Sex-Dependent Impact of Transcutaneous Vagal Nerve Stimulation on the Stress Response Circuitry and Autonomic Dysregulation in Major Depression

项目2.总结 严重抑郁障碍(MDD)是世界范围内发病率和残疾的主要原因，并伴有异常 在应激反应回路和中枢自主神经网络中。这些区域中的许多是性二态的 并与情绪和下丘脑-垂体-肾上腺(HPA)轴调节的性别差异有关 它的失调与荷尔蒙和对应激、自主神经的免疫反应的改变有关 功能障碍和心血管风险增加。本计分提案的总体临床发现任务 是为了确定应激免疫途径失调的性别依赖性影响，从胎儿开始 发展，情绪回路，MDD本身，免疫生理学，中枢和外周血管 在中年时发挥作用。项目2的主要目标是使用非侵入性神经调制刺激 迷走神经(即自主神经系统)靶向与应激免疫功能相关的回路和 按性别映射其在MDD中的神经解剖学和生理学效应。迷走神经刺激(VNS)，FDA 然而，被批准用于MDD的药物调节与情绪/焦虑和自主神经调节有关的大脑回路， 它是植入的，因此是侵入性的。我们建议使用生理增强的经皮VNS (TVNS)是一种低风险、非侵入性和廉价的替代方案。虽然TVNS对 抑郁症状和自主神经调节，当前的刺激参数基于 IVNS的历史数据，其中大部分是男性人口。我们提出了TVNS对调节的影响 特定的脑干-皮质通路受性别的影响。此外，由于延髓背侧迷走神经系统 我们最近证明，tVNS可以通过门控刺激来优化 到呼吸。因此，项目2建议确定呼气门TVNS对性别的影响 复发性MDD应激反应回路改变和生理失调的调节。我们会 评估80例复发的MDD成人样本(年龄51-，按性别均分)随机分为 在功能性磁共振期间接受主动TVNS或主动假刺激(耳垂刺激) 成像(FMRI)会议。功能磁共振成像课程将包括一个旨在引起共鸣的压力挑战-- 兴奋状态，同时进行情绪和生理评估，包括荷尔蒙和动态 心率变异性(HRV)评估。我们假设呼气门TVNS会 有效地调节应激反应回路的特定脑干-皮质通路，并将减弱 复发性MDD患者的生理缺陷。我们进一步假设tVNS将影响大脑活动 以及生理上的性别依赖。虽然项目2不是临床试验或干预，但最终， 结果的转换可能会导致一种新的性别依赖干预，在晚年之前具有有益的效果 与MDD相关的健康后果。 好了！

PROJECT 2. SUMMARY Major depressive disorder (MDD) is a leading cause of morbidity and disability worldwide with abnormalities in the stress response circuitry and central autonomic network. Many of these regions are sexually dimorphic and related with sex differences in mood and hypothalamic-pituitary-adrenal (HPA) axis modulation, the dysregulation of which is associated with alterations of hormone and immune responses to stress, autonomic dysfunction and increased cardiovascular risk. The overall clinical discovery mission of this SCORE proposal is to identify the sex-dependent impact of stress-immune pathway dysregulation, beginning in fetal development, on mood circuitry, MDD per se, immune physiology, and central and peripheral vascular function in midlife. The primary goal of Project 2 is to use non-invasive neuromodulatory stimulation of the vagus (i.e., autonomic nervous system) to target the circuitry associated with stress-immune function and map its neuroanatomic and physiological effects in MDD by sex. Vagal nerve stimulation (VNS), FDA- approved for MDD, modulates brain circuitry implicated in mood/anxiety and autonomic regulation, however, it is implanted and thus invasive. We propose the use of a physiologically-enhanced transcutaneous VNS (tVNS) as a low risk, non-invasive, and inexpensive alternative. While tVNS has had beneficial effects on depressive symptomatology and autonomic regulation, current stimulation parameters are based on historical iVNS data that included mostly male populations. We propose that tVNS effects on the regulation of specific brainstem-cortical pathways is modulated by sex. Moreover, as the dorsal medullary vagal system operates in tune with respiration, we recently demonstrated that tVNS can be optimized by gating stimulation to respiration. Thus, Project 2 proposes to identify the sex-dependent impact of expiratory-gated tVNS on the modulation of stress response circuitry alterations and physiological dysregulation of recurrent MDD. We will evaluate a sample of 80 adults with recurrent MDD (ages 51-64, equally divided by sex) randomized to receive active tVNS or active sham stimulation (earlobe stimulation) during a functional magnetic resonance imaging (fMRI) session. The fMRI session will include a stress challenge designed to elicit a sympatho- excitatory state, with simultaneous mood and physiological assessments, including hormonal and dynamic cardiovagal heart rate variability (HRV) evaluations. We hypothesize that expiratory-gated tVNS will effectively modulate specific brainstem-cortical pathways of the stress response circuitry and will attenuate physiological deficits of recurrent MDD patients. We further hypothesize that tVNS will impact brain activity and physiology in sex-dependent ways. Although Project 2 is not a clinical trial or intervention, ultimately, translation of results may lead to a novel sex-dependent intervention with beneficial effects prior to later-life health outcomes associated with MDD. !