Empirical validation of a cerebellar-cortical hallucination circuit

小脑皮质幻觉回路的实证验证

• 批准号: 10364077
• 负责人: Roscoe O. Brady
• 金额: $ 66.44万
• 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/10364077
• 关键词: Address; Auditory Hallucination; Award; BRAIN initiative; Behavior; Biological; Brain; Brain region; Cerebellar Diseases; Cerebellum; Clinic; Clinical; Data; 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; base; cohort; disabling symptom; experimental study; imaging approach; imaging biomarker; imaging study; individual variation; neural circuit; neuroimaging; neuroregulation; novel strategies; psychiatric symptom; psychotic symptoms; recruit; reduce symptoms; restoration; severe mental illness; sham-controlled study; standard care

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.

项目摘要 /摘要 诸如大脑启动之类的项目具有从根本上进行新的治疗方法 严重的精神疾病。神经调节技术有望允许选择性干预 病理生理学专门针对矫正。这些举措在关键上取决于正确的 导致精神病症状的电路功能障碍的识别。 NIMH将其视为一种策略 目的：确定并表征有助于人类行为及其其行为的神经回路机制 精神疾病的破坏。 神经影像学研究产生了诺言，而几乎从未证明这些 调查结果代表可以从事治疗益处的目标。因此，我们缺乏关键的建议 翻译成诊所：要想成像生物标志物，以使翻译使用跃升，他们需要 准确地确定引起症状的电路。 在这个项目中，我们试图了解脑电路功能障碍如何引起听觉幻觉 精神分裂症。发表的技术挑战成像研究提供了关键的线索：这些'症状 捕获”在幻觉期间收集MRI成像的实验已经确定了不同的模式 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 是单个电路的一部分，而不是跨越小脑，丘脑和皮质脑区域。在我们的初步数据中 能够识别该电路的小脑节点，然后在独立的参与者中 精神分裂症，我们使用神经调节来操纵该电路。我们观察到无创的 神经调节可以在整个电路上操纵连通性。恢复该电路中的连通性 反映在降低幻觉的严重程度上。 在此提案中，我们寻求确认并扩展此结果。我们将使用非侵入性神经调节 特别针对该电路，并观察在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如何因果生理学的理解 与幻觉有关。这种对精神分裂症症状的机械理解将是 前所未有的，将确定参与的生物学目标以减少这些符号。