Effort and Fatigue-Related Functional Connectivity in Mild Traumatic Brain Injury

Abstract

Mental fatigue in healthy individuals is typically observed under conditions of high cognitive demand, particularly when effort is required to perform a task for a long period of time—thus the concepts of fatigue and effort are closely related. In brain injured individuals, mental fatigue can be a persistent and debilitating symptom. Presence of fatigue after brain injury is prognostic for return to work/school and engagement in activities of daily life. As such, it should be a high priority for treatment in this population, but because there is little understanding of its behavioral and neural underpinnings, the target for such treatment is unknown. Here, the neural underpinnings of fatigue and effort are investigated in active duty military service members with mild traumatic brain injury (mTBI) and demographically-matched orthopedic controls. Participants performed a Constant Effort task for which they were to hold a pre-defined effort level constant for long durations during fMRI scanning. The task allowed for investigation of the neural systems underlying fatigue and their relationship with sense of effort. While brain activation associated with effort and fatigue did not differentiate the mTBI and controls, functional connectivity amongst active brain regions did. The mTBI group demonstrated immediate hyper-connectivity that increased with effort level but diminished quickly when there was a need to maintain effort. Controls, in contrast, demonstrated a similar pattern of hyper-connectivity, but only when maintaining effort over time. Connectivity, particularly between the left anterior insula, rostral anterior cingulate cortex, and right-sided inferior frontal regions, correlated with effort-level and state fatigue in mTBI participants. These connections also correlated with effort level in the Control group, but only the connection between the left insula and superior medial frontal gyrus correlated with fatigue, suggesting a differing pattern of connectivity. These findings align, in part, with the dopamine imbalance, and neural efficiency hypotheses that pose key roles for medial frontal connections with insular or striatal regions in motivating or optimizing performance. Sense of effort and fatigue are closely related. As people fatigue, sense of effort increases systematically. The data propose a complex link between sense of effort, fatigue, and mTBI that is centered in what may be an inefficient neural system due to brain trauma that warrants further investigation.

Cingulo-Opercular and Frontoparietal Network Control of Effort and Fatigue in Mild Traumatic Brain Injury

“…Interestingly, the symptom of post concussive syndrome that is most strongly related to resilience is fatigue ( Losoi et al, 2015b ). While this symptom, in particular, has only been investigated in a few studies involving military service members (c.f., Ramage et al, 2019 ; Lewis et al, 2021 ), one study validates that persistent fatigue in this population is associated with poorer rates of return to productivity ( Mortera et al, 2018 ). Thus, relationships among mild TBI, fatigue, and potential for recovery are intertwined and particularly prevalent in military service members.…”

“…Additionally, Ramage et al (2019) found that the strength of the left claustrum's connections with the rostral and dorsal anterior cingulate cortex, medial frontal gyrus, and right inferior frontal gyrus (orbital and opercular) was correlated with fatigue evidenced by mTBI participants. While some of these additional functionally connected regions are considered part of the CO network, the others are more consistently considered to be within the FP network.…”

Mental Fatigue after Mild Traumatic Brain Injury in Relation to Cognitive Tests and Brain Imaging Methods

“…Left insula and superior medial frontal gyrus correlated with fatigue. The authors propose a complex link between effort and fatigue and that it may be related to an inefficient neuronal system [73]. Activation assessed with rCBF within the cerebellar cortex correlated with PASAT, measuring information processing and sustained and divided attention in controls, while mTBI participants with self-reported cognitive fatigue showed significant correlations in the inferior frontal and superior temporal cortices [74].…”

Noninvasive magnetic resonance imaging techniques in mild traumatic brain injury research and diagnosis

“…CE : Left anterior insula, rostral anterior cingulate cortex, and right‐sided inferior frontal regions (Ramage et al, 2019)…”