Empirical validation of a cerebellar-cortical hallucination circuit

项目总结/摘要 像BRAIN倡议这样的项目有可能为治疗癌症提供一种全新的方法。 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纠正。这些举措在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将其作为战略重点 目的：识别和描述影响人类行为的神经回路机制， 精神疾病的中断。 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 这些发现代表了可以用于治疗益处的靶点。因此，我们缺乏一个关键的特权， 翻译到临床：对于成像生物标志物，使飞跃到翻译使用，他们将需要 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个关键线索：这些“症状” 在幻觉期间收集MRI成像的“捕获”实验已经确定了一种完全不同的模式， 多个皮层下和皮层脑区的激活。我们的假设是这些大脑区域 是一个单一回路的一部分，而不是跨越小脑，丘脑和皮质脑区域。在我们的初步数据中， 能够识别这个回路的小脑节点，然后，在一个独立的参与者队列中， 精神分裂症，我们用神经调节来操纵这个回路。我们观察到， 神经调节可以操纵整个回路的连通性。恢复此电路中的连接 反映在幻觉严重程度的降低上。 在本建议中，我们试图确认和扩展这一结果。我们将使用非侵入性神经调节， 专门针对这个回路，并观察在假控制的幻觉回路上引起的变化。 study.如果成功，这个项目将建立一个电路级的理解，病理生理学是如何因果关系， 与幻觉有关这种对精神分裂症症状的机械理解 这是前所未有的，并将确定生物目标，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.