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

项目总结/摘要 有了这个指导病人为导向的研究职业发展奖，候选人-精神病学家与 强大的临床研究背景-渴望实现成为独立的长期目标， 联邦政府资助的研究人员（i）使用神经科学知情的实验医学方法来确定 神经回路机制和（ii）进行临床试验，以开发下一代的电路特异性抗体， 抑制剂治疗，以改善公众健康负担的易怒，一个重要的，但understudy- 抑郁症的IED特征，与较低的生活质量和较高的自杀意念水平有关。 候选人提出结构化的研究经验和正规培训（1）超高场[7 Testa（7 T）] func- 功能性磁共振成像（fMRI），（2）易怒的情感神经科学[包括使用任务- 基于功能磁共振成像模型的挫折性非奖励（FNR），一种进化保守的反应，省略前 预期奖励]，以及（3）实验治疗学方法，以进行神经回路变化的临床试验 作为利益的结果衡量，这将是由一个著名的专家小组在neuroim监督， 衰老、精神神经科学和实验治疗学。为了填补知识空白， rocircuit机制的易怒，候选人提出的研究策略，旨在确定功能障碍的神经， 产生易怒的神经回路（目标1），并确定神经回路功能的变化如何与 （目标2）。本研究将招募18-55岁的男性和女性成年人[n=30例健康 对照组（HC）和n=60例重度抑郁症（MDD）成人]。所有受试者将接受休息状态， 基于任务的7 T fMRI，以表征（i）功能连接模式（目标1.1）和（ii）神经反应 FNR（目标1.2）的行为任务，与易怒（用5项易怒量化）相关 简明相关症状跟踪量表（Concise Associated Symptom Tracking Scale）。MDD队列（n=60）随后将随机分配至2组 每周两次静脉输注氯胺酮（0.5 mg/kg）或咪达唑仑（0.02 mg/kg）， 双盲平行臂模式末次输注后将重复进行临床评估和MRI扫描， 使用静息状态（目标2.1）和FNR（目标2.2）评价治疗前后神经回路功能的变化 氯胺酮与咪达唑仑的基于任务的功能磁共振成像，并探讨神经环变化之间的关系， 功能紊乱和易怒。候选人在7 T功能磁共振成像，情感神经科学， 实验性治疗方法将使研究战略得以成功实施。研究活动， 例如收集、存储、分析和解释来自MRI扫描和临床评估的数据， 提供有价值的实践培训。成功完成拟议的研究将允许候选人（1）ac- 在使用实验治疗方法进行神经科学知情的研究方面寻求专业知识 以及（2）生成试点数据，以寻求NIH的资助，并建立这个高度创新的研究项目。

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.