Cognitive control and cocaine dependence

描述（由申请人提供）：强制性药物寻求和消费是可卡因依赖的一个定义特征。认知控制能力的损害有助于这种强制性药物使用行为。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中药物使用复发相关尚未探讨。目前的提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优势的习惯性行为（如强制性药物寻求）。与组件的方法，我们已经隔离的反应抑制，冲突/错误处理，和错误后的行为调整的关键措施，在SST的认知控制。在功能磁共振成像研究中，我们已经确定了内侧上级额叶和前扣带回激活过程中的反应抑制，顺序背扣带回/内侧皮层激活和失活过程中的错误处理，和腹外侧前额叶激活过程中的错误后补救措施。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，这种改变的皮质激活模式区分PCD复发者和非复发者。这些初步数据首次突出了预测PCD中药物使用复发的认知控制的神经方面。此外，与早期的报告一致，我们观察到可卡因戒断行为随着时间的推移在PCD中减少，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可卡因依赖，并建议解决这些具体目标：第一，PCD和HC不同的大脑激活过程中的反应抑制，错误处理和补救行动？其次，这些差异如何预测PCD中可卡因使用的复发？第三，在禁欲的早期和后期，认知控制的大脑激活是否不同？在PCD中，在戒断早期和晚期的认知控制缺陷是否能不同地预测药物使用的复发？第四，这些区域的大脑激活预测男性和女性PCD之间的复发不同吗？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”的新治疗策略的开发，该机制感知可卡因依赖中的药物寻求和复发。药物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如何行使抑制控制和监控我们的行为，以及这些过程在可卡因依赖患者中是如何改变的。这项提议的目标是将联合收割机功能性脑成像与行为任务结合起来，作为认知代理来检查这些问题。从拟议的项目中收集的结果将有助于我们了解“可卡因依赖性大脑”，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.