Structural and Functional Alterations of the Dorsolateral Prefrontal Cortex Across Chronic Pain Cohorts

Background Chronic pain is associated with structural and functional brain alterations, particularly within prefrontal, insular, and cingulate cortices. The dorsolateral prefrontal cortex (DLPFC) shows consistent structural abnormalities across chronic pain conditions, whereas findings on intrinsic functional connectivity (FC) remains inconsistent. Anchoring FC analyses to structural alterations may help identify consistent patterns across chronic pain conditions. Methods We employed a voxel-based morphometry (VBM)-guided, seed-based resting-state FC approach. Structural and functional MRI data were obtained from patients with chronic neck pain (CNP; n=21) and healthy controls (HC; n=25). Regions showing significant gray matter volume (GMV) differences were used as seeds for whole-brain FC analysis. Associations with pain intensity and pain-related fear were examined. Findings were further evaluated in an independent cohort with chronic primary pain (CPP; n=38). Results VBM revealed reduced GMV in the left DLPFC in CNP compared with HC, replicated in CPP. Seed-based FC analysis demonstrated reduced connectivity between the left DLPFC and the right hippocampus in CNP, with a similar pattern in CPP. In CNP, GMV in the DLPFC was positively associated with DLPFC-hippocampal connectivity (r = 0.45, 95% CI 0.02 to 0.74, p = 0.043). Reduced DLPFC-hippocampal connectivity was associated with higher activity avoidance (r = -0.50, 95% CI -0.77 to -0.09, p = 0.021), whereas no associations were observed with pain intensity. Conclusions These findings indicate consistent structural and functional alterations across chronic pain cohorts. Reduced DLPFC-hippocampal connectivity may reflect altered interactions between prefrontal and hippocampal circuits involved in pain-related cognitive and affective processes.