While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

Inflammation-induced sickness is associated with a large set of behavioral alterations; however, its motivational aspects remain poorly explored in humans. The present study assessed the effect of lipopolysaccharide (LPS) administration at a dose of 2 ng/kg of body weight on motivation in 21 healthy human subjects in a double-blinded, placebo (saline)-controlled, cross-over design. Incentive motivation and reward sensitivity were measured using the Effort Expenditure for Rewards Task (EEfRT), in which motivation for high-effort/high-reward trials vs low-effort/low-reward trials are manipulated by variations in reward magnitude and probability to win. Because of the strong interactions between sleepiness and motivation, the role of sleepiness was also determined. As expected, the probability to win predicted the choice to engage in high-effort/high-reward trials; however, this occurred at a greater extent after LPS than after saline administration. This effect was related to the level of sleepiness. Sleepiness increased motivation to choose the high-effort/high-reward mode of response, but only when the probability to win was the highest. LPS had no effect on reward sensitivity either directly or via sleepiness. These results indicate that systemic inflammation induced by LPS administration causes motivational changes in young healthy subjects, which are associated with sleepiness. Thus, despite its association with energy-saving behaviors, sickness allows increased incentive motivation when the effort is deemed worthwhile.

Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.

Introduction Experimental pain studies can provide unique insight into the dimensions of pain and into individual differences in pain responsiveness by controlling different aspects of pain-eliciting stimuli and pain measures. In experimental pain studies, pain responsiveness can be assessed as pain threshold, pain tolerance or pain ratings. The test-theoretical qualities of these different measures, however, have not yet been completely documented. In the current study, several of these qualities were investigated in a pain experiment applying different algometric techniques. The objective of the study was to investigate the reliability (test-retest) and the convergent validity (correspondence) of the different methods found in the literature of measuring pressure-pain threshold, and the interrelationship between pressure-pain threshold, pressure-pain tolerance, and pressure-pain ratings. Methods Sixty-six healthy female subjects were enrolled in the study. All pressure stimuli were applied by a trained investigator, using a digital algometer with a 1 cm2 rubber tip. Pressure-pain thresholds were assessed repeatedly on six different body points (i.e. left and right calf one third of total calf muscle length below the popliteal space), the lower back (5 cm left and right from the L3), and left and right forearm (thickest part of brachioradialis muscle). Next, pressure-pain tolerance was measured on the thumbnail of the non-dominant hand, followed by rating affective and sensory components (on visual analogue scales) of a stimulus at tolerance level. Last, affective and sensory ratings were obtained for two pressure intensities. Results With intraclass correlations above .75 for pain responses per body point, test-retest reliability was found to be good. However, values obtained from all first measurements were significantly higher as compared with the two succeeding ones. Convergent validity of pain thresholds across different body points was found to be high for all combinations assessed (Cronbach's alpha values >.80), but the highest for bilateral similar body parts (>.89). Finally, principal components analysis including measures of threshold, tolerance and pain ratings yielded a three-factor solution that explained 81.9% of the variance: Moderate-level stimulus appraisal & pain tolerance; Pain threshold; Tolerance-level stimulus appraisal. Conclusion and implications Findings of the current study were used to formulate recommendations for future algometric pain studies. Concerning pressure-pain threshold, it is recommended to exclude first measurements for every body point from further analyses, as these measurements were found to be consistently higher compared with the following measurements. Further, no more than two consecutive measurements (after the first measurement) are needed for a reliable mean threshold value per body point. When combining threshold values of several body points into one mean-aggregated threshold value, we suggest to combine bilateral similar points, as convergent validity values w...

The finding of symptom specific patterns in clusters which could not be differentiated on overall symptom severity is in favor of the splitters' view. The finding that all other clusters could be discriminated on overall symptom severity and that the 2-cluster solution had the best fit is in favor of the lumpers' view.