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) 是全世界范围内发病和残疾的主要原因 在压力反应电路和中央自主网络中。其中许多区域是性别二态性的 并且与情绪和下丘脑-垂体-肾上腺（HPA）轴调节的性别差异有关， 其失调与激素和免疫对压力、自主神经反应的改变有关 功能障碍和增加心血管风险。 SCORE提案的总体临床发现任务 的目的是确定从胎儿开始的应激免疫途径失调的性别依赖性影响 发展、情绪回路、MDD 本身、免疫生理学以及中枢和外周血管 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节刺激 迷走神经（即自主神经系统）针对与应激免疫功能相关的电路， 按性别绘制 MDD 中神经解剖学和生理学的影响。迷走神经刺激 (VNS)、FDA- 批准用于 MDD，调节与情绪/焦虑和自主调节有关的大脑回路，但是， 它是植入的，因此具有侵入性。我们建议使用生理增强的经皮 VNS （tVNS）作为一种低风险、非侵入性且廉价的替代方案。虽然 tVNS 对以下方面产生了有益影响： 抑郁症状和自主调节，当前刺激参数基于 iVNS 历史数据主要包括男性人群。我们建议 tVNS 对监管的影响 特定的脑干皮质通路受性别调节。此外，由于背髓迷走神经系统 与呼吸协调运行，我们最近证明可以通过门控刺激来优化 tVNS 到呼吸。因此，项目 2 建议确定呼气门控 tVNS 对性别的影响 调节应激反应电路的改变和复发性 MDD 的生理失调。我们将 评估 80 名患有复发性 MDD 的成年人（年龄 51-64 岁，按性别均等划分）的样本，随机分为 在功能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。功能磁共振成像会议将包括旨在引发同情心的压力挑战 兴奋状态，同时进行情绪和生理评估，包括激素和动态 心迷走心率变异性（HRV）评估。我们假设呼气门控 tVNS 将 有效调节应激反应回路的特定脑干皮质通路，并会减弱 复发性 MDD 患者的生理缺陷。我们进一步假设 tVNS 会影响大脑活动 和生理学以性别依赖的方式。尽管项目 2 不是临床试验或干预，但最终， 结果的转化可能会导致一种新颖的性别依赖性干预措施，在晚年之前产生有益的影响 与 MDD 相关的健康结果。 ！