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: 10467980
• 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/10467980
• 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; Compensation; Complement component C4a; Complex; Data; Dendrites; Deterioration; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Electric Stimulation; Environment; Favorable Clinical Outcome; Fiber; Forcep; Gene Dosage; Genetic Markers; Goals; Hereditary Disease; IL6 gene; Image; Impaired cognition; Impairment; Inflammation; Interleukin-6; Interneurons; Intervention; 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; Rodent; Schizophrenia; Signal Transduction; Social outcome; Structure; Superior temporal gyrus; Synapses; Techniques; Tissues; Transcranial magnetic stimulation; Variant; Veterans; cognitive enhancement; cognitive performance; cohort; cost; density; design; diffusion anisotropy; disability; evidence base; extracellular; genetic selection; genome-wide; gray matter; imaging modality; imaging study; improved; improved outcome; inflammatory marker; innovation; loss of function; magnetic field; multimodal neuroimaging; multimodality; neural circuit; neural model; neuroimaging; neuronal cell body; novel; novel strategies; patient subsets; protein expression; resilience; schizophrenia risk; severe mental illness; sex; structural imaging; sustained attention; symptom treatment; synaptic pruning; therapy design; transcranial direct current stimulation; 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果低至14％。因为这， 大量的SZ受试者患有严重和长期残疾。一个重要的促成因素 精神分裂症的长期结局不佳是对当前治疗有抵抗力的认知障碍。 因此，检查认知障碍以设计新疗法的基本机制至关重要。 最近的证据表明，将它们连接的脑皮质区域和白质途径适应 病理生理过程。这种适应可以减轻选定的认知领域的损害 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性 神经影像学技术，皮质神经胶质之间的适应（突触，树突及其分支， 轴突结尾和中间神经元）和白质完整性，使用水扩散特征在 可以研究白质纤维。该项目的目的是表征皮质的并发变化 神经纤维扩散的神经和各向异性是神经回路适应性的模型 （NCA）及其对健康对照受试者（HC）的SZ受试者对认知性能的影响。 我们将在超高磁场（7特斯拉）处使用磷磁共振光谱（31p MRS） 通过测量膜磷脂（MPL）代谢物在研究神经肽中提供更大的敏感性 整个大脑的多个解剖学上明确的区域。 MPL是神经元的关键成分 自然形成脂质双层的膜，分隔了细胞内和细胞外环境。期间 发育和疾病，膜的合成与降解之间的不平衡可以可靠 被捕获。广义上，较高的MPL前体水平与膜扩张有关，而MPL较高 分解产物表明神经膜膜收缩。由于这种动态变化是显着的 在神经胶质中观察到的31p MRS可以提供​​与结构成像相比，可以提供更具体的神经肽测量方法 包括神经胶质以及神经元空间，微脉管系统和神经元体体的措施。神经突 方向分散和密度成像（NODDI） - 一种测量水扩散的最新方法 沿着白质区和神经突密度 - 将用于检查白质途径的完整性 比较旧的扩散张量成像方法可靠。该提案的创新性质由 MPL代谢产物和各向异性的同时变化是NCA与认知障碍有关的措施 因为使用单一模态成像无法测量多个组织中的自适应变化。使用我们的模型 NCA通过使用多模式31p MRS-NODDI数据，我们试图检查NCA与认知的关联 整个脑的性能（AIM 1）。另外，与NCA相关的因素尚不清楚。自SZ以来 是一种高度遗传的疾病，炎症与SZ有关，我们将检查选定的贡献 遗传和周围炎症标记（白介素6，IL6和C反应蛋白，CRP）。我们的 研究发现，补体C4A（C4A）基因拷贝数与Neuropil的变化以及IL-6和IL-6和 CRP水平随着神经和白质各向异性的改变。基于这个证据，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的措施的关联 在SZ和HC中（AIM 2）。应用综合最新方法来检查不太了解的 SZ中NCA的概念使该提案高度独特，并可能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新颖的干预措施（例如定制）的适应性区域 使用经颅磁刺激的认知增强疗法和电刺激策略 （TMS）或针对选定网络的针对目标的（TMS）或经颅直流刺激（TDC）。