Chase Jordan

Background: Traumatic brain injury (TBI) alters brain function due to an external mechanical force.³ TBI is found in 2.5 million yearly emergency room visits in the United States, with higher prevalence among males and the elderly.³ Neuroinflammation as a result of TBI contributes to blood-brain barrier breakdown, excitotoxicity, and diffuse cell death which induces widespread damage to the brain.³ Migraine is defined as episodic headaches with varying, associated neurological symptoms such as photophobia, dizziness, and nausea linked to observable changes in CNS homeostasis.¹ Migraines affect more than one billion individuals each year, and despite current treatments including NSAIDs, triptans targeting 5-HT receptors, and prophylactic CGRP inhibitors, migraine remains prevalent, supporting the need to better explain the mechanistic origin.^1,5 TBI has been identified as an independent risk factor for migraine development.⁴ Impairment of astrocytes glutamatergic regulation and ionic homeostasis could serve as potential mechanism to explain the increased risk of migraine post-TBI.^7,8

Objectives: This review seeks to explore TBI-induced astrocyte dysfunction as a mechanism for increased migraine risk, with the aim to better understand migraine pathogenesis.

Search Methods: A literature search was conducted on PubMed from 2019 to 2026 using the following keywords: “traumatic brain injury”, “migraine”, “astrocyte dysfunction”, “glutamate transport”, and “neuronal hyperexcitability”.

Results: A large retrospective cohort study found a significantly increased incidence of migraine among those with a history of TBI compared to those without, establishing TBI as an independent risk factor for migraine development.⁴ Analysis of astrocyte metabolic function in a post-TBI rat model found widespread metabolic disruptions, including dysfunction in glutamate clearance, indicating deficits in astrocytic homeostatic function.⁸ A zebrafish model of EAAT2 glutamate transporter knockout displayed spontaneous and light-induced seizures, signifying a relationship between astrocytic transport dysfunction and hyperexcitability.⁶ A familial hemiplegic migraine type 2 mouse model, which has reduced expression of astrocytic Na,K-ATPases, revealed enhanced NMDA spikes via patch clamp recordings in cingulate cortex pyramidal neurons, with reduction in neuronal dysfunction upon gene rescue, highlighting the impact of astrocytes in cortical excitability.⁷ A familial hemiplegic migraine type 3 mouse model displayed that hyperactivity of inhibitory interneurons contributed to cortical spreading depression, with associated increases in extracellular potassium suggesting failure of astrocytes to regulate ionic concentrations.²

Conclusion: Studies have illustrated the mechanism by which TBI induces astrocyte dysfunction in glutamatergic regulation and ionic homeostasis, leading to neuronal hyperexcitability and cortical spreading depression, contributing to increased incidence of migraine post-TBI. These findings may serve to better explain the origin of migraine and show the potential in therapies targeting astrocyte function. Further research is needed to better understand the progression of astrocytic changes post-TBI and to determine if restoration of astrocytic function can substantially reduce migraine onset.

Works Cited:

1. Amiri P, Kazeminasab S, Nejadghaderi SA, et al. Migraine: A review on its history, global epidemiology, risk factors, and comorbidities. Frontiers in neurology. 2022;12:800605. doi: 10.3389/fneur.2021.800605.
2. Auffenberg E, Hedrich UBS, Barbieri R, et al. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model. Journal of Clinical Investigation. 2021. doi: 10.1172/JCI142202.
3. Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic brain injury: An overview of epidemiology, pathophysiology, and medical management. The Medical clinics of North America. 2020;104(2):213. doi: 10.1016/j.mcna.2019.11.001.
4. Chen M, Sung Y, Chien W, Chung C, Chen J. Risk of migraine after traumatic brain injury and effects of injury management levels and treatment modalities: A nationwide population-based cohort study in Taiwan. Journal of clinical medicine. 2023;12(4):1530. doi: 10.3390/jcm12041530.
5. de Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacology & therapeutics (Oxford). 2020;211:107528. doi: 10.1016/j.pharmthera.2020.107528.
6. Hotz AL, Jamali A, Rieser NN, et al. Loss of glutamate transporter eaat2a leads to aberrant neuronal excitability, recurrent epileptic seizures, and basal hypoactivity. Glia. 2022;70(1):196–214. doi: 10.1002/glia.24106
7. Romanos J, Benke D, Pietrobon D, Zeilhofer HU, Santello M. Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine. Science advances. 2020;6(23):eaaz1584. doi: 10.1126/sciadv.aaz1584.
8. Wilson KA, Talty C, Parker BC, VandeVord PJ. Integrative constraint-based modeling and proteomics uncover astrocytic metabolic adaptations to the post-TBI microenvironment. International journal of molecular sciences. 2025;26(13):6456. doi: 10.3390/ijms26136456.