Searching for the representation of fatigue in the brain

This research project was aimed at improving our understanding of the neuronal mechanism that causes fatigue in patients with a brain tumor. In chapter one, we aimed to better understand the neuronal representation of an alertness response compared to a task response. The alertness response and the task response showed similarity, which supported our hypothesis that alertness is represented by activation and inhibition of task relevant regions, therefore reflecting expectations about an upcoming challenge. The alertness activation pattern could be task specific, or, generalized alertness activation could be present in both during alertness and task execution. In chapter two, we aimed to improve our understanding of the tuning of alertness to expected task difficulty. Alertness was represented by activation in the central executive network and deactivation in the default mode network. The default mode deactivation was tuned to the expected task difficulty while the central executive activation was not. Assuming that people are more alert if they expect a difficult challenge, these results suggest that alertness is primarily tuned via their default mode inhibition response. Default mode activation has been associated with mind wandering and parasympathetic regulation. Participants likely suppress these processes in service of alertness. In chapter three, we aimed to improve our understanding of the neuronal representation of fatigue by correlating the alertness brain response (measured with fMRI) with the level of self-reported fatigue of brain tumor patients. We found that fatigue correlated with default mode inhibition. These results suggest that default mode activity in highly fatigued patients is constantly high or low. This might reflect a permanent need for, or lack of parasympathetic processes. Additionally, these findings may be a first step in the development of a biomarker for self-reported fatigue that can be used in future research aimed at a better understanding why people experience severe and invalidating fatigue and how to solve it. In chapter four, we aimed to deepen our understanding of the neuronal representation of fatigue by addressing the effect of demographic, clinical, and psychological control variables on the correlation between fatigue and the default mode network response. Of the control variables, specifically depression was strongly associated with fatigue which is in line with previous research. Despite this strong association, we found that the level of default mode inhibition explained a unique part of the variance in fatigue. These findings are a first indication that fatigue might be causally related to default mode inhibition. CONCLUSION Activity in the default mode network (which primarily occurs when resting) might be needed to resolve fatigue and continuing difficult tasks (default mode network activity remains suppressed) could prevent a person to recover from fatigue. Patients with high levels of fatigue might lack default mode activity and parasympathetic (rest and restore) processes in periods of rest. These results endorse the idea that default mode activity is involved in the control of parasympathetic processes, which has the potential to explain why people with a brain tumor (or other diseases) experience invalidating fatigue.