Deficient Belief Updating as a Convergent Computational Mechanism of Psychosis

信念更新不足作为精神病的收敛计算机制

基本信息

批准号：
9766401
负责人：
Guillermo Horga
金额：
$ 74.51万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766401
关键词：
Address Auditory area Behavior Behavioral Belief Biological Brain Clinical Cognitive Computer Simulation Conflict (Psychology)Corpus striatum structure Data Delusions Dissociation Dopamine Feedback Foundations Functional Magnetic Resonance Imaging Functional disorder Future Hallucinations Health Benefit Hearing Human Image Imaging Techniques Impairment Individual Knowledge Lead Link Magnetic Resonance Imaging Measures Mediating Medical Medical Care Costs Medicine Mental disorders Methodology Methods Midbrain structure Modeling Nature Neurobiology Neurocognitive Neurosciences Parietal Parietal Lobe Pathologic Pathway interactions Patients Pattern Perception Prefrontal Cortex Process Psychiatry Psychotic Disorders Public Health Rest Schizophrenia Sensory Severities Signal Transduction Stigmatization Stimulus Substantia nigra structure Symptoms Syndrome System Testing Update Voice Work base common symptom computational neuroscience convict design experience high resolution imaging ideation indexing individualized medicine neuroimaging neuromelanin neuroregulation nigrostriatal dopaminergic pathway nigrostriatal pathway novel pars compacta pre-clinical predictive modeling psychotic symptoms relating to nervous system sensory cortex theories tool

项目摘要

The psychotic syndrome of schizophrenia, comprising hallucinations and delusions, remains one of the most devastating and costly medical conditions in the US and worldwide. Despite progress in the understanding of its neurobiology, a unifying mechanism remains elusive. Elucidating such mechanism would be a major advance in medicine, as it would provide a scientific explanation to symptoms that have long been considered synonymous with irrationality. This would contribute to de-stigmatization of mental illness. It would also potentially lead to important public health benefits by identifying novel targets that could enable new treatments for a substantial proportion of patients (~1/3) who do not respond to or tolerate current treatments. Previous work has separately studied the substrates of hallucinations (false percepts without corresponding stimuli) and of delusions (false ideas that are maintained with high conviction despite contradictory evidence). However, recent theories of the brain suggest that perception and ideation are part of a unitary process, whereby the brain generates and updates internal predictive models of the external world, that can explain both our idiosyncratic perceptual experiences and how we reach certain conclusions or ideas based on these experiences. Extensions of these ‘Bayesian’ theories have been proposed to explain pathological abnormalities in perception (e.g., hallucinations) and ideation (e.g., delusions) in psychosis as deriving from a common deficit. We suggest that this common deficit is a dopamine-related deficit in updating of beliefs (defined via computational modeling) given excessive reliance of prior beliefs relative to new sensory evidence. We posit that this deficit can occur at two different levels of a hierarchy: a lower level (in sensory cortex) abnormalities in which would cause hallucinations, and a higher level (higher-order prefrontal and parietal cortices supporting inference) abnormalities in which would cause delusions. We propose a converging approach to directly test this novel model it by leveraging cutting-edge tools in computational neuroscience applied to functional neuroimaging (fMRI) and behavioral tools designed to dissect hierarchical belief updating. Specifically, we hypothesize a behavioral and neural double dissociation whereby deficits in the former will be specifically associated with severity of hallucinations while deficits in the latter will be specifically associated with severity of delusions in unmedicated patients with schizophrenia. By anchoring our model on the well-established dopamine dysfunction in psychosis, we will explain how increased dopamine in the midbrain (specifically, in the nigrostriatal pathway, here measured via a novel, high- resolution imaging technique known as neuromelanin-sensitive MRI) alters common neural computations leading to psychotic symptoms (i.e., how it results in deficient belief updating at low and high levels, leading to hallucinations and delusions, respectively). Finally, we will define neural targets to set up future work developing novel neuromodulation approaches aimed at normalizing belief updating deficits downstream from dopamine abnormalities. Thus, we will establish novel downstream mechanisms of psychosis that can be further dissected in preclinical work and can be directly targeted in humans depending on individuals’ symptom profiles.

精神分裂症的精神病综合症，包括幻觉和妄想，仍然是最严重的精神病综合症之一。尽管人们对其的了解有所进展，但美国和世界各地的医疗状况却是毁灭性的、代价高昂的。在神经生物学中，统一的机制仍然难以捉摸。阐明这种机制将是神经生物学领域的重大进步。医学，因为它将为长期以来被认为与疾病同义的症状提供科学的解释这也将有助于消除精神疾病的污名化。通过确定新的目标，可以为很大一部分患者提供新的治疗方法，从而造福公共健康患者（~1/3）对当前的治疗没有反应或耐受。之前的工作已经单独研究过幻觉（没有相应刺激的错误知觉）和妄想（错误的想法尽管证据相互矛盾，但人们仍然坚信这一点）然而，最近的大脑理论表明，感知和构思是统一过程的一部分，大脑通过该过程生成并更新内部预测外部世界的模型，可以解释我们特殊的感知体验以及我们如何达到某些目标基于这些经验的结论或想法已被提出来扩展这些“贝叶斯”理论。将精神病中知觉（例如幻觉）和意念（例如妄想）的病理异常解释为源自常见的缺陷。我们认为这种常见的缺陷是与多巴胺相关的更新缺陷信念（通过计算模型定义）过度依赖先前的信念相对于新的感官证据。我们假设这种缺陷可能发生在一个层次结构的两个不同级别：较低级别（在感觉皮层）异常。其中会引起幻觉，并且更高级别（高阶前额叶和顶叶皮质支持推理）会导致妄想的异常现象。我们提出了一种聚合方法来直接测试这部小说。利用计算神经科学中应用于功能神经成像 (fMRI) 的尖端工具对其进行建模，旨在剖析等级信念更新的行为工具。具体来说，我们假设行为和神经。双重解离，前者的缺陷将与幻觉的严重程度具体相关，而后者的缺陷将与未接受药物治疗的患者妄想的严重程度特别相关。通过将我们的模型锚定在精神病中公认的多巴胺功能障碍上，我们将解释精神分裂症。中脑中的多巴胺（特别是黑质纹状体通路中的多巴胺）如何增加，这里通过一种新颖的高- 分辨率成像技术（称为神经黑色素敏感 MRI）改变了常见的神经计算，导致精神病症状（即，如何导致低水平和高水平的信念更新不足，导致幻觉和最后，我们将定义神经目标，以开展未来开发新型神经调节的工作旨在使信念正常化、更新多巴胺异常下游缺陷的方法。建立新的精神病下游机制，可以在临床前工作中进一步剖析，并且可以根据个人的症状特征直接针对人类。