Graeme M. Clark

Clinical findings for a group of infants and young children with auditory neuropathy

OBJECTIVE To examine the prevalence of auditory neuropathy in a group of infants at risk for hearing impairment and to present an overview of the clinical findings for affected children. DESIGN Results for 20 subjects who showed repeatable cochlear microphonic potentials in the absence of click-evoked auditory brain stem responses are included in this study. Behavioral and steady state evoked potential thresholds were established in each case. Where possible, otoacoustic emission and speech perception results (unaided and aided) also were obtained. RESULTS One in 433 (0.23%) of the children in our series had evidence of auditory neuropathy. The audiometric findings for these subjects varied significantly, with behavioral thresholds ranging from normal to profound levels. Discrimination skills were also variable. Approximately half of the subjects showed little understanding, or even awareness, of speech inputs in both the unaided and aided conditions. There were, however, a number of children who could score at significant levels on speech discrimination tasks and who benefited from the provision of amplification. CONCLUSION The results suggest that auditory neuropathy is more common in the infant population than previously suspected. The effects of neuropathy on auditory function appear to be idiosyncratic, producing significant variations in both the detection and discrimination of auditory signals. As such, the management of children with this disorder must allow for individual differences.

Electrical stimulation of the auditory nerve: The effect of electrode position on neural excitation

Histological studies have shown that the Melbourne/Cochlear electrode array lies along the outer wall of the scala tympani and is therefore some distance from the residual VIIIth nerve elements. In order to investigate the influence of electrode position on neural excitation we systematically varied the position of the electrode array within the cat scala tympani while recording electrically evoked auditory brainstem responses (EABRs). Using both normal hearing and long-term deafened animals, we observed significant reductions in EABR thresholds as the electrode array was moved from the outer wall towards the modiolus. Further threshold reductions were observed when the array was placed underneath the osseous spiral lamina (OSL) close to the peripheral dendrites. These changes were independent of the bipolar inter-electrode separation, and were observed over a wide range of cochlear pathologies varying from normal to a moderate spiral ganglion cell loss. Interestingly, the one animal exhibiting extensive neural loss showed no correlation between EABR threshold and electrode position. There was also a general decrease in the gradient of the EABR input-output function as the electrode array was moved closer to the neural elements. This was, however, only statistically significant when the electrode was positioned adjacent to the peripheral dendrites. Significant reductions in EABR threshold were also observed as the inter-electrode spacing of the bipolar electrodes was increased. The gradient of the EABR input-output function also increased with increasing inter-electrode spacing, although again, this was only significant when the electrode array was positioned close to the neural elements. The present results indicate that the optimum placement of a Melbourne/Cochlear electrode array is adjacent to the peripheral dendrites. However, such a site would be difficult to achieve in practice while minimizing insertion trauma. An array lying adjacent to the modiolus would be a safe alternative while ensuring a significant reduction in threshold compared with the existing site (outer wall). This placement should result in more localized neural excitation patterns, an increase in the number of bipolar electrodes available, together with an increase in their dynamic range. These changes may lead to further improvements in speech perception among cochlear implant patients.

A comparison of steady‐state evoked potentials to modulated tones in awake and sleeping humans

Steady-state evoked potential responses were measured to binaural amplitude-modulated (AM) and combined amplitude- and frequency-modulated (AM/FM) tones. For awake subjects, AM/FM tones produced larger amplitude responses than did AM tones. Awake and sleeping responses to 30-dB HL AM/FM tones were compared. Response amplitudes were lower during sleep and the extent to which they differed from awake amplitudes was dependent on both carrier and modulation frequencies. Background EEG noise at the stimulus modulation frequency was also reduced during sleep and varied with modulation frequency. A detection efficiency function was used to indicate the modulation frequencies likely to be most suitable for electrical estimation of behavioral threshold. In awake subjects, for all carrier frequencies tested, detection efficiency was highest at a modulation frequency of 45 Hz. In sleeping subjects, the modulation frequency regions of highest efficiency varied with carrier frequency. For carrier frequencies of 250 Hz, 500 Hz, and 1 kHz, the highest efficiencies were found in two modulation frequency regions centered on 45 and 90 Hz. For 2 and 4 kHz, the highest efficiencies were at modulation frequencies above 70 Hz. Sleep stage affected both response amplitude and background EEG noise in a manner that depended on modulation frequency. The results of this study suggest that, for sleeping subjects, modulation frequencies above 70 Hz may be best when using steady-state potentials for hearing threshold estimation.

Speech perception as a function of electrical stimulation rate: using the nucleus 24 cochlear implant system

Objective To investigate the effect of varying electrical stimulation rate on speech comprehension by cochlear implant users, while keeping the number of stimulated channels constant. Design Three average rates of electrical stimulation, 250, 807, and 1615 pulses per second per channel (pps/ch), were compared using a speech processing strategy that employed an electrode selection technique similar to that used in the Spectral Ma-ima Sound Processor strategy (McDermott, McKay, & Vandali, 1992; McDermott & Vandali, Reference Note 1; McKay, McDermott, Vandali, & Clark, 1991) and the Spectral Peak strategy (Skinner et al., 1994; Whitford et al., 1995). Speech perception tests with five users of the Nucleus 24 cochlear implant system were conducted over a 21-wk period. Subjects were given take-home experience with each rate condition. A repeated ABC evaluation protocol with alternating order was employed so as to account for learning effects and to minimize order effects. Perception of open-set monosyllabic words in quiet and open-set sentences at signal to noise ratios ranging from +20 to 0 dB, depending on the subject’s ability, were tested. A comparative performance questionnaire was also administered. Results No statistical differences in group performance between the 250 and 807 pps/ch rates were observed in any of the speech perception tests. However, significantly poorer group performance was observed for the 1615 pps/ch rate for some tests due predominantly to the results of one subject. Analysis of individual scores showed considerable variation across subjects. For some subjects, one or more of the three rate conditions evaluated provided benefits on some speech perception tasks. The results of the comparative performance questionnaire indicated a preference for the 250 and 807 pps/ch rates over the 1615 pps/ch rate for most listening situations. Conclusions For the speech processing strategy, implant system, and subjects evaluated in this study, the group results indicated that the use of electrical stimulation rates higher than 250 pps/ch (up to 1615 pps/ch) generally provided no significant improvement to speech comprehension. However, individual results indicated that perceptual benefits could be obtained by adjusting rate of stimulation optimally to suit each subject. Results from one subject, together with tinnitus problems arising from high-rate stimulation for another subject, indicated that high rates of stimulation may in fact be undesirable for some subjects.

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.

The automated prediction of hearing thresholds in sleeping subjects using auditory steady-state evoked potentials

Objective To examine the relationship between auditory steady-state evoked potentials (SSEPs) and behavioral thresholds in sleeping subjects. Design 60 adults and children with hearing thresholds ranging from normal to profound were selected on the basis of appropriate audiograms. Behavioral audiograms were determined at the octave frequencies 250-4000 Hz. These behavioral thresholds were then compared with the SSEP thresholds obtained during natural sleep for adults, or natural or sedated sleep for children. Results A strong relationship between behavioral and SSEP thresholds was observed. The strength of the relationship increased with increasing frequency and increasing degree of the loss. On the basis of these data, the prediction of behavioral thresholds from SSEP levels was determined. It was found that the standard deviation of the error in this prediction decreased with increasing frequency and increasing degree of the loss. There was no significant age effect in the results obtained at any of the frequencies. Conclusion The results suggest that the SSEP technique can be used as a predictor of behavioral thresholds in adults and children at the frequencies 250-4000 Hz.

Chronic electrical stimulation of the auditory nerve at high stimulus rates: a physiological and histopathological study.

A major factor associated with recent improvements in the clinical performance of cochlear implant patients has been the development of speech-processing strategies based on high stimulation rates. While these processing strategies show clear clinical advantage, we know little of their long-term safety implications. The present study was designed to evaluate the physiological and histopathological effects of long-term intracochlear electrical stimulation using these high rates. Thirteen normal-hearing adult cats were bilaterally implanted with scala tympani electrode arrays and unilaterally stimulated for periods of up to 2100 h using either two pairs of bipolar or three monopolar stimulating electrodes. Stimuli consisted of short duration (25-50 microseconds/phase) charge-balanced biphasic current pulses presented at 1000 pulses per second (pps) per channel for monopolar stimulation, and 2000 pps/channel for bipolar stimulation. The electrodes were shorted between current pulses to minimize any residual direct current, and the pulse trains were presented using a 50% duty cycle (500 ms on; 500 ms off) in order to simulate speech. Both acoustic (ABR) and electrical (EABR) auditory brainstem responses were recorded periodically during the chronic stimulation program. All cochleas showed an increase in the click-evoked ABR threshold following implant surgery; however, recovery to near-normal levels occurred in approximately half of the stimulated cochleas 1 month post-operatively. The use of frequency-specific stimuli indicated that the most extensive hearing loss generally occurred in the high-frequency basal region of the cochlea (12 and 24 kHz) adjacent to the stimulating electrode. However, thresholds at lower frequencies (2, 4 and 8 kHz), appeared at near-normal levels despite long-term electrode implantation and electrical stimulation. Our longitudinal EABR results showed a statistically significant increase in threshold in nearly 40% of the chronically stimulated electrodes evaluated; however, the gradient of the EABR input/output (I/O) function (evoked potential response amplitude versus stimulus current) generally remained quite stable throughout the chronic stimulation period. Histopathological examination of the cochleas showed no statistically significant difference in ganglion cell densities between cochleas using monopolar and bipolar electrode configurations (P = 0.67), and no evidence of cochlear damage caused by high-rate electrical stimulation when compared with control cochleas. Indeed, there was no statistically significant relationship between spiral ganglion cell density and electrical stimulation (P = 0.459), or between the extent of loss of inner (IHC, P = 0.86) or outer (OHC, P = 0.30) hair cells and electrical stimulation. Spiral ganglion cell loss was, however, influenced by the degree of inflammation (P = 0.016) and electrode insertion trauma. These histopathological findings were consistent with the physiological data. Finally, electrode impedance, measured at completion of the chronic stimulation program, showed close correlation with the degree of tissue response adjacent to the electrode array. These results indicated that chronic intracochlear electrical stimulation, using carefully controlled charge-balanced biphasic current pulses at stimulus rates of up to 2000 pps/channel, does not appear to adversely affect residual auditory nerve elements or the cochlea in general. This study provides an important basis for the safe application of improved speech-processing strategies based on high-rate electrical stimulation.

Factors predicting postoperative sentence scores in postlinguistically deaf adult cochlear implant patients

A sample of 64 postlinguistically profoundly to totally deaf adult cochlear implant patients were tested without lipreading by means of the Central Institute for the Deaf (CID) sentence test 3 months postoperatively. Preoperative promontory stimulation results (thresholds, gap detection, and frequency discrimination), age, duration of profound deafness, cause of deafness, lipreading ability, postoperative intracochlear thresholds and dynamic ranges for electrical stimulation, depth of insertion of the electrode array into the scala tympani, and number of electrodes in use were considered as possible factors that might be related to the postoperative sentence scores. A multiple regression analysis with stepwise inclusion of independent variables indicated that good gap detection and frequency discrimination during preoperative promontory testing, larger numbers of electrodes in use, and greater dynamic ranges for intracochlear electrical stimulation were associated with better CID scores. The CID scores tended to decrease with longer periods of profound deafness.

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.

Skeletal muscle cell proliferation and differentiation on polypyrrole substrates doped with extracellular matrix components

Conducting polymers have been developed as substrates for in vitro studies with a range of cell types including electrically-excitable cells such as nerve and smooth muscle. The goal of this study was to optimise and characterise a range of polypyrrole materials to act as substrates for electrical stimulation of differentiating skeletal myoblasts. Although all of the polymer materials provided suitable substrates for myoblast adhesion and proliferation, significant differences became apparent under the low-serum conditions used for differentiation of primary myoblasts. The significance of the work lies in the design and control of polymer materials to facilitate different stages of skeletal muscle cell proliferation and/or differentiation, opening up opportunities for engineering of this tissue. This paper therefore constitutes not just a biocompatibility assessment but a comprehensive study of how synthesis conditions affect the final outcome in terms of cell response.