Mapping Neurodevelopmental Trajectories for Adult Psychiatric Disorder: ALSPAC-MRI-II

雅芳父母与儿童纵向研究（ALSPAC）表明，超过9%的18岁青少年有幻觉和妄想等精神病经历（pe），经过训练有素的心理学家验证，并使用严格的标准。如果持续存在，pe会增加一个人患上精神分裂症等精神障碍、其他精神疾病（如抑郁症）和失业等不良社会心理后果的可能性。pe有时会随着人们从青春期进入成年期而消退，但我们不知道大脑的变化是如何在这些年里继续发育和成熟的，这是pe的基础和影响。多亏了MRC的资助，我们最近使用磁共振成像（MRI）脑部扫描显示，在20岁以上的年龄，患有pe的ALSPAC个体在区域脑容量和全球和局部连通性方面有微小的变化，这不能归因于有精神病诊断或药物治疗的后果。我们还表明，来自ALSPAC的个体，由于他们的基因构成（使用由许多基因的贡献组成的“风险评分”，当这些基因加在一起时，与精神分裂症的小但显着增加的风险相关）可能有轻微的精神病风险增加，他们的大脑厚度和体积也有微妙的变化。我们的目标是重新扫描这些人，总共约450人，在26岁时使用全套MRI扫描技术。这将使我们能够验证这样的假设，即与没有pe的患者相比，持续性pe是由大脑发育的异常路径或轨迹以及功能异常所支撑的。额外的目标是绘制认知变化（使用智商测试），我们预计这些变化可能会在持续性pe患者中显示出一些下降。我们将利用ALSPAC提供的全基因组关联研究中最新的精神分裂症遗传风险评分，来检验我们的大脑测量方法作为基因和临床结果之间的中间联系的潜力。最后，我们将看看是否血液中的炎症标记物可以作用于大脑，在同一个人身上测量，当他们是儿童和成人时，也许可以解释我们在核磁共振成像上看到的大脑变化。我们将使用位于卡迪夫的强大的MRI脑部扫描仪来获得详细的结构图像和灰质和白质体积的测量，以及一种称为扩散MRI的特殊扫描变体，它可以量化白质束的微观特性-自然的电线-将脑细胞群连接在一起。功能性核磁共振成像（Functional MRI）会在参与者试图记住一串字母的时候以及他们休息的时候（尽管他们的大脑仍在工作）进行，它会捕捉到在任务中更活跃的大脑部分。这将有助于我们确定pe和结构改变患者大脑中明显的生理妥协/代偿程度。这也将帮助我们了解大脑的不同专门部分是如何作为一个连贯的单位一起工作的。这个项目将使我们能够绘制出有或没有潜在重要精神病经历（pe）的年轻人的大脑发育变化图，这些经历来自ALSPAC，这是医学科学中研究得最充分的流行病学样本之一。因为有如此丰富的可用信息，这意味着当我们分析大脑扫描时，我们可以考虑到许多其他因素，这些因素可能会掩盖或错误地夸大pe的影响，比如大麻和酒精滥用。作为一个整体，该项目有可能促进我们对精神病和相关疾病的生物学基础的理解，并有助于指导精神卫生保健初级预防和早期干预战略的发展。

The Avon Longitudinal Study of Parents and Children (ALSPAC) has shown that over 9% of 18 year olds have psychotic experiences (PEs) such as hallucinations and delusions, verified by trained psychologists and using strict criteria. When persistent, PEs increase the likelihood of a person developing psychotic disorders such as schizophrenia, other psychiatric conditions (eg depression) and poor psychosocial outcomes such as unemployment. PEs can sometimes recede as people pass from adolescence to adulthood but we don't know how changes in the brain, which continues to develop and mature through these years, underlie and affect PEs. Thanks to grants from the MRC, we have recently shown, using magnetic resonance imaging (MRI) brain scans, that at age 20+, individuals from ALSPAC with PEs have small changes in regional brain volumes, and global and local connectivity which cannot be ascribed to the consequences of having a psychiatric diagnosis or treatment with medication. We have also shown that individuals from ALSPAC who may be at a slightly increased risk of psychosis due to their genetic makeup (using a 'risk score' made out of the contribution of the many genes which when added together, are associated with a small but significantly increased risk of schizophrenia) also have subtle changes in brain thickness and volume.Our objective is to re-scan these same individuals, numbering about 450 in total, at age 26 using the full range of MRI scanning techniques. This will enable us to test the hypothesis that persistent PEs are underpinned by anomalous pathways or trajectories of brain development and abnormalities in function, as compared with those without PEs and against their original baseline scans. Additional objectives are to plot changes in cognition (using IQ tests) that we expect might show some decline in those with persistent PEs. We will make use of the latest genetic risk score for schizophrenia from genome-wide association studies available in ALSPAC to examine the potential of our brain measures to be used as intermediate links between genes and clinical outcomes. Finally we will see if blood markers of inflammation which can act on the brain, measured in the same individuals when they were children and again when adults, might explain the brain changes we see on MRI.We will use a powerful MRI brain scanner located in Cardiff to obtain detailed structural images and measures of grey and white matter volumes and a particular variant of scanning called diffusion MRI that quantifies the microscopic properties of white matter tracts - nature's wires - that connect together groups of brain cells. Functional MRI, which picks up those parts of the brain that are more active during a task, will be carried out while participants are trying to remember a sequence of letters and also while they are at rest (although their brains will still be working). This will help us to determine the degree of physiological compromise/compensation evident in the brain in those with PEs and structural changes. This will also help us look at how the different specialised parts of the brain are working together as a coherent unit. This project will enable us to map the change in brain development in young people with and without potentially important psychotic experiences (PEs) taken from ALSPAC, one of the most well-studied epidemiological samples available to medical science. Because there is such a wealth of information available, it means that when we analyse the brain scans we can take into account lots of other factors that might otherwise obscure or falsely exaggerate the effects of PEs such as cannabis and alcohol misuse. The project as a whole has the potential to advance our understanding of the biological basis of psychotic and related disorders and to help guide the development of primary prevention and early intervention strategies in mental health care.