The effect of iron deposition on cognitive fatigue in multiple sclerosis

Cognitive fatigue (CF) is a prevalent and disabling symptom in multiple sclerosis (MS), but its neural underpinnings remain poorly understood. Emerging evidence suggests that iron accumulation in deep gray matter, particularly the basal ganglia, may contribute to CF by disrupting neural activity. This study examined the relationship between brain iron deposition and CF in individuals with MS using functional MRI (fMRI) and quantitative susceptibility mapping (QSM). Seventy participants with relapsing-remitting MS (RRMS) and 30 matched healthy controls underwent a task-switching paradigm during fMRI, alternating between color and speed judgments to induce CF. Iron concentration in the caudate, putamen, and globus pallidus was measured using multi-echo gradient echo (ME-GRE) sequences. CF was evaluated with a visual analog scale (VAS-F), and behavioral performance was assessed by response time and accuracy. MS participants showed significantly greater CF over time, with increasing VAS-F scores and slower, less accurate responses compared to controls. Higher iron levels in the left caudate correlated with steeper CF slopes and reduced activation in fatigue-related regions, including the dorsolateral and ventromedial prefrontal cortex and anterior cingulate cortex. A significant Group × Iron × CF interaction indicated opposite patterns of activation: while MS patients showed decreased activation with higher iron, controls exhibited increased activation, suggesting a compensatory response. These findings suggest that abnormal iron accumulation contributes to CF in MS and may impair functional compensation. Iron-sensitive MRI may offer a promising biomarker to identify individuals at risk for debilitating fatigue and guide interventions targeting iron metabolism.