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

候选人：我在神经影像学和药物滥用的神经生物学方面接受过广泛的培训。我 工作集中在研究多巴胺信号在神经回路中的作用，重点是风险 决策和成瘾相关的表型。这项工作已导致在顶级期刊上发表了12篇论文， 6次作为第一作者，多次演讲和6次NIH奖学金。具有悠久的 致力于促进退伍军人的健康，我致力于开发一个独立的研究 在VA的职业生涯专注于使用多模态成像来了解成瘾的病理生理学，但 注重治疗和干预。 环境：我在弗吉尼亚州波特兰卫生保健系统和俄勒冈州卫生与健康中心从事这一工作。 科学大学，这是物理连接的室内天桥，并允许完全访问一个 许多合作实验室和研讨会。通过联合任命， 一系列技术和计算资源，沿着科学/咨询支持服务。的活动 拟议的项目将在共享资源和设施的情况下进行，包括先进的成像设备 例如Siemens 3 T PRISMA TOMTrio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。退伍军人 与MA使用障碍的患者更有可能经历护理中断， 传统的治疗选择和药物干预是必不可少的，在发展一个全面的 治疗方案虽然炎症和MA都使用多巴胺功能失调，但其机制是， MA诱导的神经炎症和多巴胺能脑缺陷之间的联系尚未研究。本研究 因此，将测试MA诱导的神经炎症及其用异丁司特影响的减轻的模型 患有MA使用障碍的退伍军人的脑功能和行为。 该项目的第一个目标将比较退伍军人与非MA使用障碍，以确定是否 MA诱导的神经炎症与认知控制障碍和认知功能异常有关。 中皮层边缘区神经网络的功能连接和大脑对奖赏的反应 系统神经影像学测量将包括PET以量化神经炎症;静息状态功能 磁共振成像（fMRI）评估神经网络的功能连接， 金钱奖励延迟任务（MID），测量大脑对奖励的反应。然后我们将 评估为期6周的异丁司特（一种抗炎药）治疗是否能减少神经炎症并改善 脑功能和行为在一项随机安慰剂对照研究的退伍军人与马使用障碍。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，结果将在识别相关生物标志物方面具有重要价值。 与兴奋剂的使用有关，并有可能推进成瘾治疗策略。 研究和培训目标为了为该项目开发一套广泛的研究工具， 我的目标是成为一名独立的研究人员，我的培训计划旨在拓宽我在神经成像方面的技能， 药物治疗以及临床试验的设计和开发。培训将包括正式的教学 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 专注于这些目标。此外，我将接受我的导师和共同导师的职业培训， 实验室最佳实践，包括人事管理和财务会计。正式讲习班将 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大这种培训 skills.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，并在更临床的水平上研究神经缺陷的机制。

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.