Chuanxu Luo, Wanting Liu, Xiaoyi Liu, Xu Han, Hao Gu, Yapan Zhang, Fengchao Shi, Wenhui Li, Siyu Gu
Objective The central pathophysiology of chronic low back pain (CLBP) secondary to lumbar disc herniation (LDH) remains poorly understood, particularly the link between macroscale brain network dysfunction and its microscale biological underpinnings. This study aimed to bridge this critical gap by integrating resting-state fMRI, graph theory, and imaging transcriptomics. Methods Resting-state fMRI data were acquired from 62 CLBP patients with LDH and 67 matched healthy controls (HCs). Whole-brain functional networks were constructed for each participant by calculating functional connectivity (FC) between 90 anatomical regions. Graph theoretical analysis was employed to derive global and nodal topological metrics. Group differences were identified and correlated with clinical variables. Crucially, these neuroimaging phenotypes were spatially mapped against the Allen Human Brain Atlas (AHBA) to uncover potential spatial molecular vulnerabilities. Results At the connectional level, CLBP patients with LDH exhibited widespread hypoconnectivity across sensorimotor, ventral attention, and default mode networks. Further topological analysis revealed a profound focal degradation of hub function in the cingulate cortex, characterized by significantly reduced nodal degree, efficiency, and betweenness centrality ( p < 0.001), alongside decreased nodal efficiency in the right supplementary motor area, while global network architecture was preserved. Critically, these deficits in cingulate hub topology were significantly correlated with pain intensity. Imaging transcriptomics linked this focal topological failure to genes enriched for neuroinflammatory and synaptic plasticity pathways. Conclusion These findings reveal multi-level functional network alterations in CLBP with LDH, linking focal hub failure to potential spatial molecular vulnerabilities associated with neuroinflammation and synaptic remodeling.