Imaging biomarkers of ECT response in major depressive disorder

描述(由申请人提供)：严重抑郁障碍(MDD)每年扰乱数百万人的生活，并带来巨大的社会和经济负担。尽管之前进行了研究，但MDD治疗反应和复发的潜在机制仍不清楚。有几种治疗MDD的方法可用，但建立最佳治疗形式可能是一个旷日持久的试验和错误过程，一些患者仍然没有反应。本拟议补充材料的母公司R01正在应用一种前沿的多模式成像方法来识别生物标记物，这些生物标记物索引治疗诱导的大脑可塑性的互补方面，重点放在电惊厥治疗(ECT)治疗模型中的额缘和纹状体回路。在4个时间点进行磁共振成像(MRI)，包括结构、功能、扩散和灌注成像以及磁共振质子磁共振波谱(1HMRS)：第一次ECT治疗前、第二次ECT治疗后、ECT指数系列结束后一周以及治疗后6个月确定复发情况。在另外两个间隔时间点进行临床评估。对人口学上相似的对照受试者进行两次成像，以估计与系列评估相关的方差，并确定与MDD治疗成功相关的生物标记物的正常化。利用R01的基础设施，内部资助使我们能够在每个成像时间点获取血液样本，用于补充成像和临床数据的另外两个生物学重要指标：外周淋巴细胞基因表达水平和炎症的精神神经免疫学(PNI)指标。对初步基因表达数据的分析支持这些措施的潜力，当与成像结果结合使用时，可以更准确地表征MDD的神经生物学基础和与治疗成功相关的神经过程。在本补充资料中，我们建议扩展我们的神经成像生物标记物的目标，以包括基因表达和PNI目标。与家长R01一样，拟议的研究对科学和健康的潜在影响是巨大的。新的科学线索可以为新的治疗方法提供信息，识别患抑郁症的风险个体，阐明与疾病相关的基因组或内表型因素，识别更有可能从特定治疗中受益的MDD患者亚群，并可能预测性地识别复发的高风险患者，从而允许使用替代或更积极的个体化治疗策略。基因表达和PNI标志物的纵向测量，结合ECT快速临床反应的神经成像，是一种创新的方法，非常适合绘制精神疾病的轨迹图，以确定在哪里、何时和如何进行干预。

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) disrupts the lives of millions of people each year and presents a substantial societal and economic burden. Despite prior research, the mechanisms underlying treatment response and relapse in MDD remain unclear. Several treatments for MDD are available, but establishing the best form of treatment can be a protracted trial and error process where some patients remain unresponsive. The parent R01 for this proposed supplement is applying a leading-edge multimodal imaging approach to identify biomarkers indexing complementary aspects of treatment-induced brain plasticity focusing on fronto-limbic and striatal circuitry in an electroconvulsive therapy (ECT) treatment model. Magnetic resonance imaging (MRI) that includes structural, functional, diffusion and perfusion imaging and MR proton magnetic resonance spectroscopy (1HMRS) is being performed at 4 time points: prior to the 1st ECT treatment, after the 2nd ECT session, 1 week after completion of the ECT index series and at 6-months post treatment when relapse will be determined. Clinical assessments are being made at two additional interval time points. Demographically similar control subjects are being imaged twice to allow estimation of the variance associated with serial assessments and to determine normalization of biomarkers in association with treatment success in MDD. Leveraging the infrastructure of the R01, intramural funding has allowed us to also obtain blood samples at each of the imaging time points for two other biologically important measures complementary to the imaging and clinical data: peripheral lymphocyte gene expression levels and psychoneuroimmunology (PNI) measures of inflammation. Analysis of the preliminary gene expression data supports the potential for these measures, when used in concert with the imaging results, to more precisely characterize the neurobiological bases of MDD and the neural processes associated with treatment success. In this supplement, we propose to extend our neuroimaging biomarker aims to also include gene expression and PNI aims. As with parent R01, the potential impact of the proposed research to science and health is large. New scientific leads may inform novel treatment approaches, identify individuals at risk for developing depression, elucidate disease-related genomic or endophenotypic factors, identify subpopulations of MDD patients who are more likely to benefit from a particular treatment, and may predictively identify patients at high risk for relapse thereb allowing for the use of alternate or more aggressive individualized treatment strategies. Longitudinal measurements of gene expression and PNI markers, in combination with neuroimaging in the context of the rapid clinical response to ECT, is an innovative approach ideally suited for charting the trajectory of mental illness to determine where, when and how to intervene.