Iron Deposition and Cognitive Fatigue in Multiple Sclerosis

Cognitive fatigue remains one of the most disabling and least understood symptoms of multiple sclerosis (MS). In a recent study, Yao and colleagues explore whether abnormal iron deposition in the deep gray matter of MS patients, specifically in the basal ganglia, contributes to cognitive fatigue by altering brain activation during sustained mental effort.

Here’s a brief overview of the trial and its findings.

A Look at the Study’s Design

This cross-sectional neuroimaging study enrolled 70 adults aged 30 to 65 years with relapsing-remitting multiple sclerosis (RRMS) and 30 age- and sex-matched healthy controls. To examine cognitive fatigue, participants completed a fatigue-inducing task-switching paradigm during functional MRI (fMRI), alternating between two types of judgments: a color task, which required identifying the color of a rotating stimulus, and a more cognitively demanding speed task, which required judging the speed of its rotation. The task was performed across seven consecutive fMRI runs to elicit sustained mental effort.

Cognitive fatigue was assessed using a visual analog scale (VAS-F) at baseline and after each run, enabling characterization of fatigue accumulation over time. Brain iron concentration was estimated using multi-echo gradient echo MRI–derived R2* measures, with quantitative susceptibility mapping (QSM) used as a complementary technique to characterize iron deposition.

Fatigue Builds Differently in MS

Behaviorally, both groups began the task with similar baseline fatigue. Over time, however, their trajectories diverged. Individuals with MS showed a significant increase in cognitive fatigue across task runs, while controls demonstrated a slight decline (p < 0.05).

Increasing cognitive fatigue was significantly associated with slower response times and reduced accuracy across all participants. However, the impact of cognitive fatigue was more pronounced in MS, with longer response times compared with healthy controls (888 ms vs 788 ms, respectively), while accuracy data remained comparable between groups.

Task-specific analyses showed that accuracy declined with increasing fatigue during the color task in both groups, whereas fatigue-related accuracy decline during the more demanding speed task was observed only in participants with MS.

Iron Links Fatigue to Brain Activation

Interesting findings emerged when iron levels were integrated with fatigue and brain activation. In MS, higher iron concentration in the left caudate nucleus was associated with steeper increases in cognitive fatigue over time (p < 0.05). Importantly, iron levels did not differ significantly between groups, suggesting that vulnerability, not absolute iron burden, distinguishes MS from healthy aging.

Neuroimaging revealed a three-way interaction between the groups, iron deposition, and fatigue in key regulatory regions such as the ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC). In healthy controls, higher iron was associated with increased activation during fatigue, consistent with compensatory response for fatigue. In contrast, individuals with MS showed the opposite pattern—as iron increased, activation in these regions declined, signaling an impairment in compensation.

Why These Findings Matter

This study reframes cognitive fatigue in MS as a failure of neural compensation rather than an inevitable consequence of iron accumulation alone. In MS, iron appears to amplify dysfunction in cognitive fatigue, limiting the brain’s ability to sustain effort under cognitive load. Clinically, these findings suggest the potential role of iron-sensitive MRI as a biomarker for fatigue vulnerability and highlight basal ganglia–prefrontal circuits as promising targets for future interventions aimed at reducing cognitive fatigue in MS.

Reference

Yao B, DeLuca J, Wylie GR. The effect of iron deposition on cognitive fatigue in multiple sclerosis. Neuroimage Clin. Published online January 18, 2026. doi:10.1016/j.nicl.2026.103953