Mechanisms of impaired subcortical auditory processing in schizophrenia

精神分裂症皮层下听觉处理受损的机制

基本信息

批准号：
10247065
负责人：
John Connor Williams
金额：
$ 5.1万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2023-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247065
关键词：
22q11.2 Antipsychotic Agents Assessment tool Attenuated Auditory Auditory Perception Auditory area Base of the Brain Bayesian Analysis Brain Chicago Chronic Clinical Clinical Medicine Code Conscious Corpus striatum structure Data Development DiGeorge Syndrome Diagnosis Disease Dopamine Dopamine D2 Receptor Dose Economic Burden Environment Ethics Etiology Failure Functional Magnetic Resonance Imaging Funding Generations Geniculate body structure Goals Hallucinations Haloperidol Homelessness Human Impairment Imprisonment Individual Lead Learning Life Expectancy Linear Models Link Location Magnetic Resonance Imaging Measures Medial Mediating Mediation Medical Methods Modeling Mus Neurobiology Overweight Pathogenesis Patients Perception Perceptual disturbance Physicians Play Process Psychoses Psychotic Disorders Rattus Reporting Research Research Personnel Research Proposals Research Training Resources Rest Risk Role Schizoaffective Disorders Schizophrenia Scientist Sensory Severities Signal Transduction Speech Discrimination Stimulus Symptoms Synapses Syndrome Testing Thalamic Nuclei Thalamic structure Training Training Programs Translational Research Unemployment United States United States National Institutes of Health Verbal Auditory Hallucinations Weight auditory discrimination auditory processing base clinical imaging clinical predictors cognitive neuroscience disability disorder risk expectation experience genetic risk factor imaging study improved microdeletion mouse model novel novel strategies relating to nervous system sensory input social transmission process

22q11.2 Antipsychotic Agents Assessment tool Attenuated Auditory Auditory Perception Auditory area Base of the Brain Bayesian Analysis Brain Chicago Chronic Clinical Clinical Medicine Code Conscious Corpus striatum structure Data Development DiGeorge Syndrome Diagnosis Disease Dopamine Dopamine D2 Receptor Dose Economic Burden Environment Ethics Etiology Failure Functional Magnetic Resonance Imaging Funding Generations Geniculate body structure Goals Hallucinations Haloperidol Homelessness Human Impairment Imprisonment Individual Lead Learning Life Expectancy Linear Models Link Location Magnetic Resonance Imaging Measures Medial Mediating Mediation Medical Methods Modeling Mus Neurobiology Overweight Pathogenesis Patients Perception Perceptual disturbance Physicians Play Process Psychoses Psychotic Disorders Rattus Reporting Research Research Personnel Research Proposals Research Training Resources Rest Risk Role Schizoaffective Disorders Schizophrenia Scientist Sensory Severities Signal Transduction Speech Discrimination Stimulus Symptoms Synapses Syndrome Testing Thalamic Nuclei Thalamic structure Training Training Programs Translational Research Unemployment United States United States National Institutes of Health Verbal Auditory Hallucinations Weight auditory discrimination auditory processing base clinical imaging clinical predictors cognitive neuroscience disability disorder risk expectation experience genetic risk factor imaging study improved microdeletion mouse model novel novel strategies relating to nervous system sensory input social transmission process

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项目摘要

Project Summary Schizophrenia is among the most severe and burdensome medical conditions worldwide, yet the pathophysiological basis for symptoms experienced by patients remain unknown. This F30 application presents a research and training program that will support the applicant on a path towards becoming an NIH- funded independent investigator and physician-scientist focused on understanding the neurobiology of schizophrenia and related psychotic disorders. The activities in this application build on the candidate’s prior training and are set in a resource-rich environment that will facilitate the development of expertise in: 1) principles of clinical imaging in schizophrenia, 2) methods in cognitive neuroscience and functional magnetic resonance imaging (fMRI), 3) model-based analysis of auditory processing using fMRI, 4), fundamentals of clinical medicine and translational research, and 5) the responsible and ethical conduct of research. This research proposal aims to determine the relationships between auditory verbal hallucinations (AVH) experienced by individuals with schizophrenia and previous findings of: 1) impaired thalamocortical connectivity in mouse models of 22q11 deletion syndrome (22q11DS), the strongest known genetic risk factor for psychosis; 2) reduced resting-state functional connectivity between MGN and AC in patients with schizophrenia; and 3) impaired computational processes in auditory cortex and MGN. The overarching goal of the research to be carried out in this application is to use resting-state, task-based, and model-based multiband fMRI to identify impairments that correlate with the presence and severity of AVH in: 1) connectivity between medical geniculate nucleus (MGN) and auditory cortex (AC), and 2) auditory learning and percept generation in medial geniculate nucleus. I aim to study the following groups of individuals: unmedicated patients with SCZ and schizoaffective disorder (n=30) and matched healthy controls (varying degrees of subclinical perceptual disturbances; n=30). Using a thalamic localizer fMRI task, voxels comprising the medial geniculate nucleus will be identified in each subject. Subsequently, resting-state functional connectivity (RSFC) between MGN and AC will be determined using task-free fMRI. Using a model-based auditory discrimination fMRI task, neurocomputational underpinnings of auditory learning and percept generation will be measured. Neurobiological impairments detected via fMRI will be correlated with clinical measures of AVH severity. Such evidence would have important implications for our understanding of the brain bases of auditory verbal hallucinations and the pathogenesis of schizophrenia and would help generate new targets for treatment of this devastating illness.

项目摘要精神分裂症是全球最严重，最朴实的医疗状况之一，但患者经历的症状的病理生理基础尚不清楚。此F30应用程序提出了一项研究和培训计划，该计划将支持该应用程序，以成为NIH的道路资助的独立研究者和身体科学家专注于理解神经生物学精神分裂症和相关的精神病。本申请中的活动基于候选人的先验培训并设置在资源丰富的环境中，该环境将促进专业知识的发展：1）精神分裂症的临床成像原理，2）认知神经科学和功能磁性的方法共振成像（fMRI），3）基于fMRI的基于模型的听觉处理分析，4），基本原理临床医学和翻译研究，以及5）研究的负责任和道德行为。这项研究建议旨在确定听觉言语幻觉（AVH）之间的关系精神分裂症患者经历了：1）丘脑皮层受损 22q11缺失综合征的小鼠模型中的连通性（22q11ds），是强烈的已知遗传风险因素用于精神病； 2）在患者中，MGN和AC之间的静息状态功能连接降低精神分裂症; 3）听觉皮层和MGN中的计算过程受损。总体目标在本应用程序中进行的研究是使用静止状态，基于任务和基于模型的多班 fMRI确定与AVH存在和严重性相关的损害：1）医学遗传核（MGN）和听觉皮层（AC）和2）听觉学习和感知产生在内侧基因核中。我的目的是研究以下个体：未经药物的SCZ患者和受伤的患者疾病（n = 30）和匹配的健康对照（亚临床感知疾病的变化程度； n = 30）。使用丘脑定位器fMRI任务，将在每个中识别完成内侧基因核的体素随后，将确定MGN和AC之间的静止状态功能连接性（RSFC）使用无任务fMRI。使用基于模型的听觉歧视fMRI任务，神经计算将测量听觉学习和感知产生的基础。神经生物学障碍通过功能磁共振成像检测到的将与AVH严重程度的临床指标相关。这样的证据会有对我们对听觉言语幻觉的大脑基础的理解以及精神分裂症的发病机理，将有助于产生新的靶标治疗这种毁灭性疾病。