David J. Sly

Factors influencing the efficacy of round window dexamethasone protection of residual hearing post-cochlear implant surgery

AIM To protect hearing in an experimental model of cochlear implantation by the application of dexamethasone to the round window prior to surgery. The present study examined the dosage and timing relationships required to optimise the hearing protection. METHODS Dexamethasone or saline (control) was absorbed into a pledget of the carboxymethylcellulose and hyaluronic acid and applied to the round window of the guinea pig prior to cochlear implantation. The treatment groups were 2% w/v dexamethasone for 30, 60 and 120min; 20% dexamethasone applied for 30min. Auditory sensitivity was determined pre-operatively, and at 1 week after surgery, with pure-tone auditory brainstem response audiometry (2-32kHz). Cochlear implantation was performed via a cochleostomy drilled into the basal turn of the cochlea, into which a miniature cochlear implant dummy electrode was inserted using soft-surgery techniques. RESULTS ABR thresholds were elevated after cochlear implantation, maximally at 32kHz and to a lesser extent at lower frequencies. Thresholds were less elevated after dexamethasone treatment, and the hearing protection improved when 2% dexamethasone was applied to the round window for longer periods of time prior to implantation. The time that dexamethasone need be applied to achieve hearing protection could be reduced by increasing the concentration of steroid, with a 20% application for 30min achieving similar levels of protection to a 60min application of 2% dexamethasone. CONCLUSIONS Hearing protection is improved by increasing the time that dexamethasone is applied to the round window prior to cochlear implantation, and the waiting time can be reduced by increasing the steroid concentration. These results suggest that the diffusion dexamethasone through the cochlea is the prime determinant of the extent of hearing protection.

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.

Round window delivery of dexamethasone ameliorates local and remote hearing loss produced by cochlear implantation into the second turn of the guinea pig cochlea

Application of dexamethasone to the round window has been shown to ameliorate high frequency hearing loss resulting from the trauma of cochlear implantation in experimental animals, but elucidation of the factors influencing protection of the high frequencies has been confounded by the local trauma from electrode array insertion. In this experiment, a second turn cochleostomy and implantation was performed on guinea pigs, to examine protection in the basal turn without the confounding effect of local trauma, as well as to test the efficacy of hearing protection in the second cochlear turn. The implantation resulted in an increase in hearing thresholds across all frequencies examined (2-32 kHz). Local delivery of dexamethasone to the round window prior to implantation protected hearing across frequencies from 2 to 32 kHz. Auditory thresholds improved over the first week after surgery, and then remained stable for the month of the experiment. The protection of hearing in the basal turn increased with longer periods of drug application prior to implantation. The level of hearing protection in the second turn was similar irrespective of the time that the drug was applied, but was greater when a higher steroid concentration was used. It was concluded that steroids protect hearing in the basal turn of the cochlea even when there was no local trauma. The level of hearing protection in the second turn exceeded that expected from models of steroid diffusion through the cochlea, suggesting that inner ear surgery alters the distribution of dexamethasone within the cochlea.

Targeted Therapy of the Inner Ear

Background: There is experimental evidence that targeted delivery of steroids to the inner ear can protect hearing during cochlear implant surgery. The best protection appears to be achieved through pre-treatment of the cochlea, but the time period required for treatment is long compared with the duration of surgery, and needs further optimization. The stability of hearing thresholds is determined over a 3-month period after hearing preservation cochlear implantation. Methods: Adult guinea pigs were implanted with a miniature cochlear implant electrode, and pure tone auditory brainstem response (ABR) thresholds were estimated in response to pure tones of 2–32 kHz immediately after surgery and at 1 week, 1 month and 3 months. Spiral ganglion cell (SGC) densities were estimated from mid-modular histological sections of the cochlea. Thirty minutes prior to implantation, a polymeric sponge (SeprapackTM, Genzyme) was loaded with either a 2% solution of dexamethasone phosphate or normal saline (control) and placed onto the round window. Results: Implantation was associated with an immediate elevation in thresholds across frequencies, with a full recovery below 2 kHz over the next week and a partial recovery of thresholds at higher frequencies. These thresholds remained unchanged for the next 3 months. There was an immediate and sustained reduction in the elevation of thresholds at 32 kHz in dexamethasone-treated animals. SGC densities were greater in steroid-treated animals than controls in the basal turn of the cochlea (at the region of implantation) 3 months after implantation. Conclusion: It is concluded that ABR thresholds remain stable for 3 months after cochlear implantation in the guinea pig, and that local application of steroids to the inner ear prior to implantation is an effective method of preserving SGC populations when there is residual hearing at the time of 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.

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.

Intraoperative Real-time Cochlear Response Telemetry Predicts Hearing Preservation in Cochlear Implantation.

Aim: To monitor cochlear function during cochlear implantation and determine correlations with postoperative acoustic hearing. Background: Cochlear response telemetry measures cochlear function directly from cochlear implant electrodes. We have adapted this system to provide real-time cochlear response telemetry (RT-CRT) monitoring of a patients acoustic hearing as the cochlear implant electrode array is inserted. Methods: Eighteen subjects (1 child and 17 adults) with sloping high frequency hearing loss were implanted with Cochlear Ltd slim straight arrays (CI422/CI522). Tone bursts (500 Hz, 100–110 dB) were presented at 14 Hz continuously during the array insertion. RT-CRT amplitudes were correlated with surgical manoeuvres recorded on the video from the operating microscope and with postoperative pure tone audiograms. Results: Despite an excellent overall rate of complete or partial hearing preservation (79%), RT-CRT identified that in 47% of these implantations there was transient or permanent reduction in the amplitude of the cochlear microphonic (CM). Patients with a preserved CM at the end of insertion had on average 15 dB better low-frequency hearing preservation. The CM amplitude was most vulnerable during the last few millimeters of insertion or when inadvertent movement of the array occurred after full insertion. Physical contact/elevation of the basilar membrane is hypothesized as a likely mechanism of hearing loss rather than overt physical trauma. Conclusion: RT-CRT can be used to predict early postoperative hearing loss and to potentially refine surgical technique. In the future, feedback of RT-CRT may prove to be a valuable tool for maximizing preservation of residual hearing or providing feedback on electrode contact with the basilar membrane.

Neurons in the lamina terminalis which project polysynaptically to the kidney express angiotensin AT1A receptor.

The retrograde transynaptic transport of pseudorabies virus was used in conjunction with hybridisation histochemistry for the angiotensin II AT1A receptor, to characterise neurons in the lamina terminalis projecting to the kidney. These data demonstrate that some neurons in the lamina terminalis, that project polysynaptically to the kidney, may be responsive to angiotensin II.

Training of cochlear implant users to improve pitch perception in the presence of competing place cues.

Objectives: Perception of musical pitch in cochlear implant (CI) systems is relatively poor compared with normal hearing and can be adversely affected by changes in spectral timbre coded by stimulation place. In this study, we evaluated whether the perception of musical pitch could be improved through specific training designed to teach listeners to attend to fundamental frequency (F0) exclusively for judgment of pitch and to spectral envelope exclusively for discrimination of spectral timbre. Design: A computer-based training program to improve musical pitch perception was developed that required listeners to match acoustic patterns of pitch and spectral timbre to visual patterns. Ten adult CI recipients participated: five used the training program and five acted as controls. Before training, F0 and center frequency discrimination for band-limited complex harmonic stimuli presented in the sound field were measured in all subjects using their standard clinical device(s). The F0 tests were conducted with and without spectral variations. The trainees subsequently used the training program at home for a period of 4 months, during which they were asked to train for approximately 30 min per day. The training schedule comprised two successive phases, each lasting 2 months. In the first phase, training employed a single cue (i.e., F0 for pitch or center frequency for spectral timbre) in the absence of other cue variations. In the second phase, training incorporated more complex sounds in which multiple cues were varied. Discrimination thresholds were remeasured in all subjects after each phase and again with trainees 3 months after training had ceased. Results: Trainees obtained significant improvements in F0 and center frequency discrimination as compared with control subjects for tests conducted at 2 months. The improvements in F0 discrimination were observed both in the absence and presence of small variations in place. However, the effect of training diminished for large variations in place or for higher F0s. Neither group showed further improvement in tests after additional training in the second phase. Tests conducted with trainees after training had ceased showed that F0 discrimination improvements were retained. Conclusions: The results showed that performance on pitch and timbre discrimination can be improved by training with single cues (F0 and center frequency) in the absence of other cue variations. Although results indicated that training with single cues can improve F0 discrimination within more complex sounds in which multiple cues vary, little improvement was seen when large variations in place were present, which suggests a diminishing effect of the training with increased influence of place-pitch. These data imply that although such training techniques may help listeners to follow melody in music, changes in instrument are likely to affect perception of melody. Results of subsequent training with complex sounds in which multiple cues varied were less conclusive and showed no further improvement. Follow-up evaluations with trainees conducted well after training had ceased verified the robustness of the training effect on F0 but not center frequency discrimination. Further studies are needed, however, to determine whether and to what degree subject motivation may be an important factor in these outcomes.

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 &mgr;l bolus of neurotrophins (brain-derived neurotrophic factor 1 &mgr;g/&mgr;l, and neurotrophin-3 1 &mgr;g/&mgr;l) 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.