Neural mechanisms of galantamine treatment for cocaine dependence

 描述(由申请者提供)：在此指导研究科学家发展奖(MRSDA)K01申请中描述的研究和培训计划将为候选人提供必要的技能，以成为成瘾神经科学领域的独立研究员，研究新兴药物疗法的神经机制，以改进可卡因依赖的治疗。为了实现这一目标，应聘者建议在三个主要领域进行进一步培训：(1)临床干预研究科学；(2)成瘾药理学(特别是新兴药物的药理学)；(3)高级功能磁共振(FMRI)分析方法(例如，空间独立成分分析；SICA)。K01机制提供的机会将使应聘者能够开始一项严格的、结构化的5年培训和研究计划，旨在为她提供上述三个领域的必要技能。这一学习计划将结合正式的教学培训(例如，医学院临床调查中的伦理和实践问题以及药理学课程)、一对一教程、参加科学研究会议和指导研究经验。这一五年计划的研究部分涉及应用先进的功能磁共振分析方法来确定与以下相关的脑功能机制：1)加兰他明治疗可卡因依赖：60名参与新完成的加兰他明随机临床试验(RCT)并与计算机化认知行为疗法(2x2析因设计)联合使用的患者的治疗前和治疗后的fMRI数据将使用SICA进行分析。这项工作将集中在fMRI Stroop任务数据上，以了解认知控制过程与加兰他明治疗后可卡因使用结果之间的关系。2)N-乙酰半胱氨酸(NAC)在可卡因依赖中的应用：采用随机、安慰剂对照、交叉设计(n=40)收集服用NAC 7天前后的fMRI数据，并使用SICA进行分析。这项工作将集中在反应抑制和情绪调节过程中涉及的神经网络，以提供对最近完成的和正在进行的NAC治疗可卡因依赖的临床试验结果的机械性洞察。这种二次数据分析和新颖数据收集的组合旨在通过提供以下两方面的实践经验来最大限度地提高应聘者的培训：(1)分析和解释来自大规模药物治疗试验(CBT4CBT和Galantamin；P50DA009241)的神经成像数据；(2)在公认专家的指导下进行她自己的fMRI-药物联合研究的理论和实施。

 DESCRIPTION (provided by applicant): The program of research and training described in this Mentored Research Scientist Development Award (MRSDA) K01 application will provide the candidate with the requisite skills to become an independent investigator in the field of addictions neuroscience, studying the neural mechanisms of emerging pharmacotherapies in order to improve treatments for cocaine-dependence. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (1) clinical intervention research science; (2) addictions pharmacology (in particular the pharmacology of emerging medications); and (3) advanced functional magnetic resonance (fMRI) analysis methods (e.g., spatial independent component analysis; sICA). The opportunities afforded by the K01 mechanism would enable the candidate to embark on a rigorous, structured 5-year program of training and research, designed to provide her with the necessary skills in the three areas highlighted above. This program of study will combine formal didactic training (e.g., courses on Ethical and Practical Issues in Clinical Investigation and on Pharmacology at the School of Medicine), one-on-one tutorials, attendance at scientific research conferences and mentored research experience. The research component of this 5-year plan involves the application of advanced fMRI analysis methods to identify the functional brain mechanisms associated with: 1) Galantamine treatment for cocaine dependence: Pre- and post-treatment fMRI data from 60 individuals who participated in a newly completed randomized clinical trial (RCT) of galantamine alone and in combination with computerized cognitive behavioral therapy (2x2 factorial design) will be analyzed using sICA. This work will focus on fMRI Stroop-task data to understand the relationship between cognitive control processes and cocaine-use outcomes following treatment with galantamine. 2) N-acetylcysteine (NAC) administration in cocaine dependence: FMRI data will be collected before and after 7-day NAC administration using a randomized, placebo-controlled, cross-over design (n=40) and will be analyzed using sICA. This work will focus on the neural networks engaged during response-inhibition and during emotion-regulation, in order to provide mechanistic insight into findings from recently completed and ongoing clinical trials of NAC treatment for cocaine-dependence. This combination of secondary data analyses and novel data collection is designed to maximize the candidate's training via provision of hands-on experience in both: (1) the analysis and interpretation of neuroimaging data from a large-scale pharmacotherapy trial (CBT4CBT & Galantamine; P50DA009241) and; (2) the theory and conduct of her own combined fMRI-medication study under guided supervision of recognized experts.