Functional and neurochemical brain changes in first episode

双相情感障碍是一个动态的条件与症状波动在整个过程中。这些 波动表明，双相神经生理学涉及大脑网络的功能障碍， 情绪稳态人类的情绪行为似乎是由腹侧前额叶皮层调节的 和皮层下的大脑区域形成了“前边缘网络”。因此，我们假设， 双相情感障碍的症状源于该网络内的功能障碍。具体来说，功能成像 功能磁共振成像（fMRI）研究表明，在双相情感障碍患者中，前边缘网络可能过度激活， 产生了这种症状此外，磁共振波谱（MRS）研究 提示这种过度激活是由前边缘系统代谢亢进引起的。此外，在躁狂症期间，MRS 研究报告谷氨酸（Glx）浓度升高;过量的谷氨酸能神经传递可能 是前边缘系统过度代谢和双相情感障碍激活的基础。 双相情感障碍是渐进的，在病程早期发作频率增加，导致 一种已确定的复发性疾病与躁狂相关的兴奋性神经传递的反复增加 发作可引起多巴胺能神经毒性，从而引发神经生理学变化， 进行性情绪不稳定目前尚不清楚双相情感障碍的标准治疗方法是否 阻止这些变化。尽管如此，也许通过减少兴奋性突触能神经传递， 这些药物可以纠正假设的过度前边缘激活和高代谢， 并降低神经毒性的风险，从而防止疾病进展。早期课程研究 需要患者在显著的疾病进展之前做出这些确定。 基于这些考虑，本研究的目的是：1）使用1H-MRS识别 在第一次躁狂发作时，双相情感障碍的神经代谢异常，然后确定 这些异常在锂和奥氮平治疗后如何变化; 2）确定 接受锂时，fMRI脑激活对认知探针（CRT-END）的相应变化， 奥氮平治疗; 3）证明局部脑激活变化与 局部代谢变化。为了实现这些目标，我们将获得综合神经代谢（MRS） 和功能性神经解剖学（fMRI）的测量，首次发作躁狂双相和健康受试者， 为了完善双相情感障碍的神经生理学模型（中心目标1）;识别MRS和fMRI 急性躁狂症对两种机制不同的药物治疗反应的标志物（中心目标2）; 并为未来的研究确定治疗反应的潜在预测因素（中心目标3）。

Bipolar disorder is a dynamic condition with symptomatic fluctuations throughout its course. These fluctuations suggest that bipolar neurophysiology involves dysfunction of brain networks that maintain emotional homeostasis. Human emotional behavior appears to be modulated by ventral prefrontal cortical and subcortical brain regions that form the 'anterior limbic network.' Consequently, we hypothesize that the symptoms of bipolar disorder arise from dysfunction within this network. Specifically, functional imaging (fMRI) studies suggest that the anterior limbic network may be over-activated in bipolar patients, thereby producing the symptoms of this condition. Additionally, magnetic resonance spectroscopy (MRS) studies suggest that this over-activation results from anterior limbic hypermetabolism. Moreover, during mania, MRS studies report elevated glutamate (Glx) concentrations; excessive glutamatergic neurotransmission may underlie the excessive anterior limbic metabolism and activation of bipolar disorder. Bipolar disorder is progressive with increasing episode frequency early in the illness course, leading to an established, recurrent illness. Repeated increases in excitatory neurotransmission associated with manic episodes may cause glutamatergic neurotoxicity, thereby initiating neurophysiologic changes that produce progressive emotional instability. It is not known whether any of the standard treatments for bipolar disorder prevent these changes. Nonetheless, perhaps by decreasing excitatory glutamatergic neurotransmission, these medications might correct the hypothesized excessive anterior limbic activation and hypermetabolism, and diminish the risk of neurotoxicity, thereby preventing disease progression. Studies of early course patients, prior to significant disease progression, are needed to make these determinations. With these consideration in mind, the goals of this study are: 1) To use 1H-MRS to identify neurometabolic abnormalities in bipolar disorder at the time of the first manic episode, and then determine how these abnormalities change in response to lithium and olanzapine treatment; 2) To identify corresponding changes in fMRI brain activation to a cognitive probe (CRT-END) while receiving lithium and olanzapine therapy; and 3) To demonstrate that regional brain activation changes are associated with regional metabolic changes. To accomplish these aims, we will acquire integrated neurometabolic (MRS) and functional neuroanatomic (fMRI) measurements in first-episode manic bipolar and healthy subjects in order to refine neurophysiological models of bipolar disorder (Center goal 1); to identify MRS and fMRI markers of treatment response of acute mania to two mechanistically different medications (Center goal 2); and to identify potential predictors of treatment response for future studies (Center goal 3).