Dissecting and alleviating post-stroke fatigue: Cognitive phenotype, brain disconnectome mapping and non-invasive brain stimulation

The overarching aim of this thesis has been to contribute to a better understanding of fatigue in the chronic phase after stroke. In three different studies comprising an overlapping sample of 84 stroke survivors, the thesis addresses the cognitive phenotype of post-stroke fatigue (PSF) using cognitive computational modeling, the neuronal correlates of PSF using an advanced brain disconnectivity approach, and lastly, the potential of non-invasive brain stimulation in combination with computerized cognitive training to alleviate symptoms of fatigue and depression, respectively. The results of the first study revealed that fatigue, but not depression, was associated with a slowing of responses throughout a 20 minutes attentional task, suggesting that fatigue entails an increased vulnerability for performance deterioration when the attentional system is put under sustained pressure. We found no associations between baseline cognitive performance and fatigue, demonstrating the relevance of the temporal and sustained aspects of task performance when addressing the cognitive correlates of PSF. Applying a novel approach to study the brain correlates of fatigue, in the second study we indirectly estimated the white matter pathway disconnection caused by the lesion, thus capturing not only the immediate damage caused by the stroke lesions but also distal effects. The analysis provided no evidence supporting a simple association between fatigue severity and disconnection or lesion characteristics, but revealed associations between fatigue, depression and sleep quality. Together, the findings supports that chronic phase PSF is a complex condition that is not simply explained by lesion characteristics such as extent and distribution of structural brain disconnection. Lastly, in the third study we report results from a sham-controlled, randomized trial evaluating the effect of repeated transcranial direct current stimulation (tDCS) combined with computerized cognitive training on symptoms of fatigue and depression. The analysis revealed no added effect of tDCS with regards to fatigue or depression. Also, patients withdrawing from the study had higher baseline fatigue scores and younger age than the patients completing, underscoring the need of individually tailored treatment for this patient group. This thesis is the first to assess the effect of repeated tDCS on fatigue in chronic stroke. In conclusion, this thesis provides new insight into fatigue after stroke, regarding cognitive manifestations, the relationship with structural brain disconnection and tDCS treatment. Jointly, the results from the three studies suggest that subjective fatigue is associated with a time-dependent reduction in processing efficiency during sustained attentional effort, but do not provide evidence for a simple association between fatigue in the chronic phase and lesion characteristics or structural disconnectivity. tDCS did not demonstrate beneficial effects on self-reports of fatigue or depression. Future studies should aim to generalize the findings to a broader spectrum of the stroke patient population, both in terms of stroke severity and functional outcome