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Epidural Stimulation is the practice of surgically implanting micro-electrode arrays on the epidural layer of the spinal cord. The micro- electrode arrays can be programmed to electrically stimulate the spinal cord in specific patterns to help alleviate conditions from chronic pain, to recovery of volitional locomotion.[1].

X-Ray of Patient with Implanted Spinal Cord Stimulator

Spinal Cord Injury

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Disruption of Tracts

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The spinal cord is made up of long nerves that carry information to and from the brain to the rest of body and is securely wrapped with layers of fascia and a hard skeletal cage. Spinal cord injuries fall under two categories, complete or incomplete, complete being there is a cut completely through the entire cord; while incomplete there are remaining parts of the spinal cord still intact.[2] Depending on the level of the spinal cord that is injured the resulting impairment can be as severe as loss of the ability to breathe (C1-C5) to inadequate limb strength and control (L1-L5). [3].

Remaining Tracts

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Severity of impairment depends heavily on the level of injury and the remaining tracts post injury. Completely spinal cord injuries lead to paralysis and several non motor issues. Incomplete spinal cord injuries can lead to several different levels of impairment including partial paralysis to complete paralysis. Depending on the exact tracts injured there can be issues with walking, coordination, sensation, or all of the above. Several specific injuries' have been described such as Brown-Séquard syndrome that will have predictable affects to locomotion, sensation, and even autonomic functions such as urination. A majority of spinal cord injuries are incomplete leading to a wide range of impairments in the clinical population.

History and Progress of Epidural Stimulation and Locomotion

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  1. Epidural Stimulation was first used in 1967[4] to be used as a treatment for chronic pain. Epidural Stimulation is now one of the cutting edge tools in recovery from spinal cord injury, both complete and incomplete[1].
  2. Epidural stimulation and its link to recovering the ability to walk may have been started by Dr. M R Dimitriveci in 1998 when he showed evidence for Central pattern generator's in humans using epidural stimulation; in a patient with an incomplete spinal cord injury[5]. This ability to elicit stepping like behavior pointed towards evidence of the Central pattern generator and the potential to recover locomotion in patients with spinal cord injuries. Since this discovery, placement, stimulation parameters, and training programs have been studied in various animal models and humans all with the goal of understanding underlying mechanism of the spinal cord and recovery from injury.
  3. In 2001 Dr. Gerasimenko et al, were able to initiate locomotor activity in spinalized cats through epidural stimulation of the L5 region of the spinal cord [6].
  4. In 2005 Dr. Reggie Edgerton et al. showed the same ability that epidural spinal cord stimulation could initiate stepping in a rat with a complete spinal cord injury [7]. The stepping only occurred while the stimulations was on, meaning the animal had no control over the actual stepping.
  5. in 2012 Dr. Gregoire Courtine at "École Polytechnique Fédérale de Lausanne" also know as EPFL was able to repeat Dr. Edgertons experiment with small variations in the stimulation that showed the ability for the mouse to start and stop walking with their own volition[8]. While a major feat it is important to note the gait cycle was not perfect, transition from swing phase to stance phase was inconsistent and comparable to normal movement but clearly lacking some of the intricacies of intact walking. Dr. Courtine's group at EPFL looked to improve the quality of gait by mimic natural activation patterns of locomotion. Adding a spatio-temporal aspect to the stimulation allowed selective stimulation of nerves to mimic locomotion proved to increase the quality of walking in mice[9]. This advancement lead to a more complex set of stimulations, no longer would consistent stimulation yield the best results, using very specifically timed stimulation locomotion can be further improved. The problem is the new stimulation parameters are only optimized for walking, and nothing else. The researchers can switch between goal optimized parameters manually, but the mouse could not switch tasks on their own.
  6. In 2016 a major collaboration again led by Dr. Courtine created a brain implanted device to record the intended movement in primates. The brain recordings that can be captured are actually firing several neurons in very specific patterns, machine learning can be applied to decode the firing patterns to intended movement. The intended movement was then sent to the spinal cord stimulator to use a stimulation parameter optimized for the intended movement, creating one of the first Brain Controlled Epidural Stimulators of this magnitude[10].
  7. In 2018 Dr. Courtine's group implanted a small number human patients with these epidural stimulation devices (no brain implants) to research the efficacy at the human level. The recovery of locomotion to some extent was successful in each case, even when the subject was completely paralyzed[11].

Mechanisms of Epidural Stimulation

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Basic Spinal Cord Anatomy

Basic Mechanism

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While the intricacies and overall affect of epidural stimulation is still debated, it is commonly accepted that the basic mechanisms is the increased level of excitation of the dorsal aspect of the spinal cord. Stretch reflex is a good proxy for explaining the reasoning behind why this helps. If the signal is too small then when it goes to the spinal cord nothing happens, there has to be a threshold of activity reached before there will be a reaction. After spinal cord injury the overall level resting level and excitability of the spinal cord is much lower. This lower level of activity leads to information going into the spinal cord but no reaction occurring. The stimulation raises the background activity, thus increasing proprioception information going into the spinal cord allowing for easier activation of remaining tracts and interneurons. The actual mechanism and reason this allows volitional movement is debated, but reorganization of the cortico-spinal tract and an increased number of connections after repetitive use of epidural stimulation[12], suggests this pathway plays a role.

Spatiotemporal Mechanism

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The spinal cord is housed and protected by the spinal processes and many layers of tissue to shield it from any trauma. This leads to branching of the spinal neurons out from underneath the spine at each level of the spine. Each one of these branches or roots is responsible for innervating a select group of muscles that will activate when a signal from the spinal cord is transmitted to them through these roots. The signal can be recorded by various methods that allow someone to understand the patterns of activation. The most common method of recording theses signals is through electromyography that will track the electrical activity of each muscle. Knowing which muscle is activated when allows you to recreate the patterns, by stimulating selective branches at specific times. This is the spatiotemporal idea used by Dr. Courtine et al. to allow for more natural locomotion. This idea can be applied for all repetitive movements in any animal model allowing a vast range of movements to be produced.

Current Research

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Along with continuing research into restoration of movement, research in the field of Epidural Stimulation is looking at possible remedies of non-movement problems including pain, and autonomic functions. Persons with spinal cord injuries often lose control of basic autonomic functions such as thermal regulation, urinate, defecate, and research looking at the potential aid of epidural stimulation is a growing field.

See:

R. Edgeerton Lab (UCLA): https://edgertonlab.ibp.ucla.edu/

G. Courtine Lab (EPFL): https://people.epfl.ch/gregoire.courtine?lang=en

R. Gaunt (Pitt): http://www.rnel.pitt.edu/people/robert-gaunt-phd

Reeves Foundation: https://www.christopherreeve.org/

References

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  1. ^ a b Brand, Rubia van den; Heutschi, Janine; Barraud, Quentin; DiGiovanna, Jack; Bartholdi, Kay; Huerlimann, Michèle; Friedli, Lucia; Vollenweider, Isabel; Moraud, Eduardo Martin; Duis, Simone; Dominici, Nadia (2012-06-01). "Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury". Science. 336 (6085): 1182–1185. doi:10.1126/science.1217416. ISSN 0036-8075. PMID 22654062.
  2. ^ "Spinal Cord Injury". Department of Rehabilitation and Regenerative Medicine. 2020-08-18. Retrieved 2021-04-19.
  3. ^ "Spinal Cord Injury". Department of Rehabilitation and Regenerative Medicine. 2020-08-18. Retrieved 2021-04-19.
  4. ^ "Spinal Cord Stimulation". www.neuromodulation.com. Retrieved 2021-04-19.
  5. ^ Dimitrijevic, M. R.; Gerasimenko, Y.; Pinter, M. M. (1998-11-16). "Evidence for a spinal central pattern generator in humans". Annals of the New York Academy of Sciences. 860: 360–376. doi:10.1111/j.1749-6632.1998.tb09062.x. ISSN 0077-8923. PMID 9928325.
  6. ^ Gerasimenko, Iu P.; Avelev, V. D.; Nikitin, O. A.; Lavrov, I. A. (2001-09). "[Initiation of locomotor activity in spinalized cats by epidural stimulation of the spinal cord]". Rossiiskii Fiziologicheskii Zhurnal Imeni I.M. Sechenova. 87 (9): 1161–1170. ISSN 0869-8139. PMID 11763528. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Ichiyama, R. M.; Gerasimenko, Yu P.; Zhong, H.; Roy, R. R.; Edgerton, V. R. (2005-08-05). "Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation". Neuroscience Letters. 383 (3): 339–344. doi:10.1016/j.neulet.2005.04.049. ISSN 0304-3940. PMID 15878636.
  8. ^ Brand, Rubia van den; Heutschi, Janine; Barraud, Quentin; DiGiovanna, Jack; Bartholdi, Kay; Huerlimann, Michèle; Friedli, Lucia; Vollenweider, Isabel; Moraud, Eduardo Martin; Duis, Simone; Dominici, Nadia (2012-06-01). "Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury". Science. 336 (6085): 1182–1185. doi:10.1126/science.1217416. ISSN 0036-8075. PMID 22654062.
  9. ^ Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G.; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R. (2016-02). "Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury". Nature Medicine. 22 (2): 138–145. doi:10.1038/nm.4025. ISSN 1546-170X. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Capogrosso, Marco; Milekovic, Tomislav; Borton, David; Wagner, Fabien; Moraud, Eduardo Martin; Mignardot, Jean-Baptiste; Buse, Nicolas; Gandar, Jerome; Barraud, Quentin; Xing, David; Rey, Elodie (2016-11). "A brain–spine interface alleviating gait deficits after spinal cord injury in primates". Nature. 539 (7628): 284–288. doi:10.1038/nature20118. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Wagner, Fabien B.; Mignardot, Jean-Baptiste; Le Goff-Mignardot, Camille G.; Demesmaeker, Robin; Komi, Salif; Capogrosso, Marco; Rowald, Andreas; Seáñez, Ismael; Caban, Miroslav; Pirondini, Elvira; Vat, Molywan (2018-11). "Targeted neurotechnology restores walking in humans with spinal cord injury". Nature. 563 (7729): 65–71. doi:10.1038/s41586-018-0649-2. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Brand, Rubia van den; Heutschi, Janine; Barraud, Quentin; DiGiovanna, Jack; Bartholdi, Kay; Huerlimann, Michèle; Friedli, Lucia; Vollenweider, Isabel; Moraud, Eduardo Martin; Duis, Simone; Dominici, Nadia (2012-06-01). "Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury". Science. 336 (6085): 1182–1185. doi:10.1126/science.1217416. ISSN 0036-8075. PMID 22654062.
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