Functional and neurochemical brain changes in first episode

第一集大脑功能和神经化学变化

• 批准号: 8099705
• 负责人: STEPHEN M STRAKOWSKI
• 金额: $ 17.96万
• 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/8099705
• 关键词: Acute; Address; Affective; Aftercare; Anterior; Antimanic Agents; Area; Behavior; Behavioral; Bipolar Disorder; Brain; Brain region; Brodmann' s area; Choline; Chronic; Cognition; Cognitive; Corpus striatum structure; Development; Disease Progression; Emotional; Energy Metabolism; Exhibits; Financial compensation; Frequencies; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamates; Glycolysis; Goals; Homeostasis; Human; Inositol; Lithium; Magnetic Resonance Spectroscopy; Manic; Measurement; Measures; Metabolic; Metabolism; Mind; Modeling; Mood stabilizers; Moods; N-acetylaspartate; Neurobehavioral Manifestations; Neurons; Onset of illness; Oxidative Phosphorylation; Patients; Pattern; Pharmaceutical Preparations; Phospholipid Metabolism; Prefrontal Cortex; Recurrence; Reporting; Risk; Sampling; Structure; Subgroup; Symptoms; System; Task Performances; Time; Work; cingulate cortex; excitotoxicity; experience; myoinositol; neurochemistry; neurophysiology; neurotoxicity; neurotransmission; olanzapine; prevent; response; response marker; restoration; standard care; treatment response

Bipolar disorder is a dynamic condition with symptomatic fluctuations throughout its course. These fluctuations suggest that bipolar neurophysiology involves dysfunction of brain networks that maintain emotional homeostasis. Human emotional behavior appears to be modulated by ventral prefrontal cortical and subcortical brain regions that form the 'anterior limbic network.' Consequently, we hypothesize that the symptoms of bipolar disorder arise from dysfunction within this network. Specifically, functional imaging (fMRI) studies suggest that the anterior limbic network may be over-activated in bipolar patients, thereby producing the symptoms of this condition. Additionally, magnetic resonance spectroscopy (MRS) studies suggest that this over-activation results from anterior limbic hypermetabolism. Moreover, during mania, MRS studies report elevated glutamate (Glx) concentrations; excessive glutamatergic neurotransmission may underlie the excessive anterior limbic metabolism and activation of bipolar disorder. Bipolar disorder is progressive with increasing episode frequency early in the illness course, leading to an established, recurrent illness. Repeated increases in excitatory neurotransmission associated with manic episodes may cause glutamatergic neurotoxicity, thereby initiating neurophysiologic changes that produce progressive emotional instability. It is not known whether any of the standard treatments for bipolar disorder prevent these changes. Nonetheless, perhaps by decreasing excitatory glutamatergic neurotransmission, these medications might correct the hypothesized excessive anterior limbic activation and hypermetabolism, and diminish the risk of neurotoxicity, thereby preventing disease progression. Studies of early course patients, prior to significant disease progression, are needed to make these determinations. With these consideration in mind, the goals of this study are: 1) To use 1H-MRS to identify neurometabolic abnormalities in bipolar disorder at the time of the first manic episode, and then determine how these abnormalities change in response to lithium and olanzapine treatment; 2) To identify corresponding changes in fMRI brain activation to a cognitive probe (CRT-END) while receiving lithium and olanzapine therapy; and 3) To demonstrate that regional brain activation changes are associated with regional metabolic changes. To accomplish these aims, we will acquire integrated neurometabolic (MRS) and functional neuroanatomic (fMRI) measurements in first-episode manic bipolar and healthy subjects in order to refine neurophysiological models of bipolar disorder (Center goal 1); to identify MRS and fMRI markers of treatment response of acute mania to two mechanistically different medications (Center goal 2); and to identify potential predictors of treatment response for future studies (Center goal 3).

躁郁症是一种动态状况，整个过程中有症状波动。这些 波动表明，双极神经生理学涉及维持大脑网络功能障碍 情绪稳态。人类的情感行为似乎是由腹前额叶皮质调节的 以及构成“前边缘网络”的皮质下大脑区域。因此，我们假设 躁郁症的症状来自该网络中功能障碍。具体而言，功能成像 （fMRI）研究表明，双极患者可能会过度激活前边缘网络，从而 产生这种情况的症状。此外，磁共振光谱（MRS）研究 表明这种过度激活是由前边缘多代谢引起的。而且，在躁狂期间，太太 研究报告说升高的谷氨酸（GLX）浓度；过度谷氨酸能神经传递可能 是前边缘代谢过多和双相情感障碍的激活的基础。 躁郁症是渐进的，随着疾病课程早期发作频率的增加，导致 已建立的复发性疾病。与躁狂相关的兴奋性神经传递的重复增加 发作可能引起谷氨酸能神经毒性，从而启动产生神经生理学的变化 渐进的情绪不稳定。尚不清楚躁郁症是否有任何标准治疗 防止这些变化。尽管如此，也许是通过减少兴奋性谷氨酸能神经传递的方法 这些药物可能会纠正假设的过度前缘激活和超定代谢， 并降低神经毒性的风险，从而预防疾病进展。早期课程的研究 在重大疾病进展之前，患者需要做出这些决定。 考虑到这些考虑，本研究的目标是：1）使用1H-MRS来识别 第一次躁狂发作时，躁郁症的神经代谢异常，然后确定 这些异常如何响应锂和奥氮平治疗而变化； 2）识别 fMRI脑激活对认知探针（CRT末端）的相应变化在接受锂和 奥氮平疗法； 3）证明区域大脑激活的变化与 区域代谢变化。为了实现这些目标，我们将获得综合神经代谢（MRS） 和功能性神经解剖学（fMRI）测量，在第一集躁狂双极和健康受试者中 为了完善躁郁症的神经生理模型（中心目标1）；识别MRS和fMRI 急性躁狂对两种机械上不同药物的治疗反应标记（中心目标2）； 并确定未来研究的治疗反应的潜在预测指标（中心目标3）。