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: 7834016
• 负责人: Caleb M Adler
• 金额: $ 73.01万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7834016
• 关键词: 1,2-diacylglycerol; Acute; Address; Affect; Affective; Amygdaloid structure; Anterior; Area; Attention; Behavioral; Behavioral Symptoms; Bipolar Depression; Bipolar Disorder; Brain region; Calcium; Clinical; Clinical Data; Clinical Markers; Cognitive; Control Groups; Corpus striatum structure; Coupled; Data; Data Analyses; Data Set; Defect; Diagnostic; Diglycerides; Dorsal; Dose; Emotional; Enzymes; Exhibits; Failure; Feedback; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Glycolysis; Goals; Grant; Hydrolysis; Image; Indium-111; Individual; Inositol; Intervention; Lead; Link; Lithium; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Manic; Measurement; Measures; Medial; Mediating; Metabolic; Metabolic Marker; Metabolism; Methodology; Mind; Mitochondria; Modeling; Mood stabilizers; Moods; Morbidity - disease rate; Multimodal Imaging; N-acetylaspartate; Neurons; Neuropathy; Oxidative Phosphorylation; Patients; Pattern; Performance; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphocreatine; Population; Predictive Value; Prefrontal Cortex; Procedures; Process; Property; Protein Kinase C; Recruitment Activity; Regulation; Research Personnel; Resolution; Scanning; Second Messenger Systems; Short-Term Memory; Source; Statistical Models; Stream; Structure; Symptoms; System; Systems Biology; Task Performances; Techniques; Temporal Lobe; Thalamic structure; Therapeutic; Therapeutic Effect; Time; Upper arm; cingulate gyrus; clinical efficacy; clinically significant; cohort; depressed; depression; depressive symptoms; executive function; experience; imaging modality; improved; mitochondrial dysfunction; mortality; neurochemistry; neurophysiology; neurotoxicity; parent grant; phosphomonoester; predictive modeling; psychosocial; public health relevance; receptor binding; response; second messenger; showing emotion; symptomatic improvement; trait; treatment response; tripolyphosphate; uptake

DESCRIPTION (provided by applicant): Both bipolar mania and depression are characterized by mood instability and marked behavioral changes that appear to involve dysfunction of the anterior limbic network (ALN), a group of brain regions 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 to inhibit overt manifestations of mania and depression. Affective episodes represent a failure of these compensatory mechanisms, marked by decreased VLPFC activity and concomitant increases in activation of the amygdala and portions of the striatum. These neurofunctional changes are accompanied by a spectrum of neurochemcial changes including increased prefrontal glutamate and decreased concentrations of prefrontal N-acetyl-aspartate a marker of neuronal integrity. ALN dysregulation is also marked 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 in both mania and depression have been linked to its actions on the PI-cycle; elevated concentrations of myo-inositol in affective patients are normalized with lithium treatment prior to amelioration of behavioral symptoms. As part of grant R01MH078043 we are obtaining fMRI and magnetic resonance spectroscopy (MRS) scans from manic patients at baseline, as well as one and eight weeks after beginning lithium. In this Revision Application, we propose to study a matched cohort of depressed bipolar patients. Because identical scanners and imaging methodologies will be employed, we will be able to compare neurochemical and neurofunctional effects of lithium treatment across mood state to address issues of state- vs. trait-related changes. Finally, we have added an exploratory specific aim to use a newer, systems biology approach to exploring the predictive value of baseline findings and early lithium effects. With these considerations in mind, we propose in this Revision Application to: 1) Use fMRI and MRS to measure neurofunctional and neurochemical differences between depressed and manic bipolar patients, and healthy controls at baseline, 2) Use fMRI and MRS to measure changes in neurofunctional and neurometabolic measures after one and eight weeks of lithium treatment, with the goal of refining neurophysiological models of lithium response across mood states, and 3) Identify MRS and fMRI markers and potential predictors of treatment response, using an exploratory Bayesian modeling methodology. PUBLIC HEALTH RELEVANCE: Although it is perhaps the most widely used bipolar medication in the world, the neurofunctional and neurochemical effects of lithium remain poorly understood. In this Revision Application we are proposing to add a depressed bipolar cohort to our ongoing fMRI and MRS study of manic patients to better understand the neurochemistry underlying the therapeutic effects of lithium across mood state. Ultimately, these findings could lead to more focused therapeutics and better predictors of lithium response.

描述（由申请人提供）：躁郁症和抑郁症的特征都是情绪不稳定和明显的行为变化，这些变化似乎涉及前边缘网络（ALN）的功能障碍，ALN 是一组涉及情绪调节和调节的大脑区域。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，从而抑制躁狂和抑郁的明显表现。情感发作代表这些代偿机制的失败，其特征是 VLPFC 活性降低，并伴随杏仁核和部分纹状体激活的增加。这些神经功能变化伴随着一系列神经化学变化，包括前额叶谷氨酸增加和前额叶 N-乙酰-天冬氨酸浓度降低（神经元完整性的标志）。 ALN 失调还以神经元代谢和磷脂酰肌醇循环（PI 循环）异常为标志，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。锂对躁狂症和抑郁症的治疗作用与其对 PI 循环的作用有关。在改善行为症状之前，通过锂治疗可以使情感患者体内升高的肌醇浓度恢复正常。作为 R01MH078043 拨款的一部分，我们正在获取躁狂患者基线以及开始锂治疗后 1 周和 8 周的功能磁共振成像 (fMRI) 和磁共振波谱 (MRS) 扫描。在此修订申请中，我们建议研究一组匹配的抑郁双相情感障碍患者。由于将采用相同的扫描仪和成像方法，我们将能够比较锂治疗在不同情绪状态下的神经化学和神经功能效应，以解决状态与特质相关变化的问题。最后，我们增加了一个探索性的具体目标，即使用更新的系统生物学方法来探索基线发现和早期锂效应的预测价值。考虑到这些因素，我们在此修订申请中建议：1) 使用 fMRI 和 MRS 测量抑郁症和躁狂双相情感障碍患者与健康对照组之间的神经功能和神经化学差异，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，目标是完善锂盐反应的神经生理学模型。 情绪状态，以及 3) 使用探索性贝叶斯建模方法识别 MRS 和 fMRI 标记以及治疗反应的潜在预测因子。 公众健康相关性：尽管锂可能是世界上使用最广泛的双相情感障碍药物，但人们对锂的神经功能和神经化学作用仍知之甚少。在此修订申请中，我们建议在我们正在进行的躁狂患者 fMRI 和 MRS 研究中添加抑郁双相情感障碍队列，以更好地了解锂在不同情绪状态下的治疗效果背后的神经化学。最终，这些发现可能会带来更有针对性的治疗方法和更好的锂反应预测因子。