Investigation of neurofunctional reorganization in cocaine addiction using mGluR5 PET and fMRI

项目总结/摘要 可卡因使用障碍（CUD）仍然是一个重大的公共卫生问题，对目前的药物治疗具有抗药性。 治疗和与影响多种认知功能的神经生物学改变相关。挑战 包括神经功能系统的不平衡，“重新连接”大脑， 而习惯性过程则直接导致了不适应的决策和行为。拟议的研究旨在 通过研究与以下相关的神经功能系统，深入了解CUD中的这种重组回路： 谷氨酸和功能性大脑网络。 代谢型谷氨酸5受体（mGluR 5）是参与神经可塑性的突触后受体。 机制，并与调制的收购和持久的成瘾行为在CUD。 对CUD中mGluR 5的研究表明，在早期戒断期间，mGluR 5的可用性普遍降低; 然而，关于mGluR 5在当前使用者中的可用性以及与重组大脑的关系， 认知功能的基础电路休眠状态和基于任务的（例如，反应抑制）性能 涉及已知功能性大脑网络的协调活动和CUD中连接模式的改变 在电路的重组中提供洞察力（例如，额顶叶系统）是成瘾行为的中心。这 该申请提出使用高选择性的PET成像来研究mGluR 5的分布。 放射性配体[18F]FPEB（Aim 1）和静息状态下与反应抑制相关的功能网络活性 在当前使用的CUD患者和匹配的健康人中，在fMRI（目标2）期间使用Go/NoGo任务 对比参与者。其他复杂的分析（例如，独立成分分析） 整合这些多模态数据（目标3），为这些数据之间的关系提供新的见解 CUD中的神经功能系统。 这项研究和培训计划将整合最先进的生物医学成像设施， 耶鲁大学医学院。导师团队由国际知名的成瘾专家组成 精神病学、计算统计学和分子神经科学。该计划将为候选人提供 必要的技能和经验，成为成瘾领域的独立调查员 神经科学为了实现这一目标，候选人建议在三个主要领域接受进一步培训。 领域：（一）人类PET研究协议和图像分析方法的行为;（二）复杂的 多模态神经影像数据整合的统计学;以及（iii） 成瘾精神病学该奖项所提供的机会将使候选人能够开始一个 全面的，结构化的5年培训和研究计划，旨在发展专业知识， 创新的神经生物学研究方法，作为一个独立的成瘾调查员的职业生涯。

PROJECT SUMMARY/ABSTRACT Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments and associated with neurobiological alterations impacting multiple cognitive functions. Challenges to treating CUD include an imbalance in neurofunctional systems that ‘re-wire’ the brain such that appetitive and habitual processes direct maladaptive decision-making and behavior. The proposed research aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamate and functional brain networks. The metabotropic glutamate 5 receptor (mGluR5) is a postsynaptic receptor involved in neuroplastic mechanisms, and associated with modulating the acquisition and persistence of addictive behavior in CUD. Studies of mGluR5 in CUD demonstrate a widespread reduction in availability during early abstinence; however, less is known regarding mGluR5 availability in current users, and relationships to reorganized brain circuitry underlying cognitive functioning. Resting-state and task-based (e.g., response inhibition) performance involve coordinated activity in known functional brain networks and alterations in connectivity patterns in CUD lend insight in a reorganization of circuitry (e.g., fronto-parietal systems) central to addictive behaviors. This application proposes to investigate the distribution of mGluR5 through PET imaging using the highly-selective radioligand [18F]FPEB (Aim 1), and functional network activity at resting-state and related to response inhibition using a Go/NoGo task during fMRI (Aim 2) in currently-using individuals with CUD and matched healthy comparison participants. Additional sophisticated analytics (e.g., independent component analysis) will be used to integrate these multi-modal data (Aim 3), providing novel insight into the relationship between these neurofunctional systems in CUD. This program of research and training will integrate state-of-the-art biomedical imaging facilities at the Yale School of Medicine. The mentorship team consists of internationally renowned experts in addiction psychiatry, computational statistics and molecular neuroscience. The program will provide the candidate with the requisite skills and experience to become an independent investigator in the field of addictions neuroscience. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (i) the conduct of human PET research protocols and image analysis methods; (ii) sophisticated statistics toward the integration of multi-modal neuroimaging data; and (iii) the molecular neuroscience of addictions psychiatry. The opportunities afforded by this award would enable the candidate to embark on a comprehensive, structured 5-year program of training and research designed to develop an expertise in innovative neurobiological research methods toward a career as an independent addictions investigator.