Neural mechanisms of sensory predictions in schizophrenia with hallucinations

精神分裂症幻觉感觉预测的神经机制

• 批准号: 9262998
• 负责人: Guillermo Horga
• 金额: $ 19.63万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262998
• 关键词: Animal Model; Auditory; Auditory Hallucination; Auditory area; Award; Belief; Brain; Chronic; Clinical assessments; Code; Cognition; Computer Simulation; Computing Methodologies; Cues; Development; Disease; Economic Burden; Environment; Ethics; Event; Experimental Designs; Fostering; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Generations; Goals; Hallucinations; Hearing; Homelessness; Human; Hybrids; Imprisonment; Lead; Learning; Life Expectancy; Light; Link; Magnetic Resonance; Maps; Medical; Mentors; Methods; Modeling; Neurobiology; Neurosciences Research; Participant; Patients; Perception; Pharmacotherapy; Phenotype; Phonation; Probability; Process; Psychotic Disorders; Recording of previous events; Refractory; Research; Research Personnel; Research Proposals; Research Training; Resources; Rest; Risk; Role; Schizophrenia; Sensory; Signal Transduction; Speech; Speech Discrimination; Stimulus; Symptoms; Telephone; Testing; Thalamic structure; Time; Training; Training Programs; Unemployment; United States National Institutes of Health; Verbal Auditory Hallucinations; Voice; Vulnerable Populations; Work; analytical method; attenuation; base; brain abnormalities; brain dysfunction; career; computational neuroscience; design; disability; expectation; experience; experimental study; functional outcomes; imaging approach; imaging modality; improved; insight; neural correlate; neurobiological mechanism; neuroimaging; neuromechanism; neuropsychiatric disorder; new therapeutic target; novel; novel strategies; patient oriented research; persistent symptom; programs; psychotic symptoms; public health relevance; relating to nervous system; response; sensory cortex; sensory mechanism; sensory stimulus; sensory system; social; therapy development

DESCRIPTION (provided by applicant): Active psychosis in schizophrenia is among the most severe and burdensome medical conditions worldwide. However, the mechanisms of psychotic symptoms in this disorder, such as hallucinations (i.e., abnormal percepts in the absence of external sensory stimuli), remain elusive. This K23 application presents a research and training program that will support the applicant on a path towards becoming an NIH-funded independent investigator focused on the application of functional neuroimaging to the study of psychotic symptoms in schizophrenia. The activities in this application build on the candidate's prior training and are set in a resource-rich environment that will foster his development of expertise in (1) advanced analytic methods and study conduct for functional magnetic resonance imaging (fMRI) research; (2) computational neuroscience; (3) perception and cognition research; (4) pathophysiology and clinical assessment of schizophrenia; and (5) responsible and ethical conduct in scientific research with vulnerable populations. Combining functional magnetic resonance imaging (fMRI) and computational modeling, the current research proposal seeks to (1) define the neural mechanisms that generate hallucinations in schizophrenia; and (2) inform the development of a computational model of hallucinations based on predictive coding, an empirically-validated theoretical framework that supports a role of sensory systems in learning and predicting regularities in the external environment. The overarching hypothesis is that abnormal prediction-based attenuation of sensory cortical function produces excessive activity in the sensory cortex that generates hallucinations. To test this hypothesis, the present study will employ a novel speech discrimination fMRI paradigm, two groups of patients with schizophrenia, those with active, frequent auditory verbal hallucinations and those without a significant history of hallucinations, and a third group of healthy controls. This design will allo for testing a direct link between dysfunction in sensory predictive-coding mechanisms and the online experience of hallucinations in patients with schizophrenia, and will thus inform the neurobiological basis of psychotic symptoms in this disorder. Together, this training and research program will facilitate the candidate's transition to an independent research career and will help identify new therapeutic targets for refractory psychosis. RELEVANCE: The novel application of the predictive-coding framework and model-based fMRI to the study of psychotic symptoms will shed new light on the mechanisms of generation of psychotic symptoms, thus filling an important gap in schizophrenia research. This project will serve to develop an explanatory model of hallucinations that can be used to generate specific, testable hypotheses for future neuroscience research in both humans and non-human animal models, and to uncover novel targets (sensory prediction deficits) likely modifiable by treatment via learning or pharmacotherapy.

描述(由申请人提供)：精神分裂症的主动性精神病是世界上最严重和最繁重的医疗条件之一。然而，这种疾病的精神病症状的机制，如幻觉(即在没有外部感觉刺激的情况下感觉异常)，仍然难以捉摸。这份K23申请提供了一个研究和培训计划，将支持申请者在成为NIH资助的独立调查员的道路上，专注于将功能神经成像应用于精神分裂症的精神症状研究。此应用程序中的活动建立在应聘者之前的培训基础上，并设置在资源丰富的环境中，这将促进他在以下方面的专业知识的发展：(1)功能磁共振成像(FMRI)研究的先进分析方法和研究行为；(2)计算神经科学；(3)感知和认知研究；(4)精神分裂症的病理生理学和临床评估；以及(5)在弱势群体的科学研究中负责任和符合道德的行为。结合功能磁共振成像(FMRI)和计算建模，目前的研究方案寻求(1)定义精神分裂症产生幻觉的神经机制；以及(2)基于预测编码的幻觉计算模型的开发，这是一个经经验验证的理论框架，支持感觉系统在学习和预测外部环境中的规律性方面的作用。最重要的假设是，基于预测的感觉皮质功能异常衰减会在感觉皮层产生过度活动，从而产生幻觉。为了验证这一假设，本研究将使用一种新的语音识别功能磁共振成像范式，两组精神分裂症患者，那些有活跃的、频繁的听觉语言幻觉的患者和那些没有明显幻觉病史的患者，以及第三组健康对照。这项设计将测试精神分裂症患者感觉预测编码机制功能障碍与幻觉在线体验之间的直接联系，从而为这种疾病的精神症状提供神经生物学基础。总而言之，这一培训和研究计划将促进候选人向独立研究职业的过渡，并将有助于确定难治性精神病的新治疗目标。相关性：预测编码框架和基于模型的功能磁共振成像在精神症状研究中的新应用将为精神症状的产生机制提供新的线索，从而填补精神分裂症研究的一个重要空白。该项目将用于开发幻觉的解释性模型，该模型可用于为未来在人类和非人类动物模型中的神经科学研究生成特定的、可验证的假说，并发现可能通过学习或药物治疗而改变的新靶点(感觉预测缺陷)。