Percentage of patients with brain tissue experiencing increased metabolic stress decreases with HU. These population heat maps illustrate the percentage of participants within each white matter voxel that has an OEF exceeding the defined threshold overlaid on a T1 atlas (OEF threshold of 40%, left column; 42.5%, middle column; 45%, right column). The highest prevalence of elevated OEF consistently falls within the internal border zone in all 3 cohorts. The percentage of participants exceeding these thresholds is decreased in participants treated with HU compared with those not receiving disease-modifying therapy, but not to the extent of the participants receiving CTT.