Aaron Ebeweber

Background:  Spinal cord injury (SCI) affects approximately 54 cases per one million people, and it is estimated that there are more than 250,000 people living with traumatic SCIs in the US alone¹. SCIs are devastating events, disrupting communication between the brain and body, and fundamentally altering one’s quality of life². SCIs damage the spinal cord in two ways: there is first the primary injury occurring at the time of trauma, and then secondary injury processes including inflammation or swelling further exacerbate the damage^3,4. Current treatments for injury include surgical decompression and blood pressure augmentation, but there is no way to protect the spinal neurons of promote regeneration. Despite numerous treatments being tested in clinical trials, few have translated into practical use². One of the methods currently being researched is the use of electrical stimulation of the spinal cord and a target muscle to induce changes in neuronal circuitry to strengthen connections. This strategy takes advantage of the plasticity of the spinal cord and is based on the premise that remodeling might allow for some recovery of sensation or motor function³.

Objective:  The aim of this research was to review current knowledge on spinal plasticity and explore the potential of electrical stimulation to enhance recovery of function after SCI.

Search Method:The research initially utilized PubMed to identify review articles published between 2019 and 2024, focusing on the current understanding of SCI and its impact on quality of life. Subsequently, a refined search in PubMed, incorporating Mesh Terms such as Electrical Stimulation, Spinal Cord Injury, Spinal Plasticity, and Hebbian Plasticity, identified current articles of electrical stimulation for recovery among SCI patients.

Results:  Over the last five decades, research has challenged the long-standing belief that the spinal cord solely serves as a conduit between the brain and the body⁵. It is now accepted that the spinal cord is capable of remodeling and demonstrates plasticity comparable to that of the brain. For example, plasticity was induced using Acute Intermittent Hypoxia (AIH) to cause phrenic long-term facilitation⁶. AIH triggers the release of brain-derived neurotrophic factors and serotonin, promoting plasticity in the neurons supplying the inspiratory muscles⁶. This leads to an increased inspiratory pressure during breathing in individuals with SCI⁶. Epidural electrical stimulation (EES) has also been demonstrated to induce plasticity by eliciting cellular changes within the neuronal subpopulation SC^{Vsx2::Hoxa10  7}. Using EES, mice were able to perform voluntary motor actions following a spinal contusion injury⁷. Chemogenetic and photogenic silencing experiments were also conducted in the mice to determine the roles of specific spinal neurons. When the neurons were silenced walking was disrupted, and the mice were dragged on a treadmill. Conversely. when silencing was turned off, the mice were able to walk with the aid of a support device⁷. When combined with rehabilitation, like motor training, electrical stimulation has the potential to induce Hebbian plasticity, characterized by the adage “neurons that fire together wire together”⁸. This method promotes long-term potentiation, enhancing neuronal connections and resulting in heightened responsiveness to the same stimuli by increasing receptor density on dendrites⁸.

Conclusion:  Research has also demonstrated the potential of electrical stimulation to induce spinal cord plasticity and enhance recovery in SCI patients. Preclinical studies in mice and rats demonstrate that this plasticity alters neuronal gene expression, receptor density, and signaling pathways to restore motor function. To optimize these benefits while minimizing harm, it is crucial to regulate plasticity induction and “rewiring” of the spinal cord accurately. Exploration of factors such as microenvironmental alterations and optimal electrical stimulation parameters (timing, frequency, exercise regimen) will significantly advance our understanding of spinal plasticity.

Works Cited:

1. National Spinal Cord Injury Statistical Center, Traumatic Spinal Cord Injury Facts and Figures at a Glance. Birmingham, AL: University of Alabama at Birmingham, 2023
2. Karsy M, Hawryluk G. Modern Medical Management of Spinal Cord Injury. Curr Neurol Neurosci Rep. 2019;19(9):65. Published 2019 Jul 30. doi:10.1007/s11910-019-0984-1
3. Fouad K, Popovich PG, Kopp MA, Schwab JM. The neuroanatomical-functional paradox in spinal cord injury [published correction appears in Nat Rev Neurol. 2023 Oct;19(10):635]. Nat Rev Neurol. 2021;17(1):53-62. doi:10.1038/s41582-020-00436-x
4. Eli I, Lerner DP, Ghogawala Z. Acute Traumatic Spinal Cord Injury. Neurol Clin. 2021;39(2):471-488. doi:10.1016/j.ncl.2021.02.004
5. Grau JW, Hudson KE, Johnston DT, Partipilo SR. Updating perspectives on spinal cord function: motor coordination, timing, relational processing, and memory below the brain. Front Syst Neurosci.
6. Sutor T, Cavka K, Vose AK, et al. Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. Exp Neurol. 2021;342:113735.
7. Kathe C, Skinnider MA, Hutson TH, et al. The neurons that restore walking after paralysis. Nature. 2022;611(7936):540-547. doi:10.1038/s41586-022-05385-7
8. Jo HJ, Kizziar E, Sangari S, et al. Multisite Hebbian Plasticity Restores Function in Humans with Spinal Cord Injury. Ann Neurol. 2023;93(6):1198-1213. doi:10.1002/ana.26622