A New fMRI Method to Measure Substantia Nigra Signaling During Reward Processing

 描述（由申请人提供）：药物滥用和相关疾病是复杂，常见和昂贵的疾病。更好地了解引起这些疾病的神经机制可能会为开发新的更有效的治疗方法提供有价值的线索。虽然我们现在知道，在广泛的条件下，多巴胺和它的奖励加工的调节参与了药物滥用的发病机制，仍然有很多要了解的细节，多巴胺能机制的奖励加工可能会被颠覆，并导致成瘾，特别是在人类模型。中脑多巴胺能核是调节多巴胺功能的最重要的结构之一，因为它们储存和释放大脑中的大部分多巴胺。因此，一个灵活的，广泛可用的，非侵入性的手段来测量他们的信号在人类的奖励过程中可能被证明是有用的，在阐明多巴胺能机制。然而，这些核由于其小尺寸和位置而非常难以成像。我们最近开发了一种新的，简单的，但精确的高分辨率功能磁共振成像方法来测量信号的主要多巴胺能核之一，黑质，一个结构，现在被认为发挥重要作用，奖励相关的过程密切相关的物质滥用和成瘾。使用众所周知的事实，其高铁含量呈现黑质作为一个独特的区域的低强度功能磁共振成像卷，我们将使用一组独特的图像处理步骤，已被优化，本地化和区分黑质直接从附近的结构上的任务图像。然后，我们将能够获得任务诱发的功能磁共振成像信号的估计，以及验证黑质内的显着活动的本地化。我们建议验证这种方法 用于物质滥用研究，通过测试它可以测量奖励处理相关的黑质信号的假设。我们将扫描一个健康的年轻成年人的样本，同时他们完成一个奖励处理任务，该任务已被很好地验证为人类中与奖励相关的黑质多巴胺信号的驱动因素。然后，我们将比较奖励与非奖励试验期间的黑质信号，并验证黑质内发生的显著奖励活动。该项目的成功完成将提供一个新的功能磁共振成像方法测量多巴胺功能，可能是有用的在体内人类模型的物质滥用的初步确认。此外，该计划亦可让首席研究员在药物滥用研究方面取得宝贵经验，使他能获得更广泛的赠款，并在这方面进行进一步的研究。

 DESCRIPTION (provided by applicant): Substance abuse and related conditions are complex, common, and costly disorders. A better understanding of the neural mechanisms giving rise to these conditions may yield valuable clues for the development of new and more effective treatments. While we now know in broad terms that dopamine and its regulation of reward processing are involved in the pathogenesis of substance abuse, there is still much to learn about the details of how dopaminergic mechanisms of reward processing may be subverted and lead to addiction, particularly in human models. The midbrain dopaminergic nuclei are among the most important structures regulating dopamine function because they store and release the majority of dopamine in the brain. Thus, the availability of a flexible, widely available, non-invasive means of measuring their signaling during reward processing in humans could prove to be useful in elucidating dopaminergic mechanisms. However, these nuclei are very difficult to image due to their small size and location. We have recently developed a new, simple, yet precise high resolution fMRI method for measuring the signal from one of the major dopaminergic nuclei, the substantial nigra, a structure that is now recognized to play an important role in reward related processes closely associated with substance abuse and addiction. Using the well-known fact that its high iron content renders the nigra as a distinct region of hypointensity on fMRI volumes, we will use a unique set of image processing steps that have been optimized to localize and distinguish nigra from nearby structures directly on task images. We will then be able to derive estimates of task evoked fMRI signal from as well as verify the localization of significant activity within the nigra. We propose validating this method for use in substance abuse research by testing the hypothesis that it can measure reward processing related nigral signaling. We will scan a sample of healthy young adults while they complete a reward processing task that has been well validated as a driver of reward associated nigral dopamine signaling in humans. We will then compare nigral signal during reward vs. non-reward trials, as well as verify that significant reward activity occurs within the nigra. The successful completion of this project will provide preliminary confirmation of a new fMRI method for measuring dopamine function that may be useful in in vivo human models of substance abuse. In addition, it will alllow the PI to obtain valuable experience in substance abuse research that may enable him to obtain more extensive grants and conduct further research in this field.