Background & Aims
Sickle Cell Disease (SCD) is a genetic disorder characterized by abnormal hemoglobin and is often associated with vaso-occlusive crises (VOCs), which are painful acute episodes caused by sickled red blood cells obstructing blood flow. The insula, pivotal in pain processing, has shown altered connectivity in SCD in our previous work. Recent pain research also suggests that explosive synchronization (ES), marked by abrupt and widespread synchronization of neuronal activity influencing the brain’s functional network dynamics, is prevalent in fibromyalgia patients with chronic pain, and in SCD individuals with increased VOCs. Yet, the relationship between ES and functional connectivity (FC) in any pain state has not been investigated. This exploration may inform how sudden neural activity changes can alter broader network behaviors. Here, we investigate the role of insular connectivity in SCD-related pain, exploring how the relationship between FC and ES may contribute to chronic pain.
Methods
We explored how FC between the insula and the entire brain relates to frequency disassortativity, a measure of ES indicating the likelihood of high-frequency nodes linking with low-frequency nodes in a network. The study cohort included 18 SCD patients and 16 healthy subjects, matched for age and sex. All participants underwent an EEG session and an fMRI scan during tonic pressure pain stimulation, applied via a computerized cuff on the left gastrocnemius muscle. The insula was selected as the primary seed region for our analysis, given its role in modulation of chronic pain. Seed-to-whole-brain connectivity maps were constructed, and a flexible factorial design was used to contrast the association of FC with ES across both groups. Additionally, Pearson correlations were computed between connectivity and clinical measures such as the frequency and recency of pain episodes in SCD, measured by the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-ME).
Results
The analysis revealed distinct group differences in the association of ES with FC between the insula and the right inferior frontal gyrus (IFG) in SCD patients compared to healthy controls. In SCD individuals, reduced FC between the left insula and right IFG (T=3.39, pFWE<0.001) and between the right insula and right IFG (T=3.39, pFWE=0.01) was linked to greater ES (more negative frequency disassortativity values), whereas the opposite was observed in healthy controls. Furthermore, greater frequency of sickle cell pain events in SCD patients, as measured by the ASCQ-ME, were associated with decreased FC between the IFG and both the left (r = -0.49, p = 0.047) and right (r = -0.53, p = 0.027) insula. Although not significant, similar trending relationships were detected with the frequency of VOCs in the preceding 12 months (r = -0.36, CI = [-0.71, 0.12]).
Conclusions
Our results highlight that reduced insulae-IFG FC is related to greater ES and more recurrent pain episodes in SCD. One theory of ES suggests that gradual increases in network synchronization seen in healthy controls may prevent ES due to more connected networks. Conversely, suppression of network synchronization due to impaired connectivity may lead to signal accumulation, reaching a critical threshold, followed by an abrupt burst or “explosion” such as ES. Our findings support this theory, suggesting that in SCD, reduced FC, particularly between the insula and IFG, may contribute to more frequent ES due to suppression of local synchronization. These results align with studies highlighting the right IFG’s role in cognitive control and emotional regulation of pain, suggesting that reduced connectivity may indicate the right IFG’s diminished capacity to regulate pain signals. Our findings could reveal new pain modulation pathways in SCD, potentially through treatments that reduce ES.
References
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Presenting Author
Apeksha Sridhar
Poster Authors
Apeksha Sridhar
MSc
University of California, Irvine
Lead Author
Pangyu Joo
PhD
University of Michigan
Lead Author
Eric Ichesco BS
University of Michigan Chronic Pain and Fatigue Research Center
Lead Author
Alexandre Dasilva
DDS
University of Michigan
Lead Author
UnCheol Lee
PhD
University of Michigan
Lead Author
Ying Wang
MD
Indiana University School of Medicine
Lead Author
Richard E. Harris
Lead Author
Topics
- Pain Imaging