Transcriptional correlates of structure-function coupling plasticity in trigeminal neuralgia: unveiling the synaptic and metabolic associations

Background: Trigeminal neuralgia (TN) is characterized by severe facial pain, transitioning from peripheral vascular compression to central sensitization. However, the core central pathophysiological mechanisms—particularly how the brain structurally and functionally reorganizes to maintain pain or recover after surgical treatment (primarily microvascular decompression or percutaneous interventions)—remain to be fully elucidated. Methods: We employed a longitudinal multi-scale design using a graph harmonic model to quantify structure-function (S-F) coupling, a metric reflecting brain network integrity. We analysed multimodal magnetic resonance imaging data from 87 patients with TN and 42 healthy controls (HCs). Post-treatment follow-up data were acquired for 46 patients, of whom 39 had complete longitudinal paired data. We further utilised partial least squares (PLS) regression with rigorous spatial permutation testing (spin-tests) to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas. Results: Patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with baseline pain severity and disease duration. Following treatment, global S-F coupling returned to levels statistically indistinguishable from healthy baselines (). Crucially, the magnitude of postoperative reorganization (S-F coupling) significantly correlated with postoperative pain reduction percentages and long-term follow-up NRS scores. This recovery extended beyond focal repair, involving extensive adaptive reorganization in the visual and default mode networks. Molecularly, disease-related decoupling was spatially associated with genes linked to neuronal energy metabolism, cellular ionic homeostasis, and neuroinflammation. Conversely, treatment-induced plasticity strongly correlated with genes modulating chemical synaptic transmission and endogenous opioid signaling. Conclusions: TN pathophysiology is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by facilitating synaptic plasticity-based adaptive reorganization rather than merely through focal repair. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging indicators for developing brain network-targeted therapeutic strategies.