Localizing post-stroke fatigue

Abstract

Introduction: Fatigue is a common and debilitating consequence of stroke. However, the neural mechanisms underlying post-stroke fatigue remain poorly understood. The aim of this study was to identify the neural substrates of poststroke fatigue (PSF) by studying stroke lesion locations and their structural and functional connections. Methods: 414 stroke patients were included in the study. PSF was measured as change in Fatigue Severity Scale (FSS) scores from pre- to poststroke. Association between PSF and lesion locations was investigated using voxel-lesion symptom mapping, structural disconnectome mapping and functional lesion network mapping. Results: There were no stroke specific lesion locations significantly associated with PSF. Structurally, PSF was associated with damage to the right anterior limb of the internal capsule and genu of corpus callosum (pFWE <0.05). Functionally, PSF was associated with positive connectivity to the right dorsolateral prefrontal cortex, lentiform nucleus, and thalamus, and negative connectivity to the ventromedial prefrontal cortex and left temporal pole (pFWE <0.05). The significance of the structural and positive functional connectivity results were robust to controlling for age, sex, lesion volume, stroke type, post-stroke PHQ9 and NIHSS scores, analyzing patients without prestroke fatigue only (n=304), or using poststroke FSS instead of PSF. Damage to the identified network predicted poststroke fatigue in an independent dataset of stroke patients (n=12; p=0.04), and aligned with the previously identified multiple sclerosis fatigue network (p=0.02). Conclusion: The results demonstrate that poststroke fatigue localizes to a right-sided fronto-striatal-thalamic network, providing novel insights into neural mechanisms underlying poststroke fatigue