Functional connectivity alterations among opioid users in treatment

项目总结/摘要 这项拟议的研究是朝着成为一名独立研究人员的职业发展目标迈出的一步， 重点研究阿片类药物使用者之间的功能连接改变。阿片类药物过量 在1999年至2018年期间，近45万人死亡，美国每天有128人死于阿片类药物 2018年过量服用。滥用处方阿片类药物可能是由于影响中脑边缘和皮质的因素， 在大脑中的纹状体系统，包括多巴胺释放的改变和认知控制的丧失。最近 临床前研究表明，从眶额皮质（OFC）到背侧纹状体的较高输入是 与尽管有负面影响的强迫性寻求奖励行为相关（例如，惩罚）。目前已 目前尚不清楚阿片类药物的使用是否与眶额皮层之间的功能连接改变有关， 和背侧纹状体。 表征功能连接的金标准是将脑刺激与神经成像配对。 经颅磁刺激（TMS）是一种非侵入性的，FDA批准的抑郁症脑刺激， 其也被用作阿片类药物使用障碍的治疗。TMS可以与fMRI同时配对 TMS-fMRI实验来表征功能性神经回路的因果操纵。总体目标 本申请的一个目的是使用新的方法，同时TMS功能磁共振成像，以调查阿片类药物的使用是否是 与中脑边缘和皮质-纹状体系统之间的功能连接改变有关， 人类我将描述的功能之间的连接OFC，背侧纹状体，和缰在两个健康的 受试者和阿片类药物使用者（目标1）。然后，我将评估大脑对重复TMS（rTMS）治疗的反应， 类阿片使用者（目标2）。这项提议的结果将在发展神经系统方面迈出重要的一步， 基于回路的策略作为阿片类药物使用障碍的治疗。 候选人目前是精神病学系的终身助理教授。本申请 将为候选人提供多学科培训，以学习所需的技能：（1）学习神经生物学 成瘾的基础，并学习以证据为基础的评估和治疗方法，为个人与 阿片类药物成瘾，特别是阿片类药物使用障碍（OUD）：（2）rTMS在阿片类药物成瘾中的作用机制及临床应用 使用，包括设计和进行随机对照试验的经验;（3）学习临床 使用先进的统计方法进行结果数据分析和解释。完成培训和 研究目标将建立一个坚实的基础，从候选人将获得的技能和知识 开展独立的科学事业，并提供公开的大脑刺激解决方案， 阿片类药物使用者

PROJECT SUMMARY/ABSTRACT This proposed study is a step toward the career development goal of becoming an independent researcher who focused on the study of the functional connectivity alterations among opioid users. The opioid overdose results in almost 450,000 deaths during 1999-2018, and 128 people in the United States die every day from the opioid overdose in 2018. Abuse of prescription opioids is likely due to factors that affect the mesolimbic and cortico- striatal system in the brain, including alteration of dopamine release and loss of cognitive control. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum is associated with compulsive reward-seeking behavior despite negative effects (e.g., punishment). At present, it remains unknown whether opioid use is associated with the functional connectivity alterations between the OFC and dorsal striatum in humans. The gold standard to characterize the functional connectivity is to pair brain stimulation with neuroimaging. Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-approved brain stimulation for depression, which is also being pursued as a treatment for opioid use disorder. TMS can be paired with fMRI in concurrent TMS-fMRI experiments to characterize causal manipulations of functional neural circuits. The overarching goal of this application is to use the novel method, concurrent TMS-fMRI, to investigate whether opioid use is associated with the functional connectivity alterations between the mesolimbic and cortico-striatal system in human. I will characterize functional connectivity between the OFC, dorsal striatum, and habenula in both healthy subjects and opioid users (Aim 1). I will then evaluate brain response to the repetitive TMS (rTMS) treatment in opioid users (Aim 2). The results from this proposal will yield a significant step forward in developing the neural- circuit based strategies as treatments for opioid use disorder. The candidate is currently a tenure-track Assistant Professor in the Department of Psychiatry. This application will provide multidisciplinary training for the candidate to learn the needed skills: (1) learn the neurobiological basis of addiction, and learn evidence-based methods of assessment and treatment for individuals with addiction, specifically opioid use disorders (OUD); (2) learn mechanisms and clinical application of rTMS in opioid use, including the experience in designing and conducting randomized controlled trials; and (3) learn clinical outcomes data analysis and interpretation using advanced statistical methods. Completion of the training and research aims will establish a strong foundation from which the candidate will acquire the skills and knowledge to launch an independent scientific career, as well as provide a publicly available brain stimulation solution to opioid users.