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繁重的医疗疾病之一，但 患者所经历症状的病理生理学基础尚不清楚。此F30应用程序 介绍了一项研究和培训计划，将支持申请者走上成为NIH的道路- 资助的独立研究员和医生兼科学家专注于了解脑血管疾病的神经生物学 精神分裂症和相关的精神障碍。此应用程序中的活动建立在应聘者的 培训，并设置在资源丰富的环境中，这将促进以下方面的专门知识的发展：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学方法 磁共振成像(FMRI)，3)使用fMRI的基于模型的听觉处理分析，4)，基础 临床医学和转化性研究，以及5)研究的负责任和道德行为。 这项研究计划旨在确定听觉言语幻觉(AVH)之间的关系 精神分裂症患者的经历和先前的发现：1)丘脑皮质受损 22q11缺失综合征(22q11DS)小鼠模型的连通性，已知的最强遗传风险因素 对于精神病患者；2)MGN和AC之间的静息状态功能连接性降低 精神分裂症；以及3)听觉皮质和MGN的计算过程受损。的首要目标是 在这一应用中要进行的研究是使用静息状态、基于任务和基于模型的多波段 功能磁共振成像在以下方面识别与AVH的存在和严重程度相关的损害：1) 医学膝状体(MGN)和听觉皮质(AC)；2)听觉学习和知觉产生 在内侧膝状核。 我的目标是研究以下几组个人：未服药的SCZ患者和分裂情感性患者 精神障碍组(n=30)和匹配的健康对照组(不同程度的亚临床知觉障碍；n=30)。 使用丘脑定位fmri任务，将在每个 主题。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任务，神经计算 我们将测量听觉学习和感知生成的基础。神经生物学损伤 通过功能磁共振检测将与AVH严重程度的临床测量相关联。这样的证据会有 对我们理解听觉语言幻觉的大脑基础和 这将有助于研究精神分裂症的发病机制，并有助于为治疗这一毁灭性疾病创造新的靶点。

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.