Cognitive, behavioral, and brain functional connectivity correlates of fatigue in amyotrophic lateral sclerosis

Abstract

Introduction Fatigue 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. Methods One 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. Results Multivariate 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). Conclusions Although 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.

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update

“…Moreover, the mental fatigue score is directly related to FC in the right and left insula (within the SN) and inversely related to that in the left middle temporal gyrus (within the DMN), thus correlating with CI due to alterations of FCs in extramotor networks [142]. Decreased FC was observed for the SMN and DMN in the left medial frontal and left postcentral gyrus, for DMN in the right medial frontal gyrus and left precuneus, for FPN in the right and left middle frontal and left inferior frontal gyrus, and for subcortical network in the right and left anterior insular cortex and anterior cingulate cortex, whereas the DMN showed increased FC in the middle temporal cortex [142] (Figure 2). Furthermore, some alterations of fronto-temporo-parietal-cerebellar circuits could be related to the pseudobulbar effect in ALS.…”

“…Resting-state fMRI showed that FC within the DMN, as well as between the DMN, the sensorimotor network (SMN), the frontoparietal network and the salience network (SN), are predictive of both global cognition and motor function in ALS [141]. Moreover, the mental fatigue score is directly related to FC in the right and left insula (within the SN) and inversely related to that in the left middle temporal gyrus (within the DMN), thus correlating with CI due to alterations of FCs in extramotor networks [142]. Decreased FC was observed for the SMN and DMN in the left medial frontal and left postcentral gyrus, for DMN in the right medial frontal gyrus and left precuneus, for FPN in the right and left middle frontal and left inferior frontal gyrus, and for subcortical network in the right and left anterior insular cortex and anterior cingulate cortex, whereas the DMN showed increased FC in the middle temporal cortex [142] (Figure 2).…”

“…Furthermore, some alterations of fronto-temporo-parietal-cerebellar circuits could be related to the pseudobulbar effect in ALS. In particular, abnormal FC between the cerebellum and posterior cingulate and the left middle frontal cortex indicates a crucial role of the cerebellum in regulating emotional expression in ALS [142]. In conclusion, brain network analyses revealed involvement of multiple FC dysfunctions related to CI in ALS, particularly affecting fronto-striatal, frontotemporal, and frontoparietal systems, the Papez circuit, fronto-temporo-parieto-cerebellar circuits, and DMN, SMN and SN, with the affection of different networks contributing to specific cognitive and motivation disorders.…”