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Fascicular Perineurium Thickness, Size, and Position Affect FASCICULAR PERINEURIUM THICKNESS, SIZE, AND POSITION AFFECT MODEL PREDICTIONS OF NEURAL EXCITATION by YANINA GRINBERG Submitted in partial fulfillment of the requirements For the degree of Masters of Science Thesis Advisor: Dr. Kenneth J. Gustafson Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY May, 2008 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________ degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents I. Introduction ..................................................................................................................... 8 Motivation....................................................................................................................... 8 Peripheral Nerve Anatomy ............................................................................................. 8 Computer Modeling of Neural Anatomy...................................................................... 10 Project Aims and Hypotheses ....................................................................................... 11 II. Methods........................................................................................................................ 12 Overview....................................................................................................................... 12 Effects of Perineurial Thickness on Activation Thresholds ......................................... 14 Effects of Fascicle Diameter on Activation Thresholds ............................................... 15 Effects of Fascicles on Neighboring Fascicles ............................................................. 16 Realistic Geometry Based on Cadaveric Nerve............................................................ 17 Perineurial Conductivity Sensitivity Analysis.............................................................. 19 III. Results......................................................................................................................... 20 Effects of Perineurial Thickness on Activation Thresholds ......................................... 20 Effects of Fascicle Diameter on Activation Thresholds ............................................... 22 Effects of Fascicles on Neighboring Fascicles ............................................................. 23 Realistic Geometry Based on Cadaveric Nerve............................................................ 25 Perineurial Conductivity Sensitivity Analysis.............................................................. 27 IV. Discussion................................................................................................................... 29 Effects of Perineurial Thickness on Activation Thresholds ......................................... 29 Effects of Fascicle Diameter on Activation Thresholds ............................................... 31 Effects of Fascicles on Neighboring Fascicles ............................................................. 33 Realistic Geometry Based on Cadaveric Nerve............................................................ 36 Sensitivity Analyses...................................................................................................... 38 V. Conclusion ................................................................................................................... 40 VI. Future Directions ........................................................................................................ 41 Validation of Model Predictions................................................................................... 41 Measurement of Mammalian Perineurium Conductivity ............................................. 42 Fixing Perineurial Thickness While Varying its Conductivity..................................... 43 Neural Anatomy and Alternate Stimulation Methods .................................................. 43 VII. Appendix I................................................................................................................. 45 VIII. References................................................................................................................ 47 3 List of Tables Table 1: Conductivities used for modeling...................................................................... 13 Table 2: Relationship between perineurial thickness and fascicle diameter categorized by nerve type.......................................................................................................................... 21 4 List of Figures Figure 1: Peripheral nerve schematic demonstrating the classification, respective connective tissue layers, and cross-sectional anatomy. ...................................................... 9 Figure 2: Finite element models used to examine effects of fascicle perineurial thickness, diameter, and neighbroing fascicles on model predictions of axonal thresholds and fascicle recruitment........................................................................................................... 16 Figure 3: Cross-section of human femoral nerve model inside an nerve cuff electrode . 19 Figure 4: Physio-anatomical thickness of human perineurium vs the fascicle diameter. 20 Figure 5: Effects of perineurial thickness on activaiton thresholds................................. 21 Figure 6: Effects of fascicle diameter on activation thresholds....................................... 22 Figure 7: Effects of a neighboring fascicle on control fascicle activation....................... 24 Figure 8: Effect of distance between fascicles on control fascicle activation. ................ 25 Figure 9: The effects of perineurium thickness, fascicle diameter, and neighboring fascicles on activation of fascicles in a realistic nerve model. ......................................... 27 Figure 10: The effect of perineurial conductivity on center axon threshold. .................. 28 Figure 11: Sensitivity of the neighboring fascicle effects to perineurial conductivity.... 29 Figure 12: Finite element model used to examine the effect of position of neighboring fascicle on control fascicle activation............................................................................... 45 Figure 13: Effect of position of neigboring fascicle on control fascicle activation......... 46 5 Acknowledgements I would like to acknowledge several individuals who have helped me with the completion of this work. First and foremost, I would like to thank my advisor Dr. Kenneth Gustafson, for the guidance he provided throughout my academic career. I would also like to acknowledge my committee members, Dr. Dominique Durand and Dr. Dustin Tyler, who have provided critical feedback on this project. I would like to especially thank Matt Schiefer, who helped me with this project from the beginning to the end. Matt not only taught me the programs necessary to complete this work, he also provided templates for much of the code that was used to obtain the results. A section of the project was completed by Matt and included in an Appendix of this thesis. I am very grateful for the discussions we had and the guidance he provided during this project. Additionally, I would like to thank my lab members, Dr. Narendra Bhadra, Adam Boger, Tim Bruns, and Tim Mariano, for their advice and for sharing their expertise with me. Many thanks also go to Tina Emancipator for training me on animal monitoring procedures. Additionally, I am very grateful for the support of my family. Thank you for believing in me and teaching me to never give up! I would have never made it this far without your love and support. This work was funded by the Department of Veterans Affairs RR&D B3675R, and the NIH EB001889, HD40298, and DK077089. 6 Fascicular Perineurium Thickness, Size, and Position Affect Model Predictions of Neural Excitation Abstract by YANINA GRINBERG This project evaluated the effects of fascicle perineurial thickness, diameter, and position on axon stimulation thresholds and target fascicle recruitment using finite element models and Neuron simulations. The perineurial thickness of human fascicles was found to be 3.0% ± 1.0% of the fascicle diameter. Increased perineurial thickness and fascicle diameter resulted in increased activation thresholds. A large neighboring fascicle caused a significant change in percent activation of the smaller target fascicle by as much as 80%, as compared to models without a neighboring fascicle. Therefore, smaller fascicles were recruited at lower amplitudes than the neighboring larger fascicles. These effects were further presented in a realistic nerve model using a section of a human femoral nerve and nerve cuff electrode. These results demonstrate that fascicular selectivity is strongly dependent on the nerve anatomy. Therefore, physiologically accurate computer models are recommended for evaluation and optimization of electrode designs for neural prosthesis applications. 7 I. INTRODUCTION Motivation Electrical stimulation of the nervous system
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