PET and fMRI insights into experimentally-induced premonitory symptoms in migraine: A systematic review

BackgroundMigraine attacks are believed to unfold through discrete but interrelated phases, among which the premonitory phase has garnered increasing attention. This early phase, occurring hours to days before pain onset, might reflect neurobiological processes that promote subsequent headache generation. Neuroimaging of experimentally induced attacks enables controlled investigation of the brain mechanisms underlying these early symptoms. This systematic review synthesizes and critically appraises current neuroimaging evidence on the experimentally induced premonitory phase in individuals with migraine.MethodsA systematic literature search of MEDLINE and Embase was performed from database inception through June 1, 2025, using predefined terms related to migraine and premonitory symptoms. Studies were eligible if they reported original neuroimaging findings on experimentally induced migraine attacks and specifically addressed the premonitory phase. Two independent reviewers screened all titles, abstracts, and full-text articles and extracted relevant data. Due to methodological heterogeneity in study design, a narrative synthesis was applied to summarize findings and assess the consistency of reported brain activity patterns across included studies.ResultsSeven studies met the inclusion criteria, all of which used glyceryl trinitrate to induce migraine attacks and applied either positron emission tomography or magnetic resonance imaging to assess brain changes. Across studies, reported alterations in cerebral perfusion and functional connectivity-used as surrogates for neural activity-during the premonitory phase were inconsistent and lacked replication. While some investigations suggested involvement of the thalamus and pons, these findings were derived exclusively from exploratory or uncorrected analyses. Hypothalamic involvement-a hypothesized migraine generator-was only sporadically observed, and reproducibility not investigated. The inconsistencies across studies likely reflect small sample sizes (ranging from 5 to 21 participants), suboptimal definitions of the premonitory phase, absence of appropriate controls, and unconventional use of neuroimaging statistics.ConclusionsNeuroimaging studies investigating the experimentally induced premonitory phase of migraine have largely produced inconsistent findings, likely due to small sample sizes, non-standardized symptom definitions, and exploratory imaging analyses lacking statistical rigor. Current evidence offers limited support for specific neural correlates of this phase, and its translatability to spontaneous migraine remains uncertain. To improve interpretability and clinical relevance, future research should prioritize standardized definitions, adequate control groups, and use of appropriate neuroimaging statistics.Trial RegistrationPROSPERO - Identifier: CRD42023415959.