Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Mania

描述(申请人提供)：双相躁狂症的特征是情绪高涨和/或易怒，明显的行为变化，以及似乎与涉及前边缘网络(ALN)的神经功能变化有关的认知缺陷，ALN是一个假设参与情绪调节和调制的大脑网络。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，如杏仁核，以抑制明显的躁狂表现。双相躁狂症代表着这些代偿机制的失败，其显著特征是VLPFC活性降低，伴随而来的是杏仁核和部分纹状体激活的增加，导致情感不稳定和去抑制的增加。互补磁共振波谱(MRS)研究表明，纹状体-前额叶通路中这种活动的增加与前额叶谷氨酸的增加有关，谷氨酸是一种兴奋性神经递质。谷氨酸浓度的增加反过来可能与躁狂症患者前额叶N-乙酰-天冬氨酸(NAA)浓度的降低以及前额叶皮质进行性的形态变化有关。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-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。锂是一种有效的抗躁药，其疗效与其对PI循环的作用有关。A/fyo-inositol(Ml)在服药和未服药的双相躁郁症患者中是正常的，但在躁狂症患者中显著升高。加锂可降低m1，并使依赖PI周期的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，可能与功能改变的逐渐解决有关。相比之下，服用锂的躁狂症患者体内谷氨酸和NAA持续增加。结合成像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的关系。此外，我们将探讨锂引起的早期ML变化的预测价值。考虑到这些考虑，我们建议：1)使用功能磁共振成像和MRS来衡量躁狂症患者和精神分裂症患者以及基线状态的健康对照组之间的神经功能和神经化学差异，以及：2)使用功能磁共振成像和MRS来衡量锂治疗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症的神经生理学模型；识别MRS和fMRI标记物和潜在的治疗反应预测因子。

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.