Trends in Neurosciences
ReviewThe neuroimmune basis of fatigue
Section snippets
The many facets of fatigue
Many definitions of fatigue have been proposed. One that is often cited refers to fatigue as ‘an overwhelming, debilitating, and sustained sense of exhaustion that decreases one's ability to carry out daily activities, including the ability to work effectively and to function at one's usual level in family or social roles’ [1]. There are at least two dimensions to fatigue: ‘I cannot do it, I am exhausted’ versus ‘I do not feel like doing it, it is not worth it’. The first dimension is
Inflammation, sickness, incentive motivation, and fatigue
The conceptualization of inflammation-induced fatigue requires an evolutionary perspective. In a seminal paper, Hart suggested that the behavior of sick animals is not a maladaptive response or the effect of debilitation but an organized, evolved strategy to facilitate the role of fever in combating viral and bacterial infections [10]. Subsequent studies have focused on the mechanistic aspects of inflammation-induced sickness. Evolutionary conserved structures of pathogens activate a limited
Inflammation and fatigue: clinical findings
At the clinical level, there has been little attempt thus far at deconstructing fatigue when studying its relation with inflammation, with the sole exception of a preliminary study in which inflammation was more related to physical than to mental fatigue in patients with advanced cancer [16]. Most of what is known about the role of proinflammatory cytokines in the development and severity of fatigue comes from cross-sectional clinical studies in patients who were physically ill and suffering
Neural basis of inflammation-induced fatigue
There have been only a few studies on the neural mechanisms of inflammation-induced fatigue, in contrast to a large number on inflammation-induced sickness and depression 11, 27. Peripheral cytokines can affect central neurotransmission indirectly by modulating the bioavailability of amino acid precursors of neurotransmitters (Figure 1). In addition, peripherally released cytokines activate immune-to-brain communication pathways, enabling the brain to be informed about immune events even in the
Concluding remarks and perspectives
There is a wide consensus that inflammation has a key role in the development and persistence of fatigue in patients with physical illnesses. We have seen that this hypothesis is supported by several clinical studies demonstrating associations between fatigue and biomarkers of inflammation, and by preclinical studies in which animals exposed to inflammatory stimuli behave in a way reminiscent of fatigue (i.e., they display reduced motor activity and incentive motivation). Among the
Disclaimer statement
R. Dantzer works as a consultant for Ironwood Pharma, Cambridge, MA, USA.
Acknowledgments
Research reported here was supported by the National Institute of Neurological Diseases and Stroke of the National Institutes of Health under award numbers RO1NS073939 and RO1NS074999. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.D. is supported by MD Anderson Cancer Center research funds. A.K. is supported by a STARS award of the University of Texas System.
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