We've known about post stroke fatigue for years, if not decades. WHOM is going to solve it, meaning cure it?
Post-stroke fatigue is associated with resting state posterior hypoactivity and prefrontal hyperactivity
Georgia Cotter1, Mohamed Salah Khlif2, Laura Birdhttps://orcid.org/0000-0001-7073-725X2, Mark E Howard1,3,4,5, Amy Brodtmann2, and Natalia Egorova-Brumleyhttps://orcid.org/0000-0002-9244-29001,2
Background
Background
Fatigue 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.
Aim
This observational study aimed to identify resting state brain activity markers of post-stroke fatigue.
Method
Sixty-three stroke survivors (22 women; age 30–89 years; mean 67.5 ± 13.4 years) from the Cognition And Neocortical Volume After Stroke study, a cohort study examining cognition, mood, and brain volume in stroke survivors following ischemic stroke, underwent brain imaging three months post-stroke, including a 7-minute resting state functional magnetic resonance imaging. We calculated the fractional amplitude of low-frequency fluctuations, which is measured at the whole-brain level and can detect altered spontaneous neural activity of specific regions.
Results
Forty-five participants reported experiencing post-stroke fatigue as measured by an item on the Patient Health Questionnaire-9. Fatigued compared to non-fatigued participants 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).
Conclusions
Post-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 whole-brain resting-state study provides new targets for further investigation of post-stroke fatigue beyond the lesion approach.
Keywords
Calcarine/lingual gyrus, fractional amplitude of low-frequency fluctuations, medial prefrontal cortex, post-stroke fatigue, resting state functional magnetic resonance imaging, stroke subtypes
1Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia
2Dementia Theme, the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
3Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, Australia
4Institute for Breathing and Sleep, Melbourne, Australia
5Victorian Respiratory Support Service, Austin Health, Heidelberg, Australia
*These authors are joint senior authors.
Corresponding author(s):
Natalia Egorova-Brumley, Melbourne School of Psychological Sciences, Redmond Barry Building, The University of Melbourne, Melbourne, VIC 3010, Australia. Email: natalia.egorova@unimelb.edu.au
Introduction
Post-stroke fatigue (PSF) is a common sequela of ischemic or hemorrhagic stroke and is reported by stroke survivors as one of their most disruptive symptoms. It is associated with poor functional outcomes and reduced quality of life, a reduction in the likelihood of returning to work, and increased mortality.1 Prevalence rates of PSF vary from 29% to 92% of stroke survivors,2 far exceeding the 10–23% prevalence of fatigue in the general population.3
Prior studies aiming to identify the neural mechanisms of PSF have focused on associations with stroke types and lesion locations.4 No associations have been found with the kind of stroke (ischemic or hemorrhagic), stroke severity, stroke side, or infarct volume.4 In contrast, some work in the field suggested that stroke subtype (e.g., lacunar, partial, or total anterior or posterior circulation) could be associated with PSF.5,6
Posterior circulation infarctions (POCIs), which account for roughly 20% of ischemic strokes, have been linked to higher levels of fatigue than other stroke subtypes,5,6 albeit not universally supported.7 With regard to lesion locations, many studies did not find any links with PSF,8–10 or reported heterogeneous findings. PSF was linked to right-sided lesions,11 caudate and putamen,12 and most consistently to posterior circulation lesions, including the brainstem, cerebellum, midbrain, and thalamus,6 reinforcing the association between PSF and POCI.
To date, few researchers have utilized functional magnetic resonance imaging (MRI) to explore the neural correlates of PSF. An association between high fatigue and perceived effort in stroke and a greater activation in the pre-supplementary motor area and the ipsilateral inferior frontal gyrus has been reported,14 as well as functional connectivity in the fronto-striato-thalamic (FST) network15 predictive of the response to the alertness-promoting treatment modafinil for PSF.16 The FST circuitry has been implicated in fatigue in other conditions, including in multiple sclerosis,17 traumatic brain injury,18 Parkinson’s disease,19 and chronic fatigue syndrome (CFS).20
We aimed to identify the neural correlates of PSF in terms of stroke subtype, lesion locations, and resting-state brain functioning at the whole-brain level. Specifically, we measured the fractional amplitude of low-frequency fluctuations (fALFF), computed as the relative contribution of the low-frequency band (0.01–0.08 Hz) to the entire detectable frequency range (0–0.25 Hz). fALFF indexes local spontaneous neuronal activity and thus is suitable to probe the neural basis of PSF. We hypothesized that there would be an association between PSF and posterior circulation ischemic stroke, posterior lesion locations, as well as a difference in the resting-state neural activity between stroke survivors with and without PSF in the FST network.
Keywords
Calcarine/lingual gyrus, fractional amplitude of low-frequency fluctuations, medial prefrontal cortex, post-stroke fatigue, resting state functional magnetic resonance imaging, stroke subtypes
1Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia
2Dementia Theme, the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
3Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, Australia
4Institute for Breathing and Sleep, Melbourne, Australia
5Victorian Respiratory Support Service, Austin Health, Heidelberg, Australia
*These authors are joint senior authors.
Corresponding author(s):
Natalia Egorova-Brumley, Melbourne School of Psychological Sciences, Redmond Barry Building, The University of Melbourne, Melbourne, VIC 3010, Australia. Email: natalia.egorova@unimelb.edu.au
Introduction
Post-stroke fatigue (PSF) is a common sequela of ischemic or hemorrhagic stroke and is reported by stroke survivors as one of their most disruptive symptoms. It is associated with poor functional outcomes and reduced quality of life, a reduction in the likelihood of returning to work, and increased mortality.1 Prevalence rates of PSF vary from 29% to 92% of stroke survivors,2 far exceeding the 10–23% prevalence of fatigue in the general population.3
Prior studies aiming to identify the neural mechanisms of PSF have focused on associations with stroke types and lesion locations.4 No associations have been found with the kind of stroke (ischemic or hemorrhagic), stroke severity, stroke side, or infarct volume.4 In contrast, some work in the field suggested that stroke subtype (e.g., lacunar, partial, or total anterior or posterior circulation) could be associated with PSF.5,6
Posterior circulation infarctions (POCIs), which account for roughly 20% of ischemic strokes, have been linked to higher levels of fatigue than other stroke subtypes,5,6 albeit not universally supported.7 With regard to lesion locations, many studies did not find any links with PSF,8–10 or reported heterogeneous findings. PSF was linked to right-sided lesions,11 caudate and putamen,12 and most consistently to posterior circulation lesions, including the brainstem, cerebellum, midbrain, and thalamus,6 reinforcing the association between PSF and POCI.
To date, few researchers have utilized functional magnetic resonance imaging (MRI) to explore the neural correlates of PSF. An association between high fatigue and perceived effort in stroke and a greater activation in the pre-supplementary motor area and the ipsilateral inferior frontal gyrus has been reported,14 as well as functional connectivity in the fronto-striato-thalamic (FST) network15 predictive of the response to the alertness-promoting treatment modafinil for PSF.16 The FST circuitry has been implicated in fatigue in other conditions, including in multiple sclerosis,17 traumatic brain injury,18 Parkinson’s disease,19 and chronic fatigue syndrome (CFS).20
We aimed to identify the neural correlates of PSF in terms of stroke subtype, lesion locations, and resting-state brain functioning at the whole-brain level. Specifically, we measured the fractional amplitude of low-frequency fluctuations (fALFF), computed as the relative contribution of the low-frequency band (0.01–0.08 Hz) to the entire detectable frequency range (0–0.25 Hz). fALFF indexes local spontaneous neuronal activity and thus is suitable to probe the neural basis of PSF. We hypothesized that there would be an association between PSF and posterior circulation ischemic stroke, posterior lesion locations, as well as a difference in the resting-state neural activity between stroke survivors with and without PSF in the FST network.
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