Modulation of Cerebellar Activity by Electrical and Focused Ultrasound Stimulation

几十年来，小脑在神经调节方面的潜力一直被忽视。传统上被认为对运动协调至关重要的解剖学、临床和影像证据现在表明，小脑在认知和情感方面也起着核心作用，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，小脑核(CN)靶区通过丘脑、皮质和基底节的运动和非运动区的投射也是如此。因此，小脑输出的调节应该能够影响整个前脑的区域，因此有可能治疗许多疾病。先前研究中的差距：近50年前的临床试验中，对小脑皮质的刺激产生了好坏参半的结果，这阻碍了进一步的尝试。而刺激CN，即来自小脑皮质的传出轴突汇聚之处，最近已被证明在患者和动物模型中具有临床益处，重新唤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需要手术将深部脑刺激引线植入小脑。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凭借其卓越的聚焦和转向能力，有可能直接刺激CN。TES是刺激小脑皮质的首选方法，因为它易于应用，所涉及的设备也不贵。在过去的二十年里，功能成像和解剖标测的进展使人们对小脑皮质的回路及其与CN的联系有了更好的了解。因此，我们有了新的工具和知识库来开发有效的方案，既可以直接刺激CN，也可以通过刺激小脑皮质间接调节它们。当前建议：该建议的首要目标是通过使用FUS直接刺激CN和通过电刺激小脑皮质间接调制CN来开发有效的小脑输出调制范例。最优刺激参数将被研究用于选择性刺激皮质和CN中的神经元亚型。神经调节的新机制也将被研究，这些机制可以通过两种方法在小脑回路上的联合应用而出现。所开发的调制范例应该推广到小脑涉及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.