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: 9922362
• 负责人: Amit Anand
• 金额: $ 73.12万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922362
• 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; Structure; Suicide; Symptoms; Testing; Time; behavioral outcome; clinical effect; clinical efficacy; connectome; diffusion weighted; drug development; effective therapy; experimental study; functional MRI scan; 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 锂是双相情感障碍（BD）最具体和最有效的治疗方法之一，但其机制 行动尚不清楚。这阻碍了监测其效果和新的发展的方法 具有相似功效和特异性的药物。锂在躁郁症中的临床功效及其 对多种脑生理功能的复杂作用，最好使用网络解密 属性 - 金属方法。这种方法至关重要，因为它可以洞悉 大脑网络（例如，对破坏的弹性，中央枢纽），可能与 行为结果。此外，锂及其神经影像效应的关系 人类的分子效应的研究甚至更少。该提议解决了这些重要的 急性前后，通过测量大脑功能和结构连接组来测量知识的差距 并用锂治疗长期治疗。我们将研究90次无药躁郁症抑郁症 （BDD）基线时II型受试者以及锂单药治疗2、8和26周后。我们也会 研究30紧密匹配的健康对照，他们将在同一时间点进行成像，但不会 接受任何治疗。 BDD II受试者将接受静止状态功能磁共振 成像（fMRI）扫描和扩散加权结构成像扫描。除了成像，我们还将 还从外周血淋巴细胞中收集RNA样品，以探索锂诱导的外周基因 表达变化。将使用图理论指标分析功能和结构扫描 （GTM）和独立组件分析（ICA）。图理论指标超越简单 大脑连接性的描述并提供对网络功能的见解（例如，对破坏的弹性， 区域枢纽）。 ICA分析已经确定了一致且定义明确的独立组件 休息状态数据，例如默认模式和显着性网络。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变化的相关性 临床改进的指标。在此提案中，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最先进的GTM和ICA分析。我们将 将GTA和ICA指标的变化与短期和情绪的改善相关 BDD II受试者的长期稳定性。此外，我们将进行探索性分析 关于周围基因表达变化与改善的关联 使用GTA指标的症状和情绪稳定性随着介体的变化而变化并使用ICA 多模式融合分析。这将是探索性分析，以产生未来更确定性的数据 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 关于锂单一疗法的成像和分子相关性及其与锂的关系 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质量指标作为生物标志物，可用于生物标志物 治疗监测和药物开发。