Multimodal Study of Brain Structural Alterations, Functional Gradient Perturbations, and Transcriptomic Specialization in Trigeminal Neuralgia Using 5.0 Tesla MRI

Objective: This study aimed to harness the superior imaging capability of 5.0 T MRI to comprehensively characterize structural brain alterations, functional connectome gradient perturbations, and their underlying transcriptomic correlates in patients with trigeminal neuralgia (TN). By constructing an interpretative framework linking macroscopic gradient changes to microscale gene specialization. Methods: Thirty‑five TN patients and sixty‑four healthy controls (HC) were enrolled. All participants underwent 3D high‑resolution T1 and resting‑state functional MRI (rs-fMRI) on a 5.0 T scanner. Functional connectome gradients were derived from the functional connectivity (FC) matrix via diffusion map embedding. Gray matter volume (GMV) was computed using voxel‑based morphometry (VBM), and structure‑function coupling was assessed via spatial correlations. Partial least squares (PLS) regression was employed to identify gene sets associated with gradient perturbations, followed by enrichment analysis to reveal the underlying biological processes. Results: TN patients exhibited attenuated extreme values and increased intermediate values on the primary gradient, with altered gradient scores across multiple networks, indicative of a global gradient compression. GMV reductions was observed in the medial prefrontal cortex (mPFC) and superior frontal gyrus (SFG), while gradient scores were decreased in the mPFC and ventral anterior cingulate cortex (vACC). Spatial correlation analyses revealed structure‑function decoupling in the sensorimotor (SMN), limbic (LIB), and frontoparietal (FPN) networks. Transcriptomic analyses showed that cortical gradient perturbations were strongly associated with genes involved in voltage‑gated ion channels, membrane potential regulation, and neurotransmitter release. Significant enrichment of sodium channel, Na⁺/K⁺‑ATPase, and GABA receptor genes further corroborated the ion channelopathy basis of TN. Conclusion: 5.0T MRI-based connectome gradient analysis reveals global compression and network-specific reorganization in TN. mPFC/vACC dedifferentiation reflects hierarchical collapse of descending pain inhibition, underpinning chronification. Gene enrichment corroborates ion channelopathy and suggests novel targets. This multi-scale framework integrates structure, function, and transcriptomics to advance mechanistic insights.