Empirical validation of a cerebellar-cortical hallucination circuit

项目摘要/摘要 像大脑计划这样的项目可能会带来一种全新的治疗方法 严重的精神疾病。神经调节技术承诺允许选择性干预 病理生理学是专门针对矫正的。这些计划在很大程度上取决于正确的 识别导致精神症状的电路功能障碍。NIMH已将此作为战略优先事项 目的：确定和描述影响人类行为的神经回路机制及其 精神疾病中的分裂。 神经成像研究产生了有希望的线索，但几乎从未证明这些 这些发现代表了可以用于治疗效益的靶点。因此，我们缺乏一项关键的特权， 转化为临床：为了使成像生物标记物跃升为翻译用途，它们需要 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是如何导致脑部幻听的 精神分裂症。发表的具有技术挑战性的成像研究提供了一个关键线索：这些“症状” 在幻觉中收集核磁共振成像的“捕获”实验已经确定了一种截然不同的模式 多个皮质下和皮质脑区的激活。我们的假设是这些大脑区域 是单个环路的一部分，而不是横跨小脑、丘脑和皮质脑区。在我们的初步数据中，我们 能够识别这个回路的小脑结节，然后，在一个独立的参与者队列中 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的 神经调节可以操纵整个回路的连接。恢复此电路中的连接 反映在幻觉严重程度的降低上。 在这项提议中，我们寻求确认和推广这一结果。我们将使用非侵入性神经调节来 特别针对这个回路，观察在假控制的幻觉回路上所诱导的变化 学习。如果成功，这个项目将建立起对病理生理学因果关系的电路层面的理解。 与幻觉有关。这种对精神分裂症症状的机械性理解将是 这是史无前例的，并将确定参与行动的生物目标，以减少这些症状。

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.