Department of Biomedical Engineering The University of Melbourne Bionic Vision Australia (BVA) The Bionics Institute of Australia National ICT Australia (NICTA) Prediction and Shaping of Visual Cortex Activity for Retinal Prostheses Kerry J. Halupka Submitted in total fulfillment of the requirements of the degree of Doctor of Philosophy April, 2017 ii Abstract Retinal prostheses are a promising treatment for blindness caused by photoreceptor degen- eration. 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 cor- tex 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 covari- ance technique. The recovered model accurately predicted cortical responses to arbitrary patterns of stimulation, and demonstrated that interactions between electrodes are pre- dominantly 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 iii were evaluated in unilaterally, chronically blind anaesthetised cats, bilaterally implanted with suprachoroidal retinal prostheses. Significant differences were found between re- sponses 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 pat- terns of stimulation indicated that it may provide a basis for optimising stimulation strate- gies 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 stimula- tion 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 pre- dominantly 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. iv Declaration I hereby declare that this thesis comprises of my original work towards the degree of Doc- tor of Philosophy at the University of Melbourne. All work included in this thesis, except where acknowledged in the Declaration of Authorship, is my original work. All other work has been duly acknowledged. This thesis is fewer than the maximum word limit of 100,000 words exclusive of tables, figures, bibliographies and appendices. Signed: Kerry Halupka 13th April, 2017 v vi Declaration of Authorship I hereby declare that this thesis and the work presented in it are original and generated by me as the result of my own investigations. Except where acknowledged below, I was responsible for the data collection, data analysis, software programming, and generation of images and graphical data. Due to the multidisciplinary aspect of this work, the following thesis would not have been possible if it were not for the contributions detailed below. • Joel Villalobos and Chris Williams designed the stimulating arrays. • Owen Burns and Vanessa Maxim fabricated the stimulating arrays. • Penelope Allen and Chi Luu surgically implanted the stimulating arrays. • Carla Abbott, Alice Brandli, Alexia Saunders, Michelle McPhedran, Alison Neil, Dimitra Stathopoulos, Stephanie Epp, and Ceara McGowan assisted with electro- physiological experiments and animal handling during surgery. • Evgeni Sergeev developed the stimulator software. • James Fallon developed the software used to perform artefact removal from electro- physiological data. • Thomas Spencer, Faith Lamont, Ali Almasi, Felix Aplin, Rosemary Cicione, Patrick Thien, Emma Johnson and Ronald Leung assisted with data collection during the long overnight shifts. • Carla Abbott, Chi Luu, and Alice Brandli performed intraocular injection of ATP and clinical assessments of retinal structure and function (full-field flash electroretino- gram, optical coherence tomography and funduscopy) in Chapter 3. vii The following chapters include published works that have resulted from the research pre- sented in this thesis. • Chapter3 is a slightly modified version of the published article: Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Wong, Y.T., Burkitt, A.N., and Meffin, H. Prediction of cortical responses to simultaneous electrical stimulation of the retina. Journal of Neural Engi- neering, 14(1):016006, 2016. • Chapter4 is a modified version of the published article: Halupka, K.J., Abbott, C.J., Wong, Y.T., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Sergeev, E.N., Luu, C.D., Brandli, A., Allen, P.J., Meffin, H., and Shivdasani, M.N. Neural responses to multi-electrode stimulation of healthy and degenerate retina. Investigative Ophthalmology & Visual Science, 58(9):3770-3784, 2017. • While not included in this thesis, the following article was also published during my candidature: Wong, Y.T., Halupka, K.J., Kamenevam T., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H., and Shivdasani, M.N. Spectral distribu- tion of local field potential responses to electrical stimulation of the retina. Journal of Neural Engineering, 13(3):036003, 2016. • A number of conference abstracts have also been published: Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Ibbotson, M.R., Meffin, H. Prediction of cortical responses to si- multaneous retinal electrical stimulation using a linear-nonlinear model, Society for Neuroscience (Chicago, Illinois USA), October 17-21, 2015. Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. Predicting cortical responses to simultaneous electrical stimulation of the retina using a linear-nonlinear model, Joint Symposium on Cognitive Neuroengineering and Computational Neuroscience (Ade- laide, Australia), February 5-6, 2015. viii Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. Predicting cortical spiking responses to simultaneous elec- trical stimulation of the retina using a linear-nonlinear model, Students of Brain Research (Melbourne, Australia), October 30, 2014. Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. A linear-nonlinear model predicts cortical spiking re- sponses to simultaneous electrical stimulation of the retina, The Eye and the Chip (Dearborn, Michigan, USA), September 28-30, 2014. Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. Prediction of cortical responses to simultaneous electri- cal stimulation of the retina using a linear-nonlinear model, St Vincents Research Week (Melbourne, Australia), August 18-22, 2014. Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. A linear-nonlinear model accurately predicts cortical responses to simultaneous electrical stimulation with a retinal implant, Twenty-Third Annual Computational Neuroscience Meeting (Qu´ebec City, Canada), July 26-31, 2014. Halupka, K.J., Shivdasani, M.N., Cloherty, S.L., Grayden, D.B., Burkitt, A.N., Meffin, H. Modelling cortical responses to simultaneous electrical stimulation of the retina, NeuroEng (Adelaide, Australia), February 2-3, 2014. ix x Acknowledgements It has taken me a long time to write these acknowledgments because a simple thank you seems insufficient for the amount of support I’ve received. This body of work would not have been possible without the guidance, support, and encouragement of my supervisors, Dr. Mohit Shivdasani, Dr. Hamish Meffin, Dr. Shaun Cloherty, Professor Anthony Burkitt and Professor David Grayden. I would like to thank Mohit Shivdasani for his