Check out our new review about the role of glymphatic transport in ocular diseases. doi.org/10.1016/j.preteyeres…

Galen of Pergamon who gave name to the disorder “hemicrania” which eventually became migraine, thought vile fluids filling up half of the head caused migraine. The discoverer of CSF, Domenico Cotugno, hypothesized that inflamed CSF around DRGs was responsible for sciatica pain.

We are now really interested in looking into the remaining signaling proteins identified and their corresponding receptors, because perhaps the next important drug target in migraine prevention and abortion is hiding somewhere in here! (13)

One of the identified proteins was CGRP, which is known to induce migraine, which is targeted in migraine therapy. CGRP was able to induce activity in the sensory neurons in the ganglion, suggesting that CGRP exerts some of its migraine inducing effects through this pathway. (12)

We applied migraine with aura CSF to trigeminal ganglions and saw that it increased activity in sensory neurons suggesting that the proteins identified above indeed were able to activate the sensory system. (11)

This was interesting because CSD is known to increase production of inflammatory molecules which might be washed out to CSF. Mass Spect revealed massive changes in CSF protein concentrations after CSD including several proteins that could potentially be migraine triggers. (10)

We next asked if this fluid pathway between brain and trigeminal ganglion was involved in migraine with aura, where aura is caused by cortical spreading depression resulting in transient neurological deficits which are followed by migraine headache after 5-60 minutes. (8)

Another interesting finding was that molecules released in one side of cortex primarily flows to the trigeminal ganglion in the same side. This could potentially explain why migraine in most cases is a unilateral headache. (7)

How does molecules released in visual cortex (most common site of aura) distribute to sites of sensory innervation? We found 4 times higher levels in CSF spaces of the ganglion vs dura mater, previously considered the most important site for CNS-PNS communication in migraine. (6)

CSF inflow into the trigeminal extracellular space was unexpected. We did immunohistochemistry and CE-MRI and found that CSF solutes flow into the root portion of the nerve because the external epineurial barrier only forms one third after the nerve leaves pons. (5/X)