOTHESIS: Mechanical stimulation of the round window (RW) with an active middle ear implant (AMEI) with and without experimentally induced stapes fixation (SF) results in equivalent electrophysiologic measures of cochlear microphonic (CM), compound action potential (CAP), and auditory brainstem response (ABR). BACKGROUND: Where normal oval window functionality is mitigated, the RW provides a pathway to mechanically stimulate the inner ear. METHODS: Measurements of the CM, CAP, and ABR were made in 5 ears of 4 chinchillas with acoustic stimulation and with application of the AMEI to the RW with and without experimentally induced SF using pure-tone stimuli (0.25-20 kHz) presented at differing intensities (-20 to 80 dB SPL vs. 0.01 mV to 3.16 V). RESULTS: Morphologies of the CM, CAP, and ABR were similar between acoustic and RW stimulation with and without SF. Stapes fixation increased CM thresholds relative to RW stimulation without fixation by a frequency-dependent 4- to 13-dB mV (mean, 7.9 +/- 3.2 dB mV). Although the thresholds changed with SF, CM sensitivities and amplitude dynamic range were identical to normal. The CAP in all conditions demonstrated equivalent decreasing amplitudes and increasing latency with decreasing intensity (decibel sound pressure level versus decibel millivolt). Stapes fixation increased the CAP thresholds at all frequencies, ranging from 9 to 24 dB mV (mean, 17.7 +/- 4.9 dB mV). Auditory brainstem response waveforms were preserved across experimental conditions. CONCLUSION: Mechanical stimulation of the RW in an animal model of SF generates functionally similar inputs to the cochlea as normal acoustic and RW mechanical inputs but with increased thresholds. With further study, AMEIs may provide a surgical option for correction of otosclerosis and ossicular chain disruption.

Does cochlear implantation and electrical stimulation affect residual hair cells and spiral ganglion neurons?

Increasing numbers of cochlear implant subjects have some level of residual hearing at the time of implantation. The present study examined whether (i) hair cells that have survived one pathological insult (aminoglycoside deafening), can survive and function following long-term cochlear implantation and electrical stimulation (ES); and (ii) chronic ES in these cochleae results in greater trophic support of spiral ganglion neurons (SGNs) compared with cochleae devoid of hair cells. Eight cats, with either partial (n=4) or severe (n=4) sensorineural hearing loss, were bilaterally implanted with scala tympani electrode arrays 2 months after deafening, and received unilateral ES using charge balanced biphasic current pulses for periods of up to 235 days. Frequency-specific compound action potentials and click-evoked auditory brainstem responses (ABRs) were recorded periodically to monitor the residual acoustic hearing. Electrically evoked ABRs (EABRs) were recorded to confirm the stimulus levels were 3-6 dB above the EABR threshold. On completion of the ES program the cochleae were examined histologically. Partially deafened animals showed no significant increase in acoustic thresholds over the implantation period. Moreover, chronic ES of an electrode array located in the base of the cochlea did not adversely affect hair cells in the middle or apical turns. There was evidence of a small but statistically significant rescue of SGNs in the middle and apical turns of stimulated cochleae in animals with partial hearing. Chronic ES did not, however, prevent a reduction in SGN density for the severely deaf cohort, although SGNs adjacent to the stimulating electrodes did exhibit a significant increase in soma area (p<0.01). In sum, chronic ES in partial hearing animals does not adversely affect functioning residual hair cells apical to the electrode array. Moreover, while there is an increase in the soma area of SGNs close to the stimulating electrodes in severely deaf cochleae, this trophic effect does not result in increased SGN survival.

Age-related hearing loss: the status of Schuknecht's typology.

PURPOSE OF REVIEW: Recent developments in age-related hearing loss (ARHL) are reviewed with an emphasis on their relation to the framework advocated by Schuknecht. More than a classification scheme, Schuknecht's typology incorporates testable hypotheses about the bases of ARHL. Since there is presently no widely accepted competing framework, research in this area should be aimed at supporting, modifying, or replacing Schuknecht scheme. Only recently has our understanding of cellular changes and gene/environment interactions in ARHL achieved the level needed for hypothesis-driven experiments in this area. RECENT FINDINGS: New findings largely support or amplify aspects of Schuknecht's framework. Consideration of the kinds of cells involved in ARHL has broadened to include more nonsensory and supporting cells. This should provide more complete criteria for comparing models, and for diagnosing particular forms of ARHL. Newly discovered genetic effects and more detailed comparisons have imparted mechanistic significance to the often-noted similarity between sensory ARHL and noise injury. Recent comparative studies, and studies of cell replacement in the cochlear lateral wall, suggest variations in the relation between strial and ligament pathology, and indicate why cell loss occurs during aging. Mouse models carrying mutations affecting processes that may give rise to ARHL are receiving increased attention, even as detailed studies bolster support for mice as valid ARHL models. SUMMARY: Using Schuknecht's framework as a guide, basic research can now seek to model specific forms of ARHL by combining genetic defects and appropriate environmental conditions. Identification of distinct risk factors for age-related degeneration of organ of Corti, afferent neurons, and stria would verify a key tenet of Schuknecht's scheme, and point the way to interventions.

Cellular correlates of progressive hearing loss in 129S6/SvEv mice.

Several strains of mice hear well initially but show progressive sensorineural hearing loss. Affected cochlear cell types include all those known to be affected in human age-related hearing loss (ARHL), or presbycusis. Thus these mice have been offered as models of human ARHL. At present, however, few mouse ARHL models are sufficiently well described to serve as the basis for specific hypotheses about human ARHL. We examined 1-month-old and 15-month-old 129S6/SvEv (129S6) mice and compared them with BALB/cJ and CBA/J mice. Age-related elevation of compound action potential thresholds was interpreted in the light of endocochlear potentials and changes in hair cells, afferent neurons, fibrocytes in spiral limbus and ligament, and supporting cells within the organ of Corti. Aging in 129S6 mice was associated with high-frequency hearing loss. Four components of age-related cochlear degeneration emerged from quantitative analyses, including 1) basal loss of outer hair cells; 2) basal loss of type IV fibrocytes in the spiral ligament; 3) apical loss of fibrocytes in spiral limbus, and 4) anomalies of supporting cells in the cochlear base. Although neuronal loss was not consistently found, two mice showed loss of afferent dendrites and cell bodies in the cochlear apex without inner hair cell loss. Despite multifaceted degeneration, hearing loss in 129S6 mice appears to be best explained by degenerative changes in outer hair cells and in the organ of Corti, conforming to human sensory ARHL. Age-related changes in the apical spiral limbus may promote pathology of the medial organ of Corti and eventual loss of afferent neurons, with possible implications for human neural ARHL.

Effects of chronic stimulation on auditory nerve survival in ototoxically deafened animals.

For almost 10 years, chronic stimulation has been known to affect spiral ganglion cell (SGC) survival in the deaf ear. However, the reported effects of chronic stimulation vary across preparations and studies. In this review, the effects of chronic stimulation on the deafened auditory periphery are examined, and variables that may impact on the efficacy of chronic stimulation are identified. The effects of deafening on the unstimulated peripheral and central auditory system are also described, as the deafened, unstimulated system is the canvas upon which stimulation-mediated effects are imposed. Discrepancies in the effects of chronic stimulation across studies may be attributable in large part to the combined effects of the deafening method and the post-deafening delay prior to chronic stimulation, which vary across studies. Emphasis is placed on the need to consider the natural progression of SGC loss following deafening in the absence of chronic stimulation, as the rate of SGC loss almost certainly affects both the efficacy of stimulation, and the impact of any delay between deafening and initiation of stimulation. The differences across preparations complicate direct comparison of protective efficacy of stimulation. At the same time, these differences can be used to our advantage, aiding characterization of the effects of different factors on the efficacy of chronic stimulation as a neuroprotective intervention.