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

项目摘要/摘要 这是对授予奖R01MH59299的竞争性续签，由体内显著的新多模式增强 功能成像方向(1H FMR和fMRI)。这些创新促进了前所未有的尝试 对强迫症青少年神经生物学功能障碍的具体认识 (强迫症)。强迫症是一种严重的、流行的、长期致残的疾病，出现在儿童/青少年时期。 (80%的病例)具有清楚的临床现象学/病因学。然而，两国之间的关系 临床现象学和脑功能障碍的模式只被普遍理解。例如，我们的前任 使用~1H MRS和功能磁共振成像的研究已经牵涉到一般的神经化学和背侧前部的功能 扣带皮质(DACC)。然而，dACC参与上下文依赖的兴奋或抑制模式。 可能导致稳态兴奋性和抑制性(E/I)突触改变的行为/控制 DACC的驱动器。然而，这些反应模式中的哪一种(以及它们引起的E/I平衡的变化)是 尤其与强迫症有关，及其对强迫症维度(强迫症或强迫症)和共病的敏感性 焦虑症状是完全未知的。在这里，我们旨在分析兴奋性和/或兴奋性功能障碍 DACC抑制音与强迫症的关系。在此过程中，我们提供了一种变革性的证据延伸 在之前的赠款迭代中提供支持，表明dACC在 强迫症青年。现在，我们使用专门设计的运动模式，具有明显的兴奋或抑制反应 诱导对dACC功能的互补需求的模式。在多任务期间管理这些任务 模式功能成像采集，包括？H FMR和fMRI。1H FMR，这允许理解 DACC的功能生物化学的一部分，与血流动力学分离，非常适合于 研究dACC E/I突触驱动的功能失衡。在相同的参与者中使用 同样的任务，将获得功能磁共振成像，以了解任务诱导的全脑网络的变化 动力学和连接学。这一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成像专业知识对功能障碍进行了革命性的解释 强迫症的神经生物学。将在100名强迫症青年和100名强迫症青年中获得？H FMR和fMRI的组合 匹配的健康对照组(12-19岁)，使我们能够测量：a)通过谷氨酸调节的大脑功能 (H FMR)和BOLD信号(FMRI)；b)与E/I突触驱动转移有关的脑可塑性(1H FMR)； 以及c)网络动力学和连接学(FMRI)。除了提供具有说服力和临床相关性的 强迫症病理生理学中兴奋性与抑制性信号紊乱的活体特征 该提案为多模式成像如何解释活体大脑功能提供了科学蓝图。这个 积累的知识将通过更详细的 强迫症的病理生理学特征。

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.