U of Cincinnati Bipolar Disorder Imaging & Treatment Research Center (BITREC)

描述（由申请人提供）：双相情感障碍是一种动态状态，在整个过程中症状波动。这些波动表明双相神经生理学涉及维持情绪稳态的大脑网络功能障碍。人类的情绪行为似乎是由形成“前边缘网络”的前额叶皮层腹侧和皮层下大脑区域调节的。因此，我们假设双相情感障碍的症状是由这个网络中的功能障碍引起的。具体来说，功能成像（fMRI）研究表明，双相患者的前边缘网络可能过度激活，从而产生这种情况的症状。此外，磁共振波谱（MRS）研究表明，这种过度激活是由前边缘代谢过度引起的。此外，在躁狂期间，MRS研究报告谷氨酸（Glx）浓度升高；过度的谷氨酸能神经传递可能是过度的前边缘代谢和双相情感障碍激活的基础。双相情感障碍是进行性的，在病程早期发作频率增加，导致一个确定的，反复发作的疾病。与躁狂发作相关的兴奋性神经传递的反复增加可引起谷氨酸能神经毒性，从而引发神经生理变化，产生进行性情绪不稳定。目前尚不清楚双相情感障碍的标准治疗方法是否能预防这些变化。尽管如此，也许通过减少兴奋性谷氨酸能神经传递，这些药物可能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。需要对早期病程患者进行研究，在重大疾病进展之前，才能做出这些决定。考虑到这些因素，本研究的目标是：1)使用1H-MRS识别双相情感障碍患者首次躁狂发作时的神经代谢异常，然后确定这些异常在锂和奥氮平治疗后的变化；2)观察锂+奥氮平治疗时脑功能磁共振成像（fMRI）对认知探针（CRT-END）激活的相应变化；3)证明脑区域激活变化与区域代谢变化相关。为了实现这些目标，我们将在首发躁狂双相情感障碍和健康受试者中获得综合神经代谢（MRS）和功能神经解剖学（fMRI）测量，以完善双相情感障碍的神经生理模型（中心目标1）；鉴定急性躁狂症患者对两种机制不同的药物治疗反应的MRS和fMRI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）。

DESCRIPTION (provided by applicant): 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).