Effects of Early-Life Stress on Brain Dysfunction in HIV+ Adults: An fMRI Study

描述(由申请人提供)：尽管联合抗逆转录病毒疗法(CART)的进步允许更好地控制病毒感染后进入大脑的迁移，但近一半的艾滋病毒患者最终会出现神经精神障碍。因此，在CART时代，人们越来越重视了解共病条件在艾滋病毒相关神经认知和心理障碍的病因学中所起的作用。这项K23提案采用了研究早期生活应激(ELS)的新方法，将其作为艾滋病毒患者神经精神损害增加的共生风险因素。鉴于高ELS在HIV+患者中很常见，这种调查是至关重要的，因为ELS高已知会导致严重的大脑异常。初步的结构MRI结果表明，艾滋病毒和高ELs对脑体积有联合影响，特别是在杏仁核，这与艾滋病毒患者的认知障碍有关。拟议的K23研究将使用功能磁共振成像(FMRI)来研究HIV和高ELS对杏仁核功能的独立和联合影响，这提供了一种比结构MRI更直接的检测脑功能障碍的方法。这项研究采用横断面2x2设计，将包括50名HIV+和50名HIV血清阴性对照参与者，有和没有高ELS(4组，每组25名参与者)。主要的因变量将是在认知和情绪任务中对fMRI血氧水平依赖(BOLD)反应的测量，以及在MRI扫描仪之外评估的认知和心理测量的表现。这项研究将测试HIV和高ELs是否相互作用：1)增加杏仁核fMRI大胆反应的异常，以及2)减少杏仁核和额叶区域之间的功能连接。它还将测试这两种功能磁共振成像措施是否与艾滋病毒患者的认知和心理功能障碍有关。探索性分析将测试fMRI措施与血浆炎症生物标志物(例如细胞因子)的关系。据推测，HIV+高ELS患者将表现出杏仁核大胆反应增强和杏仁核-额叶连接减少，这将与认知和心理障碍以及生物标志物异常相关。这项研究的长期目标是更好地了解高ELS增加HIV患者神经功能障碍的机制，以提高我们预防、评估和治疗HIV相关神经精神疾病的能力。这个为期5年的奖项旨在促进PI转变为一名独立的功能磁共振研究人员，其研究检查艾滋病毒患者神经精神障碍的病因学。PI接受过艾滋病毒相关神经异常的临床神经心理学和结构磁共振研究方面的培训。拟议的培训计划将在布朗大学提供课程和指导，以建立PI在三个重要领域的专业知识：功能磁共振成像方法学，神经艾滋病的认知后遗症，以及ELS的生物学相关性。这本K23解决了神经艾滋病病因学的关键问题，并将为PI在这一领域进行独立的以患者为导向的研究做好充分准备。

DESCRIPTION (provided by applicant): Nearly half of all HIV patients eventually develop neuropsychiatric difficulties, despite advances in combined antiretroviral therapy (cART) permitting greater control of viral migration into the brain post-infection. Increased importance has thus been placed on understanding the role that comorbid conditions play in the etiology of HIV-related neurocognitive and psychological disorders in the cART era. This K23 proposal takes the novel approach of investigating early-life stress (ELS), as a comorbid risk factor for increased neuropsychiatric impairments in HIV patients. Such an investigation is critical given that high ELS, which is known to cause significant brain abnormalities, is common among HIV+ individuals. Preliminary structural MRI findings indicate that HIV and high ELS have combined effects on brain volume, specifically in the amygdala, which correlate with cognitive impairments in HIV patients. The proposed K23 study will investigate the independent and combined effects of HIV and high ELS on amygdala function using functional magnetic resonance imaging (fMRI), which offers a more direct method of examining brain dysfunction than structural MRI. The study employs a cross sectional 2x2 design that will include 50 HIV+ and 50 HIV-seronegative control participants, with and without high ELS (4 groups of 25 participants). The primary dependent variables will be measures of fMRI blood oxygen level dependent (BOLD) response during cognitive and emotional tasks, and performances on cognitive and psychological measures assessed outside of the MRI scanner. The study will test whether HIV and high-ELS interact to: 1) increase abnormalities in amygdala fMRI BOLD response, and 2) reduce the functional connectivity between amygdala and frontal lobe regions. It will also test whether these two fMRI measures are associated with cognitive and psychological dysfunction in HIV patients. Exploratory analyses will test the relation of fMRI measures to plasma biomarkers of inflammation (e.g., cytokines). It is hypothesized that HIV+ high-ELS patients will display increased amygdala BOLD response and reduced amygdala-frontal lobe connectivity, which will correlate with cognitive and psychological dysfunction and biomarker abnormalities. The long-term objective of this research program is to better understand the mechanisms through which high ELS increases neural dysfunction in HIV patients, in order to improve our ability to prevent, assess, and treat HIV-related neuropsychiatric disorders. This 5-year award aims to foster the PI's transition into becoming an independent fMRI investigator whose research examines the etiology of neuropsychiatric disorders in HIV patients. The PI is trained in clinical neuropsychology and structural MRI investigations of HIV-related neural abnormalities. The proposed training plan will provide coursework and mentorship at Brown University to build the PI's expertise in 3 vital areas: fMRI methodology, the cognitive sequelae of neuroAIDS, and the biological correlates of ELS. This K23 addresses key issues in the etiology of neuroAIDS, and will fully prepare the PI to conduct independent patient-oriented research in this field.