Iron deposition network mapping of disease occurrence and clinical manifestations in migraine: A prospective study

Background Excessive iron deposition is associated with migraine occurrence, disease severity, and related dysfunction. The migraine attack is a coordinated, whole-nervous-system event, while previous research has predominantly focused on discrete brain regions. This study aims to explore the associations between network-level iron deposition and both disease occurrence and clinical manifestations in migraine using the functional connectome. Methods Seventy-three migraine patients, including 32 episodic migraine (EM) and 41 chronic migraine (CM), and 37 age- and sex-matched healthy controls (HCs) were recruited. All participants underwent magnetic resonance imaging (MRI) to acquire quantitative susceptibility mapping (QSM) data. First, individual iron deposition maps were defined by comparing iron levels in each patient versus HCs. Next, the network coupling with each patient's site of iron deposition was calculated using seed-based functional connectivity (FC) in a large ( n = 1000) normative connectome, termed the iron deposition network map (IDNM). We then performed inter-group analysis to identify disease- and symptom-associated brain regions and measured the FC strength between these regions and the patients’ iron deposition maps. Finally, we investigated the relationships between IDNM-derived metrics and various clinical manifestations, including headache characteristics, migraine-related symptoms, disability measures, and comorbidities. Results IDNM group comparisons revealed significant differences in the superior temporal gyrus (STG), insula, and cerebellum in both migraine vs. HCs and CM vs. HCs comparisons, whereas no statistically significant differences were found for EM compared to either CM or HCs. FC strength between the peak site of the regions and individual iron deposition maps showed good discriminative performance in receiver operating characteristic (ROC) analysis (AUC > 0.70), effectively distinguishing migraine patients from HCs. Moreover, we identified clinical manifestation-related networks based on the IDNMs: the cerebellum for monthly headache days (MHDs; r = 0.349, p = 0.003); the orbitofrontal cortex (OFC) and nucleus accumbens (NAC) for poor sleep quality ( r = 0.604, p < 0.001); and the globus pallidus (GP) for vomiting ( p < 0.001). Conclusion Network-level iron deposition may distinguish migraine patients from HCs and is associated with clinical manifestations including MHDs, poor sleep quality, and vomiting symptoms, suggesting that iron deposition may play a role in migraine through the functional connectome.