NEURAL REPRESENTATION OF FORCE, GRASP, AND VOLITIONAL STATE IN INTRACORTICAL BRAIN-COMPUTER INTERFACE UERS WITH TETRAPLEGIA BY ANISHA RASTOGI Submitted in partial fulfillment of the requirements For the degree of doctor of philosophy Dissertation Advisor: Dr. A. Bolu Ajiboye Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY January, 2021 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Anisha Rastogi candidate for the degree of Doctor of Philosophy* Committee Chair Dr. Dominique Durand Committee Member Dr. A. Bolu Ajiboye Committee Member Dr. Dawn M. Taylor Committee Member Dr. Jonathan P. Miller Date of Defense 22 June 2020 *We also certify that written approval has been obtained for any proprietary material contained therein Dedication To Bill Kochevar, for dedicating his last days to bettering the world for people with disabilities. This research is a way to honor your faith in a brighter future. i Table of Contents Dedication ........................................................................................................................ i Table of Contents ............................................................................................................ ii List of Figures ................................................................................................................. vi List of Tables ................................................................................................................ viii List of Abbreviations ....................................................................................................... ix Abstract ......................................................................................................................... xii Chapter 1: Introduction ................................................................................................... 1 Introduction to Brain Computer Interfaces ................................................................... 1 The Implications of Tetraplegia ................................................................................ 1 Brain Computer Interface System Overview ............................................................ 1 Recording Modalities Used in BCIs ......................................................................... 2 Review of iBCI Research ............................................................................................ 6 Brain Computer Interfaces as a Tool for Neuroscience ............................................ 7 Brain Computer Interfaces to Restore Reaching and Grasping ..............................10 Brain Computer Interfaces that Incorporate Force Control ......................................13 Brain Computer Interfaces that Incorporate Volitional State Information .................16 Dissertation Specific Aims and Hypotheses ...............................................................18 Aim 1: Characterize the extent to which neural activity is modulated by observed, imagined, and attempted hand grasping forces. .....................................................19 Aim 2: Determine whether force-related neural activity depends on the hand grasps used to produce forces ...........................................................................................20 Chapter 2: The evolution of intracortical brain-machine interfaces and trends toward restorative devices: A comprehensive review ................................................................22 Introduction ................................................................................................................22 Intracortical Electrode Technology .............................................................................25 History of Intracortical Electrodes ...........................................................................26 Current Electrode Technology and Developments ..................................................27 Limitations in Electrode Longevity and Durability ....................................................29 Efforts to improve intracortical electrode longevity ..................................................30 Targeted Brain Areas and Neural Information Content ...............................................37 Motor Cortex ..........................................................................................................37 Other cortical targets for iBMI investigations ...........................................................38 Signal information content from targeted brain areas..............................................42 iBMI Signal Pre-Processing and Feature Extraction ...................................................43 ii Extraction of Neural Features .................................................................................44 Open-Loop Signal Characterization ........................................................................49 Real-time Signal Decoding .........................................................................................50 Decoding methods in early clinical iBMI applications ..............................................51 Decoders employed in iBMI systems ......................................................................52 Decoder optimization ..............................................................................................54 iBMI Applications: the End-effector ............................................................................59 Computer cursor control for typing and tablet use ..................................................60 Intracortical brain control in three-dimensional virtual environment .........................61 Robotic arm control ................................................................................................62 Brain controlled FES...............................................................................................63 Bi-directional iBMI with sensory feedback ..................................................................66 Critical role of somatosensory feedback .................................................................66 Sensory restoration options ....................................................................................67 Intracortical Microstimulation in the human somatosensory cortex .........................69 Future work to develop bi-directional intracortical BMIs ..........................................70 Conclusion .................................................................................................................71 Tables ........................................................................................................................73 Chapter 3: Neural representation of observed, imagined, and attempted grasping force in motor cortex of individuals with chronic tetraplegia ....................................................85 Abstract......................................................................................................................86 Introduction ................................................................................................................86 Results .......................................................................................................................89 Characterization of Individual Features ..................................................................89 Neural Population Analyses....................................................................................95 Discussion ............................................................................................................... 100 Force representation persists in motor cortex after tetraplegia ............................. 100 Volitional state modulates neural activity to a greater extent than force ................ 101 Limitations of open-loop task ................................................................................ 106 Force representation differences across participants ............................................ 107 Implications for iBCI development ........................................................................ 108 Methods ................................................................................................................... 109 Study permissions and participants ...................................................................... 109 Neural recordings and feature extraction .............................................................. 110 Behavioral task ..................................................................................................... 111 iii Effects of audio vs. audiovisual cues .................................................................... 113 Assessment of kinetic vs. kinematic activity .......................................................... 114 Characterization of individual features .................................................................. 114 Neural population analysis and decoding ............................................................. 115 Data availability .................................................................................................... 118 Code availability ................................................................................................... 118 Acknowledgements .................................................................................................. 118 Author Contributions 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