FUnctional relevance of white matter abnormalities in bipolar DisOrder development

双相情感障碍（BD）是一种高度遗传性的精神障碍，是全世界十大最重要的致残原因之一，给患者、家庭成员和国家卫生系统造成巨大负担。双相障碍的高遗传性表明，神经生物学机制对该疾病的发展有重要贡献，对其进行识别将提高早期和更准确诊断的可能性，并开发有效的预防和干预措施，以减轻疾病的病程。然而，我们对双相障碍发展的神经生物学机制的理解仍然不完整。经过二十年的研究，双相障碍的神经生物学共识模型已经出现，该模型假设情绪处理和控制网络的结构和功能异常，包括作为关键结构的腹侧前额叶皮层和杏仁核。有人提出，这些异常起源于早期白质发育障碍，例如轴突髓鞘形成减少和前额叶修剪减少，这为躁狂或抑郁发作的发展提供了基础，例如，应激生活事件，引发不稳定的生物过程。事实上，在BD患者和BD高风险的健康个体中也观察到额边缘和半球间纤维束白质完整性异常，这表明白质异常确实在BD的发展中发挥了作用，并且是BD的易感性标志。当前研究的一个主要缺点是缺少BD患者白质完整性降低的发现与功能相关结果之间的联系，例如预测良好就业结果和恢复率的神经心理功能。另一个缺点是缺乏对DTI结果的组织学理解，这使我们无法理解双相障碍中白质改变的分子机制。为了克服这些限制，本项目将通过先进的扩散张量成像方法，以及神经心理功能和情绪失调作为两个标志，仔细描述首发和慢性双相i型障碍患者以及有患双相障碍风险的健康个体的白质宏观和微观结构本研究的总体目标是：(1)将神经生物学和神经心理学测量相关联，从而确定双相障碍患者认知功能紊乱和情绪失调与白质改变的相关性；(2)阐明BD患者白质异常的机制；(3)明确白质异常和神经心理障碍在双相障碍的发生和病程中的作用。

Bipolar disorder (BD) is a highly heritable mental disorder that ranks amongst the ten most significant reasons of disability worldwide and that causes immense burden on patients, family members and national health systems. The high heritability of BD suggests a major contribution of neurobiological mechanisms to the development of the disorder and their identification would improve possibilities of earlier and more accurate diagnosis as well as the development of effective preventions and interventions to alleviate the course of the disease. However, our understanding of the neurobiological mechanisms underlying BD development, are still incomplete. From two decades of research a neurobiological consensus model of BD has emerged, assuming abnormalities in the structure and function of an emotional processing and control network, including as key structures the ventral prefrontal cortex and the amygdala. It has been proposed that these abnormalities origin from disturbances in early white matter development, e.g., reduced myelination of axons and reduced prefrontal pruning, providing a basis for the development of manic or depressive episodes in the light of, e.g., stressful life events, triggering unstable biological processes. Indeed, abnormalities in white matter integrity in fronto-limbic and inter-hemispheric fiber tracts have been observed in BD patients and also in healthy individuals at higher risk to develop BD, suggesting that white matter abnormalities indeed play a role in the development of the disorder and represent a vulnerability marker of BD. However, one major shortcoming of current research is the missing link between findings of reduced white matter integrity in BD patients and functionally relevant outcomes, such as neuropsychological functioning that predicts, for example, favorable employment outcomes and recovery rates. Another shortcoming is the lack of histological understanding of the DTI results, which precludes us from understanding the molecular mechanisms of white matter alterations in BD. To overcome these limitations the present project will carefully characterize first-episode and chronic patients with bipolar-I disorder as well as healthy individuals at risk to develop BD with respect to white matter macro- and microstructure by means of advanced diffusion tensor imaging methods and with respect to neuropsychological functioning as well as emotional dysregulation as two hallmark features of BD. The overarching goals of the present study are (1) to relate neurobiological and neuropsychological measures and thereby to determine the relevance of white matter alterations for disturbed cognitive functioning and emotional dysregulation in BD; (2) to elucidate on mechanisms underlying white matter abnormalities in BD patients; (3) to delineate the role of white matter abnormalities and neuropsychological impairments in the development of BD and in the course of the disease.