Functional Magnetic Resonance Imaging for Investigating the Role of the Hippocampus in Migraine with Aura

Background/Objectives: Migraine with aura (MwA) is a heterogeneous disorder comprising pure visual aura (MwAv) and more complex phenotypes with additional somatosensory and/or dysphasic symptoms (MwAvsd). Previous structural magnetic resonance imaging (MRI) studies have demonstrated hippocampal subfield volume reductions associated with aura complexity, suggesting a role for the hippocampus in MwA pathophysiology. However, functional network mechanisms underlying these structural differences remain unclear. This study aimed to investigate hippocampal resting-state functional connectivity (FC) in MwA subtypes and healthy controls (HCs), and to determine whether hippocampal connectivity patterns differ according to aura complexity. Methods: In this comparative cross-sectional study, 27 patients with MwAvsd, 18 with MwAv, and 29 age- and sex-matched HCs underwent resting-state functional MRI on a 3T scanner. Seed-based FC analyses were performed using both hippocampi as regions of interest. Results: MwAvsd patients demonstrated significantly increased FC between the right hippocampus and the left dorsal parietal cortex and right sensory association cortex compared with MwAv patients. In contrast, MwAv patients showed increased FC between the left hippocampus and the right dorsolateral prefrontal cortex compared with MwAvsd patients. Additionally, MwAv patients exhibited stronger FC between the left hippocampus and bilateral anterior prefrontal cortices and the left angular cortex compared with HCs. No other significant hippocampal FC differences were observed. Conclusions: Hippocampal FC is altered in MwA and varies according to aura phenotype. Complex aura is characterized by enhanced hippocampal coupling with multisensory integration regions and reduced connectivity with executive control areas, whereas pure visual aura demonstrates increased hippocampal-prefrontal and hippocampal-parietal associative connectivity compared with HCs. These findings suggest that the hippocampus might serve as a target for future neuromodulatory and therapeutic investigations in MwA patients.