Multimodal Neuroimaging of Alcohol Withdrawal: The Role of Glutamate in Neural Reorganization

酒精戒断的多模式神经影像学：谷氨酸在神经重组中的作用

• 批准号: 10092045
• 负责人: Ansel Hillmer
• 金额: $ 17.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092045
• 关键词: Abstinence; Age; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Area; Behavior; Brain; Chronic; Clinical; Clinical Treatment; Cognitive; Coupling; Data; Dependence; Development; Doctor of Philosophy; Evaluation; Exhibits; Extinction (Psychology); Functional Magnetic Resonance Imaging; Future; GTP-Binding Proteins; Glutamates; Goals; Growth; Human; Image; Impaired cognition; Impairment; Individual; Investigation; Learning; Longitudinal Studies; Macaca mulatta; Magnetic Resonance; Measures; Mentored Research Scientist Development Award; Mentors; Methods; Modality; N-Methyl-D-Aspartate Receptors; Neuronal Plasticity; Neurons; Neurotransmitters; Outcome Measure; Patients; Performance; Positron-Emission Tomography; Prefrontal Cortex; Public Health; Recovery; Relapse; Research; Research Personnel; Rest; Role; Scientist; Severities; Shapes; Short-Term Memory; Societies; Structure; System; Techniques; Testing; Therapeutic; Training; Treatment outcome; Withdrawal; Withdrawal Symptom; Work; alcohol exposure; alcohol research; alcohol use disorder; base; brain dysfunction; cognitive function; data fusion; data integration; disorder later incidence prevention; experience; experimental study; improved; independent component analysis; innovation; insight; metabotropic glutamate receptor 5; multimodality; neurochemistry; neuroimaging; novel; pre-clinical; problem drinker; radioligand; receptor; receptor function; recruit; relating to nervous system; responsible research conduct; spatiotemporal; synergism

PROJECT ABSTRACT This Mentored Research Scientist Development Award application proposes support for Ansel Hillmer, Ph.D., in his transition to independent research using neuroimaging to study alcohol use disorders in humans. Glutamate's role in both alcohol dependence and neuroplasticity make it a critical system to examine the neurochemical underpinnings of dynamic changes in brain structure and function in alcohol dependence and withdrawal. The goal of this proposed research is to study the role of the metabotropic glutamate 5 receptor (mGluR5), a promising target for alcohol dependence therapeutics, in neural reorganization during alcohol withdrawal. Specific focus is given to examining relationships between neurochemical changes and clinical correlates of alcohol dependence throughout the course of withdrawal. We propose to perform longitudinal neuroimaging in 40 alcohol dependent patients during withdrawal at 7-10 days abstinence and 4 weeks abstinence, and single sessions in 30 matched healthy controls. The recruitment and evaluation of alcohol dependent patients will be mentored by Kelly Cosgrove, Ph.D. and Stephanie O'Malley, Ph.D. Neuroimaging sessions will feature 18F-FPEB PET scans to measure mGluR5 availability, and resting state fMRI connectivity to examine neural organization. First, we will assess differences in both mGluR5 availability and resting state connectivity in patients longitudinally and relative to controls. Next, we will determine relationships of neuroimaging measures with clinical and cognitive correlates of alcohol dependence. The acquisition and analysis of mGluR5-specific PET data will be mentored by Dr. Cosgrove and Richard Carson, Ph.D.; while acquisition and analysis of connectivity measures will be mentored by Todd Constable, Ph.D. Finally, we will develop analysis methods, using techniques such as parallel Independent Component Analysis, to analyze multimodal mGluR5 PET and whole-brain connectivity data in synergy. This work will be co-mentored by Drs. Carson, Constable, and Godfrey Pearlson, Ph.D. These proposed experiments will provide insight into possible uses of mGluR5 therapeutics for alcohol dependence, examine how clinical correlates of dependence change during withdrawal in relation to mGluR5 function and neural organization, and develop analysis methods evaluating neurotransmitter-specific function in neuronal connectivity. The research experience will be supported by a complementary training plan providing scientific development in four key areas: clinical alcohol research, functional Magnetic Resonance neuroimaging (fMRI), Positron Emission Tomography (PET) neuroimaging, and responsible conduct of research. Thus this K01 award will advance the field's understanding of evolving brain function during alcohol withdrawal, and supply a uniquely qualified scientist blending innovative techniques from clinical alcohol research and neuroimaging to advance future understanding of brain dysfunction in alcohol use disorders.

项目摘要 此指导研究科学家发展奖申请建议支持 Ansel Hillmer 博士， 他过渡到使用神经影像学来研究人类酒精使用障碍的独立研究。 谷氨酸在酒精依赖和神经可塑性中的作用使其成为检查酒精依赖和神经可塑性的关键系统 酒精依赖和大脑结构和功能动态变化的神经化学基础 撤回。这项研究的目的是研究代谢型谷氨酸 5 受体的作用 (mGluR5)，酒精依赖治疗的一个有前途的靶点，在酒精期间的神经重组中 撤回。具体重点是检查神经化学变化与临床之间的关系 整个戒断过程中酒精依赖的相关性。我们建议进行纵向 40 名酒精依赖患者在戒断 7-10 天和 4 周期间的神经影像学检查 禁欲，并在 30 名匹配的健康对照中进行单次治疗。酒精的招募和评估 受抚养患者将由 Kelly Cosgrove 博士指导。和斯蒂芬妮·奥马利博士神经影像学 会议将采用 18F-FPEB PET 扫描来测量 mGluR5 可用性和静息状态 fMRI 连接性 检查神经组织。首先，我们将评估 mGluR5 可用性和静息状态的差异 患者纵向和相对于对照的连通性。接下来，我们将确定以下关系 神经影像学测量与酒精依赖的临床和认知相关性。此次收购及 mGluR5 特异性 PET 数据的分析将由 Cosgrove 博士和 Richard Carson 博士指导；尽管 连通性测量的获取和分析将由 Todd Constable 博士指导。最后，我们将 开发分析方法，使用并行独立成分分析等技术来分析 多模式 mGluR5 PET 和全脑连接数据的协同作用。这项工作将由博士共同指导。 卡森、康斯特布尔和戈弗雷·珀尔森博士这些拟议的实验将深入了解可能的情况 使用 mGluR5 疗法治疗酒精依赖，检查依赖变化的临床相关性 戒断期间与 mGluR5 功能和神经组织的关系，并开发分析方法 评估神经元连接中的神经递质特异性功能。研究经历将是 由补充培训计划支持，提供四个关键领域的科学发展： 临床酒精 研究、功能磁共振神经影像 (fMRI)、正电子发射断层扫描 (PET) 神经影像学和负责任的研究行为。因此，这个 K01 奖项将推动该领域的发展 了解戒酒过程中大脑功能的演变，并提供一位独特的合格科学家 融合临床酒精研究和神经影像学的创新技术，推动未来发展 了解酒精使用障碍中的大脑功能障碍。

项目成果

Data-driven analysis of kappa opioid receptor binding in major depressive disorder measured by positron emission tomography.

• DOI: 10.1038/s41398-021-01729-5
• 发表时间: 2021-11-27
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Smart K;Yttredahl A;Oquendo MA;Mann JJ;Hillmer AT;Carson RE;Miller JM
• 通讯作者: Miller JM

PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain.

活体人脑区域乙酰胆碱浓度变化的 PET 成像估计。

• DOI: 10.1093/cercor/bhaa387
• 发表时间: 2021
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Smart,Kelly;Naganawa,Mika;Baldassarri,StephenR;Nabulsi,Nabeel;Ropchan,Jim;Najafzadeh,Soheila;Gao,Hong;Navarro,Antonio;Barth,Vanessa;Esterlis,Irina;Cosgrove,KellyP;Huang,Yiyun;Carson,RichardE;Hillmer,AnselT
• 通讯作者: Hillmer,AnselT

Improving SUVR quantification by correcting for radiotracer clearance in tissue.

通过校正组织中放射性示踪剂的清除率来提高 SUVR 定量。

• DOI: 10.1177/0271678x231196804
• 发表时间: 2024
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Honhar,Praveen;Matuskey,David;Carson,RichardE;Hillmer,AnselT
• 通讯作者: Hillmer,AnselT

The Importance of Drug and Sex Effects in Psychiatric Research.

药物和性影响在精神病学研究中的重要性。

• DOI: 10.1016/j.biopsych.2018.08.011
• 发表时间: 2018
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Hillmer,AnselT

Binding of the synaptic vesicle radiotracer [11C]UCB-J is unchanged during functional brain activation using a visual stimulation task.

使用视觉刺激任务激活功能性大脑期间，突触小泡放射性示踪剂 [11C]UCB-J 的结合没有变化。

• DOI: 10.1177/0271678x20946198
• 发表时间: 2021
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Smart,Kelly;Liu,Heather;Matuskey,David;Chen,Ming-Kai;Torres,Kristen;Nabulsi,Nabeel;Labaree,David;Ropchan,Jim;Hillmer,AnselT;Huang,Yiyun;Carson,RichardE
• 通讯作者: Carson,RichardE