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When a person presents with somatic symptoms that cannot (fully) be explained by a known organic pathology, these symptoms will be labeled ‘medically unexplained’ or ‘functional’. Often, more than one symptom is present and certain constellations of symptoms give way to a diagnosis of a specific functional somatic (FS) syndrome like, for example, chronic fatigue syndrome. An immunological perspective on FS symptoms was put forward based on the resemblance between common FS symptoms and the changes in behavior that occur in response to activation of the innate immune system. When the immune system is activated, immune cells secrete messenger cells which communicate with the brain through several pathways. This immune-to-brain communication leads to changes in behavior and mood, together called sickness behavior. Animal models now also implicate the possibility of sensitization of immune-to-brain communication by exposure to (multiple) stressors. This seems of specific relevance for FS symptoms in humans as many FS symptom patients seem to fulfil the conditions for sensitization of immune-to-brain communication. Research is needed that puts the theory of a sensitized immune-to-brain communication in FS symptoms to the test. The aim of this thesis is to provide with the necessary tools to set up such research and to present preliminary evidence for sensitized immune-to-brain communication in humans. The first part of this thesis addresses some of the methodological issues that will come up when designing research on immune-to-brain communication in FS symptom patients. The first issue that is addressed is whether or not to use symptom patterns to differentiate between FS symptom patients. Although most studies on FS symptoms include patients with specific FS syndrome diagnoses, we show that that differences between patients are mostly seen in overall symptom severity and less in symptom patterns, implicating that the inclusion of a sample with heterogeneous symptoms in future research is also sound. Second, we provide a protocol for assessing several aspects of pain sensitivity through algometry and present two studies aimed at identifying objective measures of cognitive fatigue, thereby addressing the need for objective outcome measures of immune-to-brain communication in humans. The second part of the thesis presents preliminary evidence for sensitized immune-to-brain communication in humans. We show that pain sensitivity appears to be affected both by psychological stress-mechanisms and by immunological mechanisms, suggesting the possibility of synergistic effects of psychological and immunological factors in increasing pain sensitivity. Further, we show that patients with a somatoform disorder diagnosis (presenting with severe and chronic FS symptoms) have experienced more infections in the past than had a group without FS symptoms, supporting the hypothesis that patients with a somatoform disorder may have developed a sensitized immune-to-brain communication as a result of frequent exposure to immunological stressors. We also present a preliminary experimental demonstration of the synergistic effects of stress vulnerability and an immunological stressor on subsequent sickness behavior in healthy subjects. Finally, a study design is proposed aimed at demonstrating sensitized immune-to-brain communication in FS symptom patients.

Orientation: There is some evidence that job demands and job resources such as job control and humorous coping may contribute to the risk of upper respiratory tract infections (URTI). Research purpose: The purpose of this study was to test a model including these variables as well as job-related affect, in order to explore their role in the explanation of the frequency of upper respiratory tract infection. Motivation of the study: This study has been conducted in order to extend our understanding of the role of traditional variables like job demands and job control with humorous coping styles and affective variables with regard to the explanation of the frequency of URTI. Research design, approach and method: A sample of 2094 employees filled out questionnaires assessing job demands, job control, generic (MSHS-C), antecedent-focused and responsefocused humorous coping (QOHC) and job-related affect (JAWS). Main findings: Job demands were indirectly related to the frequency of upper respiratory tract infections, mediated by their relationships with job control and negative job-related affect. Generic and response-focused humorous coping were less relevant for the explanation of the frequency of upper respiratory tract infections than the presumably ‘healthy’ antecedentfocused humorous coping style. The latter showed a negative association with negative jobrelated affect. The frequency of upper respiratory tract infections was better predicted by job control and negative job-related affect than by humorous coping, in the expected directions. Practical/managerial implication: These findings may have practical relevance for the improvement of stress management interventions in organisations. Contribution/value-add: Although it was shown that healthy humorous coping does contribute to decreases in upper respiratory tract infection, job demands, job resources and negative affective state seem the most important predictors.

Aim and Method. To examine in obese people the potential effectiveness of a six-week, two times weekly aquajogging program on body composition, fitness, health-related quality of life, and exercise beliefs. Fifteen otherwise healthy obese persons participated in a pilot study.Results. Total fat mass and waist circumference decreased 1.4 kg (P=.03) and 3.1 cm (P=.005), respectively. The distance in the Six-Minute Walk Test increased 41 meters (P=.001). Three scales of the Impact of Weight on Quality of Life-Lite questionnaire improved: physical function (P=.008), self-esteem (P=.004), and public distress (P=.04). Increased perceived exercise benefits (P=.02) and decreased embarrassment (P=.03) were observed.Conclusions. Aquajogging was associated with reduced body fat and waist circumference and improved aerobic fitness and quality of life. These findings suggest the usefulness of conducting a randomized controlled trial with long-term outcome assessments.

Chronic severe somatoform disorder (SFD) is resistant to treatment. In a prospective observational study, we evaluated an intensive multidisciplinary treatment focusing on body-related mentalization and acceptance. Patients included in the study were 183 (146 women, 37 men) of 311 eligible patients with chronic severe SFD, referred consecutively to a specialized tertiary care center between 2002 and 2009. Primary outcome measures were somatic symptoms (SCL-90) and health-related quality of life (EuroQol 5-Dimensional [EQ-5D]). These measures were assessed four times before treatment (on intake, twice during an observation period, at start of treatment) and four times after treatment (during follow-up for 2 years). Multilevel analysis was used to separate effects of time (maturation) and treatment. Results revealed significant improvements in SCL-90 somatic symptoms (d = 0.51), EQ-5D index (d = 0.27), and EQ visual analogue scale (d = 0.56). Significant reductions were also observed in SCL-90 anxiety, depression, and overall psychopathology as well as in medical consumption associated with psychiatric illness (Trimbos/iMTA Questionnaire for Costs Associated With Psychiatric Illness). Large interindividual differences were found in treatment outcome. The long-term improvement seen in many patients suggests that intensive multidisciplinary tertiary care treatment is a useful approach to chronic severe SFD.

Aim and Method. To examine in obese people the potential effectiveness of a six-week, two times weekly aquajogging program on body composition, fitness, health-related quality of life, and exercise beliefs. Fifteen otherwise healthy obese persons participated in a pilot study. Results. Total fat mass and waist circumference decreased 1.4 kg (P = .03) and 3.1 cm (P = .005), respectively. The distance in the Six-Minute Walk Test increased 41 meters (P = .001). Three scales of the Impact of Weight on Quality of Life-Lite questionnaire improved: physical function (P = .008), self-esteem (P = .004), and public distress (P = .04). Increased perceived exercise benefits (P = .02) and decreased embarrassment (P = .03) were observed. Conclusions. Aquajogging was associated with reduced body fat and waist circumference and improved aerobic fitness and quality of life. These findings suggest the usefulness of conducting a randomized controlled trial with long-term outcome assessments.