Sodium MRI has been applied to multiple sclerosis (MS) with a focus on sodium concentration measurement, as Na+ ions are involved in axonal injury and demyelination^1-4. However, the relaxation mechanism of ²³Na, i.e. the alignment of the nuclear electric quadrupole moment in an environment-driven electric field gradient, could also provide novel micro-structural information. Rapid biexponential T₂ relaxation with a fast component (T_2f) on the order of 1-3 ms is produced in dense and ordered macromolecular environments like myelin. In this study we compare the MS lesion contrast of two different relaxation-weighted ²³Na sequences with that of a ²³Na density-weighted sequence. We also present the novel relative combination of these relaxation-weighted images to eliminate sodium concentration dependence and highlight the effects of ²³Na relaxation change alone in MS lesions. Whole brain images were acquired from 10 MS volunteers (48±13 yr; 8F/2M; 5-RRMS/5-PPMS) on a Varian Inova 4.7T MRI. Using a single-tuned birdcage head coil, three ²³Na sequences were acquired from each volunteer: (i) a density-weighted sequence – NaDW⁵ (TR/TE = 85/0.11 ms, flip-angle = 30°, twisted projections TwP = 6000, NEX = 1, 3.2×3.2×6.4 mm³, time = 8.5 minutes); (ii) a ~T_2f/T₁ sequence – NaPACMAN⁶ (TR/TE = 25/2.5 ms, flip-angle = 110°, TwP = 6000, NEX = 3, 3.2×3.2×6.4 mm³, time = 7.5 minutes); and (iii) a fluid-suppressed sequence with ~1/(T_2f*T₁) contrast – NaSIRFLA⁷ (TR/TI/TE = 150/37/0.22 ms, rectangular inversion pulse = 5 ms, flip-angle = 64^o, TwP = 3000, NEX = 1, 4.5×4.5×9.0 mm³, time = 7.5 minutes). Standard FLAIR images (1x1x4 mm³) were acquired as part of a subsequent ¹H imaging session (following a 10 minute break). A total of 72 lesions were drawn on the FLAIR images, and these ROIs transferred to the coregistered (SPM) sodium images. The average ²³Na signal was measured in each lesion and in a comparable normal appearing (on FLAIR) ROI. A paired t-test was used to test for statistical difference in lesion contrast between sequence types. Linear regression of ²³Na signal with lesion volume was also performed. Novel image contrast was created by dividing NaSIRFLA with NaPACMAN to yield approximately inverse T_2f dependent contrast without contribution from ²³Na concentration. Compared to non-lesion brain, the average MS lesion signal was increased by 13% for NaDW and 27% for NaPACMAN, but decreased by 6% for NaSIRFLA (example images from one patient in Figure 1). Although there is considerable scatter between lesions, most follow a similar contrast pattern between sequences (Figure 2). The mean contrast difference between NaDW and NaPACMAN is 14% ± 4% (confidence interval), and between NaDW and NaSIRFLA it is -19% ± 4%. Much of the intra-sequence ²³Na signal variability can be attributed to lesion volume with larger lesions showing more sodium signal (Figure 3). Large intensity reduction is exhibited in the lesion of the NaSIRFLA/NaPACMAN map with expected inverse T_2f-weighting (Figure 4). We show that different types of sodium sequences (i.e. NaDW, NaPACMAN, and NaSIRFLA) produce significantly different MS lesion contrast, and for larger lesions the contrast difference between sequences becomes more pronounced. A probable source of contrast correlation with lesion volume is smearing from rapid signal decay; higher resolution imaging may be required to offset this effect. Alternatively, or in addition, lesion pathology may correlate with lesion volume. The sodium concentration (NaDW) increase in lesions likely reflects an increased extracellular fluid volume fraction. This could result from the loss of macromolecules (e.g. myelin) in the extracellular space, and more severely from cell atrophy or death. Altered cellular Na+ metabolism may also contribute to the NaDW lesion contrast. T_2f increase is to be expected with the loss of macromolecular density and structure⁶. While T_2f increase enhances the contrast of NaPACMAN, this increase (along with an expected T₁ increase) is sufficient to drive the inversion recovery of NaSIRFLA sufficiently close to the null point so as to overcome the sodium concentration increase. Alternative ²³Na sequences and their relative combination (e.g. NaSIRFLA / NaPACMAN - which eliminates sodium concentration dependence) may provide a useful starting point to assess ²³Na relaxation change with pathology.