Keeping mind and body in sync: Non-invasive vagus nerve stimulation as a tool to modulate stomach-brain coupling in depression

身体信号通过根据自我平衡的需求调整目标导向的行为来确保有机体的长期生存。这些来自外周器官（如胃和肠道）的身体信号主要通过迷走神经传递，迷走神经可以用放置在耳朵处的电极非侵入性地刺激，以靶向投射到脑干的传入纤维。虽然躯体症状是许多常见精神障碍的特征，如重性抑郁症（MDD），但目前还没有充分了解调节脑-体信号传导的机械治疗是否可以从根本上提高干预的有效性。（通过胃电图（EGG）测量）和休息时和食物奖励任务期间的大脑信号（通过fMRI测量），样本包含80名参与者，其中包括40名患有MDD的患者。重要的是，为了改变身体和大脑信号之间的对应关系，我们建议使用经皮迷走神经刺激（tVNS）。为了更好地解决胃和大脑之间的复杂联系及其随时间的演变，我们将使用随机交叉设计。首先，我们将进行两次功能磁共振成像，同时进行tVNS或假手术，并记录身体信号（EGG和心电图，ECG）。第二，为了研究长时间内的变化，参与者将接受六次额外的刺激（tVNS和假手术，随机顺序），同时我们将使用游戏化的奖励任务和生态瞬时评估（EMA）来跟踪基于价值的决策和代谢以及情绪状态的潜在变化。每个重复的刺激期将在实验室进行，我们将记录身体信号并收集症状数据，以评估中期变化。基于临床前研究结果和我们的初步数据，我们预计tVNS将急性改变迷走神经传入网络内的胃-脑同步性。我们的理论是，tVNS的延长管理将有助于改善MDD患者的症状，并假设这将反映在胃肌电频率的变化。最后，我们将探讨循环激素（如ghrelin）的个体间差异是否与胃-脑耦合有关，这将有助于将胃网络的新兴工作嵌入到更大的关于内感受信号调节能量稳态的文献中。总之，通过关注在饮食行为以及能量和情绪稳态中起重要作用的通路，这项计划可能会为机械疗法铺平新的道路，帮助更迅速、最终更有效地针对精神病理学的各种症状。

Bodily signals ensure long-term survival of an organism by tuning goal-directed behavior according to homeostatic demands. These bodily signals from peripheral organs, such as the stomach and the gut, are primarily routed via the vagus nerve, which can be stimulated non-invasively with electrodes placed at the ear to target afferent fibers projecting to the brainstem. Although somatic symptoms characterize many common mental disorders, such as major depressive disorder (MDD), it is currently not sufficiently understood if mechanistic treatments modulating brain-body signaling could fundamentally improve the effectiveness of interventions.To close this crucial knowledge gap, we propose to investigate the coupling between gastric myoelectic activity (as measured by an electrogastrogram, EGG) and brain signals at rest and during food reward tasks (as measured by fMRI) in a sample of 80 participants, including 40 patients who are suffering from MDD. Importantly, to alter the correspondence between signals of the body and the brain, we propose to use transcutaneous vagus nerve stimulation (tVNS). To better resolve the intricate link between the stomach and the brain and its evolution over time, we will use a randomized cross-over design. First, we will conduct two fMRI sessions with concurrent tVNS or sham and recordings of bodily signals (EGG and electrocardiography, ECG). Second, to investigate changes over an extended period, participants will receive six additional sessions with stimulation (tVNS and sham, randomized order) while we will track potential changes in value-based decision-making and metabolic as well as mood states using a gamified reward task with ecological momentary assessments (EMA). Each repeated stimulation period will be flanked by sessions in the lab, where we will record bodily signals and collect data on symptoms to evaluate mid-term changes. Based on preclinical findings and our preliminary data, we expect that tVNS will acutely alter stomach-brain synchrony within the vagal afferent network. We theorize that extended administration of tVNS will help improve symptoms in patients suffering from MDD and hypothesize that this will be reflected in changes of gastric myoelectic frequency. Lastly, we will explore whether inter-individual differences in circulating hormones, such as ghrelin, are associated with stomach-brain coupling, which would help embed the emerging work on the gastric network in the larger literature on interoceptive signals regulating energy homeostasis.To conclude, by focusing on a pathway that plays a vital role in eating behavior as well as energy and mood homeostasis, the proposed project may pave new avenues for mechanistic therapies that help target diverse symptoms of psychopathology more rapidly and, ultimately, more effectively.