Project 2: Functional and neurochemical brain changes following successful trea..

项目 2：成功治疗后大脑功能和神经化学变化

• 批准号: 8099706
• 负责人: STEPHEN M STRAKOWSKI
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099706
• 关键词: Address; Affective; Aftercare; American; Amygdaloid structure; Anterior; Area; Attention; Bipolar Depression; Bipolar Disorder; Brain; Brain region; Brodmann' s area; Chemicals; Choline; Chronic; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Decision Making; Depressed mood; Development; Diagnosis; Disease Marker; Disease Progression; Early treatment; Emotional; Energy Metabolism; Exhibits; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamates; Glycolysis; Goals; Homeostasis; Image; Impairment; Inositol; Intervention; Life; Link; Lithium; Magnetic Resonance Spectroscopy; Manic; Matched Group; Measurement; Measures; Medial; Mediating; Memory; Mental Depression; Metabolism; Methods; Mind; Modeling; Mood stabilizers; Moods; Morbidity - disease rate; N-acetylaspartate; Neurons; Oxidative Phosphorylation; Patients; Pattern; Pharmaceutical Preparations; Phase; Phospholipid Metabolism; Play; Positron-Emission Tomography; Prefrontal Cortex; Process; Productivity; Randomized; Recruitment Activity; Reporting; Research Personnel; Role; Scanning; Signal Transduction; Source; Structure; Symptoms; System; Task Performances; Testing; atypical antipsychotic; cingulate cortex; cohort; depressive symptoms; effective intervention; effective therapy; experience; interest; mortality; neurochemistry; neuroimaging; neurophysiology; novel strategies; olanzapine; open label; phosphomonoester; programs; response; restoration; single episode major depressive disorder; treatment effect; treatment response

Depressive states are the predominant feature of bipolar disorder and a major source of morbidity and mortality in bipolar patients. Symptoms include affective changes, neurovegetative signs, and significant cognitive deficits. Several lines of evidence suggest that these symptoms are linked to neuropathological abnormalities in structures making up the anterior limbic network (ALN), a brain network hypothesized to modulate emotional homeostasis. These abnormalities are manifest by functional neuroimaging changes in regions involved in emotional control including the ventrolateral prefrontal cortex (VLPFC), anterior cingulate (ACC) and amygdala, as well as by neurochemical changes consistent with elevated neuronal metabolism. Magnetic resonance spectroscopy (MRS) studies of depressed bipolar patients suggest that abnormalities in energy metabolism may underlie increased prefrontal and medial temporal activity observed with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Patients with bipolar disorder demonstrate significant changes in prefrontal concentrations of N-acetyl aspartate (NAA), as well as changes in phosphomonoesters (PME) and the presence of lactate, that suggest altered energy metabolism. Evidence of increased glutamate in the prefrontal cortex suggests that this increased neuronal activity is related to increased intraneuronal excitatory signaling within the prefrontal cortex. Together, these data support a model in which bipolar depression is marked by a loss of emotional modulation linked with increased ACC and VLPFC activation, and inhibition of, or interference with other brain regions, including the dorsolateral prefrontal cortex, which mediates cognitive domains impacted by bipolar disorder. These prefrontal changes in neuronal activity appear to be responsive to pharmacologic intervention. With these consideration in mind, the goals of this study are: 1) To use 1H-MRS to identify neurometabolic abnormalities in early-episode depressed bipolar patients, and to determine how abnormalities change in response to specific treatments; and 2) To identify corresponding changes in fMRI brain activation, in order to provide neurofunctional correlates to neurochemical markers of treatment response. To accomplish these aims, we will acquire integrated neurometabolic (MRS) and neurofunctional (fMRI) measurements in earlyepisode depressed bipolar patients and a matched cohort of healthy subjects in order to refine neurophysiological models of bipolar disorder (Center goal 1); to identify MRS and fMRI markers of treatment response in bipolar depression to two mechanistically different medications (Center goal 2); and to identify potential predictors of treatment response for future studies (Center goal 3).

抑郁状态是双相情感障碍的主要特征，也是发病率和抑郁症的主要来源。 双相情感障碍患者的死亡率。症状包括情感变化、植物神经体征和显着的 认知缺陷。多项证据表明这些症状与神经病理学有关 构成前边缘网络（ALN）的结构异常，该网络被假设为 调节情绪稳态。这些异常表现为功能性神经影像学变化 涉及情绪控制的区域包括腹外侧前额叶皮层（VLPFC）、前扣带回 （ACC）和杏仁核，以及与神经元代谢升高一致的神经化学变化。 对抑郁双相情感障碍患者的磁共振波谱 (MRS) 研究表明， 能量代谢可能是功能性观察到的前额叶和内侧颞叶活动增加的基础 磁共振成像（fMRI）和正电子发射断层扫描（PET）。双相情感障碍患者 证明前额叶 N-乙酰天冬氨酸 (NAA) 浓度的显着变化，以及 磷酸单酯（PME）的变化和乳酸的存在，表明能量代谢发生了变化。 前额皮质中谷氨酸含量增加的证据表明，这种神经元活动的增加是 与前额皮质内神经元内兴奋信号的增加有关。这些数据加在一起 支持一种模型，其中双相抑郁症的特点是情绪调节丧失，与 增加 ACC 和 VLPFC 的激活，并抑制或干扰其他大脑区域，包括 背外侧前额叶皮层，调节受双相情感障碍影响的认知域。这些 前额叶神经元活动的变化似乎对药物干预有反应。 考虑到这些因素，本研究的目标是： 1) 使用 1H-MRS 来识别神经代谢 早期抑郁双相情感障碍患者的异常，并确定异常如何变化 对特定治疗的反应； 2) 识别 fMRI 大脑激活的相应变化，以便 提供与治疗反应的神经化学标记物相关的神经功能。为了完成这些 目标是，我们将在早期获得综合神经代谢 (MRS) 和神经功能 (fMRI) 测量 抑郁双相情感障碍患者和一组匹配的健康受试者，以完善 双相情感障碍的神经生理学模型（中心目标 1）；识别 MRS 和 fMRI 标记 双相抑郁症对两种机制不同的药物的治疗反应（中心目标 2）；并到 确定未来研究治疗反应的潜在预测因素（中心目标 3）。