Empirical validation of a cerebellar-cortical hallucination circuit

小脑皮质幻觉回路的实证验证

• 批准号: 10543553
• 负责人: Roscoe O. Brady
• 金额: $ 67.15万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543553
• 关键词: Address; Auditory Hallucination; Award; BRAIN initiative; Behavior; Biological; Brain; Brain region; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Clinic; Clinical; Data; Disparate; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hallucinations; Human; Image; Intervention; Link; Location; Magnetic Resonance Imaging; Mental disorders; Modeling; National Institute of Mental Health; Observational Study; Participant; Pattern; Phenotype; Psychotic Disorders; Publishing; Recording of previous events; Role; Schizophrenia; Severities; Symptoms; Technology; Testing; Thalamic structure; Therapeutic; Translations; Validation; cohort; disabling symptom; experimental study; imaging biomarker; imaging study; individual variation; neural circuit; neuroimaging; neuroregulation; novel strategies; outcome disparities; psychiatric symptom; psychotic symptoms; recruit; reduce symptoms; restoration; severe mental illness; sham-controlled study; standard care; translational applications

Project Summary / Abstract Projects like the BRAIN initiative hold the potential for a fundamentally new approach to therapeutics for severe mental illness. Neuromodulation technologies promise to allow selective intervention in which pathophysiology is specifically targeted for correction. These initiatives are critically dependent on the correct identification of circuit dysfunction that causes psychiatric symptoms. NIMH has prioritized this as a strategic objective: Identify and characterize the neural circuit mechanisms contributing to human behavior and their disruption in mental illnesses. Neuroimaging studies have generated promising leads while almost never demonstrating that these findings represent targets that can be engaged for therapeutic benefit. We thus lack a key perquisite for translation into the clinic: For imaging biomarkers to make the leap to translational use, they would need to accurately identify the circuits that give rise to symptoms. In this project we seek to understand how brain circuit dysfunction causes auditory hallucinations in schizophrenia. Published, technically challenging imaging studies provide a critical clue: These “symptom capture” experiments that collect MRI imaging during hallucinations have identified a disparate pattern of activations across multiple subcortical and cortical brain regions. Our hypothesis is that these brain regions are part of a single circuit than spans cerebellar, thalamic, and cortical brain regions. In our preliminary data we are able to identify the cerebellar node of this circuit, and then, in an independent cohort of participants with schizophrenia, we used neuromodulation to manipulate this circuit. We observe that non-invasive neuromodulation can manipulate connectivity across this entire circuit. Restoration of connectivity in this circuit is reflected in reduction of hallucination severity. In this proposal we seek to confirm and extend this result. We will use non-invasive neuromodulation to specifically target this circuit and observe change induced on the hallucination circuit in a sham-controlled study. If successful, this project will establish a circuit-level understanding of how pathophysiology is causally linked to hallucinations. This kind of mechanistic understanding of schizophrenia symptoms would be unprecedented and would identify biological target for engagement to reduce these symptoms.

项目概要/摘要 像 BRAIN 计划这样的项目有可能为以下疾病提供一种全新的治疗方法： 严重的精神疾病。神经调节技术有望允许选择性干预 病理生理学是专门针对纠正的。这些举措很大程度上取决于正确的 识别导致精神症状的回路功能障碍。 NIMH 已将此作为一项战略优先事项 目标：识别并描述影响人类行为的神经回路机制及其特征 精神疾病的干扰。 神经影像学研究已经产生了有希望的线索，但几乎从未证明这些线索 研究结果代表了可用于治疗益处的目标。因此，我们缺乏一个关键的先决条件 转化为临床：对于成像生物标志物来说，要实现转化应用的飞跃，他们需要 准确识别引起症状的电路。 在这个项目中，我们试图了解大脑回路功能障碍如何导致幻听 精神分裂症。已发表的、技术上具有挑战性的成像研究提供了一条关键线索：这些“症状 “捕获”实验在幻觉期间收集 MRI 成像，发现了一种不同的模式 多个皮质下和皮质大脑区域的激活。我们的假设是这些大脑区域 是单个回路的一部分，跨越小脑、丘脑和皮质脑区域。在我们的初步数据中，我们 能够识别该回路的小脑节点，然后，在一个独立的参与者队列中 对于精神分裂症，我们使用神经调节来操纵这个回路。我们观察到非侵入性 神经调节可以操纵整个电路的连接。恢复该电路的连接 反映在幻觉严重程度的减轻。 在本提案中，我们寻求确认并扩展这一结果。我们将使用非侵入性神经调节 专门针对该电路并观察假手术控制中幻觉电路上引起的变化 学习。如果成功，该项目将建立对病理生理学因果关系的电路级理解 与幻觉有关。这种对精神分裂症症状的机械理解将是 史无前例的，并将确定参与减少这些症状的生物目标。