Cortical and Subcortical Mechanisms of Human Cognitive Control

描述(由申请人提供)：这是一份重新提交的申请，要求对当前资助的赠款进行竞争性续期(R01-DA13165-10)。该项目的总体目标是调查健康成年人认知控制的心理和神经基础。自上次竞争性综述以来，我们已经发表了19篇参考文献，阐述了使用功能磁共振成像(FMRI)和适当设计的行为范式来解释注意转移和任务转换中的认知控制机制。成功的认知控制既需要稳定性(在分心的情况下保持注意力和记忆的状态)，也需要灵活性(根据正在进行的事件快速重新配置注意力和认知)。拟议的项目将使用新的方法进一步探索这些问题，重点放在皮质和皮质下的大脑机制上。Aim 1研究的是纯粹自愿的控制行为--即不是由提示提示的任务切换，而是纯粹自愿决定的结果。我们将使用我们开发的一种新的多变量模式分析方法(多体素模式时间进程或MVPtc)，当这些状态随着时间的推移展开时，它动态跟踪大脑活动的多体素模式-以及它们产生的相应注意力或任务投入状态。这种方法允许我们将大脑活动与行为表现模式联系起来，并探索与这些认知状态相关的大脑回路中的功能连接。在目标2中，我们使用BOLD功能磁共振成像和PET多巴胺成像，研究了在任务切换过程中，基底神经节在认知灵活性和稳定性中的作用。我们将详述最近关于基底神经节--特别是多巴胺系统--在认知控制的非运动性行为中所起作用的最新证据。最后，在目标3中，我们将考察当分心刺激损害知觉表现时认知控制的失败，特别强调经验价值和奖励历史在刺激吸引注意力的程度上的作用。使用MVPtc，我们将跟踪显著知觉事件或先前与奖励相关的刺激对分心易感性的波动，并测量自上而下控制可以调节注意力捕获的程度。最后，我们将使用平行的PET多巴胺成像和BOLD功能磁共振成像来测量显著或高值刺激引起的纹状体多巴胺释放的变化，并将其与分心的行为测量相关联。这些实验将为认知控制的大脑机制提供新的见解，认知控制是人类的一种核心精神能力，由于药物和酒精成瘾、精神分裂症、帕金森氏症和亨廷顿病、强迫症以及注意力缺陷多动障碍等疾病而受到削弱。该项目将为临床研究执行功能受损的原因和治疗奠定基础。

DESCRIPTION (provided by applicant): This is a resubmission application for a Competing Renewal of a currently funded grant (R01-DA13165-10). The overall aim of this project is to investigate the psychological and neural basis of human cognitive control in healthy adults. Since the last competing review of this project, we have published 19 refereed publications that have elucidated the mechanisms of cognitive control in attention shifting and task switching using functional magnetic resonance imaging (fMRI) and suitably designed behavioral paradigms. Successful cognitive control requires both stability (maintained states of attention and memory despite distraction) and flexibility (to rapidly reconfigure attention and cognition in light of ongoing events). The proposed project will further explore these issues using novel methods and with a focus on both cortical and subcortical brain mechanisms. Aim 1 investigates purely voluntary acts of control-that is, task switching that is not prompted by a cue, but instead results from a purely voluntary decision. We will use a novel multivariate pattern analysis method we have developed (Multivoxel Pattern Time Course or MVPtc) that dynamically tracks multivoxel patterns of brain activity-and the corresponding states of attention or task engagement they engender-as these states unfold over time. This method permits us to relate brain activity with patterns of behavioral performance, as well as to explore functional connectivity within brain circuits that are associated with these cognitive states. In Aim 2 we examine the role of the basal ganglia in cognitive flexibility and stability during task switching, using both BOLD fMRI and PET dopamine imaging. We will elaborate upon recent evidence for the role of the basal ganglia- and specifically the dopamine system-in nonmotoric acts of cognitive control. Finally, in Aim 3, we will examine failures of cognitive control when distracting stimuli impair perceptual performance, with a particular emphasis on the role of experienced value and reward history on the degree to which a stimulus may capture attention. Using MVPtc, we will track fluctuations in the susceptibility to distraction by salient perceptual events or by stimuli previously associated with reward, and we will measure the degree to which top-down control can modulate attentional capture. Finally, we will use parallel PET dopamine imaging and BOLD fMRI to measure changes in striatal dopamine release evoked by salient or high-value stimuli, and correlate this with behavioral measures of distraction. Together these experiments will provide new insights about the brain mechanisms of cognitive control, a core human mental faculty that is subject to debilitating impairment due to afflictions such as drug and alcohol addiction, schizophrenia, Parkinson's and Huntington's Disease, OCD, and attention deficit hyperactivity disorder. This project will contribute to the basic-research foundation for clinical research into the causes and treatment of executive function impairments.