Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities

Abstract

Background: Fatigue ranks among the most common and disabling symptoms in multiple sclerosis (MS). Recent theoretical works have surmised that this trait might be related to alterations across interoceptive mechanisms. However, this hypothesis has not been empirically evaluated. Objectives: To determine whether fatigue in MS patients is associated with specific behavioral, structural, and functional disruptions of the interoceptive domain. Methods: Fatigue levels were established via the Modified Fatigue Impact Scale. Interoception was evaluated through a robust measure indexed by the heartbeat detection task. Structural and functional connectivity properties of key interoceptive hubs were tested by magnetic resonance imaging (MRI) and resting-state functional MRI. Machine learning analyses were employed to perform pairwise classifications. Results: Only patients with fatigue presented with decreased interoceptive accuracy alongside decreased gray matter volume and increased functional connectivity in core interoceptive regions, the insula, and the anterior cingulate cortex. Each of these alterations was positively associated with fatigue. Finally, machine-learning analysis with a combination of the above interoceptive indices (behavioral, structural, and functional) successfully discriminated (area under the curve > 90%) fatigued patients from both non-fatigued and healthy controls. Conclusion: This study offers unprecedented evidence suggesting that disruptions of neurocognitive markers subserving interoception may constitute a signature of fatigue in MS.

At the Heart of Neurological Dimensionality: Cross-Nosological and Multimodal Cardiac Interoceptive Deficits

“…This metric presents advantages to capture ongoing and temporally subtle adaptations across the task ( 18 , 78 ). Moreover, cardiac interoceptive accuracy proves more sensitive than cardiac interoceptive learning ( 10 , 13 , 30 ) across cardiac and neurological conditions. Regarding b) metacognition, the top feature was afforded by sensibility (i.e., confidence about one’s own performance ( 7 , 79 , 80 )) of the learning condition.…”

“…Data were collected between January 2014 and July 2017. The study was approved by the ethics committee of the Institute of Cognitive Neurology as part of an ongoing protocol ( 9 , 10 , 13 , 17 , 18 , 43 ). All participants provided informed consent in accordance with the Declaration of Helsinki, and the study was carried out observing the privacy rights of human participants and in line with the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals ( 44 ).…”

“…In ST, cardiac interoceptive accuracy deficits can emerge despite spared awareness, accompanied by reduced HEP modulations and insular damage but no FC alterations ( 10 ). In MS, a more diffuse model with abnormal body signal processing, cardiac interoceptive deficits (atypical HEP, atrophy, and FC) have been observed without behavioral impairments ( 9 ) and in association with fatigue ( 30 ). In combination, these findings suggest that markers of cardiac interoceptive attention (accuracy and HEP modulations) might be transnosologically affected across neurological conditions, whereas other signatures (cardiac interoceptive learning and awareness, structural and functional neuroimaging markers) may prove more idiosyncratically affected in them.…”

Cognitive Fatigue Is Associated with Altered Functional Connectivity in Interoceptive and Reward Pathways in Multiple Sclerosis

“…According to this framework, the subjective feeling of fatigue may reflect the brain’s metacognitive interpretation of the body’s failure to control internal states, due to disruptions in the interoceptive pathways. Consistent with this hypothesis, Gonzalez Campo and colleagues [ 13 ] empirically identified interoceptive deficits among fatigued pwMS, along with decreased gray matter volume and increased functional connectivity in the insula and the anterior cingulate cortex (ACC)—both key regions involved in interoception; these behavioral and brain alterations were not present in non-fatigued pwMS or healthy controls (HCs). Supporting both reward processing and interoceptive hypotheses, a motivational fatigue network consisting of the dorsal ACC (dACC), the dorsolateral prefrontal cortex (DLPFC), the vmPFC, and the insula have been proposed in recent reviews [ 12 , 14 ].…”

Dynamic neurocognitive changes in interoception after heart transplant

“…To assess cardiac interoception, we applied a heartbeat detection (HBD) task ( Couto et al , 2014 , 2015 ; Canales-Johnson et al , 2015 ; García-Cordero et al., 2016 , 2017 ; Yoris et al , 2017 , 2018 ; Salamone et al , 2018 ; Gonzalez Campo et al , 2019 ) involving two interlaced conditions. First, an exteroceptive accuracy (EA) condition was used as control measure of external monitoring skills ( Critchley et al , 2004 ; García-Cordero et al., 2016 , 2017 ; Salamone et al , 2018 ; Yoris et al , 2018 ).…”