Search

Introduction The role of inflammation in common psychiatric diseases is now well acknowledged. However, the factors and mechanisms underlying inter-individual variability in the vulnerability to develop psychopathology-related symptoms in response to inflammation are not well characterized. Herein, we aimed at investigating morphological brain regions central for interoception and emotion regulation, and if these are associated with acute inflammation-induced sickness and anxiety responses. Methods Systemic inflammation was induced using an intravenous injection of lipopolysaccharide (LPS) at a dose of 0.6 ng/kg body weight in 28 healthy individuals, while 21 individuals received an injection of saline (placebo). Individuals’ gray matter volume was investigated by automated voxel-based morphometry technique on T1-weighted anatomical images derived from magnetic resonance imaging (MRI). Plasma concentrations of TNF-α and IL-6, sickness symptoms (SicknessQ), and state anxiety (STAI-S) were measured before and after the injection. Results A stronger sickness response to LPS was significantly associated with a larger anterior insula gray matter volume, independently from increases in cytokine concentrations, age, sex and body mass index (R2 = 65.6%). Similarly, a greater LPS-induced state anxiety response was related to a larger anterior insula gray matter volume, and also by a stronger increase in plasma TNF-α concentrations (R2 = 40.4%). Discussion Anterior insula morphology appears central in the sensitivity to develop symptoms of sickness and anxiety in response to inflammation, and could thus be one risk factor in inflammation-related psychopathologies. Because of the limited sample size, the current results need to be replicated.

Today’s treatment for chronic pain is inadequate, and novel targets need to be identified. This requires a better understanding of the mechanisms involved in pain sensitization and chronification. In this review, we discuss how peripheral inflammation, as occurs during an infection, modulates the central pain system. In rodents, neonatal inflammation leads to increased pain sensitivity in adulthood by priming immune components both peripherally and centrally. The excitability of neurons in the spinal cord is also altered by neonatal inflammation and may add to pain sensitization later in life. In adult humans, inflammation modulates pain sensitivity as well, partly by affecting the activity in brain areas that process and regulate pain signals. Low-grade inflammation is common in clinical populations both peripherally and centrally, and priming of the immune system has also been suggested in some pain populations. The nociceptive and immune systems are primed by infections and inflammation. The early life programming of nociceptive responses following exposure to infections or inflammation will define individual differences in adult pain perception. Immune-to-brain mechanisms and neuroimmune pathway need further investigation as they may serve both as predictors and therapeutic targets in chronic pain.

Sandra Tamm,1– 3 Catarina Lensmar,1 Anna Andreasson,2 John Axelsson,1,2 Anton Forsberg Morén,4 Johan Grunewald,5 Pär Gyllfors,6 Bianka Karshikoff,1,2 Eva Kosek,1,7 Jon Lampa,8 Caroline Olgart Höglund,1,5,9 Victoria Strand,6 Simon Cervenka,4 Mats Lekander1,2 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 2Stress Research Institute, Stockholm University, Stockholm, Sweden; 3Department of Psychiatry, University of Oxford, Oxford, UK; 4Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services,Region Stockholm, Stockholm, Sweden; 5Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 6Asthma & Allergy Clinic at S:t Görans Hospital, Stockholm, Sweden; 7Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 8Department of Medicine, Rheumatology Unit, Center of Molecular Medicine (CMM), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 9Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SwedenCorrespondence: Sandra TammStress Research Institute, Stockholm University, Stockholm, 106 91, SwedenEmail sandra.tamm@su.seIntroduction: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods.Aim: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness.Methods: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion.Results: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA.Conclusion: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups.Keywords: sleep, inflammation, allergy, rheumatoid arthritis

Introduction Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods. Aim The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness. Methods In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion. Results Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA. Conclusion This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups.

Background Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning. Methods Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n ​= ​38) and patients with chronic pain (n ​= ​190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n ​= ​29), primary care patients (n ​= ​163), individuals from the general population (n ​= ​155) and healthy subjects (n ​= ​48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population. Results LPS-injected individuals (M ​= ​16.3), patients with ME/CFS (M ​= ​16.1), chronic pain (M ​= ​16.1) and primary care patients (M ​= ​10.7) reported significantly higher SicknessQ scores than individuals from the general population (M ​= ​5.4) and healthy subjects (M ​= ​3.6) all p’s ​, Highlights • Investigation of the level of subjective sickness behavior, assessed with a validated questionnaire, in patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and in patients with chronic pain compared to clinical, non-clinical and experimental groups. • The level of sickness behavior is similarly high in ME/CFS and chronic pain, and equal to the level in experimentally induced inflammation via injection of bacterial endotoxin. • Higher levels of sickness behavior showed significant associations with lower levels of self-rated health and functioning.

Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.

International audience; Increasing evidence from animal and human studies suggests that inflammation may be involved in mood disorders. Sickness behavior and emotional changes induced by experimental inflammatory stimuli have been extensively studied in humans and rodents to better understand the mechanisms underlying inflammation-driven mood alterations. However, research in animals and humans have remained compartmentalized and a comprehensive comparison of inflammation-induced sickness and depressive-like behavior between rodents and humans is lacking. Thus, here, we highlight similarities and differences in the effects of bacterial lipopolysaccharide administration on the physiological (fever and cytokines), behavioral and emotional components of the sickness response in rodents and humans, and discuss the translational challenges involved. We also emphasize the differences between observable sickness behavior and subjective sickness reports, and advocate for the need to obtain both subjective reports and objective measurements of sickness behavior in humans. We aim to provide complementary insights for translational clinical and experimental research on inflammation-induced behavioral and emotional changes, and their relevance for mood disorders such as depression

Background Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. Methods Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-α, before and after injection. Results Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p’s

Contagious disease is a major threat to survival, and the cost of relying on the immune system to defeat pathogens is high; therefore, behavioral avoidance of contagious individuals is arguably an adaptive strategy. Animal findings demonstrate the ability to detect and avoid sick individuals by the aid of olfactory cues, and a recent study indicated that human axillary odor also becomes more aversive as a function of immune activation. By injecting healthy human participants with lipopolysaccharide (0.6 ng/kg body weight) to experimentally induce inflammation, this study demonstrates that natural daily rhythms of urine odor-its perceived dimensions and volatile profile-are altered within hours of inflammation onset. Whereas healthy human urine decreases in averseness over the course of a single day, inflammation interrupts this process and results in an increased urine odor averseness and an altered volatile composition. These results support the notion that subtle and early cues of sickness may be detected and avoided, thereby complementing the immune system in its role of keeping us alive and healthy.

Human models demonstrate that experimental activation of the innate immune system has profound effects on brain activation and behavior, inducing fatigue, worsened mood and pain sensitivity. It has been proposed that inflammation is a mechanism involved in the etiology and maintenance of depression, chronic pain and long-term fatigue. These diseases show a strong female overrepresentation, suggesting that a better understanding of sex differences in how inflammation drives behavior could help the development of individualized treatment interventions. For this purpose, we here review sex differences in studies using experimental inflammatory models to investigate changes in brain activity and behavior. We suggest a model in which inflammation accentuates sex differences in brain networks and pre-existing vulnerability factors. This effect could render women more vulnerable to the detrimental effects of immune-to-brain communication over time. We call for systematic and large scale investigations of vulnerability factors for women in the behavioral response to inflammation.

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 [

Chronic pain is a debilitating condition that still is challenging both clinicians and researchers. Despite intense research, it is still not clear why some individuals develop chronic pain while others do not or how to heal this disease. In this review, we argue for a multisystem approach to understand chronic pain. Pain is not only to be viewed simply as a result of aberrant neuronal activity but also as a result of adverse early-life experiences that impact an individual’s endocrine, immune, and nervous systems and changes which in turn program the pain system. First, we give an overview of the ontogeny of the central nervous system, endocrine, and immune systems and their windows of vulnerability. Thereafter, we summarize human and animal findings from our laboratories and others that point to an important role of the endocrine and immune systems in modulating pain sensitivity. Taking “early-life history” into account, together with the past and current immunological and endocrine status of chronic pain patients, is a necessary step to understand chronic pain pathophysiology and assist clinicians in tailoring the best therapeutic approach.

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

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

Chronic pain is a debilitating condition that still is challenging both clinicians and researchers. Despite intense research, it is still not clear why some individuals develop chronic pain while others do not or how to heal this disease. In this review, we argue for a multisystem approach to understand chronic pain. Pain is not only to be viewed simply as a result of aberrant neuronal activity but also as a result of adverse early-life experiences that impact an individual’s endocrine, immune, and nervous systems and changes which in turn program the pain system. First, we give an overview of the ontogeny of the central nervous system, endocrine, and immune systems and their windows of vulnerability. Thereafter, we summarize human and animal findings from our laboratories and others that point to an important role of the endocrine and immune systems in modulating pain sensitivity. Taking “early-life history” into account, together with the past and current immunological and endocrine status of chronic pain patients, is a necessary step to understand chronic pain pathophysiology and assist clinicians in tailoring the best therapeutic approach.

Symptoms after inflammatory activation, so-called sickness behaviour, overlap with trans-diagnostic complaints. As no self-report questionnaire to assess sickness behaviour exists, we aimed to develop such an instrument, the Sickness Questionnaire. Items responsive to experimentally induced inflammatory activation (randomized double-blind study endotoxin (0.6 ng/kg) versus placebo, n = 52) were selected and the statistical properties were examined in 172 primary care patients. A principal component analysis indicated a one-factor solution (Cronbach’s alpha = .86). This 10-item scale correlated with depression ( β = .41, p

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.

Self-rated health (SRH) is a powerful and reliable predictor of future ill-health albeit many of its determinants, such as fatigue, pain and mood, are known to fluctuate over time. The aim of the present study was to study to if sickness behavior mediates the effect of inflammation on self-rated health. In two RTCs (n = 51 and n = 8) lipopolysaccharide injections (0.6 and 0.8 ng/kg, respectively) were used to provoke an acute inflammation and a sickness response. Sickness behavior (Sickness Questionnaire) and plasma levels of pro-inflammatory cytokines were assessed at baseline and 1.5 h post injection. Current SRH (“How is your health right now”) and general SRH (“How is your general health?”) was measured 1.5 h post injection. Using path analysis, we tested the hypothesis that LPS-increased inflammation provokes sickness behavior, which in turn results in worsened SRH. SRH deteriorated 1.5 h after LPS injection (general: b = .44, p

Seasonal allergy is associated with increased prevalence of psychiatric symptoms and disorders, as well as fatigue and cognitive difficulties that aggravate during pollen season. It is unclear if this results from the impact of peripheral allergic inflammation on the immune system in brain. We studied 15 allergic patients and 13 healthy controls in and out of pollen season in a balanced design. Positron emission tomography (PET) and the radioligand [11C]PBR28 was used to measure TSPO (translocator protein); a marker for immune cells (including microglia) in the brain. TSPO binding was quantified as total distribution volume of [11C]PBR28 in grey matter, controlled for polymorphisms in the TSPO gene that affect binding affinity. There were no differences between allergics and controls in TSPO levels, and no interaction with time of year. In peripheral blood, there was an increase in TNF-alpha (p = 0.04) but not IL-6 in allergics during pollen season. IL-5 was higher in allergics, and increased further during pollen season, with a corresponding pattern in the ratio between Th2 and Th1 cytokines (IL-5/IFN gamma; p’s

We have previously shown that acute inflammatory response causes robust alterations of state and trait dimensions of self-rated health. Here, we repeat the previous study using a higher dose of endotoxin and investigate consequences of inflammation that may mediate changes in health appraisal. 22 healthy subjects were injected twice, once with endotoxin (lipopolysaccharide 2.0 ng/kg) and once with placebo, with a minimum of 20 days between. Self-rated health, sickness behavior (using the Sickness Questionnaire) and interleukin (IL)-6, IL-8 and TNF-alpha were assessed before, 3 and 7 h after injection. Three hours after injection, current health (“How is your health right now?”) was significantly poorer in the endotoxin group ( b = 2.82, p b = 0.50, p

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.

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.

Despite the existing knowledge regarding the neuropathology of Alzheimer's disease (AD), the cause of sporadic forms of the disease is unknown. It has been suggested that systemic inflammation may have a role, but the exact mechanisms through which inflammatory processes influence the pathogenesis and progress of AD are not obvious. Allergy is a chronic inflammatory disease affecting more than 20% of the Western population, but the effects of allergic conditions on brain functions are largely unknown. The aim of this study was to investigate whether or not chronic peripheral inflammation associated with allergy affects the expression of AD-related proteins and inflammatory markers in the brain. On the basis of previously described models for allergy in mice we developed a model of chronic airway allergy in mouse, with ovalbumin as allergen. The validity of the chronic allergy model was confirmed by a consistent and reproducible eosinophilia in the bronchoalveolar lavage (BAL) fluid of allergic animals. Allergic mice were shown to have increased brain levels of both immunoglobulin (Ig) G and IgE with a widespread distribution. Allergy was also found to increase phosphorylation of tau protein in the brain. The present data support the notion that allergy-dependent chronic peripheral inflammation modifies the brain inflammatory status, and influences phosphorylation of an AD-related protein, indicating that allergy may be yet another factor to be considered for the development and/or progression of neurodegenerative diseases such as AD.

Brain areas involved in emotional regulation have been shown to be sensitive to experimental inflammatory stimulation with LPS (lipopolysaccharide) during task based fMRI. However, it is not known how LPS affects the brain at rest, which is relevant for understanding how inflammation affects the general condition of an individual. In a randomized study, we injected 0.6 ng/kg LPS or placebo in 50 healthy humans. Subjects were instructed to relax with closed eyes during resting-state fMRI for 8 min. Independent component analysis revealed 25 components, 20 of which were judged to represent physiologically meaningful brain networks. Of these 20 networks, 3 showed greater strength in the endotoxin condition: a cerebellar network (peak level p

Animal research suggests that systemic inflammation may induce pain hypersensitivity through central mechanisms such as glia cell activation, a mechanism that has also been proposed to be central in several clinical pain conditions. In two placebo controlled studies we used two low doses of lipopolysaccharide (LPS) injections (0.6 ng/kg and 0.8 ng/kg) as experimental models of systemic inflammation in healthy human subjects and investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) endogenous pain modulation. LPS induced significantly lower pressure pain thresholds as compared to placebo, whereas heat and cold threshold pain thresholds remained unaffected. Women in the LPS group rated suprathreshold noxious stimuli as more painful than the placebo group, whereas suprathreshold pain ratings of LPS treated men were similar to male controls. LPS impaired endogenous pain inhibition, but this effect was also restricted to women. The pattern of results was here observed in two consecutive and independent experiments of pain sensitivity. This study extends the findings of animal research to humans, suggesting a link between inflammation and pain regulation in humans.

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.

Self-rated health is often viewed as a relatively stable construct and few studies have investigated short-term variations or used experimental approaches to manipulate subjective health perception. We have previously showed that higher levels of inflammatory cytokines are generally connected with less favorable self-rated health. Therefore, we explored the subjective health experience in response to a canonical activation of an inflammatory response with endotoxin in healthy subjects. In a first study, eight healthy participants were injected at two occasions: once with 0.8 ng/kg lipopolysaccharide (LPS) and once with placebo. In a second study, a between-subject design was used where 51 healthy subjects were injected with either LPS (now reduced to 0.6 ng/kg) or placebo. Stimulation resulted in a peak response in pro-inflammatory cytokines after 90–120 min. Ninety minutes after injection, perceived health framed to represent the present day (“How is your health right now?”), was significantly lowered in the endotoxin condition in both studies ( p ’s p ’s

The sickness response consists of a set of evolutionary stable behaviors facilitating recovery. Animals increase their pain sensitivity during sickness, but this has not been shown in humans. The present study investigated how an experimentally induced sickness response affected pain sensitivity in humans. Fifty healthy subjects (half women) were injected with a low dose of LPS (Escherichia coli, 0.6 ng/kg) or saline in a double-blinded procedure. Pain tests were conducted at different time points; pressure pain threshold (0 h and 1.5 h), heat- and cold pain thresholds, noxious heat (0 h and 3.5 h), and noxious cold (3.5 h). Blood was taken at 0, 1.5, 3.5 and 5 h for cytokine analysis. LPS injected participants had higher cytokine levels (TNF, IL-6, IL-10 and IL-8) and increased anxiety as compared to placebo (all p