Stephen O'Leary

Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons.

Sensorineural hearing loss is associated with gradual degeneration of spiral ganglion neurons (SGNs), compromising hearing outcomes with cochlear implant use. Combination of neurotrophin delivery to the cochlea and electrical stimulation from a cochlear implant protects SGNs, prompting research into neurotrophin-eluting polymer electrode coatings. The electrically conducting polypyrrole/para-toluene sulfonate containing neurotrophin-3 (Ppy/pTS/NT3) was applied to 1.7 mm2 cochlear implant electrodes. Ppy/pTS/NT3-coated electrode arrays stored 2 ng NT3 and released 0.1 ng/day with electrical stimulation. Guinea pigs were implanted with Ppy/pTS or Ppy/pTS/NT3 electrode arrays two weeks after deafening via aminoglycosides. The electrodes of a subgroup of these guinea pigs were electrically stimulated for 8 h/day for 2 weeks. There was a loss of SGNs in the implanted cochleae of guinea pigs with Ppy/pTS-coated electrodes indicative of electrode insertion damage. However, guinea pigs implanted with electrically stimulated Ppy/pTS/NT3-coated electrodes had lower electrically-evoked auditory brainstem response thresholds and greater SGN densities in implanted cochleae compared to non-implanted cochleae and compared to animals implanted with Ppy/pTS-coated electrodes (p<0.05). Ppy/pTS/NT3 did not exacerbate fibrous tissue formation and did not affect electrode impedance. Drug-eluting conducting polymer coatings on cochlear implant electrodes present a clinically viable method to promote preservation of SGNs without adversely affecting the function of the cochlear implant.

Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3.

Degeneration of auditory neurons occurs after deafening and is associated with damage to the organ of Corti. The administration of neurotrophins can protect auditory neurons against degeneration if given shortly after deafening. However, it is not known whether the delayed administration of neurotrophins, when significant degeneration has already occurred, will provide similar protection. Furthermore, little is known about the effects of neurotrophins on the peripheral processes of the auditory neurons or whether these neurons can resprout. This study examined the morphological effects on auditory neurons following deafening and the administration of brain‐derived neurotrophic factor and neurotrophin‐3. Results showed that neurotrophins were effective in preventing death of auditory neurons if administered 5 days after deafening and were also effective in preventing the continued loss of neurons if the administration was delayed by 33 days. The peripheral processes of auditory neurons in cochleae that received neurotrophins were in greater number and had larger diameters compared with the untreated cochleae. Localized regions of resprouting peripheral processes were observed in deafened cochleae and were enhanced in response to neurotrophin treatment, occurring across wider regions of the cochlea. These findings have significant implications for an improvement in the performance of the cochlear implant and for future therapies to restore hearing to the deaf. J. Comp. Neurol. 487:147–165, 2005.

Conducting polymers, dual neurotrophins and pulsed electrical stimulation — Dramatic effects on neurite outgrowth

In this study the synergistic effect of delivering two neurotrophins simultaneously to encourage neuron survival and neurite elongation was explored. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were incorporated into polypyrrole (PPy) during electrosynthesis and the amounts incorporated and released were determined using iodine-125 ((125)I) radio-labelled neurotrophins. Neurite outgrowth from cochlear neural explants grown on the conducting polymer was equivalent to that on tissue culture plastic but significantly improved with the incorporation of NT-3 and BDNF. Neurite outgrowth from explants grown on polymers containing both NT-3 and BDNF showed significant improvement over PPy doped only with NT-3, due to the synergistic effect of both neurotrophins. Neurite outgrowth was significantly improved when the polymer containing both neurotrophins was electrically stimulated. It is envisaged that when applied to the cochlear implant, these conducting and novel polymer films will provide a biocompatible substrate for storage and release of neurotrophins to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes.

Factors Affecting Auditory Performance of Postlinguistically Deaf Adults Using Cochlear Implants: An Update with 2251 Patients

Objective: To update a 15-year-old study of 800 postlinguistically deaf adult patients showing how duration of severe to profound hearing loss, age at cochlear implantation (CI), age at onset of severe to profound hearing loss, etiology and CI experience affected CI outcome. Study Design: Retrospective multicenter study. Methods: Data from 2251 adult patients implanted since 2003 in 15 international centers were collected and speech scores in quiet were converted to percentile ranks to remove differences between centers. Results: The negative effect of long duration of severe to profound hearing loss was less important in the new data than in 1996; the effects of age at CI and age at onset of severe to profound hearing loss were delayed until older ages; etiology had a smaller effect, and the effect of CI experience was greater with a steeper learning curve. Patients with longer durations of severe to profound hearing loss were less likely to improve with CI experience than patients with shorter duration of severe to profound hearing loss. Conclusions: The factors that were relevant in 1996 were still relevant in 2011, although their relative importance had changed. Relaxed patient selection criteria, improved clinical management of hearing loss, modifications of surgical practice, and improved devices may explain the differences.

Pre-, Per- and Postoperative Factors Affecting Performance of Postlinguistically Deaf Adults Using Cochlear Implants: A New Conceptual Model over Time

Objective To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance with a CI as a function of the significant factors. Study Design Retrospective multi-centre study. Methods Data from 2251 patients implanted since 2003 in 15 international centres were collected. Speech scores in quiet and in noise were converted into percentile ranks to remove differences between centres. The influence of 15 pre-, per- and postoperative factors, such as the duration of moderate hearing loss (mHL), the surgical approach (cochleostomy or round window approach), the angle of insertion, the percentage of active electrodes, and the brand of device were tested. The usual factors, duration of profound HL (pHL), age, etiology, duration of CI experience, that are already known to have an influence, were included in the statistical analyses. Results The significant factors were: the pure tone average threshold of the better ear, the brand of device, the percentage of active electrodes, the use of hearing aids (HAs) during the period of pHL, and the duration of mHL. Conclusions A new model was designed showing a decrease of performance that started during the period of mHL, and became faster during the period of pHL. The use of bilateral HAs slowed down the related central reorganization that is the likely cause of the decreased performance.

A stochastic model of the electrically stimulated auditory nerve: single-pulse response

Most models of neural response to electrical stimulation, such as the Hodgkin-Huxley equations, are deterministic, despite significant physiological evidence for the existence of stochastic activity. For instance, the range of discharge probabilities measured in response to single electrical pulses cannot be explained at all by deterministic models. Furthermore, there is growing evidence that the stochastic component of auditory nerve response to electrical stimulation may be fundamental to functionally significant physiological and psychophysical phenomena. In this paper authors present a simple and computationally efficient stochastic model of single-fiber response to single biphasic electrical pulses, based on a deterministic threshold model of action potential generation. Comparisons with physiological data from cat auditory nerve fibers are made, and it is shown that the stochastic model predicts discharge probabilities measured in response to single biphasic pulses more accurately than does the equivalent deterministic model. In addition, physiological data show an increase in stochastic activity with increasing pulse width of anodic/cathodic biphasic pulses, a phenomenon not present for monophasic stimuli. Those and other data from the auditory nerve are then used to develop a population model of the total auditory nerve, where each fiber is described by the single-fiber model.

Effects of Localized Neurotrophin Gene Expression on Spiral Ganglion Neuron Resprouting in the Deafened Cochlea

A cochlear implant may be used to electrically stimulate spiral ganglion neurons (SGNs) in people with severe sensorineural hearing loss (SNHL). However, these neurons progressively degenerate after SNHL due to loss of neurotrophins normally supplied by sensory hair cells (HCs). Experimentally, exogenous neurotrophin administration prevents SGN degeneration but can also result in abnormal resprouting of their peripheral fibers. This study aimed to create a target-derived neurotrophin source to increase neuron survival and redirect fiber resprouting following SNHL. Adenoviral (Ad) vectors expressing green fluorescent protein (GFP) alone or in combination with brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT3) were injected into the cochlear scala tympani or scala media of guinea-pigs (GPs) deafened via aminoglycosides for 1 week. After 3 weeks, cochleae were examined for gene expression, neuron survival, and the projection of peripheral fibers in response to gene expression. Injection of vectors into the scala media resulted in more localized gene expression than scala tympani injection with gene expression consistently observed within the partially degenerated organ of Corti. There was also greater neuron survival and evidence of localized fiber responses to neurotrophin-expressing cells within the organ of Corti from scala media injections (P < 0.05), a first step in promoting organized resprouting of auditory peripheral fibers via gene therapy.

A stochastic model of the electrically stimulated auditory nerve: pulse-train response

The single-pulse model of the companion paper [see ibid., vol. 46, no. 6, p. 617-29, 1999] is extended to describe responses to pulse trains by introducing a phenomenological refractory mechanism. Comparisons with physiological data from cat auditory nerve fibers are made for pulse rates between 100 and 800 pulses/s. First, it is shown that both the shape and slope of mean discharge rate curves are better predicted by the stochastic model than by the deterministic model. Second, while interpulse effects such as refractory effects do indeed increase the dynamic range at higher pulse rates, both the physiological data and the model indicate that much of the dynamic range for pulse-train stimuli is due to stochastic activity. Third, it is shown that the stochastic model is able to predict the general magnitude and behavior of variance in discharge rate as a function of pulse rate, while the deterministic model predicts no variance at all.

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Spiral ganglion neurons (SGNs) are the target cells of the cochlear implant, a neural prosthesis designed to provide important auditory cues to severely or profoundly deaf patients. The ongoing degeneration of SGNs that occurs following a sensorineural hearing loss is, therefore, considered a limiting factor in cochlear implant efficacy. We review neurobiological techniques aimed at preventing SGN degeneration using exogenous delivery of neurotrophic factors. Application of these proteins prevents SGN degeneration and can enhance neurite outgrowth. Furthermore, chronic electrical stimulation of SGNs increases neurotrophic factor-induced survival and is correlated with functional benefits. The application of neurotrophic factors has the potential to enhance the benefits that patients can derive from cochlear implants; moreover, these techniques may be relevant for use with neural prostheses in other neurological conditions

Promoting neurite outgrowth from spiral ganglion neuron explants using polypyrrole/BDNF‐coated electrodes

Release of neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF) from hair cells in the cochlea is essential for the survival of spiral ganglion neurons (SGNs). Loss of hair cells associated with a sensorineural hearing loss therefore results in degeneration of SGNs, potentially reducing the performance of a cochlear implant. Exogenous replacement of either or both neurotrophins protects SGNs from degeneration after deafness. We previously incorporated NT3 into the conducting polymer polypyrrole (Ppy) synthesized with para-toluene sulfonate (pTS) to investigate whether Ppy/pTS/NT3-coated cochlear implant electrodes could provide both neurotrophic support and electrical stimulation for SGNs. Enhanced and controlled release of NT3 was achieved when Ppy/pTS/NT3-coated electrodes were subjected to electrical stimulation. Here we describe the release dynamics and biological properties of Ppy/pTS with incorporated BDNF. Release studies demonstrated slow passive diffusion of BDNF from Ppy/pTS/BDNF, with electrical stimulation significantly enhancing BDNF release over 7 days. A 3-day SGN explant assay found that neurite outgrowth from explants was 12.3-fold greater when polymers contained BDNF (p < 0.001), although electrical stimulation did not increase neurite outgrowth further. The versatility of Ppy to store and release neurotrophins, conduct electrical charge, and act as a substrate for nerve-electrode interactions is discussed for specialized applications such as cochlear implants.