I read with interest the article by Messina et al.1 that focused on gray matter (GM) volume changes in migraine. The number of episodic migraineurs evaluated (73) was too small for any biologically significant meaning to emerge. The limits of every research tool—including randomized controlled trials as well as advanced neuroimaging—have to be accepted, particularly in the absence of basic comprehension of disease mechanisms.2,3 Statistical significance also may have no biological significance.3 Messina et al.1 offer no correlation between GM volume changes and lateralization of headache, the most important pathophysiologic facet of migraine. Migraine literature is deluged with perceived differences between migraine with aura (MwA) and migraine without aura (MwoA), the single most important nosologic stumbling block in the evolution of a comprehensive theory for the entity.2,3 Messina et al.1 offer no such distinction.

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