PET-fMRI Study of Glutamate and Frontal Function in Bi- and Uni-polar Depression

双相和单相抑郁症中谷氨酸和额叶功能的 PET-fMRI 研究

• 批准号: 9279267
• 负责人: Irina Esterlis
• 金额: $ 69.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279267
• 关键词: Adverse effects; Amygdaloid structure; Autopsy; Behavior; Behavior assessment; Behavioral; Behavioral Research; Biological; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain imaging; Clinical; Cognitive; Data; Depressed mood; Depressive disorder; Detection; Development; Diagnosis; Dimensions; Early identification; Early treatment; Effectiveness; Emotional; Emotions; Face; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Imaging Techniques; Impairment; Impulsivity; Individual; Interdisciplinary Study; Lead; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measurement; Measures; Mental Depression; Mood Disorders; Neuronal Plasticity; Neurons; Pattern; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Process; Regulation; Reporting; Research Personnel; Research Support; Role; Signal Transduction; Structure; Symptoms; Synapses; System; Task Performances; Unipolar Depression; behavioral study; benzonitrile; cognitive testing; comparison group; emotion regulation; emotional stimulus; excitotoxicity; executive function; high risk; imaging study; improved; in vivo; interest; multidisciplinary; neurotransmission; novel; outcome forecast; public health relevance; receptor; receptor density; receptor downregulation; response; suicidal risk; therapy design; trait; trait impulsivity; treatment strategy

 DESCRIPTION (provided by applicant): There is a critical need for the correct diagnosis and treatment of depression in bipolar disorder - I (BD-Dep). BD is a devastating illness with a lifetime prevalence of 1%, and depression is the most common and most frequent presenting episode type, and is associated with a high risk of suicide. No marker has been identified that distinguishes the depression of BD from that of major depressive disorder (MDD-Dep). Individuals with BD may receive treatments designed for MDD that may have negative consequences, and currently available treatments for BD-Dep are limited in effectiveness and can have adverse effects. These factors highlight the critical importance of identifying a new mechanism that distinguishes BD-Dep from MDD-Dep and that could serve as a target for novel treatment strategies for BD- Dep. Convergent functional magnetic resonance imaging (fMRI) evidence supports a central role in BD for the ventral prefrontal cortex (vPFC), an important region for regulation of emotions and impulses, which are significantly impaired in individuals with BD. Evidence suggests particular abnormalities of responses in the vPFC, and in its regulation of limbic structures such as the amygdala, during the processing of positive emotional stimuli in BD, not evident in MDD. Recent evidence points to glutamatergic system abnormalities in the vPFC specific to BD, with magnetic resonance spectroscopy studies showing different glutamate levels in BD-Dep than in MDD-Dep. Postmortem research supports the specific involvement of PFC metabotropic glutamatergic receptors (mGluR5) in BD-Dep. Our exciting new pilot data from in vivo measurement of mGluR5 using positron emission tomography (PET) provide preliminary evidence for vPFC mGluR5 involvement in BD-Dep, but not MDD-Dep, supporting mGluR5 as a biomarker to help differentiate and diagnose BD-Dep and as a potential novel treatment target. Moreover, we observed associations between the PET and fMRI findings, as well as relationships of those measures to deficits in executive control and impulse regulation. We propose a multidisciplinary PET, fMRI and behavioral study comparing 40 individuals with BD- Dep to 40 with MDD-Dep and 40 healthy comparison (HC) individuals to identify differences in vPFC mGluR5 levels and determine whether they may underlie functional differences between BD-Dep and MDD-Dep, and serve as a biomarker to differentiate them. It is hypothesized that vPFC mGluR5 will be lower in the BD-Dep group, as compared to the MDD-Dep and HC groups. It is also hypothesized that vPFC functional activation and connectivity during processing of positive emotional faces will be reduced in BD-Dep group, as compared to MDD-Dep and HC groups. Finally, it is hypothesized that the lower mGluR5 availability in BD-Dep will be significantly associated with the vPFC dysfunction, as well as behaviors reflecting impaired vPFC system regulation. These results may lead to a breakthrough in characterization and differentiation of BD-Dep from MDD-Dep, as well as to the development of more specifically targeted and efficacious treatments for BD-Dep.

 描述（由申请人提供）：目前急需正确诊断和治疗双相情感障碍I型（BD-Dep）中的抑郁症。BD是一种毁灭性的疾病，终生患病率为1%，抑郁症是最常见和最频繁的发作类型，并与高自杀风险相关。没有标记物已被确定，区分抑郁症的BD从抑郁症（MDD-Dep）。BD患者可能会接受针对MDD设计的治疗，这些治疗可能会产生负面影响，目前可用的BD-Dep治疗有效性有限，并且可能会产生不良反应。这些因素突出了识别区分BD-Dep与MDD-Dep的新机制的关键重要性，并且该新机制可以用作BD-Dep的新治疗策略的靶标。会聚功能磁共振成像（fMRI）的证据支持的中央作用，在BD的腹前额叶皮层（vPFC），一个重要的区域，调节情绪和冲动，这是显着受损的个人与BD。有证据表明，在BD的积极情绪刺激的处理过程中，vPFC及其对边缘系统结构（如杏仁核）的调节反应特别异常，而在MDD中不明显。最近的证据表明，在特定于BD的vPFC中，谷氨酸能系统异常，磁共振波谱研究显示BD-Dep中的谷氨酸水平与MDD-Dep不同。死后研究支持PFC代谢型谷氨酸能受体（mGluR 5）在BD-Dep中的特异性参与。我们使用正电子发射断层扫描（PET）体内测量mGluR 5的令人兴奋的新试验数据提供了vPFC mGluR 5参与BD-Dep而不是MDD-Dep的初步证据，支持mGluR 5作为生物标志物帮助区分和诊断BD-Dep以及作为潜在的新治疗靶点。此外，我们还观察了PET和fMRI结果之间的关联，以及这些措施与执行控制和冲动调节缺陷之间的关系。我们提出了一项多学科PET、fMRI和行为研究，比较了40名BD- Dep患者、40名MDD-Dep患者和40名健康对照（HC）患者，以确定vPFC mGluR 5水平的差异，并确定它们是否可能是BD-Dep和MDD-Dep之间功能差异的基础，并作为区分它们的生物标志物。假设BD-Dep组中的vPFC mGluR 5低于MDD-Dep和HC组。我们还假设，与MDD-Dep和HC组相比，BD-Dep组在积极情绪面孔加工过程中的vPFC功能激活和连接将减少。最后，假设BD-Dep中较低的mGluR 5可用性将与vPFC功能障碍以及反映vPFC系统调节受损的行为显著相关。这些结果可能导致BD-Dep与MDD-Dep的表征和区分的突破，以及开发更特异性靶向和有效的BD-Dep治疗。