DEFINING THE FOREBRAIN REWARD CIRCUITS IN ADULT VOLUNTEERS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 物质使用障碍（SUD）在美国是一个全国性的健康问题，一些重要的政府举措已经针对SUD的公共健康影响（例如，2010年）。此外，国家吸毒问题研究所将预防和及早发现青少年吸毒成瘾问题作为高度优先领域。然而，药物使用的隐蔽性和早期发病以及某些方法的侵入性（例如，用于研究成人的PET成像限制了对SUD高风险儿童和青少年人群的研究。 非侵入性功能磁共振成像（fMRI）的发展提供了第一个机会，以检查药物暴露前的神经回路前驱特征。最近的功能磁共振成像研究测试了健康青少年的前脑奖励回路，证实了大量的发现，这些发现涉及到丘脑核（NAcc）和眶额皮质，边缘前脑结构，以及支配这两个区域的中脑边缘多巴胺能（DA）系统，在对一系列刺激（包括滥用药物）的享乐反应中。在奖励相关任务中，青少年腹侧纹状体（包括NAcc）和眶额皮质有很强的激活，前者与预期奖励有关，后者与奖励结果的处理有关。此外，腹侧纹状体的奖励相关激活的发展趋势表明，青少年比成人激活少。这些发现，连同证据表明，低中脑边缘DA张力赋予SUD的脆弱性，表明SUD的风险的早期神经生物学标记可能会发现在腹侧纹状体和/或眶额皮质。然而，功能磁共振成像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风险儿童人群。 我们设计了预期，冲突和奖励（ACR）混合任务作为一个事件相关的适应金钱激励延迟（MID）的任务，以前用于健康的青少年和年轻人的研究。在原始任务的奖励预期和结果部分增加了冲突解决措施，并简化了响应要求。 具体而言，MID中的简单反应时（RT）任务被替换为基于注意力网络任务的侧翼任务。 因此，ACR提供了三个时间上不同的探针奖励预期，冲突解决和奖励结果。此外，该任务还包含比较，以确定线索和冲突相关的大脑激活，并将这种激活从奖励预期和反馈中分离出来。 ACR任务将用于在最近资助的K23赠款中测试患有ADHD的儿童的SUD高风险与低风险（K23 PA-00-003; P.I.：伊万诺夫）和一个R21的建议，正在准备的P.I.然而，这种新的ACR任务尚未在任何样本中进行试点，因此必须在MRI扫描仪中对健康成人进行测试，以确保MID任务的条件在任务适应中没有改变，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也会使丘脑产生强有力的双侧激活 下顶叶和上级顶叶 (2)在前扣带回和前扣带回， 前额皮质 (3)腹侧纹状体会被奖赏的预期激活，但不会被 非奖励。 (4)对奖励反馈或结果的处理会激活眶额皮层，但非 奖励反馈则不会。

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.