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: 7866599
• 负责人: Caleb M Adler
• 金额: $ 35.01万
• 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/7866599
• 关键词: Affective; Amygdaloid structure; Anterior; Antimanic Agents; Behavioral; Behavioral Symptoms; Brain; Chemicals; Cognitive; Cognitive deficits; Corpus striatum structure; Disinhibition; Emotional; Exhibits; Failure; Functional Magnetic Resonance Imaging; Glutamates; Goals; Inositol; Irritable Mood; Link; Lithium; Magnetic Resonance Spectroscopy; Manic; Measurement; Measures; Metabolism; Mind; Modeling; N-acetylaspartate; Neurons; Neurotransmitters; Pathway interactions; Patients; Performance; Phosphatidylinositols; Predictive Value; Prefrontal Cortex; Regulation; Resolution; Second Messenger Systems; Structure; Symptoms; Task Performances; Therapeutic Effect; imaging modality; improved; neurochemistry; neurophysiology; response; second messenger; showing emotion; treatment response

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）：双相躁狂的特征是情绪升高和/或烦躁症状、明显的行为改变和认知缺陷，这些缺陷似乎与涉及前边缘网络（ALN）的神经功能变化有关，前边缘网络是一种假设参与情绪调节和调制的大脑网络。功能性 MRI (fMRI) 研究表明，腹外侧前额叶皮层 (VLPFC) 和其他区域的活动增加可以调节参与情绪表达的 ALN 结构，例如杏仁核，从而抑制躁狂的明显表现。双相躁狂代表这些代偿机制的失败，其特征是 VLPFC 活性降低，同时杏仁核和纹状体部分的激活增加，导致情感不稳定性和去抑制增加。补充磁共振波谱（MRS）研究表明，纹状体前额叶通路活性的增加与前额叶谷氨酸（一种兴奋性毒性神经递质）的增加有关。谷氨酸浓度的增加可能与前额叶 N-乙酰天门冬氨酸 (NAA) 浓度的降低有关，NAA 是躁狂患者神经元完整性的标志，也与前额叶皮层的进行性形态变化有关。 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 循环）的异常，磷脂酰肌醇循环是具有多种下游神经元效应的第二信使级联反应。锂是一种有效的抗躁狂剂，其治疗效果与其对 Pi 循环的作用有关。 A/fyo-肌醇（ml）的浓度在药物治疗和未药物治疗的正常双相情感障碍患者中均正常，但在躁狂患者中显着升高。锂给药可降低 ml，并使 Pi 周期依赖性第二信使系统的其他成分正常化。此外，锂对毫升浓度的影响先于行为症状的改善，并且可能与功能变化的逐渐解决有关。相比之下，接受锂治疗的躁狂患者的谷氨酸和 NAA 持续增加。结合成像方式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，以及锂与双相情感障碍标志物之间的关系。此外，我们将探讨早期锂引起的毫升变化的预测价值。考虑到这些因素，我们建议：1) 使用 fMRI 和 MRS 测量躁狂患者和正常患者以及健康对照组之间的神经功能和神经化学差异，以及：2) 使用 fMRI 和 MRS 测量锂治疗 1 周和 8 周后神经功能和神经代谢指标的变化，目的是完善双相躁狂的神经生理学模型；识别 MRS 和功能磁共振成像标记以及治疗反应的潜在预测因子。