ASH 2025 | The impact of SCD on brain function and how this affects pain perception

If I can take you back a little bit, sickle cell disease is a condition that impacts blood. In the blood, you have hemoglobin, which is the molecule that carries oxygen to the brain and to the rest of the body. In sickle cell disease, hemoglobin is impaired, and instead of having normal hemoglobin that is shaped like a balloon, round, patients with sickle cell disease have a sickle-shaped hemoglobin. That sickle shape makes it hard for the hemoglobin to carry oxygen, and for the brain itself, the brain demands a large amount of oxygen at rest and during activities. In order for the brain to meet that demand, it has to increase the blood flow to the brain to meet what is called the cerebral metabolic rate of oxygen, how much oxygen we need at rest in order to function normally. That increase is what we see happen in patients that have sickle cell disease. And even with that increase, you would think that a patient gets enough oxygen to the brain. They do not. Because at rest, they do not even have enough healthy hemoglobin in their cells so that they can’t carry as much oxygen as is needed. The increasing cerebral blood flow to the brain, the reduced amount of oxygen leads to impairment in the patient’s brain and we can see that in both the cerebral blood flow that the patients that have sickle cell disease have and also in the effective connectivities in the brain. And what that is, is how much our brain fluctuates, the neurons in our brain, how much they fluctuate at rest and during activity. Low oxygen delivery to the brain, low signal strength in the brain, low response for the patients that have sickle cell disease. And for them, it gets even worse. Not only are they not able to activate all of the neurons at the same intensity as the patients that do not have sickle cell disease, but eventually, because of the damage in their brain, a lot of these neurons get overactivated and hyperactivated because of the cascading effect of the damage, and their brain becomes hyperactive. So when you think about pain, at rest we’re able to regulate our oxygen delivery, our emotions, and our aptitudes and our performance, but the damage in their brain makes it difficult for them to regulate that, and all those hyperactive neurons lead to a state of almost constant fight and flight, and it just leads to them being hypersensitive to pain and makes it hard for them to regulate their pain.

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