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

经皮迷走神经刺激对重度抑郁症应激反应回路和自主神经失调的性别依赖性影响

• 批准号: 10349464
• 负责人: VITALY NAPADOW
• 金额: $ 19.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349464
• 关键词: Adult; Adult Children; Age; Algorithms; Amygdaloid structure; Anatomy; Anterior; Anxiety; Arousal; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Baroreflex; Behavioral; Blood Pressure; Blood Vessels; Brain; Brain Stem; Brain region; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Clinical; Clinical Trials; Concha; Corticotropin-Releasing Hormone; Data; Development; Dorsal; Elderly; Evaluation; FDA approved; Fetal Development; Fiber; Functional Magnetic Resonance Imaging; Future; Goals; Health; Hippocampus (Brain); Hormonal; Hormones; Hydrocortisone; Hypothalamic structure; Immune; Immune response; Immunologic Markers; Implant; Inflammatory; Intervention; Lead; Major Depressive Disorder; Maps; Measurement; Methods; Mission; Modeling; Moods; Morbidity - disease rate; Nerve; Neural Pathways; Neurons; Operating System; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peripheral; Physiological; Physiology; Population; Prefrontal Cortex; Process; Randomized; Recurrence; Regulation; Resistance; Respiration; Risk; Sampling; Sampling Studies; Sex Differences; Sexual Dysfunction; Site; Skin; Stress; Synapses; System; Techniques; Therapeutic; Time; Translations; Vagus nerve structure; Visual; Woman; Work; advanced analytics; antidepressant effect; base; biological adaptation to stress; brain circuitry; brain magnetic resonance imaging; cardiovascular risk factor; cytokine; depressive symptoms; design; disability; expiration; external ear auricle; heart rate variability; hypothalamic-pituitary-adrenal axis; immune function; interest; locus ceruleus structure; male; men; middle age; mood regulation; neuroregulation; novel; nucleus ambiguus; prenatal stress; raphe nuclei; response; sex; sexual dimorphism; side effect; steroid hormone; symptomatology; transcutaneous stimulation; vagus nerve stimulation

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. !

项目2。摘要 重度抑郁症（MDD）是全球发病率和残疾的主要原因，异常 在压力响应电路和中央自主网络中。这些区域中有许多是性二态的 与情绪的性别差异和下丘脑 - 垂体 - 肾上腺（HPA）轴调节有关， 其失调与激素改变和对压力的免疫反应有关 功能障碍并增加心血管风险。该分数建议的整体临床发现任务 是从胎儿开始确定压力免疫途径失调的性别依赖性影响 开发，情绪电路，MDD本身，免疫生理学以及中央和周围血管 中年的功能。项目2的主要目标是使用非侵入性神经调节性刺激 迷走神经（即自主神经系统）针对与应力免疫功能相关的电路 通过性别绘制其在MDD中的神经解剖学和生理效应。迷走神经刺激（VNS），FDA- 批准用于MDD，调节与情绪/焦虑和自主法规有关的脑电路，但是 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VN （TVN）是一种低风险，无创和廉价的替代品。虽然电视对 抑郁症状和自主法规，当前刺激参数基于 历史IVNS数据主要包括男性人群。我们建议TVNS对法规的影响 特定的脑干皮层途径是通过性别调节的。而且，作为背髓迷走神经系统 我们最近表明，可以通过门控刺激来优化TVNS 呼吸。因此，项目2提议确定呼气门控电视对性别的影响 应力反应回路改变和复发MDD的生理失调的调节。我们将 评估一个复发性MDD的80名成年人的样本（51-64岁，同样由性别划分）随机分为 在功能磁共振中接收主动TVN或主动假刺激（耳垂刺激） 成像（fMRI）会话。 fMRI会议将包括旨在引起同情心的压力挑战 兴奋状态，同时情绪和生理评估，包括荷尔蒙和动态 心脏心率变异性（HRV）评估。我们假设呼气门控电视将 有效地调节应力反应电路的特定脑干皮层途径，并将减弱 复发性MDD患者的生理缺陷。我们进一步假设TVN会影响大脑活动 和生理学的方式。尽管项目2不是临床试验或干预措施，但最终 结果的翻译可能会导致一种新型的性别依赖性干预措施，并在以后的生活之前具有有益的效果 与MDD相关的健康结果。 呢