Transcriptional Correlates of Structure-Function Coupling Plasticity in Trigeminal Neuralgia: Unveiling the Synaptic and Metabolic Mechanisms of Recovery

Background Trigeminal neuralgia (TN) is a neurological disorder characterised by severe facial pain and is a common cause of orofacial headache. While vascular compression is a known peripheral trigger, the condition involves a transition to central sensitization. However, the core central pathophysiological mechanisms—particularly how the brain structurally and functionally reorganises itself to maintain pain or recover after treatment—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 (HC). 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 to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas. Results Compared with HC, patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with disease duration, suggesting a progressive central impact. Following treatment, S-F coupling returned towards normal levels. However, this recovery was not driven by direct repair of the originally damaged nodes but by a complex neural reorganisation process dominated by compensation in the visual and default mode networks. At the molecular level, disease-related decoupling was spatially associated with the expression of genes linked to neuronal energy metabolism and sodium ion channels. In contrast, treatment-induced plasticity was strongly related to the expression of genes involved in cholesterol metabolism, synaptic organisation, and the endogenous opioid system. Conclusions Our findings indicate that the pathophysiology of TN is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by initiating adaptive, synaptic plasticity-based compensatory mechanisms rather than through direct repair of pathological regions. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging and molecular biomarkers for developing brain network-targeted therapeutic strategies.