Fatigue, defined as an overwhelming feeling of lack of both mental and physical energy, has been reported in over 90% of individuals with multiple sclerosis (MS) ¹. Studies have shown basal ganglia structures play a central role in fatigue ². Meanwhile, abnormal iron deposition has been observed in the deep gray matter structures including basal ganglia in MS ³. In this study, we aimed to examine the correlation between brain iron concentration indicated by susceptibility contrast imaging and the severity of fatigue in MS.Six clinically definite MS patients (F/M = 6/0, age = 40.7±9.7 y/o) participated in this study. MRI: A 3D multi-echo gradient-echo acquisition was performed on a 3T Siemens Skyra scanner with a standard 20-ch head/neck coil. The parameters were as follows: TE = 8.49/16.86/25.23/33.60/41.97 ms, TR = 49 ms, resolution = 0.9×0.9×2 mm², flip angle= 20°, bandwidth= ±38.4 kHz. A total of 52 axial slices were acquired to cover the whole brain. A GRAPPA of 2 was used to shorten the scan time down to 5 minutes. Quantitative R₂^* maps were derived from exponential fitting over the 5 echo data. The Laplacian algorithm was used to unwrap the raw phase and remove the phase background. The susceptibility maps were then calculated using the LSQR algorithm based on the unwrapped phase maps and averaged over three echo data (25.23, 33.60 and 41.97 ms) ⁴. Six regions of interest (ROIs) including substantia nigra (SN), red nucleus (RN), globus pallidus (GP), putamen (PU), caudate nucleus (CN), and thalamus (TH) were manually drawn on the magnitude images. A registered MP-RAGE image was used as an additional reference for the ROI drawing. Each ROI was drawn on multiple successive images to almost entirely cover each structure. R2^*, and susceptibility values were averaged in each ROI, respectively, and then averaged across all the subjects in the group. Fatigue measures: Each individual were administrated a Fatigue Severity Scale (FSS) test and a Modified Fatigue Impact Scale (MFIS) test to measure their fatigue levels. The FSS scores and total MFIS scores with its subcategories (Physical, Cognitive, Psychosocial) subscales from each individual were correlated with R₂^*, Frequency and QSM values in all ROIs.Two representative axial slices of the MR images containing the ROIs from one MS patientare shown in Fig. 1. The SN, RN, GP, PU, and CN are readily identifiable in the magnitude, and R₂^*, frequency and QSM maps. Comparing to the magnitude and R₂^* maps, these iron-rich structures are clearly visible and distinguishable with clear boundaries in the QSM. Significant positive correlations between Frequency and FSS Total, MFIS Total, MFIS Physical subscale and MFIS Psychosocial subscale are found in CN. QSM also correlates with MFIS Total and MFIS Physical subscales significantly. Based on the data from six subjects, no significant consistent positive correlations in the other ROIs are found. No significant correlations between R₂^* and all fatigue measures are observed. Fig. 2 shows the correlation between MRI indices (Frequency, QSM) with fatigue measures (FSS Total, MFIS Total and its three subscales) in CN. Table 1 summarizes the Pearson correlation values and their significant levels in CN. Cognitive fatigue represents a failure of physical and mental tasks that require self-motivation and internal cures in the absence of demonstrable cognitive failure ore motor weakness. Based on a well-established model of cognitive fatigue by Chaudhuri and Behan ² and our previous research on this topic ⁵, the basal ganglia is of particular interest as its damage is often associated with clinical disorders including MS, where cognitive fatigue is one of the most common symptoms. Our results show a promising correlation between iron-related MRI indices with fatigue scores, indicating the severity of fatigue may correspond to iron accumulation in CN. This result is consistent with our previous findings that iron deposition is found to be higher in basal ganglia in MS patients comparing to healthy control individuals ³. A larger sample data is being acquiring to validate these results.Our findings on the correlation between iron deposition measured by MR susceptibility contrast imaging and severity of fatigue is of particular interesting to understanding the fatigue mechanisms, which may lead to developing an effective treatment on reducing clinical symptoms in MS patients.