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      Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms

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          Abstract

          Fatigue is a highly disabling symptom in various medical conditions. While inflammation has been suggested as a potential contributor to the development of fatigue, underlying mechanisms remain poorly understood. In this review, we propose that a better assessment of central fatigue, taking into account its multidimensional features, could help elucidate the role and mechanisms of inflammation in fatigue development. A description of the features of central fatigue is provided, and the current evidence describing the association between inflammation and fatigue in various medical conditions is reviewed. Additionally, the effect of inflammation on specific neuronal processes that may be involved in distinct fatigue dimensions is described. We suggest that the multidimensional aspects of fatigue should be assessed in future studies of inflammation-induced fatigue and that this would benefit the development of effective therapeutic interventions.

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          Adaptive goal-directed behavior involves monitoring of ongoing actions and performance outcomes, and subsequent adjustments of behavior and learning. We evaluate new findings in cognitive neuroscience concerning cortical interactions that subserve the recruitment and implementation of such cognitive control. A review of primate and human studies, along with a meta-analysis of the human functional neuroimaging literature, suggest that the detection of unfavorable outcomes, response errors, response conflict, and decision uncertainty elicits largely overlapping clusters of activation foci in an extensive part of the posterior medial frontal cortex (pMFC). A direct link is delineated between activity in this area and subsequent adjustments in performance. Emerging evidence points to functional interactions between the pMFC and the lateral prefrontal cortex (LPFC), so that monitoring-related pMFC activity serves as a signal that engages regulatory processes in the LPFC to implement performance adjustments.
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            Dimensional assessment of chronic fatigue syndrome.

            The absence of laboratory tests and clear criteria to identify homogeneous (sub)groups in patients presenting with unexplained fatigue, and to assess clinical status and disability in these patients, calls for further assessment methods. In the present study, a multi-dimensional approach to the assessment of chronic fatigue syndrome (CFS) is evaluated. Two-hundred and ninety-eight patients with CFS completed a set of postal questionnaires that assessed the behavioural, emotional, social, and cognitive aspects of CFS. By means of statistical analyses nine relatively independent dimensions of CFS were identified along which CFS-assessment and CFS-research can be directed. These dimensions were named: psychological well-being, functional impairment in daily life, sleep disturbances, avoidance of physical activity, neuropsychological impairment, causal attributions related to the complaints, social functioning, self-efficacy expectations, and subjective experience of the personal situation. A description of the study sample on these dimensions is presented.
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              Common regions of the human frontal lobe recruited by diverse cognitive demands.

              Though many neuroscientific methods have been brought to bear in the search for functional specializations within prefrontal cortex, little consensus has emerged. To assess the contribution of functional neuroimaging, this article reviews patterns of frontal-lobe activation associated with a broad range of different cognitive demands, including aspects of perception, response selection, executive control, working memory, episodic memory and problem solving. The results show a striking regularity: for many demands, there is a similar recruitment of mid-dorsolateral, mid-ventrolateral and dorsal anterior cingulate cortex. Much of the remainder of frontal cortex, including most of the medial and orbital surfaces, is largely insensitive to these demands. Undoubtedly, these results provide strong evidence for regional specialization of function within prefrontal cortex. This specialization, however, takes an unexpected form: a specific frontal-lobe network that is consistently recruited for solution of diverse cognitive problems.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                20 January 2017
                2017
                : 8
                : 21
                Affiliations
                [1] 1Division for Psychology, Department of Clinical Neuroscience, Karolinska Institutet , Solna, Sweden
                [2] 2Stress Research Institute, Stockholm University , Stockholm, Sweden
                [3] 3Department of Psychology, Stockholm University , Stockholm, Sweden
                [4] 4Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen , Essen, Germany
                Author notes

                Edited by: Sanae Hasegawa-Ishii, Pennsylvania State University, USA

                Reviewed by: Urs Nater, University of Marburg, Germany; Anna Fogdell-Hahn, Karolinska Institutet, Sweden

                *Correspondence: Julie Lasselin, julie.lasselin@ 123456uk-essen.de

                Specialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00021
                5247454
                28163706
                c25b6161-74a8-4285-ad31-af13e7b36d02
                Copyright © 2017 Karshikoff, Sundelin and Lasselin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 September 2016
                : 05 January 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 146, Pages: 12, Words: 10115
                Funding
                Funded by: Alexander von Humboldt-Stiftung 10.13039/100005156
                Funded by: Vetenskapsrådet 10.13039/501100004359
                Funded by: Forskningsrådet för Arbetsliv och Socialvetenskap 10.13039/501100001861
                Funded by: Hjärt-Lungfonden 10.13039/501100003793
                Funded by: Hjärnfonden 10.13039/501100003792
                Categories
                Immunology
                Review

                Immunology
                central fatigue,inflammation,immune system,multidimensional assessments,motivation,ventral striatum,anterior cingulate cortex,insula

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