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Network Localization of Fatigue in Multiple Sclerosis.

Olli Likitalo^1,2,3, Jaakko Kungshamn^1,2,3, Albert Bellmunt-Gil¹

¹Clinical Neurosciences, Turku Brain and Mind Center, University of Turku, Turku, Finland.

Annals of Clinical and Translational Neurology

|November 18, 2025

Summary

Fatigue in multiple sclerosis (MS) is linked to a brain network, not specific lesion sites. Lesion connectivity to the premotor cortex is associated with MS fatigue severity.

Keywords:

fatigue lesion network mapping multiple sclerosis stroke

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Area of Science:

Neuroscience
Neurology
Medical Imaging

Background:

Fatigue is a prevalent symptom in multiple sclerosis (MS), significantly impacting patient quality of life.
The precise neurobiological underpinnings of MS-related fatigue remain incompletely understood.
This study investigates brain networks associated with fatigue in MS patients by examining lesion locations and their connectivity patterns.

Purpose of the Study:

To identify specific brain networks and neural substrates linked to fatigue in multiple sclerosis (MS).
To explore the relationship between lesion connectivity and fatigue severity in MS patients.
To determine if the identified MS fatigue network is reproducible in other neurological conditions like stroke.

Main Methods:

Voxel-lesion symptom mapping and lesion network mapping were employed to analyze lesion-symptom associations.
The study included 38 MS patients with fatigue and 21 without, with findings validated in two independent datasets (199 MS patients, 85 stroke patients).
Resting-state functional connectivity MRI (rs-fcMRI) was utilized in one validation dataset.

Main Results:

No specific anatomical lesion locations were directly associated with fatigue in MS.
Lesions linked to fatigue showed connectivity to a network peaking in the right premotor cortex and negatively with the left temporal pole.
Connectivity from the premotor cortex to other brain regions correlated with MS fatigue severity and was reproducible in post-stroke fatigue.

Conclusions:

Fatigue in multiple sclerosis (MS) localizes to a specific brain network, rather than isolated lesion sites.
Lesion connectivity, particularly involving the premotor cortex, is a key neural substrate for MS fatigue.
The findings provide crucial insights into the neurobiological mechanisms driving fatigue in MS and related conditions.