Graeme Clark Collection

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 37
  • Item
    Thumbnail Image
    Neurotrophin survival effects on auditory neurons in vivo [Abstract]
    Gillespie, Lisa N. ; Clark, Graeme M. ; Marzella, Phillip L. ( 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.
  • Item
    Thumbnail Image
    Expression of the guidance molecule netrin-1 in the postnatal rat cochlea [Abstract]
    Gillespie, Lisa. N. ; Clark, Graeme M. ; Marzella, Phillip L. ; Crook, Jeremy M. ( 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.
  • Item
    Thumbnail Image
    Neurotrophins support auditory neuron survival in vivo following an extended period of deafness [Abstract]
    Gillespie, L. N. ; Clark, Graeme M. ; Marzella, P. L. ( 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.
  • Item
    Thumbnail Image
    Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs [Abstract]
    Gillespie, Lisa. N. ; Clark, Graeme M. ; Marzella, Phillip L. ( 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.
  • Item
    Thumbnail Image
    Lateral inhibition in ventral cochlear nucleus chopper neurons: contribution to coding of a speech feature [Abstract]
    Needham, K. ; Paolini, A. G. ; Clarey, J. C. ; Clark, Graeme M. ( 2002)
    Lateral inhibition in the auditory system enhances excitatory responses by suppressing off-best frequency (BF) neural activity. Previous work has suggested that lateral inhibition activated by high frequency frication noise associated with stop consonant plays a role in coding voice onset time (VOT), the period between consonant release and onset of the ensuing vowel.
  • Item
    Thumbnail Image
    Improved sound processing for cochlear implants
    James, C.J. ; Just, Y. ; Knight, M.R. ; Martin, L.F.A. ; McKay, C.M. ; Plant, K.L. ; Tari, S. ; Vandali, A.E. ; Clark, Graeme M. ; Cowan, R.S.C. ; McDermott, H. J. ; Blamey, P. J. ; Dawson, P. ; Fearn, R. A. ; Grayden, D. B. ; Henshall, K. R. ( 2002)
    Four signal processing schemes currently under development aim to improve the perception of sounds/ especially speech, for children and adults using the Nucleus cochlear implant system. The schemes are (1) fast-acting input-signal compression, (2) Adaptive Dynamic Range Optimisation (ADRO), (3) TESM, a scheme that emphasises transients in signals, and (4) DRSP, a strategy that applies different stimulation rates to selected sets of electrodes.
  • Item
    Thumbnail Image
    A continuous supply of BDNF is necessary for sustained auditory neuron survival in deafened guinea pigs
    Gillespie, L. N. ; Clark, Graeme M. ; Bartlett, P. F. ; Marzella, P. L. ( 2002)
    Neurotrophic factors are well known to be involved in the development and maintenance of the auditory system, and have also been reported to act as survival factors for auditory neurons in 90th in vitro and in vivo deafness models. In this study we tested the longevity of the survival effects of brain-derived neurotrophic factor (BDNF) on auditory neurons in deafened guinea pigs -specifically, we aimed to determine if a single dose of BDNF is sufficient to maintain auditory neuron survival following loss of hair cells, or whether sustained delivery is required. Normal hearing guinea pigs were bilaterally deafened, and the left cochleae infused with 200 µl of BDNF (62.5µg/ml) over a period of 28 days via a cannula connected to a mini-osmotic pump. The right cochleae acted as deafened and untreated internal controls. Survival periods following the completion of the BDNF treatment varied from zero to two or four weeks. For all surgical procedures. guinea pigs were anaesthetised using ketamine (40mglkg) and xylazil (4mg/kg). Treatment with BDNF prevented the degeneration of auditory neurons normally seen following loss of hair cells, however, upon cessation of BDNF delivery, auditory neuron survival rates dropped rapidly, indicating that if trophic factor therapy is to be used in the treatment of hearing loss, continuous delivery is likely to be necessary.
  • Item
    Thumbnail Image
    Factors affecting speech perception outcomes for older children using multichannel cochlear implants
    Dowell, Richard C. ; Dettman, Shani J. ; Hill, Katie ; Winton, Elizabeth ; Hollow, Rod ; Clark, Graeme M. ( 2002)
    Experience with cochlear implantation in early-deafened teenagers or young adults has been somewhat disappointing, however, in recent years a proportion of older children have demonstrated excellent speech perception performance. There appears to be a wide gap between the good and poor performers within this group. It is important to investigate the possible factors influencing performance so that adolescents and their families are able to make informed decisions regarding cochlear implant surgery. This study considered a number of factors in a group of 25 children implanted in Melbourne between the ages of 8 and 18 years. Each subject completed open set speech perception testing using BKB sentences before and after implantation and pre-operative language testing using the Peabody Picture Vocabulary Test. Data were collected regarding the type of hearing loss, age at implant, age at hearing aid fitting, audiometric details, and the pre-and postoperative communication mode. Multivariate analysis suggested that three factors have a significant predictive value for post-implant speech perception: pre-operative open-set sentence score, duration of profound hearing loss and equivalent language age. These three factors accounted for 66% of the variance in this group. The results of this study suggest that children who have useful pre-implant speech perception, and higher age-equivalent scores on language measures, would be expected to do well with a cochlear implant. A shorter duration of profound hearing loss is also advantageous. Mean speech perception scores for the older group were not significantly different from younger children.
  • Item
    Thumbnail Image
    Post-implant habilitation for children using cochlear implants: effects on long-term outcome
    Dowell, Richard C. ; Dettman, Shani J. ; WILLIAMS, SARAH ; TOMOV, ALEXANDRA ; Hollow, Rod ; Clark, Graeme M. ( 2002)
    Most clinicians working in the cochlear implant field advocate a regular habilitation program for young children receiving implants. The development of auditory skills and the incorporation of these skills into language development are thought to be key areas for such programs. Studies of speech perception and language outcomes demonstrate that an educational approach that emphasises spoken language development appears to enhance the results for implanted children. It remains difficult, however, to demonstrate clearly the effect of habilitation objectively and to determine how much individual attention is desirable for each child. This pilot study considered the long term speech perception and language outcomes for two groups of children who received Nucleus cochlear implants in Melbourne. One group (n=17) was identified as receiving regular habilitation from the Melbourne Cochlear Implant Clinic over a four year post-operative period. Another group (n=l1) was identified as receiving very little regular habilitation over the post-operative period. The language and speech perception results for these two groups showed a significant difference in performance on a wide range of measures with the group receiving regular formal habilitation demonstrating better performance on all measures. These groups included only congenitally, profoundly hearing-impaired children and did not differ significantly on mean age at implant or experience at the time of assessment. Further studies are needed to clarify these results on a larger group of children, and to control for additional confounding variables. Nonetheless, these preliminary results provide support for the incorporation of regular long-term habilitation into cochlear implant programs for children.
  • Item
    Thumbnail Image
    Predicting speech perception outcomes for children using multichannel cochlear implants [Abstract]
    Dowell, Richard C. ; Dettman, Shani J. ; WILLIAMS, SARAH ; Hill, Katie ; TOMOV, ALEXANDRA ; Clark, Graeme M. ( 2002)
    The ability to predict outcomes for children who are cochlear implant candidates is most helpful in counselling families and making clinical recommendations. Open-set speech perception results have been collected for all children implanted with the Nucleus device in Melbourne. Speech perception as assessed at six month intervals following implantation. Information wascollected for each child regarding type of hearing loss, duration and age at onset of profound hearing loss, age at implantation, pre and post-implant communication mode, developmental delay, speech coding scheme and implant experience.