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

绘制成人精神疾病的神经发育轨迹：ALSPAC-MRI-II

• 批准号: MR/S003436/1
• 负责人: Anthony David
• 金额: $ 236.26万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS003436%2F1
• 关键词: Mapping; Neurodevelopmental; Trajectories; Adult; Psychiatric

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.

雅芳家长和儿童纵向研究(ALSPAC)显示，超过9%的18岁青少年有过幻觉和妄想等精神错觉(PE)，经过训练有素的心理学家的验证，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障碍(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。当人们从青春期到成年期时，PES有时会消退，但我们不知道大脑的变化是如何影响和支撑PES的，大脑在这些年里继续发育和成熟。多亏了MRC的资助，我们最近使用磁共振成像(MRI)脑扫描显示，在20岁以上的ALSPAC患者中，患有PES的人的局部脑体积以及全局和局部连接都有微小的变化，这不能归因于进行精神诊断或药物治疗的后果。我们还发现，来自ALSPAC的个体由于他们的基因构成(使用由许多基因共同作用而产生的风险分数，当这些基因加在一起时，与患精神分裂症的风险小但显著增加相关)可能会有轻微的精神病风险增加，也有细微的大脑厚度和体积变化。我们的目标是在26岁时使用全面的MRI扫描技术重新扫描这些人，总共约450人。这将使我们能够测试这一假设，即与没有PES的人和他们最初的基线扫描相比，持续性PES是由大脑发育和功能异常的异常路径或轨迹支撑的。其他目标是绘制认知变化的图表(使用智商测试)，我们预计这些变化可能会显示出持续性PE患者的一些下降。我们将利用ALSPAC中可用的全基因组关联研究中最新的精神分裂症遗传风险得分，来检查我们的大脑指标作为基因和临床结果之间的中间联系的潜力。最后，我们将看看可以作用于大脑的炎症血液标志物是否可以解释我们在加的夫看到的大脑变化。我们将使用位于加的夫的一台强大的MRI脑扫描仪来获得详细的结构图像和灰质和白质体积的测量，以及一种特定的扫描变体，称为扩散MRI，它可以量化连接脑细胞组的白质束--自然的导线--的微观属性。当参与者试图记住字母序列时以及在休息时(尽管他们的大脑仍在工作)，就会进行功能磁共振成像，它会捕捉到任务中大脑中比较活跃的部分。这将帮助我们确定在那些有PE和结构改变的人的大脑中明显的生理妥协/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元一起工作的。这个项目将使我们能够绘制出有和没有潜在重要精神病经历(PES)的年轻人的大脑发育变化图，ALSPAC是医学上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，否则可能会模糊或错误地夸大PE的影响，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障碍和相关障碍的生物学基础的了解，并有助于指导精神卫生保健一级预防和早期干预战略的制定。

项目成果

Variant connective tissue (joint hypermobility) and its relevance to depression and anxiety in adolescents: a cohort-based case-control study.

变异结缔组织（关节活动过度）及其与青少年抑郁和焦虑的关系：一项基于队列的病例对照研究。

• DOI: 10.1136/bmjopen-2022-066130
• 发表时间: 2022-11-30
• 期刊: BMJ open
• 影响因子: 2.9

The impact of cumulative obstetric complications and childhood trauma on brain volume in young people with psychotic experiences.

• DOI: 10.1038/s41380-023-02295-6
• 发表时间: 2023-09
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Merritt, Kate;Laguna, Pedro Luque;Sethi, Arjun;Drakesmith, Mark;Ashley, Sarah A.;Bloomfield, Michael;Fonville, Leon;Perry, Gavin;Lancaster, Tom;Dimitriadis, Stavros I.;Zammit, Stanley;Evans, C. John;Lewis, Glyn;Kempton, Matthew J.;Linden, David E. J.;Reichenberg, Abraham;Jones, Derek K.;David, Anthony S.
• 通讯作者: David, Anthony S.

Longitudinal Structural MRI Findings in Individuals at Genetic and Clinical High Risk for Psychosis: A Systematic Review.

精神病遗传和临床高风险个体的纵向结构 MRI 结果：系统评价。

• DOI: 10.3389/fpsyt.2021.620401
• 发表时间: 2021
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Merritt K;Luque Laguna P;Irfan A;David AS
• 通讯作者: David AS

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

• DOI: 10.1038/s41380-023-01991-7
• 发表时间: 2023-05
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Merritt, Kate;McCutcheon, Robert;Aleman, Andre;Ashley, Sarah;Beck, Katherine;Block, Wolfgang;Bloemen, Oswald J. N.;Borgan, Faith;Boules, Christiana;Bustillo, Juan R.;Capizzano, Aristides;Coughlin, Jennifer Q.;David, Anthony;de la Fuente-Sandoval, Camilo;Demjaha, Arsime;Dempster, Kara;Do, Kim;Du, Fei E.;Falkai, Peter;Galinska-Skok, Beata;Gallinat, Juergen;Gasparovic, Charles;Ginestet, Cedric E.;Goto, Naoki;Graff-Guerrero, Ariel;Ho, Beng-Choon;Howes, Oliver;Jauhar, Sameer;Jeon, Peter;Kato, Tadafumi;Kaufmann, Charles A.;Kegeles, Lawrence S.;Keshavan, Matcheri S.;Kim, Sang-Young;King, Bridget;Kunugi, Hiroshi;Lauriello, J.;Leon-Ortiz, Pablo;Liemburg, Edith;Mcilwain, Meghan;Modinos, Gemma;Mouchlianitis, Elias;Nakamura, Jun;Nenadic, Igor;Ongur, Dost;Ota, Miho;Palaniyappan, Lena E.;Pantelis, Christos;Patel, Tulsi F.;Plitman, Eric;Posporelis, Sotirios R.;Purdon, Scot;Reichenbach, Juergen R.;Renshaw, Perry C.;Reyes-Madrigal, Francisco;Russell, Bruce A.;Sawa, Akira;Schaefer, Martin;Shungu, Dikoma C.;Smesny, Stefan;Stanley, Jeffrey;Stone, James G.;Szulc, Agata;Taylor, Reggie;Thakkar, Katharine N.;Theberge, Jean J.;Tibbo, Philip;van Amelsvoort, Therese;Walecki, Jerzy;Williamson, Peter;Wood, Stephen;Xin, Lijing;Yamasue, Hidenori;McGuire, Philip K.;Egerton, Alice
• 通讯作者: Egerton, Alice

A Computational Analysis of Abnormal Belief Updating Processes and Their Association With Psychotic Experiences and Childhood Trauma in a UK Birth Cohort.

• DOI: 10.1016/j.bpsc.2021.12.007
• 发表时间: 2022-07
• 期刊: Biological psychiatry. Cognitive neuroscience and neuroimaging