Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable

Abstract

Background Post-stroke fatigue (PSF) is a significant and highly prevalent symptom, whose mechanisms are poorly understood. The third Stroke Recovery and Rehabilitation Roundtable paper on PSF focussed primarily on defining and measuring PSF while mechanisms were briefly discussed. This companion paper to the main paper is aimed at elaborating possible mechanisms of PSF. Methods This paper reviews the available evidence that potentially explains the pathophysiology of PSF and draws parallels from fatigue literature in other conditions. We start by proposing a case for phenotyping PSF based on structural, functional, and behavioral characteristics of PSF. This is followed by discussion of a potentially significant role of early inflammation in the development of fatigue, specifically the impact of low-grade inflammation and its long-term systemic effects resulting in PSF. Of the many neurotransmitter systems in the brain, the dopaminergic systems have the most evidence for a role in PSF, along with a role in sensorimotor processing. Sensorimotor neural network dynamics are compromised as highlighted by evidence from both neurostimulation and neuromodulation studies. The double-edged sword effect of exercise on PSF provides further insight into how PSF might emerge and the importance of carefully titrating interventional paradigms. Conclusion The paper concludes by synthesizing the presented evidence into a unifying model of fatigue which distinguishes between factors that pre-dispose, precipitate, and perpetuate PSF. This framework will help guide new research into the biological mechanisms of PSF which is a necessary prerequisite for developing treatments to mitigate the debilitating effects of post-stroke fatigue.

The impact of post-stroke fatigue on inpatient rehabilitation outcomes: An observational study

“…However, a decline in physical function and changes in psychological factors can often lead to post-stroke fatigue [7]. Fatigue can adversely affect rehabilitation compliance, undermine confidence in the rehabilitation process, and even exacerbate negative emotions, thereby prolonging the overall recovery journey [10].…”

International Stroke Recovery and Rehabilitation Roundtable Consensus Statements Are Driving Growth and Progress in Our Field

“…In a second paper from this taskforce, they expanded on biological mechanisms which has been published alongside the taskforce papers in this edition. 22 The brain stimulation taskforce identified outstanding translational bench-bedside barriers to provide a roadmap for use of transcranial magnetic stimulation and transcranial Direct Current Stimulation for stroke recovery and rehabilitation. To facilitate the implementation of their recommendations, a new SRRR3 Unified Non-Invasive Brain Stimulation Research Checklist was developed.…”

Early poststroke clinically significant fatigue predicts functional independence: a prospective longitudinal study

“…Moreover, the immune system’s response to a stroke can also exacerbate fatigue. As part of the body’s natural response to injury, an inflammatory process is activated, potentially flooding the system with inflammatory cytokines, fostering a protective response but also contributing to a pervasive sense of exhaustion ( 2 , 10 , 11 ). Emotional well-being is compromised following a stroke, with depressive mood, anxiety, and stress frequently taking hold.…”

“…The complexity of PSF is further amplified by changes in neuroplasticity after a stroke, which can affect the excitability of cortical neurons. An imbalance may arise between excitatory and inhibitory signals in the brain, either ramping up neural activity or causing a lull, each contributing to fatigue in its own way ( 2 , 11 ).…”

“…The connectivity between different brain regions may be reshaped, potentially altering the efficiency with which these areas communicate. Such changes are thought to impact the personal experience of fatigue ( 2 , 11 ).…”