Post-stroke fatigue is linked to resting state posterior hypoactivity and prefrontal hyperactivity

Abstract

AbstractBackground and PurposeFatigue is associated with poor functional outcomes and increased mortality following stroke. Survivors identify fatigue as one of their key unmet needs. Despite the growing body of research into post-stroke fatigue, the specific neural mechanisms remain largely unknown.MethodsThis observational study included 63 stroke survivors (22 women; age 30-89 years; mean 67.5±13.4 years) from the Cognition And Neocortical Volume After Stroke (CANVAS) study, a cohort study examining cognition, mood, and brain volume in stroke survivors following ischaemic stroke. Participants underwent brain imaging 3 months post-stroke, including a 7-minute resting state fMRI echoplanar sequence. We calculated the fractional amplitude of low-frequency fluctuations, a measure of resting state brain activity at the whole-brain level.ResultsForty-five participants reported experiencing post-stroke fatigue as measured by an item on the Patient Health Questionnaire-9. A generalised linear regression model analysis with age, sex, and stroke severity covariates was conducted to compare resting state brain activity in the 0.01-0.08 Hz range, as well as its subcomponents - slow-5 (0.01-0.027 Hz), and slow-4 (0.027-0.073 Hz) frequency bands between fatigued and non-fatigued participants. We found no significant associations between post-stroke fatigue and ischaemic stroke lesion location or stroke volume. However, in the overall 0.01-0.08 Hz band, participants with post-stroke fatigue demonstrated significantly lower resting-state activity in the calcarine cortex (p<0.001, cluster-corrected pFDR=0.009, k=63) and lingual gyrus (p<0.001, cluster-corrected pFDR=0.025, k=42) and significantly higher activity in the medial prefrontal cortex (p<0.001, cluster-corrected pFDR=0.03, k=45), attributed to slow-4 and slow-5 oscillations, respectively.ConclusionsPost-stroke fatigue is associated with posterior hypoactivity and prefrontal hyperactivity, reflecting dysfunction within large-scale brain systems such as fronto-striatal-thalamic and frontal-occipital networks. These systems in turn might reflect a relationship between post-stroke fatigue and abnormalities in executive and visual functioning. This first whole-brain resting-state study provides new targets for further investigation of post-stroke fatigue beyond the lesion approach.