Longitudinal Imaging Studies in Bipolar Disorder

描述（由申请人提供）：候选人要求支持一个为期五年的培训和研究项目，以更好地了解双相情感障碍患者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，候选人将利用他之前在基础神经科学研究和临床精神病学方面的经验，在麦克莱恩医院和贝斯-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)应用磁共振波谱（MRS）进行体内神经递质活性和脑代谢研究的培训；2)使用功能磁共振成像（fMRI）检查神经网络活动的培训；3)设计和执行面向患者的调查的培训；4)负责任的研究行为的培训。双相情感障碍的一个显著特征是，它在本质上是间歇性的，似乎是自发地过渡到病理状态，随后又恢复到精神状态或过渡到另一种状态。人们对导致这种情绪状态不稳定的生物学原理或使这种状态短暂的过程知之甚少。本研究认为双相情感障碍的病理生理特征是：1)参与情感调节的脑区之间的原始异常功能耦合，2)神经传递的代偿性改变。这些改变引发了一系列的力量，导致了大脑功能的不稳定。该候选人的研究计划旨在：1)探索双相情感障碍患者大脑网络活动与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特征相关的改变。

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.