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

雅芳父母和儿童纵向研究（ALSPAC）表明，超过9%的18岁奥尔兹有精神病经历（PE），如幻觉和妄想，由训练有素的心理学家使用严格的标准进行验证。当持续存在时，PE会增加一个人患精神疾病（如精神分裂症）、其他精神疾病（如抑郁症）和不良心理社会后果（如失业）的可能性。随着人们从青春期到成年期的过渡，PE有时会消退，但我们不知道大脑的变化如何在这些年中继续发展和成熟，并影响PE。由于MRC的赠款，我们最近使用磁共振成像（MRI）脑部扫描显示，在20岁以上，患有PE的ALSPAC患者的局部脑容量以及全球和局部连通性发生了微小变化，这不能归因于精神病诊断或药物治疗的后果。我们还表明，来自ALSPAC的个体由于其遗传组成可能会略微增加精神病的风险，（使用由许多基因的贡献制成的“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）也有大脑厚度和体积的微妙变化。我们的目标是重新扫描这些相同的个体，总共有大约450人，年龄在26岁，使用全方位的MRI扫描技术。这将使我们能够测试以下假设：与没有PE的人相比，以及与他们最初的基线扫描相比，持续性PE是由大脑发育的异常途径或轨迹以及功能异常所支撑的。其他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显示持续PE患者的一些下降。我们将利用ALSPAC中全基因组关联研究中最新的精神分裂症遗传风险评分来研究我们的大脑测量作为基因和临床结果之间的中间联系的潜力。最后，我们将观察是否有炎症的血液标志物可以作用于大脑，在同一个人的儿童和成人再次测量，我们将使用位于卡迪夫的功能强大的MRI大脑扫描仪来获得详细的结构图像和灰色和白色物质体积的测量，以及一种称为扩散MRI的特殊扫描变体，它可以量化微观结构。白色物质束的性质--大自然的电线--将脑细胞群连接在一起。功能性核磁共振成像可以检测大脑中在任务中更活跃的部分，将在参与者试图记住一系列字母时以及休息时进行（尽管他们的大脑仍在工作）。这将有助于我们确定PE和结构变化患者大脑中明显的生理损害/补偿程度。这也将帮助我们了解大脑的不同专业部分是如何作为一个连贯的单位一起工作的。该项目将使我们能够绘制年轻人大脑发育的变化，这些年轻人有和没有从ALSPAC中获得的潜在重要精神病经历（PE），ALSPAC是医学科学中研究最充分的流行病学样本之一。因为有如此丰富的信息可用，这意味着当我们分析大脑扫描时，我们可以考虑许多其他因素，这些因素可能会掩盖或错误地夸大PE的影响，如大麻和酒精滥用。该项目作为一个整体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，并帮助指导精神卫生保健的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.