Elucidating the Neurocircuitry of Irritability with Ultra-High-Field Neuroimaging to Identify Novel Therapeutic Targets

项目摘要/摘要 有了这个以患者为导向的研究职业发展奖，候选人-精神病学家 扎实的临床研究背景-渴望实现成为一个独立的， 联邦资助的研究人员，(I)使用神经科学知识的实验医学方法来确定 神经回路机制和(Ii)进行临床试验，以开发下一代电路特异性抗凝剂-- 为了减轻易激惹的公共卫生负担的压力治疗，一个重要而又被理解的- 抑郁的IED特征，与较差的生活质量和较高的自杀意念水平有关。 候选人建议在(1)超高场[7 Testa(7T)]函数方面有组织的研究经验和正式培训- 常规磁共振成像(FMRI)，(2)易怒的情感神经科学[包括任务-任务的使用- 基于fMRI的挫折性无奖赏(FNR)模型，一种进化上保守的对前任遗漏的反应 预期回报]，以及(3)进行神经回路改变的临床试验的实验治疗学方法 作为兴趣的结果衡量标准，它将由一个著名的神经学专家团队监督- 衰老、精神神经科学和实验治疗学。为了填补关于中大的知识空白- 应激性的环路机制，候选人提出的研究策略旨在识别神经功能障碍。 产生易激性的环路(目标1)，并确定神经回路功能的变化如何与变化相关 在易怒方面(目标2)。这项拟议的研究将招募18-55岁的男性和女性成年人[n=30健康 对照组(HC)和n=60名患有严重抑郁障碍(MDD)的成年人]。所有受试者都将经历休息状态和 基于任务的7T fMRI用于表征(I)功能连接模式(目标1.1)和(Ii)神经反应 与易怒(用5项易怒量化)相关的FNR(目标1.2)的行为任务 简明相关症状跟踪量表的领域)。然后，MDD队列(n=60)将被随机分配到2 每周两次静脉滴注氯胺酮(0.5 mg/kg)或咪达唑仑(0.02 mg/kg)。 双盲平臂时尚。在最后一次输液后将重复进行临床评估和核磁共振扫描 用静息状态(Aim 2.1)和FNR(Aim 2.2)评估治疗前后神经回路功能的变化 使用氯胺酮和咪达唑仑进行基于任务的功能磁共振成像，并探索神经回路变化之间的联系。 性情功能和易怒。应聘者在7T功能磁共振成像、情感神经科学和 实验治疗方法将使研究战略的成功实施成为可能。研究活动， 例如收集、存储、分析和解释来自MRI扫描和临床评估数据，将 提供有价值的实践培训。成功完成拟议的研究将使候选人能够(1)- Quire在使用实验治疗学方法进行神经科学知情研究方面的专业知识 以及(2)生成试点数据，以便继续为NIH提供资金，并建立这一高度创新的研究计划。

PROJECT SUMMARY/ABSTRACT With this Mentored Patient-Oriented Research Career Development Award, the candidate – a psychiatrist with strong background in clinical research – aspires to achieve the long-term goal of becoming an independent, federally funded investigator who (i) uses a neuroscience-informed experimental medicine approach to identify neurocircuit mechanisms and (ii) conducts clinical trials to develop the next generation of circuit-specific antide- pressant treatments in order to ameliorate the public health burden of irritability, an important yet understud- ied feature of depression that is associated with poorer quality of life and elevated levels of suicidal ideation. Candidate proposes structured research experience and formal training in (1) ultra-high-field [7 Testa (7T)] func- tional magnetic resonance imaging (fMRI), (2) the affective neuroscience of irritability [including the use of task- based fMRI to model frustrative nonreward (FNR), an evolutionarily conserved response to omission of an ex- pected reward], and (3) experimental therapeutics approach to conduct clinical trials with changes in neurocircuit function as the outcome measure of interest, that will be supervised by a team of prominent experts in neuroim- aging, psychiatric neuroscience and experimental therapeutics. To fill the knowledge gaps regarding the neu- rocircuit mechanisms of irritability, candidate’s proposed research strategy aims to identify dysfunctions in neu- rocircuitry that engender irritability (Aim 1) and determine how changes in neurocircuit function relate to changes in irritability (Aim 2). The proposed study will enroll male and female adults aged 18-55 years [n=30 healthy controls (HC) and n=60 adults with major depressive disorder (MDD)]. All subjects will undergo resting-state and task-based 7T fMRI to characterize the (i) patterns of functional connectivity (Aim 1.1) and (ii) neural responses to a behavioral task of FNR (Aim 1.2) that are associated with irritability (quantified with the 5-item irritability domain of Concise Associated Symptom Tracking scale). The MDD cohort (n=60) will then be randomized to 2 weeks of twice-weekly intravenous infusions of either ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) in a double-blind parallel-arm fashion. Clinical assessments and MRI scans will be repeated after the last infusion to evaluate pre-to-post treatment changes in neurocircuit function using resting-state (Aim 2.1) and FNR (Aim 2.2) task-based fMRI with ketamine versus midazolam and to explore the association between changes in neurocir- cuit function and irritability. Candidate’s didactic and mentored training in 7T fMRI, affective neuroscience, and experimental therapeutic approach will enable successful execution of the research strategy. Research activities, such as collecting, storing, analyzing, and interpreting data from MRI scans and from clinical assessments, will provide valuable hands-on training. Successful completion of the proposed study will allow candidate to (1) ac- quire expertise in the conduct of neuroscience-informed studies that use experimental therapeutics approach and (2) generate pilot data in order to pursue NIH funding and build this highly innovative program of research.