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

应激与包括重度抑郁症（MDD）在内的多种精神疾病之间的联系，在素质应激模型中早已被提出。最近的实验室和自然主义研究通过指出反刍认知过程的中介作用，进一步阐明了重度抑郁症的这种联系。反刍在重度抑郁症中很常见，其特征是对过去、自己的失败和缺点抱有悲观的想法，很少或没有目标导向。在我们自己之前的研究中，我们在临床和亚临床样本中表明，压力下的前额叶功能障碍介导了压力-反刍联系。在这些研究中，我们在自然环境中应用Trier社会压力测试（TSST），同时使用功能近红外光谱（fNIRS）测量前额皮质氧合。在临床和亚临床实验中，TSST诱发了应激情境后的反刍反应，这种反刍反应是由TSST期间背外侧前额叶皮层（DLPFC）和额下回（IFG）的活动介导的。计划中的项目以这些结果为基础。在计划中的安慰剂对照研究中，我们的目标是在给予TSST之前，通过抑制和兴奋性θ波爆发刺激（cTBS/iTBS）在临床模拟（研究1，n=44名高特质反刍者vs. n=44名低特质反刍者）和临床样本（研究2，n=44名重度抑郁症患者vs. n=44名健康对照）中直接影响左DLPFC。在实际的临床组之前调查一个临床类似样本将允许控制潜在的混淆因素（例如药物）并测量特征反刍的整个连续体。在这两项研究中，在应用TSST之前，受试者将随机选择iTBS或cTBS方案。每个随机分组组的受试者将分别在实验室的两天内完成两次TSST测试——一次接受积极刺激，另一次接受安慰剂/假刺激。刺激的顺序将是随机的，但在受试者之间是平衡的，两次测量之间的时间间隔约为4至5周。本文将探讨以下研究假设：(1)高特质反刍者和重度抑郁症患者的应激诱导的状态反刍增加是否与左DLPFC的TBS有关？这将证实DLPFC在压力-反刍联系中的核心（因果关系？）作用。(2)这些效应是否依赖于个体特质反刍水平？这项计划中的研究将为压力-反刍-抑郁联系的神经科学模型提供信息。除了有关基础研究问题的信息外，该项目还将提供有关TBS方案治疗机制的关键信息，因此对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.