Review
The neuroimmune basis of fatigue

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Highlights

  • Despite its prevalence, the pathophysiology of fatigue remains elusive.

  • We focus on the etiology of fatigue in chronic inflammatory diseases, cancer or neuropathologies.

  • Fatigue can be decomposed into specific neurobehavioral units such as decreased incentive motivation.

  • Convergent data from many disciplines point to the importance of inflammation in the pathophysiology of fatigue.

  • Peripheral inflammation can ultimately disrupt monoaminergic neurotransmission.

  • Resulting alteration in frontostriatal and/or insular networks underlies specific neurobehavioral aspects of fatigue.

The exact nature and pathophysiology of fatigue remain largely elusive despite its high prevalence in physically ill patients. Studies on the relationship between the immune system and the central nervous system provide a new perspective on the mechanisms of fatigue. Inflammatory mediators that are released by activated innate immune cells at the periphery and in the central nervous system alter the metabolism and activity of neurotransmitters, generate neurotoxic compounds, decrease neurotrophic factors, and profoundly disturb the neuronal environment. The resulting alterations in fronto-striatal networks together with the activation of insula by inflammatory interoceptive stimuli underlie the many dimensions of fatigue including reduced incentive motivation, decreased behavioral flexibility, uncertainty about usefulness of actions, and awareness 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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