Resting-state functional heterogeneity of the right insula contributes to pain sensitivity

Abstract

Previous studies have described the structure and function of the insular cortex in terms of spatially continuous gradients. Here we assess how spatial features of insular resting state functional organization correspond to individual pain sensitivity. From a previous multicenter study, we included 107 healthy participants, who underwent resting state functional MRI scans, T1-weighted scans and quantitative sensory testing on the left forearm. Thermal and mechanical pain thresholds were determined. Connectopic mapping, a technique using non-linear representations of functional organization was employed to describe functional connectivity gradients in both insulae. Partial coefficients of determination were calculated between trend surface model parameters summarizing spatial features of gradients, modal and modality-independent pain sensitivity. The dominant connectopy captured the previously reported posteroanterior shift in connectivity profiles. Spatial features of dominant connectopies in the right insula explained significant amounts of variance in thermal (R2 = 0.076; p < 0.001 and R2 = 0.031; p < 0.029) and composite pain sensitivity (R2 = 0.072; p < 0.002). The left insular gradient was not significantly associated with pain thresholds. Our results highlight the functional relevance of gradient-like insular organization in pain processing. Considering individual variations in insular connectopy might contribute to understanding neural mechanisms behind pain and improve objective brain-based characterization of individual pain sensitivity.

Pain-related learning signals in the human insula

“…In fact, recent meta-analytic evidence of resting-state functional connectivity points to the existence of a pain-related network centered on the anterior insula [40]. The activation associated with both pain-related (posterior insula) activation, and that associated with PE-related (anterior insula) activation correspond well with connectivity gradients observed along the posterior-anterior axis [41][42][43].…”

Supraspinal Mechanisms Underlying Ocular Pain

“…However, recent investigation has suggested the region may be better appreciated as a gradually changing topographical gradient of functional and anatomical connections along the rostrocaudal axis. While discrete subunits are described throughout this manuscript, selecting small/discrete subregions of interest for analysis may provide significant results that may not reflect the totality of activations or connectivity in a given brain region ( 162 , 163 ).…”

“…Anterior insula (AI) is involved in processing emotion, including empathy, and activation of this subregion is found in affective processing ( 161 , 164 ). AI has strong functional and anatomical connections with the thalamus and cognitive and emotional parts of the prefrontal cortex as well as the amygdala and some cingulate regions, particularly the ACC, and can have increased or decreased functional associations with these areas in chronic pain ( 163 , 164 ). The strongest connections to the prefrontal cortex are to the dorsolateral prefrontal cortex, as well as areas associated with cognitive-evaluative processing and outcome anticipation (orbitofrontal cortex) and with the regulation of emotions and cognitive pain modulation (ventrolateral prefrontal cortex) ( 163 , 164 ).…”

“…AI has strong functional and anatomical connections with the thalamus and cognitive and emotional parts of the prefrontal cortex as well as the amygdala and some cingulate regions, particularly the ACC, and can have increased or decreased functional associations with these areas in chronic pain ( 163 , 164 ). The strongest connections to the prefrontal cortex are to the dorsolateral prefrontal cortex, as well as areas associated with cognitive-evaluative processing and outcome anticipation (orbitofrontal cortex) and with the regulation of emotions and cognitive pain modulation (ventrolateral prefrontal cortex) ( 163 , 164 ). Expectation and behavioral avoidance of a negative outcome activate AI, and the region is thought to impose emotional states that are informed by the evaluation of affective events ( 161 , 164 ).…”

“…Posterior insular (PI) regions are thought to process interoceptive, somatosensory, visceral, and pain stimuli ( 7 , 161 , 164 , 165 ). PI has its strongest connections to SII (structural and resting state analyses) and SI (structural) along with other somatosensory areas, and has some resting state association with the pMCC as well ( 163 , 164 ). Activations in PI are found as stimuli progress from innocuous to painful in intensity with little activation in the absence of noxious input.…”