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 ([Formula: see text]). Crucially, the magnitude of postoperative reorganization ([Formula: see text]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.