Cognitive control and cocaine dependence

描述（由申请人提供）：强制寻求和消费毒品是可卡因依赖的一个决定性特征。认知控制障碍导致了这种强制性的药物使用行为。尽管有大量的行为证据表明可卡因依赖（PCD）患者的认知控制受损，但这种缺陷背后的神经过程仍不清楚。特别是，认知控制障碍如何与PCD患者的药物使用复发相关联还没有被探索。目前的建议通过将功能性磁共振成像（fMRI）与停止信号任务（SST）相结合来填补这一重要空白。在停止信号任务中，成功的表现需要抑制潜在的习惯性行为（如强制寻求药物）。通过组成部分方法，我们将孤立的反应抑制、冲突/错误处理和错误后行为调整作为SST期间认知控制的关键措施。在fMRI研究中，我们发现反应抑制期间内侧上额带和前扣带激活，错误处理期间连续的背扣带/内侧皮层激活和失活，以及错误后补救行动期间腹外侧前额叶激活。此外，与健康个体（HC）相比，PCD在SST期间表现出这些皮质结构的激活改变。重要的是，这种改变的皮层激活模式区分了PCD复发者和非复发者。这些初步数据首次强调了认知控制的神经方面预测PCD患者药物使用复发。此外，与早期报告一致，我们观察到可卡因戒断症状随着时间的推移而减少，这表明在戒断过程中认知过程也可能发生变化。在这些初步结果的基础上，我们假设受损的反应抑制、错误处理和补救行动协同促成可卡因依赖，并提出解决这些具体目标：首先，PCD和HC在反应抑制、错误处理和补救行动期间的大脑激活是否不同？其次，这些差异如何预测PCD患者可卡因使用的复发？第三，在禁欲的早期和后期，认知控制下的大脑激活是否有所不同？戒断早期和晚期的认知控制缺陷对PCD患者复发的预测是否不同？第四，这些区域脑激活预测男性和女性PCD复发是否不同？因此，该项目提出了一种创新的方法来研究PCD中的认知控制，并促进了针对失败的“制动机制”的新治疗策略的发展，该机制可以感知可卡因依赖的药物寻求和复发。可卡因依赖是一种慢性、复发性疾病。可卡因依赖患者经常报告说，他们了解使用可卡因的严重后果，但他们无法“控制”自己的行为。因此，成瘾神经科学的主要目标之一是了解我们的大脑是如何进行抑制控制和监控我们的行为的，以及这些过程在可卡因依赖患者中是如何改变的。这项建议的目标是将功能性脑成像与行为任务相结合，作为认知代理来检查这些问题。从拟议项目中收集的结果将有助于我们了解“可卡因依赖大脑”，并促进开发新的治疗策略来治疗可卡因依赖患者。

DESCRIPTION (provided by applicant): Compulsory drug seeking and consumption is a defining feature of cocaine dependence. Impairment in cognitive control contributes to such compulsory drug using behaviors. Despite abundant behavioral evidence for impaired cognitive control in patients with cocaine dependence (PCD), the neural processes underlying such a deficit remain unclear. In particular, how impairment in cognitive control is associated with relapse to drug use in PCD has not been explored. The current proposal fills this important gap by combining functional magnetic resonance imaging (fMRI) with a stop signal task (SST), in which successful performance requires prepotent, habitual behaviors (as in compulsory drug seeking) to be inhibited. With a component approach we have isolated response inhibition, conflict/error processing, and post-error behavioral adjustment as critical measures of cognitive control during the SST. In fMRI studies we have identified medial superior frontal and anterior cingulate activation during response inhibition, sequential dorsal cingulate/medial cortical activation and deactivation during error processing, and ventrolateral prefrontal activation during post-error remedial action. Furthermore, compared to healthy individuals (HC), PCD demonstrated altered activation of these cortical structures during the SST. Importantly, this altered pattern of cortical activations distinguished between PCD relapsers and non-relapsers. These preliminary data highlight, for the first time, neural aspects of cognitive control that predict relapse to drug use in PCD. Additionally, consistent with earlier reports, we observed that cocaine abstinence symptomatology decrease over time in PCD, suggesting that cognitive processes may also change, during the course of abstinence. On the basis of these preliminary results, we hypothesize that impaired response inhibition, error processing and remedial action contribute synergistically to cocaine dependence, and propose to address these specific aims: First, do PCD and HC differ in brain activations during response inhibition, error processing and remedial action? Second, how do these differences predict relapse to cocaine use in PCD? Third, does cerebral brain activation underlying cognitive control differ between early and later during abstinence? Do deficits in cognitive control early and later during abstinence predict relapse to drug use differently in PCD? Fourth, do these regional brain activations predict relapse differently between men and women PCD? This project thus proposes an innovative approach to study cognitive control in PCD and facilitates the development of novel therapeutic strategies targeting the failed "braking mechanisms," which perceptuate drug seeking and relapse in cocaine dependence. PUBLIC HEALTH RELEVANCE Cocaine dependence is a chronic, relapsing disorder. Patients with cocaine dependence oftentimes report that they understand the serious consequences of using cocaine, but they are not able to "control" their behaviors. One of the major goals of addiction neuroscience is thus to understand how our brain exercises inhibitory control and monitor our behaviors and how these processes are altered in the patients of cocaine dependence. The goal of this proposal is to combine functional brain imaging with a behavioral task as a cognitive proxy to examine these issues. The results gathered from the proposed projects will help us understand the "cocaine- dependent brain" and facilitate the development of novel therapeutic strategies to treat patients with cocaine dependence.