About 25% of migraine patients experience an aura prior to the onset of headache. The physiological phenomenon believed to underlie migraine aura, cortical spreading depression (CSD), is a depolarization wave in the cortex and is thought to trigger headaches. However, while this phenomenon occurs in the cortex, the onset of migraine is believed to be linked to triggering of nociceptors in the trigeminal ganglon. In the present study the researchers investgated the connection between the CSD in the visual cortex and the trigeminal ganglion, and found that these might be connected through CSF flow (1).
To investigate this the researchers used a mice both with tracer injections and a model of CSD, together with magnetic resonace imaging (MRI), immunohistochemistry, mass spectrometry and epifluorescence gradient-index lens imaging. First they discovered that the proximal third of the trigeminal ganglion was loosely attached to the brain membranes, which formed a cistern around it, allowing cerebrospinal fluid (CSF) and solutes to come into contact with the ganglion. Next, they found that by injecting tracer extracellularly in visual cortex, the majority of the tracer ended up in the cistern surrounding the ipsilateral trigeminal.
To further explore the relationship between cortical spreading depression (CSD) and migraine, the researchers utilized a mouse model of CSD to investigate its effect on cerebrospinal fluid (CSF) flow. They discovered that immediately following CSD, the influx of a tracer increased fourfold in the ipsilateral hemisphere. Additionally, they observed an 11% upregulation of proteins in the CSF, including calcitonin gene-related peptide (CGRP), which doubled in concentration. Finally, they conducted imaging of the trigeminal ganglion to analyze the effects of CSD. They found that approximately 74% of the trigeminal cells were activated after CSD, starting on average 11.2 minutes later. The researchers concluded that they may have identified a communication pathway connecting the CSD phenomena in the visual cortex to the pain arising from the trigeminal ganglion.
Key Points:
- The researchers found that the proximal third of the trigeminal ganglion features a cistern instead of being tightly bound to the membranes, allowing for direct contact with cerebrospinal fluid (CSF).
- By employing tracer injection methods in mice, the researchers discovered that solutes drain from the visual cortex to the trigeminal ganglion, with this flow increasing after cortical spreading depression (CSD), a phenomenon believed to underlie migraine aura. They also observed that CSD leads to an elevated concentration of proteins in the CSF, including a doubling of calcitonin gene-related peptide (CGRP).
- Through simultaneous imaging of the trigeminal ganglion while the mice underwent CSD, the researchers found that neurons in the trigeminal ganglion were activated, on average, 11 minutes after the onset of CSD. Similar activation was observed when CGRP was topically applied to the trigeminal ganglion.
References:
- Kaag Rasmussen, M., Møllgård, K., Bork, P. A., Weikop, P., Esmail, T., Drici, L., ... & Nedergaard, M. (2024). Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model. Science, 385(6704), 80-86.
Publish on behalf of the Coordinating Panel on Neuroscience/ Translational Neurology