Multimodal Investigation of Excitatory/Inhibitory Imbalances and Network Dysfunction Related to Motor Control in OCD Youth: ùH fMRS and fMRI Applications

与强迫症青少年运动控制相关的兴奋性/抑制性不平衡和网络功能障碍的多模态研究：�H fMRS 和 fMRI 应用

• 批准号: 10577843
• 负责人: Vaibhav A. Diwadkar
• 金额: $ 63.61万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-20 至 2025-10-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577843
• 关键词: Address; Adolescence; Adrenal Cortex Hormones; Age; Anterior; Anxiety; Apical; Architecture; Automobile Driving; Award; Behavior; Biochemistry; Brain; Childhood; Chronic; Clinical; Complex; Corpus striatum structure; Cross-Sectional Studies; Data; Diagnostic; Dimensions; Disease; Dorsal; Early Intervention; Equilibrium; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Grant; Graph; Image; Impairment; Intervention; Investigation; Knowledge; Magnetic Resonance Spectroscopy; Measures; Mediating; Motor; Movement; Multimodal Imaging; Neurobiology; Neurons; Obsession; Obsessive-Compulsive Disorder; Onset of illness; Participant; Pathway interactions; Periodicals; Process; Psychopathology; Research Design; Role; Sampling; Science; Services; Severities; Signal Transduction; Specificity; Stimulus; Structure; Symptoms; Synapses; Task Performances; Thalamic structure; Theoretical model; Time Series Analysis; Titrations; Universities; Work; Youth; anxiety symptoms; brain dysfunction; causal model; cingulate cortex; clinical predictors; clinically relevant; cognitive control; comorbidity; compulsion; density; design; disease classification; hemodynamics; in vivo; innovation; motor control; multimodality; network dysfunction; network models; neural; neurochemistry; neuroimaging; neuropathology; novel; phenomenological models; precision medicine; response; sample fixation

PROJECT SUMMARY/ABSTRACT This is a competitive renewal of grant award R01MH59299, enhanced by significant new in vivo multi-modal functional imaging directions (1H fMRS and fMRI). These innovations facilitate a never-before attempted understanding of specific aspects of dysfunctional neurobiology in youth with Obsessive Compulsive Disorder (OCD). OCD is a severe, prevalent, and chronically disabling disorder emerging during childhood/adolescence (80% of cases) with well-delineated clinical phenomenology/nosology. However, the relationship between the clinical phenomenology and modes of brain dysfunction is only generally understood. For example, our prior work using 1H MRS and fMRI has implicated general neurochemistry and function of the dorsal anterior cingulate cortex (dACC). However, dACC engages in contextually dependent excitatory or inhibitory modes of behavior/control that are likely to induce changes in the steady-state excitatory and inhibitory (E/I) synaptic drive of the dACC. However, which of these response modes (and the shift in the E/I balance they induce) is particularly relevant to OCD, and its sensitivity to OCD dimensions (Obsessions or Compulsions) and comorbid anxiety symptoms are completely unknown. Here, we aim to parse apart dysfunction in excitatory and/or inhibitory tone of the dACC in relation to OCD. In doing so, we provide a transformative extension of evidence supported under prior grant iterations demonstrating dysfunctional activation and connectivity of the dACC in OCD youth. Now, we use specifically designed motor paradigms with distinct excitatory or inhibitory response modes which induce complementary demands on dACC function. The tasks are administered during multi- modal functional imaging acquisition that includes ¹H fMRS and fMRI. 1H fMRS, which permits understanding of the functional biochemistry of the dACC, is uncoupled from hemodynamics and is ideally suited to investigate functional imbalances in the E/I synaptic drive of the dACC. In the same participants and using the same tasks, fMRI will be acquired in the service of understanding changes in task-induced whole brain network dynamics and connectomics. This unique project combines the clinical and multi-modal functional neuroimaging expertise at Wayne State University to achieve a transformative explication of the dysfunctional neurobiology of OCD. The combination of ¹H fMRS and fMRI will be acquired in 100 OCD youth and 100 matched healthy controls (12 - 19 years), allowing us to measure: a) brain function via glutamate modulation (¹H fMRS) and the BOLD signal (fMRI); b) brain plasticity related to shifts in the E/I synaptic drive (1H fMRS); and c) network dynamics and connectomics (fMRI). In addition to providing compelling and clinically relevant in vivo characterization of disordered excitatory vs. inhibitory signaling in the pathophysiology of OCD, the proposal provides a scientific blueprint for how multi-modal imaging can explicate in vivo brain function. The accumulated knowledge will promote better diagnostic and treatment approaches through a more detailed characterization of OCD pathophysiology.

项目摘要/摘要 这是对赠款奖R01MH59299的竞争续订，可通过大量新的体内多模式增强 功能成像方向（1H fMR和fMRI）。这些创新促进了从未尝试过的 了解强迫症的青年神经生物学功能失调的特定方面 （OCD）。强迫症是一种严重的，普遍的且在儿童时期出现的长期残疾障碍 （80％的病例）具有良好的临床现象学/细胞学。但是， 临床现象学和脑功能障碍的模式仅被普遍理解。例如，我们的先前 使用1H MRS和fMRI的工作已经实施了背前的一般神经化学和功能 扣带皮质（DACC）。但是，DACC参与上下文依赖的兴奋性或抑制模式 可能引起稳态兴奋性和抑制性（E/I）突触的行为/控制 DACC的驱动器。但是，以下哪种响应模式（以及E/I平衡的转变它们的影响）是 与强迫症及其对强迫症维度（强迫症或强迫症）和合并症的敏感性特别相关 焦虑符号是完全未知的。在这里，我们的目标是解析兴奋性和/或的功能障碍 DACC与强迫症的抑制作用。这样，我们提供了证据的变革性扩展 在先前的授予迭代中支持，证明了DACC功能失调的激活和连通性 强迫症青年。现在，我们使用具有独特兴奋性或抑制作用的专门设计的运动范例 对DACC功能的完全需求的模式。任务是在多个期间管理的 模态功能成像采集，包括fMR和fMRI。 1H fMR，允许理解 DACC的功能生物化学是与血液动力学无关的，非常适合 研究DACC的E/I突触驱动器中的功能失衡。在同一参与者中，并使用 相同的任务，将获得fMRI，以服务理解任务引起的整个大脑网络的变化 动力学和连接组学。这个独特的项目结合了临床和多模式功能 韦恩州立大学的神经影像学专家，以实现功能失调的变革性解释 强迫症的神经生物学。 FMR和fMRI的组合将在100名OCD青年和100个 匹配的健康对照（12-19年），使我们能够测量：a）通过谷氨酸调节的脑功能 （fMR）和粗体信号（fMRI）； b）与E/I合成驱动器的变化有关的大脑可塑性（1H fMR）； c）网络动力学和连接组学（fMRI）。除了提供引人注目的临床和临床相关 无效兴奋性与抑制性信号传导的体内表征在强迫症的病理生理学中 提案为多模式成像如何在体内脑功能中解释了科学蓝图。这 积累的知识将通过更详细的促进更好的诊断和治疗方法 OCD病理生理学的表征。