Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF.

Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug-delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain-derived neurotrophic factor (BDNF) via this catheter with a mini-osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter - whether dry or when delivering AP or BDNF for 4 weeks - was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

Applying Neurotrophins to the Round Window Rescues Auditory Function and Reduces Inner Hair Cell Synaptopathy After Noise-induced Hearing Loss.

HYPOTHESIS: Applying neurotrophins to the round window immediately after a single noise exposure will prevent noise-induced hidden hearing loss. BACKGROUND: Loud noise can eliminate neural connections between inner hair cells and their afferent neurons (thereby diminishing sound perception) without causing a detectable change on audiogram. This phenomenon is termed hidden hearing loss. METHODS: Guinea pigs were exposed for 2 hours to 4 to 8 kHz noise at either 95 or 105 dB SPL. Immediately afterward a 4 µl bolus of neurotrophins (brain-derived neurotrophic factor 1 µg/µl, and neurotrophin-3 1 µg/µl) was delivered to the round window of one ear, and saline to the other. Auditory brainstem responses to pure-tone pips were acquired preoperatively, and at 1 and 2 weeks' postexposure. Cochleae were removed and whole mounted for immunohistochemical analysis, with presynaptic ribbons of inner hair cells and associated postsynaptic glutamatergic AMPA receptors identified using CtBP2 and GluA2 antibodies respectively. RESULTS: After exposure to 105 dB noise, threshold did not change, but the amplitude growth of the auditory brainstem response was significantly reduced in control ears in response to 16 and 32 kHz tones. The amplitude growth was also reduced neurotrophin ears, but to a lesser degree and the reduction was not significant. Similar results were obtained from control ears exposed to 95 dB, but amplitude growth recovered in neurotrophin-treated ears, this reaching statistical significance in response to 16 kHz tones. There were significantly more presynaptic ribbons, postsynaptic glutamate receptors, and colocalized ribbons after neurotrophin treatment. CONCLUSION: A single dose of neurotrophins delivered to the round window reduced synaptopathy and recovered high-frequency hearing in ears exposed to 95 dB noise. These findings suggest that hidden hearing loss may be reduced by providing trophic support to the cochlea after injury.

A microelectromechanical system artificial basilar membrane based on a piezoelectric cantilever array and its characterization using an animal model.

We proposed a piezoelectric artificial basilar membrane (ABM) composed of a microelectromechanical system cantilever array. The ABM mimics the tonotopy of the cochlea: frequency selectivity and mechanoelectric transduction. The fabricated ABM exhibits a clear tonotopy in an audible frequency range (2.92-12.6 kHz). Also, an animal model was used to verify the characteristics of the ABM as a front end for potential cochlear implant applications. For this, a signal processor was used to convert the piezoelectric output from the ABM to an electrical stimulus for auditory neurons. The electrical stimulus for auditory neurons was delivered through an implanted intra-cochlear electrode array. The amplitude of the electrical stimulus was modulated in the range of 0.15 to 3.5 V with incoming sound pressure levels (SPL) of 70.1 to 94.8 dB SPL. The electrical stimulus was used to elicit an electrically evoked auditory brainstem response (EABR) from deafened guinea pigs. EABRs were successfully measured and their magnitude increased upon application of acoustic stimuli from 75 to 95 dB SPL. The frequency selectivity of the ABM was estimated by measuring the magnitude of EABRs while applying sound pressure at the resonance and off-resonance frequencies of the corresponding cantilever of the selected channel. In this study, we demonstrated a novel piezoelectric ABM and verified its characteristics by measuring EABRs.

Brain-derived neurotrophic factor modulates auditory function in the hearing cochlea.

Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and click-evoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

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.

Deafness alters auditory nerve fibre responses to cochlear implant stimulation.

Here we characterized the relationship between duration of sensorineural hearing loss and the response of the auditory nerve to electrical stimulus rate. Electrophysiological recordings were made from undeafened guinea pigs and those ototoxically deafened for either 5 weeks or 6 months. Auditory neuron survival decreased significantly with the duration of deafness. Extracellular recordings were made from auditory nerve fibres responding to biphasic, charge-balanced current pulses delivered at rates of 20 and 200 pulses/s via a monopolar scala tympani stimulating electrode. The response to 20 pulses/s electrical stimulation of the deafened cochlea exhibited a decrease in spike latency, unaltered temporal jitter and unaltered dynamic range (of nerve firing rate against stimulus current), and a reduction in threshold after 6 months of deafness. The response to a 200-pulse/s stimulus was similar except that the dynamic range was greater than with 20 pulses/s and was also greater in deafened animals than in undeafened animals. Deafness and pulse rate are related; in deaf animals spike recovery appears to be complete between successive stimulus pulses at a low rate (20 pulses/s), but incomplete between pulses at a moderate pulse rate (200 pulses/s). These results suggest that changes in the function of individual auditory nerve fibres after deafness may affect clinical responses during high-rate stimulation such as that used in contemporary speech processing strategies, but not during lower rate stimulation such as that used to record evoked potentials.