Functional and Structural Neuroanatomy in Late-Life Generalized Anxiety Disorder

晚年广泛性焦虑症的功能和结构神经解剖学

• 批准号: 8213703
• 负责人: Carmen Andreescu
• 金额: $ 16.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213703
• 关键词: Address; Affective; Age; Age of Onset; Aging; Alleles; American; Amygdaloid structure; Anterior; Anxiety; Anxiety Disorders; Area; Board Certification; Brain; Brain region; Childhood; Clinic; Clinical; Clinical Research; Communities; Consultations; Data; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Elderly; Emotional; Employee Strikes; Ethics; Event; Exposure to; Fellowship; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Generalized Anxiety Disorder; Genetic; Goals; Health; Health Services Research; Homozygote; Image; Impaired cognition; Incidence; Institutes; Insula of Reil; Intervention; Intervention Studies; Journals; Knowledge; Literature; Magnetic Resonance Imaging; Maintenance; Medical; Mental disorders; Mentors; Modeling; Mood Disorders; Nerve Degeneration; Neuroanatomy; Neurobiology; Neurosciences; Paper; Pathway interactions; Peer Review; Population; Prevalence; Process; Psychiatrist; Psychopathology; Public Health; Publications; Publishing; Quality of life; Recovery; Research; Research Design; Research Personnel; Research Project Grants; Residencies; Rest; Role; Scientist; Statistical Methods; Structure; Training; Training Programs; Translational Research; Treatment outcome; Universities; Vascular Diseases; Weight; Work; affective neuroscience; age related; aging brain; base; career; career development; cingulate cortex; cognitive neuroscience; design; experience; gene therapy; genetic analysis; geriatric depression; health care service utilization; improved; meetings; middle age; neural circuit; neuroimaging; novel; older patient; professor; programs; relating to nervous system; research study; skills; stem; stressor; tool; treatment response; treatment strategy; white matter

DESCRIPTION (provided by applicant): This K23 application, titled "Functional and Structural Neuroanatomy in Late-Life Generalized Anxiety Disorder" represents the revision of 1 K23 MH086686-1. By 2030 as many as 20% of older Americans will meet the diagnostic criteria for an anxiety disorder. Generalized Anxiety Disorder (GAD) is the most prevalent anxiety disorder in the elderly, but it remains one of the most underdiagnosed and less studied mental disorders. It is well known that the aging brain experiences neuroanatomical change, and it has been observed that the incidence of GAD increases in the elderly. Taken together, these statements suggest that different pathophysiological pathways may be involved in late-life GAD. There is a striking discrepancy between the notable public health impact of late-life GAD and the paucity of literature describing its neuroanatomical basis. To date, there has been no neuroimaging research in late-life GAD although late-life GAD offers a good platform for translational research in aging, allowing for mechanistic inferences regarding the role of emotional control networks and the effect of impaired connectivity in the disruption of these networks. The applicant is a geriatric psychiatrist who aspires to become an independent investigator in affective cognitive neuroscience. She is a Research Assistant Professor working in the Advanced Center for Interventions and Services Research for Late-life Mood Disorders (ACISR) at the University of Pittsburgh. She obtained her board certification after completing her residency and clinical fellowship at the Western Psychiatric Institute and Clinic at the University of Pittsburgh. From 2006 she has been first author on 11 publications in peer- reviewed journals and co-authored four additional papers. Dr. Andreescu's overall career goal is to become an independent translational scientist, focused on the affective and cognitive neuroscience of late-life anxiety disorders. This area of research will seek to integrate the functional neural circuits relevant to anxious apprehension with the neurobiology of age-related changes. Her K23 career development goals comprise: 1) Gain advanced knowledge in the affective and cognitive neuroscience of late-life anxiety disorders; 2) Develop skills and experience in the acquisition and processing of structural and functional MRI data in older adults; 3) Gain knowledge in the imaging genetics of late-life anxiety disorders; 4) Strengthen knowledge of study design and statistical methods for geriatric clinical research. Her long-term career goals include 1) developing into an independent investigator in the neuroscience of late-life anxiety and 2) extending affective and cognitive neuroscience constructs and tools to improve treatment outcomes of late-life anxiety. This K23 application details an educational and mentored training program that integrates guided didactics, consultations with experts and a research study focused on late-life GAD. The didactic training will address functional and structural neuroanatomy, affective and cognitive neuroscience, imaging genetics, intervention study design, and the ethical conduct of research. This mentored training period will allow the applicant to gain expertise in neuroimaging in the elderly and generate pilot data for a future definitive study. The details of the mentored research project acknowledge the tenet that pathological anxiety involves the dysregulation of the amygdala-anterior cingulate cortex (ACC) axis. Whereas pediatric and midlife GAD are characterized by a hyperactive amygdala, we posit that the pathophysiological changes in late-life GAD are related to the poor modulatory interplay between the frontal and the limbic structures stemming from age- related disconnectivity. The applicant intends to examine this model by applying a personalized worry probe that explores the dynamic interplay of the amygdala and the subgenual ACC in the induction and maintenance of worry in the elderly. The specific age-related structural abnormalities will be examined in the white matter tracts connecting the amygdala and the anterior cingulate cortex with T2-weighted FLAIR MR images and Diffusion Tensor Imaging (DTI). The applicant will also conduct an exploratory analysis of the genetic correlates of functional neuroanatomic changes in late-life GAD. Specific Aims and Hypothesis Aim 1. Characterize the functional neuroanatomy of late-life generalized anxiety disorder. Hypothesis 1: Compared to non-anxious elderly comparison subjects, late-life GAD subjects will present with: (1) decreased resting state functional connectivity in the default-mode network; (2) increased activation of the amygdala, subgenual ACC and insula during an affective reactivity task; and (3) decreased limbic- prefrontal functional connectivity during both worry induction and worry suppression. Aim 2. Characterize the relationship between functional neuroanatomic changes and structural brain changes in late-life generalized anxiety disorder. Hypothesis 2: Compared with non-anxious elderly subjects, late-life GAD subjects will have a greater burden of white matter abnormalities. This burden of white matter abnormalities will correlate with decreased functional connectivity in the both the default-mode network and the limbic-prefrontal circuit. Aim 3 (exploratory): Identify genetic correlates of functional neuroanatomic changes in late- life generalized anxiety disorder. Hypothesis 3: Late-life GAD subjects with a 5-HTTLPR S allele will present more sustained amygdala activation during worry suppression and a decreased functional connectivity of the amygdala-sACC circuit compared with late-life GAD subjects who are LL homozygotes. This project is novel in three ways: (1) it examines an understudied population burdened by high rates of generalized anxiety; (2) it correlates functional disconnectivity with age-related structural abnormalities; and (3) it uses a functional imaging paradigm (fMRI) designed to elicit the specific emotional processes of GAD. Generating neural signatures corresponding to clinical constructs represents a first step in the direction of tailoring more efficacious and personalized treatments for elderly patients with GAD. This developmental program initiates an integrative strategy for the long-term goal of bridging psychopathology and treatment response with the neuroanatomy of late-life anxiety disorders.

描述（由申请人提供）：此K23申请的标题为“晚期焦虑症中的功能和结构神经解剖学”，代表1 K23 MH086686-1的修订。到2030年，多达20％的美国人将符合焦虑症的诊断标准。普遍的焦虑症（GAD）是老年人中最普遍的焦虑症，但仍然是最诊断和研究最少的精神障碍之一。众所周知，衰老的大脑经历了神经解剖学的变化，并且已经观察到GAD的发生率增加了老年人。综上所述，这些陈述表明，晚期GAD可能涉及不同的病理生理途径。晚年GAD对公共卫生的显着影响与描述其神经解剖学基础的文学差异之间存在明显的差异。迄今为止，尽管晚期GAD为衰老方面的转化研究提供了一个很好的平台，但还没有对情绪控制网络的作用以及连接受损在破坏这些网络的影响的效果的机械推断，但尚无神经影像学研究。申请人是一位老年精神科医生，渴望成为情感认知神经科学领域的独立研究者。她是一名研究助理教授，在匹兹堡大学的晚期情绪障碍（ACISR）高级干预与服务研究中心工作。她在西方精神病学研究所和匹兹堡大学的诊所完成居住和临床奖学金后获得了董事会认证。从2006年开始，她一直是同行评审期刊的11篇出版物的第一作者，并由共有4篇论文合着。安德烈斯（Andreescu）博士的整体职业目标是成为一名独立的翻译科学家，专注于晚期焦虑症的情感和认知神经科学。该研究领域将旨在将与焦虑恐惧相关的功能性神经回路与与年龄相关的变化的神经生物学相关。她的K23职业发展目标包括：1）在晚年焦虑症的情感和认知神经科学方面获得高级知识； 2）在老年人中获得和处理结构和功能性MRI数据方面发展技能和经验； 3）在晚期焦虑症的成像遗传学方面获得知识； 4）增强老年临床研究的研究设计知识和统计方法。她的长期职业目标包括1）在晚年焦虑的神经科学方面发展成独立研究者，以及2）扩展情感和认知神经科学结构和工具，以改善晚期焦虑的治疗结果。该K23应用程序详细介绍了一项教育和指导的培训计划，该计划将指导的教学法，与专家的磋商以及针对晚期GAD的研究。教学训练将解决功能和结构性神经解剖学，情感和认知神经科学，成像遗传学，干预研究设计以及研究的道德行为。这个受过指导的培训期将使申请人获得老年人神经影像学方面的专业知识，并为未来的确定研究生成试点数据。指导研究项目的细节承认，病理焦虑症涉及杏仁核扣带回皮层（ACC）轴的失调。尽管小儿和中年GAD的特征是多活跃的杏仁核，但我们认为，晚期GAD的病理生理变化与额叶和边缘结构之间的较差的调节性相互作用有关，源于年龄相关的障碍性。申请人打算通过应用个性化的忧虑探测来检查该模型，该探针探讨了杏仁核的动态相互作用和在老年人中诱导和维持忧虑中的亚属ACC的动态相互作用。特定年龄相关的结构异常将在连接杏仁核和前扣带回皮质的白质区与T2加权的Flair MR图像和扩散张量成像（DTI）。申请人还将对晚期GAD功能性神经解剖学变化的遗传相关性进行探索性分析。具体目的和假设目标1。表征晚期普遍焦虑症的功能性神经解剖学。假设1：与非焦虑的老年人比较对象相比，将会出现晚期GAD受试者：（1）默认模式网络中静止状态功能连接降低； （2）在情感反应性任务期间，杏仁核，亚果ACC和岛的激活增加； （3）在担心诱导和抑制恐惧期间，边缘 - 前额叶功能连通性降低。目的2。表征功能性神经解剖学变化与晚期广泛性焦虑症的结构大脑变化之间的关系。假设2：与非焦虑的老年受试者相比，晚期GAD受试者将承担更大的白质异常负担。这种白质异常的负担将与默认模式网络和边缘前额外电路的功能连通性降低相关。 AIM 3（探索性）：确定晚期一般焦虑症中功能性神经解剖学变化的遗传相关性。假设3：具有5-HTTLPR等位基因的晚期GAD受试者在忧虑抑制期间会呈现更多持续的杏仁核激活，并且与ll homozygotes的后期GAD受试者相比，杏仁核-SACC回路的功能连通性降低。该项目以三种方式是新颖的：（1）它检查了一个受到普遍焦虑率高的人口负担； （2）它与年龄相关的结构异常相关的功能断开性； （3）它使用功能成像范式（fMRI），以引起GAD的特定情感过程。与临床构建体相对应的神经信号是朝着针对老年GAD患者定制更有效和个性化治疗的方向的第一步。该发展计划启动了一项综合策略，用于与晚期焦虑症的神经解剖学弥合心理病理学和治疗反应的长期目标。