Immune-to-brain communication in functional somatic symptoms

Abstract

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.