Impaired insula functional connectivity associated with persistent pain perception in patients with complex regional pain syndrome

<div><p>Given that the insula plays a contributory role in the perception of chronic pain, we examined the resting-state functional connectivity between the insular cortex and other brain regions to investigate neural underpinnings of persisting perception of background pain in patients with complex regional pain syndrome (CRPS). A total of 25 patients with CRPS and 25 matched healthy controls underwent functional magnetic resonance imaging at rest. With the anterior and posterior insular cortices as seed regions, we compared the strength of the resting-state functional connectivity between the two groups. Functional connectivity between the anterior and posterior insular cortices and the postcentral and inferior frontal gyri, cingulate cortices was reduced in patients with CRPS compared with controls. Additionally, greater reductions in functional connectivity between the anterior insula and right postcentral gyrus were associated with more severe sensory pain in patients with CRPS (short-form McGill Pain Questionnaire sensory subscores, <i>r</i> = -.517, <i>P</i> = .023). The present results imply a possible role of the insula in aberrant processing of pain information in patients with CRPS. The findings suggest that a functional derangement of the connection between one of the somatosensory cortical functions of perception and one of the insular functions of awareness can play a significant role in the persistent experience of regional pain that is not confined to a specific nerve territory.</p></div

Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

<p>Cyclin-dependent kinase (Cdk) in complex with a corresponding cyclin plays a pivotal role in neurogenic differentiation. In particular, Cdk4 activity acts as a signaling switch to direct human mesenchymal stem cells (MSCs) to neural transdifferentiation. However, the molecular evidence of how Cdk4 activity converts MSCs to neurogenic lineage remains unknown. Here, we found that Cdk4 inhibition in human MSCs enriches the populations of neural stem and progenitor pools rather than differentiated glial and neuronal cell pools. Interestingly, Cdk4 inhibition directly inactivates Smads and subsequently STAT3 signaling by hypophosphorylation, and both Cdk4 and Smads levels are linked during the processes of neural transdifferentiation and differentiation. In summary, our results provide novel molecular evidence in which Cdk4 inhibition leads to directing human MSCs to a multipotent neurogenic fate by inactivating Smads-STAT3 signaling.</p

Resting state functional connectivity networks of the anterior insula.

<p>(A) Functional connectivity patterns in healthy controls and (B) patients with CRPS (FDR < 0.01, within-group analysis). (C) Brain areas showing a significant reduction in anterior insula functional connectivity in patients with CRPS relative to healthy controls (<i>P</i> < 0.005 for permutation test, between-group analysis).</p

Brain regions showing decreased functional connectivity with the anterior and posterior insular cortices in patients with CRPS relative to healthy control subjects.

<p>Brain regions showing decreased functional connectivity with the anterior and posterior insular cortices in patients with CRPS relative to healthy control subjects.</p

Scatter plots showing the correlations of functional connectivity in the anterior insula and right postcentral gyrus with (A) pain severity and (B) illness duration.

<p>Abbreviations: MPQ, McGill Pain Questionnaire.</p

Demographic and clinical characteristics of the study participants.

<p>Demographic and clinical characteristics of the study participants.</p

Resting-state functional connectivity networks of the posterior insula.

<p>(A) Functional connectivity patterns in healthy controls and (B) patients with CRPS (FDR < 0.01, within-group analysis). (C) Brain areas showing a significant reduction in posterior insula functional connectivity in patients with CRPS relative to healthy controls (<i>P</i> < 0.005 for permutation test, between-group analysis).</p