Brain sulcal folding and mental illness: investigating causal associations and stratification approaches for psychosis

大脑外表面的折叠方式因人而异。折叠的变化与大脑功能有关，可能会导致精神疾病。大脑的一些褶皱在个体之间表现出特别高的可变性，包括扣带褶皱（或被科学家称为扣带回及其相关的沟，扣带沟），在一些人身上表现为单褶皱，在另一些人身上表现为双褶皱。扣带折叠的可变性几乎是人类独有的特征。虽然其他哺乳动物也有扣带褶皱，但人类和黑猩猩是仅有的具有双扣带褶皱的动物。最初的证据表明，折叠模式可能对心理健康问题的脆弱性也很重要，但由于样本规模小，以及在脑部扫描中测量折叠程度的技术挑战，提供明确的答案受到限制。为了推进这项工作，我们改进了在脑部扫描中测量可变折叠的方法。目前，测量脑沟的黄金标准方法是，训练有素的专家每次扫描一个可变脑沟，花大约30分钟的时间，从屏幕上的不同角度观察大脑扫描结果，然后用电脑鼠标在扫描结果上画线进行测量。这种方法容易出现人为错误，而且速度太慢，无法大规模使用。我们已经开发了一个新的计算机程序来快速、可靠和准确地测量扣带折叠，我们将改进这个程序，扩展它来测量大脑其他部分的折叠，并使它在未来免费提供给其他科学家和临床医生使用。我们将在5万多人（来自英国生物银行和美国ABCD研究）的大脑扫描上运行这个程序，给每个参与者几个变量折叠的总结测量。我们将把结果存入相关数据库，以便研究这一备受赞誉的资源的研究人员可以轻松访问结果，并将扣带折叠与其他感兴趣的测量方法联系起来。我们根本不知道是什么导致了折叠的可变性。我们将进行第一项研究，以检查脑沟折叠变异的分子遗传基础，我们将使用一种称为孟德尔随机化的遗传技术，该技术利用遗传信息来检查特定的大脑折叠变异是否会导致精神疾病。我们将通过测试折叠是否可以预测精神分裂症的一个重要临床结果，即对治疗的反应，来说明折叠的临床重要性。如果我们能在一开始就识别出那些需要治疗的病人，而这些治疗通常只是作为最后的手段，我们就有可能改善早期的结果。我们的项目将比以前更详细、更大规模地阐明折叠对心理功能和精神疾病的重要性。为此，我们将利用几项现有的高质量研究，这些研究已经收集了数据，我们将利用这些数据来阐明PCS在健康和疾病中的作用。特别是，我们将通过扫描来自欧洲和美国的1100多名精神分裂症患者来研究扣带折叠与幻觉的关系——这个样本比之前最大的研究大五倍。我们将在超过5万人的大型研究中检验扣带折叠对普通人群的影响。我们将利用这些研究的数据，看看扣带折叠模式是否与某些精神症状、心理能力和大脑线路模式的脆弱性有关。这项工作令人兴奋：我们的计算机程序将来可以用于脑部扫描，以计算“生物标志物”，帮助医生和病人做出更好的治疗决定，并将提供有关大脑如何折叠以及这对我们的思维和对精神疾病的脆弱性有何影响的新知识。

The folding of the outer surface of the brain is highly variable across individuals. Variations in folding are associated with brain function, potentially contributing to mental illness. Some folds of the brain shows a particularly high level of variability between individuals, including the cingulate fold (or known to scientists as the cingulate gyrus and its associated furrow, the cingulate sulcus), which presents as a single fold in some people and a double fold in others. Variability in cingulate folding is an almost uniquely human feature. Whilst the cingulate fold is present in other mammals, humans and chimpanzees are the only animals that can have a double cingulate fold. Initial evidence suggests that the folding pattern may also be important for vulnerability to mental health problems, but providing definitive answers has been limited by small samples sizes and technical challenges in measuring the degree of folding on brain scans.To drive this work forward, we have improved the way we can measure variable folding on brain scans. Currently the gold standard way to measure it is for a trained expert to spend about 30 minutes per scan per variable sulcus, looking at a brain scan from various points of view on a screen and measuring it using a computer mouse to draw lines on the scan. This method is prone to human error and is too slow to do at scale. We have developed a new computer program to measure cingulate folding rapidly, reliably and accurately, and we will refine this program, extending it to measure folding in other parts of the brain, and make it freely available for other scientists and clinicians to use in future. We will run the program on the brain scans in over 50,000 people (from the large UK Biobank and USA ABCD studies), giving each participant summary measures of several variable folds. We will deposit the results in the relevant database so that researchers studying this acclaimed resource can easily access the results and relate cingulate folding to other measures of interest. It is not at all known what causes folding variability. We will conduct the first study to examine the molecular genetic basis of sulcal folding variation, and we will use a genetic technique called mendelian randomisation that uses genetic information to check whether particular brain folding variants are contributory causes to mental illness. We will illustrate the clinical importance of folding by testing whether it can predict an important clinical outcome in schizophrenia, namely response to treatment. If we can identify, at first presentation, those patients who will need to treatments that are usually only introduced as last resort, we could potentially improve early outcomes.Our project will clarify the importance of folding for psychological function and mental illness in much greater detail and in much larger numbers than has been done before. To do this we will take advantage of several existing high quality studies that have already collected data that we will use to clarify the role of the PCS in health and illness. In particular, we will look at cingulate folding in relation to hallucinations using scans from over 1100 patients with schizophrenia in studies drawn from Europe and the USA - a sample five time larger than the largest previous study. We will examine the effects of cingulate folding in the general population in large studies of over 50,000 people. We will use data from these studies to see if the cingulate folding pattern is linked to vulnerability to certain psychiatric symptoms, psychological abilities, and the wiring patterns of the brain. This line of work is exciting: our computer program could in future be used on brain scans to calculate "biomarkers" that help doctors and patients make better treatment decisions, and will provide new knowledge on how the brain folds and what difference this makes to our thinking and vulnerability to mental illness.