Browsing by Author "Gillespie, Lisa"

Now showing 1 - 11 of 11
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    The Appearance of Phosphenes Elicited Using a Suprachoroidal Retinal Prosthesis
    (iOVS, 2016-09) Sinclair, Nicholas; Shivdasani, Mohit; Perera, Thushara; Gillespie, Lisa; McDermott, Hugh; Ayton, Lauren; Blamey, Peter
    Purpose: Phosphenes are the fundamental building blocks for presenting meaningful visual information to the visually impaired using a bionic eye device. The aim of this study was to characterize the size, shape, and location of phosphenes elicited using a suprachoroidal retinal prosthesis. Methods: Three patients with profound vision loss due to retinitis pigmentosa were implanted with a suprachoroidal electrode array, which was used to deliver charge-balanced biphasic constant-current pulses at various rates, amplitudes, and durations to produce phosphenes. Tasks assessing phosphene appearance, location, overlap, and the patients' ability to recognize phosphenes were performed using a custom psychophysics setup. Results: Phosphenes were reliably elicited in all three patients, with marked differences in the reported appearances between patients and between electrodes. Phosphene shapes ranged from simple blobs to complex forms with multiple components in both space and time. Phosphene locations within the visual field generally corresponded to the retinotopic position of the stimulating electrodes. Overlap between phosphenes elicited from adjacent electrodes was observed with one patient, which reduced with increasing electrode separation. In a randomized recognition task, two patients correctly identified the electrode being stimulated for 57.2% and 23% of trials, respectively. Conclusions: Phosphenes of varying complexity were successfully elicited in all three patients, indicating that the suprachoroidal space is an efficacious site for electrically stimulating the retina. The recognition scores obtained with two patients suggest that a suprachoroidal implant can elicit phosphenes containing unique information. This information may be useful when combining phosphenes into more complex and meaningful images that provide functional vision.
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    Cell-based neurotrophin treatment for auditory neuron survival in deafness
    (2012) Gillespie, Lisa; Zanin, Mark; Shepherd, Robert
    The cochlear implant provides auditory cues to patients with profound hearing loss by electrically stimulating the auditory neurons within the cochlea, but the ongoing regeneration of auditory neurons that occurs in sensorineural hearing loss may be a limiting factor in cochlear implant efficacy. The exogenous application of neurotrophins such as BDNF can rescue auditory neurons from this deafness induced degeneration; however, these survival effects are not maintained. A safe and efficient means of delivering neurotrophins to the cochlea, which can be used in conjunction with a cochlear implant for long-term survival of auditory neurons, is required for this therapy to be clinically transferable. We investigated the survival-promoting effects of cell-based neurotrophin treatment and electrical stimulation, using fibroblasts genetically modified to express BDNF and encapsulated in a biocompatible matrix, on auditory neurons in the deaf guinea pig.
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    Cell-based neurotrophin treatment supports long-term auditory neuron survival in the deaf guinea pig
    (Elsevier B.V, 2015-01-28) Gillespie, Lisa; Zanin, Mark; Shepherd, Robert
    The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the primary auditory neurons (ANs) of the cochlea. However, ANs degenerate in deafness; the preservation of a robust AN target population, in combination with advances in cochlear implant technology, may provide improved hearing outcomes for cochlear implant patients. The exogenous delivery of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 is well known to support AN survival in deafness, and cell-based therapies provide a potential clinically viable option for delivering neurotrophins into the deaf cochlea. This study utilised cells that were genetically modified to express BDNF and encapsulated in alginate microspheres, and investigated AN survival in the deaf guinea pig following (a) cell-based neurotrophin treatment in conjunction with chronic electrical stimulation from a cochlear implant, and (b) long-term cell-based neurotrophin delivery. In comparison to deafened controls, there was significantly greater AN survival following the cell-based neurotrophin treatment, and there were ongoing survival effects for at least six months. In addition, functional benefits were observed following cell-based neurotrophin treatment and chronic electrical stimulation, with a statistically significant decrease in electrically evoked auditory brainstem response thresholds observed during the experimental period. This study demonstrates that cell-based therapies, in conjunction with a cochlear implant, shows potential as a clinically transferable means of providing neurotrophin treatment to support AN survival in deafness. This technology also has the potential to deliver other therapeutic agents, and to be used in conjunction with other biomedical devices for the treatment of a variety of neurodegenerative conditions.
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    Cell-based neurotrophin treatment supports long-term auditory neuron survival in the deaf guinea pig.
    (Elsevier B.V., 2015-01) Gillespie, Lisa; Zanin, Mark; Shepherd, Robert
    The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the primary auditory neurons (ANs) of the cochlea. However, ANs degenerate in deafness; the preservation of a robust AN target population, in combination with advances in cochlear implant technology, may provide improved hearing outcomes for cochlear implant patients. The exogenous delivery of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 iswell known to support AN survival in deafness, and cell-based therapies provide a potential clinically viable option for delivering neurotrophins into the deaf cochlea. This study utilized cells that were genetically modified to express BDNF and encapsulated in alginate microspheres, and investigated AN survival in the deaf guinea pig following (a) cell-based neurotrophin treatment in conjunction with chronic electrical stimulation from a cochlear implant, and (b) long-term cell-based neurotrophin delivery. In comparison to deafened controls, there was significantly greater AN survival following the cell-based neurotrophin treatment, and there were ongoing survival effects for at least six months. In addition, functional benefits were observed following cell-based neurotrophin treatment and chronic electrical stimulation, with a statistically significant decrease in electrically evoked auditory brainstem response thresholds observed during the experimental period. This study demonstrates that cell-based therapies, in conjunction with a cochlear implant, shows potential as a clinically transferable means of providing neurotrophin treatment to support AN survival in deafness. This technology also has the potential to deliver other therapeutic agents, and to be used in conjunction with other biomedical devices for the treatment of a variety of neurodegenerative conditions.
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    Development of a cell-based treatment for long-term neurotrophin expression and spiral ganglion neuron survival.
    (Elsevier, 2014-09) Zanin, Mark; Hellstrom, Mats; Shepherd, Robert; Harvey, Allan; Gillespie, Lisa
    Spiral ganglion neurons (SGNs), the target cells of the cochlear implant, undergo gradual degeneration following loss of the sensory epithelium in deafness. The preservation of a viable population of SGNs in deafness can be achieved in animal models with exogenous application of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3. For translation into clinical application, a suitable delivery strategy that provides ongoing neurotrophic support and promotes long-term SGN survival is required. Cell-based neurotrophin treatment has the potential to meet the specific requirements for clinical application, and we have previously reported that Schwann cells genetically modified to express BDNF can support SGN survival in deafness for 4 weeks. This study aimed to investigate various parameters important for the development of a long-term cell-based neurotrophin treatment to support SGN survival. Specifically, we investigated different (i) cell types, (ii) gene transfer methods and (iii) neurotrophins, in order to determine which variables may provide long-term neurotrophin expression and which, therefore, may be the most effective for supporting long-term SGN survival in vivo. We found that fibroblasts that were nucleofected to express BDNF provided the most sustained neurotrophin expression, with ongoing BDNF expression for at least 30 weeks. In addition, the secreted neurotrophin was biologically active and elicited survival effects on SGNs in vitro. Nucleofected fibroblasts may therefore represent a method for safe, long-term delivery of neurotrophins to the deafened cochlea to support SGN survival in deafness.
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    Drug delivery to the inner ear
    (IOP Science, 2012-12) Wise, Andrew; Gillespie, Lisa
    Bionic devices electrically activate neural populations to partially restore lost function. Of fundamental importance is the functional integrity of the targeted neurons. However, in many conditions the ongoing pathology can lead to continued neural degeneration and death that may compromise the effectiveness of the device and limit future strategies to improve performance. The use of drugs that can prevent nerve cell degeneration and promote their regeneration may improve clinical outcomes. In this paper we focus on strategies of delivering neuroprotective drugs to the auditory system in a way that is safe and clinically relevant for use in combination with a cochlear implant. The aim of this approach is to prevent neural degeneration and promote nerve regrowth in order to improve outcomes for cochlear implant recipients using techniques that can be translated to the clinic.
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    Electro-acoustic stimulation: now and into the future
    (Hindawi Publishing Corporation, 2014) Irving, Samuel; Gillespie, Lisa; Richardson, Rachael; Rowe, David; Fallon, James; Wise, Andrew
    Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway play a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing-protective drug and gene therapies is promising for EAS recipients. This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients.
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    Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3
    (Macmillan Publishers Limited, 2016-06-23) Wright, Tess; Gillespie, Lisa; O'Leary, Stephen; Needham, Karine
    Primary auditory neurons rely on neurotrophic factors for development and survival. We previously determined that exposure to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) alters the activity of hyperpolarization-activated currents (Ih) in this neuronal population. Since potassium channels are sensitive to neurotrophins, and changes in Ih are often accompanied by a shift in voltage-gated potassium currents (IK), this study examined IK with exposure to both BDNF and NT3 and the impact on firing entrainment during high frequency pulse trains. Whole-cell patch-clamp recordings revealed significant changes in action potential latency and duration, but no change in firing adaptation or total outward IK. Dendrotoxin-I (DTX-I), targeting voltage-gated potassium channel subunits KV1.1 and KV1.2, uncovered an increase in the contribution of DTX-I sensitive currents with exposure to neurotrophins. No difference in Phrixotoxin-1 (PaTX-1) sensitive currents, mediated by KV4.2 and KV4.3 subunits, was observed. Further, no difference was seen in firing entrainment. These results show that combined BDNF and NT3 exposure influences the contribution of KV1.1 and KV1.2 to the low voltage-activated potassium current (IKL). Whilst this is accompanied by a shift in spike latency and duration, both firing frequency and entrainment to high frequency pulse trains are preserved.
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    Identification of Characters and Localization of Images Using Direct Multiple-Electrode Stimulation With a Suprachoroidal Retinal Prosthesis
    (IOVS, 2017-08) Shivdasani, Mohit; Sinclair, Nicholas; Gillespie, Lisa; Petoe, Matthew; Titchener, Samuel; Fallon, James; Perera, Thushara; Pardinas-Diaz, Darien; Barnes, Nick; Blamey, Peter; Bionic Vision Australia Consortium
    Purpose: Retinal prostheses provide vision to blind patients by eliciting phosphenes through electrical stimulation. This study explored whether character identification and image localization could be achieved through direct multiple-electrode stimulation with a suprachoroidal retinal prosthesis. Methods: Two of three retinitis pigmentosa patients implanted with a suprachoroidal electrode array were tested on three psychophysical tasks. Electrode patterns were stimulated to elicit perception of simple characters, following which percept localization was tested using either static or dynamic images. Eye tracking was used to assess the association between accuracy and eye movements. Results: In the character identification task, accuracy ranged from 2.7% to 93.3%, depending on the patient and character. In the static image localization task, accuracy decreased from near perfect to <20% with decreasing contrast (patient 1). Patient 2 scored up to 70% at 100% contrast. In the dynamic image localization task, patient 1 recognized the trajectory of the image up to speeds of 64 deg/s, whereas patient 2 scored just above chance. The degree of eye movement in both patients was related to accuracy and, to some extent, stimulus direction. Conclusions: The ability to identify characters and localize percepts demonstrates the capacity of the suprachoroidal device to provide meaningful information to blind patients. The variation in scores across all tasks highlights the importance of using spatial cues from phosphenes, which becomes more difficult at low contrast. The use of spatial information from multiple electrodes and eye-movement compensation is expected to improve performance outcomes during real-world prosthesis use in a camera-based system. (ClinicalTrials.gov number, NCT01603576.).
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    Time-dependent activity of primary auditory neurons in the presence of neurotrophins and antibiotics
    (Elsevier, 2017-04) Cai, Helen; Gillespie, Lisa; Wright, Tess; Brown, William; Minter, Ricki; Nayagam, Bryony; O'Leary, Stephen; Needham, Karina
    In vitro cultures provide a valuable tool in studies examining the survival, morphology and function of cells in the auditory system. Primary cultures of primary auditory neurons have most notably provided critical insights into the role of neurotrophins in cell survival and morphology. Functional studies have also utilized in vitro models to study neuronal physiology and the ion channels that dictate these patterns of activity. Here we examine what influence time-in-culture has on the activity of primary auditory neurons, and how this affects our interpretation of neurotrophin and antibiotic-mediated effects in this population. Using dissociated cell culture we analyzed whole-cell patch-clamp recordings of spiral ganglion neurons grown in the presence or absence of neurotrophins and/or penicillin and streptomycin for 1-3 days in vitro. Firing threshold decreased, and both action potential number and latency increased over time regardless of treatment, whilst input resistance was lowest where neurotrophins were present. Differences in firing properties were seen with neurotrophin concentration but were not consistently maintained over the 3 days in vitro. The exclusion of antibiotics from culture media influenced most firing properties at 1 day in vitro in both untreated and neurotrophin-treated conditions. The only difference still present at 3 days was an increase in input resistance in neurotrophin-treated neurons. These results highlight the potential of neurotrophins and antibiotics to influence neural firing patterns in vitro in a time-dependent manner, and advise the careful consideration of their impact on SGN function in future studies.
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    Treating hearing disorders with cell and gene therapy
    (IOP Publishing, 2014-10) Gillespie, Lisa; Richardson, Rachael; Nayagam, Bryony; Wise, Andrew
    Hearing loss is an increasing problem for a substantial number of people and, with an aging population, the incidence and severity of hearing loss will become more significant over time. There are very few therapies currently available to treat hearing loss, and so the development of new therapeutic strategies for hearing impaired individuals is of paramount importance to address this unmet clinical need. Most forms of hearing loss are progressive in nature and therefore an opportunity exists to develop novel therapeutic approaches to slow or halt hearing loss progression, or even repair or replace lost hearing function. Numerous emerging technologies have potential as therapeutic options. This paper details the potential of cell- and gene-based therapies to provide therapeutic agents to protect sensory and neural cells from various insults known to cause hearing loss; explores the potential of replacing lost sensory and nerve cells using gene and stem cell therapy; and describes the considerations for clinical translation and the challenges that need to be overcome.