Reward, Impulsivity and Cocaine Addiction; fMRI Studies

描述（由申请人提供）：证据表明，两个主要因素诱发个人开始和维持药物滥用是奖励和惩罚的异常反应和抑制优势反应的能力受损。这些因素可能部分地通过腹侧纹状体、杏仁核、额叶皮质和相关“动机”回路中的突触病理作用，使易受伤害的个体易于持续滥用药物。从认知/行为神经科学的角度来看，证据支持这种脆弱性的第一部分，部分地表现为延迟奖励和惩罚、使个人偏向立即奖励（以可卡因为例）和冲动行为，从而使正常的激励回路能力普遍受损。这种脆弱性的一个特定部分被假设为涉及大脑回路中的奖励和惩罚预期的问题-一个“奖励缺陷假说”。“脆弱性的第二个方面被假设为涉及抑制优势反应的能力减弱，从而冲动行事。以前很少有研究在健康对照组或物质滥用者的行为或大脑水平上研究这两个因素之间的关系。我们将研究每组80名成人受试者（50%男性），他们目前是可卡因依赖者，以前是可卡因依赖者，但目前戒断或匹配的对照。240名受试者将通过量表和访谈进行表征，评估冲动性和几项测量行为冲动性的计算机任务：（延迟折扣，风险/奖励决策，抑制优势反应），并评估潜在的协变量，包括精神病/反社会人格，ADHD和终身物质使用。通过功能性MRI，我们将使用两个不同但互补的行为任务来检查奖励缺陷，第三个任务检查反应抑制，以剖析相关回路的潜在功能解剖。前两个任务量化的情况下，涉及的期望和接收的奖励和惩罚，并倾向于承担风险的任务之一，激励电路的反应，范例是一个货币激励延迟任务，评估预期的奖励和惩罚，分离预期（激励）从结果（完善）的奖励处理组件。另一个是多米诺骨牌任务，涉及在不确定性条件下的决策，对结果的预期，对结果的反应，冒险行为和社会互动环境。反应抑制任务是Go/No Go范式。在任务执行过程中表现出的主观反应将被量化为重要的依赖措施。我们将区分近期和过去长期使用可卡因对任务相关的大脑激活模式的影响。总之，我们计划阐明两个重要的物质滥用相关因素之间的相互关系，在行为和神经回路水平。

DESCRIPTION (provided by applicant): Evidence suggests that two major factors predisposing individuals to initiate and maintain substance abuse are abnormal responses to rewards and punishments and impaired ability to inhibit prepotent responses. These factors may act, in part, through synaptic pathology in the ventral striatum, amygdala, frontal cortex and related "motivation" circuitry to predispose vulnerable individuals to persistent substance abuse. From a cognitive/behavioral neuroscience perspective, evidence supports the first part of this vulnerability as being expressed, in part, as general impairments in the normal ability to engage motivational circuitry by delayed rewards and punishments, biasing individuals toward immediate rewards (exemplified by cocaine), and impulsive behaviors. A specific part of this vulnerability is hypothesized to involve problems in the brain circuitry for reward and punishment expectation - a "Reward Deficit Hypothesis." The second aspect of vulnerability is hypothesized to involve a diminished ability to inhibit prepotent responses and thus act impulsively. Little prior research has examined the relationship between these two factors at a behavioral or brain level in healthy controls or substance abusers. We will study 80 per group of adult subjects (50% male) who either are currently cocaine dependent, formerly cocaine dependent but currently abstinent or matched controls. The 240 subjects will be characterized on scales and interviews assessing aspects of impulsivity and several computer tasks measuring behavioral impulsivity: (delay discounting, risk/reward decision-making, inhibition of prepotent response), and also assessed on potential covariates including psychopathy/antisocial personality, ADHD and lifetime substance use. With functional MRI we will use two distinct but complementary behavioral tasks to examine reward deficit and a third to examine response inhibition, to dissect the underlying functional anatomy of the relevant circuits. The first two tasks quantify responses in motivational circuitry to situations involving both expectation of and receipt of rewards and punishments and the propensity to take risks on one of the tasks, The paradigms are a Monetary Incentive Delay Task that assesses anticipation of reward and punishment, separating anticipatory (motivational) from outcome (consummatory) components of reward processing. The other, the Domino Task involves decision making under conditions of uncertainty, anticipation to outcome, response to outcome, risk taking behavior, and a social interaction context. The response inhibition task is a Go/No Go paradigm. Subjective responses evinced during task performance will be quantified as important dependent measures. We will separate out effects of recent versus past chronic cocaine use on task-related brain activation patterns. Overall, we thus plan to elucidate the inter-relationship between two important substance abuse-related factors at both a behavioral and a neural circuit level.