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

描述（由申请人提供）：这是一份由新研究者提交的独立研究奖修订申请，最初由RPIA研究部门于2007年3月审查（1 R 01 DA 023579 -01）。我们将使用功能性磁共振成像（fMRI）来比较可卡因成瘾者和健康对照者之间对药物Stroop任务（一种新开发的受损反应抑制和显著性归因任务）的血流动力学和行为反应（目的1）。我们将比较这些fMRI结果与口服哌甲酯（MPH），多巴胺激动剂，在这里使用，以提高药物相关线索的显着性（目的2）。最后，我们将使用这个药理学fMRI结果来预测最初戒断的可卡因成瘾受试者在180天随访时的复发（目标3）。我们有三个主要假设：（1）与对照组相比，可卡因成瘾者将更多的显着性归因于药物相关的词，而不是匹配的中性词，如前额叶皮层（PFC）和纹状体的增强的血液动力学反应，增加的行为冲动和更高的自我报告的药物需求（即，渴望）。(2)口服MPH（一种类似于可卡因阻断多巴胺转运体并增加细胞外多巴胺的兴奋剂）将增强PFC中的活性，导致归因于药物Stroop任务上的药物相关词的显著性增强。（3）基线时（尤其是MPH激发期间）药物Stroop任务的药物相关干扰越高，随访时复发时间越快或复发越严重。使用这种药理学功能磁共振成像设计，我们将间接评估多巴胺的参与过度的显着性归因和冲动在药物成瘾的个人在药物相关的背景下。更好地了解成瘾受试者大脑中药物线索的变化及其通过兴奋剂药物增强的显著性，将有助于开发行为或药理学干预措施，这些干预措施可能有利于抵消药物成瘾个体中药物相关线索的压倒性显著性（并可能增加非药物线索的显著性），以最大限度地减少渴望，增强自我控制，并防止复发。自上次提交以来的主要变化包括：增加了初步结果，现在证明（1）药物Stroop fMRI任务在可卡因成瘾受试者中诱导了独特的行为干扰;（2）在我们选定的受试者组中进行这种特定药理学研究的可行性;其他变化包括（3）发表了我们先前在可卡因成瘾个体中进行的fMRI研究;以及（4）针对审评员提出的具体问题作出的其他澄清（例如，纳入当前可卡因使用者作为活性对照组，以增强结果的可解释性;纳入灌注MRI，以解决有关MPH对脑血流影响的问题;以及与MPH敏感性和预期、实践效果、受试者排除和匹配、复发评估以及其他关键脑区域（如小脑半球）研究相关的其他澄清和变化。因此，目前形式的提案有了很大改进。该项目的结果可能具有治疗意义，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，并尽量减少复发，这仍然是治疗药物滥用的主要问题。因此，在我们的研究中使用药理学功能激活和行为结果，我们可能能够突出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.