Abstract
Resting-state functional connectivity (FC) has proven a powerful approach to understand the neural underpinnings of chronic pain, reporting altered connectivity in 3 main networks: the default mode network (DMN), central executive network, and the salience network (SN). The interrelation and possible mechanisms of these changes are less well understood in chronic pain. Based on emerging evidence of its role to drive switches between network states, the right anterior insula (rAI, an SN hub) may play a dominant role in network connectivity changes underpinning chronic pain. To test this hypothesis, we used seed-based resting-state FC analysis including dynamic and effective connectivity metrics in 25 people with chronic osteoarthritis (OA) pain and 19 matched healthy volunteers. Compared with controls, participants with painful knee OA presented with increased anticorrelation between the rAI (SN) and DMN regions. Also, the left dorsal prefrontal cortex (central executive network hub) showed more negative FC with the right temporal gyrus. Granger causality analysis revealed increased negative influence of the rAI on the posterior cingulate (DMN) in patients with OA in line with the observed enhanced anticorrelation. Moreover, dynamic FC was lower in the DMN of patients and thus more similar to temporal dynamics of the SN. Together, these findings evidence a widespread network disruption in patients with persistent OA pain and point toward a driving role of the rAI.
Highlights
Attention to the external world is driven by the salience of perceived stimuli, which is relevant for threat and pain stimuli
Group comparison revealed a cluster of increased right anterior insula (rAI) functional connectivity (FC) within the cuneus in patients (FWE P, 0.05, Fig. 1A and Table 2) and several clusters of decreased rAI FC in patients compared with controls in areas associated with the default mode network (DMN) including the posterior cingulate cortex (PCC), bilateral parietal areas, and the superior frontal gyrus (FWE P, 0.05, Fig. 1A and Table 2)
Estimates of effective connectivity derived from Granger causality analysis between these network hubs revealed a significant difference between patient and control groups for the influence rAI exerts (-.) on the PCC
Summary
Attention to the external world is driven by the salience of perceived stimuli, which is relevant for threat and pain stimuli. There is a mutual link between, and interdependence of, perception and attention to pain known from everyday life experience and demonstrated at the neural level.[59] A brain network implicated in this process is the “salience network” (SN).[50] The core SN is formed by the bilateral anterior insula and the anterior middle cingulate cortex supporting the integration of external information, previous experience, and concurrent homeostatic state, to orient attention.[39] the SN is Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. The SN is Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, United Kingdom, b NIHR Nottingham Biomedical Research Centre, Queen’s Medical Centre, University of Nottingham, Nottingham, United Kingdom, c Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
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