Prefrontal cortex in reward devaluation in human cocaine addiction: an fMRI study

描述（由申请人提供）：这是一份经修订的R21 （PA-03-107）申请，最初由NPAS研究部门于2005年6月和2006年10月审查。利用事件相关的奖励条件功能磁共振成像（fMRI）任务，我们建议研究药物成瘾中奖励贬值（通过消失）和复发的神经认知基础。在本任务中，货币条件刺激（CS）的条件反射、消退和消退保留分为三个阶段。我们假设，与对照受试者（N=25）相比，正在康复的可卡因成瘾个体（N=80）保留有关金钱奖励条件提示价值减少的信息的能力受损，这些信息由皮肤电导反应（SCR）、价值或强度评级以及腹内侧前额叶皮层（vmPFC）信号变化所指示，这些信号变化是针对先前奖励的目标CS (CS+Tgt)，而非奖励的目标CS （CS+nTgt）或从未奖励的CS （CS-）。我们进一步预测，在CS+Tgt与CS+nTgt的心理生理、自我评价或神经元反应方面的有限差异，特别是在消退保留和非初始消退测试期间，将预测6个月随访时的复发（通过各种定性和定量测量进行评估）。这一建议的创新和新颖之处在于使用功能磁共振成像来识别PFC的亚区，以预测戒毒个体对复发的易感性。此外，尽管消退范式主要用于具有恐惧诱导刺激的恐惧相关障碍，但我们建议在以奖励处理受损为特征的障碍中使用类似的范式，使用食欲刺激。我们的基本假设是，对吸毒成瘾的人来说，食欲暗示在情感上是显著的，因此很难消除，就像恐惧刺激对创伤后应激障碍患者一样。因此，目前的建议将促进我们对可能预测可卡因成瘾个体长期复发的核心情感学习机制的理解。自上次申请以来的主要变化包括：1)澄清了审稿人提出的具体问题（例如，实验操作的强度，慢性可卡因使用/渴望的影响，其他混杂因素，ROI定义，招募）；2)修改我们的事件相关范式，以紧跟我们的顾问（E. Phelps）开发的fMRI经典条件反射任务；3)增加SCR记录（与fMRI同时进行）作为反应的客观测量；4)与住院治疗机构主任（R. Sinha）新建立的合作，将成瘾个体的数量增加一倍，以进行复发预测。

DESCRIPTION (provided by applicant): This is a revised R21 (PA-03-107) application originally reviewed by the NPAS study section in June 2005 and October 2006. Using an event-related reward conditioning functional magnetic resonance imaging (fMRI) task, we propose to study the neurocognitive substrates underlying reward devaluation (through extinction) and relapse in drug addiction. In this task, three phases distinguish between conditioning, extinction, and extinction retention of monetary conditioned stimuli (CS). We hypothesize that compared to control subjects (N=25), recovering cocaine addicted individuals (N=80) are impaired in the ability to retain information about reductions in the value of monetary reward conditioned cues as indexed by skin conductance responses (SCR), value or intensity ratings, and ventromedial prefrontal cortical (vmPFC) signal changes to a previously rewarded target CS (CS+Tgt) compared to a still rewarded non-target CS (CS+nTgt) or a never rewarded CS (CS-). We further predict that a restricted differential in the psychophysiological, self-rating, or neuronal responses to the CS+Tgt vs. the CS+nTgt, specifically during the extinction retention and not initial extinction testing, would be predictive of relapse (assessed by a variety of qualitative and quantitative measures) at six-months follow-up. The innovation and novelty of this proposal lie in the use of fMRI to identify subregions of the PFC to predict susceptibility to relapse in recovering drug addicted individuals. Furthermore, while extinction paradigms have primarily been used in fear related disorders with fear inducing stimuli, we suggest implementing similar paradigms using appetitive stimuli in disorders characterized by compromised reward processing. Our underlying assumption is that appetitive cues are as emotionally salient and thus difficult to extinguish to the drug addicted individual as fear stimuli are to the post-traumatic stress disorder patient. The current proposal will therefore advance our understanding of the core affective learning mechanisms that may predict longer-term relapse in cocaine addicted individuals. Major changes since the previous application include: 1) clarifications in response to specific concerns raised by the reviewers (e.g., strength of experimental manipulation, effects of chronic cocaine use/craving, other confounding factors, ROI definitions, recruitment); 2) modification of our event-related paradigm to closely follow the classical conditioning task for fMRI developed by our consultant (E. Phelps); 3) addition of SCR recordings (conducted simultaneously with fMRI) as an objective measure of response; and 4) a newly established collaboration with director of an inpatient treatment facility (R. Sinha) to double the number of addicted individuals recruited for relapse prediction.