Imperial College of Science, Technology and Medicine Department of Electrical and Electronic Engineering Enhancing Selectivity of Minimally Invasive Peripheral Nerve Interfaces using Combined Stimulation and High Frequency Block: from Design to Application Adrien Rapeaux Submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy in Electrical and Electronic Engineering of Imperial College London, April 2020 Declaration of Originality This thesis represents my own work unless otherwise stated. Any text, figures, tables or other material that is not my own has been appropriately referenced. Any material that I have adapted for this work has been identified as such and where applicable the original source cited. i ii Copyright Declaration ‘The copyright of this thesis rests with the author. Unless otherwise indicated, its contents are licensed under a Creative Commons Attribution-NonCommercial 4.0 International Licence (CC BY-NC).Under this licence, you may copy and redis- tribute the material in any medium or format. You may also create and distribute modified versions of the work. This is on the condition that: you credit the author and do not use it, or any derivative works, for a commercial purpose.When reusing or sharing this work, ensure you make the licence terms clear to others by nam- ing the licence and linking to the licence text. Where a work has been adapted, you should indicate that the work has been changed and describe those changes. Please seek permission from the copyright holder for uses of this work that are not included in this licence or permitted under UK Copyright Law.’ iii iv Abstract The discovery of the excitable property of nerves was a fundamental step forward in our knowl- edge of the nervous system and our ability to interact with it. As the injection of charge into tissue can drive its artificial activation, devices have been conceived that can serve healthcare by substituting the input or output of the peripheral nervous system when damage or disease has rendered it inaccessible or its action pathological. Applications are far-ranging and trans- formational as can be attested by the success of neuroprosthetics such as the cochlear implant. However, the body’s immune response to invasive implants have prevented the use of more se- lective interfaces, leading to therapy side-effects and off-target activation. The inherent tradeoff between the selectivity and invasiveness of neural interfaces, and the consequences thereof, is still a defining problem for the field. More recently, continued research into how nervous tissue responds to stimulation has led to the discovery of High Frequency Alternating Current (HFAC) block as a stimulation method with inhibitory effects for nerve conduction. While leveraging the structure of the peripheral nervous system, this neuromodulation technique could be a key component in efforts to improve the selectivity-invasiveness tradeoff and provide more effective neuroprosthetic therapy while retaining the safety and reliability of minimally invasive neural interfaces. This thesis describes work investigating the use of HFAC block to improve the se- lectivity of peripheral nerve interfaces, towards applications such as bladder control or vagus nerve stimulation where selective peripheral nerve interfaces cannot be used, and yet there is an unmet need for more selectivity from stimulation-based therapy. An overview of the underlying neuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Original contributions are the design of a custom multi-channel stimulator able to combine conventional and high frequency stimulation, establishing a suitable experimental platform for ex-vivo electrophysiology of the rat sciatic nerve model for HFAC block, and exploratory ex- periments to determine the feasibility of using HFAC block in combination with conventional stimulation to enhance the selectivity of minimally-invasive peripheral nerve interfaces. v vi Acknowledgements I would like to express my most heartfelt thanks to: • My supervisor Dr. Timothy G. Constandinou, who gave me the freedom to pursue this somewhat unusual line of inquiry within an electronic engineering research group. His expertise in technical matters, pragmatic approach to research focusing on impact and follow-through, his enthusiasm for neuroscience and relentlessly positive outlook have enabled me to cross gaps and scale walls in my pursuit. I have been, am and continue to be honoured to work with him, and I look forward to future endeavours in the group. • Dr. Ian Williams of Imperial College, who was a first contact when meeting my current research group and has remained a close friend and knowledgeable expert throughout. Discussions with him over coffee have sparked many ideas, to solve existing problems or identify unexplored paths. • Dr. Lieuwe Leene, previously of Imperial College, now at Novelda AS. His intuitive understanding of complex circuits and vast engineering knowledge completely changed my understanding of the field and pushed me to look ‘outside of the box’. His good cheer and no-nonsense approach are sorely missed. • Dr. Jerry Hunsberger of Galvani Bioelectronics for his expertise on maintaining viability of tissues ex-vivo and knowledge of neurophysiology which was instrumental in the design of an adapted experimental platform in the laboratory at Imperial College. • The Biomaterials Research Group, Imperial College, comprising Dr. Rylie Green, Dr. Omaer Syed and Mz. Estelle Cuttaz for contributions to the ex-vivo experiments, es- pecially for giving me access to animal tissue using their license. Our partnership has yielded concrete and useful results and I hope for it to continue. • The NGNI research group: my colleagues, and dare I say my friends. They are part of what makes this such a good work environment: strong ethic, commitment to high quality output, and kindness. Their expertise and support is invaluable. vii • The CBIT or Center for Bioinspired Technology of Imperial College, a collection of amaz- ing individuals of varied background showing how diversity coupled with a sense of com- munity can be such a strong combination for science. • Last but not least, my family and friends, who’ve heard me complain more times than I can count and always encouraged me to keep going. I can’t thank them enough. viii Dedication I dedicate this thesis to my wife, who has been incredibly patient with me during the entire PhD period (5 years compared to the usual 3), and especially towards the end of the write-up period as we were both working from home due to the extraordinary circumstances in the UK and around the world. I cannot thank her enough for her support, and keeping me sane. ix x Contents Declaration of Originality i Copyright Declaration iii Abstract v Acknowledgements vii Dedication ix Table of Contents xi List of Figures xix List of Tables xxv Abbreviations xxvii 1 Introduction 2 2 Background 14 2.1 Foreword........................................ 14 xi 2.2 PeripheralNervousSystemCompartments . ....... 14 2.2.1 SomaticnervousSystem . 16 2.2.2 AutonomicNervousSystem . 18 2.2.3 EntericNervousSystem . 20 2.3 NerveMicrostructureandExcitability . ........ 21 2.3.1 Thevoltage-gatedionchannel . .... 21 2.3.2 Formalism for the peripheral nerve cable model . ........ 23 2.3.3 Nervemicrostructure . 26 2.3.4 Reversal of physiological recruitment order when usingelectrodes . 27 2.4 Peripheralnerveelectrodetypes . ........ 29 2.5 Electrochemical theory for stimulation electrodes . .............. 32 2.6 ElectrodeMaterials.............................. .... 34 2.7 Premise for selective stimulation using combined stimulationandblock . 35 2.7.1 Bladder control after Spinal Cord Injury as a clinical scenario that could benefit from enhanced cuff electrode selectivity. ..... 35 2.7.2 Simulation of combined block and stimulation for selective activation of smallfibersinacompoundnerve . 37 2.7.3 BlockthresholdsintheFHmodel . .. 39 2.7.4 Relationship between inter-electrode spacing and technique selectivity . 40 2.7.5 Compared performance of monopolar block and bipolar block ...... 41 2.7.6 Compatibility of the proposed technique with existing stimulation ther- apiesforbladdercontrol . 42 xii 2.8 Conclusion...................................... 44 3 A multi-channel, block capable, modular stimulator for acute neurophysiol- ogy experiments 64 3.1 Introduction.................................... .. 64 3.2 Stimulator topologies for control of injected charge . .............. 65 3.2.1 Current-controlledstimulators . ....... 66 3.2.2 Switchedcapacitorstimulators. ...... 67 3.3 ChargeBalance ................................... 68 3.3.1 Electrode polarisation and the water window . ........ 70 3.3.2 DCleakageincurrent-modestimulators . ...... 70 3.4 Compensation techniques for charge accumulation . ............ 71 3.4.1 PassivedischargeandDCfiltering. ..... 71 3.4.2 Activechargebalancing . 72 3.4.3 Ongoing research on charge balance for safe neural stimulation . 75 3.5 DesigningforHighFrequencyStimulation . ........ 77 3.6 Development paradigm: discrete vs integrated electronics............. 79 3.7 Embedded system design with electrically isolated modules............ 80 3.8 Address-event representation of stimulation commands . ............. 82 3.9 Stimulator integration into experimental platforms . ............... 83 3.10 HFAC-capable current source using discrete