Quantitative susceptibility mapping of the fear circuit: Associations with silent symptoms in relapsing-remitting multiple sclerosis

<b>Background:</b> Multiple sclerosis (MS) is a long-term autoimmune inflammatory disorder that affects the central nervous system leading to neurodegeneration, and can involve a variety of symptoms. These symptoms can include fatigue, anxiety, depression, and cognitive decline, which may be silent. The objective of this study was to explore changes in brain iron deposition in people with relapsing-remitting MS (pw-RRMS) compared to healthy controls (HCs), with a particular focus on regions of fear circuit. Additionally, the study aimed to evaluate relationship between iron deposition in these areas and clinical measurements. <b>Methods:</b> Pw-RRMS and HCs participants underwent brain MRI scans using quantitative susceptibility mapping (QSM) to assess iron deposition in the fear circuit between the two groups. The study analyzed correlations between brain susceptibility changes and clinical measurements. <b>Results:</b> We recruited 35 pw-RRMS (mean age = 46.7 ± 11 years; median EDSS = 2.5) and 18 HCs (mean age = 40.6 ± 17.8 years). Our research revealed significant increases in QSM signals relating to iron deposition in pw-RRMS compared to HCs, whole fear circuit (β = 5.82, <i>p</i> < 0.001), caudate (β = 21.48, <i>p</i> < 0.001), and putamen (β = 17.53, <i>p</i> = 0.03), showing the greatest difference. The whole fear circuit and particularly the caudate are strongly associated with fatigue in pw-RRMS. QSM values in the anterior cingulate cortex significantly differed between pw-RRMS with normal and abnormal depression scores (<i>p</i> = 0.007). <b>Conclusions:</b> These results strengthen the relationship between increased iron deposition in fear circuit regions and specific silent symptoms in pw-RRMS. However, further studies are required to confirm these findings and clarify the implications of iron accumulation in MS pathophysiology.