Medical Bionics - Theses
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ItemPrediction and shaping of visual cortex activity for retinal prostheses( 2017)Retinal prostheses are a promising treatment for blindness caused by photoreceptor degeneration. Electrodes implanted in the retina deliver electrical stimuli in the form of current pulses that activate surviving neurons to restore a sense of vision. Clinical trials for such devices have shown that the visual percepts evoked are informative, and can improve the day-to-day life of recipients. However, the spatial resolution of retinal prostheses is a limiting factor, with those who have the highest reported acuity measures still classified as legally blind. Simultaneous stimulation of multiple electrodes is a possible strategy to improve device resolution without increasing the number of physical electrodes. However, electrode interactions that occur during simultaneous stimulation are not well understood. This thesis investigates the characteristics of cortical responses to simultaneous stimulation of multiple electrodes. We formulated a quantitative model to characterise the responses of visual cortex neurons to multi-electrode stimulation of the retina to understand how simultaneous stimulation can improve resolution. Activity was recorded in the visual cortex of normally sighted, anaesthetised cats in response to temporally sparse, spatially white stimulation with 21 or 42 electrodes in the suprachoroidal space of the retina. These data were used to constrain the parameters of a linear-nonlinear model using a spike-triggered covariance technique. The recovered model accurately predicted cortical responses to arbitrary patterns of stimulation, and demonstrated that interactions between electrodes are predominantly linear. The linear filters of the model, which can be considered as weighting matrices for the effect of the stimulating electrodes on each cortical site, showed that cortical responses were topographically organised. Photoreceptor degeneration results in a number of changes in the surviving cells of the retina that can negatively impact stimulation strategies. Therefore, in the second study, we investigated the effect of multi-electrode stimulation on the degenerate retina. Characteristics of cortical responses to simultaneous stimulation of multiple electrodes were evaluated in unilaterally, chronically blind anaesthetised cats, bilaterally implanted with suprachoroidal retinal prostheses. Significant differences were found between responses to stimulation of the normally sighted and blind eyes, which may help to explain the varied perceptual observations in clinical trials with simultaneous stimulation. The success of the linear-nonlinear model in predicting responses to arbitrary patterns of stimulation indicated that it may provide a basis for optimising stimulation strategies to shape cortical activity. Therefore, we investigated the possibility of inverting the model to generate stimuli aimed at reliably altering the spatial characteristics of cortical responses. An in vivo preparation with a normally sighted, anaesthetised cat showed that the response characteristics derived by the model could be exploited to steer current and evoke predictable cortical activity. Overall, these results demonstrate that cortical responses to simultaneous stimulation of both the normal and degenerate retina are repeatable, and can be predicted by a simple linear-nonlinear model. Furthermore, the interactions between electrodes are predominantly linear, and can be harnessed to shape cortical activity through inversion of the model. The method shows promise for improving the efficacy of retinal prostheses and patient outcomes.
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ItemInvestigating the effect of focused multipolar stimulation for cochlear implants: preclinical studies( 2016)Multichannel cochlear implants have been well accepted as an effective and safe treatment for severe to profound sensorineural hearing loss through electrical stimulation of residual spiral ganglion neurons. However, speech intelligibility with existing cochlear implants is thought to be limited by poor spatial selectivity and interactions between channels caused by overlapping activation with contemporary stimulation strategies such as monopolar (MP) stimulation. Focused intracochlear stimulation, resulting in an increase in the number of truly independent stimulating channels available for simultaneous activation, may enable better speech and pitch recognition and also improve temporal resolution. Various current focusing stimulation strategies such as tripolar (TP) stimulation have been reported to produce sharper excitation patterns and reduced channel interactions compared to MP stimulation at the cost of higher stimulation current levels. Focused multipolar (FMP) stimulation is another such focusing technique; utilizing simultaneous stimulation of multiple channels to create focused electrical fields. FMP stimulation has been validated in a small group of cochlear implant recipients showing that focusing can be achieved, however this was at the expense of higher stimulation currents compared to MP stimulation. There have been no previous attempts to systematically compare the efficacy of FMP stimulation against TP stimulation or to determine whether factors such as neural survival and the electrode position within the cochlea would affect the performance of FMP stimulation. Controlled preclinical studies in experimental animals can reduce the possible confounding effects of neural survival in human studies. It is also important to test if FMP produces non-auditory sensations since the simultaneous nature of the stimuli would be expected to require greater charge to evoke neural responses. The primary objectives of this thesis were to determine the efficacy of FMP stimulation, compared to both MP and TP stimulation, by evaluating a) the spatial extent of neural activation b) interactions between cochlear implant channels and c) modulation sensitivity to sinusoidal amplitude-modulated pulse trains. The effects of factors such as degeneration of spiral ganglion neurons, induced by long-term deafness, and the electrode position within the cochlea on the effectiveness of FMP, TP and MP stimulation were also examined. These objectives were achieved by implanting a multichannel cochlear implant into cats and guinea pigs, and recording the neural responses in the inferior colliculus in acute electrophysiological experiments. Neural thresholds and the spread of activation along the tonotopic gradient were measured. In summary, the main results of this thesis showed that FMP and TP stimulation resulted in more restricted neural activation and reduced channel interaction compared to MP stimulation and these advantages were maintained in cochleae with significant neural degeneration. Moreover, these effects were not adversely affected by the position of the electrode array within the scala tympani. Although greater charge was required to achieve threshold levels, no evidence of ectopic stimulation of non-auditory neurons was observed with FMP or TP stimulation. Systematically varying the degree of current focusing lowered threshold levels for FMP stimulation while still maintaining a selectivity advantage. Modulation detection of MP was found to be significantly better than FMP and TP stimulation at low stimulation levels, but similar at high stimulation levels. Importantly, there was no benefit in terms of restricted neural activation, reduced channel interaction or better modulation sensitivity for FMP compared to TP stimulation. The greater spatial selectivity, reduced channel interactions and the ability to convey modulation using FMP and TP stimulation would be expected to result in improved clinical performance. The insights into current focusing described in this thesis may also be helpful in other neural prostheses such as deep brain stimulation devices and visual prostheses, when more selective stimulation is desired.
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ItemNeural network models of pitch perception in normal and implanted ears( 2015)Pitch is the perceptual correlate of sound frequency and is important for using speech prosody, understanding tonal languages, and music appreciation. According to pitch perception theories, pitch is encoded by the place along the cochlea that has the maximum rate of excitation and the timing of the neural activity caused by cochlear excitation. As one of the most successful neural prosthesis, cochlear implants (CIs) have enabled most recipients to achieve good speech perception in favourable listening conditions. Perceiving a precise pitch, however, is still a challenge for many CI users. The goal of this study is to develop computational models of normal and CI hearing to advance our understanding of the mechanisms of pitch perception in both cases and to investigate the factors that affect pitch perception in electrical hearing. Based on the two possible neural codes for pitch perception, two models of pitch perception were developed: the place model and the integrated model. The models simulated a common psychophysical experiment usually referred to as pitch ranking − where subjects are asked to decide which of the two sequentially presented sounds has a higher pitch – by receiving two stimuli and generating two outputs, the higher-amplitude of which would indicate the higher-pitched stimulus. Synthesised vowels with defined pitches were the sound stimuli used in this study. An artificial neural network (ANN) constituted the core of the models. Inputs to the ANN were place pitch information for the place model and both place and temporal pitch information for the integrated model. Applying the error back-propagation algorithm, the ANN was trained on a training set of pitch pairs. The performance of the pitch perception model was measured using a previously unseen test set of pitch pairs. Place code for pitch perception was extracted from simulated auditory peripheral outputs by averaging the rate of activity in the auditory nerve (AN) over time. An acoustical and an electrical model of the auditory periphery were used to simulate the activity of the AN in normal and CI hearing, respectively. The activity of the AN was further processed through a spiking neural network (SNN) to extract the temporal code of pitch. Synaptic connections in the SNN were modified by spike-timing-dependent-plasticity (STDP) to generate pitch-related precisely-timed neural activities in the SNN output neurons. Pooled inter-spike-interval histogram (ISIH) across the SNN output neurons was found to be indicative of pitch. Validation of both pitch perception models was performed by comparing their performance with psychophysical results. The place model was applied to investigate the impact of stimulation field spread on pitch perception in CI hearing using two commercial sound processing strategies. Simulation results showed that 1) the model could replicate the performance of normal and average-performing CI listeners and 2) providing focused stimulation fields in CI hearing can be beneficial, depending on the type of sound processing strategy. The integrated model was used to explore the role of and interaction between place and temporal cues in performing simulated pitch ranking tasks. Simulation results associated with the integrated model revealed that 1) temporal cues for pitch perception compensated for missing place cues in listening conditions such as a telephone conversation where low-frequency content of the signal was suppressed and 2) new strategies with improved temporal information can improve pitch perception in CI hearing, provided temporal and place information are consistent. Although drawing general conclusions about auditory perception would eventually require psychophysical experiments, computational models of auditory perception such as this work assists in focusing human testing upon factors that demonstrate the strongest impact on the auditory performance of normal and CI listeners. This would therefore lead to the more rapid development of CI sound processing strategies.
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ItemSafety of a suprachoroidal retinal prosthesis( 2014)Light is transformed into neural signals by the retina. Certain conditions, such as retinitis pigmentosa, can cause extensive degeneration of the outer retinal layers, resulting in profound vision impairment. Prosthetic devices have the potential to restore visual percepts in these patients by electrically stimulating the remaining retinal neurons. One such device, the suprachoroidal retinal prosthesis, is placed between the vascular choroid and sclera. It is currently under development and is the focus of this thesis. Safety is an important aspect of medical device design. This thesis focuses on several key aspects of suprachoroidal retinal prosthesis safety. Retinal prostheses must be designed to allow for the ability to safely remove and replace the device in the case of infection, device malfunction, or a device upgrade. This thesis explores the safety and feasibility of explanting or replacing prototype suprachoroidal electrode arrays using clinical and laboratory analysis techniques in a feline model. The results indicate that suprachoroidal electrode arrays can be safely removed or replaced with minimal damage to the retina and surrounding tissues. Furthermore, the device replacement procedures were not detrimental to the retinal response to electrical stimulation. However, careful wound closure was required to minimise post-operative complications. Another key requirement of electrically active neural prostheses is that they should not cause damage that could adversely affect the efficacy of the device. The safe stimulation levels of the platinum macroelectrodes used in the prototype suprachoroidal retinal prosthesis is unknown. In addition to the above, this thesis aims to determine the safe stimulation levels of platinum macroelectrodes using electrochemical methods in vitro and in vivo. Furthermore, methods to safely increase the safe stimulation limit by altering the stimulation waveform or by using nitrogen-doped ultra-nanocrystalline diamond as an electrode material are explored. The results indicate that electrochemically safe stimulation limits were lower than stimulation levels likely to cause histologically observable damage and that altering the stimulus waveform has the potential to increase electrochemically safe stimulation limits. Also, nitrogen-doped ultra-nanocrystalline diamond electrodes have a higher safe stimulation limit than platinum and showed no signs of degradation when stimulated in vitro. The results of this thesis have helped to ensure the safety of patients implanted with prototype suprachoroidal retinal prosthesis (ClinicalTrials.gov, NCT01603576). Furthermore, this thesis has important implications on safe suprachoroidal retinal prosthesis design and makes significant contributions towards our understanding of stimulation safety.
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ItemPeripheral nerve stimulation for the treatment of chronic neuropathic pain( 2014)Neuropathic pain is a chronic health condition with a severe impact on the quality of life of affected patients. The condition is often difficult to manage and refractory to traditional pain treatment strategies such as pharmacological management, physiotherapy and psychological therapy. Peripheral nerve stimulation has been proposed as an alternative treatment with numerous successful clinical reports. Nevertheless, the systematic understanding of the underlying mechanism of action is still limited. Efficacy studies in the form of randomised controlled trials have predominantly been conducted for occipital nerve stimulation to treat various headache conditions. Without trials of a wide range of neuropathic conditions, the commercial availability of approved medical devices is limited. The overall objective of this thesis was to advance towards the development of a peripheral nerve stimulation system for a small-scale clinical trial that will be used to gain a deeper understanding of the underlying mechanisms of pain modulation. Design features of electrode arrays and new stimulation strategies were tested in order to facilitate the development of advanced clinical peripheral nerve stimulation systems. The first part of the work consisted of the development of a small, wearable neural stimulator for the use in clinical trials. Chapter 2 presents the design and characterisation of the stimulator. It was shown that safe and efficacious neural activation could be achieved and the system will be suitable for use during a short-term clinical trial of electrode arrays with a percutaneous leadwire system. In the second part, a model electrode setup was used to investigate a bipolar stimulation strategy. Chapter 3 documents an electrophysiological study on the maximisation of the therapeutic window available for stimulation. An electrode screening strategy was developed in order to increase the efficiency of intra- and post-operative testing of stimulation arrays with a large number of electrode combinations. The third part of the work focussed on the development of single-source multipolar stimulation as a novel method to perform current focussing for increased selectivity of the neural activation. Chapter 4 presents the in vitro investigation that showed that a successful reduction of voltages at electrode sites other than the centre electrode was achieved when compared to monopolar stimulation. Furthermore, a significant improvement of the voltage reduction was also found compared to tripolar and common ground stimulation. The promising results from the in vitro tests were followed by an in vivo evaluation as presented in Chapter 5. However, the focussing effects found in vitro did not translate to functional benefits in vivo for the investigated setup. Rather, increased neural activation thresholds were found resulting in potentially higher power requirements for a clinical system. Monopolar stimulation was identified as the favourable mode under the tested conditions. In conclusion, the results of this thesis suggest that a safe and reliable, tailored electrode array in combination with a monopolar stimulation strategy forms a promising system in order to progress towards the overall objective, a short-term clinical trial. This will help to gain a deeper understanding of the underlying mechanism of action of peripheral nerve stimulation for the treatment of chronic neuropathic pain.