Mechanisms of impaired subcortical auditory processing in schizophrenia

项目摘要 精神分裂症是世界上最严重和最沉重的医疗条件之一，但 患者经历的症状的病理生理学基础仍然未知。F30应用 提出了一个研究和培训计划，将支持申请人的道路上成为国家卫生研究院- 受资助的独立调查员和医生科学家专注于了解神经生物学 精神分裂症和相关精神障碍。此应用程序中的活动建立在候选人的先前 培训和设置在一个资源丰富的环境，将促进发展的专门知识：1） 精神分裂症的临床影像学原理，2）认知神经科学和功能磁共振成像方法 共振成像（fMRI），3）使用fMRI进行基于模型的听觉处理分析，4） 临床医学和转化研究，以及5）负责任和道德的研究行为。 本研究的目的是确定听觉言语幻觉（AVH）之间的关系， 精神分裂症患者的经验和以前的发现：1）受损的丘脑皮质 22 q11缺失综合征（22 q11 DS）小鼠模型的连接性，这是已知最强的遗传风险因素 精神病; 2）MGN和AC之间的静息状态功能连接减少， 精神分裂症; 3）听觉皮层和MGN的计算过程受损。的首要目标 在该应用中要执行研究是使用基于静止状态、基于任务和基于模型的多频带 功能磁共振成像，以确定与AVH的存在和严重程度相关的损伤：1）连接之间 医学膝状体核（MGN）和听觉皮层（AC）; 2）听觉学习和听觉感受产生 内侧膝状体。 我的目标是研究以下人群：未用药的SCZ患者和情感障碍患者。 疾病（n=30）和匹配的健康对照（不同程度的亚临床感知障碍; n=30）。 使用丘脑定位功能磁共振成像任务，包括内侧膝状体核的体素将被确定在每个 话题吧随后，将确定MGN和AC之间的静息状态功能连通性（RSFC 使用无任务功能磁共振成像。使用基于模型的听觉辨别功能磁共振成像任务，神经计算 将测量听觉学习和感知生成的基础。神经生物学损伤 通过功能磁共振成像检测的AVH将与AVH严重程度的临床测量相关联。这样的证据 这对我们理解幻听和幻听的大脑基础具有重要意义。 精神分裂症的发病机制，并将有助于产生治疗这种毁灭性疾病的新靶点。

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.