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

项目总结 近一半的严重抑郁障碍(MDD)患者患有共病焦虑症(AD)， 与治疗耐药性、发病率和死亡率有关。然而，潜在的过程功能障碍 AD和MDD(AD-MDD)的共病特征目前知之甚少。这项提议的前提是 总体上夸大威胁敏感度，以及潜在威胁与严重威胁特别区分AD- 来自MDD的MDD。这个项目建立在我们的试点数据的基础上，这些数据表明，患有AD-MDD的人夸大了 与患有MDD的人在多个水平上的威胁敏感性比较(自我报告、惊吓肌电 [EMG]、功能磁共振成像[fMRI]和行为学)，目的是描绘和量化 相对于MDD，AD-MDD潜在的威胁敏感性(潜在威胁和急性威胁)的神经回路功能障碍 和AD。如果得到证实，拟议的研究将提供行为、神经和电生理 既可用于定量严重性评估，也可用作AD-MDD治疗目标的流程。 而AD-MDD和MDD个体都表现出钝化的奖赏和内感/显著加工，仅 AD-MDD表现出夸大的威胁敏感性。然而，威胁敏感度的神经基础是复杂的 包括与潜在威胁(PT；“焦虑”)和严重威胁(AT；“恐惧”)相关的过程，这涉及 未在AD-MDD中检查的不同电路。这项提案着眼于这一关键差距，以更好地 勾勒出神经回路。苯二氮卓类药物是常见的抗焦虑药物，是GABA能激动剂和 减少PT而不是AT。我们建议使用苯二氮类药物洛拉西潘作为一种急性药理作用 探讨威胁通路与AD-MDD、MDD和AD-MDD的神经机制 广告。这项建议的目的集中在：(1)在多个层次的分析中探讨PT和AT的差异 AD-MDD、MDD和AD；以及(2)确定针对PT的药物操作在其急性发作中的不同 神经、电生理和行为对AD的影响-MDD与MDD与AD。我们建议：(1) 增加的威胁敏感度和奖励/显著程度钝化的交互作用有助于形成独特的神经 行为反应与AD-MDD比MDD更大的疾病负担相关；以及 (2)AD-MDD的这种敏感性与特定的神经激活改变有关。 与PT相关的目标电路。这一机制的R01使用苯二氮卓类在实验中 对AD中威胁处理系统及相关电路进行因果调制的医学模型方法 MDD(N=55)、MDD(N=55)和AD(N=55)。在交叉设计中，参与者将只接受1毫克的剂量 使用洛拉西潘和安慰剂，并完成威胁任务，在眨眼惊吓肌电(AIM)期间描绘PT/AT 1/3)和fMRI(Aim 2/3)。本研究的最终目标是建立AD-MDD的治疗目标 新的干预措施，并为未来临床试验中分离MDD和AD-MDD提供证据。

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.