Background: The purpose of this study was to compare the ultrastructural appearance and protein expression of the zygomaticotemporal branch of the trigeminal nerve in patients with and without migraine headaches. Methods: After confirmation of migraine headache diagnosis on 15 patients, a 5-mm segment of the zygomaticotemporal branch of the trigeminal nerve that is routinely removed during migraine surgery was compared to similarly sized nerve segments obtained from 15 control patients without a history of migraine headaches, who underwent an endoscopic forehead lift where this nerve is routinely transected. The segments were snap-frozen at-80°C for the downstream proteomics analysis. In addition, the cytoarchitectural differences of the nerve segments obtained from the 15 migraine and 15 control subjects were examined in detail under the electron microscope. Results: Analysis of liquid chromatography/tandem mass spectrometry data sets identified differentially expressed proteins and networks composed of highly connected molecular modules (p = 10-44 and p = 10-34) in patients with migraine headaches. The nerves from patients with migraine headaches had a linear organization, disrupted myelin sheaths and target axons, and discontinuous neurofilaments that were poorly registered with the discontinuous myelin sheaths, suggesting axonal abnormality. Conclusions: This study offers electron microscopic and proteomic evidence of axonal abnormality and deregulation of the myelination process in patients with migraine headaches compared with controls, offering the first objective evidence to support the role of peripheral mechanisms in the migraine headache cascade and an explanation as to why the surgical treatment of migraine headaches is efficacious.
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