Neural mechanisms of galantamine treatment for cocaine dependence

 描述（由申请人提供）：本指导研究科学家发展奖（MRSDA）K 01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，成为成瘾神经科学领域的独立调查员，研究新兴药物治疗的神经机制，以改善可卡因依赖的治疗。为了实现这一目标，候选人建议在三个主要领域进行进一步的培训：（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）;和（3）先进的功能性磁共振（fMRI）分析方法（例如，空间独立分量分析; sICA）。K 01机制提供的机会将使候选人能够开始一个严格的，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。该研究计划将结合联合收割机正式教学培训（例如，此外，还提供了一系列培训，包括临床研究中的伦理和实践问题课程以及医学院的药理学课程）、一对一辅导、参加科研会议以及接受指导的研究经验。 该5年计划的研究部分涉及应用先进的功能磁共振成像分析方法来确定与以下相关的脑功能机制：1）加兰他敏治疗可卡因依赖：来自60名参与新完成的加兰他敏单药治疗和与计算机认知行为疗法联合治疗的随机临床试验（RCT）的个体的治疗前和治疗后fMRI数据（2x2析因设计）将使用sICA进行分析。这项工作将集中在fMRI Stroop任务数据，以了解认知控制过程和加兰他敏治疗后可卡因使用结果之间的关系。 2)可卡因依赖的N-乙酰半胱氨酸（NAC）给药：将使用随机、安慰剂对照、交叉设计（n=40）在NAC给药7天前后收集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期间的神经网络，以提供对最近完成和正在进行的NAC治疗可卡因依赖的临床试验结果的机械见解。这种二级数据分析和新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候选人的培训：（1）分析和解释来自大规模药物治疗试验的神经影像学数据（CBT 4CBT &加兰他敏; P50 DA 009241）和;（2）在公认专家的指导监督下，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.