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

使用 mGluR5 PET 和 fMRI 研究可卡因成瘾的神经功能重组

基本信息

批准号：
10224694
负责人：
Patrick D Worhunsky
金额：
$ 17.97万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224694
关键词：
Abstinence Addictive Behavior Affect Animal Model Area Award Behavior Brain Brain Chemistry Chronic Cocaine Cocaine Dependence Cognitive Communities Complex Compulsive Behavior Computational Technique Corpus striatum structure Data Decision Making Desire for food Disease Exhibits Extinction (Psychology)Functional Magnetic Resonance Imaging Funding Glutamates Goals Health Human Image Analysis Impairment Impulsivity Individual International Intervention Investigation Joints Knowledge Link Mentorship Methods Modality Molecular Nature Neurobiology Neuronal Plasticity Neurosciences Neurotransmitters Parietal Participant Pattern Performance Positron-Emission Tomography Procedures Process Protocols documentation Psychiatry Public Health Quality of life Regimen Relapse Research Research Design Research Methodology Research Personnel Research Training Resistance Rest Self Administration Societies Structure System Testing Training Training Programs addiction base bioimaging brain circuitry career cocaine exposure cocaine self-administration cocaine use cognitive function data fusion design effective therapy experience imaging facilities improved independent component analysis innovation insight medical schools metabotropic glutamate receptor 5 multimodal data multimodality neural circuit neural correlate neurobiological mechanism neuroimaging novel postsynaptic programs radioligand receptor recruit response skills statistics treatment strategy

项目摘要

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.

项目概要/摘要可卡因使用障碍（CUD）仍然是一个重大的公共卫生问题，目前对可卡因使用障碍（CUD）有抵抗力治疗并与影响多种认知功能的神经生物学改变相关。挑战治疗 CUD 的方法包括神经功能系统的不平衡，该系统会“重新连接”大脑，从而降低食欲习惯性过程直接导致适应不良的决策和行为。拟议的研究旨在通过研究与 CUD 相关的神经功能系统，深入了解 CUD 中的这种重组电路谷氨酸和功能性大脑网络。代谢型谷氨酸 5 受体 (mGluR5) 是一种参与神经可塑性的突触后受体机制，并与调节 CUD 成瘾行为的获得和持续相关。 CUD 中 mGluR5 的研究表明，早期戒断期间其可用性普遍降低；然而，关于 mGluR5 在当前用户中的可用性以及与重组大脑的关系知之甚少认知功能的基础电路。静息状态和基于任务（例如反应抑制）的表现涉及已知功能性大脑网络中的协调活动以及 CUD 中连接模式的改变为成瘾行为的核心回路（例如额顶叶系统）的重组提供见解。这应用程序建议使用高度选择性的 PET 成像来研究 mGluR5 的分布放射性配体 [18F]FPEB（目标 1），以及静息状态下与反应抑制相关的功能网络活动在当前使用的 CUD 患者和匹配的健康个体中，在 fMRI（目标 2）期间使用 Go/NoGo 任务比较参与者。将使用其他复杂的分析（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颖的见解 CUD 中的神经功能系统。该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成为成瘾领域独立调查员所需的技能和经验神经科学。为了实现这一目标，候选人建议在三个主要方面进行进一步培训领域： (i) 进行人体 PET 研究方案和图像分析方法； (二) 复杂的多模式神经影像数据整合的统计； (iii) 分子神经科学成瘾精神病学。该奖项提供的机会将使候选人能够踏上全面、结构化的 5 年培训和研究计划，旨在培养以下方面的专业知识创新的神经生物学研究方法，以成为一名独立的成瘾调查员。