Brain connectivity and the role of myelin in Psychosis

尽管有大量的磁共振成像（MRI）研究支持神经元的连接障碍模型， 精神分裂症，我们对潜在的神经生理机制的理解仍然有限。 髓鞘形成中的缺失是一个合理的候选者，因为髓鞘形成是协调活动所必需的， 支持认知功能和行为的神经网络。此外，髓磷脂相关的病理学长期以来 根据尸检和基因表达证据，髓鞘形成不良 也是精神分裂症神经发育理论的关键组成部分，因为大脑皮层的髓鞘形成 青春期后期和成年早期的关联区域与疾病风险的高峰期一致 发病该应用将利用超高场MRI的强大功能， 算法来检测和量化皮质髓磷脂的方式，从来没有可能的，并测试 髓鞘形成与精神分裂症相关连接障碍的相关性我们提供了皮质内 新近发作的精神分裂症患者的髓鞘异常，并证明其对连接的影响 疾病的严重性。在这个应用程序中，我们提出了一系列的实验，有三个具体的目标。一是 目的是证明我们对精神分裂症相关皮质内髓鞘的初步发现的可重复性 最近发作的精神病患者的独立样本中的变化，并将这些变化与 功能和结构连接体的拓扑特性;我们还将研究功能连接体的拓扑特性。 髓鞘完整性受损与临床特征和认知的相关性（目的1）。其次，我们计划测试 精神分裂症患者2年随访期间髓鞘形成的纵向变化， 研究其与疾病严重程度和病程的相关性（目标2）。第三，我们将测试是否异常， 髓鞘形成与精神分裂症的家族风险有关， 功能和结构连接体和患者的未受影响的兄弟姐妹的认知， 在2年的随访期内（目标3）。包括未受影响的兄弟姐妹也将允许 精神分裂症相关髓鞘异常的研究 药这项研究的结果将为解开机械“黑匣子”提供新的证据， 精神分裂症，并将开辟新的途径，治疗使用干预措施，可能针对髓鞘病理。

Despite the wealth of magnetic resonance imaging (MRI) studies supporting the dysconnectivity model of schizophrenia, our understanding of the underlying neurophysiological mechanisms remains limited. Abnormalities in myelination are a plausible candidate as myelination is essential for the coordinated activity of neural networks that support cognitive function and behaviour. Moreover, myelin-related pathology has long been postulated in schizophrenia on the basis of post-mortem and gene expression evidence. Dys-myelination is also a key component of neurodevelopment theories of schizophrenia because myelination of cortical association areas in late adolescence and early adulthood coincides with the peak period of risk for disease onset. This application will harness the power of ultra-high-field MRI coupled with advanced analyses algorithms to detect and quantify cortical myelin in a way that has never been possible before and test the relevance of myelination for schizophrenia-related dysconnectivity. We provide initial evidence for intracortical myelin abnormalities in patients with recent onset schizophrenia and demonstrate their impact on connectivity and disease severity. In this application, we propose a series of experiments with three specific aims. First, we aim to demonstrate the reproducibility of our initial findings on schizophrenia-related intracortical myelin changes in an independent sample of patients with recent onset psychosis and relate these changes to the topological properties of the functional and structural connectome; we will also examine the functional correlates of compromised myelin integrity on clinical features and cognition (Aim 1). Second, we plan to test for longitudinal changes in myelination in patients with schizophrenia over a 2-year follow-up period and investigate their relevance to disease severity and course (Aim 2). Third, we will test whether abnormalities in myelination are related to familial risk of schizophrenia by investigating intracortical myelin and its effect on the functional and structural connectome and cognition in unaffected siblings of patients, both cross-sectionally and over a 2-year follow-up period (Aim 3). The inclusion of unaffected siblings will also allow for the investigation of myelin-related abnormalities relevant to schizophrenia without the confounding effect of medication. The results of this study will provide novel evidence for unlocking the mechanistic “black box” in schizophrenia and will open new avenues for treatment using interventions that may target myelin pathology.