Individual Differences in Acute Response to Experimental Inflammation: Microcirculatory Changes and Psychological Predictors

Background Acute illness manifest itself not only by physiological responses such as e.g. fever, pain and nausea, but is often accompanied by psychological and behavioral changes such as sleep/wake disturbances, fatigue, loss of appetite and depression. The physiological and behavioral responses to inflammatory activation vary greatly between individuals. The knowledge about what causes these differences is sparse, but plausible explanations are variations in sensitivity to peripheral inflammation and inflammation-induced brain changes. As the skin is readily accessible, it provides an appropriate site to assess microvascular reactivity during inflammation. Moreover, recent technological advances have provided simple and non-invasive methods to assess skin microvascular function. Therefore, human cutaneous circulation could be used as a surrogate marker of systemic microvascular function in inflammation. In the present study, we use experimentally induced immunological activation in healthy humans to study microcirculatory skin changes as well as behavioral predictors of individual sensitivity to an acute inflammatory stimulus.

The model of experimental endotoxemia to induce acute inflammation The model of experimental endotoxemia is a well-accepted and frequently used model to study the neuropsychiatric effects of pro-inflammatory cytokines, both in animals and in humans. The model is based on the sterile activation of the immune system, obtained by intravenous injection of an endotoxin, lipopolysaccharide (LPS), a wall component of gram-negative bacteria such as E. coli. Injection of LPS will affect the functionality of the vascular endothelium. Positioned at the interface between circulating blood and surrounding tissue, endothelial cells, which line the inner walls of blood vessels, play a crucial role in the response to pathogens. The endothelium serves various functions essential for maintaining organ homeostasis, including vasoregulation, selective vascular permeability, and providing an anticoagulant surface. However, during infection, the normal physiological functions of the endothelium are disrupted, contributing to the organ failure characteristic of sepsis. Importantly, the response to inflammation during experimental endotoxemia differs substantially across individuals. This holds for the degree of increase in inflammatory cytokines, the neural response, as well as the behavioral changes that entail inflammation. It should be noted that the neuropsychiatric response to inflammation is not explained fully by the magnitude of the inflammatory response, indicating that other factors are involved. Recent research points toward the importance of top-down mechanisms in modifying the effect of inflammation on behavior. Such mechanisms might include pre-existent emotional status and beliefs about the intensity of which one will become sick after an infection. Identifying the predictors of a heightened behavioral response to inflammation would help identifying markers of inflammation-associated neuropsychiatric vulnerability, but this has rarely been investigated.

General aim The general aim of the study is to assess microcirculatory changes in skin of the face, chest, hands and feet using different optical imaging techniques, and to identify psychological predictors in the acute behavioral response to experimentally induced inflammation.

Primary research questions

The main research questions are:

1. to assess how acute inflammation affects:

• the microcirculation in skin such as face, chest, arms, hands and feet as investigated with different non-invasive optical imaging techniques:
• Core temperature changes
• Facial temperature changes
• Changes in equivalents to red blood cell concentration and blood flow
• Spectral changes in skin possibly correlated with fluids and other proteins affected by microcirculatory changes

1. to assess whether a stronger behavioral response (i.e. sickness behavior, negative mood, fatigue, anxiety, pain) to experimental endotoxemia is predicted by:

• higher interoceptive sensitivity as measured by self-report and an objective task (heartrate discrimination task);
• less cognitive resilience (i.e. self-efficacy, optimism, perseverance, coping strategies, ability to update beliefs in the fact of contradictory evidence);
• worse baseline emotional status (i.e. trait anxiety, fatigue, perceived stress);
• stronger health anxiety and disgust tendencies;
• Sociocultural factors that have been found to relate to sickness behavior, such as stoic endurance of pain and discomfort, familism, individualism, and collectivism;
• baseline biological motion pattern (walking speed, rigidity of gait, and slumped posture);

Methods Research principals The research principals are Region Östergötland, Karolinska Institutet and Stockholm University, Sweden. Data collection will be conducted at the Emergency Medicine Research Center (EMRC). Processing of data will be conducted at EMRC, Region Östergötland, Karolinska Institutet and Stockholm University.

Study design The study will be conducted at the Emergency Medicine Research Center at the University Hospital of Linköping. The study will follow a double-blind within-subject crossover placebo-controlled design. All subjects will receive an intravenous administration of LPS at a dose of up to 0.8 ng/kg body weight once, and an intravenous administration of placebo once, in a randomized order and with at least 4 weeks of wash-out period. Upon arrival, volunteers will be placed on a hospital bed in a single room and a catheter will be placed in the forearm or hand to avoid multiple needle insertion. A urine sample for pregnancy testing and drug screening will be obtained for safety reasons. The participants will then complete the baseline questionnaires, and the baseline blood sample will be drawn. After the baseline assessments, volunteers will receive the LPS or placebo injection. Vital signs (pulse, blood pressure, blood-oxygen saturation, respiratory frequency) will be continuously monitored and recorded at 30-minute intervals. Body temperature will be monitored and recorded every 30 minutes with regular tympanic thermometer, as well as continuously, using bio-optical imaging techniques. Blood samples will be taken approximately every hour to measure the inflammatory response (see "assessments - inflammatory markers from blood samples" below). Bio-optical imaging will be performed once before injection and at several occasions after the injection. Web-based questionnaires will be completed regularly to measure the sickness and emotional response will be completed by the participants just after acquisition of blood samples. Several behavioral tasks will be conducted during the study day. Volunteers will be discharged 6-10 hrs or when considered recovered by medical staff, after the injection, following a medical examination.