Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Abstract

Objective: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods: We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT.Interpretation: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders.

Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine

“…The occipital cerebral cortex tested in our study, is the common area for the development of CSD, a phenomenon underlying aura in the specific form of migraine with aura [ 58 ]. Accordingly, CSD is likely giving rise to multiple visual abnormalities at the initiation of migraine attacks [ 59 , 60 , 61 , 62 ]. Temporal, frontal cortical lobes and the cerebellum were also reported to be altered in chronic migraine patients during pain signaling events [ 63 , 64 , 65 , 66 ].…”

Evidence that blood–CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen

“…For example, PET imaging has shown that the migraine medication dihydoergotamine does not enter the brain, 14 and no gadolinium crosses into the CSF in dynamic contrast‐enhanced MRI in migraine; 15 conversely, BBB breakdown was demonstrated in hemiplegic migraine 16,17 . Recently, inflammation in the occipital cortex in migraine with visual aura was reported 18 . A leak has been inferred from nonspecific blood surrogates of the BBB 19 and in animal model studies 20,21 .…”

Shared biological foundations of post‐traumatic headache and migraine

“…The human skull bone marrow contains numerous microvascular channels that serve in animals as conduits for inflammatory cell migration into the meninges and possibly to other intracranial structures related to headache, 3 as documented in experimental stroke and chemical meningitis. Interestingly, most nerve fibers in the bone marrow are nociceptive and CGRP‐containing 9 . The same study also reported that CGRP is involved in mobilization of myeloid cells from the bone marrow 9 .…”

“…Interestingly, most nerve fibers in the bone marrow are nociceptive and CGRP‐containing 9 . The same study also reported that CGRP is involved in mobilization of myeloid cells from the bone marrow 9 . It could therefore be speculated that calvarial bone marrow provides a source of inflammatory cells and proinflammatory molecules in meninges and overlying bone following trauma to the calvarium.…”