Sandra Zhi

Background: After a devastating spinal cord injury, it has been shown that glial signals are responsible for the inhibition of axonal regeneration and functional recovery. There exist two classes of axonal growth inhibitors in the Central Nervous System (CNS): membrane-associated myelin-associated inhibitors (MAIs) and matrix-associated chondroitin sulfate proteoglycans.¹The MAI proteins are Nogo-A (RTN4A), myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein. These oligodendrocyte membrane-associated ligands bind to Nogo-66 receptor 1 and too paired immunoglobulin-line receptor B. It has been found that Nogo-A is proteolyzed and secreted as an exosome protein after injury to become a diffusible inhibitor of axonal regeneration. These ligands and their receptors aim to main affect firing rate and biochemical signaling.¹ In a larger scale picture of traumatic spinal cord injury, primary mechanical damage from SCI is largely attributed to the severing of topical capillaries, thus causing bleeding into the parenchyma, which creates free radicals toxic to the surrounding environment. Additionally, the interstitial pressure caused by neural tissue edema would increase, thus compressing surrounding intact vessels. ²Much of the microscopic changes of spinal tissue in spinal cord injuries are due to the large amount of inflammatory activity from injury. The selectivity of ion channels in the spinal cord is altered due to proinflammatory factors from the surrounding cells. The concentrations of Na+ and Ca2+ are upregulated intracellularly while K+ and Mg+ are upregulated extracellularly. High Na+ concentrations contribute to edema within spinal tissue. High Ca2+ concentrations within the cell signal to the cell to undergo apoptosis. K+ concentrations have a large impact on myelination of the axons; with disruption of those concentrations, demyelination will occur.³ Macrophages and microglia also can become polarized, thus contributing to the electrical profile of a spinal cord injury. There are two polarization phenotypes, M1 and M2. The ratio of M1 and M2 contributes to the homeostasis of the microenvironment. During trauma, high levels of reactive oxygen species (ROS) are present, thus M1 macrophages/microglia become predominant, with creates a production of proinflammatory cytokines.⁴

Objective: The investigation hypothesized that electrical stimulation can enhance neurite growth and thus assist paraplegics with regaining some spinal cord function for walking.

Search Methods: To evaluate the effectiveness of electrical stimulation in neurite development, a review was conducted using the MeSH database and PubMed search engine. Key terms included “neurite development”, “electrical stimulation”, “spinal cord injuries”, and “electrical profile of spinal cord injury”.

Results: The results of the review suggest that various methods of electrical stimulation in humans have been shown to improve range of motion, reduce upper limb impairment, and allow these patients to regain function from before traumatic injury.⁵ Neuroprosthetic Functional Electrical Stimulation (FES) aims to promote movement by allowing neural networks to form around existing lesions.⁵ Experimental methods focus on giving subjects descending intentional motor commands and proprioceptive inputs to improve the functionality of epidural stimulation. Results showed that subjects with active intention to improve steppage, along with body-weight support (BWS), were able to activate lower extremity muscles more than a control group with who were told to passively step.⁶ This method of dynamic, task-specific training was termed Multi-modal rehabilitation (MMR).⁷ Another study explored the implementation of multi-modal rehabilitation while using epidural electrical stimulation as a longer-term recovery strategy for paraplegics. Activation of the gastrocnemius and the rectus femoris were recorded with skin surface electromyography (EMG) with regards to gait analysis. Both muscles showed elevated activity during the swing phase of the step cycle and EMG of flexor muscles such as the medial hamstring and the tibialis anterior were active in the early portion of the swing phase, however both showed signs of inhibition initially. After 43 weeks of MMR, and individual’s ability to step on a treadmill without help from a trainer or BWS improved greatly, showing that electrical stimulation improved the individual’s coordination of muscles that previously were dysfunctional.⁷ Computer modeling of regenerated neural networks after electrical stimulation have also been created in order to uncover such an enigmatic process. These models show that Epidural Electrical Stimulation (EES) primarily activate large myelinated fibers associated with proprioceptive pathways or cutaneous feedback circuits. At higher intensities, EES recruited both afferent and efferent fibers in both a computer model and, in the case of this study, in their in vivo rat models.⁸

Conclusions: While the initial investigation on the role of neurites in regaining spinal function is promising, there is still a lack of complete understanding of the physiological processes behind spinal regeneration. Additionally, our systems of delivering spinal electrical stimulation are not yet sophisticated enough to mimic smooth and organic gait. This is a field that contains a landscape open for further investigation.

Works Cited:

1.  Sekine Y, Lindborg JA, Strittmatter SM. A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration. J Biol Chem. 2020;295(8):2175-2183. doi:10.1074/jbc.RA119.009896
2. Fan B, Wei Z, Yao X, et al. Microenvironment Imbalance of Spinal Cord Injury. Cell Transplant. 2018;27(6):853-866. doi:10.1177/0963689718755778
3. Zhang, Q., Beirne, S., Shu, K. et al. Electrical Stimulation with a Conductive Polymer Promotes Neurite Outgrowth and Synaptogenesis in Primary Cortical Neurons in 3D. Sci Rep 8, 9855 (2018). https://doi.org/10.1038/s41598-018-27784-5
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5. Carda S, Biasiucci A, Maesani A, et al. Electrically Assisted Movement Therapy in Chronic Stroke Patients With Severe Upper Limb Paresis: A Pilot, Single-Blind, Randomized Crossover Study. Arch Phys Med Rehabil. 2017;98(8):1628-1635.e2. doi:10.1016/j.apmr.2017.02.020
6. Gill ML, Linde MB, Hale RF, et al. Alterations of Spinal Epidural Stimulation-Enabled Stepping by Descending Intentional Motor Commands and Proprioceptive Inputs in Humans With Spinal Cord Injury. Frontiers in Systems Neuroscience. 2021;14. doi:10.3389/fnsys.2020.590231
7. Gill, M.L., Grahn, P.J., Calvert, J.S. et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat Med 24, 1677–1682 (2018). https://doi.org/10.1038/s41591-018-0175-7
8. Moraud EM, Capogrosso M, Formento E, et al. Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury. Neuron. 2016;89(4):814-828. doi:10.1016/j.neuron.2016.01.009