Cognitive control and cocaine dependence: thalamic noradrenergic processes

描述(申请人提供)：可卡因成瘾的一个重要致病过程是认知控制障碍。可卡因依赖(CD)者经常报告无法控制他们的药物使用，尽管知道这会造成不良后果。行为和成像研究也同样提供了CD患者认知控制缺陷的证据。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。认知控制是一种执行功能，涉及复杂的生物学。这项R01研究的研究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预期队列中的复发。结合功能磁共振成像(FMRI)和停止信号任务(一种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。与健康对照组参与者相比，慢性阻塞性肺病患者在这些过程中表现出区域大脑激活减少和表现改变。重要的是，Logistic和Cox回归确定了性别共享和特定的与错误相关的神经过程，这些过程预测复发和复发时间。男性和女性的背侧前扣带回皮质和丘脑的错误相关活动减少都预示着复发。认知控制的丘脑皮质连接性也区分了CD复发者和非复发者。[在一项对少数CD患者进行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，更大的净可利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与错误相关的异常认知控制的基础，并使个人倾向于再次吸毒。该R01的更新试图继续这些发现，并明确改变的丘脑去甲肾上腺素能信号在CD患者认知功能障碍中的作用。通过结合多模式MRI、PET成像和纵向随访，我们将检查在丘脑相关的认知过程中，净可用性是否以及如何与改变的区域激活以及功能和结构连接相关联，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记物，并加快开发治疗可卡因依赖的新药物。

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.