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 该R21提案旨在详细了解该分区的分区 听觉皮层（AC）在功能上相互连接，并且在精神分裂症中与小脑区域 （SZ）具有听觉幻觉的患者（AH）。啊可能是禁用的，并不总是对现有的响应 治疗。需要对AH病理生理学有清晰的了解来指导更有效的发展 AH的治疗方法，但目前缺乏这种知识。先前的研究表明AC是异常的 在AH中，提出了AH的可能感知基础。但是，AC是实施的许多大脑区域之一 在AH发病机理中，需要更好地了解AC与其他关键大脑区域的相互作用。 小脑会协调许多脑皮质功能 - 包括高级认知， 如传统上所相信的那样，情感和感知过程不仅是运动功能。与 这个框架，已经提出了无数精神病的症状来反映“障碍”或不协调的情况， 由于脑脑电路中的破坏而引起的心理活动（Andreasen等，1996； Schmahmann，1998）。 有证据表明小脑与AC相互连接并协调听觉处理， 是了解异常的交流电路电路可能导致“听觉障碍”和啊的动机。 我们建议通过利用AH的本地交流电路和AC-CereBellar电路的特征 基于静止状态功能磁共振的创新且高度可靠的交流分割策略 成像（RSFMRI）。这种分析方法，该方法计算AC中体素之间的功能连接性（FC） 大脑的其余部分将用于将AC分割为多个亚洲。在此精细的 只有在验尸（例如，细胞结构）方法之前，才能达到水平。在这里，这些 个体特异性和功能定义的AC次序列将充当AC Subares之间的FC种子 在交流和小脑之间。我们的目的是确定AC Inberabarea FC（AIM 1）和功能的功能 AC-Cerebellar FC（AIM 2）在SZ中具有AH严重性的跟踪。我们还旨在验证这些标记如何改变 使用独立的介入纵向研究的数据，具有AH（AIM 3）的受试者内变化（AIM 3）。 我们的假设是两个倍：（1）AC由两个主要感觉的复杂局部网络组成 与AC亚序列之间的关联下区和FC与AH有意义地相关联。 （2）小脑 在AC subareas中的协调活动中起关键作用，此过程是AH中的“非对称”。这个项目是 意义重大，因为这是一项连续研究的第一步，预计会导致发展 AH的更多针对性和个性化治疗方法。重复的经颅磁刺激（RTMS）是一个 有希望的非药物治疗AH。我们建议对小脑区域的刺激 与AC的关联亚地区相连的可能会提供对AH中对称障碍的圆圈的访问。我们期望 该建议将确定可以在以后的临床试验中测试的RTM的潜在小脑靶标。