Modulation of Frontoparietal Dynamics in Adolescent Working Memory Deficits

项目摘要/摘要 工作记忆缺陷(WM)是儿童和青少年的核心、跨诊断特征 精神变态学。WM是临床和功能结果的最强有力的预测因子之一，但仍有 缺乏治疗腰椎白质缺乏症的方法。WM在历史上被概念化，仅仅局限于 背外侧前额叶皮质，而现代技术已经确立了前额叶更广泛的作用 大脑皮质(PFC)和后顶叶皮质(PPC)。有证据表明，购买力平价接受直接输入 来自PFC，尽管其他证据表明PPC对传入的刺激进行编码并前馈到PFC 用于启动控制功能。我之前发现，额顶顶叶的θ/伽马振荡， 尤其是theta-Gamma耦合，是WM过程的一种神经机制。新的方法可以 非侵入性脑刺激，如间歇性电波刺激(ITBS)，现在可以调节这些 明确的振荡动力学，并随后检查可能的因果关系或时间关系。本奖项 将以我的初步发现为基础，将我的职业生涯从临床医生过渡到独立研究人员。 这个以患者为导向的研究职业发展奖(K23)的目标是提供必要的 对我进行培训，以实现我的职业目标，即利用多模式神经科学方法来测量和 调节儿童和青少年神经认知缺陷的神经动力学 精神变态学。根据NIMH的优先顺序，建议的培训计划将建立在我的临床基础上 神经心理学和临床研究基金会在两个月内提供全面的培训和指导 核心领域：1)神经调节和2)计算神经科学。在2x2析因双盲设计中，我们 将随机抽取40名青少年(13-17岁)，在左侧DLPFC或其下方的ITBS中发现WM缺陷 顶叶(IPL)。参与者将完成一次积极的ITBS会议和一次假的ITBS会议。初级阶段 结果将是在WM需求期间的theta-Gamma偶联，这是通过脑电在 紧接在ITBS之前和之后的空间工作记忆任务。目标1将研究ITBS对PPC的影响 WM的编码阶段，而Aim 2将研究ITBS对PFC的影响 WM。目标3将利用计算神经模型来识别振荡背后的新皮质回路 调制。我的中心假设是，PFC和PPC区域在执行过程中具有互补作用 WM过程。此外，ITBS可以调节这些区域的theta-Gamma偶联，以改善行为 性能。我们将建立一个框架来调节儿童精神病学中的振荡动力学，并设置 我的第一次R01关于WM相关的额顶振荡动力学和最佳治疗参数的阶段 青少年WM缺乏症。这将为我的职业生涯提供所需的基础，以衡量和 调节儿童精神病学中的振荡异常。

Project Summary/Abstract Deficits in working memory (WM) comprise a core, transdiagnostic feature of childhood and adolescent psychopathology. WM is one of the strongest predictors of clinical and functional outcomes, yet there remains a dearth of treatments available for WM deficits. WM was historically conceptualized as solely localized to the dorsolateral prefrontal cortex, while modern technology has established the broader role of the prefrontal cortex (PFC) and posterior parietal cortex (PPC). There is evidence to suggest that PPC receives direct input from PFC, although other evidence suggests the PPC encodes incoming stimuli and feeds forward to the PFC for the initiation of control functions. I have previously found that frontoparietal theta/gamma oscillations, particularly theta-gamma coupling, is a neural mechanism underlying WM processes. Novel approaches to non-invasive brain stimulation, such as intermittent theta burst stimulation (iTBS) can now modulate these distinct oscillatory dynamics and subsequently examine possible causal or temporal relationships. This award would build on my preliminary findings and transition my career from a clinician to an independent researcher. The objective of this Patient-Oriented Research Career Development Award (K23) is to provide the necessary training for me to obtain my career goal of utilizing a multimodal neuroscientific approach to measure and modulate the neural dynamics underlying neurocognitive deficits in childhood and adolescent psychopathology. In line with NIMH priorities, the training plan proposed will build upon my clinical neuropsychology and clinical research foundation to provide comprehensive training and mentorship in two core areas: 1) Neuromodulation and 2) Computational Neuroscience. In a 2x2 factorial double-blind design, we will randomize a sample of 40 adolescents (13-17 years) with WM deficits to iTBS at the left DLPFC or inferior parietal lobule (IPL). Participants will complete an active iTBS session and a sham iTBS session. The primary outcome will be theta-gamma coupling during WM demands, as measured via electroencephalography during a spatial WM task immediately before and after iTBS. Aim 1 will examine the effect of iTBS to the PPC on the encoding stage of WM, while Aim 2 will examine the effect of iTBS to the PFC on the maintenance stage of WM. Aim 3 will utilize computational neural modeling to identify the neocortical circuitry underlying oscillatory modulation. My central hypothesis is that the PFC and PPC regions have complimentary roles in executing WM processes. Further, iTBS can modulate theta-gamma coupling in these regions to improve behavioral performance. We will establish a framework for modulating oscillatory dynamics in child psychiatry and set the stage for my first R01 on WM-related frontoparietal oscillatory dynamics and optimal treatment parameters for adolescent WM deficits. This will provide the foundation required to dedicate my career to measuring and modulating oscillatory abnormalities in child psychiatry.