Fatigue in brain injury and chronic pain : attention, emotional aspects, and neuronal correlates

Fatigue is common in patients with acquired brain injury (ABI), including traumatic brain injury as well as non-traumatic conditions, i.e., stroke, subarachnoid hemorrhage, anoxia, and brain tumors, and in patients with chronic pain (CP), and it has a negative impact on quality of life and working capacity. A major obstacle in fatigue research has been the absence of a clear definition of the concept. One model to sorting it out is to make a distinction between subjective self-assessed fatigue as opposed to objective performance-based cognitive fatigability (CF).

This thesis aims to deepen the understanding of fatigue in patients with ABI or CP by investigating relationships with attention functions and emotional factors, and the communication in the brain's networks in patients with CP, and, furthermore, to explore whether targeted attention training might reduce CF in patients with ABI.

Study I investigated the association between subjective fatigue and brain injury localization, diagnosis, and depression in a clinical group of ABI patients. A significantly higher proportion of patients with posterior and non-specific lesions reported fatigue compared to those with subcortical/frontal injuries. Stroke patients exhibited lower rates of fatigue compared to the other diagnostic groups. However, following logistic regression, only depression remained as an explanatory factor for self-reported fatigue. Nonetheless, while all depressed patients reported fatigue, not all fatigued patients were depressed.

Study II evaluated the effect of targeted attention training in reducing CF in patients with ABI. The result showed a small baseline correlation between CF and automatic processing speed and attention span. Also, the group receiving targeted attention training reduced their CF significantly more than the group receiving activity-based attention training. After control for the baseline value of CF, revealing that the targeted attention training-group started at a lower level, there was no significant effect of type of intervention.

Study III investigated the presence of CF in patients with CP and its relation to attention functions, self-rated fatigue, emotional factors, and pain characteristics. The patients with CP did not exhibit more CF than healthy controls. Self-rated fatigue measures and pain characteristics were not associated with CF, though there was an association between CF and processing speed on a test of sustained and selective attention in the CP group. Self-rated fatigue was strongly associated with self-rated pain intensity, spreading of pain, depression, anxiety, and sleep disturbance.

Study IV examined the presence of CF in patients with CP during a vigilance task, and whether there was a difference in Blood oxygen level dependent (BOLD) signal during the performance of the task between patients and healthy subjects. While no effect of time was found when comparing regional blood flow across the vigilance task, there were group differences in the patterns of brain activation throughout the task. Patients with CP showed stronger activation in frontal areas, and lower activation primarily in the left middle orbital gyrus and right insula, regions associated with expected reward-value, as compared to healthy controls.

Part V is a study protocol describing a research project targeting chronic pain, fatigue and cognition, encompassing study III and IV.

In conclusion, the results showed that subjective fatigue was strongly correlated with depression in both CP and ABI. In CP, subjective fatigue also correlated strongly with self-rated pain characteristics. No correlation between subjective fatigue and CF was found, in line with what has previously been shown in other neurological conditions. Concerning ABI, the result suggests that although depression contributes significantly to fatigue post ABI, fatigue should be recognized as partly distinct from depression in the context of brain injury. CF, in turn, was, although weakly, related to attention functions both in ABI and CP, and furthermore the results indicate that attention training might be a viable method for reducing CF in ABI. Patients with CP showed CF and reduced activation in reward-related brain areas during performance of a vigilance task, implicating deficits in reward processing in CP. This finding is interesting from both theoretical and clinical perspectives, and merits further investigation.

List of scientific papers

I. Holmqvist, A., Lindstedt, M. B., & Möller, M. C. (2018). Relationship between fatigue after acquired brain injury and depression, injury localization and aetiology: An explorative study in a rehabilitation setting. J Rehabil Med, 50(8), 725-731. https://doi.org/10.2340/16501977-2365

II. Holmqvist, A., Bartfai, A., Markovic, G., & Möller, M. C. (2021). Does Intensive Training of Attention Influence Cognitive Fatigability in Patients With Acquired Brain Injury? Front Neurosci, 15, 656876. https://doi.org/10.3389/fnins.2021.656876

III. Holmqvist, A., Berginström, N., Löfgren, M., Stålnacke, B. M., & Möller, M. C. (2024). Fatigue and cognitive fatigability in patients with chronic pain. Scand J Pain, 24(1). https://doi.org/10.1515/sjpain-2023-0085

IV. Holmqvist, A., Engström Nordin, L., Berginström, N., Löfgren, M., Nyberg, L., Stålnacke, B-M., Möller, M. C. Cognitive fatigability and neuronal correlates in chronic pain - a cross-sectional fMRI study. [Manuscript]

V. Moller, M. C., Berginstrom, N., Ghafouri, B., Holmqvist, A., Lofgren, M., Nordin, L., & Stalnacke, B. M. (2023). Cognitive and mental fatigue in chronic pain: cognitive functions, emotional aspects, biomarkers and neuronal correlates-protocol for a descriptive cross-sectional study. BMJ Open, 13(3), e068011. https://doi.org/10.1136/bmjopen-2022-068011