AbstractIntroductionFatigue is defined as a symptom of exhaustion unexplained by drug effects or psychiatric disorders and comprises two main components (i.e., central or “mental” and peripheral or “physical” components), both influencing global disability in amyotrophic lateral sclerosis (ALS). We aim at investigating the clinical correlations between “physical” and “mental” components of fatigue, measured by the Multidimensional Fatigue Inventory scale, and motor and cognitive/behavioral disability in a large sample of patients with ALS. We also investigated the correlations between these measures of fatigue and resting‐state functional connectivity of brain functional magnetic resonance imaging (RS‐fMRI) large‐scale networks in a subset of patients.MethodsOne hundred and thirty ALS patients were assessed for motor disability, cognitive and behavioral dysfunctions, fatigue, anxiety, apathy, and daytime sleepiness. Moreover, the collected clinical parameters were correlated with RS‐fMRI functional connectivity changes in the large‐scale brain networks of 30 ALS patients who underwent MRI.ResultsMultivariate correlation analysis revealed that “physical” fatigue was related to anxiety and respiratory dysfunction, while “mental” fatigue was related to memory impairment and apathy. Moreover, the mental fatigue score was directly related to functional connectivity in the right and left insula (within the salience network), and inversely related to functional connectivity in the left middle temporal gyrus (within the default mode network).ConclusionsAlthough the “physical” component of fatigue may be influenced by the disease itself, in ALS the “mental” component of fatigue correlates with cognitive and behavioral impairment, as well as with alterations of functional connectivity in extra‐motor networks.