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.

项目总结/摘要 这一R21提案旨在提供详细的了解， 在精神分裂症患者中，听觉皮层（AC）在功能上相互联系，并与小脑区域联系 (SZ)幻听（AH）患者。AH可以禁用，并且不总是响应现有的 治疗。需要对AH的病理生理学有清楚的了解，以指导开发更有效的治疗方法。 治疗AH，但目前缺乏这样的知识。以前的研究表明，AC是不正常的， 在AH中，提出了AH的可能感知基础。然而，AC是许多大脑区域之一， 在AH发病机制中，以及更好地了解AC如何与其他关键脑区相互作用是必要的。 小脑协调大脑皮层的一系列功能，包括更高层次的认知， 情感和感知过程，而不仅仅是运动功能，如传统上认为的那样。符合 在这一框架下，精神病的无数症状被认为反映了“辨距障碍”，或不协调， 由于小脑-小脑回路的中断而导致的精神活动（Andreasen，et al.，1996; Schmahmann，1998）。 有证据表明，小脑与AC相连，并协调听觉处理， 是理解异常AC-小脑回路如何导致“听觉辨距障碍”和AH的动机。 我们建议检查的特点，当地交流电路和交流小脑电路的基础AH利用 基于静息状态功能性磁共振的创新且高度可靠的AC分组策略 磁共振成像（rsfMRI）。这种分块方法计算AC中体素之间的功能连通性（FC 以及大脑的其他部分，将被用来将AC分割成多个子区域。把空调细分到这么细- 粒度水平只能在死后才能达到（例如，细胞结构学）方法。这里，这些 个体特异性和功能定义的AC子区域将作为AC子区域之间的FC的种子 AC和小脑之间的关系。我们的目标是识别AC分区间FC（目标1）的特征和特征 AC-小脑FC（Aim 2）在SZ中跟踪AH严重程度。我们还旨在验证这些标记物如何变化 AH（目标3）的受试者内变化，使用来自独立干预性纵向研究的数据。 我们的假设是双重的：（1）AC是由一个复杂的局部网络， AC亚区之间的FC与AH之间存在有意义的关联。(2)小脑 在协调AC次区域的活动方面发挥着关键作用，而这一进程在AH中是“不对称的”。这个项目是 重要的是，这是一系列研究的第一步，预计将导致发展 针对AH的更有针对性和个性化的治疗。重复经颅磁刺激（rTMS）是一种 有希望的AH非药物治疗。我们认为，刺激小脑区域， 连接到AC的关联子区域可以提供对AH中不对称的电路的访问。我们预计 这项建议将确定潜在的小脑目标rTMS可以在未来的临床试验进行测试。