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: 8090343
• 负责人: Caleb M Adler
• 金额: $ 34.66万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090343
• 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/或易怒症状、明显的行为变化和认知缺陷，似乎与涉及前边缘网络（ALN）的神经功能变化有关，ALN是一种假设参与情绪调节和调制的脑网络。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，以抑制躁狂症的明显表现。双相躁狂代表这些代偿机制的失败，并且以VLPFC活性降低和伴随的杏仁核和纹状体部分激活增加为特征，导致情感不稳定性和去抑制增加。互补磁共振波谱（MRS）研究表明，这种纹状体-前额叶通路活动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反过来与前额叶N-乙酰天冬氨酸（NAA）浓度的降低有关，NAA是躁狂患者神经元完整性的标志物，也是前额叶皮质进行性形态学变化的标志物。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，这是一种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，其治疗作用与其对Pi循环的作用有关。A/fyo-肌醇的浓度（ml），这是正常的药物和未用药的正常双相情感患者，是显著升高躁狂患者。锂管理减少ml，并正常化的PI循环依赖性第二信使系统的其他组件。此外，锂对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。相比之下，增加谷氨酸和NAA持续躁狂患者接受锂。结合影像学方法研究锂的作用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以及锂与双相情感障碍标志物之间关系的理解。此外，我们将探讨早期锂诱导的ml变化的预测价值。考虑到这些因素，我们建议：1）使用fMRI和MRS测量躁狂和正常心境患者与健康对照组之间基线时的神经功能和神经化学差异; 2）使用fMRI和MRS测量锂治疗1 & 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模型;鉴定MRS和fMRI标记物和治疗反应的潜在预测因子。

项目成果

Correlations of inflammatory gene pathways, corticolimbic functional activities, and aggression in pediatric bipolar disorder: a preliminary study.

• DOI: 10.1016/j.pscychresns.2014.07.009
• 发表时间: 2014-11-30
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Barzman D;Eliassen J;McNamara R;Abonia P;Mossman D;Durling M;Adler C;DelBello M;Lin PI
• 通讯作者: Lin PI