Alterations in Functional Connectivity Density in Patients With Phantom Limb Pain

Phantom limb pain (PLP) is prevalent and challenging to treat in amputees, which likely stems from maladaptive cortical reorganization, but the precise mechanisms remain unclear. This study aimed to comprehensively investigate the cortical remodeling patterns in amputees experiencing PLP, pinpointing key brain regions and neural circuits directly associated with the pain. Eighteen PLP patients and 20 healthy participants were recruited for resting-state functional magnetic resonance imaging (rs-fMRI). The functional connectivity density (FCD) mapping method was used to identify PLP-related abnormal local and global signaling hubs. FCD changes were observed within the sensorimotor, pain-processing, and visual stream networks in PLP patients, with the precentral gyrus (PreCG), insula (INS), precuneus (PCUN), and middle occipital gyrus (MOG) identified as key hubs correlated with the visual analog scale (VAS) pain ratings. A voxel-wise functional connectivity (FC) analysis was further performed between the VAS-correlated FCD hubs and the rest of the brain. FC was significantly decreased between the hubs and widespread brain regions. In contrast, increased FC was revealed between the hubs and subregions of the dorsolateral prefrontal cortex (DLPFC) (the dorsolateral superior frontal gyrus [SFGdor] and middle frontal gyrus [MFG]). FC of the SFGdor-INS and MFG-PCUN pathways was negatively correlated with VAS pain ratings specifically, likely playing crucial roles in PLP. These results provide novel insights into the critical neural mechanisms of PLP, highlighting valuable targets for developing long-term effective neuromodulation modalities.