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  • 1. Albrecht, Daniel S.
    et al.
    Forsberg, Anton
    Sandstrom, Angelica
    Bergan, Courtney
    Kadetoff, Diana
    Protsenko, Ekaterina
    Lampa, Jon
    Lee, Yvonne C.
    Hoglund, Caroline Olgart
    Catana, Ciprian
    Cervenka, Simon
    Akeju, Oluwaseun
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Cohen, George
    Halldin, Christer
    Taylor, Norman
    Kim, Minhae
    Hooker, Jacob M.
    Edwards, Robert R.
    Napadow, Vitaly
    Kosek, Eva
    Loggia, Marco L.
    Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 75, p. 72-83Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Jones, M. P.
    Walker, M. M.
    Talley, N. J.
    Nyhlin, H.
    Agréus, L.
    Prediction pathways for innate immune pathology, IBS, anxiety and depression in a general population (The POPCOL Study)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, p. e46-e46Article in journal (Other academic)
    Abstract [en]

    The aim of this study was to ascertain whether low grade innate inflammation contributes to a pathway of depression and anxiety via irritable bowel syndrome (IBS). We evaluated innate immune cell counts in colonic mucosa in normal subjects and those with IBS (Rome III) from a population based study in which 745 randomly selected subjects had a colonoscopy (mean age 51 years;57% women). Intraepithelial lymphocytes (IELs) per 100 enterocytes and eosinophils (eos) per five non-overlapping high power fields (HPF) were counted in 90 controls and 100 cases; immunocytochemistry (CD117) was performed for mast cells per 5HPF in 80 controls and 81 cases. IELs, mast cells and eos were individually summed over 5 sites (terminal ileum, caecum, transverse colon, sigmoid colon and rectum). Anxiety and depression scores were calculated from HADS. A causal model path model which hypothesises immune cells being associated with IBS which, in turn, is associated with elevated anxiety and depression was tested using path analysis implemented in the MPlus software. All hypothesised paths reached statistical significance (p < .05) supporting the individual hypothesized pathways. The overall model fit was reasonable although imperfect. In conclusion, a significant contribution of innate immune inflammatory load leading to anxiety and depression via IBS was found. Whether therapy directed to decreasing this inflammatory load also lifts depression and anxiety should be further explored.

  • 3.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Schiller, Helena
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Contemplate your symptoms and re-evaluate your health2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e38-e39Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Wicksell, B.
    Karshikoff, B.
    Lodin, K.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Development and preliminary validation of the Sickness Questionnaire (SicknessQ)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, article id e14Article in journal (Refereed)
    Abstract [en]

    The lack of questionnaires to measure subjective feelings of being sick made us develope the Sickness Questionnaire (SicknessQ) for assessment of sickness behavior in people. The objective of the present investigation was to test its internal consistency, criteria validity, and sensitivity to capture the sickness response in an experimental setting. An initial pool of items was developed based on previous research. The statistical properties of SicknessQ was assessed in 172 men and women primary care patients with acute complaints and involved three steps: (1) principal component analyses to reduce the number of items and to identify latent factor structures, (2) tests of internal consistencies of subscales, and (3) hierarchical regression analyses to test criteria validity of the subscales. Subsequently, sensitivity to change was tested in a placebo controlled experiment in which 31 blinded healthy men and women were injected with endotoxin (LPS) to provoke sickness behavior. Principal components analysis suggested a 3-factor solution with a total of 11 items measuring fatigue (5 items), pain (4 items) and emotion (2 items). The total scale as well as each of the three separate factors were significantly changed 90 min after endotoxin injection as compared to baseline (p’s < .01). In all, the new 11-item SicknessQ is highly sensitive to a mild systemic inflammation. Further studies are planned to test its usefulness and prognostic value in clinical settings.

  • 5.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Morey, Jennifer N.
    Segerström, Suzanne C.
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 226-232Article in journal (Refereed)
    Abstract [en]

    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; Mage=75years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6months over a period up to 5years. 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.

  • 6. Athanasiu, Lavinia
    et al.
    Giddaluru, Sudheer
    Fernandes, Carla
    Christoforou, Andrea
    Reinvang, Ivar
    Lundervold, Astri J.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Kauppi, Karolina
    Adolfsson, Rolf
    Eriksson, Elias
    Sundet, Kjetil
    Djurovic, Srdjan
    Espeseth, Thomas
    Nyberg, Lars
    Steen, Vidar M.
    Andreassen, Ole A.
    Le Hellard, Stephanie
    A genetic association study of CSMD1 and CSMD2 with cognitive function2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 209-216Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, B.
    Hedman, E.
    Is health anxiety related to disease avoidance?2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, article id e47Article in journal (Refereed)
  • 8. Fondell, Elinor
    et al.
    Axelsson, John
    Franck, Kristina
    Ploner, Alexander
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Bälter, Katarina
    Gaines, Hans
    Short natural sleep is associated with higher T cell and lower NK cell activities2011In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 25, no 7, p. 1367-1375Article in journal (Refereed)
    Abstract [en]

    Short sleep duration increases the risk of several diseases, possibly involving compromised immune function. However, most previous studies are based on experimentally induced sleep deprivation, and only a few have studied natural variations in sleep duration. Thus our aim was to study how natural variations in sleep duration affect immune function. In total, 36 healthy men and women, aged 20-54, donated blood; 29 on three consecutive mornings, and seven on one morning. Each morning, participants self-reported sleep duration the night prior to blood draw. General sleep patterns, physical activity and stress were also assessed. A flow-cytometric assay was used to measure natural killer cell activity (NKCA), T cell function (in response to PHA, influenza, and SEA+B), and B cell function (in response to PWM) per volume whole blood. Short sleep duration prior to blood draw (<7h) was associated with 49% higher PHA-induced T cell function (95% CI 7/109%) and 30% lower NKCA compared with normal prior sleep (7-9h) (95% CI -46/-8%). In addition, high perceived stress was associated with 39% higher PHA-induced T cell function (95% CI 0/94%). High general physical activity was associated with 47% increased numbers of B cells and 28% increased numbers of T cells, but not with immune function. Our results suggest strong relationships between short sleep duration and T- and NK-cell functions. The stability of the findings as well as the clinical consequences of the link between short sleep and immune function should be explored in future studies.

  • 9. Henderson, Audrey J.
    et al.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Institute of Medical Psychology and Behavioral Immunobiology, Germany.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olsson, Mats J.
    Powis, Simon J.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Perrett, David I.
    Skin colour changes during experimentally-induced sickness2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, p. 312-318Article in journal (Refereed)
    Abstract [en]

    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.

  • 10. Kanegawa, Naoki
    et al.
    Collste, Karin
    Forsberg, Anton
    Schain, Martin
    Arakawa, Ryosuke
    Jucaite, Aurelija
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, Caroline
    Kosek, Eva
    Lampa, Jon
    Halldin, Christer
    Farde, Lars
    Varrone, Andrea
    Cervenka, Simon
    In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 149-157Article in journal (Refereed)
    Abstract [en]

    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 [(11)C]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 [(11)C]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.

  • 11. Karshikoff, B.
    et al.
    Jensen, K. B.
    Ingvar, M.
    Kosek, E.
    Kalpouzos, G.
    Soop, A.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, J.
    LPS increases pain sensitivity by decreased pain inhibition and increased insular activation2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e1-e1Article in journal (Refereed)
    Abstract [en]

    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.

  • 12. Karshikoff, B.
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Soop, A.
    Lindstedt, F.
    Ingvar, M.
    Kosek, E.
    Olgart Höglund, C.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Modality and sex differences in pain sensitivity during human endotoxemia2014In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 46, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

  • 13.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Jensen, K. B.
    Kosek, E.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soop, A.
    Ingvar, M.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Why sickness hurts: A central mechanism for pain induced by peripheral inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 57, p. 38-46Article in journal (Refereed)
    Abstract [en]

    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.

  • 14.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. INRA-Bordeaux University, France.
    Dexpert, S.
    Aubert, A.
    Beau, C.
    Ledaguenel, P.
    Magne, E.
    Layé, S.
    Capuron, L.
    Inflammation in the visceral adipose tissue of obese subjects: relationship with circulating inflammation and association with bariatric surgery outcomes2014In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 40, p. e29-e29Article in journal (Refereed)
    Abstract [en]

    The inflammatory state of the adipose tissue, in particular visceral adipose tissue, is believed to contribute to systemic chronic low-grade inflammation associated with obesity. Nevertheless, the precise characterization of the inflammatory profile of obese subjects, associating adipose and systemic inflammatory markers, is still needed. In addition, the question whether inflammatory specificities in obesity influence the outcomes of bariatric surgery, such as weight reduction, remains to be elucidated. To address these questions, thirty-seven obese patients were included in the present study and about 70% of them were followed up to fourteen months after bariatric surgery. Systemic concentrations of inflammatory markers were assessed using ELISA before bariatric surgery. Samples of visceral adipose tissue were extracted during bariatric surgery and gene expression of cytokines and immune cells markers were evaluated using qRT-PCR. Our results indicate that cytokines were strongly inter-correlated in the adipose tissue. In addition, we have found significant associations of adipose expression of macrophage and T cells markers with adipose expression and with systemic levels of cytokines, including TNF-α and IL-6. Importantly, a higher inflammatory state of the visceral adipose tissue before bariatric surgery predicted a lower weight reduction after surgery, notably at early stages post-surgery. Taking together, these findings highlight the importance of the inflammatory state of the visceral adipose tissue in obesity-related inflammation, and its relevance regarding its impact on outcomes of obesity treatments.

  • 15.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University of Duisburg-Essen, Germany.
    Elsenbruch, Sigrid
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Grigoleit, Jan-Sebastian
    Engler, Harald
    Schedlowski, Manfred
    Benson, Sven
    Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 57, p. 30-37Article in journal (Refereed)
    Abstract [en]

    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.

  • 16.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Ingre, Michael
    Regenbogen, Christina
    Olsson, Mats J.
    Garke, Maria
    Brytting, Mia
    Edgar, Rachel
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sleep during naturally occurring respiratory infections: A pilot study2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 79, p. 236-243Article in journal (Refereed)
    Abstract [en]

    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.

  • 17.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianca
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Engler, H.
    Elsenbruch, S.
    Grigoleit, J.
    Benson, S.
    Pre-existent anxiety symptoms is associated with modified behavioral response during endotoxemia2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e29-e30Article in journal (Refereed)
    Abstract [en]

    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.

  • 18.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University of Bordeaux, France; Universitätsklinikum Essen, Germany.
    Magne, Eric
    Beau, Cedric
    Aubert, Agnes
    Dexpert, Sandra
    Carrez, Julie
    Laye, Sophie
    Forestier, Damien
    Ledaguenel, Patrick
    Capuron, Lucile
    Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 58, p. 63-68Article in journal (Refereed)
    Abstract [en]

    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.

  • 19.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Petrovic, Predrag
    Olsson, Mats J.
    Paues Göranson, Sofie
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Jensen, Karin B.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sickness behavior is not all about the immune response: Possible roles of expectations and prediction errors in the worry of being sick2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 74, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Background

    People 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.

    Methods

    Twenty-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.

    Results

    Participants 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).

    Conclusion

    The 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.

  • 20.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Rehman, Javaid-Ur
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Effect of long-term sleep restriction and subsequent recovery sleep on the diurnal rhythms of white blood cell subpopulations.2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 47, no SI, p. 93-99Article in journal (Refereed)
    Abstract [en]

    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.

  • 21.
    Lekander, Mats
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Andreasson, Anna Nixon
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Ekman, Rolf
    Ingre, Michael
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Åkerstedt, Torbjorn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Axelsson, John
    Subjective health perception in healthy young men changes in response to experimentally restricted sleep and subsequent recovery sleep2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 34, p. 43-46Article in journal (Refereed)
    Abstract [en]

    Sleep and subjective health are both prospectively related to objective indices of health and health care use. Here, we tested whether five days with restricted sleep and subsequent recovery days affect subjective health and is related to increased levels of circulating IL-6 and TNF-α and fatigue. Nine healthy men (23-28years) went through a 6-week sleep protocol with subjects as their own controls in a repeated measures design with a total of 11 nights in a sleep laboratory. The experimental part of the protocol included three baseline days (sleep 23-07h), five days with sleep restriction (03-07h) and three recovery days (23-07h) in the sleep laboratory. Subjective health and fatigue was recorded daily. Eight blood samples were drawn each day (every third hour) on 8days of the protocol and analyzed with respect to IL-6 and TNF-α. Subjective health deteriorated gradually during restricted sleep (p=.002) and returned to baseline levels after three days of recovery. IL-6 and TNF-α did not change significantly. Fatigue increased gradually during sleep restriction (p=.001), which significantly contributed to the association between restricted sleep and subjective health. The study is the first to show that subjective health is directly responsive to changes in sleep length and related to increased fatigue. Thus, subjective health is differently appraised after manipulation of one of its presumed determinants. Larger experimental studies would be beneficial to further distinguish causation from association regarding the underpinnings of subjective health.

  • 22.
    Lekander, Mats
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Arnberg, Filip K.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Segerström, S. C.
    Longitudinal relationship between inflammation and poor self-rated health in elderly2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e37-e37Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Lekander, Mats
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Johansson, Emilia
    Soop, Anne
    Fransson, Peter
    Lundström, Johan N.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Ingvar, Martin
    Petrovic, Predrag
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Nilsonne, Gustav
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 56, p. 34-41Article in journal (Refereed)
    Abstract [en]

    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.

  • 24.
    Lodin, Karin
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Syk, J.
    Undén, K.
    Alving, K.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Nixon Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Self-rated health is associated with fatigue, but not inflammatory cytokines or fraction of exhaled nitric oxide in men and women with allergic asthma2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, no Suppl., p. e31-e31Article in journal (Other academic)
    Abstract [en]

    Allergic asthma is a chronic inflammatory disorder with both local and systemic inflammation and is associated with elevated levels of cytokines as well as exhaled fraction of nitric oxide (FeNO). Fatigue is a prominent symptom. Poor self-rated health has previously been associated to fatigue and inflammatory markers. However, it is not known if self-rated health is associated with fatigue and inflammation also in patients with asthma. Here, we investigated the associations between self-rated health, fatigue, inflammatory cytokines and FeNO in patients with asthma. Self-rated health, fatigue, levels of cytokines and FeNO were assessed in 184 (93 men, 91 women) non-smoking patients with allergic asthma aged 18–64 years in a one-year longitudinal study with five repeated measurements, two for cytokine levels. Analyses of associations between repeated measurements were performed using mixed regression models. More fatigue was associated with poor self-rated health in both men and women (p < 0.001). Fatigue was also associated to elevated levels of IL-1beta and TNF-alpha in women (p < 0.01). However, no association between self-rated health, inflammatory cytokines and FeNO were found. In conclusion, fatigue is an important determinant of self-rated health also in patients with asthma. In addition, fatigue was associated to elevated levels of inflammatory cytokines in women. Possibly, variance in inflammation may be of less importance in a chronic inflammatory condition such as asthma in relation to how subjective health is appraised.

  • 25.
    Magnusson Hanson, Linda L.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Virtanen, Marianna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of Uppsala, Sweden.
    Rod, Naja H.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of Copenhagen, Denmark.
    Steptoe, Andrew
    Head, Jenny
    Batty, G. D.
    Kivimäki, Mika
    Westerlund, Hugo
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    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 study2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 78, p. 153-160Article in journal (Refereed)
    Abstract [en]

    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.

  • 26. O'Toole, M. S.
    et al.
    Bovbjerg, D. H.
    Renna, M. E.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Mennin, D. S.
    Zachariae, R.
    Effects of psychological interventions on systemic levels of inflammatory biomarkers in humans: A systematic review and meta-analysis2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 74, p. 68-78Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 27. Sarolidou, Georgia
    et al.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; New York University, USA.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Regenbogen, Christina
    Sorjonen, Kimmo
    Lundström, Johan N.
    Stockholm University, Faculty of Humanities, Department of Linguistics. Karolinska Institutet, Sweden; Monell Chemical Senses Center, USA; University of Pennsylvania, USA.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olsson, Mats J.
    Emotional expressions of the sick face2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 80, p. 286-291Article in journal (Refereed)
    Abstract [en]

    To handle the substantial threat posed by infectious diseases, behaviors that promote avoidance of contagion are crucial. Based on the fact that sickness depresses mood and that emotional expressions reveal inner states of individuals to others, which in turn affect approach/avoidance behaviors, we hypothesized that facial expressions of emotion may play a role in sickness detection. Using an experimental model of sickness, 22 volunteers were intravenously injected with either endotoxin (lipopolysaccharide; 2 ng/kg body weight) and placebo using a randomized cross-over design. The volunteers were two hours later asked to keep a relaxed expression on their face while their facial photograph was taken. To assess the emotional expression of the sick face, 49 participants were recruited and were asked to rate the emotional expression of the facial photographs of the volunteers when sick and when healthy. Our results indicate that the emotional expression of faces changed two hours after being made temporarily sick by an endotoxin injection. Sick faces were perceived as more sick/less healthy, but also as expressing more negative emotions, such as sadness and disgust, and less happiness and surprise. The emotional expressions mediated 59.1% of the treatment-dependent change in rated health. The inclusion of physical features associated with emotional expressions to the mediation analysis supported these results. We conclude that emotional expressions may contribute to detection and avoidance of infectious individuals and thereby be part of a behavioral defense against disease.

  • 28.
    Sundelin, Tina
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Karshikoff, B.
    Axelsson, E.
    Höglund, C. Olgart
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sick man walking: Perception of health status from body motion2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 48, p. 53-56Article in journal (Refereed)
    Abstract [en]

    An ability to detect subtle signs of sickness in others would be highly beneficial, as it would allow for behaviors that help us avoid contagious pathogens. Recent findings suggest that both animals and humans are able to detect distinctive odor signals of individuals with activated innate immune responses. This study tested whether an innate immune response affects a person's walking speed and whether other people perceive that person as less healthy. 43 subjects watched films of persons who were experiencing experimental immune activation, and rated the walking individuals in the films with respect to health, tiredness, and sadness. Furthermore, the walking speed in the films was analyzed. After LPS injections, participants walked more slowly and were perceived as less healthy and more tired as compared to when injected with placebo. There was also a trend for the subjects to look sadder after LPS injection than after placebo. Furthermore, there were strong associations between walking speed and the appearance of health, tiredness, and sadness. These findings support the notion that walking speed is affected by an activated immune response, and that humans may be able to detect very early signs of sickness in others by merely observing their gait. This ability is likely to aid both a "behavioral immune system", by providing more opportunities for adaptive behaviors such as avoidance, and the anticipatory priming of biochemical immune responses.

  • 29.
    Sundelin, Tina
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Andreasson, Anna N.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Centre for Family Medicine, Sweden.
    Axelsson, J.
    Sleep loss and subjective health2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, article id e22Article in journal (Refereed)
    Abstract [en]

    Both insufficient sleep and subjective health predict mortality and are related to sickness-like symptoms as well as immune activation. Cross-sectional data show a strong association between sleep and subjective health, but there is a lack of experimental data that may distinguish causation from association. We investigated the effects of restricted sleep on subjective health in two experimental studies. The first study consisted of 23 subjects (11 women) who rated their subjective health twice, once after 31 h of wakefulness and once after normal sleep (8 h sleep/night). The second study had 25 subjects (14 women) who rated their subjective health after two consecutive nights with 4 h sleep/night and after normal sleep (8 h sleep/night). In the group deprived of sleep for 31 h, participants rated themselves as less healthy that day (−1.7 on a 7-point scale, p < 0.01) compared to after normal sleep. In the group with partially restricted sleep, participants also rated their health as worse compared to after normal sleep, both their current health (−0.8 on a 7-point scale, p < 0.05) and general health (−0.6 on a 5-point scale, p < 0.05). This study shows that an experimental reduction of sleep, complete as well as partial, leads to poorer subjective health. Considering the predictive qualities of this measure, future studies should determine the underlying mechanisms of the connection between insufficient sleep and worse subjective health.

  • 30.
    Tamm, Sandra
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Cervenka, Simon
    Forsberg, Anton
    Estelius, Johanna
    Grunewald, Johan
    Gyllfors, Pär
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kosek, Eva
    Lampa, Jon
    Lensmar, Catarina
    Strand, Victoria
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Halldin, Christer
    Ingvar, Martin
    Olgart Höglund, Caroline
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [11C]PBR28 PET study2018In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 68, p. 146-157Article in journal (Refereed)
    Abstract [en]

    Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.

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