FUnctional relevance of white matter abnormalities in bipolar DisOrder development

双相情感障碍(BD)是一种高度可遗传的精神障碍，是全球十大致残原因之一，给患者、家庭成员和国家卫生系统带来巨大负担。BD的高遗传率表明，神经生物学机制对BD的发展做出了重大贡献，识别它们将提高早期和更准确诊断的可能性，以及开发有效的预防和干预措施来缓解疾病的病程。然而，我们对BD发生的神经生物学机制的了解仍然不完整。经过20年的研究，BD的神经生物学共识模型已经出现，假设情绪处理和控制网络的结构和功能异常，包括腹侧前额叶皮质和杏仁核作为关键结构。有人提出，这些异常起源于早期白质发育的障碍，例如轴突髓鞘减少和前额叶修剪减少，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患者和患BD的高危健康人中，已经观察到额缘和大脑半球间纤维束中白质完整性的异常，这表明白质异常确实在BD的发展中发挥了作用，并代表了BD的易感性标志。然而，目前研究的一个主要缺陷是，BD患者脑白质完整性降低的发现与功能相关的结果之间缺乏联系，例如预测有利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，这阻碍了我们理解BD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，从脑白质宏观和微观结构以及神经心理功能和情绪调节障碍作为BD的两个标志性特征，仔细描述首发和慢性双相I型障碍患者以及有患BD的健康个体的特征。本研究的总体目标是(1)联系神经生物学和神经心理学方法，从而确定脑白质改变与BD认知功能障碍和情绪调节障碍的相关性；(2)阐明BD患者脑白质异常的机制；(3)阐明脑白质异常和神经心理障碍在BD的发生发展和疾病过程中的作用。

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.