A neurocognitive and computational study of inhibitory control in substance use

描述（由申请人提供）：兴奋剂滥用和依赖是美国年轻人面临的重大问题。大约20%的年轻人报告在18-20岁之间使用非法药物，大约七分之一的受试者开始使用兴奋剂，最终发展到依赖。有强有力的证据表明，药物使用和依赖与抑制控制缺陷有关。然而，这种去抑制性精神病理背后的基本认知和神经过程尚不清楚。该项目的长期目标是描述偶然兴奋剂使用者抑制性失调的神经来源和行为后果，这将为开发识别高危个体、预防性干预以及行为和药物补救的新工具提供价值。具体目的是：(1)调查兴奋剂使用者和正常对照之间的认知差异，特别是评估兴奋剂使用者错误处理和/或时间感知的改变导致抑制控制受损的假设；(2)确定不同大脑区域在停止行为方面的不同贡献，以及兴奋剂使用者和匹配对照之间的神经生理差异。(3)发现早期行为和神经生理标记，预测偶然的兴奋剂使用者最终是否会发展成依赖。为了实现目标1，一种新的抑制控制定量模型将用于分析兴奋剂使用者和执行停止信号范式的匹配对照，该模型将区分各种认知过程（如感官辨别、时间感知、奖励/错误处理、学习和适应）的贡献。为了实现目标2，受试者和试验特定的参数回归，对应于目标1定量模型的不同认知过程，将用于识别各种认知过程的神经基质（使用fMRI数据），并表征兴奋剂使用者和匹配对照组之间的任何神经生理差异。为了实现目标3，将进行为期三年的随访调查，以表明临时使用者最终会产生依赖，并将其与原始fMRI/行为实验中收集的行为和神经生理指标相关联，以确定预测从临时使用到依赖转变的早期行为和神经生理标志物。行为和功能磁共振成像数据已经在另一项拨款下收集；由另一笔拨款资助的后续调查将很快完成。

DESCRIPTION (provided by applicant): Stimulant abuse and dependence are significant problems facing young adults in the United States. Around 20% of young adults report the use of illicit drugs between the ages of 18-20 years, and approximately one in seven subjects initiating stimulant use progress eventually to dependence. There is strong evidence that drug use and dependence are associated with deficits in inhibitory control. However, the basic cognitive and neural processes underlying such disinhibitory psychopathology are poorly understood. The long-term goal of this project is to delineate the neural provenance and behavioral consequence of inhibitory dysregulation in casual stimulant users, which would be valuable for developing novel tools for the identification of at-risk individuals, for preventative intervention, and for behavioral and pharmacological remediation. The specific aims are (1) to investigate the cognitive differences between stimulant users and normal controls, specifically evaluating the hypotheses that altered error processing and/or temporal perception in stimulant users contribute to impaired inhibitory control, (2) to identify the differential contributions of various brain regions in stopping behavior, as well as neurophysiological differences between stimulant users and matched controls, and (3) to uncover early behavioral and neurophysiological markers that predict whether a casual stimulant user will eventually develop dependent use or not. To achieve Aim 1, a novel, quantitative model for inhibitory control, differentiating the contributions of various cognitive processes such as sensory discrimination, temporal perception, reward/error processing, learning and adaptation, will be used to analyze stimulant users and matched controls performing the stop signal paradigm. To achieve Aim 2, subject- and trial-specific parametric regressors, corresponding to distinct cognitive processes of the quantitative model of Aim 1, will be used to identify the neural substrate (using fMRI data) of the various cognitive processes, and to characterize any neurophysiological differences between stimulant users and matches controls. To achieve Aim 3, three-year follow-up surveys, indicating which casual users eventually develop dependence, will be correlated with behavioral and neurophysiological measures collected in the original fMRI/behavioral experiments, to identify early behavioral and neurophysiological markers that predict transition from casual use to dependence. The behavioral and fMRI data have already been collected under a different grant; the follow-up survey, funded by another grant, will soon be completed. PUBLIC HEALTH RELEVANCE: Stimulant abuse and dependence are significant problems among young adults, making it imperative to identify the causative factors for stimulant use, as well as the nature of cognitive deficits in problem use, in order to develop more powerful diagnostic, preventative, and remedial procedures. In this project, a sophisticated, novel, quantitative model of inhibitory control will be developed, yielding a rich set of cognitive and behavioral measures that can characterizes subtle differences between stimulant users and control populations at different stages of drug use and addiction. The model will be applied to a large set of behavioral and functional MRI data of casual stimulant users and matched control subjects, with the goal of identifying behavioral and neural features that best predict whether an individual eventually develops addiction or not.