Modulation of Cerebellar Activity by Electrical and Focused Ultrasound Stimulation

小脑在神经调节方面的潜力几十年来一直被忽视。传统上认为小脑对运动协调至关重要，解剖学、临床和影像学证据现在表明，小脑在认知和情感中也起着核心作用，而小脑功能障碍会影响这些功能。与这些小脑参与运动和非运动功能的发现一致，小脑核（CN）的投射通过丘脑靶向皮层的运动和非运动区域以及基底神经节。因此，对小脑输出的调节应该能够影响整个前脑区域，因此具有治疗许多疾病的潜力。先前研究的空白：在近50年前的临床试验中，刺激小脑皮层产生了不同的结果，这阻碍了进一步的尝试。然而，最近在患者和动物模型中显示，刺激CN（来自小脑皮层的传出轴突会聚的地方）具有临床益处，重新引起了人们对小脑刺激作为治疗工具的兴趣。然而，直接刺激CN需要手术植入深部脑刺激导线进入小脑。研究机会：聚焦超声（Focused Ultrasound， FUS）和经颅电刺激（Transcranial Electrical Stimulation, tES）是两种具有临床应用潜力的非侵入性脑刺激方法，为小脑刺激提供了理想的工具。FUS具有直接刺激CN的潜力，其优越的聚焦和转向能力。tES是刺激小脑皮层的首选方法，因为它易于使用且设备便宜。在过去的二十年中，在功能成像和解剖制图方面的进展使我们对小脑皮层的电路及其与中枢神经网络的联系有了更好的了解。因此，我们有了新的工具和知识基础来开发有效的方案，既可以直接刺激CN，也可以通过刺激小脑皮层间接调节它们。当前提案：本提案的总体目标是通过使用FUS直接刺激CN和通过小脑皮质电刺激间接CN调制来开发有效的小脑输出调制范式。我们将研究如何选择性地刺激皮层和中枢神经网络中的神经元亚型。神经调节的新机制也将被研究，从两种方法在小脑回路上的联合应用中可能出现。所开发的调制范式应该推广到小脑参与的许多运动和非运动功能。

The cerebellum has been overlooked for its potential for neuromodulation for decades. Traditionally thought of as critical for motor coordination, anatomical, clinical and imaging evidence now indicate that the cerebellum also has central roles in cognition and emotion, and that cerebellar dysfunction impacts these functions. Consistent with these findings of cerebellar involvement in motor and non-motor functions, projections from the cerebellar nuclei (CN) target, via the thalamus, both motor and non-motor areas of the cortex and the basal ganglia. Thus, modulation of cerebellar outputs should be able to affect areas throughout the forebrain, and therefore has the potential to treat numerous disorders. Gap in Prior Research: Stimulation of the cerebellar cortex produced mixed results in clinical trials almost fifty years ago, which discouraged further attempts. Whereas stimulation of the CN, where the efferent axons from the cerebellar cortex converge, has recently been shown to have clinical benefits in patients and animal models, reviving interest in cerebellar stimulation as a therapeutic tool. However, direct stimulation of the CN requires surgical implantation of deep brain stimulation leads into the cerebellum. Research Opportunity: Focused Ultrasound (FUS) and Transcranial Electrical Stimulation (tES) are two non- invasive brain stimulation methods that have great potentials for clinical applications and provide ideal tools for cerebellar stimulation. FUS has the potential to stimulate the CN directly with its superior focusing and steering capabilities. tES would be the preferred method for stimulation of the cerebellar cortex due to its ease of application and the inexpensive equipment involved. Advances in the past two decades on functional imaging and anatomical mapping provide an improved understanding of the circuitry of the cerebellar cortex and its connections to the CN. Thus, we have novel tools and the knowledge base to develop effective protocols both for direct stimulation of the CN and indirect modulation of them via stimulation of the cerebellar cortex. Current Proposal: The overarching goal of this proposal is to develop effective modulation paradigms of cerebellar output both by direct stimulation of the CN using FUS and indirect CN modulation via electrical stimulation of the cerebellar cortex. Optimal stimulation parameters will be investigated for selective stimulation of neuronal subtypes in the cortex and the CN. Novel mechanisms of neuromodulation will also be investigated that can emerge from combined application of the two methods on the cerebellar circuits. The modulation paradigms developed should generalize to numerous motor and non-motor functions in which the cerebellum is involved.