| 1. |
- Forsberg, A., et al.
(författare)
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Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [C-11]PBR28 positron emission tomography
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 334
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Tidskriftsartikel (refereegranskat)abstract
- Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [C-11] PBR28. The outcome measure was total distribution volume (V-T) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome V-T or when normalizing V-T to the lateral occipital cortex (p > 0.05). RA patients had numerically lower V-T values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [C-11]PBR28 V-T in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFN gamma and TNF-alpha were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [C-11]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.
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| 2. |
- Andreasson, Anna N., et al.
(författare)
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Development and preliminary validation of the Sickness Questionnaire (SicknessQ)
- 2013
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- 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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| 4. |
- Karshikoff, B., et al.
(författare)
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Modality and sex differences in pain sensitivity during human endotoxemia
- 2014
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 46, s. 35-43
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
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| 6. |
- 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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| 7. |
- Lidberg, Lisa, et al.
(författare)
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Self-rated health in response to experimental manipulations of inflammation is mediated by sickness behavior as assessed by the sickness questionnaire
- 2013
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Ingår i: Brain, Behavior, and Immunity. - : Elsevier BV. - 0889-1591. ; 32:Supplement, s. e34-e34
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Tidskriftsartikel (refereegranskat)abstract
- Factors that influence subjective health ratings (e.g. pain, tiredness, lack of energy) resemble immune activated sickness behavior. Accordingly, previous research has shown a relation between inflammatory cytokines and poor self-rated health. However, neither the causality of the association, nor what mediates it, is clear. In this study we investigated if a transient immune activation would affect subjective health perception and, if so, if this effect is mediated by symptoms of sickness behavior. Using a between-subject design, 51 healthy subjects were injected with either endotoxin (LPS 0.6 ng/kg) or placebo. Stimulation resulted in a peak response in pro-inflammatory cytokines after 90–120 min. Ninety minutes after injection, both perceived health framed to represent current (“How is your health right now?”) and global health (“How would you rate your general state of health”?) was significantly lower in the endotoxin condition (p’s < .01). The effect of endotoxin on self-rated health was mediated by sickness behavior as assessed by a newly developed questionnaire, Sickness Questionnaire, to 91% for current and 68 % for global health. In conclusion, it is demonstrated that a transient inflammatory activation, likely working through symptoms of sickness behavior, affects both subjectively perceived health for the moment as well as how health status on the more general level is appraised.
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| 8. |
- Sundelin, Tina, et al.
(författare)
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Sick man walking : Perception of health status from body motion
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 48, s. 53-56
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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