Cognitive control and cocaine dependence: thalamic noradrenergic processes

描述（由申请人提供）：可卡因成瘾的一个重要发病过程是认知控制障碍。可卡因依赖（CD）的人经常报告无法控制他们的药物使用，尽管知识的不良后果。行为和成像研究同样提供了证据，在CD个人的认知控制赤字。了解这种认知缺陷的系统和分子基础可能对可卡因依赖的研究和治疗有重大贡献。 认知控制是一种涉及复杂生物学的执行功能。这项R01研究的重点是描绘认知控制的组成过程，以及这些过程如何预测可卡因成瘾者的前瞻性队列复发。结合功能磁共振成像（fMRI）和停止信号任务，广泛用于研究认知控制的行为任务，我们描述了反应抑制，错误处理和错误后行为调整的神经过程。与健康对照参与者相比，CD个体在这些过程中表现出减少的区域大脑激活和改变的表现。重要的是，逻辑和考克斯回归确定性别共享和特定的错误相关的神经过程，预测复发和复发时间。背侧前扣带皮层和丘脑的错误相关活动减少可预测男性和女性的复发。用于认知控制的丘脑皮质连接也区分CD复发者和非复发者。[In在一项对少数CD患者进行的正电子发射断层扫描（PET）成像的R21研究中，我们观察到与HC参与者相比，CD患者的丘脑去甲肾上腺素转运体（NET）结合潜力增加。重要的是，更大的NET可用性与丘脑中错误处理的减少有关。这些结果表明，丘脑去甲肾上腺素能过程的改变可能是错误相关认知控制异常的基础，并使个体重新吸毒。 R01的更新旨在继续研究这些发现，并详细说明改变的丘脑去甲肾上腺素能信号在CD个体认知功能障碍中的作用。通过结合多模态MRI、PET成像和纵向随访，我们将研究NET可用性是否以及如何与丘脑相关认知过程中改变的区域激活以及功能和结构连接相关，并预测可卡因依赖的复发。我们希望这些新的发现将提供一个有用的分子生物标志物，并加快开发新的药物治疗可卡因依赖。

DESCRIPTION (provided by applicant): An important pathogenetic process of cocaine addiction is impairment in cognitive control. Cocaine dependent (CD) individuals often report inability to control their drug use despite knowledge of the untoward consequences. Behavioral and imaging studies have similarly provided evidence for deficits in cognitive control in CD individuals. Understanding the systems and molecular bases of this cognitive deficit may have significant contributions to research and treatment of cocaine dependence. Cognitive control is an executive function that involves complex biology. The research of this R01 study focuses on delineating the component processes of cognitive control and how these processes may predict relapse in a prospective cohort of cocaine addicted individuals. Combining functional magnetic resonance imaging (fMRI) and a stop signal task, a behavioral task widely used to investigate cognitive control, we described the neural processes underlying response inhibition, error processing, and post-error behavioral adjustment. CD individuals showed diminished regional brain activations and altered performance in these processes, as compared to healthy control participants. Importantly, logistic and Cox regressions identified gender shared and specific error-related neural processes that predict relapse and time to relapse. Decreased error-related activities of the dorsal anterior cingulate cortex and thalamus predict relapse in both men and women. Thalamic cortical connectivities for cognitive control also distinguish CD relapsors and non-relapsors. [In an R21 study of positron emission tomography (PET) imaging of a small number of CD individuals, we observed an increase in thalamic norepinephrine transporter (NET) binding potential in the CD as compared to HC participants. Importantly, greater NET availability is associated with diminished error processing in the thalamus. These results suggest that altered thalamic noradrenergic processes may underlie aberrant error- related cognitive control and dispose individuals to relapse to drug use. The renewal of this R01 seeks to pursue these findings and specify the role of altered thalamic noradrenergic signaling in cognitive dysfunction in CD individuals. By combining multimodal MRI, PET imaging, and longitudinal follow-up, we will examine whether and how NET availability associates with altered regional activations as well as functional and structural connectivity during thalamus-related cognitive processes and predict relapse in cocaine dependence. We hope that these new findings will provide a useful molecular biomarker and expedite development of novel pharmacotherapy for cocaine dependence.