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

急性威胁和烦躁和反应性攻击的令人沮丧的非奖励成分

• 批准号: 9086010
• 负责人: James Blair
• 金额: $ 32.4万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086010
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Affective; Age; Aggressive behavior; Amygdaloid structure; Anxiety; Anxiety Disorders; Applications Grants; Attention Deficit Disorder; Avoidance Learning; Behavior; Biological Markers; Clinical; Cognitive; Collaborations; Complement; Conduct Disorder; Corpus striatum structure; Decision Making; Depressed mood; Development; Disease; Distress; Ear; Early Intervention; Emotions; Empathy; Evaluation; Extramural Activities; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Goals; Guilt; Hypothalamic structure; Impulsivity; Individual; International; Intervention; Investigation; Knowledge; Life; London; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mining; Moods; National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neuronal Dysfunction; Oppositional Defiant Disorder; Pain; Participant; Patient Self-Report; Patients; Positioning Attribute; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Property; Psychological reinforcement; Recruitment Activity; Regulation; Research; Research Domain Criteria; Research Personnel; Resources; Risk; Role; Services; Sexual abuse; Symptoms; System; Testing; Treatment Efficacy; United States National Institutes of Health; Universities; Work; Youth; abuse neglect; base; behavioral study; cognitive neuroscience; cognitive system; college; design; effective intervention; emerging adult; experience; improved; indexing; individual patient; infancy; male; midbrain central gray substance; neuromechanism; novel; patient population; programs; public health relevance; relating to nervous system; response; social; success; symptomatology; therapy design; trait

 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.

 描述（由申请人提供）：我在 NIMH IRP 中的情感认知神经科学 (SACN) 部门重点研究三种神经认知机制，当这些机制功能失调时，个人将面临行为障碍 (CD) 的风险，这些机制是：( i) 一个以杏仁核为中心的系统，参与应对他人的痛苦（恐惧、悲伤、痛苦），当该系统受到损害时，与 CU 特征（减少内疚和同理心）和工具性攻击的增加有关； （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，我们勇敢地认为，与（基于威胁的）反应性攻击的风险增加有关；以及（iii）涉及基于强化的决策的系统；重要的是，这些机制的功能障碍会增加精神疾病中特定症状的风险。 RDoC 消极、积极和社会过程系统与理解情绪、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) 我们对健康青少年进行功能磁共振成像和行为研究。这些研究涉及旨在评估上述神经认知系统功能特性的预测的新任务，此外，它们还使我们能够确定其在青春期和成年早期的发育情况。患有 CD 的青少年的行为研究这些研究测试了所研究的神经系统的功能特性在我们的目标患者群体中是否存在功能障碍； 这些研究涉及校内（例如 David Goldman [NIAAA]、Daniel Pine [NIMH] 和 Ellen Liebenluft [NIMH]）和校外（例如西奈山的 Jeff Newcorn 和伦敦大学学院的 Essi Viding）与国内和国际的合作。研究人员对 CU 特征升高以及其他精神疾病（例如情绪和焦虑状况）的患者进行了调查，这项工作消耗了极少量的 SACN 资源，但却提供了宝贵的信息。服务：通过了解神经认知系统在其他临床条件下如何受到干扰，我们可以更好地了解与 CD 相关的神经认知系统的功能特性。拟议的研究：当前的提案基于并扩展了我之前的研究。当前的提案集中于理解基本威胁系统（杏仁核-下丘脑-PAG）和 vmPFC 的响应值表示及其在调节行为中的作用。该提案的目标是确定：（i）的相对贡献。这些系统的功能障碍与青少年的临床烦躁/反应性攻击之间的关系；以及（ii）积极关系的程度； 过去的虐待/忽视与烦躁/反应性攻击之间的关系是由目标系统的功能障碍介导的，鉴于已知大量的精神疾病与烦躁增加有关，成功识别烦躁生物标志物将具有广泛的适用性，用于指导治疗和确定具体治疗。此外，由于青春期的易怒程度很高，识别此类生物标志物将有可能使我们能够识别出有情绪和焦虑症状发展风险的个体。 360 名青少年（一半为男性，一半为 10-13 岁，一半为 14-17 岁，每个年龄范围内有 120 名患者和 60 名健康对照青少年），每个参与者将在两次功能磁共振成像会议中经历四种范例。候选神经认知机制对该电路的三种已知触发因素（即感知迫在眉睫的威胁、令人沮丧的无奖励和社会挑衅）的反应能力这将使我们能够。确定神经功能障碍和烦躁/反应性攻击之间的关系在多大程度上是特定触发的。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调节的情况下表示响应值的作用。此外，他们还将收到对自己的全面评估 我们的主要分析将基于通过重测 (ICC) 分析确定的 10 个 fMRI ROI 生物标志物参数；即，我们的 fMRI 生物标志物是所研究的功能过程的可靠指标。杏仁核-下丘脑-PAG 内的迫在眉睫的治疗、令人沮丧的无奖励和社会挑衅以及 vmPFC 相应的调节活动减少将与 vmPFC 水平的增加呈正相关。此外，我们认为目标系统的功能障碍将调节过去的虐待/忽视和烦躁/反应性攻击之间的正向关系。