Effect of Whole-Brain and Regional Silent Cerebral Ischemia on Pain and Cognition Among Adults with Sickle Cell Disease
Authors: Sop Daniel M , Zhang Yue May , Smith Wally R 
Published: December 2024

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, but is also well-known to alter pain sensitivity by adulthood in as yet unpredictable ways. We and others have previously shown that the degree of silent cerebral ischemia (measured by proxy using cerebral blood flow, or CBF), is governed by hemoglobin (Hb), heart rate, and oxygen supply, and is associated with the intensity of cognitive deficits among SCD adults. Whether and how pain sensitivity and pain expression are also prone to the effects of silent cerebral ischemia in adults with SCD, and how these effects compare to cognition, remains underexplored. We therefore investigated correlations between hemoglobin level, CBF including Regional Grey Matter Perfusion, pain expression, pain sensitivity (not using quantitative sensory testing), and fluid cognition in adults with SCD.
Methods
The study involved 9 SCD adults. Two patients were excluded from analysis due to explicit rather than silent brain damage (N=7). 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. We investigated bivariate correlations between these parameters using Pearson Correlation.
Results
Results showed that lower hemoglobin levels were strongly correlated with decreased pain sensitivity as follows PSQ_Total (R = 0.83, p = 0.02), PSQ_Minor (R = 0.87, p = 0.01), and PSQ_Moderate (R = 0.79, p = 0.03). Similarly, more cerebral ischemia (higher CBF) was moderately correlated with decreased pain sensitivity, with notable correlations in regions such as the Middle Frontal Gyrus (R = 0.76, p = 0.0484) and the Inferior Frontal Gyrus, pars triangularis (R = 0.77, p = 0.0421). No significant correlations were found between PSQ scores and fluid cognition
Regional grey matter perfusion significantly negatively correlated with cognitive flexibility in regions such as the Frontal Medial Cortex (R = -0.85, p = 0.0151), Cingulate Gyrus, anterior division (R = -0.82, p = 0.0255), Frontal Operculum Cortex (R = -0.78, p = 0.0403), and Cingulate Gyrus, posterior division (R = -0.76, p = 0.0459). Perfusion of the Middle Frontal Gyrus (R = -0.9, p = 0.0056) and the Temporal Fusiform Cortex, posterior division (R = -0.76, p = 0.0451) significantly negatively correlated with processing speed. We also found correlations between processing speed and flow in the Middle Frontal Gyrus (R = 0.76, p = 0.0484) and the Inferior Frontal Gyrus, pars triangularis (R = 0.77, p = 0.0421).
Regional grey matter perfusion in the Superior Temporal Gyrus, posterior division (R = -0.84, p = 0.0187) and the Supramarginal Gyrus, posterior division (R = -0.83, p = 0.0221) was significantly negatively correlated with PSQ scores. However, no significant correlations were found between either hemoglobin level, pain expression via PainDETECT, or BPI, versus regional grey matter perfusion
Conclusion
Paradoxically, both worse anemia and worse cerebral ischemia in SCD are associated with decreased, not increased pain sensitivity, while cerebral ischemic effects on pain expression were not noticeable in this small sample of only SCD patients. And both changes in pain sensitivity and cognitive impairments in SCD appear to be influenced by grey matter blood flow in distinct regions. Understanding these intricate regional relationships may inform the development of targeted therapies aimed at altering pain sensitivity and improving fluid cognition in SCD patients. Further research with larger sample sizes is necessary to confirm our results and amplify potential underlying mechanisms and influences.