(103) - Patients with sickle cell disease exhibit increased functional connectivity and centrality of the locus coeruleus compared to anemic controls

Abstract

Vaso-occlusive pain crises are the “hallmark” of sickle cell disease (SCD). SCD patients have a high incidence of chronic pain thought to develop via central sensitization. Research in rodents has shown that locus coeruleus (LC) function in pain regulation shifts from a pain inhibitory to a facilitative effect after exposure to continuous nociceptive input via increased activity of noradrenergic LC-prefrontal cortex (PFC) circuitry. We compared the role of the LC in anemic patients (AC) with and without SCD using fMRI assessing resting-state (RS) activity of the LC. We hypothesized SCD patients would exhibit increased functional connectivity (FC) from the LC and increased functional network (FN) centrality. Eighteen SCD patients (mean age = 21.2 ± 2.3) and 12 ACs (mean age = 24.2 ± 7.4) underwent a standardized imaging procedure: a high-resolution T1 structural scan and 8-min resting state (RS) functional scan on a 3T Philips Achieva. All scans were segmented into 167 brain regions (ROIs) using the Destrieux Atlas including two 2 mm seeds at the bilateral LC. FNs were created representing correlation coefficients of time-course BOLD signal between each ROI. A seed-to-voxel (STV) whole-brain RS-FC analysis was conducted with the initial cluster-forming threshold set at P < .001 and significance level set at p(FWE) < .05. A graph-theory FN analysis using in-house MATLAB code and Graph-Theory Toolbox investigated differences in centrality of the LC. Significance level was set at p(FDR) < .05. STV analyses revealed SCD patients had increased FC from the LC to dorsolateral prefrontal cortex (dlPFC) (p(FWE) < .03). FN analyses revealed SCD patients had increased betweenness centrality in the LC (p(FDR) < .005). These findings support increased connectivity of the LC-PFC circuit, and increased information flow from the LC to other brain regions in SCD patients. These findings provide support for investigating cellular mechanisms, including noradrenaline and GABA activity underlying this link and mind-body therapies to reduce chronic pain by decreasing connectivity within this pathway.