Topological signatures differentiating episodic and chronic phenotypes in migraine without aura: a multi-scale analysis revealing divergent network profiles

The differences between episodic and chronic migraine phenotypes imply a system-level network reorganization often obscured by traditional discrete analyses. We employed multidimensional functional gradient analysis to characterize these distinct topological patterns and anchor them to microscale mechanisms. This study utilized resting-state fMRI in 111 participants with migraine without aura (MWoA) to map functional connectome gradients. To rigorously dissect disease-state-specific features from aging effects, we compared age-matched episodic and chronic cohorts. Beyond standard gradient axes, we systematically evaluated topological reorganization using manifold eccentricity and differentiation metrics. Furthermore, macroscopic alterations were biologically decoded by analyzing spatial correlations with cerebral blood flow, neurotransmitter receptors, transcriptomic profiles, and functional enrichment analysis. We identified divergent network profiles where EM was characterized by transmodal network shifts, whereas CM exhibited a distinct principal gradient shift coupled with sensory-cognitive axis compression. Alterations in low-dimensional gradient scores, alongside increased manifold eccentricity and segregation, effectively distinguished patients from controls and were significantly associated with clinical disability. These macroscopic alterations spatially converged with cerebral blood flow and serotonin transporter density, while decoding analysis revealed enrichment in synaptic-metabolic pathways, glial populations, and neuropsychiatric genetic risks. This study identifies a novel multi-scale link between macroscopic topological architecture and microscale synaptic-metabolic patterns associated with the chronic migraine phenotype without aura. Moving beyond descriptive topology, these findings implicate “neuro-metabolic fragility” as a potential biological substrate of the disease, suggesting specific molecular targets for therapeutic interventions.