Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Mania

双相躁狂治疗反应的神经功能和神经化学标志物

• 批准号: 7260697
• 负责人: Caleb M Adler
• 金额: $ 36.08万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-14 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260697
• 关键词: Acute; Affect; Affective; Amygdaloid structure; Anterior; Antimanic Agents; Attention; Behavioral; Behavioral Symptoms; Bipolar Disorder; Brain; Brain region; Chemicals; Clinical; Cognitive; Cognitive deficits; Concentration measurement; Condition; Control Groups; Corpus striatum structure; Data; Decision Making; Defect; Depressed mood; Development; Disease Marker; Disease remission; Disinhibition; Dorsal; Dose; Elements; Emotional; Event; Exhibits; Failure; Feedback; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Glutamine; Glycolysis; Goals; Image; Impairment; Individual; Inositol; Intervention; Invasive; Irritable Mood; Label; Lead; Link; Lithium; Localized; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manic; Measurement; Measures; Medial; Metabolic; Metabolic Marker; Metabolism; Mind; Mitochondria; Modality; Modeling; Mood Disorders; Mood stabilizers; Moods; Morbidity - disease rate; N-acetylaspartate; Neurons; Neuropathy; Neurotransmitters; Oxidative Phosphorylation; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Phase; Phosphatidylinositols; Phosphocreatine; Play; Population; Predictive Value; Prefrontal Cortex; Principal Investigator; Productivity; Rate; Recruitment Activity; Regulation; Research Personnel; Resolution; Role; Scanning; Second Messenger Systems; Short-Term Memory; Source; Structure; Symptoms; System; Task Performances; Techniques; Temporal Lobe; Thalamic structure; Therapeutic; Therapeutic Effect; Thinking; Time; United States Food and Drug Administration; Week; cingulate gyrus; executive function; improved; in vivo; mitochondrial dysfunction; mortality; neurochemistry; neuroimaging; neuropathology; neurophysiology; neurotoxic; neurotransmission; phosphomonoester; programs; psychosocial; response; second messenger; showing emotion; treatment effect; uptake

DESCRIPTION (provided by applicant): Bipolar mania is characterized by elevated and/or irritable mood symptoms, marked behavioral changes, and cognitive deficits that appears to be linked to neurofunctional changes involving the anterior limbic network (ALN), a brain network hypothesized to be involved in emotional regulation and modulation. Functional MRI (fMRI) studies suggest that increased activity in the ventrolateral prefrontal cortex (VLPFC) and other regions modulates ALN structures involved in emotional expression, such as the amygdala, to inhibit overt manifestations of mania. Bipolar mania represents a failure of these compensatory mechanisms, and is marked by decreased VLPFC activity and concomitant increases in activation of the amygdala and portions of the striatum, leading to increased affective lability and disinhibition. Complementary magnetic resonance spectroscopy (MRS) studies suggest that this increased activity in striatal-prefrontal pathways is associated with increased prefrontal glutamate, an excitotoxic neurotransmitter. Increased concentrations of glutamate may, in turn be related to decreased concentrations of prefrontal N-acetyl-aspartate (NAA), a marker of neuronal integrity in manic patients, as well as for progressive morphologic changes in the prefrontal cortex. MRS studies further suggest that ALN dysregulation is accompanied by abnormalities in neuronal metabolism and of the phosphatidylinositol cycle (Pi-cycle), a second messenger cascade with multiple downstream neuronal effects. The therapeutic effects of lithium, an effective antimanic agent, have been linked to its actions on the Pi-cycle. Concentrations of A/fyo-inositol (ml), which are normal in medicated and unmedicated euthymic bipolar patients, are significantly elevated in patients with mania. Lithium administration decreases ml, and normalizes other components of Pi-cycle dependent second messenger systems. Furthermore, lithium effects on ml concentrations precede amelioration of behavioral symptoms and may be related to the gradual resolution of functional changes. In contrast, increased glutamate and NAA persist in manic patients receiving lithium. Combining imaging modalities to study the effects of lithium will improve our understanding of treatment- related changes in neurofunctional and chemical abnormalities observed in mania, and the relationship between lithium and markers of bipolar symptomatology. Furthermore, we will explore the predictive value of early lithium-induced changes in ml. With these considerations in mind, we propose to: 1) Use fMRI and MRS to measure neurofunctional and neurochemical differences between manic and euthymic patients, and healthy controls at baseline, and: 2) Use fMRI and MRS to measure changes in neurofunctional and neurometabolic measures after 1 & 8 weeks of lithium treatment, with the goal of refining neurophysiological models of bipolar mania; identifying MRS and fMRI markers and potential predictors of treatment response.

描述（由申请人提供）：双相躁狂症的特征是情绪症状升高和/或易怒，明显的行为改变和认知缺陷，似乎与涉及前边缘网络（ALN）的神经功能改变有关，前边缘网络是一个假设参与情绪调节和调节的大脑网络。功能性磁共振成像（fMRI）研究表明，腹外侧前额叶皮层（VLPFC）和其他区域活动的增加调节了参与情绪表达的ALN结构，如杏仁核，以抑制躁狂的明显表现。双相躁狂代表了这些代偿机制的失败，其特征是VLPFC活性降低，杏仁核和部分纹状体的激活随之增加，导致情感不稳定性和去抑制性增加。互补磁共振波谱（MRS）研究表明，纹状体-前额叶通路活动的增加与前额叶谷氨酸（一种兴奋毒性神经递质）的增加有关。谷氨酸浓度升高可能反过来与前额叶n -乙酰-天冬氨酸（NAA）浓度降低有关，NAA是躁狂患者神经元完整性的标志，也是前额叶皮层进行性形态学改变的标志。MRS研究进一步表明，ALN失调伴随着神经元代谢和磷脂酰肌醇循环（Pi-cycle）的异常，Pi-cycle是具有多种下游神经元效应的第二信使级联。锂是一种有效的抗躁剂，其治疗效果与其对pi循环的作用有关。A/fyo-肌醇（ml）的浓度在服药和未服药的心境型双相患者中是正常的，在躁狂症患者中显著升高。锂的使用降低了ml，并使pi循环依赖的第二信使系统的其他成分正常化。此外，锂离子对ml浓度的影响先于行为症状的改善，可能与功能变化的逐渐消退有关。相反，在接受锂治疗的躁狂患者中，谷氨酸和NAA持续升高。结合影像学方法研究锂的影响将提高我们对躁狂症中观察到的神经功能和化学异常的治疗相关变化的理解，以及锂与双相症状标志物之间的关系。此外,我们将探索早期lithium-induced变化的预测价值毫升。考虑到这些因素,我们建议:1)使用功能磁共振成像和测量neurofunctional夫人和神经化学躁狂和euthymic患者之间的差异和健康对照组基线,和:2)使用功能磁共振成像和测量neurofunctional变化和夫人neurometabolic措施1 &锂治疗8周后,用精炼的神经生理学模型双相躁狂的目标;识别MRS和fMRI标记物和治疗反应的潜在预测因子。