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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要近一半的重度抑郁症 (MDD) 患者同时患有焦虑症 (AD)，然而，潜在的过程功能障碍与治疗抵抗、发病率和死亡率有关。人们对 AD 和 MDD 共病 (AD-MDD) 的特征知之甚少。一般来说，夸大的威胁敏感性，特别是潜在威胁与急性威胁区分 AD- MDD 中的 MDD 建立在我们的试点数据之上，该数据显示 AD-MDD 患者夸大了事实。与 MDD 患者相比，在多个层面上对威胁的敏感性（自我报告、惊吓肌电图） [EMG]、功能磁共振成像 [fMRI] 和行为），旨在描述和量化 AD-MDD 相对于 MDD 的威胁敏感性（潜在和急性威胁）的神经回路功能障碍如果得到证实，拟议的研究将提供行为、神经和电生理学方面的信息。该过程可用于定量严重性评估和作为 AD-MDD 的治疗目标。 AD-MDD 和 MDD 个体都表现出迟钝的奖励和内感受/显着性处理，仅 AD-MDD 显示夸大的威胁敏感度然而，威胁敏感度的神经基础是复杂且复杂的。包括潜在威胁（PT；“焦虑”）和急性威胁（AT；“恐惧”）相关过程，其中涉及不同的电路，尚未在 AD-MDD 中进行检查，该提案重点关注这一关键差距，以更好地实现这一目标。描述神经回路。苯二氮卓类药物是常见的抗焦虑药，是 GABA 激动剂和我们建议使用苯二氮卓类药物劳拉西泮作为急性药物来减少 PT。探索因果关系研究威胁回路并描绘导致 AD-MDD、MDD 和 AD。该提案的目标集中在：（1）探讨 PT 和 AT 在多个分析层面上的差异。 AD-MDD、MDD 和 AD；以及 (2) 确定针对 PT 的药物操作在急性期有何不同 AD-MDD 与 MDD 与 AD 的神经学、电生理学和行为学影响我们建议：(1) 威胁敏感性增加和奖励/显着性钝化的相互作用有助于形成独特的神经网络与 AD-MDD 相比 MDD 疾病负担更大的行为反应；以及 (2) AD-MDD 的这种敏感性在机制上与特定的神经激活变化相关。与 PT 相关的可靶向电路该机制 R01 在实验中使用苯二氮卓类药物。医学模型方法因果调节AD-中的威胁处理系统和相关电路 MDD (N=55)、MDD (N=55) 和 AD (N=55) 在交叉设计中，参与者将接受单次 1 毫克剂量。劳拉西泮和安慰剂并完成威胁任务，在眨眼惊吓肌电图期间描绘 PT/AT（目标 1/3) 和功能磁共振成像 (目标 2/3) 本研究的最终目标是建立 AD-MDD 的治疗目标。新颖的干预措施，为未来临床试验中MDD和AD-MDD的分离提供证据。