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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：
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