Neural Circuitry Resilience in Psychotic Disorders: A Multimodal Ultra-High Field Neuroimaging Study

精神障碍中的神经回路弹性：多模态超高场神经影像研究

• 批准号: 10013729
• 负责人: Konasale M Prasad
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10013729
• 关键词: 3-Dimensional; Acute; Affect; Age; Anatomy; Anisotropy; Architecture; Attention; Attentional deficit; Autopsy; Axon; Bilateral; Biological Response Modifiers; Brain; Brain Diseases; Brain region; C-reactive protein; Cells; Characteristics; Chronic; Cognitive; Cognitive deficits; Complement; Complement component C4a; Complex; Custom; Data; Dendrites; Deterioration; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Electric Stimulation; Environment; Favorable Clinical Outcome; Fiber; Forcep; Gene Dosage; Genetic; Genetic Markers; Goals; Hereditary Disease; IL6 gene; Image; Impaired cognition; Impairment; Inflammation; Interleukin-6; Interneurons; Intervention; Lead; Lipid Bilayers; Magnetic Resonance Spectroscopy; Measures; Medical; Membrane; Methods; Minor; Morbidity - disease rate; Morphology; Nature; Neurites; Neurocognitive; Neuroglia; Neurons; Neuropil; Noise; Outcome; Parietal Lobe; Pathology; Pathway interactions; Patients; Performance; Peripheral; Phospholipids; Phosphorus; Pilot Projects; Prefrontal Cortex; Process; Psychotic Disorders; Public Health; Publishing; Recovery; Reporting; Resistance; Risk; Schizophrenia; Signal Transduction; Structure; Superior temporal gyrus; Synapses; Techniques; Tissues; Transcranial magnetic stimulation; Variant; Veterans; base; cognitive enhancement; cognitive performance; cohort; cost; density; design; disability; evidence base; genome-wide; gray matter; imaging modality; imaging study; improved; improved outcome; inflammatory marker; innovation; loss of function; magnetic field; multimodality; neural circuit; neural model; neuroimaging; neuronal cell body; novel; novel strategies; patient subsets; protein expression; resilience; severe mental illness; sex; social; sustained attention; symptom treatment; synaptic pruning; therapy design; water diffusion; white matter; young adult

Abstract: Good long-term social outcome of schizophrenia (SZ) subjects is as low as 14%. Because of this, substantial number of SZ subjects suffer from severe and protracted disability. An important contributing factor to poor long-term outcome in schizophrenia is cognitive impairments that are resistant to current treatments. Therefore, it is critical to examine novel mechanisms underlying cognitive impairments to design new treatments. Recent evidence suggests that brain cortical regions and white matter pathways that connect them adapt to pathophysiological processes. Such adaptation can mitigate impairments in selected cognitive domains offering hopes to target selected networks for interventions to improve outcome. Using state-of-art non-invasive neuroimaging techniques, adaptation between the cortical neuropil (synapses, dendrites and its branches, axonal endings and interneurons) and white matter integrity measured using characteristics of water diffusion in white matter fibers can be investigated. The goal of this project is to characterize concurrent changes in cortical neuropil and anisotropy of water diffusion in white matter fiber tracts as a model of neural circuitry adaptability (NCA) and its impact on cognitive performance among SZ subjects compared to healthy control subjects (HC). We will use phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high magnetic field (7 Tesla) that provides greater sensitivity to investigate neuropil by measuring membrane phospholipid (MPL) metabolites in multiple anatomically well-defined regions across the entire brain. MPLs are critical ingredients of neuronal membranes that naturally form lipid bilayers separating the intra- and extra-cellular environments. During development and disease, imbalance between synthesis and degradation of membranes can be reliably captured. Broadly, higher MPL precursor levels are associated with membrane expansion while higher MPL breakdown products suggest neuropil membrane contraction. Since such dynamic changes are prominently observed in the neuropil, 31P MRS can provide a more specific measure of neuropil than structural imaging measures that includes neuropil as well as interneuronal space, microvasculature and neuronal soma. Neurite Orientation Dispersion and Density Imaging (NODDI) - a state-of-the-art method to measure diffusion of water along white matter tracts and neurite density- will be used to examine integrity of white matter pathways more reliably than the older method of diffusion tensor imaging. Innovative nature of this proposal is highlighted by concurrent changes in MPL metabolites and anisotropy as measures of NCA in relation to cognitive impairments since using single modality imaging cannot measure adaptive changes in multiple tissues. Using our model of NCA by employing multi-modal 31P MRS-NODDI data, we seek to examine association of NCA with cognitive performance across the whole-brain (aim 1). Additionally, factors associated with NCA are unknown. Since SZ is a highly heritable disorder, and inflammation is associated with SZ, we will examine the contribution of selected genetic and peripheral inflammatory markers (Interleukin-6, IL6 and C-reactive protein, CRP) to NCA. Our studies found association of Complement C4A (C4A) gene copy numbers with neuropil changes, and of IL-6 and CRP levels with alterations in neuropil and white matter anisotropy. Based this evidence, our next aim is to determine the association of C4A copy numbers and peripheral immune mediator levels with measures of NCA among SZ and HC (aim 2). Application of integrated state-of-the-art methods to examine a less well understood concept of NCA in SZ makes this proposal highly unique and can have significant impact on novel treatment designs. These efforts may allow us to target adaptable tracts for novel interventions such as customized cognitive enhancement therapies and electrical stimulation strategies using transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) targeted to selected networks.

摘要：精神分裂症（SZ）受试者的良好长期社会结局低至 14%。因为这， 大量 SZ 受试者患有严重且长期的残疾。一个重要的促成因素 精神分裂症长期预后不佳的一个原因是认知障碍对目前的治疗有抵抗力。 因此，研究认知障碍的新机制以设计新的治疗方法至关重要。 最近的证据表明，大脑皮层区域和连接它们的白质通路适应 病理生理过程。这种适应可以减轻选定认知领域的损伤 希望针对选定的网络进行干预，以改善结果。使用最先进的非侵入式 神经影像技术，皮质神经纤维（突触、树突及其分支）之间的适应， 轴突末梢和中间神经元）和白质完整性使用水扩散特征测量 可以研究白质纤维。该项目的目标是表征皮质的并发变化 神经纤维和白质纤维束中水扩散的各向异性作为神经回路适应性的模型 (NCA) 及其对 SZ 受试者与健康对照受试者 (HC) 认知表现的影响。 我们将在超高磁场（7特斯拉）下使用磷磁共振波谱（31P MRS） 通过测量膜磷脂 (MPL) 代谢物，为研究神经纤维提供更高的灵敏度 整个大脑中多个解剖学明确的区域。 MPLs是神经元的重要成分 自然形成脂质双层的膜，分隔细胞内和细胞外环境。期间 发育和疾病，膜的合成和降解之间的不平衡可以可靠地 被捕获。一般来说，较高的 MPL 前体水平与膜扩张相关，而较高的 MPL 分解产物表明神经纤维膜收缩。由于这种动态变化是显着的 在神经纤维中观察到，31P MRS 可以提供比结构成像更具体的神经纤维测量 测量包括神经纤维网以及神经元间空间、微血管系统和神经元胞体。神经突 方向色散和密度成像 (NODDI) - 测量水扩散的最先进方法 沿着白质束和神经突密度 - 将用于更多地检查白质通路的完整性 比旧的扩散张量成像方法更可靠。该提案的创新性突出体现在 MPL 代谢物和各向异性的同时变化作为与认知障碍相关的 NCA 测量 因为使用单一模态成像无法测量多个组织的适应性变化。使用我们的模型 NCA 通过采用多模态 31P MRS-NODDI 数据，我们试图检查 NCA 与认知的关联 全脑的表现（目标 1）。此外，与 NCA 相关的因素尚不清楚。自深圳以来 是一种高度遗传性疾病，炎症与 SZ 相关，我们将检查选定的疾病的贡献 遗传和外周炎症标志物（白细胞介素 6、IL6 和 C 反应蛋白，CRP）到 NCA。我们的 研究发现补体 C4A (C4A) 基因拷贝数与神经纤维变化以及 IL-6 和 CRP 水平随神经纤维和白质各向异性的改变。基于这些证据，我们的下一个目标是 确定 C4A 拷贝数和外周免疫介质水平与 NCA 测量的关联 SZ 和 HC 之间（目标 2）。应用最先进的综合方法来检查不太了解的问题 深圳 NCA 的概念使得该提案非常独特，并且可以对新型治疗产生重大影响 设计。这些努力可能使我们能够针对适应性强的区域进行新颖的干预措施，例如定制 使用经颅磁刺激的认知增强疗法和电刺激策略 (TMS) 或经颅直流电刺激 (tDCS) 针对选定的网络。