DEFINING THE FOREBRAIN REWARD CIRCUITS IN ADULT VOLUNTEERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 物质使用障碍(SUD)在美国是一个如此严重的全国性健康问题，以至于政府的几个重要举措都瞄准了SUD对公共健康的影响(例如，2010年健康人)。此外，NIDA已将预防和及早识别青少年成瘾定为高度优先领域。然而，药物使用的隐蔽性和早发性，以及用于研究成人的一些方法(例如，PET成像)的侵袭性，限制了对儿童和青少年人群的调查，这些人群是SUD的高危人群。 无创功能磁共振成像(FMRI)的发展为在药物暴露前检查神经回路的前驱特征提供了第一个机会。最近的fMRI研究测试了健康青少年的前脑奖赏回路，证实了大量发现，涉及伏隔核(NAcc)和眼眶额叶皮质、边缘前脑结构以及支配这两个区域的中脑边缘多巴胺(DA)系统，在对包括滥用药物在内的一系列刺激的享乐反应中。青少年在与奖赏相关的任务中，腹侧纹状体(包括NAcc)和眶前叶皮质有较强的激活，前者与预期奖赏有关，后者与奖赏结果的加工有关。此外，腹侧纹状体奖赏相关激活的发展趋势表明，青少年的激活程度低于成人。这些发现，再加上中脑边缘DA音调低导致SUD易感性的证据，提示可能在腹侧纹状体和/或眶前皮质发现了SUD风险的早期神经生物学标志。然而，fMRI研究中使用的奖励任务的局限性，包括没有充分控制运动活动和复杂的反应要求，使它们不适合用于高危儿童群体。 我们设计了预期、冲突和奖励(ACR)混合任务，作为以前在健康青少年和年轻人研究中使用的货币激励延迟(MID)任务的事件相关适应任务。在原任务的奖励预期和结果部分增加了一项解决冲突的措施，并简化了反应要求。具体地说，MID中的简单反应时(RT)任务被基于注意网络任务的侧翼任务取代。因此，ACR提供了三个在时间上不同的关于奖励预期、冲突解决和奖励结果的探测。此外，这项任务还包括比较，以确定与线索和冲突相关的大脑激活，并将这种激活与奖励预期和反馈过程中的激活分开。ACR任务将在最近资助的K23拨款(K23 PA-00-003；P.I.：Ivanov)和P.I.正在准备的R21提案中用于测试患有ADHD的儿童的高风险与低风险的SUD。然而，这一新的ACR任务尚未在任何样本中进行试验，因此必须在健康成年人的MRI扫描仪中进行测试，以确保任务中期的条件在任务的适应过程中不会改变，然后才能用于临床人群和儿童。 假设： (1)与线索相关的运动准备将产生强健的双侧丘脑激活，以及顶下小叶和顶上小叶 (2)在前扣带回和前额叶皮质可见冲突相关神经活动。 (3)腹侧纹状体会被奖赏预期激活，但不会被非奖赏预期激活。 (4)奖赏反馈或结果的加工会激活眶前叶皮质，而非奖赏反馈不会。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Substance use disorders (SUD) present such a national health problem in the U.S that several important government initiatives have targeted the public health impact of SUD (e.g., Healthy People 2010). Further, the NIDA has established prevention and early identification of addiction among adolescents as high priority areas. However, the insidious and early onset of substance use and the invasive nature of some of the methodologies (e.g., PET imaging) used to study adults have limited the investigation of child and adolescent populations at high risk for SUD. The development of the non-invasive functional magnetic resonance imaging (fMRI) provided the first opportunity to examine the prodromal characteristics of neural circuits prior to drug exposure. Recent fMRI studies that tested forebrain reward circuits in healthy adolescents have corroborated the large body of findings that implicate the nucleus accumbens (NAcc) and orbital frontal cortex, limbic forebrain structures, and the mesolimbic dopaminergic (DA) system that innervates both regions, in the hedonic response to a range of stimuli, including drugs of abuse. Adolescents had robust activation of ventral striatum (including the NAcc) and orbitofrontal cortex during reward-related tasks, with the former specifically associated with anticipating rewards and the latter with the processing of reward outcomes. Further, developmental trends in the reward-related activation of ventral striatum indicated less activation in adolescents than adults. These findings, together with evidence that low mesolimbic DA tone confers vulnerability to SUD, suggests that an early neurobiological marker of risk for SUD might be found in the ventral striatum and/or orbitofrontal cortex. Yet, limitations of the reward tasks that have been used in fMRI studies, including not adequately controlling for motor activity and complex response requirements, make them inappropriate for use with high-risk child populations. We designed the Anticipation, Conflict, and Reward (ACR) hybrid task as an event-related adaptation of the Monetary Incentive Delays (MID) task previously used in the study of healthy adolescents and young adults. A measure of conflict resolution was added to the reward anticipation and outcome components in the original task and the response requirements were simplified. Specifically, the simple reaction time (RT) task in the MID was replaced with a flanker task based on the Attention Network Task. Thus, the ACR provides three temporally distinct probes of reward anticipation, conflict resolution, and reward outcome. Further, the task also contains comparisons to identify cue- and conflict-related brain activation, and isolate this activation from that during reward anticipation and feedback. The ACR task will be used to test children with ADHD at high- versus low-risk for SUD in a recently funded K23 grant (K23 PA-00-003; P.I.: Ivanov) and a R21 proposal that is being prepared by the P.I. However, this new ACR task has not been piloted in any sample and therefore must be tested in the MRI scanner with healthy adults to ensure that the conditions from the MID task were not changed in the adaptation of the task, before they can be used with clinical populations and children. HYPOTHESES: (1) Cue-related motor preparation will produce robust, bilateral activation of the thalamus, as well as the inferior and superior parietal lobules (2) Conflict-related neural activity will be seen in the anterior cingulate gyrus and the anterior prefrontal cortex. (3) The ventral striatum will be activated by the anticipation of reward, but not by the anticipation of non-reward. (4) The processing of reward feedback or outcome will activate the orbitofrontal cortex, but non- reward feedback will not.