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| 2. |
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| 3. |
- Aeinehband, Shahin, et al.
(författare)
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Cerebrospinal fluid kynurenines in multiple sclerosis : relation to disease course and neurocognitive symptoms
- 2016
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 51, s. 47-55
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, with a high rate of neurocognitive symptoms for which the molecular background is still uncertain. There is accumulating evidence for dysregulation of the kynurenine pathway (KP) in different psychiatric and neurodegenerative conditions. We here report the first comprehensive analysis of cerebrospinal fluid (CSF) kynurenine metabolites in MS patients of different disease stages and in relation to neurocognitive symptoms. Levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) were determined with liquid chromatography mass spectrometry in cell-free CSF. At the group level MS patients (cohort 1; n = 71) did not differ in absolute levels of TRP, KYN, KYNA or QUIN as compared to non-inflammatory neurological disease controls (n = 20). Stratification of patients into different disease courses revealed that both absolute QUIN levels and the QUIN/KYN ratio were increased in relapsing-remitting MS (RRMS) patients in relapse. Interestingly, secondary progressive MS (SPMS) displayed a trend for lower TRP and KYNA, while primary progressive (PPMS) patients displayed increased levels of all metabolites, similar to a group of inflammatory neurological disease controls (n = 13). In the second cohort (n = 48), MS patients with active disease and short disease duration were prospectively evaluated for neuropsychiatric symptoms. In a supervised multivariate analysis using orthogonal projection to latent structures (OPLS-DA) depressed patients displayed higher KYNA/TRP and KYN/TRP ratios, mainly due to low TRP levels. Still, this model had low predictive value and could not completely separate the clinically depressed patients from the non-depressed MS patients. No correlation was evident for other neurocognitive measures. Taken together these results demonstrate that clinical disease activity and differences in disease courses are reflected by changes in KP metabolites. Increased QUIN levels of RRMS patients in relapse and generally decreased levels of TRP in SPMS may relate to neurotoxicity and failure of remyelination, respectively. In contrast, PPMS patients displayed a more divergent pattern more resembling inflammatory conditions such as systemic lupus erythematosus. The pattern of KP metabolites in RRMS patients could not predict neurocognitive symptoms.
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| 4. |
- Albrecht, Daniel S., et al.
(författare)
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Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 75, s. 72-83
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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| 5. |
- Andreasson, Anna N., et al.
(författare)
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Contemplate your symptoms and re-evaluate your health
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 49, s. e38-e39
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Tidskriftsartikel (refereegranskat)abstract
- Bodily signals and how these are interpreted affect self-ratings of health. It is thus reasonable that appraisals of health are affected by imminent exposures and disease primes. We aimed to investigate whether self-ratings of health are affected by a symptom rating and if changes are substantiated in persons who report more symptoms. We used data from 813 persons who completed a questionnaire daily for 21 consecutive days. The questionnaire included a one-item self-rating of health (“pre-SRH”; 1 = excellent, 7 = very poor), a subsequent 26-item rating of physical and mental symptoms and thereafter a second (identical) self-rating of health (“post-SRH”). Paired t-tests were used to test for differences between pre-SRH and post-SRH. Mixed effect regression models were used to calculate the interaction effect of pre-SRH and symptom score on post-SRH adjusted for gender, age and if the person had been working that day (13545 observations). SRH worsened significantly (p <<.0001) after the symptom rating, from 2.72 pre-SRH (95%CI:−2.70–2.74) to 2.77 post-SRH (95%CI:2.75–2.79). There was a significant interaction between pre-SRH and symptoms on post-SRH so that persons who reported more symptoms changed their post-SRH rating to a higher degree than those who reported fewer symptoms, irrespective of their subjective health status. The results support the notion that subjective health perception is affected by focus of attention, and that the effect depends on level of symptoms.
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| 6. |
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| 7. |
- Arnberg, Filip K., et al.
(författare)
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Self-rated health and interleukin-6 : Longitudinal relationships in older adults
- 2016
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 54, s. 226-232
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Tidskriftsartikel (refereegranskat)abstract
- Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic. Objective: To study the between- and within-person associations between SRH and IL-6. Methods: Older adults (N = 131; M-age = 75 years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6 months over a period up to 5 years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models. Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p < .001) but not dynamic SRH (within-person changes; p = .93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model. Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.
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| 8. |
- Athanasiu, L., et al.
(författare)
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A genetic association study of CSMD1 and CSMD2 with cognitive function
- 2017
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 61, s. 209-216
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Tidskriftsartikel (refereegranskat)abstract
- The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease. (C) 2016 The Authors. Published by Elsevier Inc.
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| 9. |
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| 10. |
- Bay-Richter, Cecilie, et al.
(författare)
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A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality
- 2015
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 43, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. (C) 2014 Elsevier Inc. All rights reserved.
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| 11. |
- Bersani, Francesco S, et al.
(författare)
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A population of atypical CD56(-)CD16(+) natural killer cells is expanded in PTSD and is associated with symptom severity
- 2016
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 56:August 2016, s. 264-270
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity.METHODS: We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI.RESULTS: PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074).DISCUSSION: This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.
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| 12. |
- Bersani, Francesco Saverio, et al.
(författare)
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Global arginine bioavailability, a marker of nitric oxide synthetic capacity, is decreased in PTSD and correlated with symptom severity and markers of inflammation.
- 2016
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 52:oct 26, s. 153-160
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+ citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Chaskiel, Lea, et al.
(författare)
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Interleukin-1 reduces food intake and body weight in rat by acting in the arcuate hypothalamus
- 2019
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 81, s. 560-573
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Tidskriftsartikel (refereegranskat)abstract
- A reduction in food intake is commonly observed after bacterial infection, a phenomenon that can be reproduced by peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-lbeta (IL-1 beta), a pro-inflammatory cytokine released by LPS-activated macrophages. The arcuate nucleus of the hypothalamus (ARH) plays a major role in food intake regulation and expresses IL-1 type 1 receptor (IL-1R1) mRNA. In the present work, we tested the hypothesis that IL-1R1 expressing cells in the ARH mediate IL-1 beta and/or LPS-induced hypophagia in the rat. To do so, we developed an IL-1 beta-saporin conjugate, which eliminated IL-R1 expressing neurons in the hippocampus, and micro-injected it into the ARH prior to systemic IL-1 beta and LPS administration. ARH IL-1 beta-saporin injection resulted in loss of neuropeptide Y-containing cells and attenuated hypophagia and weight loss after intraperitoneal IL-1 beta, but not LPS, administration. In conclusion, the present study shows that ARH NPY-containing neurons express functional IL-1R1s that mediate peripheral IL-1 beta-, but not LPS-, induced hypophagia. Our present and previous findings indicate that the reduction of food intake after IL-1 beta and LPS are mediated by different neural pathways.
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| 17. |
- Chhor, Vibol, et al.
(författare)
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Role of microglia in a mouse model of paediatric traumatic brain injury.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 63, s. 197-209
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Tidskriftsartikel (refereegranskat)abstract
- The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.
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| 18. |
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| 19. |
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| 22. |
- Fritz, Michael, 1981-, et al.
(författare)
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Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
- 2018
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Ingår i: Brain, behavior, and immunity. - Maryland Heights : Academic Press. - 0889-1591 .- 1090-2139. ; 67, s. 54-58
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Tidskriftsartikel (refereegranskat)abstract
- Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.
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| 23. |
- Henderson, Audrey J., et al.
(författare)
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Skin colour changes during experimentally-induced sickness
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 60, s. 312-318
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Tidskriftsartikel (refereegranskat)abstract
- Skin colour may be an important cue to detect sickness in humans but how skin colour changes with acute sickness is currently unknown. To determine possible colour changes, 22 healthy Caucasian participants were injected twice, once with lipopolysaccharide (LPS, at a dose of 2ng/kg body weight) and once with placebo (saline), in a randomised cross-over design study. Skin colour across 3 arm and 3 face locations was recorded spectrophotometrically over a period of 8h in terms of lightness (L(∗)), redness (a(∗)) and yellowness (b(∗)) in a manner that is consistent with human colour perception. In addition, carotenoid status was assessed as we predicted that a decrease it skin yellowness would reflect a drop in skin carotenoids. We found an early change in skin colouration 1-3h post LPS injection with facial skin becoming lighter and less red whilst arm skin become darker but also less red and less yellow. The LPS injection also caused a drop in plasma carotenoids from 3h onwards. However, the timing of the carotenoid changes was not consistent with the skin colour changes suggesting that other mechanisms, such as a reduction of blood perfusion, oxygenation or composition. This is the first experimental study characterising skin colour associated with acute illness, and shows that changes occur early in the development of the sickness response. Colour changes may serve as a cue to health, prompting actions from others in terms of care-giving or disease avoidance. Specific mechanisms underlying these colour changes require further investigation.
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| 24. |
- Isgren, Anniella, et al.
(författare)
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Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment.
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 43, s. 198-204
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.
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| 25. |
- Isgren, Anniella, et al.
(författare)
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Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 65, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- Neuroimmune mechanisms have been linked to the pathophysiology of bipolar disorder based on studies of biomarkers in plasma, cerebrospinal fluid (CSF), and postmortem brain tissue. There are, however, no longitudinal studies investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in patients with bipolar disorder. We have in previous studies found higher CSF concentrations of interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1/CCL-2), chitinase-3-like protein 1 (CHI3L1/YKL-40), and neurofilament light chain (NF-L) in euthymic patients with bipolar disorder compared with controls. Here, we investigated the relationship of these CSF markers of neuroinflammation and neuronal injury with clinical outcomes in a prospective study. 77 patients with CSF analyzed at baseline were followed for 6-7years. Associations of baseline biomarkers with clinical outcomes (manic/hypomanic and depressive episodes, suicide attempts, psychotic symptoms, inpatient care, GAF score change) were investigated. Baseline MCP-1 concentrations were positively associated with manic/hypomanic episodes and inpatient care during follow-up. YKL-40 concentrations were negatively associated with manic/hypomanic episodes and with occurrence of psychotic symptoms. The prospective negative association between YKL-40 and manic/hypomanic episodes survived multiple testing correction. Concentrations of IL-8 and NF-L were not associated with clinical outcomes. High concentrations of these selected CSF markers of neuroinflammation and neuronal injury at baseline were not consistently associated with poor clinical outcomes in this prospective study. The assessed proteins may be involved in adaptive immune processes or reflect a state of vulnerability for bipolar disorder rather than being of predictive value for disease progression.
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| 26. |
- Kanegawa, Naoki, et al.
(författare)
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In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects
- 2016
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 54, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.
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| 27. |
- Karshikoff, B., et al.
(författare)
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LPS increases pain sensitivity by decreased pain inhibition and increased insular activation
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 49, s. e1-e1
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Tidskriftsartikel (refereegranskat)abstract
- We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders.
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| 28. |
- Karshikoff, Bianka, et al.
(författare)
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Why sickness hurts : A central mechanism for pain induced by peripheral inflammation
- 2016
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 57, s. 38-46
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Tidskriftsartikel (refereegranskat)abstract
- Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.
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| 29. |
- Kosek, Eva, et al.
(författare)
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The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia
- 2016
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 58, s. 218-227
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Tidskriftsartikel (refereegranskat)abstract
- The translocator protein (TSPO) is upregulated during glia activation in chronic pain patients. TSPO constitutes the rate-limiting step in neurosteroid synthesis, thus modulating synaptic transmission. Related serotonergic mechanisms influence if pro- or anti-nociceptive neurosteroids are produced. This study investigated the effects of a functional genetic polymorphism regulating the binding affinity to the TSPO, thus affecting symptom severity and cerebral pain processing in fibromyalgia patients. Gene-to-gene interactions with a functional polymorphism of the serotonin transporter gene were assessed. Fibromyalgia patients (n = 126) were genotyped regarding the polymorphisms of the TSPO (rs6971) and the serotonin transporter (5-HTTLPR/rs25531). Functional magnetic resonance imaging (n = 24) was used to study brain activation during individually calibrated pressure pain. Compared to mixed/low TSPO affinity binders, the high TSPO affinity binders rated more severe pain (p = 0.016) and fibromyalgia symptoms (p = 0.02). A significant interaction was found between the TSPO and the serotonin transporter polymorphisms regarding pain severity (p < 0.0001). Functional connectivity analyses revealed that the TSPO high affinity binding group had more pronounced pain-evoked functional connectivity in the right frontoparietal network, between the dorsolateral prefrontal area and the parietal cortex. In conclusion, fibromyalgia patients with the TSPO high affinity binding genotype reported a higher pain intensity and more severe fibromyalgia symptoms compared to mixed/low affinity binders, and this was modulated by interaction with the serotonin transporter gene. To our knowledge this is the first evidence of functional genetic polymorphisms affecting pain severity in FM and our findings are in line with proposed glia-related mechanisms. Furthermore, the functional magnetic resonance findings indicated an effect of translocator protein on the affective-motivational components of pain perception.
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| 30. |
- Lai, Jacqueline, 1980, et al.
(författare)
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Immune responses in perinatal brain injury.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 63, s. 210-223
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Forskningsöversikt (refereegranskat)abstract
- The perinatal period has often been described as immune deficient. However, it has become clear that immune responses in the neonate following exposure to microbes or as a result of tissue injury may be substantial and play a role in perinatal brain injury. In this article we will review the immune cell composition under normal physiological conditions in the perinatal period, both in the human and rodent. We will summarize evidence of the inflammatory responses to stimuli and discuss how neonatal immune activation, both in the central nervous system and in the periphery, may contribute to perinatal hypoxic-ischemic brain injury.
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| 31. |
- Lasselin, Julie, et al.
(författare)
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Effect of long-term sleep restriction and subsequent recovery sleep on the diurnal rhythms of white blood cell subpopulations.
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 47:SI, s. 93-99
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Tidskriftsartikel (refereegranskat)abstract
- While acute modifications of sleep duration induces a wide array of immune function alterations, less is known of how longer periods with insufficient sleep affect immune functions and how they return to normal once recovery sleep is obtained. The purpose of the present study was to investigate the effects of five days of restricted sleep and a subsequent 7-day period of sleep recovery on white blood cell (WBC) subpopulation count and diurnal rhythms. Nine healthy males participated in a sleep protocol consisting of two baseline days (8h of sleep/night), five nights with restricted sleep (4h of sleep/night) and seven days of recovery sleep (8h of sleep/night). During nine of these days, blood was drawn hourly during night-time end every third hour during daytime, and differential WBC count was analyzed. Gradual increase across the days of sleep restriction was observed for total WBC (p<.001), monocytes (p<.001), neutrophils (p<.001) and lymphocytes (p<.05). Subsequent recovery sleep resulted in a gradual decrease in monocytes (p<.001) and lymphocytes (p=.001), but not in neutrophils that remained elevated over baseline level at the end of the 7-day recovery period. These effects were associated with altered diurnal rhythms of total WBC and neutrophils, restricted sleep being associated with higher levels during the night and at awakening, resulting in a flattening of the rhythm. The diurnal alterations were reversed when recovery sleep was allowed, although the amplitude of total WBC, neutrophils and monocytes was increased at the end of the recovery period in comparison to baseline. Altogether, these data show that long-term sleep restriction leads to a gradual increase of circulating WBC subpopulations and alterations of the respective diurnal rhythms. Although some of the effects caused by five days of restricted sleep were restored within the first days of recovery, some parameters were not back to baseline even after a period of seven recovery days.
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| 32. |
- Lasselin, Julie, 1986-, et al.
(författare)
-
Inflammation-related gait- Analysis of biological motion using the Microsoft® Kinect® during experimentally-induced sickness
- 2017
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 66
-
Tidskriftsartikel (refereegranskat)abstract
- Biological motion is a powerful communication cue and we have recently shown that sickness can be detected from gait pattern. However, it is unclear which gait characteristics are modulated by health status and whether change in gait pattern relates to inflammation and to the degree of sickness. The current study aimed at answering these questions by assessing biological motion characteristics in 19 individuals during experimentally-induced sickness, obtained by intravenous injection of lipopolysaccharide (2 ng/kg bw), and after placebo administration. Joint 3-D coordinates were recorded using the Microsoft® Kinect® during a walking paradigm and a mobility test (time-up-and-go test). Results indicate that gait during experimentally-induced sickness is characterized by slower and shorter strides, resulting in slower walking speed, as well as a slower time to stand up from a chair. In addition, sick subjects appear to swing their arms and to lift their legs less than when healthy, as reflected by smaller elbow angle during arm extension and larger knee angle during leg flexion compared to the placebo condition. Alterations in the overall gait pattern during experimentally-induced sickness was associated with interleukin-6 peak concentrations and a trend was observed with sickness symptoms. Altogether, these findings suggest that gait pattern might signal sickness/inflammatory status and could be used as an objective assessment of sickness, as well as to determine evolution of health status in individuals over time.
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| 33. |
- Lasselin, Julie, et al.
(författare)
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Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects
- 2016
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 58, s. 63-68
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Tidskriftsartikel (refereegranskat)abstract
- Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra-dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5 mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra-dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5 mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects.
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| 34. |
- Lasselin, Julie, et al.
(författare)
-
Mood disturbance during experimental endotoxemia : Predictors of state anxiety as a psychological component of sickness behavior
- 2016
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 57, s. 30-37
-
Tidskriftsartikel (refereegranskat)abstract
- Lipopolysaccharide (LPS) administration is a well-established model to assess afferent immune-to-brain communication and behavioral aspects of inflammation. Nevertheless, only few studies in comparatively small samples have assessed state anxiety as a psychological component of sickness behavior despite possible clinical implications for the pathophysiology of neuropsychiatric conditions. Thus, the goal of the present analyses carried out in a large, pooled dataset from two independent study sites was to analyze the state anxiety response to LPS administration and to investigate predictors (i.e., cytokine changes; pre-existing anxiety and depression symptoms assessed with the Hospital Anxiety and Depression Scale) of the LPS-induced state anxiety changes at different time points after LPS administration. Data from 186 healthy volunteers who participated in one of six randomized, placebo-controlled human studies involving intravenous administration of LPS at doses of 0.4-0.8ng/kg body weight were combined. State anxiety as well as circulating interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 concentrations were significantly increased 2h and 3h after LPS administration, with a peak at 2h, and returned to baseline 6h after administration. Greater changes in IL-6 from baseline to 3h after LPS administration significantly and independently predicted a more pronounced LPS-induced state anxiety response. In addition, higher pre-existing subclinical anxiety symptoms significantly predicted a lower increase in state anxiety 3h and 6h after LPS-administration, which was mediated by TNF-α changes. In conclusion, our findings give additional support for a putative role of inflammatory mechanisms in the pathophysiology of stress-related and anxiety disorders and give new insight on the potential role of pre-existing subclinical affective symptoms.
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| 35. |
- Lasselin, Julie, et al.
(författare)
-
Pre-existent anxiety symptoms is associated with modified behavioral response during endotoxemia
- 2015
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 49, s. e29-e30
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental endotoxin administration is a well-established model to analyze the effect of inflammation on the development of mood impairments. However, it remains unknown from previous studies in comparatively small samples whether pre-existing inter-individual differences modulate the behavioral response during endotoxemia. We addressed this question in the present study using a merged database combining data from multiple studies performed at two study sites. In 286 healthy volunteers who either received low-dose intravenous injection of lipopolysaccharide (LPS, 0.4–0.8 ng/kg, n = 168) or saline (n = 118), plasma concentrations of TNF-alpha and IL-6 were analyzed before and 2, 3.5 and 6 hours post injection together with state anxiety symptoms (STAI). Pre-existent symptoms of anxiety and depression (HADS) were assessed before injection. LPS administration induced an increase in state anxiety 2 hours post injection that was positively correlated with increases in TNF-alpha and IL-6, but not with pre-existent HADS scores (when adjusted for age, sex, BMI, LPS dose, and study design). However, higher levels of pre-existent HADS anxiety symptoms predicted a stronger subsequent reduction in state anxiety at 3.5 and 6 hours post LPS injection. Taken together, these data suggest that although inter-individual differences in anxiety or depression symptoms do not appear to explain the extent of mood impairments during endotoxemia, at least in non-patient samples, they still lead to a modified mood response with a faster and stronger decline.
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| 36. |
- Lasselin, Julie, et al.
(författare)
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Sickness behavior is not all about the immune response : Possible roles of expectations and prediction errors in the worry of being sick
- 2018
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 74, s. 213-221
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPeople react very differently when sick, and there are only poor correlations between the intensity of the immune response and sickness behavior. Yet, alternative predictors of the individual differences in sickness are under-investigated. Based on the predictive coding model of placebo responses, where health outcomes are function of bottom-up sensory information and top-down expectancies, we hypothesized that individual differences in behavioral changes during sickness could be explained by individual top-down expectancies and prediction errors.MethodsTwenty-two healthy participants were made sick by intravenously administering lipopolysaccharide (2 ng/kg body weight). Their expectations of becoming sick were assessed before the injection.ResultsParticipants having lower expectations of becoming sick before the injection reacted with more emotional distress (i.e., more negative affect and lower emotional arousal) than those with high expectations of becoming sick, despite having similar overall sickness behavior (i.e., a combined factor including fatigue, pain, nausea and social withdrawal). In keeping with a predictive coding model, the “prediction error signal”, i.e., the discrepancy between the immune signal and sickness expectancy, predicted emotional distress (reduction in emotional arousal in particular).ConclusionThe current findings suggest that the emotional component of sickness behavior is, at least partly, shaped by top-down expectations. Helping patients having a realistic expectation of symptoms during treatment of an illness may thus reduce aggravated emotional responses, and ultimately improve patients’ quality of life and treatment compliance.Registration“Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences”, https://clinicaltrials.gov/ct2/show/NCT02529592, registration number: NCT02529592.
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| 37. |
- Lasselin, Julie, et al.
(författare)
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Sleep during naturally occurring respiratory infections : A pilot study
- 2019
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 79, s. 236-243
-
Tidskriftsartikel (refereegranskat)abstract
- There is strong experimental support that infections increase the drive for sleep in animals, and it is widely believed that more sleep is part of an adaptive immune response. While respiratory infections (RI) are very prevalent in humans, there is a striking lack of systematic knowledge on how it affects sleep. We recruited 100 people, among whom 28 became sick with an RI during the study period (fulfilling criteria for influenza-like illness, ILI, or acute respiratory infection, ARI). We measured sick participants' sleep at home, both objectively (actigraphy) and subjectively (diary ratings), for one week as well as four weeks later when healthy. During the week with RI, people spent objectively longer time in bed and had a longer total sleep time compared to the healthy week. During the infection, participants also had more awakenings, but no significant differences in sleep latency or sleep efficiency. While sick, people also reported increased difficulties falling asleep, worse sleep quality, more restless sleep and more shallow sleep, while they did not report sleep to be less sufficient. Most problems occurred at the beginning of the sickness week, when symptoms were strong, and showed signs of recovery thereafter (as indicated by interactions between condition and day/night of data collection for all the 10 sleep outcomes). The degree of symptoms of RI was related to a worse sleep quality and more restless sleep, but not to any of the objective sleep outcomes or the other subjective sleep variables. Having a higher body temperature was not significantly related to any of the sleep variables. This study suggests that having a respiratory infection is associated with spending more time in bed and sleeping longer, but also with more disturbed sleep, both objectively and subjectively. This novel study should be seen as being of pilot character. There is a need for larger studies which classify pathogen type and include baseline predictors, or that manipulate sleep, in order to understand whether the sleep alterations seen during infections are adaptive and whether sleep interventions could be used to improve recovery from respiratory infections.
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| 38. |
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| 39. |
- Lekander, Mats, et al.
(författare)
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Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation
- 2016
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 56, s. 34-41
-
Tidskriftsartikel (refereegranskat)abstract
- Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double blind randomized controlled trial, 52 healthy volunteers were injected with 0.6 ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45 minutes. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.
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| 40. |
- Lekander, Mats, et al.
(författare)
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Longitudinal relationship between inflammation and poor self-rated health in elderly
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 49, s. e37-e37
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Tidskriftsartikel (refereegranskat)abstract
- Self-rated health (SRH) predicts future objective health and summarizes information in a way that goes beyond the biomedical health model. Low-grade inflammation contributes to poor SRH, but previous findings rely on cross-sectional analyses. We therefore studied the relationship between SRH and IL-6 in a longitudinal study of elderly. Participants (m = 74 years; range 60–93; 41% male) were studied in 6-month waves over a period up to 5 years. SRH was measured with a one-item question (excellent to poor). Serum was collected following the interview visit (median interval 40 days), frozen at −80 °C and later analyzed with high-sensitivity ELISA for IL-6. Overall, 999 observations were available for analysis. When analyzed as a between-subject effect, a stable relationship was observed between SRH and logIL-6 (β = −.088; p < .001). However, the within-subject effect of SRH on IL-6 was not significant. The effects were not explained by gender, age, BMI, neuroticism, or statin use. There was no main effect of interview-to-blood sample interval, neither between nor within subjects. Putative variations over time in the relation between SRH and IL-6 could thus not be captured with the present design. With the advantage of a longitudinal design and multiple sampling occasions, the present data strongly support the stability of the previously reported cross-sectional relationship between higher levels of inflammatory cytokines and less favorable health appraisals across individuals.
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| 41. |
- Lindqvist, Daniel, et al.
(författare)
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Increased pro-inflammatory milieu in combat related PTSD - A new cohort replication study
- 2017
-
Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 59, s. 260-264
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Several lines of evidence indicate that increased inflammation is associated with Post-Traumatic Stress Disorder (PTSD). We have previously reported that peripheral inflammatory markers are significantly higher in combat-exposed veterans with than without PTSD. This study was designed to replicate these findings in a new study cohort using the same population and recruitment strategies.METHODS: Sixty-one male war veterans (31 PTSD and 30 control subjects) were included in this replication study. Levels of Interleukin-6, Tumor Necrosis Factor-alpha, Gamma interferon, and high-sensitivity C-reactive protein were quantified in blood samples. A standardized "total pro-inflammatory score" was calculated to limit the number of statistical comparisons. The Clinician Administered PTSD Scale (CAPS) rating scale was used to assess PTSD symptom severity.RESULTS: PTSD subjects had significantly higher total pro-inflammatory scores compared to non-PTSD subjects in unadjusted analysis (Cohen's d=0.75, p=0.005) as well as after adjusting for potentially confounding effects of age, BMI, smoking, and potentially interfering medications and somatic co-morbidities (p=0.023). There were no significant correlations between inflammatory markers and severity of symptoms within the PTSD group.CONCLUSIONS: We replicated, in a new sample, our previous finding of increased inflammatory markers in combat-exposed PTSD subjects compared to combat-exposed non-PTSD controls. These findings strongly add to the growing literature suggesting that immune activation may be an important aspect of PTSD pathophysiology, although not directly correlated with current PTSD symptom levels in the PTSD group.
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| 42. |
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| 43. |
- Machado, Ivana, et al.
(författare)
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Interleukin-1 beta-induced memory reconsolidation impairment is mediated by a reduction in glutamate release and zif268 expression and alpha-melanocyte-stimulating hormone prevented these effects
- 2015
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 46, s. 137-146
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Tidskriftsartikel (refereegranskat)abstract
- The immune system is an important modulator of learning, memory and neural plasticity. Interleukin 1 13 (IL-1 beta), a pro-inflammatory cytokine, significantly affects several cognitive processes. Previous studies by our group have demonstrated that intrahippocampal administration of IL-1 beta impairs reconsolidation of contextual fear memory. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (alpha-MSH). The mechanisms underlying the effect of IL-1 beta on memory reconsolidation have not yet been established. Therefore, we examined the effect of IL-1 beta on glutamate release, ERK phosphorylation and the activation of the transcription factor zinc finger- 268 (zif268) during reconsolidation. Our results demonstrated that IL-1 beta induced a significant decrease of glutamate release after reactivation of the fear memory and this effect was related to calcium concentration in hippocampal synaptosomes. IL-1 beta also reduced ERK phosphorylation and zif268 expression in the hippocampus. Central administration of a-MSH prevented the decrease in glutamate release, ERK phosphorylation and zif268 expression induced by IL-1 beta. Our results establish possible mechanisms involved in the detrimental effect of IL-1 beta on memory reconsolidation and also indicate that a-MSH may exert a beneficial modulatory role in preventing IL-1 beta effects.
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| 44. |
- Magnusson Hanson, Linda L., et al.
(författare)
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Does inflammation provide a link between psychosocial work characteristics and diabetes? Analysis of the role of interleukin-6 and C-reactive protein in the Whitehall II cohort study
- 2019
-
Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 78, s. 153-160
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Inflammation may underlie the association between psychological stress and cardiometabolic diseases, but this proposition has not been tested longitudinally. We investigated whether the circulating inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) mediate the relationship between psychosocial work characteristics and diabetes. Methods: We used three phases of data at 5 years intervals from the Whitehall II cohort study, originally recruiting 10,308 civil service employees aged 35-55 years. The data included repeat self-reports of job demands, control and social support, IL-6 from plasma samples, CRP from serum samples, and diabetes, ascertained through oral glucose tolerance test, medications, and self-reports of doctor-diagnosed diabetes. Results: Structural equation models with age, sex and occupational position considering men and women combined, showed that low social support at work, but not high job demands or low job control, was prospectively associated with diabetes (standardized beta = 0.05, 95% confidence interval (CI) 0.01-0.09) and higher levels of IL-6 (beta = 0.03, CI 0.00-0.06). The inflammatory markers and diabetes were bidirectionally associated over time. A mediation model including workplace social support, IL-6 and diabetes further showed that 10% of the association between social support and diabetes over the three repeat examinations (total effect beta = 0.08, CI 0.01-0.15) was attributable to a weak indirect effect through IL-6 (beta = 0.01, CI 0.00-0.02). A similar indirect effect was observed for CRP in men only, while job control was prospectively associated with IL-6 among women. Conclusions: This study indicates an association between poor workplace support and diabetes that is partially ascribed to an inflammatory response.
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| 45. |
- Matsuwaki, Takashi, 1978-, et al.
(författare)
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Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses
- 2017
-
Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 66, s. 165-176
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Tidskriftsartikel (refereegranskat)abstract
- Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (1(0) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120 mu g/kg; HPA-axis: 120 mu g/kg), but showed attenuated but not extinguished fever (120 g/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-alpha (TNF alpha) inhibitor etanercept nor the IL -6 receptor antibody tocilizumab abolished the LPS induced fever in IL -1R1 KO mice. Deletion of IL -1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFa, but by some yet unidentified pyrogenic factor.
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| 46. |
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| 47. |
- Nilsson, Anna, et al.
(författare)
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Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.
- 2017
-
Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 61, s. 236-243
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Tidskriftsartikel (refereegranskat)abstract
- Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.
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| 48. |
- Nilsson, Anna, et al.
(författare)
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The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent
- 2017
-
Ingår i: Brain, behavior, and immunity. - : Academic Press. - 0889-1591 .- 1090-2139. ; 60, s. 27-31
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Tidskriftsartikel (refereegranskat)abstract
- From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.
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| 49. |
- Olsen, Laura K., et al.
(författare)
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Viral mimetic priming enhances α-synuclein-induced degeneration : implications for Parkinson's disease
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 80, s. 525-535
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Tidskriftsartikel (refereegranskat)abstract
- Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson’s disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson’s disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson’s disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson’s disease.
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- O'Toole, M. S., et al.
(författare)
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Effects of psychological interventions on systemic levels of inflammatory biomarkers in humans : A systematic review and meta-analysis
- 2018
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 74, s. 68-78
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Forskningsöversikt (refereegranskat)abstract
- The purpose of the present investigation was to systematically review randomized controlled trials examining the effects of psychological interventions on inflammatory biomarkers in adult populations and to quantitatively analyze those effects by meta-analysis. Two researchers independently searched key electronic databases, selected eligible publications, extracted data, and evaluated methodological quality. Nineteen randomized controlled trials examining a total of 1510 participants were included. The overall combined effect size from pre to post psychological intervention on pro-inflammatory biomarker levels was statistically significant, showing an attenuating effect, although of a small magnitude (s’ g = 0.15, p = .008, CI [0.04–0.26]). However, this effect was not maintained into the follow-up period (g < −0.01, p = .964, CI [−0.19–0.18]). Looking at the individual biomarkers assessed across studies, only C-reactive protein (CRP) was found to significantly decrease following psychological intervention. A number of moderation analyses were conducted, none of which reached statistical significance. However, the numerically largest – and significant – within-group effect size was obtained for the group of studies that had preselected participants based on elevated psychological distress (g = 0.29, p = .047). In conclusion, psychological interventions appear efficacious in reducing pro-inflammatory biomarker levels. Future studies are recommended to carefully select individuals based on inflammatory (e.g., the presence of low-grade inflammation) and/or psychological (e.g., psychological distress) criteria.
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