Chronic pain and stress: Transdiagnostic meta-analytic evidence of convergent network signature with PTSD

Chronic pain is increasingly conceptualized within a stress-related framework. However, it remains unclear whether chronic pain and prototypical stress-related conditions-such as post-traumatic stress disorder (PTSD)-show convergence in their morphometric alterations and underlying normative functional connectivity profiles. To this end, we conducted a pre-registered transdiagnostic meta-analytic study of gray matter volume alterations in chronic pain (60 studies) and PTSD (20 studies), testing convergence at two complementary levels: direct anatomical overlap and network-level convergence within normative resting-state functional systems. Disorder-specific meta-analyses revealed that chronic pain was associated with distributed volume reductions across ventromedial prefrontal, middle cingulate, and insular cortices, whereas PTSD exhibited a single cluster of reduced volume in the anterior cingulate/dorsomedial prefrontal cortices. A direct conjunction analysis identified a spatially focal overlapping cluster of reduced volume in the bilateral medial orbitofrontal/anterior cingulate area. Importantly, using normative resting-state fMRI data (HCP 7 T dataset), we found that the disorder-specific structural abnormalities were embedded within partially overlapping large-scale systems. Specifically, chronic pain abnormalities were embedded within a distributed architecture of large-scale circuits encompassing mesocorticolimbic/reward, default mode, salience, frontoparietal, dorsal attention, and somatosensory networks. On the other hand, the PTSD focal neuroanatomical alteration was embedded in a single large-scale circuit mapping onto the mesocorticolimbic/reward, default mode, salience, and visual networks. In both conditions, the mesocorticolimbic/reward circuit emerged as the most robustly involved large-scale network. Notably, the shared cluster of reduced volume showed functional integration within the mesocorticolimbic/reward and default mode networks, with neurochemical fingerprinting revealing robust spatial correspondence with dopaminergic, serotonergic, opioid, and endocannabinoid receptor/transporter maps. Overall, these findings indicate that brain morphological alterations in chronic pain and PTSD converge in a focal medial prefrontal/anterior cingulate region and that disorder-specific abnormalities map onto partially overlapping normative functional networks, particularly involving the mesocorticolimbic/reward-related system, the default mode network, and the salience network. This network-level convergence is consistent with the hypothesis that chronic pain may, at least in part, be conceptualized within a stress-related framework.