An advanced functional MRI study of frontostriatal injury in adults with HIV

项目摘要/摘要 在联合抗逆转录病毒治疗(CART)的时代，艾滋病毒相关神经认知的流行 疾病，或手，在艾滋病毒携带者中仍然很高；因此，有越来越大的压力来 确定有效治疗的神经靶点。然而，为了开发有效的手部治疗方法，一个强烈的需求 存在于开发敏感的行为测试，可以快速筛选和有效地识别 PWH和生物标志物中可能的神经认知损害可以准确地确定手的状态和 评估治疗效果。这项为期5年的前瞻性、对照、横断面和纵向观察 研究是理论驱动的，是专门为应对这些挑战而设计的。 额纹状体环路(加上海马体、丘脑和其他相关区域)的神经损伤 长期以来一直被认为是手部的关键组成部分；然而，额纹状体损伤和 手的状态还有待阐明。最近的研究结果表明，大脑中不同关键区域的损伤 额纹状体环路可能在手中扮演不同的角色：额叶损伤在PWH中更常见，而纹状体 受伤能更好地预测手的状态。这表明在不同的情况下，对神经损伤的准确评估 额纹状体区域(除了其他关键区域，如海马体和丘脑)可能 有可能作为生物标记物来辅助手部诊断和表征。为了测试 在这一假设下，我们将使用两种已知的行为范式来研究PWH患者的额纹状体损伤 涉及不同的额纹状体区域，以及两种先进的功能磁共振成像(FMRI)技术：fMRI- 适应(fMRI-A)和多变量模式分析(MVPA)。与传统的fMRI技术相比， FMRI-A和MVPA技术可以更好地估计神经调节/选择性，这可以定量地与 行为表现。简而言之，我们假设额纹状体损伤--手头的一个中心组成部分--是 在PWH中非常普遍，可以通过两种行为范式(目标1a)评估行为，以及 通过fMRI-A和MVPA进行神经治疗(目标1b)。对其他区域/网络的神经损伤将使用 多模式磁共振成像方法(AIM 2)。AIM 1的行为和功能磁共振数据与多模式MRI的集成 来自AIM 2的数据将有助于评估额纹状体和其他区域/网络的神经损伤程度， 它又可以作为手部状态的生物标志物(目标3)。共同政策可能产生的影响 合并症也将被调查。 总之，这一建议是理论驱动的，具有很高的创新性，在未来的临床上具有很强的前景。 相关发展。这项研究的可行性得到了坚实的认知基础的支持。 神经科学和神经艾滋病毒，强大的初步数据，以及成熟的研究团队。这件事的成功 拟议的项目可能有助于开发敏感的行为测试，可以有效地检测轻微的神经认知 PWH的损害，以及有助于确定手的状态/严重程度的生物标记物。

PROJECT SUMMARY/ABSTRACT In the era of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders, or HAND, remains high in people with HIV (PWH); as a result, there is increasing pressure to identify neural targets for effective therapies. However, to develop effective HAND treatments, a strong need exists for the development of sensitive behavioral tests that can quickly screen and effectively identify probable neurocognitive impairment in PWH and biomarkers that can accurately determine HAND status and evaluate therapeutic effects. This 5-year prospective, controlled, cross-sectional and longitudinal observational study is theoretically driven and specifically designed to tackle these challenges. Neural injury to the frontostriatal circuits (plus hippocampus, thalamus, and other associated regions) has long been recognized as a key component in HAND; however, the association between frontostriatal injury and HAND status remains to be elucidated. Recent findings suggest that injury to different key regions in the frontostriatal circuits may play differential roles in HAND: frontal injury is more prevalent in PWH, but striatal injury better predicts HAND status. This suggests that an accurate assessment of neural injury at different frontostriatal regions (in addition to other key regions such as the hippocampus and thalamus) may have the potential to serve as a biomarker to assist with HAND diagnosis and characterization. To test this hypothesis, we will investigate frontostriatal injury in PWH using two behavioral paradigms that are known to involve distinct frontostriatal regions, along with two advanced functional MRI (fMRI) techniques: fMRI- adaptation (fMRI-A) and multivariate pattern analysis (MVPA). Compared to conventional fMRI techniques, fMRI-A and MVPA techniques can better estimate neural tuning/selectivity that can be quantitatively related to behavioral performance. Briefly, we hypothesize that frontostriatal injury – a central component in HAND – is highly prevalent in PWH and can be assessed behaviorally via two behavioral paradigms (Aim 1a), and neurally via fMRI-A & MVPA (Aim 1b). Neural injury to other regions/networks will be assessed using a multimodal MRI approach (Aim 2). The integration of behavioral & fMRI data from Aim 1 with multimodal MRI data from Aim 2 will help to assess the degree of neural injury at frontostriatal and other regions/networks, which in turn may serve as a biomarker for HAND status (Aim 3). The probable impact of common comorbidities will also be investigated. In summary, this proposal is theoretically driven and highly innovative, with a strong promise for future clinically relevant development. The feasibility of the proposed research is supported by a strong foundation in cognitive neuroscience and neuroHIV, strong preliminary data, and an established research team. The success of this proposed project may help to develop sensitive behavioral tests that can effectively detect mild neurocognitive impairment in PWH, and a biomarker that can assist in determining HAND status/severity.