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

压力和不同的精神疾病之间的联系，包括重性抑郁症（MDD），很久以前就已经提出了素质压力模型。最近的实验室和自然主义的研究进一步阐明了这种联系的MDD指向一个中介作用的认知过程的反刍。沉思在MDD中很常见，其特征是对过去、失败和缺点进行悲观的思考，很少或没有目标导向。在我们之前的研究中，我们在临床和亚临床样本中发现，压力下的前额叶功能障碍介导了压力-沉思的联系。在这些研究中，我们应用特里尔社会压力测试（TSST）在一个自然的环境中，同时测量前额叶皮质氧合功能的近红外光谱（fNIRS）。在临床和亚临床样本中，TSST引起了一个反刍反应的压力情况下，这是介导的活动在TSST的背外侧前额叶皮层（DLPFC）和额下回（IFG）。计划中的项目将以这些成果为基础。在计划的安慰剂对照研究中，我们的目标是在TSST给药前，通过抑制性和兴奋性Theta爆发刺激（cTBS/iTBS）直接影响临床模拟动物（研究1; n=44只高性状反刍动物vs. n=44只低性状反刍动物）以及临床样本（研究2; n=44例MDD患者vs. n=44例健康对照）的左侧DLPFC。在实际临床组之前调查临床类似样本将允许控制潜在的混杂因素（例如药物）并测量整个连续的特质反刍。在这两项研究中，在应用TSST之前，受试者将被随机分配至iTBS或cTBS方案。每个随机化组的受试者将在实验室中的两个不同的日期完成两次TSST-一次接受活性刺激，另一次接受安慰剂/假刺激。刺激顺序将是随机的，但在受试者之间保持平衡，两次测量之间的时间约为4 - 5周。本研究将探讨以下研究假设：（1）高特质反刍动物与忧郁症患者，左侧前额叶皮质的TBS是否会调节应激诱发的状态反刍增加？这将证实一个中心（因果？）DLPFC在应激-反刍联系中的作用。(2)这些影响是否取决于个体的特质反刍水平？这项计划中的研究将为神经科学模型提供关于压力-沉思-抑郁联系的信息。除了关于基础研究问题的信息外，该项目还将导致有关TBS方案治疗机制的关键信息，因此对于转化临床科学至关重要。

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.