Longitudinal Imaging Studies in Bipolar Disorder

描述(由申请人提供)：应聘者请求支持一项为期五年的培训和研究计划，以更好地了解双相情感障碍的大脑生化和神经活动是如何改变的。在拟议的培训计划中，候选人将以他以前在基础神经科学研究和临床精神病学方面的经验为基础，在麦克莱恩医院和贝丝-以色列女执事医疗中心执行一个多学科项目。他的培训计划包括：1)在神经递质活性和大脑新陈代谢的活体研究中应用磁共振波谱(MRS)的培训；2)使用功能磁共振成像(FMRI)检查神经网络活动的培训；3)设计和执行以患者为中心的调查的培训；以及4)负责任地进行研究的培训。双相情感障碍的一个显著特征是，它在本质上是间歇性的，看起来是自发地转换到病理状态，然后恢复到欣快感或转换到另一种状态。人们对导致情绪状态不稳定的生物学因素或使情绪状态短暂的过程知之甚少。本研究提出双相情感障碍的病理生理学特征为：1)参与情绪调节的脑区之间原有的异常功能耦合；2)神经传递的代偿性改变。这些变化引发了一系列导致大脑功能不稳定的力量。候选人的研究计划寻求：1)探索双相情感障碍中大脑网络活动和情绪状态之间的关系，2)测试情绪状态转换模型，该模型提出了兴奋性和抑制性神经传递的平衡，可以补偿大脑网络连接中与特征相关的变化。 这项研究建议通过观察大脑网络活动以及测量体内神经递质和神经元活动的标记物来解决这一假设。这些实验将通过躁狂症和欣快症的临床状态纵向在一组双相情感障碍的受试者中进行。在这样做的过程中，这项研究试图最大限度地减少研究这种疾病的许多实质性混淆，包括疾病异质性、诊断不稳定性和药物效应。这项研究的更广泛的目的是了解双相情感障碍状态转换的生理学。这种疾病是一种常见的、使人虚弱的疾病，目前的治疗方法只有部分有效。对状态转换的生理学基础的了解将有助于开发更好的干预措施，以防止病理性转换为躁狂或抑郁。

DESCRIPTION (provided by applicant): The candidate requests support for a five year program of training and research to better understand how brain biochemistry and neural activity are altered in bipolar disorder. In the proposed training program, the candidate will buid upon his previous experience in basic neuroscience research and clinical psychiatry to perform a multidisciplinary project at McLean Hospital and the Beth-Israel Deaconess Medical Center. His training plan includes: 1) training in the application of Magnetic Resonance Spectroscopy (MRS) to in vivo studies of neurotransmitter activity and brain metabolism 2) training in the use of functional Magnetic Resonance Imaging (fMRI) to examine neural network activity 3) training in the design and execution of patient oriented investigation and 4) training in the responsible conduct of research. A hallmark feature of bipolar disorder is that it is episodic in nature with what appear to be spontaneous transitions to pathological states and subsequent reversion to euthymia or transition to another state. There is little understood about the biology that gives rise to this instability in mood state or the processes that make these states transitory. This study proposes that the pathophysiology of bipolar disorder is characterized by: 1) original abnormal functional coupling between the brain regions involved in affective regulation, and 2) compensatory changes in neurotransmission. These alterations set in motion a series of forces that generate instability in brain function. The candidate's research plan seeks to: 1) explore th relationship between brain network activity and mood state in bipolar disorder and 2) test a model of mood state switching that proposes a balance of excitatory and inhibitory neurotransmission that can compensate for trait related alterations in brain network connectivity. This study proposes to address this hypothesis by observing brain network activity as well as measuring neurotransmitters and markers of neuronal activity in vivo. These experiments will be performed in a single cohort of subjects with bipolar disorder longitudinally through clinical states of mania and euthymia. In doing so, this study seeks to minimize many substantial confounds of studying this disorder including disease heterogeneity, diagnostic instability, and medication effects. The broader aim of this research is to understand the physiology of state switching in bipolar disorder. This disorder is a common and debilitating illness and current treatments are only partially effective. An understanding of the physiologic basis of transitions between states will allow the development of better interventions to prevent pathological switching to mania or depression.