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

通过超高场神经影像阐明烦躁的神经回路，以确定新的治疗靶点

• 批准号: 10698042
• 负责人: Manish Kumar Jha
• 金额: $ 18.36万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698042
• 关键词: Adult; Affect; Aftercare; Aging; American; Anger; Antidepressive Agents; Attention; Behavioral; Biological; Bipolar Disorder; Borderline Personality Disorder; Brain region; Childhood; Chronic; Clinical Research; Clinical Trials; Clinical assessments; Conduct Clinical Trials; Corpus striatum structure; Data; Data Analyses; Development; Double-Blind Method; Emotional; Enrollment; Event; Feedback; Feeling suicidal; Female; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Generalized Anxiety Disorder; Goals; Habenula; Human; Individual; Infusion procedures; Intravenous infusion procedures; Investigational Therapies; Ketamine; Knowledge; MRI Scans; Major Depressive Disorder; Mediating; Medicine; Mental Depression; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Midazolam; Midbrain structure; Modeling; Neurosciences; Noise; Outcome; Outcome Measure; Pattern; Personal Satisfaction; Pharmacological Treatment; Play; Post-Traumatic Stress Disorders; Psychiatrist; Public Health; Quality of life; Randomized; Research; Research Activity; Research Personnel; Resolution; Rest; Rewards; Role; Sampling; Scanning; Severities; Signal Transduction; Structure; Symptoms; Testing; Training; United States National Institutes of Health; Work; Youth; affective neuroscience; aged; arm; associated symptom; career; career development; clinically significant; cohort; dopaminergic neuron; expectation; experience; experimental study; improved; individualized medicine; innovation; interest; male; neural; neural circuit; neuroimaging; new therapeutic target; next generation; novel; pharmacologic; pre-clinical; preclinical study; programs; response; severe mood dysregulation; skills; targeted treatment; treatment effect; treatment strategy

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.

项目概要/摘要 凭借这一以患者为导向的研究职业发展奖，候选人是一位精神科医生， 强大的临床研究背景——渴望实现成为独立、 联邦政府资助的调查员 (i) 使用基于神经科学的实验医学方法来识别 神经回路机制和（ii）进行临床试验以开发下一代回路特异性抗抗体 紧急治疗，以减轻烦躁的公共卫生负担，这是一个重要但尚未充分研究的问题 抑郁症的一个特点是与生活质量较差和自杀意念水平升高有关。 候选人提出在（1）超高场[7 Testa（7T）]功能方面有结构化的研究经验和正式培训 功能磁共振成像（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来模拟挫败性无奖励（FNR），这是一种对前任遗漏的进化保守反应 预期奖励]，以及（3）实验性治疗方法来进行神经回路变化的临床试验 作为兴趣的结果衡量标准，它将由神经学领域的著名专家团队监督 衰老、精神神经科学和实验疗法。填补有关新的知识空白 烦躁的循环机制，候选人提出的研究策略旨在识别神经功能障碍 引起烦躁的神经回路（目标 1）并确定神经回路功能的变化如何与变化相关 易怒（目标 2）。拟议的研究将招募 18-55 岁的男性和女性成年人 [n=30 名健康 对照组 (HC) 和 n=60 名患有重度抑郁症 (MDD) 的成年人]。所有受试者将经历静息状态和 基于任务的 7T fMRI 来表征 (i) 功能连接模式（目标 1.1）和 (ii) 神经反应 与烦躁相关的 FNR 行为任务（目标 1.2）（用 5 项烦躁进行量化） 简明相关症状追踪量表的领域）。 MDD 队列 (n=60) 将被随机分为 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) 数周 双盲平行臂时尚。最后一次输注后将重复临床评估和 MRI 扫描 使用静息态（目标 2.1）和 FNR（目标 2.2）评估治疗前后神经回路功能的变化 使用氯胺酮与咪达唑仑进行基于任务的功能磁共振成像，并探讨神经循环变化之间的关联 cuit 功能和烦躁。候选人在 7T fMRI、情感神经科学和 实验性治疗方法将使研究策略得以成功执行。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，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）ac- 需要使用实验治疗方法进行神经科学研究的专业知识 (2) 生成试点数据，以寻求 NIH 资助并建立这一高度创新的研究计划。

项目成果

Choosing Between Ketamine and Electroconvulsive Therapy for Outpatients With Treatment-Resistant Depression-Advantage Ketamine?

对于难治性抑郁症门诊患者，选择氯胺酮还是电惊厥治疗——氯胺酮的优势？

• DOI: 10.1001/jamapsychiatry.2023.3979
• 发表时间: 2023
• 期刊: JAMA psychiatry
• 影响因子: 25.8
• 作者: Mathew,SanjayJ;Jha,ManishK;Anand,Amit
• 通讯作者: Anand,Amit