Methamphetamine and HIV status modulate the neural dynamics underlying executive dysfunction and emotion dysregulation

项目总结/摘要 病毒抑制的艾滋病毒感染者（PWH）现在的预期寿命接近普通人群，但 相对于血清反应阴性的个体，他们发展认知障碍的风险仍然显著升高。 甲基苯丙胺使用障碍（METH）是另一种在PWH中更为普遍的疾病， METH也与认知障碍有关。具体来说，艾滋病毒和甲基似乎有一个阴性 影响与认知控制和情绪调节相关的过程，包括决策， 持续的注意力和抑制任务无关的刺激。在这一领域的人类神经成像研究表明， PWH和METH患者在大脑网络中表现出低效的神经处理， 认知控制和情绪调节（例如，额顶叶，显著性）。然而，现存的 文献，特别是关于艾滋病毒和甲基对执行和情绪功能障碍的协同作用。 确定艾滋病毒和甲基苯丙胺的总体影响至关重要，因为认知控制网络的畸变一直是 显示对临床结局有负面的下游影响，包括 PWH，更强烈的甲基苯丙胺渴望，以及适应不良的决策。 国家药物滥用研究所（NIDA）最近发布了一份特别关注的通知（NOT-DA-21-030）， PWH和一种共病的物质使用障碍，如METH“通常会加剧或加速...... 认知/行为缺陷”相对于非用户，“方法涉及全脑建模或 对复杂系统的考虑可能会阐明[这些]背后的大脑网络水平机制 临床缺陷”拟议的应用程序直接解决这个问题，通过动态神经影像学研究 利用最近的发现来确定METH和HIV对大脑区域的协同作用， 执行功能障碍和情绪失调的神经网络。我们将招募PWH和血清阴性 有无METH的对照品。目标1（授予F31项目）将量化METH对艾滋病毒相关 神经振荡动力学中的异常服务于执行功能障碍。目标2（此处提出）将确定 HIV和METH如何独立和协同地对改变的振荡动力学做出贡献， 情绪失调，而目标3将阐明艾滋病毒和甲基修饰的双向途径， 控制情绪调节和执行功能的神经系统，导致两者的严重故障 域.申请人是NIDA支持的F31博士前研究员，研究认知神经科学， 已经通过四个与拟议工作直接相关的第一作者手稿而脱颖而出， 通过广泛的合作、指导和学士后研究，共同撰写了许多论文 体验.本申请中提出的工作将完成申请人的论文，作为她培训的一部分 在神经艾滋病成瘾科学的职业生涯，这将为她未来的工作，确定关键方向 新的干预目标，以减少在PWH和共病甲基苯丙胺成瘾的痛苦。

Project Summary/Abstract Virally suppressed people with HIV (PWH) now have a life expectancy near that of the general population, yet their risk of developing cognitive impairment remains substantially elevated relative to seronegative individuals. Methamphetamine use disorder (METH) is another condition that is significantly more prevalent in PWH, and METH is also associated with cognitive impairment. Specifically, both HIV and METH appear to have a negative impact on the processes associated with cognitive control and emotion regulation, including decision-making, sustained attention, and inhibiting task irrelevant stimuli. Human neuroimaging studies in this area have shown that both PWH and people with METH exhibit inefficient neural processing within the brain networks serving cognitive control and emotion regulation (e.g., frontoparietal, salience). However, there is a dearth of extant literature, specifically regarding the synergistic effects of HIV and METH on executive and emotional dysfunction. Identifying the overall impact of HIV and METH is critical, as aberrations in cognitive control networks have been shown to have negative downstream effects on clinical outcomes, including poorer medication adherence in PWH, more intense methamphetamine cravings, and maladaptive decision-making. The National Institute on Drug Abuse (NIDA) recently issued a Notice of Special Interest (NOT-DA-21-030) citing that PWH and a comorbid substance use disorder such as METH “often have exacerbated or accelerated … cognitive/behavior deficits” relative to nonusers, and that “approaches that involve whole brain modeling or consideration of complex systems are likely to illuminate brain network-level mechanisms underlying [these] clinical deficits.” The proposed application directly addresses this call through a dynamic neuroimaging study that leverages recent discoveries to identify the synergistic effects of METH and HIV on the brain regions and networks that serve executive dysfunction and emotion dysregulation. We will enroll PWH and seronegative controls with and without METH. Aim 1 (awarded F31 project) will quantify the impact of METH on HIV-related aberrations in the neural oscillatory dynamics serving executive dysfunction. Aim 2 (proposed herein) will identify how HIV and METH independently and synergistically contribute to the altered oscillatory dynamics underlying emotion dysregulation, while Aim 3 will elucidate the bidirectional pathways whereby HIV and METH modify the neural systems governing emotion regulation and executive function, leading to accentuated breakdowns in both domains. The applicant is a NIDA-supported F31 predoctoral fellow studying cognitive neuroscience who has already distinguished herself through four first-authored manuscripts directly related to the proposed work, and numerous coauthored papers through extensive collaboration, mentoring, and postbaccalaureate research experience. The work proposed in this application will complete the applicant’s dissertation, as part of her training for a career in addiction science in neuroHIV, which will provide critical direction for her future work identifying novel targets for interventions to reduce suffering in PWH and comorbid methamphetamine addiction.