Comparative Analysis of Whole-Brain and Regional Cerebral Blood Flow, Pain Expression, Pain Sensitivity, and Cognitive Function in Adults with Sickle Cell Disease Versus Healthy Controls

Background Sickle Cell Disease (SCD) is well-known to cause anemia, acute and chronic pain, organ dysfunction including silent cerebral ischemia, and subtle cognitive impairment. Treatment and prevention for all of these is poor to non-existent. SCD is also well-known to alter pain sensitivity by adulthood. Historically, pain sensitivity has best been measured using quantitative sensory testing (QST). But a recent review demonstrates inconsistency of SCD QST standards and implementation, leaving room for less burdensome, more standardized SCD pain sensitivity measures. To attempt to relate all these findings, we explored differences in hemoglobin levels, whole brain and regional cerebral blood flow (CBF, expressions of silent cerebral ischemia), pain expression, pain sensitivity not using QST, and fluid cognition in adults with SCD versus healthy controls. Method Subjects comprised 9 SCD patients and 3 healthy controls (HC). Two SCD patients were excluded due to explicit brain damage rather than possible silent ischemia (n=10). Hemoglobin was measured using standard venipuncture to obtain the blood sample, and estimated from a Coulter Counter. Whole-brain cerebral blood flow was assessed using arterial spin-labeling, and regional flows were assessed using functional magnetic resonance imaging. Pain expression was assessed using the PainDETECT survey, which contains a version of the Brief Pain Inventory (BPI). Pain sensitivity was measured using the previously validated Pain Sensitivity Questionnaire (PSQ_Total, PSQ_Minor, PSQ_Moderate). Fluid cognition was evaluated using NIH Toolbox measures of processing speed, cognitive flexibility, and executive function. Group comparative analyses of SCD patients vs HCs employed t-tests. Results SCD patients had significantly lower hemoglobin levels (8.64 ± 2.33 g/dL) compared to healthy controls (13.33 ± 0.58 g/dL, p=0.001). CBF was significantly higher in SCD patients (72.15 ± 28.90 mL/100g/min vs 47.23 ± 12.30 mL/100g/min, p=0.04). Pain experience via PainDETECT was markedly greater in SCD patients (11.71 ± 5.19 vs 2.67 ± 0.58, p=0.003). The BPI in SCD patients was correspondingly markedly greater (15.29 ± 7.13 vs 2.3 ± 1.15, p=0.002). Pain sensitivity was elevated in SCD patients vs controls (PSQ total, 5.05 ± 1.63 vs 2.31 ± 0.50, p=0.004; similarly disparate scores for PSQ minor and PSQ moderate). Fluid cognition was lower in SCD patients (processing speed 96.14 ± 7.36 vs. 123 ± 11.25, p=0.02; executive function 79.71 ± 14.03 vs. 119.33 ± 28.04, p=0.12). SCD patients had higher perfusion values in the frontal pole, superior frontal gyrus, middle frontal gyrus, and several other regions, but not in the frontal operculum cortex, central opercular cortex, superior parietal lobule, or some subcortical structures. Conclusion Compared to healthy controls, SCD patients not only have cerebral ischemia manifested by the expected elevation of cerebral blood flow from their anemia, but also enhanced pain sensitivity and worse fluid cognition. In this study, for the first time to our knowledge, we have not only replicated these findings in simultaneous evaluations, but also demonstrated in SCD patients versus controls associated regional grey matter perfusion elevations (i.e., ischemia) in several brain regions that are associated with simultaneous cognition and sensory processing differences. These findings raise the hypotheses that regional brain ischemia may explain some SCD patients' chronic pain, and that cognitive decline and pain sensitivity may progress in parallel as SCD patients age. Limitations to our study include a small sample size. Larger studies should confirm these findings. Studies should also provide a more comprehensive understanding of the effect of regional cerebral ischemia of SCD on pain processing, and should test the effects of targeted interventions intended to affect pain sensitivity in SCD.