Mental functioning, brain Tryptophan availability and affect; the role of the immune system

Everyone is confronted with stressful life events. Stressors, however, do not
affect everyone similarly. Whether stress has a detrimental effect on health
and affect is, among other factors, dependent on the individual degree of
stress resilience. Various neurobiological systems were found to mediate stress
tolerance, most importantly the mutually interacting brain serotonergic (5-HT)
system and Hypothalamic-pituitary adrenal axis (HPA) - commonly recognized as
the neuroendocrine stress adaptation system. Exposure to acute severe or
long-term persistent stress can induce abnormalities in both systems, leading
to exaggerated adaptive responsiveness to future stressors and hence increased
stress vulnerability. Indeed, mounting evidence indicates that persistent
stress can impair serotonergic neurotransmission and HPA-related stress hormone
regulation.

Recently, however, it was hypothesized that sensitization of the stress
response may have a pro-inflammatory root as well. Activation of the immune
system - more specifically the release of immune signaling molecules caused by
systemic infection/inflammation or chronic mental stress - may additionally
increase stress sensitivity by negatively affecting 5-HT synthesis and/or
neurotransmission and HPA-axis regulation.

In the current project, we aim to investigate the likeliness of this
proposition. We will examine whether chronic immune activation affects the
neuroendocrine (HPA) stress adaptation system and therefore mental- emotional
stress resilience.
By including the role of the immune system in the current biological-
psychological model of stress resilience, we may develop a better understanding
of individual differences in stress sensitivity and related affective illness.

The primary objective of the study is to explore whether immune activation
potentiates stress vulnerability by increasing serotonin dysfunction (lower
tryptophan ratio*s). This objective is based on the hypotheses that
pro-inflammatory cytokines induce a shift in tryptophan metabolism, thereby
hypothetically resulting in reduced 5-HT synthesis and diminished regulatory
control over the HPA axis.

Secondary objectives focus on group differences (patients with an inflammatory
disease versus healthy controls ) with respect to objective stress response,
inflammatory response and affective response in the face of acute stressors.

Since it is increasingly recognized that stress induces an inflammatory
response as well (irrespective of the presence of an inflammatory
disease/infection/tissue damage), which may facilitate inflammation-induced-TRP
degradation and HPA dysregulation even further, chronic stress will be included
as an additional primer of stress sensitivity.

In a repeated measure between subjects design, patients with systemic
gastrointestinal complains and healthy controls are monitored for both brain
tryptophan availability (prior to acute stress exposure), objective/ subjective
stress before and after acute stress exposure. This study uses a 2
(gastrointestinal complains, controls) x 2 (high/low stress) x 2 (before/ after
stress exposure) study design.

Participants will visit the research lab only once for a total time of 3 h. A
standardized, quick and non-invasive, laboratory stress protocol will be
applied to elicit autonomic and glucocorticoid stress responses. The stress
task lasts solely 15 minutes (5 minutes preparation time, 10 minutes acute
stress). Any risks associated with 10 minutes acute stress induction can be
considered negligible and the burden minimal. Prior and post stress induction,
participants will perform two short behavioural tasks (negative affective
priming). In addition, participants will complete a computerized mood
questionnaire four times (after arrival, pre-post stress, post-recovery) and a
life stress questionnaire. In addition, a total of six serial saliva samples
will be drawn for cortisol and cytokine assessments and one blood sample to
measure TRP/LNAA ratio*s. Participants will receive ¤75,- compensation for
participation in the experiment. In the event of early termination,
participants will be compensated pro rata.