Modulation of Cerebellar Activity by Electrical and Focused Ultrasound Stimulation

几十年来，小脑因其神经调节的潜力而被忽视。传统上被认为是运动协调的关键，解剖学，临床和成像证据现在表明小脑在认知和情感中也起着核心作用，小脑功能障碍会影响这些功能。与小脑参与运动和非运动功能的这些发现一致，来自小脑核（CN）的投射通过丘脑靶向皮质和基底神经节的运动和非运动区域。因此，小脑输出的调节应该能够影响整个前脑的区域，因此具有治疗许多疾病的潜力。先前研究的差距：在将近50年前的临床试验中，刺激小脑皮层产生了混合的结果，这阻碍了进一步的尝试。然而，最近已经证明，刺激CN（来自小脑皮质的传出轴突汇聚的地方）在患者和动物模型中具有临床益处，从而重新引起了对小脑刺激作为治疗工具的兴趣。然而，CN的直接刺激需要将脑深部刺激电极导线手术植入小脑。研究机会：聚焦超声（FUS）和经颅电刺激（tES）是两种具有巨大临床应用潜力的无创脑刺激方法，为小脑刺激提供了理想的工具。FUS具有直接刺激CN的潜力，其上级聚焦和转向能力。由于其易于应用和所涉及的廉价设备，tES将是用于刺激小脑皮层的优选方法。在过去的二十年里，功能成像和解剖映射的进展提供了一个更好的了解小脑皮质的电路及其连接到CN。因此，我们有新的工具和知识基础来开发有效的协议，直接刺激CN和间接调制它们通过刺激小脑皮层。当前提案：该建议的总体目标是通过使用FUS直接刺激CN和通过电刺激小脑皮层间接CN调制来开发小脑输出的有效调制范例。将研究最佳刺激参数，以选择性刺激皮质和CN中的神经元亚型。神经调节的新机制也将被调查，可以出现从小脑电路的两种方法的联合应用。调制范式的发展应该推广到许多运动和非运动功能，小脑参与。

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.