Distinct transcriptional signatures of large-scale functional gradient organization in acute and chronic low...

Low back-related leg pain (LBLP)-a severe subtype marked by radicular symptoms and high chronicity rates-implicates central nervous system reorganization, yet the large-scale functional gradient organization principles governing brain-wide functional shifts during chronicization remain unknown. Here, we used "Functional Gradient-Transcriptomics" analysis to characterize hierarchical brain reorganization and the underlying molecular landscape in patients with acute (n = 40) and chronic (n = 103) LBLP compared to healthy controls (n = 109). Acute LBLP showed elevated gradient values within the sensorimotor network, and genes associated with these gradient alterations were significantly enriched for processes related to dysregulated energy metabolism. In contrast, chronic LBLP exhibited enhanced activity of the limbic network and diminished attention networks, corresponding genes were significantly enriched for synaptic plasticity, neurotransmitter imbalance, neuronal hyperexcitability, and transcriptional reprogramming. Regional gradient features exhibited trending associations with clinical measures and effectively discriminated patient groups. This "Functional Gradient-Transcriptomics" framework provides a novel, multiscale perspective on LBLP pathophysiology, advancing theoretical insights and informing future therapeutic strategies.