Development of Pharmaco fMRI Challenge in Healthy Control and Aggressive Subjects

描述(由申请人提供)：在这份R21申请中，我们建议开发S-西妥普兰(S-CIT)作为一种精神药物挑战(PPC)试剂，与社交-情绪加工的功能磁共振检查结合使用。PPC研究已经在生物精神病学中使用了30多年。最理想的是，PPC研究涉及使用一种药物，该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。虽然行为和/或外周荷尔蒙反应是有用的结果指标，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的背景下使用中央结果测量。一些研究已经使用了PPC的PET成像，并开始定位患者对照差异的来源。然而，正电子发射计算机断层扫描的时间分辨率有限，通常不会与行为相关的任务一起使用。相比之下，功能磁共振成像具有极好的时间分辨率，并且总是在行为相关任务的背景下使用。我们建议发展这一方法，首先，在冲动型攻击性受试者中，因为：a)在人类受试者中，攻击性和冲动性与5-羟色胺功能呈负相关，b)社会情绪信息加工部分由5-羟色胺调节，c)冲动性攻击性受试者的社会情绪信息加工发生改变，患者对冲动性和社会情绪信息加工的控制差异局限于大脑的相关区域(例如，眶内侧前额叶皮质、前扣带回和杏仁核)。最终，本研究将研究冲动性攻击性受试者和健康对照组，以确定是否可以将S-CIT/功能磁共振成像挑战赛发展为一种新的程序，在同时位于特定大脑区域的相关行为任务的背景下检查5-羟色胺功能。从从事这些行为的个人和这些行为所针对的人和财产的角度来看，反复发生的、冲动的攻击行为对我们的社会构成了重大的关切。新出现的流行病学数据表明，“反复的、有问题的、冲动的攻击行为”远非罕见，至少在总人口寿命的5.4%(约1600万人)中存在。本研究将考察冲动性攻击性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-羟色胺是否与这些被试的冲动性和社会情绪信息加工有关，以及在这方面是否存在受试者控制的差异。此外，这项工作有可能推动神经精神药理学领域的发展，以便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指标不同，我们现在可以直接观察大脑，以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.