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：
10421074
负责人：
Guillermo Horga
金额：
$ 60.23万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421074
关键词：
Address Auditory area Behavior Behavioral Belief Biological Brain Clinical Cognitive Computer Models 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 Psychoses 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征，完成幻觉和妄想，仍然是最多的一种在美国和全球，毁灭性和昂贵的医疗状况。尽管在理解它的理解方面取得了进步神经生物学，一种统一的机制仍然弹性。阐明这种机制将是医学，这将为长期以来被认为是代名词的症状提供科学解释非理性。这将导致精神疾病的污名化。这也可能导致重要通过确定可以实现新的治疗的新目标来获得很大一部分不反应或容忍当前治疗的患者（〜1/3）。以前的工作已经分别研究了幻觉的基材（没有相应刺激的错误感知）和妄想（错误的想法尽管有矛盾的证据，但仍以高度的信念维持）。但是，大脑的最新理论表明感知和构想是统一过程的一部分，大脑会产生和更新内部预测性外部世界的模型，可以解释我们特质的感知体验以及我们如何达到一定基于这些经验的结论或想法。已经提出了这些“贝叶斯”理论的扩展解释感知的病理异常（例如，幻觉）和念头（例如，妄想）的精神病（例如妄想）源于常见赤字。我们建议这种常见的赤字是多巴胺相关的赤字相对于新的感觉证据，信念（通过计算建模定义）过度缓解先前信念。我们认为这种赤字可以在两个不同级别的层次结构上发生：较低级别（在感觉皮层）异常其中会引起幻觉，并具有更高的水平（支撑的高阶前额叶和顶叶皮层推论）异常会引起妄想。我们提出了一种直接测试这本小说的融合方法通过利用用于功能神经影像学（fMRI）和行为工具旨在剖析层次信念更新。特别是，我们假设行为和神经双重解离，因此前者的默认值将特别与幻觉的严重程度有关拉特斯特的缺陷将特别与未经药物的患者的妄想严重程度有关精神分裂症。通过将我们的模型锚定在精神病中良好的多巴胺功能障碍上，我们将解释中脑中多巴胺的增加如何（具体来说，在黑质途径中，这里通过一种新型高级测量分辨率成像技术称为神经元素敏感的MRI）改变了常见的神经计算，导致精神病症状（即，它如何导致低水平和高水平的确定信念更新，从而导致幻觉和妄想，相对）。最后，我们将定义神经目标以建立未来的工作开发新的神经调节旨在使信仰更新多巴胺异常下游缺陷的方法归一化的方法。那我们会的建立可以在临床前工作中进一步阐述的精神病的新型下游机制，可以是取决于个人的症状特征，直接针对人类。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Introspective inference counteracts perceptual distortion.

DOI：
10.1038/s41467-023-42813-2
发表时间：
2023-11-29
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Mihali, Andra;Broeker, Marianne;Ragalmuto, Florian D. M.;Horga, Guillermo
通讯作者：
Horga, Guillermo

Detecting Pharmacologically Induced Serotonin Release in Depression With Positron Emission Tomography Imaging: A New Approach.

用正电子发射断层扫描成像检测抑郁症中药物诱导的血清素释放：一种新方法。

DOI：
10.1016/j.biopsych.2023.04.008
发表时间：
2023
期刊：
Biological psychiatry
影响因子：
10.6
作者：
Slifstein,Mark;Abi-Dargham,Anissa
通讯作者：
Abi-Dargham,Anissa

Effects of Hallucination Proneness and Sensory Resolution on Prior Biases in Human Perceptual Inference of Time Intervals.

幻觉倾向和感官分辨率对人类感知时间间隔推断中先验偏差的影响。

DOI：
10.1523/jneurosci.0692-22.2023
发表时间：
2023-07-19
期刊：
JOURNAL OF NEUROSCIENCE
影响因子：
5.3
作者：
Duhamel, Emeline;Mihali, Andra;Horga, Guillermo
通讯作者：
Horga, Guillermo

The Quest for a Selective Mapping Between Striatal Dopamine Subcircuits and Psychosis Symptoms.

寻求纹状体多巴胺亚电路和精神病症状之间的选择性映射。

DOI：
10.1016/j.bpsc.2020.09.009
发表时间：
2020
期刊：
Biological psychiatry. Cognitive neuroscience and neuroimaging
影响因子：
0
作者：
Wengler,Kenneth;Horga,Guillermo
通讯作者：
Horga,Guillermo

Reliability and Reproducibility of Neuromelanin-Sensitive Imaging of the Substantia Nigra: A Comparison of Three Different Sequences.

DOI：
10.1002/jmri.27384
发表时间：
2021-03
期刊：
Journal of magnetic resonance imaging : JMRI
影响因子：
0
作者：
van der Pluijm M;Cassidy C;Zandstra M;Wallert E;de Bruin K;Booij J;de Haan L;Horga G;van de Giessen E
通讯作者：
van de Giessen E