Prefrontal functioning in the stress-rumination link: Functional measurements and effects of neuromodulation on stress-induced rumination in healthy controls and patients with major depression

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A link between stress and different mental diseases, including Major Depressive Disorder (MDD), has been proposed a long time ago in terms of the Diathesis Stress Model. Recent laboratory and naturalistic studies shed further light on this link for MDD by pointing towards a mediating effect by the cognitive process of rumination. Rumination is common in MDD and characterized by dwelling pessimistic thoughts on the past, one’s failures and shortcomings, with little or no goal-orientation. In our own previous studies, we showed in clinical and subclinical samples that prefrontal dysfunction under stress mediates the stress-rumination link . In these studies, we applied the Trier Social Stress Test (TSST) in a naturalistic environment while measuring prefrontal cortical oxygenation using functional near-infrared spectroscopy (fNIRS). The TSST elicited a ruminative response following the stressful situation in both clinical and subclinical samples, which was mediated by activity during the TSST in the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG). The planned project builds on these results. In the planned placebo-controlled studies we aim to directly influence the left DLPFC via inhibitory and excitatory Theta Burst Stimulation (cTBS/iTBS) in a clinical analogous (study 1; n=44 high trait ruminators vs. n=44 low trait ruminators) as well as a clinical sample (study 2; n=44 MDD patients vs. n=44 healthy controls) before the TSST is administrated. Investigating a clinical analogous sample before the actual clinical group will allow to control for potential confounding factors (e.g. medication) and to measure the whole continuum of trait rumination. In both studies, subjects will be randomized towards either an iTBS or cTBS protocol before the TSST will be applied. Subjects in each randomization arm will complete the TSST twice on two separate days in the lab – one time receiving an active stimulation and the other time a placebo/sham stimulation. The order of stimulation will be randomized but balanced between subjects and the time between both measurements will be approximately 4 to 5 weeks. The following research hypotheses will be investigated: (1) Does TBS of the left DLPFC modulate stress-induced increases in state rumination in high trait ruminators and patients with MDD? This would confirm a central (causal?) role of the DLPFC in the stress-rumination link. (2) Are these effects dependent on individual trait rumination levels?The planned study will inform the neuroscientific models on the stress-rumination-depression link. In addition to the information on basic research questions, the project will lead to critical information on the treatment mechanisms of TBS protocols and is therefore crucial for translational clinical science.