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），这可能反映了在评估奖励时的不适应策略。在执行赌博任务时，甲基苯丙胺依赖者比健康对照者表现出更大的冒险精神，以增加奖励的大小(3)。然而，当选择涉及到获得奖励的时间时，他们更喜欢更小、更快的奖励，而不是更大、更晚的奖励（4,5）。虽然这些观察结果表明，任务随因会影响奖励的主观效价，但这种影响施加的神经机制尚不清楚。决策的神经解剖学模型(6)假设，从腹侧被盖区到伏隔核的多巴胺能传入信号表明动机显著事件的发生，腹侧被盖区向纹状体和前额叶皮层的投射调节了随后行为的表达。在此模型的基础上，成瘾的受损反应抑制和显著性归因模型(7)认为，反复使用药物会导致额叶白质(8)和从前额皮质到纹状体的谷氨酸能投射(9)的适应，从而导致决策缺陷。本研究旨在扩展我们对ma依赖个体的错误决策过程的理解，同时调查奖励评估和相关神经回路缺陷的潜在贡献。两个任务将用于检查不同的突发事件对健康和ma依赖个体决策的影响。这些任务的表现与决策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通过功能磁共振成像（fMRI）和扩散张量成像（DTI）进行测试。将使用延迟贴现任务（DDT）（10）和气球模拟风险任务（BART）（11）来检查在风险、奖励或延迟下的决策反应。BART提供了承担风险以增加奖励规模的选择，或者兑现并保留较小的奖励。利用BART和fMRI，研究的目标是将冒险倾向和时间折扣与大脑功能联系起来，并检查两组之间在冒险时神经激活的差异。由于表现缺陷也可能反映了参与奖励评估的白质连接区域的完整性降低，我们将研究连接纹状体和前额叶皮层的白质束在多大程度上调节BART和DDT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尚未得到很好的描述。了解不同的偶然性如何影响MA依赖个体中服务于决策的神经功能，以及支持这些功能的结构连通性，可能有助于更好地理解MA依赖，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.