Graeme Clark Collection
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ItemExpression of the guidance molecule netrin-1 in the postnatal rat cochlea [Abstract]( nd)Purpose: Neurotrophic factors have been demonstrated to stimulate axonal growth from auditory neurons in both in vitro and in vivo animal models of deafness. These findings may be important to improving cochlear implant performance via an enhanced electro-neural interface, or ultimately for a regenerated auditory system. Numerous molecules exist which are involved in axon guidance during embryogenesis for the construction of a functional neural network. The netrins are a family of such guidance molecules, and are expressed within the developing cochlea. It remains to be determined, however, if these molecules are expressed in the developed mammalian cochlea, and therefore if they may be of potential use for guiding regenerated axons within the mammalian auditory system. This study seeks to investigate the expression patterns of the netrin-l protein in postnatal rats. Methods: Cochlear tissue samples were taken from rats at postnatal day I (PI), P3, P5, P7, Pl0, Pl5 and P22. Samples from each age group were separated using SDS-PAGE and protein expression was determined by western immunoblot analysis. Results: Preliminary findings suggest that the netrin-l protein may be present in the postnatal cochlea, however not in its full form. Spinal cord samples, used as positive controls, reveal an ~75kD immunoreactive band, consistent with the molecular weight (MW) of netrin-l. Cochlear samples displayed bands at a slightly lower MW, and may therefore represent proteolytic fragments of the full-length netrin-l protein. The signal showed decreasing intensity following P7, with no signal seen at P22. Conclusions: These results suggest that netrin-l may be present in the postnatal cochlea, and in decreasing levels with increasing age. Netrin-l may therefore have the potential to control new axonal growth in the adult mammalian cochlea. Further studies investigating the expression patterns of the netrin-l receptors, DCC and neogenin, will give a greater indication of the presence and role of this guidance cue within the damaged auditory system.
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ItemNeurotrophins support auditory neuron survival in vivo following an extended period of deafness [Abstract]( nd)Neurotrophic factors are important for the development and maintenance of the auditory system, and have also been reported to act as survival factors for auditory neurons in animal deafness models. Indeed, studies have demonstrated that application of neurotrophins into the inner ear shortly following deafening can prevent auditory neuron degeneration. However, little is known about the survival effects of delayed neurotrophin treatment, which is a clinically more realistic model. This study examined the capacity of various neurotrophins to support auditory neuron survival after an extended period of deafness in vivo. Specifically, we aimed to determine if the neurotrophins BDNF, NT-3, NT-4/5 and NGF could rescue neurons from degeneration after a two-week period of deafness. Normal hearing guinea pigs were bilaterally deafened; two weeks later the left cochleae were implanted with a mini-osmotic pump, which delivered 200µl of neurotrophin (62.5µg/ml) over a period of 28 days. The right cochleae acted as deafened and untreated internal controls. For all surgical procedures, guinea pigs were anaesthetised using ketamine (40mg/kg) and xylazil (4mg/kg). Delayed treatment with each of the four neurotrophins halted the degeneration of auditory neurons that is normally seen following loss of hair cells, resulting in neuronal survival rates of between 79-87% of normal hearing animals, as compared to only 52% survival in deafened, untreated controls. These results indicate that neurotrophins have the capacity to rescue auditory neurons from degeneration following an extended period of deafness. These findings suggest that neurotrophins may play a role as therapeutic agents in long-term deaf patients.
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ItemIntracellular responses of anteroventral cochlear nucleus neurones to intracochlear electrical stimulation in the rat [Abstract]( 1996)The anterior division of the ventral cochlear nucleus (AVCN) is the first relay station of the auditory pathway. Currently little is known about the intracellular physiological responses of neurones in the AVCN to electrical stimulation of the cochlea. We investigated the effect of cochlear electrical stimulation in the rat AVCN using in vivo intracellular recordings. Male rats were anaesthetised with urethane (1.3g/kg i.p), placed in a stereotaxic frame, the crania and dura removed and the cochlear nucleus exposed.
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ItemElectrophonically driven single unit responses of the anteroventral cochlear nucleus in cat [Abstract]( 1996)Electrical stimulation of the cochlea results in both direct and electrophonic excitation of auditory nerve fibres. It has been proposed that electrophonic stimulation results from the creation of a mechanical disturbance on the basilar membrane which has properties similar those resulting from acoustic stimuli. Auditory nerve compound action potential (CAP) forward masking studies1 show the level of frequency specific electrophonic stimulation is highly correlated with the spectral energy of the electrical stimulus waveform. The level of spectral energy in pulsatile biphasic electrical stimuli decreases toward low frequencies suggesting the level of electrophonic stimulation will be diminished in the low frequency region of the cochlea.
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ItemReduction in excitability of the auditory nerve in guinea pigs following acute high rate electrical stimulation [Abstract]( 1996)Electrical stimulation of neural tissue involves the transfer of charge to tissue via electrodes. Safe charge transfer can be achieved using biphasic current pulses designed to reduce the generation of direct current (DC) or the production of electrochemical products. However, neural stimulators must also use capacitors in series with electrodes, or electrode shorting between current pulses, to further minimize DC due to electrode polarization.
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ItemSafety studies and preliminary patient trails with a new perimodiolar electrode array( 2000)A new perimodiolar electrode array, the curly-with stylet (CwS), has been developed and undergone safety trials in human cadaver temporal bones. The array was developed as a result of animal and modelling studies which indicated that there are potential advantages in situating the electrode array in closer proximity to the neural elements. Preliminary studies with four patients in Melbourne implanted with a developmental pre-curved array had supported the predictions of lower current requirements and possibly more focussed spread of excitation.
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ItemDevelopment of safe and effective electrodes: a risk management approach [Abstract]( 1999)Results from studies on experimental animals, computer modelling and preliminary psychophysical studies with three patients, have confirmed the potential for subjective improvement with electrode arrays which lie closer to the modiolus than does the Nucleus straight array. Results of psychophysical studies with three cochlear implant patients, using developmental pre-curved arrays, confirm the feasibility of improving patients' performance through improvements in electrode design. In particular, it was found in psychophysical tests, with patients using a developmental pre-curved electrode array, that both maximum comfortable level and threshold reduced with decreasing distance of a stimulated electrode from the modiolus, and that the dynamic range increased. More intense neural excitation patterns were obtained with the closer electrodes. From this it is inferred that the development of more sophisticated electrode arrays, positioned closer to the modiolus than is currently the case with the Nucleus standard array, will enable the development of improved speech processing strategies. There are technical constraints in the design of a peri-modiolar array, and currently a number of approaches to this problem have been investigated. Whilst the goal of the design is that it be effective for sophisticated and variable manners of stimulus delivery, a primary constraint is safety.
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ItemGrowth factors from different superfamilies act in synergy when promoting the survival of auditory neurones in vitro [Abstract]( 1999)Several growth factor superfamilies have been implicated in normal inner ear development and in promoting auditory neurone survival. The neuronal promoting ability of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF) and transforming growth factor ß-5 (TGF-ß5), alone and in combination, were evaluated in dissociated cell cultures of early postnatal rat auditory neurones. Rat pups were anaesthetised on ice and sacrificed by rapid decapitation, followed by removal of the cochleae under aseptic conditions. Here we provide evidence that synergistic relationships exist between growth factors from diverse superfamilies when promoting auditory neurone survival in vitro. Administered alone, all factors promoted survival of between 10-15% of initially plated neurones, with NT-3 the most potent of the factors. When used in combination, LIF + BDNF, NT-3 + TGF-ß5, and BDNF + TGF-ß5 all promoted auditory neurone survival in a synergistic fashion. In contrast, NT-3 + BDNF and LIP + TGF-ß5 displayed additive survival effects. These results suggest that growth factors may act by interdependent mechanisms when sustaining neuronal integrity, and that a combination of several growth factors may provide a better approach than single factor therapy when developing pharmacological therapies for the treatment of deafness.
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ItemBenefits of pre-curved electrode arrays for the Nucleus multichannel cochlear implant [Abstract]( 1998)The purpose of the study was to evaluate whether placement of an electrode closer to the modiolus would provide a more efficient interface with the auditory nerve. A pre-curved, banded 22-electrode array has been developed. Following comprehensive safety studies, the array was inserted in three adult patients. Detailed x-ray analyses have been conducted to specify the positions of the electrode bands. Psychophysical studies have been conducted, within each subject, using electrodes which lie at differing distances from the modiolus. These studies have shown that as the distance from the modiolus decreased, electrode threshold currents decreased and dynamic ranges increased. Thresholds were lower than in a comparison group of standard array users. Forward masking studies showed current spread to be more focused at the electrodes lying closer to the modiolus. Electrode discrimination was also better at electrodes closer to the modiolus. JND for loudness, expressed as a function of dynamic range also decreased in this condition. Thus, a preliminary profile of the parameters of interest, for an improved implant design, suggest that an array which lies closer to the modiolus can result in lower current requirements and a more localised pattern of neural excitation.
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ItemThe histological and physiological effects of the auditory brainstem prosthesis of the auditory pathway [Abstract]( 1997)The cochlear implant can successfully rehabilitate the majority of profoundly deaf patients. However, some of them cannot benefit from the cochlear implant due to bilateral interruption of the auditory nerve, particularly from neurofibromatosis II. These patients can be stimulated directly with an auditory brainstem prosthesis on the cochlear nucleus. To examine the safety and the efficacy of this prosthesis, the cochlear nuclei of guinea pigs were implanted unilaterally with bipolar surface electrodes, and stimulated acutely using charge-balanced, biphasic current pulses at rates of 250, SOO or 1000 Hz and charge intensities of 1.8, 2.8, 3.5 or 7.1?C/phase/cm2.