Modulators of maladaptive decision-making in methamphetamine dependence

描述（由申请人提供）：成瘾与错误的决策有关（1，2），这可能反映了奖励评估中的适应不良策略。当执行赌博任务时，甲基苯丙胺依赖者表现出比健康对照受试者更大的冒险行为，以增加奖励的大小（3）。然而，在涉及获得奖励的时间的选择中，他们更喜欢较小的，更快的奖励，而不是较大的，更晚的奖励（4，5）。虽然这些观察结果表明，任务偶然性影响的主观效价的奖励，这种影响是不知道的神经机制。决策的神经解剖学模型（6）假设，从腹侧被盖区到脑桥核的多巴胺能传入信号发出动机性显著事件的发生，腹侧被盖区到纹状体和前额叶皮质的投射调节随后行为的表达。在此模型的基础上，成瘾的受损反应抑制和突出归因模型（7）假定重复使用药物会导致额叶白色物质（8）和从前额皮质到纹状体的谷氨酸能投射（9）的适应性变化，从而导致决策缺陷。拟议的工作旨在扩展我们对MA依赖个体错误决策过程的理解，同时调查奖励和相关神经回路评估中缺陷的潜在贡献。两个任务将被用来检查不同的突发事件对健康和MA依赖个体的决策的影响。这些任务的表现与决策的神经解剖模型中涉及的区域的结构和功能完整性之间的关系将用功能性MRI（fMRI）和扩散张量成像（DTI）进行测试。在风险、奖励或延迟下的决策过程中，将使用延迟折扣任务（DDT）（10）和气球模拟风险任务（BART）（11）来检查反应。BART提供了承担风险以增加奖励规模或兑现并保留较小奖励的选项。使用BART和fMRI，该研究的目标是将冒险和时间折扣的倾向与大脑功能联系起来，并检查各组之间冒险期间神经激活的差异。由于表现缺陷也可能反映了参与奖励评估的连接区域的白色物质的完整性降低，我们将研究连接纹状体和前额叶皮质的白色物质束在多大程度上调节BART和DDT上的神经活动和表现。行为方法是MA滥用的主要治疗方法，但影响其成功的神经缺陷并没有得到很好的描述。了解不同的突发事件如何影响辅助决策的神经功能，以及支持MA依赖性个体中这些功能的结构连接性，可能会更好地理解MA依赖性，并可能有助于改善这种疾病的治疗。

DESCRIPTION (provided by applicant): Addiction is linked to faulty decision-making (1, 2), which may reflect maladaptive strategies in evaluation of rewards. When performing gambling tasks, methamphetamine-dependent individuals exhibit greater risk-taking than healthy control subjects in order to increase the size of rewards (3). On choices that involve the time when a reward is received, however, they prefer smaller, sooner rewards over larger, later ones (4, 5). While these observations indicate that task contingencies influence the subjective valence of reward, the neural mechanisms by which this influence is exerted are not known. The Neuroanatomical Model of Decision-making (6) postulates that dopaminergic afferents from the ventral tegmental area to the nucleus accumbens signal the occurrence of motivationally salient events, and that ventral tegmental area projections to the striatum and prefrontal cortex modulate the expression of subsequent behavior. Building on this model, the Impaired Response Inhibition and Salience Attribution model of addiction (7) posits that repeated drug use leads to adaptations in frontal white matter (8) and in glutamatatergic projections from the prefrontal cortex to the striatum (9), resulting in deficits in decision-making. The proposed work aims to extend our understanding of faulty decision-making processes in MA-dependent individuals, while investigating the potential contributions of deficits in evaluation of reward and associated neural circuitry. Two tasks will be used to examine the influence of different contingencies on decision-making in healthy and MA-dependent individuals. Relationships between performance on these tasks and the structural and functional integrity of regions implicated in the Neuroanatomical Model of Decision-making will be tested with functional MRI (fMRI) and diffusion tensor imaging (DTI). Responses during decision-making under risk, reward or delay will be examined using the Delay Discounting Task (DDT) (10) and the Balloon Analog Risk Task (BART) (11). The BART presents options to take risk in order to increase reward size, or to cash out and retain smaller rewards. Using the BART with fMRI, a goal of the study is to relate the proclivity for risk-taking and temporal discounting to brain function, and to examine differences in neural activation during risk-taking between groups. As performance deficits may also reflect reduced integrity of white matter connecting regions involved in the evaluation of reward, we will examine the extent to which white matter tracts connecting the striatum and prefrontal cortex modulate neural activity and performance on the BART and DDT. Behavioral approaches are the main treatments for MA abuse, but neural deficits that can affect their success are not well delineated. Knowledge of how different contingencies affect neural function subserving decision- making, and the structural connectivity that supports these functions in MA-dependent individuals may lead to a better understanding of MA dependence, and may help improve treatment for this disorder.