Processes and circuitry underlying threat sensitivity as a treatment target for comorbid anxiety and depression

威胁敏感性的过程和电路作为共病焦虑和抑郁的治疗目标

• 批准号: 10625215
• 负责人: Maria Ironside
• 金额: $ 41.83万
• 依托单位: LAUREATE INSTITUTE FOR BRAIN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625215
• 关键词: Acute; Address; Agonist; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Benzodiazepines; Blinking; Clinical Trials; Complex; Crossover Design; Data; Depressive disorder; Disease; Dose; Electromyography; Electrophysiology (science); Exhibits; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampus; Impairment; Individual; Insula of Reil; Intervention; Literature; Lorazepam; Major Depressive Disorder; Measures; Medicine; Mental Depression; Modeling; Morbidity - disease rate; Multimodal Imaging; Neurologic; Outcome; Participant; Patient Self-Report; Persons; Physiological; Placebos; Prefrontal Cortex; Process; Relapse; Research; Resistance; Rewards; Severities; Shock; System; Treatment outcome; behavioral response; burden of illness; comorbidity; epidemiologic data; gamma-Aminobutyric Acid; midbrain central gray substance; mortality; neural; neural circuit; neuromechanism; neuroregulation; novel; pharmacologic; response; suicidal risk; therapy resistant

PROJECT SUMMARY Nearly half of individuals with Major Depressive Disorder (MDD) have a comorbid anxiety disorder (AD), which is associated with treatment resistance, morbidity, and mortality. Yet, the underlying process dysfunctions that characterize comorbid AD and MDD (AD-MDD) are poorly understood. The premise of this proposal is that exaggerated threat sensitivity in general, and potential threat vs acute threat in particular differentiates AD- MDD from MDD. This project builds on our pilot data showing that people with AD-MDD have exaggerated threat sensitivity compared to those with MDD across several levels (self-report, startle electromyogram [EMG], functional magnetic resonance imaging [fMRI] and behavioral), and aims to delineate and quantify the neural circuit dysfunctions underlying threat sensitivity (potential and acute threat) in AD-MDD relative to MDD and AD. If confirmed, the proposed studies would provide behavioral, neural, and electrophysiological processes that can be used for both quantitative severity assessment and as a treatment target for AD-MDD. Whereas both AD-MDD and MDD individuals show blunted reward and interoceptive/salience processing, only AD-MDD show exaggerated threat sensitivity. However, the neural basis for threat sensitivity is complex and consists of both potential threat (PT; “anxiety”) and acute threat (AT; “fear”) related processes, which involve different circuits, that have not been examined in AD-MDD. This proposal focuses on this crucial gap to better delineate the neural circuitry. Benzodiazepines are common anxiolytics which are GABAergic agonists and reduce PT rather than AT. We propose to use the benzodiazepine Lorazepam, as an acute pharmacological probe to causally study threat circuitry and delineate neural mechanisms contributing to AD-MDD, MDD and AD. This proposal's aims focus on: (1) probing differences in PT and AT at multiple levels of analysis between AD-MDD, MDD and AD; and (2) determining how pharmacological manipulation targeting PT differs in its acute neurological, electrophysiological and behavioral effects on AD-MDD vs MDD vs AD. We propose: (1) the interaction of increased threat sensitivity and reward/salience blunting contributes to unique neural and behavioral responses that are associated with greater disease burden for AD-MDD than MDD; and (2) this sensitivity in AD-MDD is mechanistically related to specific neural activation changes in targetable circuits associated with PT. This mechanistic R01 uses a benzodiazepine within an experimental medicine model approach to causally modulate the threat processing system and associated circuits in AD- MDD (N=55), MDD (N=55), and AD (N=55). In a crossover design, participants will receive a single 1mg dose of Lorazepam and Placebo and complete threat tasks that delineate PT/AT during eyeblink startle EMG (Aim 1/3) and fMRI (Aim 2/3). The ultimate goal of this research is to establish treatment targets for AD-MDD for novel interventions and provide evidence for the separation of MDD and AD-MDD in future clinical trials.

项目摘要 近一半的患有重度抑郁症（MDD）的人患有合并症焦虑症（AD），这是 与治疗性，发病率和死亡率有关。然而，基础过程功能障碍 合并症AD和MDD（AD-MDD）的特征很少了解。该提议的前提是 一般来说，夸大威胁敏感性，潜在的威胁与急性威胁，特别是区分 来自MDD的MDD。该项目建立在我们的试点数据的基础上，表明患有AD-MDD的人已经夸大了 与多个级别的MDD相比，威胁敏感性（自我报告，惊吓肌电图） [EMG]，功能性磁共振成像[fMRI]和行为），旨在描绘和量化 AD-MDD相对于MDD的神经回路功能障碍（潜在和急性威胁） 和广告。如果确认，拟议的研究将提供行为，神经和电生理学 可用于定量严重程度评估和AD-MDD的治疗靶点的过程。 而AD-MDD和MDD的个人都表现出钝性的奖励和际观察/显着性处理 AD-MDD显示夸张的威胁敏感性。但是，威胁敏感性的神经基础很复杂， 既由潜在威胁（PT；“焦虑”）和急性威胁（AT；“恐惧”）相关的过程 在AD-MDD中尚未检查的不同电路。该提议重点是这个关键的差距 描述神经电路。苯二氮卓类药物是常见的抗焦虑药，是GABA能激动剂和 减少PT而不是在。我们建议将苯二氮卓劳拉西m作为急性药理 探测随便研究威胁电路和描述有助于AD-MDD，MDD和的神经力学 广告。该提案的目的是：（1）探测PT的差异，在各个级别的分析之间 AD-MDD，MDD和AD； （2）确定其急性靶向PT差异的药物操纵如何 神经，电生理和行为对AD-MDD与MDD与AD的影响。我们建议：（1） 威胁敏感性和奖励/显着性的相互作用有助于独特的神经 与MDD相比，与AD-MDD更大的疾病燃烧有关的行为反应；和 （2）AD-MDD中的这种敏感性与特定的神经激活变化有关 与PT相关的可目标电路。此机械R01在实验中使用苯二氮卓 医学模型方法偶尔调节威胁处理系统和相关电路 MDD（n = 55），MDD（n = 55）和AD（n = 55）。在跨界设计中，参与者将获得一个1mg的剂量 Lorazepam和安慰剂和完整的威胁任务，这些任务划定了PT/在Eykeblink惊吓EMG时（AIM） 1/3）和fMRI（AIM 2/3）。这项研究的最终目的是为AD-MDD建立治疗目标 新的干预措施，并为将来的临床试验中的MDD和AD-MDD分离提供了证据。