Cerebro-cerebellar circuitry in the pathophysiology of auditory hallucinations: dysmetria of auditory perceptual processing?

幻听病理生理学中的脑小脑回路：听觉感知处理的辨距障碍？

• 批准号: 10015346
• 负责人: Hesheng Liu
• 金额: $ 19.84万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015346
• 关键词: Abnormal coordination; Affective; Anatomy; Antipsychotic Agents; Area; Auditory; Auditory Hallucination; Auditory area; Autopsy; Brain; Brain region; Cerebellar Cortex; Cerebellum; Cerebral cortex; Cerebrum; Clinical Trials; Cognitive; Communication; Complex; Data; Data Set; Development; Distress; Dysmetria; Enrollment; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Grain; Human; Individual; Intervention; Knowledge; Lead; Light; Longitudinal Studies; Measures; Mediating; Methodology; Methods; Motivation; Motor; Neurobiology; Pathogenesis; Patients; Play; Pontine structure; Process; Protocols documentation; Psyche structure; Psychotic Disorders; Research; Rest; Risk; Scanning; Schizophrenia; Seeds; Sensory; Severities; Solid; Symptoms; Techniques; Testing; Thalamic structure; Variant; auditory processing; base; effective therapy; human model; improved; in vivo; innovation; inter-individual variation; longitudinal dataset; neuroimaging; novel; personalized medicine; psychotic symptoms; repetitive transcranial magnetic stimulation; tool

PROJECT SUMMARY/ABSTRACT This R21 proposal aims to provide detailed understanding of how finely parcellated subareas of the auditory cortex (AC) are functionally connected with one another and with cerebellar regions in schizophrenia (SZ) patients with auditory hallucinations (AH). AH can be disabling, and do not always respond to existing treatments. A clear understanding of AH pathophysiology is needed to guide the development of more effective treatments for AH, but such knowledge is currently lacking. Previous research suggests that the AC is abnormal in AH, suggesting a possible perceptual basis for AH. The AC, however, is one of many brain regions implicated in AH pathogenesis, and a better understanding of how AC interacts with other critical brain areas is needed. The cerebellum coordinates a host of cerebral cortical functions—including higher-level cognitive, affective, and perceptual processes—rather than just motor functions, as traditionally believed. Consistent with this framework, the myriad symptoms of psychosis have been proposed to reflect “dysmetria,” or incoordination, of mental activity due to disruptions in cerebro-cerebellar circuits (Andreasen, et al., 1996; Schmahmann, 1998). Given evidence that the cerebellum is reciprocally connected to AC and coordinates auditory processing, there is motivation to understand how abnormal AC-cerebellar circuitry might lead to `auditory dysmetria', and AH. We propose to examine features of local AC circuitry and AC-cerebellar circuitry underlying AH by utilizing an innovative and highly reliable AC parcellation strategy based on resting state functional magnetic resonance imaging (rsfMRI). This parcellation method, which computes functional connectivity (FC) between voxels in AC and the rest of the brain, will be used to segment AC into multiple subareas. Subdividing the AC at this fine- grained a level could only be achieved before with postmortem (e.g., cytoarchitectonic) methods. Here, these individual-specific and functionally defined AC subareas will serve as the seeds for FC between AC subareas and between AC and cerebellum. Our aims are to identify features of AC inter-subarea FC (Aim 1) and features of AC-cerebellar FC (Aim 2) that track with AH severity in SZ. We also aim to validate how these markers change with intra-subject variations in AH (Aim 3), using data from an independent interventional longitudinal study. Our hypotheses are two-fold: (1) The AC is comprised of a complex local network of both primary sensory and association subareas, and FC between AC subareas is meaningfully associated with AH. (2) The cerebellum plays a key role in coordinating activity in AC subareas, and this process is `dysmetric' in AH. This project is significant because it is the first step in a continuum of research that is expected to lead to the development of more targeted and personalized treatments for AH. Repetitive transcranial magnetic stimulation (rTMS) is a promising non-pharmacological treatment for AH. We propose that stimulation of cerebellar regions that are connected to association subareas of AC may provide access to circuits that are dysmetric in AH. We expect that this proposal will identify potential cerebellar targets for rTMS that can be tested in a future clinical trial.

项目摘要/摘要 这份R21提案旨在提供对如何精细划分的分区的详细了解 精神分裂症患者的听觉皮质(AC)在功能上相互联系，并与小脑区相联系 (SZ)幻听患者(AH)。AH可以禁用，并且不总是响应现有的 治疗。需要对AH的病理生理学有一个清晰的认识，才能更有效地指导其发展 治疗急性早幼粒细胞白血病，但目前缺乏此类知识。先前的研究表明，AC是不正常的 在AH中，暗示了AH可能的知觉基础。然而，AC是牵涉到的许多大脑区域之一 在AH的发病机制中，需要更好地了解AC如何与其他关键脑区相互作用。 小脑协调一系列大脑皮层功能--包括更高水平的认知， 情感和知觉过程--而不是像传统认为的那样仅仅是运动功能。与一致 在这个框架下，精神病的各种症状被认为反映了“精神错乱”，即不协调， 由于大脑-小脑回路中断而导致的精神活动(Andreasen等人，1996；Schmahmann，1998)。 有证据表明，小脑与交感神经相互连接，并协调听觉处理。 是了解AC-小脑回路异常如何导致“听觉功能障碍”和AH的动机。 我们建议检查局部交流电路和交流-小脑电路潜在的AH的特点 一种创新的基于静息状态功能磁共振的高可靠交流分流策略 成像(RsfMRI)。此宗地方法，用于计算AC中体素之间的函数连通性(FC 而大脑的其余部分将被用来将AC分割成多个子区域。在这种情况下细分空调- 颗粒化的水平只能在死后(例如，细胞架构学)方法之前达到。这里，这些 特定于个人的和功能定义的AC分区将作为AC分区之间FC的种子 在AC和小脑之间。我们的目标是确定交流分区间FC的特征(目标1)和特征 的AC-小脑功能障碍(目标2)，跟踪与严重程度在深圳。我们还打算验证这些标记是如何变化的 使用来自一项独立的干预性纵向研究的数据，研究了AH的受试者内差异(目标3)。 我们的假设有两个：(1)AC是由两个初级感觉的复杂局部网络组成的 和关联亚区，AC亚区之间的FC与AH显著相关。(2)小脑 在协调AC亚区的活动方面起着关键作用，而这一过程在AH中是“动态的”。这个项目是 意义重大，因为这是一系列研究的第一步，预计将导致 更有针对性和个性化的治疗急性肝炎。重复经颅磁刺激是一种 前景看好的非药物治疗急性肝炎。我们认为，刺激小脑区域是 连接到AC的关联子区域可以提供对AH中测频的电路的访问。我们预计 这项提议将确定rTMS的潜在小脑靶点，可以在未来的临床试验中进行测试。