Reward, Impulsivity and Cocaine Addiction; fMRI Studies

描述(由申请人提供)：证据表明，导致个人开始和维持药物滥用的两个主要因素是对奖惩的异常反应和抑制优势反应的能力受损。这些因素可能在一定程度上通过腹侧纹状体、杏仁核、额叶皮质的突触病理和相关的“动机”回路发挥作用，从而使易受伤害的人容易受到持续药物滥用的影响。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，部分表现为通过延迟奖励和惩罚、使个人偏向于立即奖励(如可卡因)和冲动行为，正常参与动机回路的能力普遍受损。这种脆弱性的一个特定部分被假设涉及奖惩预期的大脑回路问题--一种“奖赏缺失假说”。脆弱性的第二个方面被假设为涉及抑制强势反应从而采取冲动行动的能力减弱。此前很少有研究在健康对照组或药物滥用者的行为或大脑水平上检查这两个因素之间的关系。我们将对每组成年受试者(50%男性)进行研究，这些受试者要么目前依赖可卡因，要么以前依赖可卡因，但目前正在戒毒或与之匹配的对照组。这240名受试者将被用量表和访谈来评估冲动的各个方面，以及几项衡量行为冲动的计算机任务：(延迟折扣、风险/回报决策、优先反应抑制)，还将评估潜在的协变量，包括精神病/反社会人格、ADHD和终生药物使用。对于功能磁共振，我们将使用两个不同但互补的行为任务来检查奖励缺陷，第三个任务来检查反应抑制，以剖析相关回路的潜在功能解剖。前两项任务在激励回路中量化了对奖惩预期和接受情况的反应，以及在其中一项任务上冒险的倾向，范式是货币激励延迟任务，它评估对奖惩的预期，将奖励加工的预期(动机)和结果(完备性)成分分开。另一种是多米诺任务，涉及在不确定条件下的决策、对结果的预期、对结果的反应、冒险行为和社会交互环境。反应抑制任务是一种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测量。我们将区分最近和过去长期使用可卡因对与任务相关的大脑激活模式的影响。总体而言，我们计划在行为和神经回路水平上阐明两个重要的物质滥用相关因素之间的相互关系。

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.