Anterior insular co-activation patterns associated with stress markers in chronic primary pain

Chronic primary pain occurs without an identifiable causal disease and is marked by persistent pain, emotional distress and functional disability. The anterior insular cortex, involved in salience processing and integration of sensory, emotional and cognitive aspects of pain, has been implicated in neural processes linking pain and stress responses. This study investigates whether specific brain state dynamics, using the anterior insula as a seed region, are associated with chronic primary pain and examines their associations with pain- and stress-related measures. Resting-state functional MRI, stress biomarkers (cortisol and alpha-amylase), a pain sensitivity test, as well as subjective measures of stress and pain were collected from patients with chronic primary pain (N = 30) and healthy controls (N = 30). Co-activation pattern analysis was used to identify brain states with the anterior insula as the seed region and to assess group differences in the temporal characteristics of these brain states. Partial least squares analysis was applied to investigate multivariate associations between specific temporal brain state characteristics and pain- and stress-related measures. Three anterior insula-seeded co-activation patterns (brain states) were identified in healthy controls. In the first co-activation pattern, the anterior insula co-activated with the default mode network; in the second, with the salience-somatomotor network; and in the third, with the visual network. Chronic primary pain patients and healthy controls differed significantly in temporal brain state characteristics, namely in the relative number of entries into co-activation pattern one (p _FDR = 0.002) and two (p _FDR = 0.022), and the relative occurrence of co-activation patterns one (p _FDR = 0.022) and two (p _FDR = 0.022). Furthermore, in chronic primary pain patients, perceived stress scores and cortisol were significantly associated with these specific temporal brain state characteristics (P = 0.002), whereas no associations were found with pain-related measures. Together, these findings suggest that in chronic primary pain, reduced coupling of the anterior insula with the default mode network and increased coupling of the anterior insula with salience-related networks are associated with psychophysiological stress markers. These brain state dynamics may potentially represent a neural correlate of altered stress processing in chronic primary pain.