Altered static-dynamic interhemispheric connectivity and transcriptional features underlying lateralization in patients with migraine

Approximately 60% of patients experience unilateral migraine, with distinct clinical manifestations between left-sided (LM) and right-sided migraine (RM). These clinical differences may stem from the modulation of macroscopic brain functional networks, underpinned by a microscopic molecular basis. However, the macroscopic and microscopic relationships between LM and RM remain poorly understood. Further investigation of these connections is crucial for the development of precision treatments for migraine. Seventy-seven patients with migraine without aura (MWoA), including 35 with LM and 42 with RM, and 77 healthy controls (HCs), underwent functional magnetic resonance imaging (fMRI). Static and dynamic voxel-mirrored homotopic connectivity (VMHC and dVMHC) were assessed to evaluate interhemispheric functional changes across the groups. Additionally, the cross-modal toolbox Juspace was used to analyze associations between VMHC and dVMHC alterations and neurotransmitter systems. The Allen Human Brain Atlas facilitated the identification of genes linked to these alterations, followed by enrichment analysis to explore underlying molecular mechanisms. Both LM and RM exhibited reduced VMHC and dVMHC in the salience network (SN). LM and RM specifically showed decreased VMHC and dVMHC within the “default mode network-sensorimotor network-visual network (DMN-SMN-VN)” and “cerebellar-limbic networks,” respectively. Notably, the reduction in VN-SN connectivity in LM correlated with pain-related emotions and quality of life, while the decrease in SN connectivity in RM was associated with pain-related sensation. In LM, decreased VMHC and dVMHC were significantly correlated with dopamine D1, dopamine D2, and noradrenaline transporter (NAT) receptor densities, whereas reductions in RM correlated with dopamine D1, dopamine D2, and gamma-aminobutyric acid type A (GABAa) neurotransmitter systems. Enrichment analysis revealed that VMHC and dVMHC abnormalities in LM were primarily associated with “energy metabolism and oxidative stress” (mitochondrial oxidative phosphorylation and DNA repair), whereas in RM, they involved “synaptic plasticity and signal transduction” (glutamate receptors, dopamine, cyclic adenosine monophosphate, and neuropeptides). These findings suggest that abnormalities in LM are linked to pain-related emotions and may involve the regulation of “dopamine D1-dopamine D2-NAT” and “energy metabolism and oxidative stress,” whereas RM abnormalities are associated with pain-related sensation and may involve the regulation of “dopamine D1-dopamine D2-GABAa” and “synaptic plasticity and signal transduction.” This study provides preliminary evidence for a potential link between macro- and micro-level pathomechanisms in LM and RM, offering new insights for precision therapy.