Cottam WJ, et al. - Given the importance of the “salience network” (SN) in orienting attention and the primacy of the right anterior insula (rAI), researchers hypothesized that chronic pain is characterized by altered rAI functional connectivity (FC) that causally alters depending network function [eg, the default mode network (DMN)]. They tested this hypothesis using seed-to-brain connectivity analysis to determine resting-state networks in subjects with chronic knee osteoarthritis (OA) pain compared with controls. Compared to controls, participants with painful knee OA showed increased anticorrelation between the rAI (SN) and DMN regions in addition to the more negative FC of left dorsal prefrontal cortex (central executive network hub) with the right temporal gyrus. As per Granger causality analysis, increased negative influence of the rAI on the posterior cingulate (DMN) was noted in patients with OA in line with the observed enhanced anticorrelation. Furthermore, dynamic FC was noted to be lower in the DMN of patients and thus more similar to temporal dynamics of the SN. Findings thereby suggest a widespread network disruption in patients with persistent OA pain and point toward a driving role of the rAI.