Functional neuromaging of cue-induced heroin craving

描述(由申请人提供)： 这是一份以患者为导向的研究事业发展奖(K23)的申请书，该奖项的题目是《线索诱发海洛因渴求的功能神经成像》。这位候选人之前的培训和经验是临床精神病学和核医学。通过这项建议，候选人寻求获得以下方面的高级培训：(1)与成瘾研究相关的功能磁共振成像(FMRI)和认知神经科学方法论；(2)临床研究设计和分析，特别强调对fMRI数据的高级统计分析和功率分析。该研究项目旨在补充这一培训计划，将使用功能磁共振成像和实验心理学的方法来研究海洛因相关线索诱导的药物渴求过程中局部脑血流量(CBF)的变化，以确定介导阿片类药物渴求的大脑网络。 研究人员在候选人的实验室和机构进行的研究列出了阿片依赖患者的药物相关条件反应原理和动脉自旋标记(灌注)功能磁共振成像原理。灌注功能磁共振特别适合于对相对较长的状态(例如，线索诱导的渴求)进行成像，以及涉及以几天或几周为间隔的重复受试者内实验的方案，例如慢性药物效应的研究。应聘者在管理阿片类药物依赖方面有丰富的经验。候选人正在进行的一项初步研究表明，在美沙酮维持患者中，腹侧被盖区的激活与阿片类药物相关线索诱导的海洛因渴求之间存在关联。拟议的项目将在以前的调查结果和技术发展的基础上加以扩展和详细说明。 具体目标1是使用功能磁共振成像来表征CBF对线索诱导的海洛因渴求的反应模式，并根据候选人获得的飞行员数据确定这种模式在阿片依赖受试者中的特异性。具体目的2是确定美沙酮维持患者对阿片类药物相关线索的CBF反应是否受到美沙酮血浆水平波动的调节。具体目标3是表征阿片类拮抗剂纳曲酮对戒断既往阿片依赖患者对阿片类药物相关线索的脑血流反应的影响。 这项研究计划将有助于确定特定大脑结构的作用，这些结构介导线索诱导的对鸦片类药物的渴望，并可能调节作用于中皮质边缘奖赏系统的其他药物滥用。这些数据将提高我们对依赖、治疗耐药和复发的潜在机制的理解。此外，它可能为药物依赖的药物治疗效果的评估和个体治疗反应预测的新方法的发展指明方向。这项培训和研究计划的实施将有助于候选人成为成瘾神经精神病学的独立研究员。

DESCRIPTION (provided by applicant): This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) entitled "Functional neuroimaging of cue-induced heroin craving". The candidate's previous training and experience was in clinical psychiatry and nuclear medicine. Through this proposal, the candidate seeks to gain advanced training in: (1) functional magnetic resonance imaging (fMRI) and cognitive neuroscience methodology relevant to addiction research; (2) clinical research design and analysis, with a special emphasis on advanced statistical analysis of fMRI data and power analyses. The research project that is designed to complement this training program will use fMRI and experimental psychology methods to investigate the regional cerebral blood flow (CBF) changes during drug craving induced by heroin-related cues to identify the brain networks mediating opiate craving. Studies by the investigators at candidates' laboratory and institution laid out the principles of drug-related conditioned response in opiate-dependent patients and of Arterial Spin Labeling (perfusion) fMRI. Perfusion fMRI is particularly well suited for imaging of relatively prolonged states (e.g. cue-induced craving) and protocols involving repeated within-subject experiments separated by days or weeks, such as the study of chronic medication effects. The candidate has extensive experience in the management of opiate dependence. An on-going pilot study by the candidate suggests an association between activation of the ventral tegmental area and heroin craving induced by opiate-related cues in methadone-maintained patients. The proposed project will expand and elaborate upon the previous findings and technological developments. Specific Aim 1 is to use fMRI to characterize the pattern of CBF response to cue-induced heroin craving and determine the specificity of this pattern in opiate-dependent subjects, building on the pilot data obtained by the candidate. Specific Aim 2 is to determine whether the CBF response to opiate-related cues in methadone-maintained patients is modulated by the fluctuation in methadone plasma levels. Specific Aim 3 is to characterize the effect of the opiate antagonist naltrexone on the CBF response to opiate-related cues in abstinent formerly opiate-dependent patients. The research plan will help determine the role of specific brain structures that mediate cue-induced craving to opiates and potentially to other drugs abuse acting on the mesocorticolimbic reward system. This data would improve our understanding of the mechanisms underlying dependence, treatment resistance and relapse. Furthermore, it may point the way for the development of novel methods for evaluation of the efficacy of pharmacotherapies and individual treatment response prediction in drug dependence. Implementation of this training and research plan will help the candidate to become an independent investigator in the neuropsychiatry of addiction.