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Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model

Abstract

Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve.

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Figure 1: Blood-flow images of MMA following CSD.
Figure 2: Sustained blood-flow response in MMA is neurogenically mediated.
Figure 3: Protein leakage in dura mater following CSD.
Figure 4: Proposed mechanism suggesting a link between CSD and trigeminovascular activation.

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Acknowledgements

We thank M. Foley for assistance and T. Dalkara for critical review of the manuscript. This study was supported by the NIH Migraine Program Project 2P01 NS10828 (to M.A.M.), NIH 1R29NS38842 (to D.A.B.), NIH K25 NS41291-01 (to A.K.D.), IHS research fellowship and Deutsche Forschungsgemeinschaft Re 1316-1 (to U.R.).

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Correspondence to Michael A. Moskowitz.

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Bolay, H., Reuter, U., Dunn, A. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8, 136–142 (2002). https://doi.org/10.1038/nm0202-136

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