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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，包括幻觉和妄想，仍然是最常见的精神病之一。在美国和世界范围内的破坏性和昂贵的医疗条件。尽管在了解其进展，神经生物学，一个统一的机制仍然难以捉摸。阐明这种机制将是一个重大的进展，医学，因为它将提供一个科学的解释，长期以来一直被认为是同义词的症状，这将有助于消除对精神疾病的歧视。这也可能导致重要的通过确定新的靶点，使新的治疗方法能够用于相当大比例的患者（约1/3）对目前的治疗没有反应或耐受。以前的工作分别研究了幻觉（没有相应刺激的错误感知）和妄想（尽管有相互矛盾的证据，但仍保持高度的信念）。然而，最近的大脑理论表明，感知和思维是一个单一过程的一部分，大脑通过这个过程产生和更新内部预测，外部世界的模型，它可以解释我们独特的感知经验，以及我们如何达到某些基于这些经验的结论或想法。这些“贝叶斯”理论的扩展已经被提出，解释感知的病理异常（例如，幻觉）和意念（例如，妄想症），我们认为，这种常见的缺陷是一种与多巴胺相关的更新缺陷，信念（通过计算建模定义），相对于新的感官证据，过度依赖先前的信念。我们认为，这种缺陷可以发生在两个不同层次的层次：一个较低的水平（在感觉皮层）异常其中会导致幻觉，以及更高的水平（高级前额叶和顶叶皮层支持我们提出了一种融合的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性神经成像（fMRI）的尖端工具对其进行建模，行为工具，旨在剖析层次信念更新。具体来说，我们假设一个行为和神经双重分离，即前者的缺陷将与幻觉的严重程度特别相关，后者的缺陷将与未用药患者的妄想严重程度特别相关，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，我们将解释如何增加多巴胺在中脑（特别是在黑质纹状体通路，这里通过一种新的，高密度的测量），分辨率成像技术称为神经黑色素敏感的MRI）改变了常见的神经计算，精神病症状（即，它如何导致低水平和高水平的信念更新不足，导致幻觉，最后，我们将定义神经靶点，以建立未来开发新型神经调节的工作方法，旨在正常化的信念更新缺陷下游多巴胺异常。因此，我们将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，根据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

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

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。