Eric Lawhead

Background: Post-traumatic epilepsy (PTE), the onset of recurrent seizures following a traumatic brain injury (TBI), is a major clinical challenge.¹ 70 million people globally experience a TBI annually. PTE develops in approximately 50% of people with severe TBIs and accounts for 20% of all epilepsy cases.^2,3 Secondary TBI damage induces neuroinflammation and increases pro-inflammatory cytokines responsible for upregulating inflammatory microglia, reactive oxygen species (ROS), and blanket neuron depolarization.^1,3,4 The same processes are implicated in seizure onset. Currently, pharmacological interventions for epilepsy, including phenytoin, valproate, and levetiracetam, have an insignificant therapeutic effect for one-third of patients with epilepsy.^1,4,5 Therefore, it is important to determine a non-pharmacological approach to alleviating epilepsy. Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved, non-invasive neuromodulation therapy primarily used for depression.⁴ However, there are limited studies on the role of rTMS in treating epilepsy.

Objectives: This literature review assesses whether rTMS can mitigate neuroinflammation, and subsequently be used to treat neuroinflammation-mediated PTE, through proinflammatory cytokine downregulation, neural immune modulation, and neural repair.

Search Methods: PubEd and Google Scholar databases were utilized to locate the appropriate articles for this review. The publication dates for the utilized studies range from 2018 to 2024. Relevant search terms include “rTMS, “neuroinflammation,” “epilepsy,” and “seizures.”

Key Results: Multiple studies highlight the use of rTMS to decrease the proliferation of inflammatory cytokines in response to neural damage or dysfunction.^6,7,8 Rats treated with rTMS exhibited significantly lower levels of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) compared to the sham-treated control groups. Conversely, levels of the anti-inflammatory cytokine IL-10 were elevated in the rTMS group.⁷  rTMS stimulation also upregulates anti-inflammatory cytokines such as interleukin-4 (IL-4), which stimulates anti-inflammatory M2 macrophages, and interleukin-10 (IL-10), which inhibits the NF-kB gene.⁶

Along with modulating neuroinflammation through direct influence on interleukin expression and production, rTMS also affects the pathways that promote neuron production and decrease apoptosis.^6,7 Results demonstrated that rTMS-treated rats exhibited significantly reduced levels of pro-apoptotic TNF-α compared to sham-treated controls.⁷ rTMS also increased pro-inflammatory M1 to anti-inflammatory M2 microglial polarization in the cultured cells. M2 microglia secrete neurotrophic molecules to stimulate neural progenitor cells and neurogenesis.⁶

In human participants with epilepsy, there was a significant decrease in seizure onset between patients who received rTMS stimulation compared to controls. The patients who received rTMS experienced a 25% reduction in seizures.⁹ However, other studies illustrate a significant decrease of 34.55% in the seizure threshold for patients subject to rTMS compared to controls.¹⁰

Conclusion: Multiple studies support the therapeutic potential of rTMS in reducing pro-inflammatory cytokine levels in inflammation-driven neurological disorders. rTMS stimulation also has been shown to directly attenuate seizure prevalence in patients with epilepsy, which is a promising sign for those experiencing PTE. Although these studies examine the connection between rTMS stimulation and the attenuation of epilepsy’s potential causative mechanisms, few direct rTMS studies have been performed on patients who have epilepsy or developed PTE after a TBI. There may be subtleties in these populations where rTMS may be more or less effective, so more research is needed to determine whether rTMS would be effective in treating PTE. Future research is also needed to determine the conditions where rTMS provokes harmful seizure activity.

Works Cited:

1. Javalgekar, M., Jupp, B., Vivash, L. et al. Inflammasomes at the crossroads of traumatic brain injury and post-traumatic epilepsy. J Neuroinflammation 21, 172 (2024). https://doi.org/10.1186/s12974-024-03167-8
2. Fordington S, Manford M. A review of seizures and epilepsy following traumatic brain injury. J Neurol. 2020;267(10):3105-3111. doi:10.1007/s00415-020-09926-w
3. Fang M, Liu W, Tuo J, et al. Advances in understanding the pathogenesis of post-traumatic epilepsy: A literature review. Frontiers in Neurology. 2023;14. doi:10.3389/fneur.2023.1141434
4. Eastman CL, D’Ambrosio R, Ganesh T. Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury. Neuropharmacology. 2020;172:107907. doi:10.1016/j.neuropharm.2019.107907
5. Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. The Lancet. 2019;393(10172):689-701. doi:10.1016/s0140-6736(18)32596-0
6. Luo J, Feng Y, Li M, Yin M, Qin F, Hu X. Repetitive transcranial magnetic stimulation improves neurological function and promotes the anti-inflammatory polarization of microglia in ischemic rats. Front Cell Neurosci. 2022;16:878345. doi:10.3389/fncel.2022.878345.
7. Yang Y, Xia C, Xu Z, et al. RTMS applied to the PFC relieves neuropathic pain and modulates neuroinflammation in CCI RATS. Neuroscience. 2024;554:137-145. doi:10.1016/j.neuroscience.2024.07.004
8. Zuo C, Cao H, Feng F, et al. Repetitive transcranial magnetic stimulation exerts anti-inflammatory effects via modulating glial activation in mice with chronic unpredictable mild stress-induced depression. Int Immunopharmacol. 2022;109:108788. doi:10.1016/j.intimp.2022.108788.
9. Wang YY, Ma L, Shi XJ, Liu Y, Wu DW, Hao JM, Leng XX, Jin L, Yuan F, Sun ZQ, Zhao JJ, Wang L, Shang L, Wang DL, Song CG, Jiang W. Cerebellar transcranial magnetic stimulation to treat drug-resistant epilepsy: A randomized, controlled, crossover clinical trial. Epilepsia. 2025 Jan;66(1):240-252. doi: 10.1111/epi.18168. Epub 2024 Nov 8. PMID: 39513971.
10. Buday J, Albrecht J, Podgorná G, Mareš T, Le TH, Čapek V, Mahrík J, Pol M, Raboch J, Anders M. Seizure threshold manipulation in electroconvulsive therapy via repetitive transcranial magnetic stimulation: a novel way of augmentation? Brain Stimul. 2020;13(6):1631-1638. doi:10.1016/j.brs.2020.09.008.