Brain Function and Connectivity in Methamphetamine Dependence: The Link to Neuroinflammation and the Effects of Ibudilast

应聘者：我在神经成像和药物滥用的神经生物学领域接受过广泛的培训。我的 工作的重点是研究多巴胺信号在神经回路中的作用，重点是高风险 决策和成瘾相关的表型。这项工作已在顶级期刊上发表了12篇文章，其中包括 6名第一作者，多次演讲，6次获得NIH奖学金。有着悠久的历史 致力于为退伍军人的健康做出贡献，我致力于发展独立的研究 在退伍军人管理局的职业生涯专注于使用多模式成像来了解成瘾的病理生理学，但 注重治疗和干预。 环境：我在退伍军人管理局波特兰医疗保健系统和俄勒冈州健康和医疗保健公司从事这项工作 科学大学，通过室内天桥物理连接，并允许完全访问 大量的协作实验室和研讨会。通过联合任命，我将能够获得完整的 一系列技术和计算资源以及科学/咨询支助服务。的活动 拟议的项目将共享资源和设施，包括先进的成像设备 例如西门子3T棱镜磁三体仪和正电子发射断层扫描(PET)。 研究甲基苯丙胺(MA)使用障碍是我们退伍军人面临的一个主要健康问题。作为退伍军人 患有MA使用障碍的人更有可能经历护理中断，综合方法结合 传统的治疗选择和药物干预对于制定全面的 治疗方案。尽管炎症和MA都使用多巴胺功能失调，但其机制 MA诱导的神经炎症和多巴胺能脑缺陷之间的联系尚未被研究。本研究 因此，我将测试一种模型，在该模型中，MA诱导神经炎症，并通过异丁司特的影响减轻其影响 退伍军人MA使用障碍患者的脑功能和行为。 该项目的第一个目标是比较患有和不患有MA使用障碍的退伍军人，以确定是否 MA诱导的神经炎症与认知控制障碍和脑功能异常有关 神经网络的功能连通性和大脑对奖赏反应的激活 系统。神经成像措施将包括PET以量化神经炎症；静息状态功能 磁共振成像(FMRI)用于评估神经网络的功能连通性，fMRI与 货币激励延迟任务(MID)测量大脑对奖励的反应。到时候我们会的 评估抗炎药异丁司特6周的治疗是否能减少神经炎症并改善 一项对患有MA使用障碍的退伍军人进行的随机安慰剂对照研究中的大脑功能和行为。如果 炎症与功能性脑缺陷有关，异丁司特被证明在恢复功能方面有效 和神经网络的连通性，这些结果将在识别相关的生物标志物方面具有重要价值 与兴奋剂的使用有关，并有可能推进成瘾的治疗策略。 研究和培训目标，以便为该项目开发一套广泛的研究工具，并促进 作为一名独立研究人员，我的目标是，我的培训计划旨在扩大我在神经成像方面的技能， 药物疗法和临床试验的设计和开发。培训将包括正式的说教 培训、实验室实践经验、一对一监督以及一系列会议和研讨会 将重点放在这些目标上。此外，我还将在以下时间接受导师和同事的职业培训 实验室最佳做法，包括人事管理和财务会计。正式的研讨会将 通过提供关于沟通和领导力的实践课程和教育研讨会来扩展这种培训 技能。获得这些新的实验能力的培训使我能够在翻译方面迈出下一步 研究并按照建议在更临床的水平上探讨神经功能缺陷的机制。

Candidate: I have had extensive training in fields of neuroimaging and the neurobiology of drug abuse. My work has focused on investigating the effects of dopamine signaling in neural circuits with a focus on risky decision-making and addiction-related phenotypes. This work has led to 12 publications in top-tier journals with 6 as first-author, multiple speaking engagements and 6 NIH fellowship awards. With a long-standing commitment to contribute to the health of veterans, I am dedicated to developing an independent research career at the VA focused on using multi-modal imaging to understand the pathophysiology of addiction but with a focus on treatment and interventions. Environment: I am pursuing this line of work at the VA Portland Health Care System and Oregon Health & Science University, which are physically connected by an indoor sky bridge and allows complete access to a multitude of collaborative laboratories and seminars. Through joint appointments I will have access to a full range of technical and computing resources along with scientific/consultative support services. The activities of the proposed project will occur with shared resources and facilities, including advanced imaging equipment such as the Siemens 3T PRISMA MAGNETOM Trio and positron emission tomography (PET). Research Methamphetamine (MA) use disorder is a major health problem facing our veterans. As veterans with MA-use disorder are more likely to experience a disruption in care, an integrated approach combining traditional treatment options and pharmacological interventions are essential in developing a comprehensive treatment program. Although both inflammation and MA use dysregulate dopamine function, the mechanistic link between MA-induced neuroinflammation and dopaminergic brain deficits has not been studied. This study will therefore test a model whereby MA-induced neuroinflammation and its reduction with ibudilast influences brain function and behavior in veterans with MA-use disorder. The first aim of the project will compare veterans with and without MA-use disorder to determine whether MA-induced neuroinflammation is associated with impairments in cognitive control and abnormalities in functional connectivity of neural networks and brain activation in response to reward in the mesocorticolimbic system. Neuroimaging measures will include PET to quantify neuroinflammation; resting-state functional magnetic resonance imaging (fMRI) to assess functional connectivity of neural networks and fMRI paired with the Monetary Incentive Delay Task (MID) to measure brain activation in response to reward. We will then assess whether a 6-week treatment of ibudilast, an anti-inflammatory reduces neuroinflammation and improves brain function and behavior in a randomized placebo-controlled study in veterans with MA-use disorder. If inflammation is associated with functional brain deficits and ibudilast is proven effective in restoring function and connectivity of neural networks, the results would be of great value in identifying biomarkers associated with stimulant use and has the potential to advance therapeutic strategies for addiction. Research and training goals In order to develop a broad set of research tools for this project and promote my goal as an independent researcher, my training plan is designed to broaden my skills in neuroimaging, pharmacotherapy and the design and development of clinical trials. The training will include formal didactic training, hands-on laboratory experience, one-on-one supervision, and a series of meetings and workshops sharply focused on these goals. In addition, I will receive career training from my mentor and co-mentors on laboratory best practices including personnel management and fiscal accounting. Formal workshops will extend this training by providing practical sessions and education seminars on communication and leadership skills. Training to acquire these new experimental capabilities allows me to take the next step in translational research and to investigate the mechanism of neural deficits at a more clinical level as proposed.