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.

翻译后摘要：精神分裂症（SZ）受试者的良好的长期社会结果是低至14%。正因为如此， 相当多的SZ受试者患有严重和长期残疾。一个重要促成因素 精神分裂症长期预后不良的原因是认知障碍，这种障碍对目前的治疗方法有抵抗力。 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色物质通路适应了 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性 神经成像技术，皮质神经元（突触，树突及其分支， 轴突末梢和中间神经元）和白色物质完整性，使用水扩散特性测量， 可以研究白色物质纤维。该项目的目标是表征皮质的并发变化， 作为神经回路适应性模型的白色物质纤维束中水扩散的神经传导和各向异性 (NCA)以及与健康对照受试者（HC）相比，其对SZ受试者的认知表现的影响。 我们将在超高磁场（7特斯拉）下使用磷磁共振波谱（31 P MRS）， 通过测量细胞膜磷脂（MPL）代谢物， 在整个大脑中有多个解剖学上定义明确的区域。MPLs是神经细胞的关键成分， 天然形成脂质双层的膜，将细胞内和细胞外环境分开。期间 发展和疾病，膜的合成和降解之间的不平衡可以可靠地 抓了广泛地说，较高的MPL前体水平与膜扩张相关，而较高的MPL前体水平与膜扩张相关。 分解产物表明神经细胞膜收缩。由于这种动态变化是突出的 在神经元中观察到，31 P MRS可以提供比结构成像更特异的神经元功能测量 测量包括神经元以及神经元间隙、微血管和神经元索马。神经突 取向弥散和密度成像（NODDI）-测量水扩散的最先进方法 沿着白色物质束和神经突密度-将用于检查白色物质通路的完整性 比旧的扩散张量成像方法更可靠。这一建议的创新性突出表现在： 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的测量 因为使用单一模态成像不能测量多个组织中的自适应变化。使用我们的模型 通过采用多模态31 P MRS-NODDI数据，我们试图检查NCA与认知的关联， 整个大脑的表现（目标1）。此外，与NCA相关的因素尚不清楚。由于SZ 是一种高度遗传性疾病，炎症与SZ相关，我们将研究选择的 遗传和外周炎症标志物（白细胞介素-6，IL 6和C反应蛋白，CRP）对NCA的影响。我们 研究发现，补体C4 A（C4 A）基因拷贝数与神经系统的变化有关，IL-6和 CRP水平与神经纤维和白色物质各向异性的改变。根据这些证据，我们的下一个目标是 确定C4 A拷贝数和外周免疫介质水平与NCA测量的相关性 在SZ和HC中（目标2）。应用最先进的综合方法来检查一个不太了解的 深圳的NCA概念使这一建议非常独特，并对新治疗产生重大影响 的设计.这些努力可能使我们能够针对适应性强的区域进行新的干预，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）。