Stretching adversely modulates locomotor capacity following spinal cord injury via activation of PDF
Preview Stretching adversely modulates locomotor capacity following spinal cord injury via activation of
UUnniivveerrssiittyy ooff LLoouuiissvviillllee TThhiinnkkIIRR:: TThhee UUnniivveerrssiittyy ooff LLoouuiissvviillllee''ss IInnssttiittuuttiioonnaall RReeppoossiittoorryy Electronic Theses and Dissertations 8-2017 SSttrreettcchhiinngg aaddvveerrsseellyy mmoodduullaatteess llooccoommoottoorr ccaappaacciittyy ffoolllloowwiinngg ssppiinnaall ccoorrdd iinnjjuurryy vviiaa aaccttiivvaattiioonn ooff nnoocciicceeppttiivvee aaffffeerreennttss.. Anastasia V. Keller Univeristy of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Medicine and Health Sciences Commons RReeccoommmmeennddeedd CCiittaattiioonn Keller, Anastasia V., "Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents." (2017). Electronic Theses and Dissertations. Paper 2791. https://doi.org/10.18297/etd/2791 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. STRETCHING ADVERSELY MODULATES LOCOMOTOR CAPACITY FOLLOWING SPINAL CORD INJURY VIA ACTIVATION OF NOCICEPTIVE AFFERENTS By Anastasia V. Keller B.S., University of Louisville, 2010 M.S., University of Louisville, 2012, 2014 A Dissertation Submitted to the Faculty of the School of Medicine at the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Physiology and Biophysics Department of Physiology and Biophysics University of Louisville Louisville, Kentucky August 2017 Copyright 2017 by Anastasia Keller All rights reserved STRETCHING ADVERSELY MODULATES LOCOMOTOR CAPACITY FOLLOWING SPINAL CORD INJURY VIA ACTIVATION OF NOCICEPTIVE AFFERENTS By Anastasia Keller B.S., University of Louisville, 2010 M.S., University of Louisville, 2012, 2014 A Dissertation Approved on June 9, 2017 by the following Dissertation Committee: __________________________________ Dissertation Director: Dr. David S. K. Magnuson __________________________________ Dr. Jeffrey Petruska __________________________________ Dr. Dena Howland __________________________________ Dr. James Hoying __________________________________ Dr. David Lominadze __________________________________ Dr. Dale Schuschke ii DEDICATION In the loving memory of my father, Valery Prokopenko (July 31, 1941 – June 2, 2010) whom I admired for his sacrificial love for our family, wisdom, dedication to excellence in all he set out to accomplish and innovative thinking in his work. I would not be here without his influence and belief in me. iii ACKNOWLEDGMENTS First, I would like to thank Dr. Magnuson for his excellent mentorship and leadership. I felt very confident and secure while navigating through the graduate school because of his steadfast support and open-door policy at all times. I truly enjoyed all of the insightful conversations that we have had pertaining not only to science. I could not have asked for a better mentor. Next, I would like to thank Dr. Petruska for providing me with direction at the very crucial and pivotal point in my PhD work. His ideas were instrumental for the last experiment. I thank all of my committee members: Dr. Lominadze, Dr. Howland, Dr. Hoying, Dr. Schuschke for helping me to refine my thoughts and ideas, the overall input and support as I journeyed through this process. I would like to extend a special and warm thank you to Alice Shum-Siu for taking me under her wing as I joined the lab. From day one she has taught me everything from how to handle animals to the magic of immunohistochemistry. I would be so lost without her guidance, friendship and loving support. This work would not be possible without the great team of lab technicians and bioengineering co-ops who have helped with the stretching sessions and data analysis, I thank them all from the bottom of my heart, this PhD thesis is stapled by the hours of their hard work. Likewise, the Kentucky Spinal Cord Injury core, specifically Christine Yarberry, Johnny Morehouse, Darlene Burke and Jason Beare have been so incredibly helpful. I could not have done all the surgeries, data collection and analysis without them. Thank you to Dr. Powel and Dr. Drake for helping me address any veterinary concerns that have come up during the studies. Because of their oversight and guidance regarding animal iv care most of my subjects were healthy and made it to the end of the study. Thank you to RRC stuff for keeping our animal housing conditions excellent and for providing special accommodation when needed for the experimental purposes and health of the animals. Thank you to my fellow graduate students: Amanda Pocratsky, Katie Harman, Katie DeVeau, Courtney Shephard and Greg States. They were always there for me with the one of a kind perspective. This experience would not be as fun without them. Thank you to all the members of the Kentucky Spinal Cord Injury Center. I thank Dr. Terson de Paleville and Dr. Swank for encouraging me to pursue my PhD. I thank my family and friends for their unwavering support, for listening and encouraging me through all the fun and hard times. I would not be where I am today without them. I thank my God for guiding me, inspiring me and giving me strength during some of the most difficult times of my life in the past five years. v ABSTRACT STRETCHING ADVERSELY MODULATES LOCOMOTOR CAPACITY FOLLOWING SPINAL CORD INJURY VIA ACTIVATION OF NOCICEPTIVE AFFERENTS Anastasia V. Keller June 9, 2017 Spinal cord injury (SCI) is the second leading cause of paralysis in the United States, affecting around 282,000 people with 17,000 new cases each year. Initial and secondary damage to the spinal cord disrupts multiple descending pathways that modulate the function of sympathetic preganglionic neurons and central pattern generating circuitry. Resulting loss of autonomic and locomotor functions, as well as decreased levels of physical activity, lead to a myriad of complications that affect multiple organ systems and significantly reduce both quality of life and life expectancy in individuals with SCI. Spasticity and muscle contractures are two common secondary conditions that develop in the chronic stages of SCI as a result of neurobiological and soft tissue adaptations. Stretching is the widely accepted initial therapy for the treatment of both spasticity and muscle contractures. Unlike humans, rats with experimental incomplete SCI have robust locomotor recovery and do not develop significant muscle contractures or spasticity. One of the long- standing operating principles in the Magnuson laboratory is that rats retrain or rehabilitate themselves through large amounts of in-cage activity. A previous graduate student in our vi lab, Krista Caudle, tested this hypothesis using custom designed wheelchairs to immobilize Sprague Dawley rats with mild-moderate SCIs. As expected, the immobilized SCI animals did not recover their locomotor function and, in addition, developed muscle contractures. To mimic the approach used in the clinic for the treatment of contractures, a hindlimb stretching protocol was developed and implemented as part of our daily care routine. As a control, non-immobilized SCI rats also received stretching therapy. Surprisingly, stretched rats and wheelchair immobilized rats showed similar impairments in locomotor recovery. This finding was alarming and warranted further studies. The work presented in this thesis is a continuation of the stretching projects in the Magnuson laboratory. Four major studies were carried out in order to improve our understanding of this stretching phenomenon and to begin uncovering the underlying physiological mechanisms. The following experiments revealed that hindlimb stretching disrupts locomotor function in rats with acute and chronic moderately-severe SCI. We also determined that dynamic “range of motion” stretching resulted in a similar pattern of locomotor impairment as our standard static stretch-and-hold protocol in rats with moderate sub-acute SCIs. Furthermore, using kinematics and electromyography (EMG), we determined that one of the most frequent responses to stretch in the rat hindlimbs is similar to human clonus. The significance of these findings are three-fold. First, to our knowledge, there has not been a specific description of clonus in the rat model of the SCI previously. Second, the similarity of the responses to stretch between rats and humans make a compelling argument for the clinical relevance of the stretching phenomenon. Finally, we determined that stretch-induced locomotor deficits depend on the presence of nociceptive afferents. Speculations about the specific physiological mechanisms of the vii
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