Dopamine Influences on Self-Regulation and Impulsivity

描述（由申请人提供）：我们最近报道了中脑多巴胺（DA）自受体的水平与自我报告的冲动性呈负相关。这一发现表明，对DA释放的自我调节控制降低的个体容易冲动，因为控制DA神经传递提供的与方法相关的动机驱动的能力降低。然而，自我报告测量不允许直接检查行为控制的核心过程，这些过程被认为在冲动中被削弱了。目前，DA自受体与冲动性背后的特定过程之间的关系尚不清楚，因为冲动性是一个多面结构，而冲动性的行为测量仅与自我报告量表有适度的关联。为了阐明DA功能与冲动性之间的联系，我们建议在28名健康成人中测量中脑DA自身受体的可用性以及冲动性的行为和fMRI指数。中脑自身受体的可用性，以及纹状体和皮层中D2样受体的可用性将通过高亲和力PET D2/D3配体[18F]fallypride来评估。所有参与者将完成一个奖励停止信号任务（SST）和一个时间（延迟）折扣（TD）范式，以提供行为控制的客观测量。SST和TD范式捕捉了冲动性的两个不同方面（停止和奖励决策），它们涉及不同的，尽管重叠的神经网络。通过在fMRI期间完成这些任务，我们将能够测试中脑DA自身受体水平的个体差异是否会影响涉及自我调节的大脑区域的反应性（例如，前扣带、腹侧纹状体、右侧额下回）。我们还将测试目标行为控制区域的d2受体可用性是否可以预测任务执行过程中BOLD的激活程度，从而提供一种能力来检验DA功能的个体差异与行为控制区域参与之间联系的机制模型。在TD的情况下，我们将评估这种假设，即降低自身受体控制导致伏隔核对即时奖励产生更大的BOLD反应，从而导致更多的冲动选择。为了将当前的DA功能理论与停止的认知科学联系起来，我们开发了一种新颖的、奖励版本的SST，用于评估奖励环境对继续和停止反应时间的影响程度。这对于确定DA对行为控制影响的具体性质可能是至关重要的。尽管大多数现实生活中的冲动控制问题都出现在高动机的背景下，但这种奖励操纵在SST范式中尚未得到广泛研究。另外100名参与者（和28名扫描的参与者）将完成奖励的SST和一系列的自我报告和冲动行为测量，以进一步表征这一新的范式。总体而言，该项目将认知和情感科学与神经科学、行为经济学、神经药理学和人格研究结合起来，为理解奖励对行为控制和自我调节的影响提供了一个框架。

DESCRIPTION (provided by applicant): We recently reported that levels of midbrain dopamine (DA) autoreceptors are inversely related to self-reported impulsivity. This finding suggests that individuals with reduced autoregulatory control of DA release are susceptible to impulsivity because of a reduced ability to control the approach-related motivational drive provided by DA neurotransmission. However, self-report measures do not allow for a direct examination of the core processes of behavioral control that are thought to be weakened in impulsivity. At present, the relation between DA autoreceptors and specific processes underlying impulsivity is unknown, as impulsivity is a multi-faceted construct and behavioral measures of impulsivity are only modestly associated with self-report scales. To clarify the link between DA functioning and impulsivity, we propose to measure midbrain DA autoreceptor availability and behavioral and fMRI indices of impulsivity in a group of 28 healthy adults. Midbrain autoreceptor availability, as well as D2-like receptor availability in the striatum and cortex will be assessed with the high affinity PET D2/D3 ligand [18F]fallypride. All participants will complete a rewarded stop signal task (SST) and a temporal (delay) discounting (TD) paradigm in order to provide objective measures of behavioral control. The SST and TD paradigms capture two distinct aspects of impulsivity (stopping and reward decision-making), which engage distinct, albeit overlapping neural networks. By completing these tasks during fMRI, we will be able to test whether individual differences in midbrain DA autoreceptor levels influence the responsivity of brain areas involved in self-regulation (e.g., anterior cingulate, ventral striatum, right inferior frontal gyrus). We will also test whether D2-receptor availability in the target behavioral control regions is predictive of the degree of BOLD activation during task performance, thus providing an ability to examine mechanistic models of the link between individual differences in DA functioning and the engagement of areas involved in behavioral control. In the case of TD, we will assess the hypothesis that lowered autoreceptor control leads to greater BOLD responses in the nucleus accumbens for immediate rewards, leading to more impulsive choice. In order to bridge current theories of DA functioning and the cognitive science of stopping, we have developed a novel, reward version of the SST that assesses the extent to which go and stop reaction times are altered by reward context. This may prove critical for defining the specific nature of DA's impact on behavioral control. Such reward manipulations have not been widely examined in the SST paradigm, despite the fact that most real-life impulse control problems arise in the context of high motivation. One hundred additional participants (and the 28 scanned participants) will complete the rewarded SST and a battery of self-report and behavioral measures of impulsivity to further characterize this new paradigm. Overall, this project bridges cognitive and affective science and neuroscience, behavioral economics, neuropharmacology and personality research to provide a framework for understanding reward influences on behavioral control and self-regulation. PUBLIC HEALTH RELEVANCE: Deficits in self regulation play a significant role in a wide range of psychiatric conditions, including substance use disorders, attention deficit hyperactivity disorder, bipolar disorder, and several personality disorders. The proposal aims to test hypotheses regarding the specific neuropharmacological substrates of impulsivity. This work will form the basis of a translational research program on the prediction and prevention of relapse in disorders characterized by impulse control deficits.