Graeme Clark Collection
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ItemNeurotrophin survival effects on auditory neurons in vivo [Abstract]( nd)Neurotrophic factors, in particular the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are well known to be 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 models of deafness. Indeed, numerous studies have demonstrated that intracochlear application of neurotrophins shortly following deafening can prevent auditory neuron degeneration. Following on from these findings, we have investigated two aspects of the time-course of neurotrophin-induced auditory neuron survival. Firstly, we tested the longevity of the survival effects of BDNF on auditory neurons in deaf guinea pigs; specifically we aimed to determine if the survival effects of BDNF are maintained beyond the period of treatment, or if sustained delivery is required. Results from this study indicated that while BDNF prevents auditory neuron degeneration during the treatment period, cessation of the trophic support leads to a rapid loss of survival effects. These findings suggest ongoing neurotrophin treatment may be required for maintained auditory neuron survival. Secondly, we examined the effects of delayed neurotrophin treatment on auditory neuron survival following deafness. Results from this study demonstrated that each of the members of the neurotrophin family BDNF, NT-3, neurotrophin 4/5 (NT-4/5) and nerve growth factor (NGF) - can rescue auditory neurons from degeneration after a two-week period of deafness. These findings show that neurotrophins can be effective survival agents even when the degenerative processes are well underway. The results of these studies provide further support to the theory that neurotrophic factors may ultimately be able to be used as therapeutic agents for the benefit of the hearing impaired community, but suggest that ongoing treatment, or combined use of alternative therapies, may be necessary.
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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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ItemDelayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs [Abstract]( nd)The cochlear implant provides auditory cues to patients with a severe profound hearing loss by direct electrical stimulation of the auditory nerve. As such, the total number and integrity of the surviving auditory neuron population may govern the benefits that patients can derive from the implants. Therefore, the rescue of auditory neurons from degeneration following the loss of hair cells is of great therapeutic significance. Neurotrophic factors are known to be important for the development and maintenance of the auditory system I, and have also been rep6rted to act as survival factors for auditory neurons in animal models of deafness. However, while studies have demonstrated that the application of neurotrophins into the inner ear shortly following deafening can prevent auditory neuron degeneration2,3, much less is known about the survival effects of delayed neurotrophin treatment, which is a clinically more realistic model. This study therefore examined the effects of delayed neurotrophin treatment on auditory neuron survival following deafening. Specifically, we aimed to determine if any or all of the neurotrophins -BDNF, NT -3, NT-4/5 and NGF -could rescue neurons from degeneration after a period of two weeks of deafuess. Normal hearing guinea pigs were bilaterally deafened J using a combination of the aminoglycoside kanamycin and the loop diuretic frusemide. Two weeks later the left cochleae were implanted with a cannula attached to a mini-osmotic pump, which delivered 10Ilg of neurotrophin over a period of 28 days. The right cochleae acted as deafened and untreated controls. Despite the delayed treatments, each of the four neurotrophins prevented the degeneration of auditory neurons that is normally seen following loss of hair cells. When compared to normal hearing animals, the neuronal survival rates of deafened, neurotrophin-treated animals ranged between 79 87%; in contrast, deafened, untreated controls displayed only 52% neuronal survival. Current work is also investigating the expression patterns of the neurotrophin Trk receptors in relation to these findings, and these results will also be discussed. The results of this study provide further support to the theory that neurotrophic factors may be able to be used as therapeutic agents for the benefit of the hearing impaired community.
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ItemCriteria of suitability for cochlear implantation [Abstract]( [1990])In order to be considered for a cochlear implant, the person should have a profound bilateral hearing 1088, with little or no benefit from hearing aids. People with minimal open-set speech discrimination can be considered, with phoneme scores of up to 20% in the better ear, provided the ear to be implanted does not obtain significant open-set speech discrimination. Where there is any degree of benefit from hearing aids, even as an aid to lipreading, the poorer hearing ear is preferred for implantation. A team approach is necessary to detect and correct medical, learning and psychosocial problems. The CT scan has been designed to measure the patency of the cochlear spiral and detect any lesions of the internal auditory meatus, air cell system or emissary veins which could make for surgical difficulty. The electrical stimulation of the remaining auditory neurones by a needle on the promontory aims to confirm the responsiveness of the auditory nerve and should be performed on all candidates 12 years and older. There is a battery of assessments available but if the pulse cannot be detected before it reaches a current level producing pain the ear should not be implanted. The threshold and minimal gap detection tests have no prognostic value but the patient's observations about the percept produced by pulses of 50, 100 and 200pps are useful. There is a relationship between the ability to detect change in pulse rate and the postoperative CID sentence score. This may be used to choose a preferred ear and to give a guide to the possibility of a high or a low speech perception score. We believe the tests are an important part in gaining realistic expectations especially when the patient can listen to speech through a FO extraction speech processor attached to the needle.
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ItemInitial speech perception results with the new multipeak speech processor for the 22-electrode cochlear prosthesis [Abstract]( [1990])A new speech processor has been developed for the 22-electrode cochlear prosthesis by Cochlear Pty Ltd working in conjunction with the Department of Otolaryngology at the University of Melbourne. The new device, known as the MSP, combines smaller, more efficient hardware with a new speech coding scheme in an attempt to provide better speech perception in everyday environments for implant users. The MSP operates with the current implant device so there is no need for existing implantees to have revision surgery to make use of the new development. The multipeak speech coding scheme, which has been implemented in the MSP, provides information from three high frequency spectral bands, in addition to the parameters of voice pitch, amplitude and first and second formants which have been provided in the existing FOFIF2 coding scheme for the last four years. Initial speech perception results with research subjects have shown significant improvements in performance for the MSP over the older system (WSP III). The most encouraging result is that open-set speech perception in the presence of competing noise has improved substantially. For example, mean scores for BKB sentences in a 10 dB signal-to-noise ratio were 64% for the MSP and 31% for the WSP III. Further investigations have shown that both the hardware improvements and the new multipeak speech coding scheme have contributed significantly to the overall improvement in performance. Studies are continuing to analyse further the potential of the new system.
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ItemMultiple-channel cochlear implants for children [Abstract]( [1991])The children's program at The University of Melbourne Cochlear Implant Clinic involves a team of ENT surgeons, audiologists, speech pathologists and a teacher of the deaf. After a child is considered suitable for implantation, he/she enters a preoperative program for a minimum of three months. During this time, there is counselling of parents, liaison with teachers, weekly training in speech production, language and speech perception and baseline assessments in these three areas. The child continues to receive weekly training and regular assessments in the postoperative period. Twenty children have been implanted in Melbourne with the 22-electrode cochlear implant to date. Formal results have been collected over time for nine of these children. Five children (aged 6.0 to 14.8 years at implantation) have known open-set speech recognition through hearing. Four of these five children were implanted before adolescence and the fifth, who had a deteriorating loss, was implanted during adolescence. The remaining children who did not demonstrate open-set recognition, were implanted during adolescence after a long duration of profound deafness. Postoperative performance on closed-set speech perception tests was better that preoperative performance for the group of five children with open-set recognition. There were also improvements in speech and language assessments.