Acute threat and frustrative non-reward components of irritability and reactive aggression

 描述(由申请人提供)：NIMH IRP中的我的部分，情感认知神经科学(SACN)部分，重点介绍三种神经认知机制，当功能障碍时，个人面临行为障碍(CD)的风险。它们是：(I)以杏仁核为中心的系统，参与对他人的痛苦(恐惧、悲伤、疼痛)做出反应，当受到损害时，与增加的CU特征(减少内疚和同理心)和工具性攻击有关；(Ii)涉及杏仁核、下丘脑和导水管周围灰质(PAG)的基本威胁系统，我们假设，与(基于威胁的)反应性攻击风险增加有关；以及(Iii)参与基于强化的决策(尤其是纹状体和vmPFC)的系统，当受到损害时，与冲动相关。重要的是，这些机制的功能障碍会增加精神障碍中特定症状集的风险。这些机制可以被认为是RDoC消极、积极和社会过程系统的组成部分，对于理解情绪、焦虑和外化障碍至关重要。SACN的工作采取三组研究的形式：(I)我们对健康的青少年和成年人进行功能磁共振成像和行为研究。这些研究涉及新的任务，旨在评估关于上文简要描述的神经认知系统功能属性的预测。此外，它们还允许我们确定他们在青春期和成年早期的发育情况。(Ii)我们对CD青年和对照青年进行了功能磁共振成像和行为研究。这些研究测试了在调查中确定的神经系统的功能特性在我们的目标患者群体中是否功能失调；(Iii)我们参与了合作 学习。这些研究涉及内部(例如David Goldman[NIAAA]、Daniel Pine[NIMH]和Ellen Liebenluft[NIMH])和外部(例如西奈山的Jeff Newcore和伦敦大学学院的Essi Viding)与国内和国际研究人员的合作，调查CU特征升高以及其他精神疾病(例如情绪和焦虑状况)的患者。这项工作消耗非常少量的SACN资源，但提供了宝贵的服务：我们通过了解它们如何在其他临床条件下变得不安，从而更好地了解与CD相关的神经认知系统的功能属性。建议的研究：当前的建议建立在我之前研究的基础上，并扩展了我的研究。特别是，目前的建议集中在了解基本的威胁系统(杏仁核-下丘脑-PAG)和vmPFC的反应价值的表征，以及这在调节行为中的作用。这项建议的目标是确定：(I)这些系统功能障碍对青少年临床易怒/反应性攻击的相对贡献；以及(Ii)正相关关系的程度 在过去的滥用/忽视和易怒/反应性攻击之间，靶系统的功能障碍起到了中介作用。鉴于人们已知的大量精神疾病与应激性增加有关，成功识别应激性生物标记物将在指导治疗和确定个别患者的具体治疗目标方面具有广泛的适用性。此外，由于青春期易怒程度高，识别这些生物标记物将潜在地使我们能够识别出情绪和焦虑状况发展的风险个体。我们将招募360名青少年(男性一半，10-13岁一半，14-17岁一半，120名患者，每个年龄段的60名健康对照青年)。每个参与者将在两次功能磁共振课程中体验四种范式。三个任务评估候选神经认知机制对这一回路的三个已知触发因素(即感知到的潜在威胁、沮丧的非奖励和社会挑衅)的反应性。这将使我们能够确定神经功能障碍和应激性/反应性攻击之间的关系是触发特异性的程度。第四个任务(被动回避学习)旨在评估vmPFC在不涉及基本威胁系统规则的背景下在反应价值表征中的作用。此外，他们还将收到对他们的 精神病症状学。我们的原理分析将基于通过重测(ICC)分析确定的10个fMRI ROI生物标记物参数；即，我们的fMRI生物标记物是所研究的功能过程的可靠指标。根据我们的初步发现，我们假设，杏仁核-下丘脑-PAG对迫在眉睫的治疗、沮丧的非奖励和社会挑衅的反应增加，以及vmPFC相应减少的调节活动将与易怒/反应性攻击水平的增加正相关。此外，我们假设靶系统的功能障碍将调节既往的虐待/忽视和易怒/反应性攻击之间的正向关系。

 DESCRIPTION (provided by applicant): My Section within the NIMH IRP, the Section on Affective Cognitive Neuroscience (SACN), focuses on three neuro-cognitive mechanisms that when dysfunctional places the individual at risk for Conduct Disorder (CD). These are: (i) an amygdala-centric system involved in responding to others' distress (fear, sadness, pain), which when compromised, is associated with increased CU traits (reduced guilt and empathy) and instrumental aggression; (ii) the basic threat systems implicating the amygdala, hypothalamus and periaqueductal gray (PAG) associated with, we hypothesize, increased risk for (threat-based) reactive aggression; and (iii) systems implicated in reinforcement-based decision-making (in particular, striatum and vmPFC), associated, when compromised, with impulsivity. Importantly, dysfunction in these mechanisms increases risk for specific symptom sets across psychiatric disorders. These mechanisms can be considered components of the RDoC negative, positive and social processes systems and are of critical relevance to the understanding of mood, anxiety and externalizing disorders. The work of the SACN takes the form of three sets of studies: (i) We conduct fMRI and behavioral studies with healthy adolescents and adults. These studies involve novel tasks designed to assess predictions regarding the functional properties of the neuro-cognitive systems briefly described above. In addition, they allow us to determine their development across adolescence and into early adulthood. (ii) We conduct fMRI and behavioral studies of youth with CD and comparison youth. These studies test whether the identified functional properties of the neural systems under investigation are dysfunctional in our target patient populations; (iii) We engage in collaborative studies. These studies involve intramural (e.g., David Goldman [NIAAA], Daniel Pine [NIMH] and Ellen Liebenluft [NIMH]) and extramural (e.g., Jeff Newcorn at Mt Sinai and Essi Viding at University College London) collaborations with national and international researchers, investigating both patients with elevated CU traits as well as other psychiatric conditions (e.g., mood and anxiety conditions). This work consumes very minimal amounts of SACN resources but provides an invaluable service: we gain a greater understanding of the functional properties of the neuro-cognitive systems relevant to CD by understanding how they can become perturbed in other clinical conditions. Proposed research: The current proposal builds upon and extends my previous research. In particular, the current proposal concentrates on understanding the basic threat systems (amygdala-hypothalamus-PAG) and vmPFC's representation of response value and the role of this in regulating behavior. The goals of this proposal are to determine: (i) the relative contribution of dysfunction in these systems to clinica irritability/reactive aggression in adolescents; and (ii) the extent that the positive relationship between past abuse/neglect and irritability/reactive aggression is mediated by dysfunction in the target systems. Given the large number of psychiatric conditions known to the associated with increased irritability, successful identification of irritability biomarkers will have widespread applicability for guiding treatment and identifying specific treatment targets for the individual patient. Moreover, since high levels of irritability in adolescence, the identification of such biomarkers will potentially allow us to identify individuals at risk for the development of mood and anxiety conditions. We will recruit 360 adolescents (half male, half 10-13 years in age, half 14-17 years in age, 120 patients and 60 healthy comparison youth within each age range). Each participant will experience four paradigms across two fMRI sessions. Three tasks assess the responsiveness of the candidate neuro-cognitive mechanisms to three known triggers of this circuitry (i.e., perceived looming threats, frustrative non-reward and social provocation). This wil allow us to determine the extent to which the relationship between neural dysfunction and irritability/ reactive aggression is trigger specific. The fourth task (passive avoidance learning)is designed to assess vmPFC's role in the representation of response value in a context not involving basic threat system regulation. In addition, they will receive a full assessment of their psychiatric symptomatology. Our principle analysis will be based on 10 fMRI ROI biomarker parameters identified through test-retest (ICC) analyses; i.e., our fMRI biomarkers are reliable indices of the functional processes investigated. Based on our preliminary findings, we hypothesize that increased responses within the amygdala-hypothalamus-PAG to looming treats, frustrative non-reward and social provocation and corresponding decreased regulatory activity by vmPFC will be positively associated with increased levels of irritability/reactive aggression. In addition, we hypothesize that dysfunction in the target systems will mediate the positive relationship of past abuse/neglect and irritability/reactive aggression.