Pathways to psychosis: Investigating environmental, cognitive and genetic mechanisms underlying development of psychotic experiences in young adults

精神分裂症是一种严重的精神疾病，给患者及其家庭带来沉重的负担，是世界范围内残疾的主要原因之一。虽然精神分裂症的治疗方法已经存在，但人们迫切需要更有效的治疗方法和干预措施来防止人们患上这种疾病。精神分裂症的特征是幻觉（例如听到声音）和妄想（例如非理性地相信人们正在策划杀死你）。这些被称为精神病经历，虽然精神分裂症在其一生中影响约1%的人口，但精神病经历更常见，影响约5%的青少年和年轻人。虽然对大多数人来说，这些经历是短暂的，并完全解决，但对一些人来说，他们持续存在，并可能随着时间的推移发展成精神病，如精神分裂症。我们的目标是研究从童年到成年早期的精神病经历的发展，以了解更多关于这些发展的原因，以及哪些因素导致这些恢复，或者相反，恶化和发展为精神病。我们特别感兴趣的是研究以下因素的作用：i）童年和青春期的社会逆境，例如童年虐待或欺凌的反复受害，ii）大麻的使用，增加了发展精神病经历的风险。社会逆境和大麻的使用会导致多巴胺的调节异常，多巴胺是大脑中一种重要的神经递质。这一点特别有趣，因为有很好的证据表明，特定大脑通路中多巴胺活性的增加是精神分裂症的关键生物学异常。然而，尽管有很好的证据表明精神分裂症的多巴胺异常，但尚不清楚过多的多巴胺如何导致人们听到不存在的声音，或者产生有人密谋杀害他们的信念。认知神经科学的研究在某种程度上解释了这一点，证明多巴胺功能的改变可以影响人们对环境刺激的感知，以及他们对这些事件的推断。例如，精神分裂症患者更有可能将不重要的背景刺激解释为具有重要的个人相关性，基于不充分的证据做出决定，并将自我产生的想法或言语错误地归因为来自外部来源。我们旨在研究感知和推理的认知测试异常是否与年轻人的精神病经历相关，以及社会逆境和大麻使用的经历是否也与这些认知测试中的缺陷有关。这项工作可以提供一个模型，即社会逆境或大麻可以通过对感知和推理的影响（通过改变多巴胺功能）导致精神病的经验。这项工作很重要，因为影响感知和推理的认知过程是可以改变的，因此，它们在发展精神病经历中发挥作用的证据将优先考虑这些作为心理干预的潜在目标，以防止人们发展为精神分裂症。虽然遗传效应在确定发展为精神分裂症的风险方面起着关键作用，但尚不清楚这种风险在精神分裂症的发展过程中是如何表达的。从童年到成年早期我们将研究精神分裂症的遗传风险如何影响广泛的精神病理学以及认知和推理测试中的智力和表现。通过结合遗传，心理和社会机制的工作，我们将增加我们对导致精神病经历发展的途径的理解，以帮助为精神分裂症的治疗和预防提供信息。

Schizophrenia is a severe psychiatric disorder that imposes a substantial burden on sufferers and their families, and is one of the leading causes of disability worldwide. Although treatments for schizophrenia exist there is a pressing need for more effective treatments and for interventions to prevent people from developing this disorder.Schizophrenia is characterised by hallucinations (for example hearing voices) and delusions (for example an irrational belief that people are plotting to kill you). These are called psychotic experiences, and whilst schizophrenia affects about 1% of the population over the course of their lives, psychotic experiences occur much more commonly, affecting about 5% of adolescents and young adults. Although for most people these experiences are short lived and resolve completely, for some they persist, and may develop over time into a psychotic illness such as schizophrenia.We aim to study the development of psychotic experiences from childhood through early adulthood to understand more about what causes these to develop, and what factors lead to recovery from these, or conversely, to deterioration and progression to a psychotic illness. We are particularly interested in examining the role of: i) social adversity during childhood and adolescence, characterised for example by childhood maltreatment or repeated victimization from bullying, and ii) cannabis use, on increasing the risk of developing psychotic experiences. Social adversity and cannabis use can cause abnormalities in regulation of dopamine, an important neurotransmitter in the brain. This is of particular interest as there is very good evidence that increased dopamine activity in a specific brain pathway is a key biological abnormality underlying schizophrenia.However, whilst there is good evidence of dopamine abnormalities underlying schizophrenia, it is not known how having too much dopamine can lead to someone hearing a voice that isn't there, or developing a belief that someone is plotting to kill them. Studies in cognitive neuroscience go some way to explaining this by demonstrating that altered dopamine function can affect how people perceive stimuli in their environment, and the inferences that they make about these events. For example, people with schizophrenia are more likely to interpret unimportant background stimuli as having important personal relevance, reach decisions based on insufficient evidence, and misattribute self-generated thoughts or speech as coming from an external source.We aim to study whether abnormalities on cognitive tests of perception and inference are associated with psychotic experiences in young adults, and whether experiences of social adversity and cannabis use are also associated with deficits in these cognitive tests. This work can provide a model whereby social adversity or cannabis can lead to psychotic experiences through effects on perception and inference (via altered dopamine function). This work is important because cognitive processes influencing perception and inference are modifiable, and therefore evidence that they play a role in developing psychotic experiences will prioritize these as potential targets for psychological interventions to prevent people from developing schizophrenia.Furthermore, although genetic effects play a critical role in determining risk of developing schizophrenia it is not known how this risk is expressed during development from childhood through early adulthood. We will examine how genetic risk for schizophrenia affects a broad range of psychopathology as well as intellectual ability and performance on cognitive tests of perception and inference. By combining work on genetic, psychological and social mechanisms we will increase our understanding of the pathways leading to development of psychotic experiences, to help inform interventions for treatment and prevention of schizophrenia.