“I am tired”. What does this sentence actually imply? In a recent review published in Frontiers in Immunology , we suggest that the different dimensions of fatigue (Figure 1) should be specifically investigated, in subjective as well as objective ways. This is especially important if we are to comprehend the role of inflammation in turning physiological fatigue into pathological fatigue (Figure 2). This notion is further supported by recent publications assessing the role of inflammation in altered motivated behavior, a core dimension of fatigue, in humans [2, 3]. While inflammation is known to induce an overall feeling of loss of motivation, these studies used objective assessment of motivated behavior and indicate that inflammation does not necessarily reduce motivation, but rather reorganizes motivational priorities depending on the context, leading sometimes to increased motivation . These findings call for studies assessing the role of inflammation in different dimensions of fatigue, and how to measure these in both subjective and objective ways.
Fatigue – a multidimensional concept
Fatigue can be highly disabling. It is very common in various medical conditions (Table 1) and is associated with impaired quality of life, reduced social relationships, and reduced treatment adherence.
Table 1. Prevalence of fatigue in various medical conditions.
But what is fatigue? Fatigue is not just fatigue. The feeling of fatigue actually involves different features (Figure 1) . You can be physically tired, having difficulties performing activities; you can be mentally tired, struggling to concentrate and perform mental tasks; you can also lack motivation to perform physical or cognitive tasks and thus have the feeling of being tired. These dimensions of fatigue can be, and often are, associated. But they do not necessarily co-exist . Hence, the involvement of each dimension in the overall feeling of fatigue can differ significantly from one condition to another and from one patient to another.
The feeling of fatigue involving different features, i.e., physical fatigue, mental fatigue and lack of motivation, which are usually associated but not do necessarily coexist.
Importantly, these fatigue dimensions may involve distinct neuronal systems and would thus require specific treatments to relieve the feeling of fatigue. Research indicate that the feeling of mental fatigue derives from high cognitive load, reflected by increased activation of the anterior cingulate cortex, whereas the motivational dimension of fatigue more likely involves the mesolimbic reward system of the basal ganglia . The “motor” pathway of the basal ganglia (nigrostriatal pathway) may instead be involved in the physical feeling of fatigue . Moreover, we argue that increased sensitivity of the insular cortex to interoceptive signals may induce an overall feeling of fatigue . As additional brain structures could also contribute to fatigue, studies assessing causes and outcomes in a multidimensional way are needed to better comprehend the neuronal mechanisms behind this debilitating state .
The understanding of fatigue is further complicated by the inaccurate common overlap between physiological and pathological fatigue. Fatigue is first and foremost an adaptive physiological process that signals the body to rest, in order to prevent injuries and avoid actions with a low cost-benefit balance [10, 12]. In some cases, however, the adaptive function is lost and fatigue instead becomes disabling (Figure 2) . Because physiological fatigue is an adaptive process known by all humans, patients who instead suffer from pathological fatigue can encounter difficulties in making their social surroundings and caregivers, who have only experienced physiological, adaptive fatigue, understand the nature of their symptoms. This has been aptly described by MJ Poulson, in Journal of Clinical Oncology in 2001 . Poulson was a 46-year-old palliative care physician who suffered from inflammatory breast cancer. She tried to describe her feeling of fatigue, the most overwhelming symptoms among her cancer-related symptoms, to her physician:
“- I [am] plagued by fatigue and lack of energy. I am feeling as if I can hardly put one foot in front of the other at times.
– I sure know how you feel, he said reassuringly. […] I didn’t stop all week. I still haven’t caught up yet. A day or two off would be so nice, wouldn’t it?
As I was that patient, I wanted to shake my doctor by the collar of his lab coat and scream. “No, that’s wrong! You have no idea how I feel!” But I did not have the energy.”
Because the same words are used to describe physiological and pathological fatigue, the latter is often misinterpreted . We therefore need a better understanding of both physiological and pathological fatigue if we are to determine the factors turning fatigue into a dysfunctional process, and learn how to prevent and overturn this maladaptive fatigue (Figure 2). One such factor, hypothesized to play a role in turning physiological into pathological fatigue, is inflammation.
Figure 2: Physiological and pathological fatigue. Fatigue is an adaptive physiological process that signals the body to rest, and which is alleviated by rest and sleep. Fatigue can also develop into a dysfunctional, pathological process, which is not alleviated by rest or sleep.
Fatigue as an inflammation-induced symptom
One of the first and most common feelings associated with the activation of the immune system (e.g., during infection) is fatigue. When the immune system is activated, immune cells produce inflammatory cytokines that coordinate the fight against the pathogen. In addition to their peripheral effects, cytokines have the ability to act on the central nervous system and to induce a large array of behavioral alterations, collectively referred to as sickness behavior . Sickness behavior is an adaptive process, allowing the body to redirect energy towards fighting the infection by reducing food consumption, physical activities, and social interactions . Fatigue, being a strong signal to rest, is thus central in sickness behavior, and appears very sensitive to the effects of cytokines. This was notably highlighted in cancer and hepatitis C patients after the instauration of immunotherapy, which increases circulating cytokines and rapidly induces the development of fatigue in up to 80% of patients .
Inflammation has therefore been suggested as a potential contributor to the development of (pathological) fatigue. Increasing clinical evidence supports the role of inflammation in fatigue in patients suffering from medical conditions that are characterized by both high rates of fatigue and alterations in inflammatory processes, such as cancer survivors, and patients with multiple sclerosis or diabetes [7, 17, 18]. For instance, previous studies have shown a significant association between circulating levels of inflammatory markers and the intensity of fatigue in these clinical populations [19-21]. Importantly, inflammation has also been shown to modulate the activity of the brain structures believed to be involved in fatigue, such as basal ganglia [22, 23], the anterior cingulate cortex [24, 25] and the insula [26, 27].
Only a few studies have investigated the association between inflammation and fatigue in a multidimensional way . Some studies in cancer patients and survivors indicate that physical, rather than mental, aspects of fatigue may be associated with inflammation [28, 29]. On the other hand, a study of type 2 diabetes found that increased levels of inflammatory markers relates particularly to mental fatigue and lack of motivation, but not to physical fatigue . In multiple sclerosis, however, inflammation appears to affect several dimensions of fatigue . Although these studies need replications in order to fully understand the role of inflammation in specific dimensions of fatigue in various medical conditions, they illustrate that inflammation does not necessarily relate to all dimensions of fatigue, and that other factors may also be involved. Importantly, these studies indicate that an “inflammation-specific type of fatigue” may not exist and that inflammation may rather affect different dimensions of fatigue in different medical conditions. This will need to be disentangled in future studies.
Inflammation induces motivational reorganization rather than loss of motivation
As mentioned earlier, loss of motivation appears as a core feature of fatigue – being able to produce a feeling of physical and/or mental fatigue. As such, it provides an important opportunity for understanding the role of inflammation in the development of fatigue. Motivation and motivated behavior also provide good examples for illustrating the importance of assessing the multidimensional aspects of fatigue in both subjective and objective ways. Indeed, subjective and objective fatigue have been found to not always correlate , indicating that they may represent distinct underlying concepts.
The common assumption of the motivational consequences of inflammation is loss of motivation, as sickness behavior includes decreased appetite, reduced activities, etc. Reduced motivation to perform activities that we usually like is indeed strongly associated with sickness. This is reflected in studies using experimental inflammation (e.g., experimentally activating the immune system using intravenous injection of a bacterial endotoxin), where individuals report an overall lack of interest , and exhibit reduced brain activity in the ventral striatum in response to monetary reward . This notion was similarly suggested in earlier work in rodents, which showed reduced willingness to expend effort in order to obtain a reward (e.g., food) during experimental inflammation [33, 34].
However, the effect of inflammation on motivated behavior appears to be more complex . Two recent studies published in Neuropsychopharmacology used objective tasks, similar to the effort-basted decision-making paradigms used in rodents, to assess the effect of experimental inflammation on motivated behavior in humans [2, 3]. Both studies showed that inflammation modulates incentive motivation (i.e., the willingness to expend effort) rather than reward sensitivity (i.e., liking of the reward). However, these two studies demonstrated opposite effects of inflammation on the willingness to expend effort in order to obtain a monetary reward. In one study, participants chose to perform fewer monetarily rewarding effortful tasks during experimental inflammation , and in the other, inflammation increased the willingness to expend effort in order to get a monetary reward when the probability to get the reward was high . However, in the second study, participants could not choose to rest. They were instead put in a forced-choice condition between high effort/high reward and low effort/low reward tasks. In other words, when some effort was required, participants chose the task that was deemed worthwhile (i.e., with a high probability to get the reward), and even more so during experimental inflammation . Interestingly, this result was in line with a previous study performed in mice, where experimental inflammation lead to proportionally choosing the high-effort, high-reward (chocolate) task more often than the low-effort, low-reward (grain) task . Increased motivation has also been measured at the subjective level during inflammation, with people exhibiting higher motivation to be close to people that may provide care, such as a family member .
Altogether, these studies strengthen the notion that inflammation induces a reorganization of motivational priorities [37, 38]. This implies that motivational changes induced by inflammation depend on the nature and context of the task . This is reflected in reduced motivation to perform tasks that could jeopardize the body while fighting infection or that can be postponed until the body has recovered, but also in increased motivation for comforting or caring rewards.
The role of inflammation in the development of pathological fatigue remains relevant but unclear. We argue for the need of multidimensional assessments as well as for a combination of subjective and objective measures to better comprehend the effects of inflammation on fatigue.
Julie Lasselin1,2,3, Bianka Karshikoff3,4, Tina Sundelin3,5 – 1 Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Essen, Germany; 2 Stress Research Institute, Stockholm University, Stockholm, Sweden; 3Department of Clinical Neuroscience, Division for Psychology, Karolinska Institutet, Stockholm, Sweden; 4 Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University School of Medicine, Palo Alto, USA; 5 Department of Psychology, New York University, New York, USA;
Contacts: Julie Lasselin, Stress Research Institute, Stockholm University, SE-106 91 Stockholm, Sweden; email: email@example.com
1 Karshikoff B, Sundelin T, Lasselin J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. Front Immunol 2017; 8: 21.
2 Lasselin J, Treadway MT, Lacourt TE, et al. Lipopolysaccharide Alters Motivated Behavior in a Monetary Reward Task: a Randomized Trial. Neuropsychopharmacology 2017; 42: 801-10.
3 Draper A, Koch RM, van der Meer JW, Aj Apps M, Pickkers P, Husain M, van der Schaaf ME. Effort but not Reward Sensitivity is Altered by Acute Sickness Induced by Experimental Endotoxemia in Humans. Neuropsychopharmacology 2017.
4 Irwin MR, Eisenberger NI. Context-Dependent Effects of Inflammation: Reduced Reward Responding is Not an Invariant Outcome of Sickness. Neuropsychopharmacology 2017; 42: 785-6.
5 Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, Powell JB. Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA 1988; 260: 929-34.
6 Kroenke K, Stump T, Clark DO, Callahan CM, McDonald CJ. Symptoms in hospitalized patients: outcome and satisfaction with care. Am J Med 1999; 107: 425-31.
7 Lasselin J, Capuron L. Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation 2014; 21: 95-101.
8 Weiland TJ, Jelinek GA, Marck CH, Hadgkiss EJ, van der Meer DM, Pereira NG, Taylor KL. Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet. PLoS One 2015; 10: e0115541.
9 Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56: 819-24.
10 DeLuca J. Fatigue as a window to the brain. The MIT Press. 2005.
11 Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315-25.
12 Boksem MA, Tops M. Mental fatigue: costs and benefits. Brain research reviews 2008; 59: 125-39.
13 Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet 2004; 363: 978-88.
14 Poulson MJ. Not just tired. J Clin Oncol 2001; 19: 4180-1.
15 Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001; 15: 7-24.
16 Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988; 12: 123-37.
17 Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun 2012; 26: 1202-10.
18 Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun 2013; 30 Suppl: S48-57.
19 Orre IJ, Reinertsen KV, Aukrust P, Dahl AA, Fossa SD, Ueland T, Murison R. Higher levels of fatigue are associated with higher CRP levels in disease-free breast cancer survivors. J Psychosom Res 2011; 71: 136-41.
20 Lasselin J, Laye S, Dexpert S, Aubert A, Gonzalez C, Gin H, Capuron L. Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun 2012; 26: 1211-9.
21 Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 2006; 77: 34-9.
22 Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 2012; 33: 315-27.
23 Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M, Harrison NA. Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue. Biol Psychiatry 2016; 79: 320-8.
24 Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS, Miller AH. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 2005; 58: 190-6.
25 Hannestad J, Subramanyam K, Dellagioia N, Planeta-Wilson B, Weinzimmer D, Pittman B, Carson RE. Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans. J Nucl Med 2012; 53: 601-7.
26 Lekander M, Karshikoff B, Johansson E, et al. Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation. Brain Behav Immun 2016; 56: 34-41.
27 Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry 2009; 66: 415-22.
28 Orre IJ, Murison R, Dahl AA, Ueland T, Aukrust P, Fossa SD. Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic cancer-related fatigue. Brain Behav Immun 2009; 23: 868-74.
29 de Raaf PJ, Sleijfer S, Lamers CH, Jager A, Gratama JW, van der Rijt CC. Inflammation and fatigue dimensions in advanced cancer patients and cancer survivors: an explorative study. Cancer 2012; 118: 6005-11.
30 Leavitt VM, DeLuca J. Central fatigue: issues related to cognition, mood and behavior, and psychiatric diagnoses. PM & R : the journal of injury, function, and rehabilitation 2010; 2: 332-7.
31 DellaGioia N, Devine L, Pittman B, Hannestad J. Bupropion pre-treatment of endotoxin-induced depressive symptoms. Brain Behav Immun 2013; 31: 197-204.
32 Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010; 68: 748-54.
33 Merali Z, Brennan K, Brau P, Anisman H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl) 2003; 165: 413-8.
34 Nunes EJ, Randall PA, Estrada A, et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Psychopharmacology (Berl) 2014; 231: 727-36.
35 Vichaya EG, Hunt SC, Dantzer R. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Neuropsychopharmacology 2014; 39: 2884-90.
36 Inagaki TK, Muscatell KA, Irwin MR, et al. The role of the ventral striatum in inflammatory-induced approach toward support figures. Brain Behav Immun 2015; 44: 247-52.
37 Aubert A, Goodall G, Dantzer R, Gheusi G. Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating mice. Brain Behav Immun 1997; 11: 107-18.
38 Larson SJ. Behavioral and motivational effects of immune-system activation. J Gen Psychol 2002; 129: 401-14.
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