Electrical and Ultrasonic Modulation of Lateral Cerebellar Nucleus Abstract 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, and 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. However, direct stimulation of the CN requires surgical implantation of deep brain stimulation leads into the cerebellum. Novel Solution by Current Technology: Focused Ultrasound (FUS) Stimulation 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. Cerebellar stimulation with ultrasound has not been reported by any other group to date and tES for the cerebellum is severely lacking animal data for understanding of underlying mechanisms. 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 cerebellar nuclei. Thus, we have novel tools and the knowledge base to develop protocols for effective modulation of the cerebellar outputs. Current Proposal: The overarching goal of this proposal is to develop a non-invasive and effective modulation paradigm for one of the cerebellar nuclei, the lateral cerebellar nucleus (LCN). Optimal stimulation parameters will be investigated for selective stimulation of neuronal subtypes in the LCN. Novel mechanisms of neuromodulation will be investigated that can emerge from combined application of the electrical and ultrasonic methods. The modulation paradigms developed in this project should generalize to numerous motor and non- motor brain functions in which the cerebellum is involved.