Sickness behavior : immune system influences on brain and behavior

Sickness behavior is a motivational state that redirects the needs and priorities of the organism during infection to aid recovery. The behavioral changes include fatigue, lowered mood and aches. Peripheral cytokines signal to the brain via autonomic nerves and the bloodbrain interface and change the inflammatory status of the brain, a mechanism that in recent years has been implied in complex syndromes like long-term pain, depression, fatigue and overall poor well-being. Epidemiological studies also suggest that chronic inflammatory disease like allergy increases the risk of developing Alzheimer disease (AD) later in life. In this thesis we explored how acute experimental immune activation affects pain sensitivity and self-rated general health. We also investigated inflammatory and degenerative effects in the brain following chronic allergic inflammation in a mouse model. In Paper I, eight healthy participants (1 woman) were injected with 0.8 ng/kg body weight lipopolysaccharide (LPS) and with saline 28 days apart in a balanced double-blind withinsubject design. Subsequently, 52 subjects were injected with 0.6 ng/kg LPS (31, 18 women) or saline (21, 11 women) in a double-blind between-subject design (data from this protocol was also used for Paper II and IV). Pro-inflammatory peripheral cytokine (TNF- α, IL-6 and IL-8) levels increased significantly in the LPS group. We demonstrated that in particular deep pain sensitivity increased during immune activation. Women were more affected than men by the inflammatory signals with regard to pain, as women also demonstrated increased cutaneous pain sensitivity and impaired descending pain inhibition during LPS provocation, whereas men did not. Pain sensitivity was associated with peripheral IL-6 and IL-8 levels for both men and women. In Paper II (second sample in Paper I), we investigated the neural correlates underlying these findings, using functional magnetic resonance imaging. LPS attenuated descending endogenous pain inhibition reflected as decreased activity in the rostral anterior cingulate (rACC) and lateral prefrontal cortices. Also, the LPS group demonstrated increased insular activity, which may reflect amplified interoceptive and/or affective processing. An overall weaker pain regulation (lower rACC activity) and an association between insular activation and peripheral pro-inflammatory cytokines were found in women, which may explain the sex differences found in pain sensitivity. The higher susceptibility to inflammation-driven pain sensitivity in women may be one of the mechanisms behind more women suffering from pain conditions. In Paper III we studied the impact of long-term peripheral inflammation on inflammatory and neurodegenerative processes in the brain. We used a murine model for chronic allergic inflammation by ovalbumin provocation and assessed AD and inflammation relevant markers. We showed that chronic allergic inflammation induces tau-phosphorylation in mice, a hallmark of AD. Also, chronic inflammation resulted in antibody increases (IgG and IgE) in the mouse brain, which in turn could lead to neuroinflammation over time. In Paper IV (same sample as Paper II) we assessed self-rated general health (SRH) and subjective sickness behavior during the peak of the peripheral inflammatory response. We showed that SRH ratings worsened markedly during experimental inflammation, and that these effects were statistically mediated by the symptoms of sickness behavior perceived by the subjects. In conclusion, our findings corroborate related clinical research findings, suggesting that the inflammatory models used in this thesis may serve as useful tools for studying neuroimmune mechanisms relevant for chronic pain, neurodegeneration and states characterized by poor subjective health. A better understanding of sickness-induced brain changes may aid future treatment strategies for such complex diseases that currently often lack successful treatment

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.publishedVersio

Baseline Pro-Inflammatory Cytokine Levels Moderate Psychological Inflexibility in Behavioral Treatment for Chronic Pain

Background: The medical and scientific communities struggle to understand chronic pain and find effective treatments. Multimodal approaches are encouraging but show significant individual differences. Methods: Seventy-eight persons (56 women) with chronic pain received Acceptance and Commitment Therapy and provided blood samples before and after treatment. The participants completed surveys with the blood sampling. Blood plasma was analyzed for IL-6 and TNF-α levels with the Olink Inflammation Panel (Olink Bioscience Uppsala, Sweden). The treatment effects and moderating effects of low-grade inflammation on changes in outcomes were analyzed using linear mixed models. Results: Pain interference (p < 0.001) and psychological inflexibility (p < 0.001) improved significantly during treatment, but pain intensity did not (p = 0.078). Cytokine levels did not change over the course of the treatment (IL-6/TNF-α p = 0.086/0.672). Mean baseline levels of IL-6 and TNF-α moderated improvement in psychological inflexibility during the course of treatment (p = 0.044), but cytokine levels did not moderate changes in pain interference (p = 0.205) or pain intensity (p = 0.536). Conclusions: Higher baseline inflammation levels were related to less improvement in psychological inflexibility. Low-grade inflammation may be one factor underlying the variability in behavioral treatment in chronic pain.publishedVersio

Detection of Inflammation via Volatile Cues in Human Urine

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

Olfactory cues of naturally occurring systemic inflammation: A pilot study of seasonal allergy

Introduction: In an attempt to avoid contact with infectious individuals, humans likely respond to generalised rather than specific markers of disease. Humans may thus perceive a non-infectious individual as socially less attractive if they look (e.g., have facial discoloration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of non-infectious individuals with a low-grade systemic inflammation. Methods: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumor necrosis factor-α, interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness. Results: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season - relative to outside of the allergy season and to healthy controls - these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual’s body odour (from out- to inside pollen season), was significantly related to the change in their interleukin-5 levels but not to tumor necrosis factor-α. Discussion: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a non-communicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and non-infectious (e.g., chronic diseases) conditions.publishedVersio

Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (&gt;6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 &gt; 10) or mild/no (GAD-7/PHQ-9 &lt; 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity

Endotoxin_self-rated health

Data from Experiment 1 and 2 in The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments by Andreasson et a

Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (&amp;gt;6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 &amp;gt; 10) or mild/no (GAD-7/PHQ-9 &amp;lt; 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity