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

项目摘要 近一半的重度抑郁症（MDD）患者患有共病焦虑症（AD）， 与治疗抗性、发病率和死亡率相关。然而，潜在的过程功能失调， 对AD和MDD共病（AD-MDD）的特征知之甚少。这一提议的前提是， 夸大的威胁敏感性，特别是潜在威胁与急性威胁的区别， 从MDD。这个项目建立在我们的试验数据的基础上，这些数据表明，患有AD-MDD的人夸大了 与MDD患者相比，威胁敏感度在几个水平上（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 与MDD相比，AD-MDD中潜在威胁敏感性（潜在和急性威胁）的神经回路功能障碍 的AD。如果得到证实，拟议的研究将提供行为、神经和电生理方面的信息 可用于定量严重程度评估和作为AD-MDD治疗靶点的过程。 然而，AD-MDD和MDD个体都表现出迟钝的奖励和内感受/突出性处理，只有 AD-MDD显示出夸大的威胁敏感性。然而，威胁敏感性的神经基础是复杂的， 由潜在威胁（PT;“焦虑”）和急性威胁（AT;“恐惧”）相关的过程组成， 不同的电路，在AD-MDD中没有检查。该提案侧重于这一关键差距，以更好地 描绘出神经回路苯二氮卓类是常见的抗焦虑药，其是GABA能激动剂， 减少PT而不是AT。我们建议使用苯二氮卓类劳拉西泮，作为急性药理学 探索因果关系研究威胁电路和描绘神经机制有助于AD-MDD，MDD和 AD.本提案的目的主要集中在：（1）在多个分析层次上探索PT和AT的差异， AD-MDD、MDD和AD;以及（2）确定靶向PT的药理学操作在其急性 对AD-MDD vs MDD vs AD的神经、电生理和行为影响。我们建议：（1） 增加的威胁敏感性和奖励/显着性钝化的相互作用有助于独特的神经 与MDD相比，AD-MDD的疾病负担更大;以及 (2)AD-MDD中的这种敏感性在机制上与特定的神经激活变化相关， 与PT相关的目标电路。这种机制R 01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，受试者将接受1 mg单次给药 的劳拉西泮和安慰剂，并完成威胁任务，描绘PT/AT在眨眼惊吓EMG（目的 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，并提供证据，为分离MDD和AD-MDD在未来的临床试验。

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.