Safety of mapping the motor networks in the spinal cord using penetrating microelectrodes in Yucatan minipigs

Soroush Mirkiani Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Soroush Mirkiani in
jns
Google Scholar
PubMed
Close
 MSc
,
Carly L. O’Sullivan Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Carly L. O’Sullivan in
jns
Google Scholar
PubMed
Close
 BSc
,
David A. Roszko Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Ontario, Canada;

Search for other papers by David A. Roszko in
jns
Google Scholar
PubMed
Close
 MSc
,
Pouria Faridi Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Pouria Faridi in
jns
Google Scholar
PubMed
Close
 MSc
,
David S. Hu Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by David S. Hu in
jns
Google Scholar
PubMed
Close
 BSc
,
Dirk G. Everaert Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Dirk G. Everaert in
jns
Google Scholar
PubMed
Close
 PhD
,
Amirali Toossi Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Amirali Toossi in
jns
Google Scholar
PubMed
Close
 PhD
,
Ryan Kang Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Ryan Kang in
jns
Google Scholar
PubMed
Close
 BSc
,
Tongzhou Fang Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Tongzhou Fang in
jns
Google Scholar
PubMed
Close
 BSc
,
Neil Tyreman Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Neil Tyreman in
jns
Google Scholar
PubMed
Close
 BSc
,
Ashley N. Dalrymple Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania;

Search for other papers by Ashley N. Dalrymple in
jns
Google Scholar
PubMed
Close
 PhD
,
Kevin Robinson School of Physical Therapy, Belmont University, Nashville, Tennessee;

Search for other papers by Kevin Robinson in
jns
Google Scholar
PubMed
Close
 PT, DSc
,
Richard R. E. Uwiera Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Richard R. E. Uwiera in
jns
Google Scholar
PubMed
Close
 DVM, PhD
,
Hamid Shah Vanderbilt University Medical Center, Nashville, Tennessee;

Search for other papers by Hamid Shah in
jns
Google Scholar
PubMed
Close
 MD
,
Richard Fox Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Neurosurgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Richard Fox in
jns
Google Scholar
PubMed
Close
 MD
,
Peter E. Konrad Department of Neurosurgery, West Virginia University, Morgantown, West Virginia; and
Integrative Neuroscience & Clinical Innovation, Rockefeller Neuroscience Institute, Morgantown, West Virginia

Search for other papers by Peter E. Konrad in
jns
Google Scholar
PubMed
Close
 MD, PhD
, and
Vivian K. Mushahwar Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada;
Institute for Augmentative and Restorative Technologies and Health Innovations (iSMART), University of Alberta, Edmonton, Alberta, Canada;
Division of Physical Medicine and Rehabilitation, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;

Search for other papers by Vivian K. Mushahwar in
jns
Google Scholar
PubMed
Close
 PhD
Restricted access

Purchase Now

USD  $45.00

Spine - 1 year subscription bundle (Individuals Only)

USD  $392.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $636.00
USD  $45.00
USD  $392.00
USD  $636.00
Print or Print + Online Sign in

OBJECTIVE

The goal of this study was to assess the safety of mapping spinal cord locomotor networks using penetrating stimulation microelectrodes in Yucatan minipigs (YMPs) as a clinically translational animal model.

METHODS

Eleven YMPs were trained to walk up and down a straight line. Motion capture was performed, and electromyographic (EMG) activity of hindlimb muscles was recorded during overground walking. The YMPs underwent a laminectomy and durotomy to expose the lumbar spinal cord. Using an ultrasound-guided stereotaxic frame, microelectrodes were inserted into the spinal cord in 8 animals. Pial cuts were made to prevent tissue dimpling before microelectrode insertion. Different locations within the lumbar enlargement were electrically stimulated to map the locomotor networks. The remaining 3 YMPs served as sham controls, receiving the laminectomy, durotomy, and pial cuts but not microelectrode insertion. The Porcine Thoracic Injury Behavioral Scale (PTIBS) and hindlimb reflex assessment results were recorded for 4 weeks postoperatively. Overground gait kinematics and hindlimb EMG activity were recorded again at weeks 3 and 4 postoperatively and compared with preoperative measures. The animals were euthanized at the end of week 4, and the lumbar spinal cords were extracted and preserved for immunohistochemical analysis.

RESULTS

All YMPs showed transient deficits in hindlimb function postoperatively. Except for 1 YMP in the experimental group, all animals regained normal ambulation and balance (PTIBS score 10) at the end of weeks 3 and 4. One animal in the experimental group showed gait and balance deficits by week 4 (PTIBS score 4). This animal was excluded from the kinematics and EMG analyses. Overground gait kinematic measures and EMG activity showed no significant (p > 0.05) differences between preoperative and postoperative values, and between the experimental and sham groups. Less than 5% of electrode tracks were visible in the tissue analysis of the animals in the experimental group. There was no statistically significant difference in damage caused by pial cuts between the experimental and sham groups. Tissue damage due to the pial cuts was more frequently observed in immunohistochemical analyses than microelectrode tracks.

CONCLUSIONS

These findings suggest that mapping spinal locomotor networks in porcine models can be performed safely, without lasting damage to the spinal cord.

ABBREVIATIONS

BF = biceps femoris; EMG = electromyographic; GM = gluteus medius; MTP = metatarsophalangeal; PTIBS = Porcine Thoracic Injury Behavioral Scale; ROM = range of motion; SCI = spinal cord injury; SCS = spinal cord stimulation; VL = vastus lateralis; YMP = Yucatan minipig.

Supplementary Materials

    • Supplemental Material (PDF 2,134 KB)
  • Collapse
  • Expand
  • 1

    World Health Organization, International Spinal Cord Society. International Perspectives on Spinal Cord Injury. World Health Organization; 2013. Accessed March 7, 2024. https://iris.who.int/bitstream/handle/10665/94190/9789241564663_eng.pdf?sequence=1

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Simpson LA, Eng JJ, Hsieh JT, Wolfe DL. The health and life priorities of individuals with spinal cord injury: a systematic review. J Neurotrauma. 2012;29(8):15481555.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bizzi E, Giszter SF, Loeb E, Mussa-Ivaldi FA, Saltiel P. Modular organization of motor behavior in the frog’s spinal cord. Trends Neurosci. 1995;18(10):442446.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Capogrosso M, Wagner FB, Gandar J, et al. Configuration of electrical spinal cord stimulation through real-time processing of gait kinematics. Nat Protoc. 2018;13(9):20312061.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Dalrymple AN, Everaert DG, Hu DS, Mushahwar VK. A speed-adaptive intraspinal microstimulation controller to restore weight-bearing stepping in a spinal cord hemisection model. J Neural Eng. 2018;15(5):056023.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Holinski BJ, Mazurek KA, Everaert DG, et al. Intraspinal microstimulation produces over-ground walking in anesthetized cats. J Neural Eng. 2016;13(5):056016.

  • 7

    Saigal R, Renzi C, Mushahwar VK. Intraspinal microstimulation generates functional movements after spinal-cord injury. IEEE Trans Neural Syst Rehabil Eng. 2004;12(4):430440.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Dalrymple AN, Mushahwar VK. Intelligent control of a spinal prosthesis to restore walking after neural injury: recent work and future possibilities. J Med Robot Res. 2020;5(01n02):2041003.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Dalrymple AN, Roszko DA, Sutton RS, Mushahwar VK. Pavlovian control of intraspinal microstimulation to produce over-ground walking. J Neural Eng. 2020;17(3):036002.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Rowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. Nat Med. 2022;28(2):260271.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Angeli CA, Boakye M, Morton RA, et al. Recovery of over-ground walking after chronic motor complete spinal cord injury. N Engl J Med. 2018;379(13):12441250.

  • 12

    Gill ML, Grahn PJ, Calvert JS, et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat Med. 2018;24(11):16771682.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Hofstoetter US, Perret I, Bayart A, et al. Spinal motor mapping by epidural stimulation of lumbosacral posterior roots in humans. iScience. 2020;24(1):101930.

  • 14

    Darrow D, Balser D, Netoff TI, et al. Epidural spinal cord stimulation facilitates immediate restoration of dormant motor and autonomic supraspinal pathways after chronic neurologically complete spinal cord injury. J Neurotrauma. 2019;36(15):23252336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Borrell JA, Frost SB, Peterson J, Nudo RJ. A 3D map of the hindlimb motor representation in the lumbar spinal cord in Sprague Dawley rats. J Neural Eng. 2017;14(1):016007.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Mushahwar VK, Horch KW. Selective activation of muscle groups in the feline hindlimb through electrical microstimulation of the ventral lumbo-sacral spinal cord. IEEE Trans Rehabil Eng. 2000;8(1):1121.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Hachmann JT, Jeong JH, Grahn PJ, et al. Large animal model for development of functional restoration paradigms using epidural and intraspinal stimulation. PLoS One. 2013;8(12):e81443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Toossi A, Everaert DG, Perlmutter SI, Mushahwar VK. Functional organization of motor networks in the lumbosacral spinal cord of non-human primates. Sci Rep. 2019;9(1):13539.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kim KT, Streijger F, Manouchehri N, et al. Review of the UBC porcine model of traumatic spinal cord injury. J Korean Neurosurg Soc. 2018;61(5):539547.

  • 20

    Toossi A, Bergin B, Marefatallah M, et al. Comparative neuroanatomy of the lumbosacral spinal cord of the rat, cat, pig, monkey, and human. Sci Rep. 2021;11(1):1955.

  • 21

    Noga BR, Santamaria AJ, Chang S, et al. The micropig model of neurosurgery and spinal cord injury in experiments of motor control. In: Whelan PJ, Sharpies SA, eds. The Neural Control of Movement: Model Systems and Tools to Study Locomotor Function. Elsevier; 2020:349-384.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lee JH, Jones CF, Okon EB, et al. A novel porcine model of traumatic thoracic spinal cord injury. J Neurotrauma. 2013;30(3):142159.

  • 23

    Lim JH, Piedrahita JA, Jackson L, Ghashghaei T, Olby NJ. Development of a model of sacrocaudal spinal cord injury in cloned Yucatan minipigs for cellular transplantation research. Cellular Reprogram. 2010;12(6):689697.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Toossi A, Everaert DG, Uwiera RRE, et al. Effect of anesthesia on motor responses evoked by spinal neural prostheses during intraoperative procedures. J Neural Eng. 2019;16(3):036003.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Toossi A, Everaert DG, Seres P, et al. Ultrasound-guided spinal stereotactic system for intraspinal implants. J Neurosurg Spine. 2018;29(3):292305.

  • 26

    Mirkiani S, Roszko DA, O’Sullivan CL, et al. Overground gait kinematics and muscle activation patterns in the Yucatan mini pig. J Neural Eng. 2022;19(2):026009.

  • 27

    Tepavac D, Field-Fote EC. Vector coding: a technique for quantification of intersegmental coupling in multicyclic behaviors. J Appl Biomech. 2001;17(3):259270.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Leblond H, L’Espérance M, Orsal D, Rossignol S. Treadmill locomotion in the intact and spinal mouse. J Neurosci. 2003;23(36):1141111419.

  • 29

    Courtine G, Roy RR, Hodgson J, et al. Kinematic and EMG determinants in quadrupedal locomotion of a non-human primate (Rhesus). J Neurophysiol. 2005;93(6):31273145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Grillner S, El Manira A. Current principles of motor control, with special reference to vertebrate locomotion. Physiol Rev. 2020;100(1):271320.

  • 31

    Sharpe AN, Jackson A. Upper-limb muscle responses to epidural, subdural and intraspinal stimulation of the cervical spinal cord. J Neural Eng. 2014;11(1):016005.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Tresch MC, Bizzi E. Responses to spinal microstimulation in the chronically spinalized rat and their relationship to spinal systems activated by low threshold cutaneous stimulation. Exp Brain Res. 1999;129(3):401416.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Gakhar H, Bommireddy R, Klezl Z, Calthorpe D. Spinal subdural hematoma as a complication of spinal surgery: can it happen without dural tear? Eur Spine J. 2013;22(Suppl 3):S346-S349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Dowdell J, Brochin R, Kim J, et al. Postoperative spine infection: diagnosis and management. Global Spine J. 2018;8(4 Suppl):37S43S.

  • 35

    Holland MT, Seaman SC, Woodroffe RW, et al. In vivo testing of a prototype intradural spinal cord stimulator in a porcine model. World Neurosurg. 2020;137:e634e641.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Slot EMH, de Boer B, Redegeld S, et al. Spinal fixation after laminectomy in pigs prevents postoperative spinal cord injury. Animal Model Exp Med. 2022;5(2):153160.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Kozai TDY, Vazquez AL, Weaver CL, Kim SG, Cui XT. In vivo two-photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes. J Neural Eng. 2012;9(6):066001.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Wellman SM, Kozai TDY. In vivo spatiotemporal dynamics of NG2 glia activity caused by neural electrode implantation. Biomaterials. 2018;164:121133.

  • 39

    Eles JR, Vazquez AL, Kozai TDY, Cui XT. In vivo imaging of neuronal calcium during electrode implantation: spatial and temporal mapping of damage and recovery. Biomaterials. 2018;174:7994.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Mushahwar VK, Collins DF, Prochazka A. Spinal cord microstimulation generates functional limb movements in chronically implanted cats. Exp Neurol. 2000;163(2):422429.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Bamford JA, Todd KG, Mushahwar VK. The effects of intraspinal microstimulation on spinal cord tissue in the rat. Biomaterials. 2010;31(21):55525563.

  • 42

    Biran R, Martin DC, Tresco PA. Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays. Exp Neurol. 2005;195(1):115126.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Obaid A, Wu YW, Hanna M, Nix W, Ding J, Melosh N. Ultra-sensitive measurement of brain penetration with microscale probes for brain machine interface considerations. bioRxiv. Preprint published online October 29, 2018. doi:10.1101/454520

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Boergens KM, Tadić A, Hopper MS, et al. Laser ablation of the pia mater for insertion of high-density microelectrode arrays in a translational sheep model. J Neural Eng. 2021;18(4):045008.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Dobariya A, El Ahmadieh TY, Good LB, et al. Recording of pig neuronal activity in the comparative context of the awake human brain. Sci Rep. 2022;12(1):15503.

Metrics

All Time Past Year Past 30 Days
Abstract Views 555 555 555
Full Text Views 25 25 25
PDF Downloads 35 35 35
EPUB Downloads 0 0 0