Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Mania

描述(申请人提供)：双相躁狂症和抑郁症的特征都是情绪不稳定和明显的行为变化，似乎涉及到前边缘网络(ALN)的功能障碍，ALN是一组涉及情绪调节和调节的大脑区域。功能磁共振成像(FMRI)研究表明，腹外侧额叶皮质(VLPFC)和其他区域的活动增加，调节了参与情绪表达的ALN结构，以抑制躁狂和抑郁的明显表现。情绪性发作代表着这些代偿机制的失败，其标志是VLPFC活性降低，并伴随着杏仁核和部分纹状体的激活增加。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，N-乙酰天冬氨酸是神经元完整性的标志。ALN失调还表现为神经元代谢和磷脂酰肌醇循环(PI-Cycle)的异常，PI-Cycle是具有多个下游神经元效应的第二信使级联。锂在躁狂症和抑郁症中的治疗作用与其对PI周期的作用有关；在行为症状改善之前，通过锂治疗，情感患者肌醇浓度升高的情况会恢复正常。作为赠款R01MH078043的一部分，我们将在基线以及开始服用锂盐后一周和八周内对躁狂症患者进行功能磁共振成像和磁共振波谱(MRS)扫描。在这项修订申请中，我们建议研究抑郁双相情感障碍患者的匹配队列。由于将使用相同的扫描仪和成像方法，我们将能够比较锂治疗对情绪状态的神经化学和神经功能影响，以解决状态与特征相关的变化问题。最后，我们增加了一个探索性的具体目标，使用一种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。考虑到这些考虑，我们在本修订申请中建议：1)使用fMRI和MRS来衡量抑郁和躁狂双相患者以及基线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来衡量锂治疗一周和八周后神经功能和神经代谢指标的变化，目的是精炼情绪状态下锂反应的神经生理学模型，以及3)使用探索性贝叶斯建模方法，识别MRS和fMRI标记物和治疗反应的潜在预测因素。 与公共健康相关：尽管锂可能是世界上使用最广泛的双相情感障碍药物，但锂的神经功能和神经化学效应仍然知之甚少。在这项修订申请中，我们建议在我们正在进行的躁狂患者的fMRI和MRS研究中增加一个抑郁的双相队列，以更好地了解锂跨情绪状态治疗效果的神经化学基础。最终，这些发现可能会导致更有针对性的疗法和更好的锂反应预测。

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.