Lithium Effects on the Brain's Functional and Structural Connectome in the Treatment of Bipolar Disorder

锂在双相情感障碍治疗中对大脑功能和结构连接体的影响

• 批准号: 9402890
• 负责人: Amit Anand
• 金额: $ 78.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402890
• 关键词: Acute; Address; Affect; Analysis of Variance; Antidepressive Agents; Basic Science; Behavioral; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain; Carnitine; Clinical; Complex; Data; Depressed mood; Development; Diffusion Magnetic Resonance Imaging; Functional Magnetic Resonance Imaging; Future; Gene Expression; Gene Expression Profiling; Graph; Human; Image; In Vitro; Insula of Reil; Investigation; Knowledge; Levocarnitine; Link; Lithium; Lymphocyte; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Mediator of activation protein; Mental Depression; Methods; Mitochondria; Molecular; Monitor; Moods; Motion; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Physiological; Property; RNA; Research; Rest; Sampling; Scanning; Severities; Specificity; Suicide; Symptoms; Testing; Time; behavioral outcome; clinical effect; clinical efficacy; connectome; diffusion weighted; drug development; effective therapy; experimental study; graph theory; imaging genetics; in vivo; independent component analysis; indexing; insight; mood symptom; multimodality; neuroimaging; neurophysiology; novel; peripheral blood; prospective; resilience; symptomatology; white matter

ABSTRACT Lithium is one of the most specific and effective treatments for bipolar disorder (BD) yet its mechanism of action remains unclear. This has impeded methods to monitor its effects and the development of new medications with similar efficacy and specificity. Clinical efficacy of lithium in bipolar disorder, and its complex effects on multiple brain physiological functions, may be best deciphered using a network properties-metric approach. This approach is critical because it provides insight into the function of brain networks (e.g., resilience to disruption, central hubs), which is likely to be more closely linked to behavioral outcomes. Furthermore, the relationship of the neuroimaging effects of lithium and its molecular effects in humans has been studied even less. This proposal addresses these important gaps in knowledge by measuring brain functional and structural connectomics before and after acute and longer term treatment with lithium. We will study 90 medication free bipolar disorder depressed (BDD) type II subjects at baseline and after 2, 8 and 26 weeks of lithium monotherapy. We will also study 30 closely matched healthy controls who will be imaged at the same time points but will not receive any treatment. BDD II subjects will undergo resting state functional magnetic resonance imaging (fMRI) scans and diffusion weighted structural imaging scans. In addition to imaging, we will also collect RNA samples from peripheral blood lymphocytes to explore lithium induced peripheral gene expression changes. Functional and structural scans will be analyzed using graph theory metrics (GTM) and Independent Component Analysis (ICA). Graph theory metrics move beyond simple description of brain connectivity and provide insight into network function (e.g., resilience to disruption, regional hubs). ICA analysis has identified consistent and well defined independent components in resting state data e.g the default mode and salience networks. Preliminary data from our studies indicates significant effect of lithium on GTM and ICA metrics and correlation of the changes in these metrics to clinical improvement. In this proposal, we will acquire images on a state-of-the-art 7-T scanner, conduct rigorous motion correction and apply cutting-edge GTM and ICA analytics. We will correlate changes in GTA and ICA metrics to improvement in depression in the short term and mood stability in the longer term in BDD II subjects. Furthermore, we will conduct an exploratory analysis regarding association between changes in peripheral gene expression and improvement in symptomatology and mood stability using the GTA metrics change as mediators and using ICA multimodality fusion analysis. This will be an exploratory analysis to yield data for future more definitive human and basic science studies of lithium effect. This study will therefore provide unique data regarding imaging and molecular correlates of lithium monotherapy and its relationship to lithium efficacy in bipolar disorder. In addition, this study will provide a novel paradigm to investigate effects of lithium and other psychotropics using network-property metrics as biomarkers which can be used for treatment monitoring and drug development.

抽象的 锂盐是双相情感障碍（BD）最特异、最有效的治疗方法之一，但其机制 行动仍不清楚。这阻碍了监测其影响的方法和新药物的开发 具有相似功效和特异性的药物。锂盐治疗双相情感障碍的临床疗效及其 对多种大脑生理功能的复杂影响，可能最好使用网络来解读 属性度量方法。这种方法至关重要，因为它可以深入了解 大脑网络（例如，对破坏的恢复能力、中央枢纽），这可能与 行为结果。此外，锂及其神经影像学效应的关系 对人类分子效应的研究甚至更少。该提案解决了这些重要问题 通过测量急性发作前后的大脑功能和结构连接组学来了解知识差距 以及长期锂治疗。我们将研究 90 名无需药物治疗的双相情感障碍患者 (BDD) II 型受试者在基线时以及锂单药治疗 2、8 和 26 周后。我们还将 研究 30 名密切匹配的健康对照者，他们将在同一时间点进行成像，但不会 接受任何治疗。 BDD II 受试者将接受静息态功能磁共振检查 成像（fMRI）扫描和扩散加权结构成像扫描。除了影像之外，我们还会 还收集外周血淋巴细胞RNA样本，探索锂诱导的外周基因 表情发生变化。将使用图论指标来分析功能和结构扫描 (GTM) 和独立成分分析 (ICA)。图论指标不再简单 描述大脑连接并提供对网络功能的洞察（例如，对破坏的恢复能力， 区域中心）。 ICA 分析已识别出一致且定义明确的独立组件 静息状态数据，例如默认模式和显着网络。我们研究的初步数据 表明锂对 GTM 和 ICA 指标的显着影响以及这些指标变化的相关性 临床改善的指标。在本提案中，我们将在最先进的 7-T 上获取图像 扫描仪，进行严格的运动校正并应用尖端的 GTM 和 ICA 分析。我们将 将 GTA 和 ICA 指标的变化与短期抑郁症和情绪的改善相关联 BDD II 受试者的长期稳定性。此外，我们将进行探索性分析 关于外周基因表达的变化与改善之间的关联 使用 GTA 指标变化作为中介并使用 ICA 来评估症状学和情绪稳定性 多模态融合分析。这将是一项探索性分析，旨在为未来提供更明确的数据 锂效应的人类和基础科学研究。因此，这项研究将提供独特的数据 关于锂单一疗法的影像学和分子相关性及其与锂的关系 对双相情感障碍的功效。此外，这项研究将提供一个新的范式来研究 锂和其他精神药物使用网络属性指标作为生物标志物，可用于 治疗监测和药物开发。