The aim of this work is to explore why brain sodium levels increase during migraines [1-3], and how these elevated levels can be normalized to treat migraines. It has been established that migraine sufferers have higher levels of sodium in their cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) than control group, while there is no significant difference between plasma concentration of sodium in migraineurs and healthy individuals. This elevated brain sodium level is likely due to altered homeostasis of sodium transport mechanisms on the blood brain barrier (BBB) and blood-CSF barrier (BCSFB). To further understand this phenomenon, we use animal and human data, and develop dynamic models which provide insight into how brain sodium levels are regulated during the onset and propagation of migraine headaches. We also simulate therapeutic impacts of different candidate migraine drugs on correction of the altered sodium homeostasis as we believe that normalizing sodium levels could treat migraine headaches.   


Mechanistic modeling of sodium regulation in a rat brain. Picture from [4]


[1] Harrington, M. G., Fonteh, A. N., Cowan, R. P., Perrine, K., Pogoda, J.M., Biringer, R. G., et al. (2006). Cerebrospinal fluid sodium increases in migraine. Headache 46, 1128–1135. doi: 10.1111/j.1526-4610.2006.00445.x

[2] Abad, N., Rosenberg, J. T., Hike, D. C.,Harrington,M. G., and Grant, S. C. (2018a). Dynamic sodium imaging at ultra-high field reveals progression in a preclinical migraine model. Pain 159, 2058–2065. doi: 10.1097/j.pain.0000000000001307

[3] Meyer, M. M., Schmidt, A., Benrath, J., Konstandin, S., Pilz, L. R., Harrington, M. G., et al. (2019). Cerebral sodium (23Na) magnetic resonance imaging in patients with migraine—a case-control study. Eur. Radiol. 29, 7055–7062. doi: 10.1007/s00330-019-06299-1

[4] Ghaffari H, Grant SC, Petzold LR, Harrington MG (2020). Regulation of CSF and brain tissue sodium levels by the blood-CSF and blood-brain barriers during migraine. Frontiers in Computational Neuroscience 4;14:4. doi: 10.3389/fncom.2020.00004