Modulation of Frontoparietal Dynamics in Adolescent Working Memory Deficits

项目总结/摘要 工作记忆缺陷是儿童和青少年的一个核心的跨诊断特征 精神病理学WM是临床和功能结局的最强预测因子之一，但仍存在 缺乏治疗WM缺陷的方法。WM在历史上被概念化为仅局限于 背外侧前额叶皮层，而现代技术已经建立了更广泛的作用，前额叶 皮质（PFC）和后顶叶皮质（PPC）。有证据表明，PPC接收直接输入 虽然其他证据表明PPC编码传入的刺激并前馈到PFC， 用于启动控制功能。我以前发现额顶叶θ/γ振荡， 特别是θ-γ耦合是WM过程的神经机制。的新方法 非侵入性脑刺激，如间歇性θ波群刺激（iTBS），现在可以调节这些 不同的振荡动力学，并随后检查可能的因果关系或时间关系。这个奖项 我将以我的初步发现为基础，将我的职业生涯从临床医生转变为独立研究人员。 这个以病人为导向的研究职业发展奖（K23）的目的是提供必要的 培训我，以实现我的职业目标，利用多模态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 精神病理学根据NIMH的优先事项，提出的培训计划将建立在我的临床 神经心理学和临床研究基金会提供全面的培训和指导，在两个 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名在左侧DLPFC或下方iTBS存在WM缺陷的青少年（13-17岁）样本 顶叶小叶（IPL）。参与者将完成一个活跃的iTBS会话和一个假iTBS会话。主 结果将是在WM需求期间的θ-γ耦合，如通过脑电图测量， 在iTBS之前和之后立即进行空间WM任务。目标1将检查iTBS对PPC的影响 目标2将研究iTBS对大脑前额叶皮层维持阶段的影响， WM.目标3将利用计算神经建模来识别振荡背后的新皮层回路 调变我的中心假设是，PFC和PPC区域在执行过程中具有互补作用， WM过程。此外，iTBS可以调节这些区域中的θ-γ耦合以改善行为 性能我们将在儿童精神病学中建立一个调节振荡动力学的框架， 阶段，我的第一个R 01对WM相关的额顶叶振荡动力学和最佳治疗参数， 青少年WM缺陷。这将为我的职业生涯提供必要的基础， 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.