Development of Pharmaco fMRI Challenge in Healthy Control and Aggressive Subjects

描述（由申请人提供）：在这个R21申请中，我们建议开发s -西酞普兰（S-CIT）作为一种精神药理学挑战（PPC）药物，与社交情绪处理的功能磁共振成像（fMRI）检查结合使用。PPC研究已经在生物精神病学中应用了30多年。最理想的是，PPC研究包括使用一种药物选择性地激活中枢神经递质突触或作用于特定神经递质系统的已知受体（或受体）。虽然行为和/或外周激素反应作为结果测量是有用的，但两者都缺乏定位患者受试者和对照组之间差异的大脑区域的能力。随着脑成像的出现，有机会在PPC的背景下使用中心结果测量。一些研究将PET成像与PPC结合使用，并开始定位患者对照差异的来源。然而，PET具有有限的时间分辨率，通常不用于与行为相关的任务。相比之下，功能磁共振成像具有出色的时间分辨率，并且总是用于与行为相关的任务。我们建议首先在冲动性攻击对象中发展这种方法，因为：a)人类受试者的攻击性和冲动性与5-HT功能呈负相关；b)社会情绪信息处理部分由5-HT介导；c)冲动性攻击受试者的社会情绪信息处理发生改变，冲动性和社会情绪信息处理的患者控制差异定位于大脑的相关区域（如眶内侧前额叶皮层、前扣带皮层和杏仁核）。最终，本研究将检查冲动性攻击受试者和健康对照组，以确定S-CIT/fMRI挑战是否可以发展为一种新的程序，在同时定位于特定大脑区域的相关行为任务背景下检查5-HT功能。从从事这些行为的个人以及这些行为所针对的人和财产的角度来看，反复出现的冲动攻击行为引起了我们社会的重大关注。新出现的流行病学数据表明，“反复出现的、有问题的、冲动的攻击行为”远非罕见，至少有5.4%的普通人群（约1600万）存在这种行为。本研究将研究冲动性攻击被试的冲动性和社会情绪信息加工的神经递质功能相关性，以确定5-HT是否与冲动性和社会情绪信息加工有关，以及在这方面是否存在被试对照差异。此外，这项工作有可能推动神经精神药理学领域的发展，使我们能够检查特定大脑区域行为任务背后的神经递质功能。与行为和神经内分泌反应等结果测量不同，我们现在可以直接观察大脑来评估特定神经递质的作用。

DESCRIPTION (provided by applicant): In this R21 application, we propose to develop S-Citalopram (S-CIT) as a Psychopharmacologic Challenge (PPC) agent used in conjunction with the fMRI examination of social-emotional processing. PPC studies have been in use in biological psychiatry for more than 30 years. Optimally, PPC studies involve the use of an agent that selectively activates a central neurotransmitter synapse or that acts at a known receptor (or receptors) of a specific neurotransmitter system. While behavioral and/or peripheral hormonal responses were useful as outcome measures both lack the ability to localize brain areas of differences between patient subjects and controls. With the advent of brain imaging there is an opportunity to use central outcome measures in the context of PPC. Some studies have used PET imaging with PPC and have begun to localize the source of patient-control differences. However, PET has limited temporal resolution and is not typically used in conjunction with behaviorally relevant tasks. In contrast, fMRI has excellent temporal resolution and is always used in the context of behaviorally relevant tasks. We propose to develop this method, first, in impulsive aggressive subjects because: a) aggression and impulsivity are inversely correlated with 5-HT function in human subjects, b) social-emotional information processing is partly mediated by 5-HT and, c) social-emotional information processing is altered in impulsive aggressive subjects and patient control differences regarding impulsivity and socio-emotional information processing are localized to relevant regions of the brain (e.g., Orbitomedial Prefrontal Cortex, Anterior Cingulate Cortex and Amygdala). Ultimately, this study will examine both Impulsive Aggressive subjects and Healthy Controls to determine if S-CIT/fMRI Challenge can be developed as a new procedure to examine 5-HT function in the context of relevant behavioral tasks that are simultaneously located to specific brain regions. PUBLIC HEALTH RELEVANCE Recurrent, impulsive aggressive behavior poses a significant concern for our society both from the viewpoint of the individual who engages in these behaviors and of the people and property that these behaviors target. Emerging epidemiological data suggest that "recurrent, problematic, impulsive aggressive behavior" is far from rare and is present in at least 5.4% of the general population lifetime (~ 16 million). This study will examine the neurotransmitter function correlates of impulsivity and social-emotional information processing in impulsive aggressive subjects to determine whether or not 5-HT is relevant to impulsivity and social-emotional information processing in these subjects and if there are subjects-control differences in this regard. In addition, this work has the potential to advance the field of neuropsychopharmacology so that we can examine neurotransmitter function underlying behavioral tasks in specific brain regions. Unlike outcome measures such as behavior and neuroendocrine responsiveness, we can now look directly into the brain to assess the role of specific neurotransmitters.