The prefrontal cortex in salience and control in cocaine addiction: phFMRI study

描述(由申请人提供)：这是一位新的研究员的独立研究奖的修订申请，最初由RPIA研究部分于2007年3月审查(1R01DA023579-01)。我们将使用功能磁共振成像(FMRI)来比较可卡因成瘾者和健康对照组(目标1)对药物Stroop任务的血流动力学和行为反应的反应。Stroop任务是一种新开发的反应抑制和显著归因受损任务。我们将比较使用和不使用口服哌醋甲酯(MPH)的fMRI结果，口服哌醋甲酯(MPH)是一种多巴胺激动剂，这里使用它来增强药物相关线索的显着性(目标2)。最后，我们将使用这一药理学功能磁共振结果来预测最初戒除可卡因成瘾的受试者180天后的复发(目标3)。我们有三个主要假设：(1)与对照组相比，可卡因成瘾者会将更多的突显归因于与毒品相关的词汇，测量结果显示，与匹配的中性词汇相比，可卡因成瘾者的前额叶和纹状体的血流动力学反应增强，行为冲动增加，自我报告的药物渴求(即渴求)更高。(2)口服MPH，一种类似于可卡因的兴奋剂，阻断多巴胺转运体并增加细胞外多巴胺，将增强PFC的活性，导致因药物Stroop任务中与药物相关的单词而增强的显著程度。(3)基线时(尤其是在MPH挑战时)药物对药物Stroop任务的干扰越大，复发时间越快，或随访时复发越严重。利用这一药理学功能磁共振成像设计，我们将间接评估多巴胺在药物成瘾个体的过度突出、归因和冲动中的作用。更好地了解成瘾受试者大脑对药物线索的变化及其被刺激性药物增强的显著程度，将有助于开发行为或药物干预措施，这些干预措施可能有助于抵消与药物有关的线索的过度突出(可能在增加非药物线索的显著程度)，以最大限度地减少渴望，增强自控力，防止复发。自上次提交以来的主要变化包括：增加了初步结果，现在表明(1)药物Stroop功能磁共振任务在可卡因成瘾受试者中诱导了独特的行为干扰；以及(2)在我们选定的受试组中进行这项特定药理学研究的可行性；其他变化包括(3)发表了我们先前对可卡因成瘾个人的功能磁共振研究；以及(4)针对审查者提出的具体问题的其他澄清(例如，将当前吸食可卡因的人纳入为积极控制组，以增强结果的可解释性；纳入灌注MRI，以解决对MPH对脑血流影响的担忧；以及与公共卫生敏感和期望、练习效果、受试者排除和匹配、复发评估以及对脑岛等其他关键大脑区域的研究有关的其他澄清和变化)。因此，目前形式的提案有了很大的改进。公共卫生相关性该项目的结果可能具有治疗相关性，并有助于设计和实施新的专门干预和治疗方案，以最大限度地提高治疗成功的可能性，并将复发降至最低，这仍然是治疗药物滥用的主要问题。因此，利用我们研究中的药理功能激活和行为结果，我们可能能够强调可能最有益的干预方法。

DESCRIPTION (provided by applicant): This is a revised application for an independent research award by a new investigator originally reviewed by the RPIA study section in March 2007 (1R01DA023579-01). We will use functional magnetic resonance imaging (fMRI) to compare the hemodynamic and behavioral responses to a drug Stroop task, a newly developed task of Impaired Response Inhibition and Salience Attribution, between cocaine addicted individuals and healthy control subjects (Aim 1). We will compare these fMRI results with and without oral methylphenidate (MPH), a dopamine agonist, used here to enhance the salience of the drug-related cues (Aim 2). Finally, we will use this pharmacological fMRI results to predict relapse at 180-day follow-up in initially abstinent cocaine addicted subjects (Aim 3). We have 3 main hypotheses: (1) compared to controls, cocaine addicted individuals will attribute more salience to drug-related words than to matched neutral words as measured with enhanced hemodynamic responses of the prefrontal cortex (PFC) and striatum, increased behavioral impulsivity and higher self-reported drug wanting (i.e., craving). (2) oral MPH, a stimulant drug that similarly to cocaine blocks dopamine transporters and increases extracellular dopamine, will enhance the activity in the PFC leading to enhanced salience attributed to the drug-related words on the drug Stroop task. And (3) the higher the drug-related interference on the drug Stroop task at baseline (especially during the MPH challenge), the faster the time to relapse or the more severe the relapse at follow-up. Using this pharmacological fMRI design we will thus indirectly assess the involvement of dopamine in the excessive salience attribution and impulsivity in a drug-related context in drug addicted individuals. A better understanding of the changes in the brain of addicted subjects with respect to drug cues and their enhanced salience by a stimulant drug will help develop behavioral or pharmacological interventions that may be beneficial in counteracting the overpowering salience of drug related cues (and possibly in increasing salience of non-drug cues) in drug addicted individuals to minimize craving, enhance self-control, and prevent relapse. The major changes since the previous submission include: addition of preliminary results that now demonstrate (1) that the drug Stroop fMRI task induces a unique behavioral interference in the cocaine addicted subjects; and (2) feasibility to conduct this particular pharmacological study in our selected subject groups; other changes include the (3) publication of our prior fMRI studies in cocaine addicted individuals; and (4) other clarifications in response to specific concerns raised by the reviewers (e.g., inclusion of current cocaine users as an active control group to enhance interpretability of results; inclusion of perfusion MRI to address concerns about effect of MPH on cerebral blood flow; and other clarifications and changes related to MPH sensitization and expectation, practice effects, subject exclusion and matching, relapse assessment, and the study of other key brain regions such as the insula). The proposal in its current form is consequently substantially improved. PUBLIC HEALTH RELEVANCE The results of this project may be of therapeutic relevance and contribute to the design and implementation of new specialized intervention and treatment programs to maximize the likelihood of treatment success and minimize relapse, which remains the primary problem in treating drug abuse. Thus, using the pharmacological functional activation and behavioral results in our study, we may be able to highlight the intervention approaches that may be most beneficial.